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1
Moreno, Eduardo, Angela McGaughran, Christian Rödelsperger, Manuel Zimmer, and Ralf J. Sommer. "Oxygen-induced social behaviours in Pristionchus pacificus have a distinct evolutionary history and genetic regulation from Caenorhabditis elegans." Proceedings of the Royal Society B: Biological Sciences 283, no. 1825 (February 24, 2016): 20152263. http://dx.doi.org/10.1098/rspb.2015.2263.
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Wild isolates of the nematode Caenorhabditis elegans perform social behaviours, namely clumping and bordering, to avoid hyperoxia under laboratory conditions. In contrast, the laboratory reference strain N2 has acquired a solitary behaviour in the laboratory, related to a gain-of-function variant in the neuropeptide Y-like receptor NPR-1. Here, we study the evolution and natural variation of clumping and bordering behaviours in Pristionchus pacificus nematodes in a natural context, using strains collected from 22 to 2400 metres above sea level on La Réunion Island. Through the analysis of 106 wild isolates, we show that the majority of strains display a solitary behaviour similar to C. elegans N2, whereas social behaviours are predominantly seen in strains that inhabit high-altitude locations. We show experimentally that P. pacificus social strains perform clumping and bordering to avoid hyperoxic conditions in the laboratory, suggesting that social strains may have adapted to or evolved a preference for the lower relative oxygen levels available at high altitude in nature. In contrast to C. elegans , clumping and bordering in P. pacificus do not correlate with locomotive behaviours in response to changes in oxygen conditions. Furthermore, QTL analysis indicates clumping and bordering to represent complex quantitative traits. Thus, clumping and bordering behaviours represent an example of phenotypic convergence with a different evolutionary history and distinct genetic control in both nematode species.
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Franco, Antonietta, Caroline E. Walton, and Xiawei Dang. "Mitochondria Clumping vs. Mitochondria Fusion in CMT2A Diseases." Life 12, no. 12 (December 15, 2022): 2110. http://dx.doi.org/10.3390/life12122110.
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Phenotypic variations in Charcot-Marie-Tooth disease type 2A (CMT2A) result from the many mutations in the mitochondrial fusion protein, mitofusin 2 (MFN2). While the GTPase domain mutations of MFN2 lack the ability to hydrolyze GTP and complete mitochondrial fusion, the mechanism of dysfunction in HR1 domain mutations has yet to be explored. Using Mfn1/Mfn2 double null cells and Mfn2 knock out (KO) fibroblasts, we measured the ability of this variant protein to change conformations and hydrolyze GTP. We found that a mutation in the HR1 domain (M376A) of MFN2 results in conformational change dysfunction while maintaining GTPase ability. Prolonged exposure to mitofusin agonist MiM 111 reverses mitochondrial fusion dysfunction in the HR1 mutant through encouraging an open conformation, resulting in a potential therapeutic model in this variant. Herein, we describe a novel mechanism of dysfunction in MFN2 variants through exploring domain-specific mitochondrial characteristics leading to CMT2A.
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Ayers, J. R., H. W. Leipold, and G. A. Padgett. "Lesions in Brangus Cattle with Chediak-Higashi Syndrome." Veterinary Pathology 25, no. 6 (November 1988): 432–36. http://dx.doi.org/10.1177/030098588802500605.
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Hair, peripheral blood leukocytes, and other tissues from two related Brangus calves with phenotypic characteristics of Chediak-Higashi syndrome were examined by light and electron microscopy. Enlarged, pleomorphic, cytoplasmic granules, morphologically compatible with lysosomes, were seen in several neutrophils, many eosinophils, renal tubular epithelial cells, and Kupffer cells. Hair shafts of the calves showed irregular distribution and clumping of melanin granules. Severe infection and a possible hemorrhagic tendency were recognized. These Brangus calves represent the third breed of cattle affected with this genetic disease.
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GONANO, M., I. HEIN, P. ZANGERL, A. RAMMELMAYR, and M. WAGNER. "Phenotypic and molecular characterization ofStaphylococcus aureusstrains of veterinary, dairy and human origin." Epidemiology and Infection 137, no. 5 (October 23, 2008): 688–99. http://dx.doi.org/10.1017/s0950268808001453.
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SUMMARYAustrian veterinary (n=91), dairy (n=86), and human strains (n=48) ofStaphylococcus aureuswere tested for various phenotypic properties including clumping factor, egg-yolk reaction, production of thermonuclease and susceptibility to 14 antibiotics. In addition the expression of enterotoxins (A–E), and the presence of enterotoxin genesseatosejandtstwas determined. Significant differences in antimicrobial susceptibility were found with 84·6% of veterinary, 57·0% of dairy, and 20·8% of human strains susceptible to all antibiotics tested (P<0·0005). More human strains produced enterotoxins (41·7%) than veterinary (9·9%) and dairy strains (12·6%) while 40·7% and 38·5% of veterinary, 47·7% and 52·3% of dairy, and 77·1% and 87·5% of human strains werese- andtst-positive, respectively. AFLP analysis revealed nine clusters with over- or under-representation of strains with specific characteristics. Strains clustered according to origin (veterinary, dairy, and human) and/or presence of toxin genes and antimicrobial resistance.
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Bhaduri, Saumya, and James L. Smith. "Virulence Plasmid (pYV)-Associated Expression of Phenotypic Virulent Determinants in PathogenicYersiniaSpecies: A Convenient Method for Monitoring the Presence of pYV under Culture Conditions and Its Application for Isolation/Detection ofYersinia pestisin Food." Journal of Pathogens 2011 (2011): 1–9. http://dx.doi.org/10.4061/2011/727313.
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InYersinia pestis,Y. pseudotuberculosis, andY. enterocolitica, phenotypic expression of virulence plasmid (pYV: 70-kb)-associated genetic determinants may include low-calcium response (Lcr, pinpoint colony, size = 0.36 mm), colony morphology (size = 1.13 mm), crystal violet (CV) binding (dark-violet colony), Congo Red (CR) uptake (red pinpoint colony, size = 0.36 mm), autoagglutination (AA = cells agglutinate), and hydrophobicity (HP = clumping of cells).Y. pseudotuberculosisis chromosomally closely related toY. pestis;whereas,Y. enterocoliticais chromosomally more distantly related toY. pestisandY. pseudotuberculosis. All three species demonstrate Lcr, CV binding, and CR uptake. The colony morphology/size, AA, and HP characteristics are expressed in bothY. pseudotuberculosisandY. enterocoliticabut not inY. pestis. Congo red uptake inY. pestiswas demonstrated only on calcium-deficient CR magnesium oxalate tryptic soy agar (CR-MOX), whereas this phenotype was expressed on both CR-MOX and low-calcium agarose media inY. pseudotuberculosisandY. enterocolitica. These phenotypes were detectable at 37°C within 24 h inY. enterocoliticaandY. pseudotuberculosisbut did not appear until 48 h inY. pestisdue to its slower growth rate at 37°C. The pYV is unstable (i.e., easily lost under a variety of culture conditions) in all three species but is more unstable inY. pestis. The specific CR uptake byY. pestisin CR-MOX and the delayed time interval to express Lcr and CR uptake provide a means to differentiateY. pestisfromY. enterocoliticaandY. pseudotuberculosis. These differences in pYV expression inY. pestiscan be used for its isolation and detection in food.
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Ramm, Susanne, Robert Vary, Twishi Gulati, Jennii Luu, Karla J. Cowley, Michael S. Janes, Nicholas Radio, and Kaylene J. Simpson. "High-Throughput Live and Fixed Cell Imaging Method to Screen Matrigel-Embedded Organoids." Organoids 2, no. 1 (December 24, 2022): 1–19. http://dx.doi.org/10.3390/organoids2010001.
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Technical advances in microscopy and automation have enabled image-based phenotypic screening of spheroids and organoids to become increasingly high throughput and high content at the same time. In particular, matrix-embedded 3D structures can recapitulate many aspects of parent (e.g., patient) tissues. Live-cell imaging of growing structures allows tremendous insight into population heterogeneity during drug treatment. However, screening for targeted markers and more detailed morphological analyses typically require fixation of 3D structures, and standard formaldehyde (FA) incubation conditions can dissolve collagen-based extracellular matrices such as Matrigel. The dislocation and clumping of the spheroids make image-based segmentation very difficult and the tracking of structures from the live cell stage to their fixed cell location virtually impossible. In this method, we present a fixation and staining protocol that is gentle enough to maintain 3D structures exactly in their live-cell location and does not alter their morphology. This opens up analytical strategies that connect the spheroid’s growth kinetics and heterogeneity of treatment responses with the more targeted fixed cell stains. Furthermore, we optimized the automated seeding and imaging of spheroids so that screening and phenotypic characterization can be performed in high-throughput at either low or high magnification and yield the same result, independent of the microscope used.
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Orjih, C. I., A. Ajayi, F. O. Alao, A. I. Adeleye, and S. I. Smith. "Characterization of biofilm formation in clinical urinary isolates of Staphylococcus aureus from five hospitals in Lagos State, Nigeria." African Journal of Clinical and Experimental Microbiology 22, no. 2 (April 7, 2021): 164–69. http://dx.doi.org/10.4314/ajcem.v22i2.8.
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Background: Biofilm formation by pathogens is of great clinical importance as it mediates persistence and resistance to antibiotics, hence posing difficulty in treatment and management of diseases. The aim of this study was to evaluate the biofilm forming potential of Staphylococcus aureus isolated from urine samples of females with urinary tract infection and to detect the presence of clumping factor (clfA) and intracellular adhesion (icaA) encoding genes.Methodology: A total of 50 S. aureus were obtained from urine samples of women in five hospitals in Lagos State, Nigeria. Isolates were confirmed by standard biochemical and novobiocin susceptibility tests. The isolates were screened for biofilm formation using three methods; Congo-red agar (CRA), tube, and tissue culture plate (TCP) methods. Detection of clfA and icaA genes was done by PCR.Results: The Congo red agar method showed that 39 (78%) of the isolates were biofilm producers while 11 (22%) were non-biofilm producers. However, the tube method indicated that 12 (24%) were strong biofilm producers, 26 (52%) were moderate biofilm producers, and 12 (24%) were non-biofilm producers. The standard TCP assay showed that strong biofilm producers (OD > 0.240) were 13 (26%), moderate biofilm producers were 22 (44%), and weak or non-biofilm producers (OD < 0.120) were 15 (30%). The tube method showed a good correlation with the TCP method for strong biofilm production. Ten (20%) isolates possessed clfA gene and 31 (62%)possessed icaA gene.Conclusion: The ability of S. aureus to form biofilm is a key risk factor that can increase morbidity and mortality from infections they cause. Hence, rapid and sensitive phenotypic methods can be used in screening for biofilm formation thereby providing data that can guide therapy and control of the pathogen.
Keywords: Staphylococcus aureus, Biofilm, Clumping factor, Intracellular adhesion
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Ericksen, Bryan. "Quantification of polysaccharides fixed to Gram stained slides using lactophenol cotton blue and digital image processing." F1000Research 4 (May 15, 2017): 1. http://dx.doi.org/10.12688/f1000research.5779.3.
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Dark blue rings and circles emerged when the non-specific polysaccharide stain lactophenol cotton blue was added to Gram stained slides. The dark blue staining is attributable to the presence of capsular polysaccharides and bacterial slime associated with clumps of Gram-negative bacteria. Since all bacterial cells are glycosylated and concentrate polysaccharides from the media, the majority of cells stain light blue. The contrast between dark and light staining is sufficient to enable a digital image processing thresholding technique to be quantitative with little background noise. Prior to the addition of lactophenol cotton blue, the Gram-stained slides appeared unremarkable, lacking ubiquitous clumps or stained polysaccharides. Adding lactophenol cotton blue to Gram stained slides is a quick and inexpensive way to screen cell cultures for bacterial slime, clumps and biofilms that are invisible using the Gram stain alone. The presence of cell clumping provides a possible explanation of the presence of persisters and paradoxical points observed in Virtual Colony Count antimicrobial assays, and suggests a phenotypic resistance mechanism to antimicrobial peptides involving capsular polysaccharides.
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Ericksen, Bryan. "Quantification of polysaccharides fixed to Gram stained slides using lactophenol cotton blue and digital image processing." F1000Research 4 (July 13, 2017): 1. http://dx.doi.org/10.12688/f1000research.5779.4.
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Dark blue rings and circles emerged when the non-specific polysaccharide stain lactophenol cotton blue was added to Gram stained slides. The dark blue staining is attributable to the presence of capsular polysaccharides and bacterial slime associated with clumps of Gram-negative bacteria. Since all bacterial cells are glycosylated and concentrate polysaccharides from the media, the majority of cells stain light blue. The contrast between dark and light staining is sufficient to enable a digital image processing thresholding technique to be quantitative with little background noise. Prior to the addition of lactophenol cotton blue, the Gram-stained slides appeared unremarkable, lacking ubiquitous clumps or stained polysaccharides. Adding lactophenol cotton blue to Gram stained slides is a quick and inexpensive way to screen cell cultures for bacterial slime, clumps and biofilms that are invisible using the Gram stain alone. The presence of cell clumping provides a possible explanation of the presence of persisters and paradoxical points observed in Virtual Colony Count antimicrobial assays, and suggests a phenotypic resistance mechanism to antimicrobial peptides involving capsular polysaccharides.
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Asante, Jonathan, Akebe L. K. Abia, Daniel Anokwah, Bakoena A. Hetsa, Dorcas O. Fatoba, Linda A. Bester, and Daniel G. Amoako. "Phenotypic and Genomic Insights into Biofilm Formation in Antibiotic-Resistant Clinical Coagulase-Negative Staphylococcus Species from South Africa." Genes 14, no. 1 (December 29, 2022): 104. http://dx.doi.org/10.3390/genes14010104.
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The work aims to investigate biofilm formation and biofilm/adhesion-encoding genes in coagulase-negative staphylococci (CoNS) species recovered from blood culture isolates. Eighty-nine clinical CoNS were confirmed using the VITEK 2 system, and antibiotic susceptibility testing of isolates was conducted using the Kirby-Bauer disk diffusion method against a panel of 20 antibiotics. Isolates were qualitatively screened using the Congo red agar medium. Quantitative assays were performed on microtiter plates, where the absorbances of the solubilised biofilms were recorded as optical densities and quantified. In all, 12.4% of the isolates were strong biofilm formers, 68.5% had moderate biofilm capacity, and 17.9% showed weak capacity. A subset of 18 isolates, mainly methicillin-resistant S. epidermidis, were investigated for adherence-related genes using whole-genome sequencing and bioinformatics analysis. The highest antibiotic resistance rates for strongly adherent isolates were observed against penicillin (100%) and cefoxitin (81.8%), but the isolates showed no resistance to linezolid (0.0%) and tigecycline (0.0%). The icaABC genes involved in biofilm formation were detected in 50% of the screened isolates. Other adherence-related genes, including autolysin gene atl (88.8%), elastin binding protein gene ebp (94.4%), cell wall-associated fibronectin-binding protein gene ebh (66.7%), clumping factor A gene clfA (5.5%), and pili gene ebpC (22.2%) were also found. The insertion sequence IS256, involved in biofilm formation, was found in 10/18 (55.5%) screened isolates. We demonstrate a high prevalence of biofilm-forming coagulase-negative staphylococci associated with various resistance phenotypes and a substantial agreement between the possession of biofilm-associated genes and the biofilm phenotype.
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Heying, Ruth, Joke Gevel, Yok-Ai Que, Philippe Moreillon, and Henry Beekhuizen. "Fibronectin-binding proteins and clumping factor A in Staphylococcus aureus experimental endocarditis: FnBPA is sufficient to activate human endothelial cells." Thrombosis and Haemostasis 97, no. 04 (2007): 617–26. http://dx.doi.org/10.1160/th06-11-0640.
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SummarySurface molecules of Staphylococcus aureus are involved in the colonization of vascular endothelium which is a crucial primary event in the pathogenesis of infective endocarditis (IE).The ability of these molecules to also launch endothelial procoagulant and proinflammatory responses, which characterize IE, is not known. In the present study we investigated the individual capacities of three prominent S. aureus surface molecules; fibronectinbinding protein A (FnBPA) and B (FnBPB) and clumping factor A (ClfA), to promote bacterial adherence to cultured human endothelial cells (ECs) and to activate phenotypic and functional changes in these ECs. Non-invasive surrogate bacterium Lactococcus lactis, which, by gene transfer, expressed staphylococcal FnBPA, FnBPB or ClfA molecules were used. Infection of ECs increased 50- to 100-fold with FnBPA- or FnBPB-positive recombinant lactococci. This coincided with EC activation, interleukin- 8 secretion and surface expression of ICAM-1 andVCAM-1 and concomitant monocyte adhesion. Infection with ClfA-positive lactococci did not activate EC. FnBPA-positive L. lactis also induced a prominent tissue factor-dependent endothelial coagulation response that was intensified by cell-bound monocytes. Thus S. aureus FnBPs, but not ClfA, confer invasiveness and pathogenicity to non-pathogenic L. lactis organisms indicating that bacterium-EC interactions mediated by these adhesins are sufficient to evoke inflammation as well as procoagulant activity at infected endovascular sites.
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Małkińska-Horodyska, Magdalena, Joanna Kubiak, Henryka Lassa, and Edward Malinowski. "Changes in Antibiotic Susceptibility Pattern of Atypical Staphylococcus Aureus Strains Isolated from Cows of the same Herd in 2008-2010." Bulletin of the Veterinary Institute in Pulawy 56, no. 2 (June 1, 2012): 139–43. http://dx.doi.org/10.2478/v10213-012-0025-1.
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Abstract The isolates of Staphylococcus aureus strains were examined phenotypically by cultural features, tube coagulase test and clumping factor (CF), and genotypically by conventional PCR. The strains had positive reaction in CF test, but were negative in tube coagulase test. The analysed strains from the same cows in each year expressed also nuc and coa genes. About 25% of the strains were examined by the disc diffusion method for their sensitivity to antibiotics. During three years, the strains were highly susceptible in vitro to amoxicillin with clavulanic acid, oxacillin, bacitracin, and cefoperazone (more than 90%), and highly resistant to tetracycline, neomycin, and streptomycin. Forty randomly chosen strains, and eight strains from the same cows in each year were analysed for minimal inhibitory concentration of penicillin G using microdilution method. An increasing resistance to the penicillin was noted. Moreover, eight strains, the same in each year, were also examined for β-lactamase production and methicillin resistance. No β-lactamase producers and no methicillin resistant strains were found using phenotypic and genotypic methods. In conclusion, it can be stated that antimicrobial susceptibility can change from one year to another.
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Chuang, John S., Zak Frentz, and Stanislas Leibler. "Homeorhesis and ecological succession quantified in synthetic microbial ecosystems." Proceedings of the National Academy of Sciences 116, no. 30 (July 10, 2019): 14852–61. http://dx.doi.org/10.1073/pnas.1901055116.
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The dynamics of ecological change following a major perturbation, known as succession, are influenced by random processes. Direct quantitation of the degree of contingency in succession requires chronological study of replicate ecosystems. We previously found that population dynamics in carefully controlled, replicated synthetic microbial ecosystems were strongly deterministic over several months. Here, we present simplified, two-species microbial ecosystems consisting of algae and ciliates, imaged in toto at single-cell resolution with fluorescence microscopy over a period of 1 to 2 weeks. To directly study succession in these ecosystems, we deliberately varied the initial cell abundances over replicates and quantified the ensuing dynamics. The distribution of abundance trajectories rapidly converged to a nearly deterministic path, with small fluctuations, despite variations in initial conditions, environmental perturbations, and intrinsic noise, indicative of homeorhesis. Homeorhesis was also observed for certain phenotypic variables, such as partitioning of the ciliates into distinct size classes and clumping of the algae. Although the mechanism of homeorhesis observed in these synthetic ecosystems remains to be elucidated, it is clear that it must emerge from the ways each species controls its own internal states, with respect to a diverse set of environmental conditions and ecological interactions.
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Olamigoke, Loretta, Elvedina Mansoor, Vivek Mann, Ivory Ellis, Elvis Okoro, Koji Wakame, Hajime Fuji, Anil Kulkarni, Marie Francoise Doursout, and Alamelu Sundaresan. "AHCC Activation and Selection of Human Lymphocytes via Genotypic and Phenotypic Changes to an Adherent Cell Type: A Possible Novel Mechanism of T Cell Activation." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/508746.
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Active Hexose Correlated Compound (AHCC) is a fermented mushroom extract and immune supplement that has been used to treat a wide range of health conditions. It helps in augmentation of the natural immune response and affects immune cell activation and outcomes. The goal of this project was to study and understand the role and mechanisms of AHCC supplementation in the prevention of immunosuppression through T cell activation. The method described here involves “in vitro” culturing of lymphocytes, exposing them to different concentrations of AHCC (0 μg/mL, 50 μg/mL, 100 μg/mL, 250 μg/mL, and 500 μg/mL) at 0 hours. Interestingly, clumping and aggregation of the cells were seen between 24 and 72 hours of incubation. The cells lay down extracellular matrix, which become adherent, and phenotypical changes from small rounded lymphocytes to large macrophage-like, spindle shaped, elongated, fibroblast-like cells even beyond 360 hours were observed. These are probably translated from genotypic changes in the cells since the cells propagate for at least 3 to 6 generations (present observations). RNA isolated was subjected to gene array analysis. We hypothesize that cell adhesion is an activation and survival pathway in lymphocytes and this could be the mechanism of AHCC activation in human lymphocytes.
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Brennan, Michael J., Giovanni Delogu, Yiping Chen, Stoyan Bardarov, Jordan Kriakov, Mohammad Alavi, and William R. Jacobs. "Evidence that Mycobacterial PE_PGRS Proteins Are Cell Surface Constituents That Influence Interactions with Other Cells." Infection and Immunity 69, no. 12 (December 1, 2001): 7326–33. http://dx.doi.org/10.1128/iai.69.12.7326-7333.2001.
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ABSTRACT The elucidation of the genomic sequence of Mycobacterium tuberculosis revealed the presence of a novel multigene family designated PE/PE_PGRS that encodes numerous, highly related proteins of unknown function. In this study, we demonstrate that a transposon insertion in a PE_PGRS gene (1818PE_PGRS) found inMycobacterium bovis BCG Pasteur, which is the BCG homologue of the M. tuberculosis H37Rv gene Rv1818c, introduces new phenotypic properties to this BCG strain. These properties include dispersed growth in liquid medium and reduced infection of macrophages. Complementation of the 1818PE_PGRS::Tn5367 mutant with the wild-type gene restores both aggregative growth (clumping) in liquid medium and reestablishes infectivity of macrophages to levels equivalent to those for the parent BCG strain. Western blot analysis using antisera raised against the 1818PE_PGRS protein shows that PE_PGRS proteins are found in cell lysates of BCG andM. tuberculosis H37Ra and in the cell wall fraction of M. tuberculosis H37Rv. Moreover, immunofluorescent labeling of mycobacteria indicates that certain PE_PGRS proteins are localized at the cell surface of BCG andM. tuberculosis. Together these results suggest that certain PE_PGRS proteins may be found at the surface of mycobacteria and influence both cell surface interactions among mycobacteria as well as the interactions of mycobacteria with macrophages.
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Cheung, Ambrose L., Yueh-tyng Chien, and Arnold S. Bayer. "Hyperproduction of Alpha-Hemolysin in asigB Mutant Is Associated with Elevated SarA Expression inStaphylococcus aureus." Infection and Immunity 67, no. 3 (March 1, 1999): 1331–37. http://dx.doi.org/10.1128/iai.67.3.1331-1337.1999.
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ABSTRACT To evaluate the role of SigB in modulating the expression of virulence determinants in Staphylococcus aureus, we constructed a sigB mutant of RN6390, a prototypic S. aureus strain. The mutation in the sigB gene was confirmed by the absence of the SigB protein in the mutant on an immunoblot as well as the failure of the mutant to activate ςB-dependent promoters (e.g., the sarC promoter) ofS. aureus. Phenotypic analysis indicated that both alpha-hemolysin level and fibrinogen-binding capacity were up-regulated in the mutant strain compared with the parental strain. The increase in fibrinogen-binding capacity correlated with enhanced expression of clumping factor and coagulase on immunoblots. The effect of thesigB mutation on the enhanced expression of the alpha-hemolysin gene (hla) was primarily transcriptional. Upon complementation with a plasmid containing the sigBgene, hla expression returned to near parental levels in the mutant. Detailed immunoblot analysis as well as a competitive enzyme-linked immunosorbent assay of the cell extract of thesigB mutant with anti-SarA monoclonal antibody 1D1 revealed that the expression of SarA was higher in the mutant than in the parental control. Despite an elevated SarA level, the transcription of RNAII and RNAIII of the agr locus remained unaltered in thesigB mutant. Because of a lack of perturbation inagr, we hypothesize that inactivation of sigBleads to increased expression of SarA which, in turn, modulates target genes via an agr-independent but SarA-dependent pathway.
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Nwobi, Obichukwu Chisom, Madubuike Umunna Anyanwu, Ishmael Festus Jaja, Innocent Okwundu Nwankwo, Chukwuemeka Calistus Okolo, Chibundo Adaobi Nwobi, Ekene Vivienne Ezenduka, and James Wabwire Oguttu. "Staphylococcus aureus in Horses in Nigeria: Occurrence, Antimicrobial, Methicillin and Heavy Metal Resistance and Virulence Potentials." Antibiotics 12, no. 2 (January 24, 2023): 242. http://dx.doi.org/10.3390/antibiotics12020242.
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Staphylococcus aureus was isolated from a total of 360 nasal and groin skin swabs from 180 systematic randomly-selected horses slaughtered for meat at Obollo-Afor, Enugu State, Southeast Nigeria and antimicrobial, methicillin and heavy metal resistance profile and virulence potentials of the isolates established. Baird-Parker agar with egg yolk tellurite was used for S. aureus isolation. S. aureus isolates were confirmed biochemically and serologically using a specific S. aureus Staphytect Plus™ latex agglutination test kit. The antimicrobial resistance profile, methicillin, vancomycin and inducible clindamycin resistance, and β-lactamase production of the isolates were determined with disc diffusion. Tolerance to Copper, Cadmium, Lead and Zinc was assessed using the agar dilution method and virulence potentials were determined using phenotypic methods. Forty-three (23.9%) of the 180 horses harbored S. aureus. Some 71 S. aureus were recovered from the 360 samples. Two (2.8%) of the 71 S. aureus were methicillin-resistant S. aureus (MRSA) and 69 (97.2%) were methicillin-susceptible. MRSA was recovered from 2 (1.1%) of the 180 horses. Some 9.4% of the isolates were multiple drug-resistant (MDR). The mean multiple antibiotic resistance indices (MARI) for the isolates was 0.24. Heavy metal resistance rate of the isolates ranged between 35.4–70.4%. The isolates, including the MRSA strains, displayed virulence potentials as clumping factor and catalase, gelatinase, caseinase, heamolysin, and biofilm was at the rate of 100%, 53.5%, 43.7%, 18.3% and 23.9%, respectively. This study showed that a considerable percentage of horses slaughtered in Obollo-Afor Southeastern Nigeria are potential reservoirs of virulent multiple drug- and heavy metal-resistant S. aureus, including MRSA, that could spread to humans and the environment.
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Alabbosh, Khulood Fahad, Tarek Zmantar, Abdulrahman S. Bazaid, Mejdi Snoussi, and Emira Noumi. "Antibiotics Resistance and Adhesive Properties of Clinical Staphylococcus aureus Isolated from Wound Infections." Microorganisms 11, no. 5 (May 22, 2023): 1353. http://dx.doi.org/10.3390/microorganisms11051353.
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Staphylococcus aureus (S. aureus) is a ubiquitous pathogen responsible for several severe infections. This study aimed to investigate the adhesive properties and antibiotic resistance among clinical S. aureus isolated from Hail Hospital Province, Kingdom of Saudi Arabia (KSA), using molecular approaches. This study was conducted according to the ethical committee at Hail’s guidelines on twenty-four S. aureus isolates. A polymerase chain reaction (PCR) was performed to identify genes encoding the β-lactamase resistance (blaZ), methicillin resistance (mecA), fluoroquinolone resistance (norA), nitric oxide reductase (norB), fibronectin (fnbA and fnbB), clumping factor (clfA) and intracellular adhesion factors (icaA and icaD). This qualitative study tested adhesion based on exopolysaccharide production on Congo red agar (CRA) medium and biofilm formation on polystyrene by S. aureus strains. Among 24 isolates, the cna and blaz were the most prevalent (70.8%), followed by norB (54.1%), clfA (50.0%), norA (41.6%), mecA and fnbB (37.5%) and fnbA (33.3%). The presence of icaA/icaD genes was demonstrated in almost all tested strains in comparison to the reference strain, S. aureus ATCC 43300. The phenotypic study of adhesion showed that all tested strains had moderate biofilm-forming capacity on polystyrene and represented different morphotypes on a CRA medium. Five strains among the twenty-four harbored the four genes of resistance to antibiotics (mecA, norA, norB and blaz). Considering the genes of adhesion (cna, clfA, fnbA and fnbB), these genes were present in 25% of the tested isolates. Regarding the adhesive properties, the clinical isolates of S. aureus formed biofilm on polystyrene, and only one strain (S17) produced exopolysaccharides on Congo red agar. All these results contribute to an understanding that the pathogenesis of clinical S. aureus isolates is due to their antibiotic resistance and adhesion to medical material.
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MacCallum, Donna M., Helen Findon, Claire C. Kenny, Geraldine Butler, Ken Haynes, and Frank C. Odds. "Different Consequences of ACE2 and SWI5 Gene Disruptions for Virulence of Pathogenic and Nonpathogenic Yeasts." Infection and Immunity 74, no. 9 (September 2006): 5244–48. http://dx.doi.org/10.1128/iai.00817-06.
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ABSTRACT Mutants of Candida albicans, Candida glabrata, and Saccharomyces cerevisiae with disruptions in the ACE2 gene and C. glabrata and S. cerevisiae swi5 disruption mutants were tested for virulence in a murine challenge model of disseminated yeast infection. All mutants showed a clumping phenotype, but clumping was minimized in challenge inocula by inclusion of chitinase in the growth medium. In animals rendered temporarily neutropenic by cyclophosphamide treatment, the C. glabrata ace2 null mutant was confirmed as hypervirulent: it led to early terminal illness and kidney, brain, and lung fungal burdens substantially and significantly larger than those in controls. The C. glabrata swi5 null mutant did not lead to terminal illness but generated significantly larger brain and lung burdens than those in controls. The C. albicans ace2 null mutant was very slightly attenuated and the S. cerevisiae ace2 and swi5 null mutants were substantially attenuated relative to their parental control strains. The phenotype of aggressive hypervirulence, unique to disruption of the C. glabrata ACE2 gene among the strains tested, was not seen when the C. glabrata ace2 strain was tested in immunologically intact mice. The different effects seen with these mutants rule out the clumping phenotype as the explanation for hypervirulence in the C. glabrata ace2 mutant. The absence of C. glabrata ace2 hypervirulence in healthy mice may be a tool for definitive future study of host-parasite cross talk in microbial opportunism.
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Frank, G. Onyambu, B. Tanui Stephen, S. O. Alwala Dominic, Chebii Kiptanui, and K. Kigen Bethwel. "Platelet-mediated clumping adhesion phenotypes of P. falciparum-infected erythrocytes: A review." Clinical Reviews and Opinions 8, no. 2 (July 31, 2017): 14–18. http://dx.doi.org/10.5897/cro2015.0097.
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Schwarzkopf, A., H. Karch, H. Schmidt, W. Lenz, and J. Heesemann. "Phenotypical and genotypical characterization of epidemic clumping factor-negative, oxacillin-resistant Staphylococcus aureus." Journal of Clinical Microbiology 31, no. 9 (1993): 2281–85. http://dx.doi.org/10.1128/jcm.31.9.2281-2285.1993.
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Castaman, Giancarlo, and Augusto Federici. "Type 2B von Willebrand Disease: A Matter of Plasma Plus Platelet Abnormality." Seminars in Thrombosis and Hemostasis 42, no. 05 (May 5, 2016): 478–82. http://dx.doi.org/10.1055/s-0036-1579638.
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Type 2B von Willebrand disease (VWD2B) is a rare, autosomal-dominant inherited bleeding disorder, characterized by an enhanced ristocetin-induced platelet aggregation in platelet-rich plasma and often with variable degree of thrombocytopenia and loss of high-molecular-weight multimers von Willebrand factor (VWF). All these phenomena are caused by a mutant VWF, normally synthesized and assembled by endothelial cells, but with heightened affinity binding to the platelet receptor glycoprotein Ib-α (GpIb-α). When this abnormal VWF is released into the circulation and under specific clinical circumstances, in vivo platelet clumping is observed. Mutations, invariably clustered in exon 28 of the VWF gene encoding for the VWF A1 domain involved in VWF binding to GpIb-α, are responsible for VWD2B phenotype. Clinical and laboratory phenotype appears strongly related to the type of VWF-causative mutations. However, recent evidences suggest that a true platelet defect is also present in this type, with several morphological and functional abnormalities being detected in a subset of VWD2B patients.
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Vaudaux, Pierre, Patrice Francois, Carmelo Bisognano, William L. Kelley, Daniel P. Lew, Jacques Schrenzel, Richard A. Proctor, Peter J. McNamara, G. Peters, and Christof Von Eiff. "Increased Expression of Clumping Factor and Fibronectin-Binding Proteins by hemB Mutants of Staphylococcus aureus Expressing Small Colony Variant Phenotypes." Infection and Immunity 70, no. 10 (October 2002): 5428–37. http://dx.doi.org/10.1128/iai.70.10.5428-5437.2002.
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ABSTRACT Small colony variants (SCVs) of Staphylococcus aureus are slow-growing subpopulations that cause persistent and relapsing infections. The altered phenotype of SCV can arise from defects in menadione or hemin biosynthesis, which disrupt the electron transport chain and decrease ATP concentrations. With SCVs, virulence is altered by a decrease in exotoxin production and susceptibility to various antibiotics, allowing their intracellular survival. The expression of bacterial adhesins by SCVs is poorly documented. We tested fibrinogen- and fibronectin-mediated adhesion of a hemB mutant of S. aureus 8325-4 that is defective for hemin biosynthesis and exhibits a complete SCV phenotype. In this strain, adhesion to fibrinogen and fibronectin was significantly higher than that of its isogenic, normally growing parent and correlated with the increased surface display of these adhesins as assessed by flow cytometry. Real-time quantitative reverse transcription-PCR demonstrated increased expression of clfA and fnb genes by the hemB mutant compared to its isogenic parent. The influence of the hemB mutation on altered adhesin expression was confirmed by showing complete restoration of the wild-type adhesive phenotype in the hemB mutant, either by complementing with intact hemB or by supplementing the growth medium with hemin. Increased surface display of fibrinogen and fibronectin adhesins by the hemB mutation occurred independently from agr, a major regulatory locus of virulence factors in S. aureus. Both agr-positive and agr-lacking hemB mutants were also more efficiently internalized by human embryonic kidney cells than were their isogenic controls, presumably because of increased surface display of their fibronectin adhesins.
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Bjeloš, Mirjana, Ana Ćurić, Benedict Rak, Mladen Bušić, and Biljana Kuzmanović Elabjer. "The First Homozygote Mutation c.499G>T (Asp167Tyr) in the RPE65 Gene Encoding Retinoid Isomerohydrolase Causing Retinal Dystrophy." Current Issues in Molecular Biology 44, no. 12 (December 16, 2022): 6397–403. http://dx.doi.org/10.3390/cimb44120436.
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RPE65, an abundant membrane-associated protein present in the retinal pigment epithelium (RPE), is a vital retinoid isomerase necessary for regenerating 11-cis-retinaldehyde from all-trans retinol in the visual cycle. In patients with inherited retinal dystrophy (IRD), precise genetic diagnosis is an indispensable approach as it is required to establish eligibility for the genetic treatment of RPE65-associated IRDs. This case report aims to report the specific phenotype–genotype correlation of the first patient with a homozygous missense variant RPE65 c.499G>T, p. (Asp167Tyr). We report a case of a 66-year-old male who demonstrated a unique phenotype manifesting less severe functional vision deterioration in childhood and adolescence, and extensive nummular pigment clusters. The underlying causes of the differences in the typical bone spicule and atypical nummular pigment clumping are unknown, but suggest that the variant itself influenced the rate of photoreceptor death. Functional studies are needed to define whether the substitution of aspartate impairs the folding of the tertiary RPE65 structure only and does not lead to the complete abolishment of chromophore production, thus explaining the less severe phenotype in adolescence.
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Pain, A., D. J. P. Ferguson, O. Kai, B. C. Urban, B. Lowe, K. Marsh, and D. J. Roberts. "Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phenotype and is associated with severe malaria." Proceedings of the National Academy of Sciences 98, no. 4 (February 13, 2001): 1805–10. http://dx.doi.org/10.1073/pnas.98.4.1805.
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Coulombe, P. A., M. E. Hutton, R. Vassar, and E. Fuchs. "A function for keratins and a common thread among different types of epidermolysis bullosa simplex diseases." Journal of Cell Biology 115, no. 6 (December 15, 1991): 1661–74. http://dx.doi.org/10.1083/jcb.115.6.1661.
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Previously we demonstrated that transgenic mice expressing a mutant keratin in the basal layer of their stratified squamous epithelia exhibited a phenotype bearing resemblance to a subclass (Dowling Meara) of a heterogeneous group of human skin disorders known as epidermolysis bullosa simplex (EBS) (Vassar, R., P. A. Coulombe, L. Degenstein, K. Albers, E. Fuchs. 1991. Cell. 64:365-380.). The extent to which subtypes of EBS diseases might be genetically related is unknown, although they all exhibit skin blistering as a consequence of basal cell cytolysis. We have now examined transgenic mice expressing a range of keratin mutants which perturb keratin filament assembly to varying degrees. We have generated phenotypes which include most subtypes of EBS, demonstrating for the first time that at least in mice, these diseases can be generated by different mutations within a single gene. A strong correlation existed between the severity of the disease and the extent to which the keratin filament network was disrupted, implicating perturbations in keratin networks as an essential component of these diseases. Some keratin mutants elicited subtle perturbations, with no signs of the tonofilament clumping typical of Dowling-Meara EBS and our previous transgenic mice. Importantly, basal cell cytolysis still occurred, thereby uncoupling cytolysis from the generation of large, insoluble cytoplasmic protein aggregates. Moreover, cell rupture occurred in a narrowly defined subnuclear zone, and seemed to involve three factors: (a) filament perturbation, (b) the columnar shape of the basal cell, and (c) physical trauma. This work provides the best evidence to date for a structural function of a cytoplasmic intermediate filament network, namely to impart mechanical integrity to the cell in the context of its tissue.
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Moreno, Eduardo, and Ralf J. Sommer. "A cilia-mediated environmental input induces solitary behaviour in Caenorhabditis elegans and Pristionchus pacificus nematodes." Nematology 20, no. 3 (2018): 201–9. http://dx.doi.org/10.1163/15685411-00003159.
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Nematodes respond to a multitude of environmental cues. For example, the social behaviours clumping and bordering were described as a mechanism of hyperoxia avoidance in Caenorhabditis elegans and Pristionchus pacificus. A recent study in P. pacificus revealed a novel regulatory pathway that inhibits social behaviour in a response to an as yet unknown environmental cue. This environmental signal is recognised by ciliated neurons, as mutants defective in intraflagellar transport (IFT) proteins display social behaviours. The IFT machinery represents a large protein complex and many mutants in genes encoding IFT proteins are available in C. elegans. However, social phenotypes in C. elegans IFT mutants have never been reported. Here, we examined 15 previously isolated C. elegans IFT mutants and found that most of them showed strong social behaviour. These findings indicate conservation in the inhibitory mechanism of social behaviour between P. pacificus and C. elegans.
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Belmamoun, Ahmed Reda, Abdelkader Ammam, Imene Berrabah, and Karima Bereksi Reguig. "Coagulase gene polymorphism and antimicrobial susceptibility of Staphylococcus aureus isolated from bovine subclinical mastitis milk in Sidi-Bel-Abbes, Algeria." South Asian Journal of Experimental Biology 7, no. 1 (September 25, 2017): 21–27. http://dx.doi.org/10.38150/sajeb.7(1).p21-27.
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The study was conducted to identify and characterize Staphylococcus aureus in raw milk derived from subclinical mastitis in Sidi-Bel-Abbes Algeria. In this paper, we explore the possibility of detection of the coagulase gene (coa), which encodes the coagulase enzyme, by PCR analysis in antibiotic-resistant isolates, with the latex agglutination phenotype and free coagulase.Out of 336 samples of raw milk examined with California mastitis test (CMT) posi-tive; a total of 142 samples were bacteriologically positive with 56.34% Staphylococcus isolates, 21 (26.25%) isolates were confirmed as S.aureus. Nineteen (90.48%) isolates of S.aureus showed free coagulase on the tube agglutination test. Two atypical S.aureus strains (9.52%) were defective for the clumping factor and / or protein A , determined with the Staphytect plus test and the tube coagulase test. The isolates of S.aureus were resistant to penicillin and tetracycline with 76.19%. Two isolates (9.52%) of S.aureus re-sistant to meticillin (MRSA) were detected in this study, with a MIC of ≥4 μg / liter and a cefoxitin screen test with a MIC of ≥8 μg / liter, and 13 (61.9%) isolates were with a multiresistance phenotype. The 21 isolates were sub-jected to PCR amplification of the 3' end of the coa gene, 18 (85.71%) were revealed on a 1% agarose gel with a single band between 547 bp and 875 bp. The use of the PCR genotypic test to identify the profile of the coa gene can be used as an appropriate identification criterion for differentiating coagulases from S.aureus and for understanding their epidemiology.
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Zhang, Zhongge, and Leland S. Pierson. "A Second Quorum-Sensing System Regulates Cell Surface Properties but Not Phenazine Antibiotic Production inPseudomonas aureofaciens." Applied and Environmental Microbiology 67, no. 9 (September 1, 2001): 4305–15. http://dx.doi.org/10.1128/aem.67.9.4305-4315.2001.
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ABSTRACT The root-associated biological control bacterium Pseudomonas aureofaciens 30-84 produces a range of exoproducts, including protease and phenazines. Phenazine antibiotic biosynthesis byphzXYFABCD is regulated in part by the PhzR-PhzI quorum-sensing system. Mutants defective in phzR orphzI produce very low levels of phenazines but wild-type levels of exoprotease. In the present study, a second genomic region of strain 30-84 was identified that, when present in trans, increased β-galactosidase activity in a genomic phzB::lacZreporter and partially restored phenazine production to aphzR mutant. Sequence analysis identified two adjacent genes, csaR and csaI, that encode members of the LuxR-LuxI family of regulatory proteins. No putative promoter region is present upstream of the csaI start codon and no lux box-like element was found in either thecsaR promoter or the 30-bp intergenic region betweencsaR and csaI. Both the PhzR-PhzI and CsaR-CsaI systems are regulated by the GacS-GacA two-component regulatory system. In contrast to the multicopy effects ofcsaR and csaI in trans, a genomic csaR mutant (30-84R2) and acsaI mutant (30-84I2) did not exhibit altered phenazine production in vitro or in situ, indicating that the CsaR-CsaI system is not involved in phenazine regulation in strain 30-84. Both mutants also produced wild-type levels of protease. However, disruption of bothcsaI and phzI or both csaRand phzR eliminated both phenazine and protease production completely. Thus, the two quorum-sensing systems do not interact for phenazine regulation but do interact for protease regulation. Additionally, the CsaI N-acylhomoserine lactone (AHL) signal was not recognized by the phenazine AHL reporter 30-84I/Z but was recognized by the AHL reportersChromobacterium violaceum CV026 andAgrobacterium tumefaciens A136(pCF240). Inactivation of csaR resulted in a smooth mucoid colony phenotype and formation of cell aggregates in broth, suggesting that CsaR is involved in regulating biosynthesis of cell surface components. Strain 30-84I/I2 exhibited mucoid colony and clumping phenotypes similar to those of 30-84R2. Both phenotypes were reversed by complementation with csaR-csaI or by the addition of the CsaI AHL signal. Both quorum-sensing systems play a role in colonization by strain 30-84. Whereas loss of PhzR resulted in a 6.6-fold decrease in colonization by strain 30-84 on wheat roots in natural soil, a phzR csaR double mutant resulted in a 47-fold decrease. These data suggest that gene(s) regulated by the CsaR-CsaI system also plays a role in the rhizosphere competence of P. aureofaciens 30-84.
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Truong-Bolduc, Que Chi, Xiamei Zhang, and David C. Hooper. "Characterization of NorR Protein, a Multifunctional Regulator of norA Expression in Staphylococcus aureus." Journal of Bacteriology 185, no. 10 (May 15, 2003): 3127–38. http://dx.doi.org/10.1128/jb.185.10.3127-3138.2003.
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ABSTRACT We characterized a Staphylococcus aureus norA gene expression regulator, NorR, initially identified from its binding to the norA promoter. The norR gene was 444 bp in length, located ∼7 kb upstream from the norA gene, and encoded a predicted 17.6-kDa protein. Overexpression of norR in wild-type S. aureus strain ISP794 led to a fourfold decrease in sensitivity to quinolones and ethidium bromide and an increase in the level of norA transcripts, suggesting that NorR acts as a positive regulator of norA expression. Overexpression of norR in sarA and agr mutants did not alter quinolone sensitivity or levels of norA transcription, indicating that the presence of these two global regulatory systems is necessary for NorR to affect the expression of norA. Insertion and disruption of norR in ISP794 increased resistance to quinolones by 4- to 16-fold but had no effect on norA transcription, suggesting that NorR acts as a repressor for another unidentified efflux pump or pumps. These mutants also exhibited an exaggerated clumping phenotype in liquid media, which was complemented fully by a plasmid-encoded norR gene. Collectively, these results indicate that NorR is a multifunctional regulator, affecting cell surface properties as well as the expression of NorA and likely other multidrug resistance efflux pumps.
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Bible, Amber N., Bonnie B. Stephens, Davi R. Ortega, Zhihong Xie, and Gladys Alexandre. "Function of a Chemotaxis-Like Signal Transduction Pathway in Modulating Motility, Cell Clumping, and Cell Length in the Alphaproteobacterium Azospirillum brasilense." Journal of Bacteriology 190, no. 19 (July 18, 2008): 6365–75. http://dx.doi.org/10.1128/jb.00734-08.
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ABSTRACT A chemotaxis signal transduction pathway (hereafter called Che1) has been previously identified in the alphaproteobacterium Azospirillum brasilense. Previous experiments have demonstrated that although mutants lacking CheB and/or CheR homologs from this pathway are defective in chemotaxis, a mutant in which the entire chemotaxis pathway has been mutated displayed a chemotaxis phenotype mostly similar to that of the parent strain, suggesting that the primary function of this Che1 pathway is not the control of motility behavior. Here, we report that mutants carrying defined mutations in the cheA1 (strain AB101) and the cheY1 (strain AB102) genes and a newly constructed mutant lacking the entire operon [Δ(cheA1-cheR1)::Cm] (strain AB103) were defective, but not null, for chemotaxis and aerotaxis and had a minor defect in swimming pattern. We found that mutations in genes of the Che1 pathway affected the cell length of actively growing cells but not their growth rate. Cells of a mutant lacking functional cheB1 and cheR1 genes (strain BS104) were significantly longer than wild-type cells, whereas cells of mutants impaired in the cheA1 or cheY1 genes, as well as a mutant lacking a functional Che1 pathway, were significantly shorter than wild-type cells. Both the modest chemotaxis defects and the observed differences in cell length could be complemented by expressing the wild-type genes from a plasmid. In addition, under conditions of high aeration, cells of mutants lacking functional cheA1 or cheY1 genes or the Che1 operon formed clumps due to cell-to-cell aggregation, whereas the mutant lacking functional CheB1 and CheR1 (BS104) clumped poorly, if at all. Further analysis suggested that the nature of the exopolysaccharide produced, rather than the amount, may be involved in this behavior. Interestingly, mutants that displayed clumping behavior (lacking cheA1 or cheY1 genes or the Che1 operon) also flocculated earlier and quantitatively more than the wild-type cells, whereas the mutant lacking both CheB1 and CheR1 was delayed in flocculation. We propose that the Che1 chemotaxis-like pathway modulates the cell length as well as clumping behavior, suggesting a link between these two processes. Our data are consistent with a model in which the function of the Che1 pathway in regulating these cellular functions directly affects flocculation, a cellular differentiation process initiated under conditions of nutritional imbalance.
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Vaudaux, Pierre E., Vincenza Monzillo, Patrice Francois, Daniel P. Lew, Tim J. Foster, and Brigitte Berger-Bächi. "Introduction of the mec Element (Methicillin Resistance) into Staphylococcus aureus Alters In Vitro Functional Activities of Fibrinogen and Fibronectin Adhesins." Antimicrobial Agents and Chemotherapy 42, no. 3 (March 1, 1998): 564–70. http://dx.doi.org/10.1128/aac.42.3.564.
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ABSTRACT Some methicillin-resistant strains of Staphylococcus aureus are defective in the production of major surface components such as protein A, clumping factor, or other important adhesins to extracellular matrix components which may play a role in bacterial colonization and infection. To evaluate the impact of methicillin resistance (mec) determinants on bacterial adhesion mediated by fibrinogen or fibronectin adhesins, we compared the in vitro attachment of two genetically distinct susceptible strains (NCTC8325 and Newman) to protein-coated surfaces with that of isogenic methicillin-resistant derivatives. All strains containing an intactmec element in their chromosomes were found to be defective in adhesion to fibrinogen and fibronectin immobilized on polymethylmethacrylate coverslips, regardless of the presence or absence of additional mutations in the femA,femB, or femC gene, known to decrease expression of methicillin resistance in S. aureus. Western ligand affinity blotting or immunoblotting of cell wall-associated adhesins revealed similar contents of fibrinogen- or fibronectin-binding proteins in methicillin-resistant strains compared to those of their methicillin-susceptible counterparts. In contrast to methicillin-resistant strains carrying a mec element in their genomes, methicillin-resistant strains constructed in vitro, by introducing the mecA gene on a plasmid, retained their adhesion phenotypes. In conclusion, the chromosomal insertion of themec element into genetically defined strains of S. aureus impairs the in vitro functional activities of fibrinogen or fibronectin adhesins without altering their production. This effect is unrelated to the activity of the mecA gene.
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Dudin, Omaya, Sébastien Wielgoss, Aaron M. New, and Iñaki Ruiz-Trillo. "Regulation of sedimentation rate shapes the evolution of multicellularity in a close unicellular relative of animals." PLOS Biology 20, no. 3 (March 29, 2022): e3001551. http://dx.doi.org/10.1371/journal.pbio.3001551.
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Significant increases in sedimentation rate accompany the evolution of multicellularity. These increases should lead to rapid changes in ecological distribution, thereby affecting the costs and benefits of multicellularity and its likelihood to evolve. However, how genetic and cellular traits control this process, their likelihood of emergence over evolutionary timescales, and the variation in these traits as multicellularity evolves are still poorly understood. Here, using isolates of the ichthyosporean genus Sphaeroforma-close unicellular relatives of animals with brief transient multicellular life stages-we demonstrate that sedimentation rate is a highly variable and evolvable trait affected by at least 2 distinct physical mechanisms. First, we find extensive (>300×) variation in sedimentation rates for different Sphaeroforma species, mainly driven by size and density during the unicellular-to-multicellular life cycle transition. Second, using experimental evolution with sedimentation rate as a focal trait, we readily obtained, for the first time, fast settling and multicellular Sphaeroforma arctica isolates. Quantitative microscopy showed that increased sedimentation rates most often arose by incomplete cellular separation after cell division, leading to clonal “clumping” multicellular variants with increased size and density. Strikingly, density increases also arose by an acceleration of the nuclear doubling time relative to cell size. Similar size- and density-affecting phenotypes were observed in 4 additional species from the Sphaeroforma genus, suggesting that variation in these traits might be widespread in the marine habitat. By resequencing evolved isolates to high genomic coverage, we identified mutations in regulators of cytokinesis, plasma membrane remodeling, and chromatin condensation that may contribute to both clump formation and the increase in the nuclear number-to-volume ratio. Taken together, this study illustrates how extensive cellular control of density and size drive sedimentation rate variation, likely shaping the onset and further evolution of multicellularity.
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Huang, Qin, Haihong Zhang, Yubo Ma, Steven Schichman, Margie Scott, Lynn Doglio, Philip M. Iannacone, Lawrence M. Weiss, and Chun-Yang Fan. "Development of Essential Thrombocythemia-Like Myeloproliferative Disorder in Transgenic Mice Overexpressing a Human 8-Oxoguanine DNA-Glycosylase Gene." Blood 104, no. 11 (November 16, 2004): 791. http://dx.doi.org/10.1182/blood.v104.11.791.791.
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Abstract Essential thrombocythemia (ET) is a clonal myeloproliferative disease that involves primarily the megakaryocytic lineage. ET is characterized by sustained thrombocytosis in the blood and increased in numbers of large, mature megakaryocytes in the marrow and, occasionally, in the extramedullary organs. Currently, there is no known genetic or biologic marker specific for ET. The etiology and pathogenesis of ET remain largely unclear, partially due to a lack of suitable animal model for the disease. We reported here the development of a transgenic (TG) mouse model, in which most aged mice presented with thrombocytosis, marrow megakaryocytic and myeloid hyperplasia, splenomegaly with marked extramedullary hematopoiesis, features that closely mimic ET in humans. TG mice were generated via microinjection of a mammalian construct consisting of a mitochondrial isoform of human 8-oxoguanine-DNA glycosylase (hOGG) under the control of a mouse metallothionein-1 (mMT-1) promoter. A total of 11 founder mice were obtained and shown to successfully integrate the transgene in their genome, as verified by PCR. Two of the male founder mice successfully transmitted the transgene to their offspring at an expected frequency of 50%. Three founder mice at the age of 12 months and 5 F1 offspring at the age of 4 months were examined. All aged hOGG TG founder mice and their offspring expressed high levels of hOGG mRNA in their liver by RT-PCR and direct DNA sequencing. Upon histologic examination, 3 TG founder mice displayed moderate to severe splenomegaly. The spleen weights were 2-, 4- and 10 times respectively in the 3 TG founder mice as compared to wild type, age-matched mice. Microscopically, the red pulp in the enlarged spleens was markedly expanded with aggregates of large, mature but dysplastic-appearing megakaryocytes, focally disrupting the normal splenic structure. Immunostaining for myeloperoxidase highlighted multiple clusters of myeloid precursors in the spleen of aged hOGG TG mice but none in the spleen of wild type aged mice. Peripheral blood from these aged TG founder mice showed marked thrombocytosis and platelet clumping. In bone marrow, the aged TG founder mice displayed marked myeloid and megakaryocytic hyperplasia without marrow fibrosis, indicative of myeloid and megakaryocytic proliferation. Of note, none of the above phenotype was seen in younger hOGG TG mice (4 months), indicating that the full development of this pathologic process was dependent on age. In summary, TG mice overexpressing the mitochondrial isoform of human OGG gene developed a phenotype, closely mimicking ET in humans and the full manifestation of this phenotype was age-dependent. The molecular basis for this process is currently unclear and remains speculative. One plausible and attractive hypothesis is related to mitochondrial DNA damage with resultant mitochondrial dysfunction, in which overexpression of hOGG gene causes more active repair of free radical-induced 8-oxoguanine from DNA, leaving an increased number of abasic sites, which may generate mutation, inhibit transcription and, ultimately, leading to mitochondrial dysfunction and development of this myeloproliferative disorder. Extensive molecular characterization is currently underway to explore this possibility.
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Yanjie, Mao, Florent Valour, Giang Vu Vi Tran, Trang Vu, Thomas Delaye, Tran Quynh Nhu Nguyen, Christine Tkaczyk, Li Cheng, Bret R. Sellman, and Binh An Diep. "713. Preventive Administration of MEDI6389, a Combination of Monoclonal Antibodies (mAbs) Targeting Alpha-Toxin (AT), Panton-Valentine Leukocidin (PVL), Leukocidin ED (LukED), Gamma-Hemolysin and Clumping Factor A (ClfA), in a Rabbit Model of USA300 MRSA Prosthetic Joint Infection (PJI)." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S320—S321. http://dx.doi.org/10.1093/ofid/ofz360.781.
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Abstract Background mAbs targeting staphylococcal virulence factors could represent an interesting preventive strategy in PJI. We evaluate here MEDI6389 compared with isotype-matched control IgG (c-IgG) in a rabbit model of USA300 MRSA PJI. Methods Rabbits were randomized for prophylaxis with either c-IgG (n = 13; 30 mg/kg; controls) or MEDI6389 (n = 13; 30 mg/kg of each mAb) administered intravenously 12h before infection. A cemented screw and ultrahigh-molecular-weight polyethylene washer were placed intraarticularly in the external femoral condyle. After suturing the joint capsule and musculocutaneous layers, 300 µL of a standardized bacterial inoculum containing 5 × 105 CFU of a USA300 MRSA clinical isolate were injected intraarticularly. Animals were euthanized on day 8 and the knee joint was harvested for bacteriological analysis (synovial bacterial counts, and enumeration of screw-adherent bacteria after sonication) and histology (conventional pathology, and transmission electron microscopy [TEM] for neutrophils analysis). In vivo observations made on neutrophils were confirmed by TEM analysis of human neutrophils incubated in vitro with purified PVL, LukED, and gamma-hemolysin with or without the corresponding mAb. Results In comparison with the control group, the average amount of pus (1.7 ± 1.8 vs. 3.1 ± 1.2 g, P = 0.026) and the number of bacteria in the synovial pus (5.9±1.5 vs. 7.2±1.4 log10 CFU, P = 0.031) and on the screw (2.7 ± 1.5 vs. 4.1 ± 1.6 log10 CFU, P = 0.035) were decreased in animals pretreated by MEDI6389. Conventional pathological examination showed a marked reduction in synovitis of MEDI6389-pretreated animals. TEM of synovitis harvested from infected knee joints of control animals showed significant greater number of abnormal neutrophils that appeared rounded, with condensed nucleus and no granules, compared with those pretreated with MEDI6389 (P = 0.002). This classical leukocidin-induced neutrophilic killing phenotype could be neutralized with anti-leukocidin mAbs using ex vivo human neutrophils incubated with PVL, LukED, HlgAB, or HlgCB. Conclusion The preventive administration of MEDI6389 allows a reduction of local inflammation and bacterial burden in this USA300 MRSA rabbit PJI model. Disclosures All authors: No reported disclosures.
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Huang, Qin, Haihong Zhang, Lawrence M. Weiss, and Chun-Yang Fan. "Mitochondria Damage Leading to High Frequency of Lymphoma and Myeloproliferative Disorder in Transgenic Mice Overexpressing a Human 8-Oxoguanine DNA-Glycosylase Gene." Blood 108, no. 11 (November 1, 2006): 2246. http://dx.doi.org/10.1182/blood.v108.11.2246.2246.
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Abstract Alterations of nuclear genes in human lymphoma and leukemias have been well investigated in past several decades and established a predominant role in the pathogenesis. However, the relationship of mitochondrial genome alteration or dysfunction and human lymphoma and leukemias remains large unknown. Mitochondria are dynamic organelles that play critical roles in oxidative phosphorylation, energy metabolism, cell growth and apoptosis. We have successfully generated a novel transgenic (TG) mouse model of mitochondrial disorder by overexpressing human hOGG1, a base excision DNA repair gene, in the mitochondria of a wide variety of tissues in mice. We reported here the high frequency of essential thrombocythemia (ET)-like myeloproliferative disorder and lymphoma in the TG mice. TG mice were generated via pronuclear microinjection of a mammalian expression construct of a mitochondrial isoform of hOGG under the control of a mouse metallothionein-1 promoter. Peripheral blood smears were prepared from TG and non-TG control mice for platelet counts and morphologic evaluation. TG mice were sacrificed and various organs were harvested for histologic, biochemical and molecular studies. Two of the male founder mice successfully transmitted the transgene to their offspring at an expected frequency of 50%. All the female mice failed to reproduction. All TG mice expressed high levels of hOGG mRNA in their liver by RT-PCR and direct DNA sequencing. Over-expression of this gene produced a wide range of adverse biological phenotype, manifesting early-onset obesity, metabolic disturbance, female infertility and high frequency of ET-like myeloproliferative disorder and lymphoma (>90%) in nodal and extranodal sites. Eight TG mice (ranging from 1 to 2 years) become moribund and subsequently sacrificed. Upon histologic examination, the TG mice displayed moderate to severe splenomegaly. The spleen weights were 2-, 4- and 10 times respectively in the 3 TG founder mice as compared to wild type, age-matched mice. Extensive abdominal lymphadenopathy and numerous enlarged nodules involving liver, spleen, peritoneum, lung and diaphragm were identified. Microscopically, the red pulp in the enlarged spleens is markedly expanded with aggregates of large, mature but dysplastic-appearing megakaryocytes, focally disrupting the normal splenic structure. Various lymphomas ranged from low-grade lymphoma to high-grade Burkitt-like or lymphoblastic lymphomas were seen. Peripheral blood from these aged TG mice showed marked thrombocytosis and platelet clumping. In bone marrow, the aged TG mice displayed marked myeloid and megakaryocytic hyperplasia with relative erythroid hypoplasia in the absence of marrow fibrosis, indicative of myeloid and megakaryocytic proliferation. Bone marrow involvement by B-cell lymphoma was also seen. Of note, none of the above phenotype was seen in younger TG mice (4 months), indicating that the full development of this pathologic process is age-dependent. The molecular basis for this process is currently under investigation. Our preliminary data showed that mitochondrial DNA deletion or decrease in DNA copy numbers due to overexpressed hOGG1 and imbalance of base excision repair resulted in defects in mitochondrial respiration and increased ROS production. We thus hypothesize that oxidative stress caused by mitochondrial malfunction may play important part in the development of hematopoietic malignancies.
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Wu, Cynthia M., Mohan K. Pai, Uma Athale, John G. Kelton, and Donnie M. Arnold. "Peripartum Management of Women with Suspected Hereditary Thrombocytopenia." Blood 110, no. 11 (November 16, 2007): 3224. http://dx.doi.org/10.1182/blood.v110.11.3224.3224.
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Introduction: Hereditary macrothrombocytopenic disorders are rare syndromes characterized by mild to moderate thrombocytopenia, large platelets, and a variable bleeding phenotype. In general, the diagnosis must be made clinically and management is empiric. Because of the autosomally inherited nature of these disorders, peripartum management must take into account the risk of bleeding for both mother and baby, during the pregnancy and at delivery. Study Purpose: To describe the peripartum management and bleeding complications in pregnant women with suspected inherited macrothrombocytopenic disorders and their children. Study Design: We performed a retrospective review of all mothers referred to our tertiary care hospital from 2004 to 2007 for evaluation of macrothrombocytopenia in pregnancy where hereditary thrombocytopenia was suspected. The diagnosis was confirmed if at least 2 of the following clinical features were present: life-long thrombocytopenia; family history of thrombocytopenia that spanned at least 2 generations; and the lack of a platelet count response to IVIG or corticosteroids. Data relating to bleeding and therapies used to treat or to prevent bleeding before or during delivery for mother and child were extracted from medical charts. Blood films were reviewed with experts in morphology, and diagnostic testing was performed when possible. Results: A total of 5 mothers and 8 babies were included. The median platelet count of mothers at delivery was 54 x 109/L (range 15–83 x 109/L) and the median MPV was 9.8 fL (range 7.4–11.3 fL). Of the 8 babies, 4 were thrombocytopenic with a median platelet count at birth of 50 x 109/L (range 9–93 x 109/L) and a median MPV of 9.4 fL (range 8.9–9.6fL). One mother and her baby had neutrophilic Dohle body inclusions, and none had skeletal, neurologic or renal abnormalities. Three mothers were previously treated with IVIG, including one who also received prednisone, with no platelet count response. During pregnancy, fetal blood sampling for platelet count measurements was not done. None of the mothers had epidural anesthesia, all delivered vaginally and 7 of 8 labours were induced. Two mothers received prophylactic tranexamic acid at the time of active labour and 1 received DDAVP. Prophylactic platelet transfusions were not given. One mother had bleeding associated with spontaneous rupture of membranes, and one had a post partum hemorrhage associated with uterine atony and vaginal laceration. The latter was repaired surgically and treated with platelet transfusions and DDAVP. None of the babies bled, but 1 was given a platelet transfusion because of severe thrombocytopenia at birth (platelet count = 9 x 109/L) with persistent platelet clumping. Conclusions: The frequency of pregnancy-related bleeding in mothers with hereditary macrothrombocytopenia was low in this cohort even in the absence of prophylaxis. There is a need for improved diagnosis and risk stratification of mothers with hereditary macrothrombocytopenia. A multicentre prospective study would assist in determining optimal peripartum management.
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LI, Q., A. Dohey, D. Codner, and P. Rahman. "POS0044 EVIDENCE OF A CAUSAL RELATIONSHIP BETWEEN HYPERLIPIDEMIA AND PSORIASIS AND PSORIATIC ARTHRITIS: A MENDELIAN RANDOMIZATION STUDY." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 231.2–231. http://dx.doi.org/10.1136/annrheumdis-2023-eular.2151.
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BackgroundPsoriatic disease (psoriasis and psoriatic arthritis) is a common inflammatory disease associated with obesity. However, recent studies suggest that lipid changes, rather than obesity, may independently drive psoriatic disease [1]. Mendelian randomization (MR) can assess the causal effect of modifiable exposure by measuring the variation of genes of known function.ObjectivesIn this study, we perform a two-sample mendelian randomization to investigate the possible causal relationship between polygenic hyperlipidemia and psoriatic disease (psoriasis and psoriatic arthritis).MethodsThe study cohorts (psoriasis, psoriatic arthritis, hyperlipidemia, and controls of European ancestry) were identified from the FinnGen biobank, an academia/industry collaboration aiming to identify genotype-phenotype correlations in the Finnish founder population. Hyperlipidemia was identified by code E4_HYPERLIPNAS, which represents disorders of lipoprotein metabolism and other lipidaemias [2]. The L12_psoriasis code and psoriatic arthritis by M13_PSORIARTH code identified psoriatic arthritis. The control population was selected after excluding E4_MEABOLIA, psoriasis, and psoriatic arthritis when appropriate. Genome-wide association studies (GWAS) and summarized data were extracted from public IEU datasets. The single-nucleotide polymorphisms (SNPs) were used as instrumental variables (IV) to identify the potential causal effect. The SNP selection was performed by considering the genome-wide significance, clumping, linkage disequilibrium, and minor allele frequency. The effect alleles were harmonized for exposures and outcomes. An inverse variance weighted (IVW) model was used to estimate causality for each IV in this two-sample MR study. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for causal estimations. The MR was performed in both directions to explore the possibility of reverse causality.Results4535 patients with hyperlipidemia, 4510 with psoriasis, and 1553 patients with psoriatic arthritis (PsA) were identified from the FinnGenn biobank based on their id as noted above. The control patients ranged from 147,221 to 212,242, depending on the cohort being compared. Genetic instruments comprising 5 SNPs for hyperlipidemia, 16 SNPs for psoriasis and 4 SNPs for PsA were used for this two-sample MR. A significant causal effect was noted in hyperlipidemia and psoriasis (OR 1.26 (95% CI 1.097-1.439; p < 0.00009) and hyperlipidemia and PsA (OR 1.35 (95% CI 1.08-1.68; p=0.007) but no causal effect was noted in the reverse direction with psoriasis leading to hyperlipidemia OR 1.02 (95% CI 0.977-1.07; p=0.31) and PsA leading to hyperlipidemia OR 1.03 (95% CI 0,987 to 1.08; p=0.15).ConclusionOur two-sample MR study genetically predicted that hyperlipidemia has a potential causal association with psoriatic disease, which leads to a higher risk of psoriasis and PsA. Further validation and molecular studies are required to understand this relationship. If these results were to be validated, targeted reduction of hyperlipidemia may help modify the expression of psoriatic disease.References[1]Snekvik, I., et al. Metabolic syndrome and risk of incident psoriasis: prospective data from the HUNT Study, Norway. Br. J. Dermatol. 2019; 180, 94–99[2]https://risteys.finngen.fi/endpoints/E4_HYPERLIPNASAcknowledgements:NIL.Disclosure of InterestsQuan Li: None declared, Amanda Dohey: None declared, Dianne Codner: None declared, Proton Rahman Speakers bureau: Abbott, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, and Pfizer, Consultant of: Abbott, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, and Pfizer, Grant/research support from: Janssen and Novartis.
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Reilly, Andreea, J. Philip Creamer, Massiel Chavez Stolla, Yuchuan Wang, Jing Du, Rachel Wellington, Stephanie Busch, et al. "Loss of Lamin B1 in Myeloid Neoplasms with 5q Deletion Causes Myeloid-Biased Hematopoiesis and Pelger-Huet Nuclear Anomaly." Blood 138, Supplement 1 (November 5, 2021): 502. http://dx.doi.org/10.1182/blood-2021-154121.
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Abstract Hematopoietic stem and progenitor cells (HSPCs) acquire somatic mutations and cytogenetic abnormalities leading to myeloid neoplasms (MDS/AML). A subgroup of 10-20% MDS and AML cases undergo complex chromosomal rearrangements associated with TP53 mutations and poor prognosis. One of the most common chromosomal events in high-risk myeloid neoplasms is deletion of chromosome 5q (del(5q)). In contrast to 5q- syndrome, characterized by a distal commonly deleted region (CDR) and good prognosis, the critical CDR in high-risk MDS/AML centers on 5q31. However, the key genes in the high-risk 5q-deleted region that contribute to dysregulation of hematopoiesis, chromosomal instability, and disease progression remain poorly characterized. Progression to high-risk MDS/AML is often accompanied by morphologic dysplasia in the form of Pelger-Huët cells, abnormal neutrophils with bilobed or unilobed nuclei and coarse clumping of the nuclear chromatin. The inherited form of Pelger-Huët anomaly (PHA) is caused by mutations in LBR, which encodes lamin B receptor. Acquired PHA or pseudo-PHA is commonly seen in myeloid malignancies, often in high risk MDS and AML with TP53 mutations. While LBR is not mutated in MDS/AML, its main interaction partner lamin B1/LMNB1 is encoded in the high-risk 5q-deleted region. Lamins organize chromatin into perinuclear compartments and regulate diverse biological processes, including gene expression and DNA repair. The frequent deletion of LMNB1 in 5q-deleted MDS and AML led us to hypothesize that LMNB1 loss drives both nuclear dysmorphology and functional HSC defects in malignant transformation. LMNB1 expression was broadly decreased in MDS and AML, particularly in del(5q) cases, 83% of which had deletions of the LMNB1 locus. We show that in a clinical cohort of MDS patients, the Pelger-Huët nuclear phenotype is strongly associated with del5q. To understand the role of LMNB1, we performed lentiviral shRNA knockdown in normal umbilical cord blood (CB) CD34 + HSPCs followed by transplantation into immunodeficient NSG mice. To study the role of lamin B1 in 5q-deleted MDS, we established an in vitro patient-derived induced pluripotent stem cell (iPSC) model by reprograming an MDS patient with TP53 mutation and complex karyotype, and deriving MDS HSPCs with TP53+/R209fs alone or TP53+/R209fs with an isolated del5q spanning 5q22-5q31.1 encoding LMNB1 (TP53;del5q). Using these model systems we show that LMNB1 loss is both necessary and sufficient to cause Pelger-Huët nuclear morphology in normal and MDS neutrophils. Additionally, we find that LMNB1-deficient human HSCs display increased self-renewal and profound myeloid lineage bias in vitro and in vivo. Single cell RNA expression data from LMNB1-deficient cells in vivo shows mis-expression of lineage-specifying transcription factors in single multipotent progenitors. LMNB1 deficiency also results in poor marking and propagation of unrepaired DNA breaks, leading to genome instability. The role of LMNB1 in maintaining chromatin organization prompted us to use chromosome conformation capture (Hi-C) to visualize the 3D chromatin organization of LMNB1-deficient HSPCs. We show that lamin B1 regulates enhancer-promoter loops suggesting that lamin B1 loss dysregulates HSC function by altering enhancer-promoter interactions at lineage-specifying transcription factor loci. Together, we identify lamin B1 as a novel 5q gene that contributes to malignant transformation by driving enhanced self-renewal, myeloid-bias, and genome instability. Furthermore, lamin B1 deletion is the genetic cause of acquired PHA in myeloid malignancies, providing a potential biomarker for high risk neoplasms. Disclosures Becker: Glycomimetics: Research Funding; CVS Caremark: Consultancy; Abbie: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Cardiff Oncology: Research Funding; SecuraBio: Research Funding.
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Wang, Louise, Alyssa Grimshaw, Catherine Mezzacappa, Navid Rahimi Larki, Yu-Xiao Yang, and Amy Justice. "Abstract 5242: Do polygenic risk scores add to clinical data in predicting pancreatic cancer? a scoping review." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5242. http://dx.doi.org/10.1158/1538-7445.am2023-5242.
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Abstract Background: Individual susceptibility to pancreatic ductal adenocarcinoma (PDAC) is determined by both genetic and clinical factors. Polygenic risk scores (PRS) represent a summation of an individual’s risk associated alleles across their genome but it is unclear whether PRS improve prognostic assessments beyond available clinical data. Specific Aims: To evaluate the characteristics of studies examining PRS discrimination for PDAC before and after accounting for clinical factors. Methods: Following the PRISMA extension for scoping reviews (DOI: osf.io/97hxw), we performed a comprehensive literature search in conjunction with a professional librarian to identify preprint and published research studies evaluating PDAC PRS. Results: Nineteen studies (of 392 reviewed citations) examined associations between a PDAC-specific PRS and PDAC. The majority were conducted among the UK Biobank (n= 8) and pancreatic cancer consortia (n=4). The rest were institutional biobanks or hospital-based studies. Thirteen studies used a case-control design, and 7 adjusted for clinical risk factors (Table). Only 3 studies (15.8%) evaluated the change in discrimination with the addition of PRS to clinical factors vs. clinical factors alone, and 2 of these reported small but statistically significant improvements in discrimination (ΔAUC: 0.030, 0.039). Source populations were younger/healthier (n=9) than those at risk for PDAC, exclusively European (n=14), or drew controls without relevant exposures such as pancreatic diseases (n=2). Conclusions: Most PDAC-specific PRS studies do not account for well-established clinical factors or evaluate changes in discrimination with the addition of PRS to clinical factors. Of the 3 studies that did, only 2 showed a modest improvement in discrimination. For PRS to be clinically useful, they must demonstrate more substantial improvements in discrimination beyond established risk factors. Studies containing PDAC-specific polygenic risk scores and clinical risk factors First Author Journal Year Study Design Aim/Purpose Population Description Population Size Ancestry Definition of Pancreatic Cancer Deriving the Polygenic Risk score Analysis Clinical risk Factors Evalulation of predictive ability of models containing PRS Evaluation of the Additive Benefit of PRS Clinical Context Byrne medRxiv 2021 cohort evaluate the effect of lifestyle and genetic risk on overall cancer risk for 13 separate cancers UK Biobank 195,822 total individuals (451 cancers) European genetic ancestry ICD codes, cancer registries 22 SNPs used for pancreatic cancer Cox proportional hazards regression Townsend Index (socioeconomic index), education, birth location, income, height no no national cohort of individuals in the UK, notably younger and of European ancestry Galeotti BMJ 2021 case/control test association of pancreatic cancer specific PRS, with addition of ABO SNPs, smoking, and diabetes PANcreaticDisease ReseArch (PANDoRA) consortium: controls were without any pancreatic diseases 9409 total individuals (3619 cases, 5790 controls) European genetic ancestry confirmed diagnosis of pancreatic cancer SNPs at GWAS significance or near significance (p<10−7); also used SNPs necessary to infer ABO blood groups logistic regression all patients: country of origin, subset: smoking, Type 2 diabetes yes, evaluated the AUC for the full prediction model no limited, controls were without pancreatic disease, such as pancreatitis or pancreatic cysts Kachuri Nature Communications 2020 cohort evaluate additive predictive value of adding PRS for 16 separate cancers UK Biobank 413,753 total individuals (493 cancers) self reported European anestry ICD codes from cancer/mortality registries and inpatient hospital encouters (NHGRI)-European Bioinformatics Institute (EBI) Catalog ofpublished GWAS using standard weights, unweighted sum of risk alleles, and inverse variance weights that incorporate the standarderror of the risk effect size Cox proportional hazards regression BMI, smoking status, cigarette pack-years,family history of cancer (prostate, breast, lung or colon/rectum) Yes, calibration (estimate risk) and discrimination (AUC, NRI of cases vs. cancer free individuals) yes, PGOF: 0.171; AUC increase with PRS: 0.030, total AUC with PRS 0.745 used a national cohort of individuals in the UK, notably younger and of European ancestry Nakatochi Plos One 2018 case/control develop a risk model to identify individuals at high risk for pancreatic cancer development in the general Japanese population two separate case- control datasets in Japan controls: matched age/sex, no diagnosis of cancer at time of recuritment from five Japanese hospitals and the epidemiology research program at Aichi Cancer Center 1,328 total individuals (664 cases, 664 controls) genetically determined Japanese ancestry clinical diagnosis or histologically diagnosed pancreatic cancer, including 1.7% endocrine tumors 5 total SNPs significantly associated with pancreatic cancer logistic regression smoking status, family history of pancreatic cancer Yes, AUC in model containing PRS no limited, controls were drawn from non-cancer patients for a epidemiology research program at Aichi Cancer Center and from inpatients at 5 separate hospitals Rothwell CGH 2022 cohort evaluate metabolic syndrome, additional clinical factors across levels of polygenic risk score UK Biobank 366,016 total individuals (478 cancers) mainly European genetic ancestry ICD codes 26 SNPs at genome wide significance level Cox proportional hazards regression total physical activity, height, alcohol use, diet, smoking, highest educational level,college/university degree, use of ibuprofen, hormone replacement therapy, fasting time no, evaluated other clinical factors stratified on PRS tertile levels no used a national cohort of individuals in the UK, notably younger and of European ancestry Salvatore Journal of Biomedical Informatics 2021 case/control evaluate various phenotype risk scores (PheRS) and assess their discriminatory ability, calibration, and accuracy in combination with polygenic risk scores and clinical risk models Michigan Genomics Initiative (MGI) and UK Biobank; controls were matched on age, sex, and length of followup 431,658 total individuals (1088 cases, 430,570 controls) European ancestry ICD codes 18 independent SNPS from the GWAS catalog using 1) LD clumping and 2) P value thresholding logistic regression BMI, alcohol, smoking yes, AUC, Hosmer-Lemeshow goodness of fit, Brier score for covariates only or PRS + covariates); separate testing and validation cohort yes, modest improvement in the AUC after covariates/risk factors with PRS (Δ AUC: 0.017, no 95% CI provided) limited, controls are likely healthier than the at risk population, as they are are either sampled during a preoperative/operative appointment or are drawn from the healthier, younger UK Biobank population Sharma Gastroenterology 2022 case/control test the performance of PRS to discriminate between new onset diabetes and long standing diabetic patients with pancreatic cancer UK Biobank 11,462 total (1042 cases, 10420 controls); age and sex matched cancer free controls European ancestry incident cases of PDAC as measured by ICD codes and self reported 5 PRS calculated from each of the previous GWASes performed Cox proportional hazards regression age at DM diagnosis, DM onset, waist circumference, family history of pancreatic cancer yes, AUC in models with and without PRS yes, AUC increase with PRS: 0.039, total AUC with PRS 0.83 (p value 0.0002) used a national cohort of individuals in the UK, notably younger and of European ancestry Citation Format: Louise Wang, Alyssa Grimshaw, Catherine Mezzacappa, Navid Rahimi Larki, Yu-Xiao Yang, Amy Justice. Do polygenic risk scores add to clinical data in predicting pancreatic cancer? a scoping review. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5242.
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Bangal, Priti, Hari Sridhar, and Kartik Shanker. "Phenotypic Clumping Decreases With Flock Richness in Mixed-Species Bird Flocks." Frontiers in Ecology and Evolution 8 (January 13, 2021). http://dx.doi.org/10.3389/fevo.2020.537816.
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Animals that live in groups may experience positive interactions such as cooperative behavior or negative interactions such as competition from group members depending on group size and similarity between individuals. The effect of group size and phenotypic and ecological similarity on group assembly has not been well-studied. Mixed-species flocks are important subsets of bird communities worldwide. We examined associations within these in relation to flock size, to understand rules of flock assembly, in the Western Ghats of India. We examined the relationship between phenotypic clumping and flock richness using four variables—body size, foraging behavior, foraging height and taxonomic relatedness. Using a null model approach, we found that small flocks were more phenotypically clumped for body size than expected by chance; however, phenotypic clumping decreased as flocks increased in size and approached expected phenotypic variation in large flocks. This pattern was not as clear for foraging height and foraging behavior. We then examined a dataset of 55 flock matrices from 24 sites across the world. We found that sites with smaller flocks had higher values of phenotypic clumping for body size and sites with larger flocks were less phenotypically clumped. This relationship was weakly negative for foraging behavior and not statistically significant for taxonomic relatedness. Unlike most single-species groups, participants in mixed-species flocks appear to be able to separate on different axes of trait similarity. They can gain benefits from similarity on one axis while mitigating competition by dissimilarity on others. Consistent with our results, we speculate that flock assembly was deterministic up to a certain point with participants being similar in body size, but larger flocks tended to approach random phenotypic assemblages of species.
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KARAMATI, Seyed Ahmad, Hamed MIRJALALI, Maryam NIYYATI, Tahereh REZAEI RIABI, Abbas YADEGAR, Hamid ASADZADEH AGHDAEI, Ali HAGHIGHI, Seyyed Javad SEYYED TABAEI, and Mohammad Reza ZALI. "Comprehensive Study of Phenotypic and Growth Rate Features of Blastocystis Subtypes 1-3 and 6 in Symptomatic and Asymp-tomatic Subjects." Iranian Journal of Parasitology, June 24, 2019. http://dx.doi.org/10.18502/ijpa.v14i2.1132.
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Background: The present study aimed to assess the grouping of subtypes 1-3 and 6 of Blastocystis according to the size and generation time of the parasite among the symptomatic and asymptomatic subjects.
Methods: Blastocystis subtypes1-3 and 6 isolated from symptomatic and asymptomatic subjects and were cultivated in DMEM medium. In order to assess inter- and intra-subtype variation in size, all the isolates were measured using morphometric criteria. Generation time was calculated using approximately 1×104 Blastocystis, which were cultivated in DMEM, every 24h for 4 days.
Results: All subtypes had 5 to 185 μm diameter range. The smallest size was attributed to ST1, followed by ST6 and ST2. ST3 showed the most variable size and phenotypes compared with the other three subtypes. Furthermore, amoeboid forms and parasite clumping were only seen in ST3-S (symptomatic subjects). Generation time analysis showed that the number of ST1 isolated from symptomatic and asymptomatic subjects peaked higher than the other subtypes.
Conclusion: This is the first study discussing inter-intra-size, phenotype and generation time variations among 4 common subtypes of Blastocystis. Accordingly, ST3 was largest subtype and showed most diversities in both size and phenotype, while ST1 was smallest subtype with lowest intra-subtype variation.
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Suwito, Widodo, Widagdo Sri Nugroho, Rahmat Setya Adji, Andriani Andriani, Eny Kusumaningtyas, and Tri Martini. "Phenotypic characteristic of Staphylococcus aureus from subclinical mastitis in Etawah-crossbreed goats in Yogyakarta, Indonesia." Veterinary World, November 15, 2022, 2587–92. http://dx.doi.org/10.14202/vetworld.2022.2587-2592.
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Background and Aim: Subclinical mastitis (SCM) in Etawah-grade (PE) goats in Yogyakarta, Indonesia, is commonly due to Staphylococcus aureus. At present, S. aureus from SCM in PE goats in Yogyakarta has not been characterized. Therefore, this study aimed to phenotypically characterize S. aureus, which has been isolated from SCM of PE goats. Materials and Methods: A total of 314 lactating PE goats were collected from 60 PE goat farms (e.g., Sleman, Bantul, and Kulonprogo) located in parts of Yogyakarta with an average age of 3–4 years old, three of which showed SCM based on the California mastitis test (CMT). Subclinical mastitis is confirmed in PE goats if CMT shows ++ or +++. Furthermore, S. aureus was detected by biochemical assays. Staphylococcus aureus could determine hemolysin (Hae), coagulase (Coa), clumping factor (Cf), and antibiotic susceptibility. Hemolytic bacteria were detected by culturing on blood agar plate, and Cf was detected by slide agglutination. The production of Coa was detected by tube coagulation. Staphylococcus aureus susceptibility was determined by antimicrobial agar diffusion using a paper disc. Results: Phenotypically characterized S. aureus from PE goats with SCM in Yogyakarta, Indonesia, Coa–, Cf–, and Hae– were found to be resistant to erythromycin (ERYTHRO), ampicillin (AMP), penicillin (PEN-G), and sulfamethoxazole (SULFA). Conclusion: The phenotypic characteristic of S. aureus, which was obtained from SCM in PE goats in Yogyakarta, consists of Coa, and Cf–. S. aureus cannot perform hemolysis of red blood cells. This phenotypic characteristic can prevent and control SCM in PE goats. Several antibiotics such as ERYTHRO, AMP, PEN-G, and SULFA were no longer effective for treating SCM in PE goats because S. aureus has developed its resistance to these antibiotics.
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He, Chun-Hui, Ning-Ning Song, Pin-Xi Xie, Yu-Bing Wang, Jia-Yin Chen, Ying Huang, Ling Hu, et al. "Overexpression of EphB6 and EphrinB2 controls soma spacing of cortical neurons in a mutual inhibitory way." Cell Death & Disease 14, no. 5 (May 6, 2023). http://dx.doi.org/10.1038/s41419-023-05825-w.
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AbstractTo establish functional circuitry, neurons settle down in a particular spatial domain by spacing their cell bodies, which requires proper positioning of the soma and establishing of a zone with unique connections. Deficits in this process are implicated in neurodevelopmental diseases. In this study, we examined the function of EphB6 in the development of cerebral cortex. Overexpression of EphB6 via in utero electroporation results in clumping of cortical neurons, while reducing its expression has no effect. In addition, overexpression of EphrinB2, a ligand of EphB6, also induces soma clumping in the cortex. Unexpectedly, the soma clumping phenotypes disappear when both of them are overexpressed in cortical neurons. The mutual inhibitory effect of EphB6/ EphrinB2 on preventing soma clumping is likely to be achieved via interaction of their specific domains. Thus, our results reveal a combinational role of EphrinB2/EphB6 overexpression in controlling soma spacing in cortical development.
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García-Marín, Luis M., Adrián I. Campos, Nicholas G. Martin, Gabriel Cuéllar-Partida, and Miguel E. Rentería. "Phenome-wide analysis highlights putative causal relationships between self-reported migraine and other complex traits." Journal of Headache and Pain 22, no. 1 (July 8, 2021). http://dx.doi.org/10.1186/s10194-021-01284-w.
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Abstract Background Migraine is a complex neurological disorder that is considered the most common disabling brain disorder affecting 14 % of people worldwide. The present study sought to infer potential causal relationships between self-reported migraine and other complex traits, using genetic data and a hypothesis-free approach. Methods We leveraged available summary statistics from genome-wide association studies (GWAS) of 1,504 phenotypes and self-reported migraine and inferred pair-wise causal relationships using the latent causal variable (LCV) method. Results We identify 18 potential causal relationships between self-reported migraine and other complex traits. Hypertension and blood clot formations were causally associated with an increased migraine risk, possibly through vasoconstriction and platelet clumping. We observed that sources of abdominal pain and discomfort might influence a higher risk for migraine. Moreover, occupational and environmental factors such as working with paints, thinner or glues, and being exposed to diesel exhaust were causally associated with higher migraine risk. Psychiatric-related phenotypes, including stressful life events, increased migraine risk. In contrast, ever feeling unenthusiastic / disinterested for a whole week, a phenotype related to the psychological well-being of individuals, was a potential outcome of migraine. Conclusions Overall, our results suggest a potential vascular component to migraine, highlighting the role of vasoconstriction and platelet clumping. Stressful life events and occupational variables potentially influence a higher migraine risk. Additionally, a migraine could impact the psychological well-being of individuals. Our findings provide novel testable hypotheses for future studies that may inform the design of new interventions to prevent or reduce migraine risk and recurrence.
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Oktavia, Siti Isrina. "Karakterisasi Fenotipe Isolat Staphylococcus aureus Dari Sampel Susu Sapi Perah Mastitis Subklinis = Phenotyping of Staphylococcus aureus ..." Jurnal Sain Veteriner 23, no. 2 (March 20, 2012). http://dx.doi.org/10.22146/jsv.371.
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Staphylococcus aureus merupakan salah satu penyebab utama mastitis pada sapi perah yang menimbulkan kerugian ekonomi yang cukup besar akibat turunnya produksi susu. Penelitian ini bertujuan untuk isolasi dan karakterisasi S. aureus yang diisolasi dan susu sapi perah di Kaliurang, Bantul, Boyolali dan Baturaden Jawa Tengah. Karakterisasi S. aureus meliputi uji clumping factor, uji koagulase, produksi hemolisin, produksi pigmen dan uji kepekaan S. aureus terhadap beberapa antibiotika. Dalam penelitian ini berhasil diisolasi dan diidentifikasi sebanyak 32 isolat S. aureus. Semua isolat positif pada uji clumping factor dan koagulase. Alfa-hemolisis dapat diamati pada 1 isolat, 7 isolat mempunyai sifat a dan 13-hemolitik, 11 isolat 13- hemolitik dan 13 isolat bersifat non-hemolitik. Berdasar produksi pigmen, 8 isolat menghasilkan pigmen berwarna oranye, 10 isolat pigmen kuning dan 8 isolat menghasilkan pigmen putih. Hasil uji resistensi antibiotik terlihat bahwa 24 isolat (75%) sensitif dan 8 isolat (25%) resisten terhadap ampisilin. Uji terhadap eritromisin diketahui 4 isolat (12,5%) sensitif, 5 isolat (15,57%) intermediet dan 23 isolat (71,97%) bersifat resisten. Sebanyak 25 isolat (78,13%) diketahui bersifat intermediet dan 7 (21,87%) resisten terhadap gentamisin. Sebanyak 4 isolat S. aureus (712,5%) bersifat sensitif dan 28 isolat (87,5%) resisten terhadap oksasilin. Terhadap tetrasiklin memperlihatkan sifat intermediet pada 19 isolat (59,38%), 12 isolat (37,46%) bersifat resisten dan hanya 1 isolat (3,16%) bersifat sensitif.
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Yang, Chengran, Anne M. Fagan, Richard J. Perrin, Herve Rhinn, Oscar Harari, and Carlos Cruchaga. "Mendelian randomization and genetic colocalization infer the effects of the multi-tissue proteome on 211 complex disease-related phenotypes." Genome Medicine 14, no. 1 (December 12, 2022). http://dx.doi.org/10.1186/s13073-022-01140-9.
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Abstract Background Human proteins are widely used as drug targets. Integration of large-scale protein-level genome-wide association studies (GWAS) and disease-related GWAS has thus connected genetic variation to disease mechanisms via protein. Previous proteome-by-phenome-wide Mendelian randomization (MR) studies have been mainly focused on plasma proteomes. Previous MR studies using the brain proteome only reported protein effects on a set of pre-selected tissue-specific diseases. No studies, however, have used high-throughput proteomics from multiple tissues to perform MR on hundreds of phenotypes. Methods Here, we performed MR and colocalization analysis using multi-tissue (cerebrospinal fluid (CSF), plasma, and brain from pre- and post-meta-analysis of several disease-focus cohorts including Alzheimer disease (AD)) protein quantitative trait loci (pQTLs) as instrumental variables to infer protein effects on 211 phenotypes, covering seven broad categories: biological traits, blood traits, cancer types, neurological diseases, other diseases, personality traits, and other risk factors. We first implemented these analyses with cis pQTLs, as cis pQTLs are known for being less prone to horizontal pleiotropy. Next, we included both cis and trans conditionally independent pQTLs that passed the genome-wide significance threshold keeping only variants associated with fewer than five proteins to minimize pleiotropic effects. We compared the tissue-specific protein effects on phenotypes across different categories. Finally, we integrated the MR-prioritized proteins with the druggable genome to identify new potential targets. Results In the MR and colocalization analysis including study-wide significant cis pQTLs as instrumental variables, we identified 33 CSF, 13 plasma, and five brain proteins to be putative causal for 37, 18, and eight phenotypes, respectively. After expanding the instrumental variables by including genome-wide significant cis and trans pQTLs, we identified a total of 58 CSF, 32 plasma, and nine brain proteins associated with 58, 44, and 16 phenotypes, respectively. For those protein-phenotype associations that were found in more than one tissue, the directions of the associations for 13 (87%) pairs were consistent across tissues. As we were unable to use methods correcting for horizontal pleiotropy given most of the proteins were only associated with one valid instrumental variable after clumping, we found that the observations of protein-phenotype associations were consistent with a causal role or horizontal pleiotropy. Between 66.7 and 86.3% of the disease-causing proteins overlapped with the druggable genome. Finally, between one and three proteins, depending on the tissue, were connected with at least one drug compound for one phenotype from both DrugBank and ChEMBL databases. Conclusions Integrating multi-tissue pQTLs with MR and the druggable genome may open doors to pinpoint novel interventions for complex traits with no effective treatments, such as ovarian and lung cancers.
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Rowe, J. Alexandra, Antoine Claessens, Ruth A. Corrigan, and Mònica Arman. "Adhesion ofPlasmodium falciparum-infected erythrocytes to human cells: molecular mechanisms and therapeutic implications." Expert Reviews in Molecular Medicine 11 (May 2009). http://dx.doi.org/10.1017/s1462399409001082.
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Severe malaria has a high mortality rate (15–20%) despite treatment with effective antimalarial drugs. Adjunctive therapies for severe malaria that target the underlying disease process are therefore urgently required. Adhesion of erythrocytes infected withPlasmodium falciparumto human cells has a key role in the pathogenesis of life-threatening malaria and could be targeted with antiadhesion therapy. Parasite adhesion interactions include binding to endothelial cells (cytoadherence), rosetting with uninfected erythrocytes and platelet-mediated clumping of infected erythrocytes. Recent research has started to define the molecular mechanisms of parasite adhesion, and antiadhesion therapies are being explored. However, many fundamental questions regarding the role of parasite adhesion in severe malaria remain unanswered. There is strong evidence that rosetting contributes to severe malaria in sub-Saharan Africa; however, the identity of other parasite adhesion phenotypes that are implicated in disease pathogenesis remains unclear. In addition, the possibility of geographic variation in adhesion phenotypes causing severe malaria, linked to differences in malaria transmission levels and host immunity, has been neglected. Further research is needed to realise the untapped potential of antiadhesion adjunctive therapies, which could revolutionise the treatment of severe malaria and reduce the high mortality rate of the disease.
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Lloyd-Jones, Luke R., Jian Zeng, Julia Sidorenko, Loïc Yengo, Gerhard Moser, Kathryn E. Kemper, Huanwei Wang, et al. "Improved polygenic prediction by Bayesian multiple regression on summary statistics." Nature Communications 10, no. 1 (November 8, 2019). http://dx.doi.org/10.1038/s41467-019-12653-0.
Full textAbstract:
Abstract Accurate prediction of an individual’s phenotype from their DNA sequence is one of the great promises of genomics and precision medicine. We extend a powerful individual-level data Bayesian multiple regression model (BayesR) to one that utilises summary statistics from genome-wide association studies (GWAS), SBayesR. In simulation and cross-validation using 12 real traits and 1.1 million variants on 350,000 individuals from the UK Biobank, SBayesR improves prediction accuracy relative to commonly used state-of-the-art summary statistics methods at a fraction of the computational resources. Furthermore, using summary statistics for variants from the largest GWAS meta-analysis (n ≈ 700, 000) on height and BMI, we show that on average across traits and two independent data sets that SBayesR improves prediction R2 by 5.2% relative to LDpred and by 26.5% relative to clumping and p value thresholding.
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Bokor, Janos, Sara Sutori, Dora Torok, Zsofia Gal, Nora Eszlari, Dorka Gyorik, Daniel Baksa, et al. "Inflamed Mind: Multiple Genetic Variants of IL6 Influence Suicide Risk Phenotypes in Interaction With Early and Recent Adversities in a Linkage Disequilibrium-Based Clumping Analysis." Frontiers in Psychiatry 12 (October 29, 2021). http://dx.doi.org/10.3389/fpsyt.2021.746206.
Full textAbstract:
Background: Understanding and predicting suicide remains a challenge, and a recent paradigm shift regarding the complex relationship between the immune system and the brain brought attention to the involvement of inflammation in neuropsychiatric conditions including suicide. Among cytokines, IL-6 has been most frequently implicated in suicide, yet only a few candidate gene studies and without considering the effect of stress investigated the role of IL6 in suicidal behaviour. Our study aimed to investigate the association of IL6 variation with a linkage disequilibrium-based clumping method in interaction with childhood adversities and recent stress on manifestations along the suicide spectrum.Methods: One thousand seven hundred and sixty-two participants provided information on previous suicide attempts, current suicidal ideation, thoughts of death, and hopelessness, and were genotyped for 186 variants in IL6. Early childhood adversities were recorded with an instrument adapted from the Childhood Trauma Questionnaire, recent life events were registered using the List of Threatening Life Events. Following a 3-step quality control, logistic and linear regression models were run to explore the effect of genotype and gene-environment interactions on suicide phenotypes. All regression models were followed by a clumping process based on empirical estimates of linkage disequilibrium between clumps of intercorrelated SNPs. Interaction effects of distinct types of recent life events were also analysed.Results: No clumps with significant main effects emerged, but we identified several clumps significantly interacting with childhood adversities on lifetime suicide attempts, current suicidal ideation, and current thoughts of death. We also identified clumps significantly interacting with recent negative life events on current suicidal ideation. We reported no clumps with significant effect on hopelessness either as a main effect or in interaction with childhood adversities or recent stress.Conclusion: We identified variant clumps in IL6 influencing suicidal behaviour, but only in interaction with childhood or recent adversities. Our results may bring us a step further in understanding the role of neuroinflammation and specifically of IL-6 in suicide, towards identifying novel biological markers of suicidal behaviour especially in those exposed to stressful experiences, and to fostering the adaptation of a new paradigm and identifying novel approaches and targets in the treatment of suicidal behaviour.