Relevant bibliographies by topics / ALS pathogenesis

Academic literature on the topic 'ALS pathogenesis'

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Published: 6 September 2023

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Journal articles on the topic "ALS pathogenesis"

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Silani, V. "ALS: Current theories of pathogenesis." Electroencephalography and Clinical Neurophysiology 103, no. 1 (July 1997): 17–18. http://dx.doi.org/10.1016/s0013-4694(97)87981-7.

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McCauley, Madelyn E., and Robert H. Baloh. "Inflammation in ALS/FTD pathogenesis." Acta Neuropathologica 137, no. 5 (November 21, 2018): 715–30. http://dx.doi.org/10.1007/s00401-018-1933-9.

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Abe, Koji. "Clinical Features, Pathogenesis, and Therapy for ALS." Spinal Surgery 26, no. 3 (2012): 270–77. http://dx.doi.org/10.2531/spinalsurg.26.270.

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Beal, M. F. "Mitochondria and the pathogenesis of ALS." Brain 123, no. 7 (July 1, 2000): 1291–92. http://dx.doi.org/10.1093/brain/123.7.1291.

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Onodera, Osamu. "Molecular pathogenesis of ALS in TDP43 era." Rinsho Shinkeigaku 53, no. 11 (2013): 1077–79. http://dx.doi.org/10.5692/clinicalneurol.53.1077.

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Li, Yun R., Oliver D. King, James Shorter, and Aaron D. Gitler. "Stress granules as crucibles of ALS pathogenesis." Journal of Cell Biology 201, no. 3 (April 29, 2013): 361–72. http://dx.doi.org/10.1083/jcb.201302044.

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Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis.
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Choi, Hyun-Jun, Sun Joo Cha, Jang-Won Lee, Hyung-Jun Kim, and Kiyoung Kim. "Recent Advances on the Role of GSK3β in the Pathogenesis of Amyotrophic Lateral Sclerosis." Brain Sciences 10, no. 10 (September 26, 2020): 675. http://dx.doi.org/10.3390/brainsci10100675.

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Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by progressive motor neuron degeneration. Although several studies on genes involved in ALS have substantially expanded and improved our understanding of ALS pathogenesis, the exact molecular mechanisms underlying this disease remain poorly understood. Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine-protein kinase that plays a critical role in the regulation of various cellular signaling pathways. Dysregulation of GSK3β activity in neuronal cells has been implicated in the pathogenesis of neurodegenerative diseases. Previous research indicates that GSK3β inactivation plays a neuroprotective role in ALS pathogenesis. GSK3β activity shows an increase in various ALS models and patients. Furthermore, GSK3β inhibition can suppress the defective phenotypes caused by SOD, TDP-43, and FUS expression in various models. This review focuses on the most recent studies related to the therapeutic effect of GSK3β in ALS and provides an overview of how the dysfunction of GSK3β activity contributes to ALS pathogenesis.
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Rossi, Simona, Mauro Cozzolino, and Maria Teresa Carrì. "OldversusNew Mechanisms in the Pathogenesis of ALS." Brain Pathology 26, no. 2 (March 2016): 276–86. http://dx.doi.org/10.1111/bpa.12355.

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Carrì, Maria Teresa, Nadia D’Ambrosi, and Mauro Cozzolino. "Pathways to mitochondrial dysfunction in ALS pathogenesis." Biochemical and Biophysical Research Communications 483, no. 4 (February 2017): 1187–93. http://dx.doi.org/10.1016/j.bbrc.2016.07.055.

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Yang, Xiaoming, Yanan Ji, Wei Wang, Lilei Zhang, Zehao Chen, Miaomei Yu, Yuntian Shen, Fei Ding, Xiaosong Gu, and Hualin Sun. "Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Biomarkers, and Therapeutic Strategies." Antioxidants 10, no. 7 (June 24, 2021): 1012. http://dx.doi.org/10.3390/antiox10071012.

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with the progressive loss of motor neurons, leading to a fatal paralysis. According to whether there is a family history of ALS, ALS can be roughly divided into two types: familial and sporadic. Despite decades of research, the pathogenesis of ALS is still unelucidated. To this end, we review the recent progress of ALS pathogenesis, biomarkers, and treatment strategies, mainly discuss the roles of immune disorders, redox imbalance, autophagy dysfunction, and disordered iron homeostasis in the pathogenesis of ALS, and introduce the effects of RNA binding proteins, ALS-related genes, and non-coding RNA as biomarkers on ALS. In addition, we also mention other ALS biomarkers such as serum uric acid (UA), cardiolipin (CL), chitotriosidase (CHIT1), and neurofilament light chain (NFL). Finally, we discuss the drug therapy, gene therapy, immunotherapy, and stem cell-exosomal therapy for ALS, attempting to find new therapeutic targets and strategies. A challenge is to study the various mechanisms of ALS as a syndrome. Biomarkers that have been widely explored are indispensable for the diagnosis, treatment, and prevention of ALS. Moreover, the development of new genes and targets is an urgent task in this field.
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Dissertations / Theses on the topic "ALS pathogenesis"

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Keskin, Isil. "SOD, ORF and ALS: On the role of SOD1 and C9ORF72 in the pathogenesis of ALS." Doctoral thesis, Umeå universitet, Klinisk neurovetenskap, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-124917.

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Amyotrophic lateral sclerosis (ALS) is characterized by adult-onset degeneration of upper and lower motor neurons. Symptoms begin focally in one muscle and then spread contiguously, resulting in progressive paralysis and death from respiratory failure. Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause, however, mutations in SOD1 were the first identified and are found in 1-9% of patients. Misfolded SOD1 aggregates in the CNS are hallmarks of ALS associated with SOD1 mutations. However, accumulation of misfolded or aggregated SOD1 protein has also been reported in sporadic and familial ALS without SOD1 mutations, suggesting that wild-type SOD1 could play a role in ALS pathology in general. The aims of this thesis are: 1) To describe the resulting disease phenotype and specific characteristics of the SOD1 protein carrying the stable disease- associated mutation L117V. 2) To set up cell-based in vitro models to study the mechanisms of SOD1 misfolding and aggregation under physiologically relevant expression levels. 3) To compare SOD1 activity in patient-derived samples and screen for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations. 1) We identified a novel L117V SOD1 mutant in two families of Syrian origin that co-segregated with the disease. This mutation was associated with slow disease progression, reduced penetrance and a uniform phenotype. The L117V mutant protein was indistinguishable from wild-type SOD1 in terms of stability, dismutation activity and misfolding in patient-derived cell lines. 2) We established patient-derived fibroblast and iPSC-MN lines expressing mutant SOD1 at physiological levels as in vitro models to study misfolding and aggregation of SOD1. We investigated the effects of several cellular pathway disturbances on SOD1 misfolding. Misfolded SOD1 was increased by inhibition of the ubiquitin-proteasome pathway in fibroblasts derived from both patients and controls. An age-related decline in proteasome activity could contribute to the late onset of ALS. Next, we studied the effects of low oxygen tension on misfolding and aggregation of SOD1 in patient-derived cells. Low O2 tensions were found to markedly increase C57-C146 disulphide reduction, misfolding and aggregation of SOD1. Importantly, the largest effects were detected in iPSC-MNs. This suggests that motor neurons are specifically vulnerable to misfolding and aggregation of SOD1 under low O2 tension. 3) We compared the enzymatic activity of SOD1 in blood samples from a large number of ALS patients and controls. We screened for potential underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations. No aberrations in copy number, other large structural changes in introns and exons or intronic mutations in the 30-50 bp flanking the exons were found in the 142 outliers, with either very low or very high SOD1 dismutation activities. However, hemoglobinopathies, including thalassemias and iron deficiency anemia, were associated with high SOD1/mg Hb ratios. Erythrocytes from patients with destabilizing SOD1 mutations showed half the normal activity. There were no significant differences in SOD1 activity between control individuals and ALS patients without a coding SOD1 mutation, or carriers of TBK1 mutations or the hexanucleotide repeat expansion in C9ORF72. Our result suggests that SOD1 enzymatic activity is not associated with the disease in non-SOD1 mutation ALS.
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Menon, Parvathi. "The role of the corticomotorneurons in pathogenesis of amyotrophic lateral sclerosis." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/11609.

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Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative disease of the motor system clinically defined by the presence of upper and lower motor neuron (LMN) signs. The site of onset of pathophysiology within the motor system in ALS remains unresolved and this thesis examines the role of the corticomotor neuron in the pathogenesis of ALS. The diagnostic utility of the split-hand sign in ALS involving preferential wasting of the ‘thenar’ group of intrinsic hand muscles namely the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) was established by recording the split-hand index (SI) which was noted to reliably differentiate ALS from mimic neuromuscular disorders. The cortical and axonal excitability characteristics of the ‘thenar’ muscles namely the APB and FDI was compared with the hypothenar abductor digiti minimi (ADM) with threshold tracking transcranial magnetic stimulation (TMS) studies revealing cortical hyperexcitability to be a feature of ALS pronounced over the ‘thenar’ muscles while axonal hyperexcitability while a feature of ALS, did not selectively affect the prominently wasted ‘thenar’ muscles. Cortical hyperexcitability was also noted to precede the development of lower motor neuron dysfunction in a clinically and neurophysiologically normal APB muscle. The selective vulnerability of muscles in ALS was further defined by the split hand plus sign with a greater degree of cortical hyperexcitability over the preferentially wasted APB muscle in ALS patients when compared with a similarly innervated and relatively preserved flexor pollicis longus (FPL) muscle. In summary, corticomotorneuronal hyperexcitability as a marker of corticomotorneuronal dysfunction predominates over the muscles which are preferentially wasted in ALS and precedes evidence of lower motor neuron loss. The findings presented in this thesis support the primacy of the corticomotor neuron in the pathogenesis of the split hand phenomenon and suggest a mechanism for the pathogenesis of ALS.
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Schmidt, Eric J. "Investigation of a Misfolded, Destabilized Profilin-1 Species as a Toxic Molecule in ALS Pathogenesis." eScholarship@UMMS, 2019. https://escholarship.umassmed.edu/gsbs_diss/1043.

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Dominant mutations in profilin-1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by motor neuron loss, paralysis, and death from respiratory failure. Our lab recently demonstrated that PFN1 mutant proteins are destabilized—they unfold at milder conditions during thermal and chemical denaturation. Furthermore, we and others have shown that mutant PFN1 is more prone to misfold and aggregate. This misfolding alters PFN1’s protein-protein interactions, as demonstrated by an affinity purification-mass spectrometry screen. While ALS-associated mutants do not show loss of interaction, several have altered interactions with several formin family proteins, a group of proteins that interacts with profilins to regulate actin polymerization. These perturbations in profilin-formin interaction result in changes in actin metabolism, as shown by stress fiber formation in a HeLa model and neurite outgrowth in an iPSC-derived neuron model. Additionally, one mutant shows increased actin filament survival time in a microfluidic experiment, indicative of tighter binding in the actin-profilin-formin complex at the growing end of a filament. Misfolding and aggregation also puts additional stress on the cell’s proteostasis pathways. A cell culture model shows that misfolded Pfn1 is processed primarily by the proteasome, with modest contributions from autophagy. Together, this evidence provides additional support for two theories of Pfn1 ALS pathogenesis: disruptions in cytoskeletal function and proteostatic stress.
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Pratt, Kenny Matthew. "Novel properties of hnRNP-UL1 : its possible role in the pathogenesis of ALS." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6583/.

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Heterogeneous nuclear ribonucleoprotein-U like 1 (hnRNP-UL1) is a protein with numerous roles within the cell, including RNA processing and responses to DNA damage. Within this study two novel aspects of the protein are explored: the role of a putative nucleotide-binding domain and the protein's possible involvement in amyotrophic lateral sclerosis (ALS). hnRNP-UL1 is known to have a putative nucleotide-binding domain within its central region containing both a Walker A and Walker B motif. This region had not been investigated previously and was therefore of great interest in this study. The Walker A motif was shown to bind adenosine triphosphate (ATP) and the region appears to possess protein kinase activity. A biological substrate and function for these activities were not established, but these observations suggest that there are still layers of complexity to hnRNP-UL1's cellular roles to be elucidated. ALS is a late-onset neurodegenerative disease with limited treatment strategies and poor patient outcomes. Many of the proteins involved in its pathogenesis have two properties in common: they have roles in RNA-processing and possess prion-like domains (PrLDs). The properties of hnRNP-UL1 appertain to both of these and therefore it was of great interest when ALS patients were discovered with heterozygous hnRNP-UL1 mutations. Results showed that cells possessing the ALS patient mutations (R639C and R468C) had no DNA damage response (DDR) defects or mislocalisation of the protein, but their ssDNA/RNA-binding capability was markedly reduced. Whilst no direct causative links to ALS pathogenesis were shown with the hnRNP-UL1 patient mutations in this study, growing evidence implies good reason for the protein to have involvement in the disease.
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Moens, Thomas Grover. "Molecular mechanisms of pathogenesis in Drosophila models of C9orf72 mutation associated ALS/FTD." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10046295/.

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A GGGGCC hexanucleotide repeat expansion within the C9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). Toxicity has been proposed to be due to loss of function of the gene, or by a toxic gain of function, mediated either by the transcription of repetitive sense and antisense RNA molecules, or by translation of RNA into five repetitive dipeptide proteins (DPRs) via repeat associated non-ATG initiated translation. In order to fully assess the role of sense and antisense RNA in vivo, Drosophila models were created where expression of sense or antisense RNA was induced whilst suppressing the formation of DPRs. Despite the formation of cardinal pathological features (RNA binding protein sequestering intranuclear RNA foci) toxicity was not observed in these models suggesting that repeat RNA plays a limited role in disease pathogenesis. When individual DPRs are expressed in Drosophila neurons a strong toxicity is induced by the arginine containing DPRs (poly-GR and poly-PR). To gain insight into the mechanism(s) by which this toxicity occurs, the protein-interactome of these DPRs was investigated in vivo using novel transgenic Drosophila that inducibly express affinity tagged DPR constructs, with identification of interacting proteins using mass spectrometry. In parallel, inclusions of dipeptide proteins were laser-capture microdissected from patient brain tissue and enriched proteins identified by mass spectrometry. The overlap of these datasets suggested that translation may be impaired by the arginine-containing DPRs and methods were adapted to assess the rate of translation in adult Drosophila brains. In parallel, enzymelinked immunosorbent assays (ELISAs) were developed against poly-GR and an abundant non-toxic DPR poly-GP. Measurement of these proteins was performed in various model systems (transfected immortalised cell lines, induced pluripotent stem cell derived neurons, Drosophila models) to confirm the validity of the assays and the potential therapeutic value of interventions.
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Bergemalm, Daniel. "Mutant superoxide dismutase-1-caused pathogenesis in amyotrophic lateral sclerosis." Doctoral thesis, Umeå : Umeå university, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-31116.

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Frakes, Ashley E. "The Role of Neuroinflammation in the Pathogenesis of Amyotrophic Lateral Sclerosis." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1417649954.

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Gregory, Jenna Mair. "Investigating the role of TDP-43 aggregation in the pathogenesis of ALS and FTD-U." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609875.

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Arechavala, Virginia. "Molecular studies on mutant SOD1 : the role of catalysis and aggregation in the pathogenesis of ALS." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414506.

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Thau, Nadine [Verfasser]. "Transcriptional regulators and neurotrophic factors in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) Histopathological and biochemical studies in the G93A ALS mouse model and in ALS post mortem tissue / Nadine Thau." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2013. http://d-nb.info/1030453691/34.

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Books on the topic "ALS pathogenesis"

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Geschichte als Lernprozess?: Zur Pathogenese politischer Modernität in Deutschland. Frankfurt am Main: Suhrkamp, 1991.

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Geschichte als Lernprozess?: Zur Pathogenese politischer Modernität in Deutschland. Frankfurt am Main: Suhrkamp, 1985.

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Radzinskiy, Viktor, Alevtina Savicheva, Sergey Vorob'ev, Elena Spasibova, Kira Shalepo, Ol'ga Budilovskaya, Tat'yana Husnutdinova, et al. Biocenosis of the vagina. Norm. Disruption. Restoration. ru: Publishing Center RIOR, 2023. http://dx.doi.org/10.29039/978-5-907218-72-7.

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A healthy reproductive system is inconceivable without normal vaginal microbiota, and full-fledged treatment cannot be carried out without detailed understanding of the arrangement and functions of the human microbiome. Today superbugs are a reality, and the role of such concepts as “microbiome” and “biofilms” is already undeniable in medical practice. Every doctor understands that it is necessary to choose antibacterial drugs based on practicability, global experience and evidence-based medicine. All this clearly demonstrates that there is a need to create an authoritative source of knowledge — a handbook for practitioners. Each chapter contains up-to-date information on the impact of female microbiota on the course and outcomes of pregnancy, on the etiology, pathogenesis and diagnostics of vaginal microbiocenosis disorders, and detailed treatment regimens. The work is intended for obstetrician-gynecologists and heads of women’s health clinics, perinatal centers, departments of general hospitals, fellows and heads of departments of obstetrics and gynecology, students of all forms of continuous medical education, graduate students and clinical residents, as well as students of medical schools.
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Harris, Brent T., Galam A. Khan, and Saed Sadeghi. Amyotrophic Lateral Sclerosis. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0029.

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Although the basic gross and microscopic pathological changes in amyotrophic lateral sclerosis (ALS) have been known for more than 100 years, emerging technology and research into the cellular and molecular changes found in this disease are challenging our understanding about the pathogenesis and pathophysiology. All cell types of the CNS/PNS as well as circulating immune cells have been implicated in the pathology of ALS. Numerous genes, their proteins, and environmental factors have also been associated. However, we still do not understand the specific gene-environmental interactions that bring about and drive this devastating disease in most cases. This short chapter does not address the causal factors and molecular pathogeneses that have been hypothesized and actively researched in the pathology of ALS-as these are discussed in other sections of this text. Here, it shows and discusses the basic pathological changes at the tissue and cellular levels that help to establish the pathological diagnosis of ALS at autopsy.
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Ferraiuolo, Laura, and Stephen J. Kolb. Amyotrophic Lateral Sclerosis. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0026.

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An overriding mystery of ALS pathogenesis orbits around the molecular basis of selective motor neuron vulnerability and clouds our view. There are likely mechanisms involved in the initiation of motor neuron loss and mechanisms involved in the progression of motor neuron loss once initiated. Motor neuron vulnerability is likely related to the unique biological characteristics of these cells. This chapter introduces central molecular pathways that appear to be involved in the pathogenesis of ALS, and highlights why dysregulation of these mechanisms could lead to motor neuron death. Indeed, there are likely mechanisms involved in the initiation of motor neuron loss and mechanisms involved in the progression of motor neuron loss once initiated. Our task is to determine those mechanisms that are relevant to ALS pathogenesis that may be targeted therapeutically to prevent onset and/or halt progression.
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Vincent, Tonia L., and Linda Troeberg. Pathogenesis of osteoarthritis. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0138.

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Understanding pathogenic mechanism in disease is critical for development of targeted therapeutic strategies. Although there are, at this time, only a handful of experimental approaches for treating osteoarthritis (OA), until 10 years ago this disease was almost universally considered an unmodifiable condition. Emerging data during this time, largely fuelled by studies in rodent models, has completely changed the paradigm of disease pathogenesis and has for the first time, generated novel, realistic targets for this highly prevalent and disabling condition. These targets include the aggrecanases, members of the ADAMTS family, and collagenases, which together are critical for the early breakdown of the extracellular matrix of cartilage. Some recent success has also been demonstrated by targeting bone in disease. Development of pain in OA is complex and likely arises from different tissues at different stages of disease. In the following section we describe the pathological features of OA, and discuss the evolution of theories of OA pathogenesis and factors that have limited mechanistic clarity in this disease. We summarize the molecular pathways that are now known to be active in disease, and consider how these identified molecular pathways could be linked to known epidemiological risk factors. We finish by discussing possible future therapeutic strategies that will emerge from these discoveries and the current limitations in implementing new therapies in OA.
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Bending, David, Kiran Nistala, and Lucy R. Wedderburn. Pathogenesis of juvenile idiopathic arthritis. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0060.

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Although the term juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of diseases, they all share a common pathological hallmark: inflammation of the synovium. Highly activated T cells, monocytes, and neutrophils are attracted to the joint and secrete mediators that not only perpetuate inflammation but also may attenuate immune regulation. In the oligoarticular and polyarticular forms of JIA, which are thought to be autoimmune conditions, dysregulated adaptive immunity is a likely factor in disease pathogenesis; the nature of the interactions between T effector (Teff) cells and T regulatory cells (Treg) is probably a key factor in controlling disease progression. Factors that affect the frequency and function of Tregs and/or the sensitivity of Teffs to mechanisms of immune suppression will therefore impact on the disease course. In the systemic form of JIA, however, dysregulation of innate immune pathways appears more central to disease pathogenesis resulting in augmented levels of interleukins IL-1β‎, IL-6, and IL-18. In the end, a final, common pathological pathway in JIA is the activation of monocytes and neutrophils, which are the principal mediators of joint inflammation and damage. This is supported by the fact that the therapies that have targeted innate cytokine pathways have shown greater success in the treatment of JIA.
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Pillai, Jagan A., and James B. Leverenz. Pathogenesis of Lewy Body Dementia. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0020.

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This chapter discusses the Pathogenesis of Lew Body Dementia. The Lewy body dementias (LBDs) are a spectrum of dementing neurodegenerative disorders underpinned by the pathological accumulation of α- synuclein protein in both intraneuronal inclusions, “Lewy bodies, ” and neuronal processes, “Lewy neurites”. The chapter concludes that, as with other forms of cognitive impairment in the aged, the pathophysiology of cognitive impairment in LBD is likely multifactorial. Although it appears that α- synuclein pathology, particularly in the limbic and neocortical regions are linked to cognitive changes, other pathologies such as AD likely also play a role. Emphasizing the complexity, a number of genetic factors have been implicated in the LBDs, some specifically with associations to the synucleinopathies and some with other pathophysiologic processes. This complexity will need to be considered as therapeutic interventions are evaluated for the LBD.
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Harms, Matthew B., and Timothy M. Miller. Amyotrophic Lateral Sclerosis. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0027.

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Recent advances in sequencing technologies have dramatically expanded the number of genes associated with amyotrophic lateral sclerosis, including rare but highly penetrant causative mutations as well as common risk alleles. This chapter discusses these gene discoveries and how they have implicated a diverse array of biological pathways essential for motor neuron health and have begun to inform our understanding of ALS pathogenesis as a heterogeneous and multistep process. Insights from these discoveries are leading to a new generation of targeted therapies directed at specific genes and are poised to inform how patients with amyotrophic lateral sclerosis are evaluated and treated in the clinic.
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Guzik, Tomasz J., and Rhian M. Touyz. Vascular pathophysiology of hypertension. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780198755777.003.0019.

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Hypertension is a multifactorial disease, in which vascular dysfunction plays a prominent role. It occurs in over 30% of adults worldwide and an additional 30% are at high risk of developing the disease. Vascular pathology is both a cause of the disease and a key manifestation of hypertension-associated target-organ damage. It leads to clinical symptoms and is a key risk factor for cardiovascular disease. All layers of the vascular wall and the endothelium are involved in the pathogenesis of hypertension. Pathogenetic mechanisms, whereby vascular damage contributes to hypertension, are linked to increased peripheral vascular resistance. At the vascular level, processes leading to change sin peripheral resistance include hyper-contractility of vascular smooth muscle cells, endothelial dysfunction, and structural remodelling, due to aberrant vascular signalling, oxidative and inflammatory responses. Increased vascular stiffness due to vascular remodelling, adventitial fibrosis, and inflammation are key processes involved in sustained and established hypertension. These mechanisms are linked to vascular smooth muscle and fibroblast proliferation, migration, extracellular matrix remodelling, calcification, and inflammation. Apart from the key role in the pathogenesis of hypertension, hypertensive vasculopathy also predisposes to atherosclerosis, another risk factor for cardiovascular disease. This is linked to increased transmural pressure, blood flow, and shear stress alterations in hypertension, as well as endothelial dysfunction and vascular stiffness. Therefore, understanding the mechanisms and identifying potential novel treatments targeting hypertensive vasculopathy are of primary importance in vascular medicine.
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Book chapters on the topic "ALS pathogenesis"

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Vucic, Steve, and Matthew C. Kiernan. "Neurotoxicity and ALS: Insights into Pathogenesis." In Handbook of Neurotoxicity, 1–19. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-71519-9_138-1.

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Vucic, Steve, and Matthew C. Kiernan. "Neurotoxicity and ALS: Insights into Pathogenesis." In Handbook of Neurotoxicity, 1435–56. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4614-5836-4_138.

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Vucic, Steve, and Matthew C. Kiernan. "Neurotoxicity and ALS: Insights into Pathogenesis." In Handbook of Neurotoxicity, 1803–21. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-031-15080-7_138.

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Kadena, Katerina, and Panayiotis Vlamos. "The Importance of Diagnostic and Prognostic Biomarker Identification and Classification Towards Understanding ALS Pathogenesis." In GeNeDis 2020, 119–20. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-78787-5_16.

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Schaefer, H. "Die Theorie der Risikofaktoren als pathogenetisches Prinzip." In Pathogenese, 118–25. Berlin, Heidelberg: Springer Berlin Heidelberg, 1985. http://dx.doi.org/10.1007/978-3-642-70512-0_9.

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Cheng, Jack C. Y., Wayne Y. W. Lee, Elisa M. S. Tam, and T. P. Lam. "Bone Metabolism in AIS." In Pathogenesis of Idiopathic Scoliosis, 125–55. Tokyo: Springer Japan, 2017. http://dx.doi.org/10.1007/978-4-431-56541-3_6.

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Bauer, A. "Zum Konzept einer Pathologie als Physiologie der Krankheit. Pathogenie und Ätiologie bei Karl Wilhelm Stark (1787–1845)." In Pathogenese, 91–103. Berlin, Heidelberg: Springer Berlin Heidelberg, 1985. http://dx.doi.org/10.1007/978-3-642-70512-0_7.

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Scheinpflug, Hans. "The Pathogenesis of Plant Diseases." In ACS Symposium Series, 73–88. Washington, DC: American Chemical Society, 1986. http://dx.doi.org/10.1021/bk-1986-0304.ch004.

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Doerr, Wilhelm. "Über die Pathogenese." In Ars longa, vita brevis, 19–29. Berlin, Heidelberg: Springer Berlin Heidelberg, 1991. http://dx.doi.org/10.1007/978-3-642-84476-8_3.

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Williams, Gary M. "Pathogenesis of Neoplasia and Influences of Pesticides." In ACS Symposium Series, 33–42. Washington, DC: American Chemical Society, 1989. http://dx.doi.org/10.1021/bk-1989-0414.ch003.

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Conference papers on the topic "ALS pathogenesis"

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Jorge, Frederico Mennucci de Haidar, Angela Genge, Ammar Al Chalabi, Orla Hardiman, Alice Shen, Jennifer Shoskes, and David Weinstein. "MERIDIAN: A phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of pegcetacoplan in patients with amyotrophic lateral sclerosis." In XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.744.

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Introduction: Inflammation underlies the pathogenesis of numerous neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In ALS, the complement system has been implicated in the neuropathology of disease and disease progression. Pegcetacoplan, a subcutaneously administered C3 complement inhibitor, is being investigated in hematology, nephrology, and neurology. The current clinical study (NCT04579666) is investigating whether pegcetacoplan can improve survival and function in people diagnosed with apparent sporadic ALS. Objectives and Methodology: Evaluate the efficacy and safety of pegcetacoplan compared to placebo among people diagnosed with ALS in a global, multicenter, randomized, double-blind, placebo-controlled, phase 2 study. Approximately 228 patients diagnosed with apparent sporadic ALS, ≥18 years of age and with an ALS Functional Rating Scale-Revised (ALSFRS-R) score ≥30, slow vital capacity (SVC) ≥60% of the predicted value at screening, and with symptom onset within 72 weeks before screening, are eligible for enrollment. After screening, patients will be randomized 2:1 to treatment groups receiving either subcutaneous pegcetacoplan (1080 mg) or placebo twice weekly for a duration of 52 weeks. The primary efficacy endpoint is the difference in the Combined Assessment of Function and Survival (CAFS) ranked score at 52 weeks after treatment initiation. Additional, secondary functional efficacy (ALSFRS-R, percent SVC, muscle strength, quality of life, and caregiver burden) and safety endpoints will be analyzed at 52 weeks. After the placebo-controlled period, all patients will have the option to receive pegcetacoplan in an open-label period for an additional 52 weeks. Results: This ongoing study is currently enrolling participants. Conclusions: Results of this study will determine the role of complement and C3 inhibition in patients with ALS.
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Zhu, Shizhen, Jeong-Soo Lee, Feng Guo, Jimann Shin, Antonio R. Perez-Atayde, Jeffery L. Kutok, Scott J. Rodig, et al. "Abstract 4252: Activated ALK collaborates with MYCN in neuroblastoma pathogenesis." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-4252.

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Dietz, S., J. Schwarz, CF Poets, C. Gille, and N. Köstlin-Gille. "Qa2-defiziente Mäuse als potentiell neues Tiermodell für die Pathogenese der Präeklampsie." In 30. Kongress der Deutschen Gesellschaft für Perinatale Medizin – „Wandel als Herausforderung“. Georg Thieme Verlag, 2021. http://dx.doi.org/10.1055/s-0041-1739857.

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Mologni, Luca, Geeta G. Sharma, Matteo Villa, Mario Mauri, Giulia Arosio, Cosimo Lobello, Hugo Larose, et al. "Abstract 4715: Characterization of potential co-drivers of pathogenesis in ALK positive ALCL." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-4715.

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Li, Xiaolu, Rong Cao, Fangfei Xiao, Lin Ye, Xufei Wang, and Yizhong Wang. "IDDF2023-ABS-0233 The study of molecular pathogenesis of pediatric clostridiodes difficile infection." In Abstracts of the International Digestive Disease Forum (IDDF), Hong Kong, 10–11 June 2023. BMJ Publishing Group Ltd and British Society of Gastroenterology, 2023. http://dx.doi.org/10.1136/gutjnl-2023-iddf.209.

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Quintero, DP, M. Bette, K. Roth, A. Teymoortash, P. Terhorst, FR Rodepeter, BA Stuck, and R. Mandic. "Glyceraldehyd-3-Phosphat Dehydrogenase (GAPDH) als mögliches Kandidatengen bei der Pathogenese von Zystadenolymphomen der Glandula Parotis." In Abstract- und Posterband – 89. Jahresversammlung der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Hals-Chirurgie e.V., Bonn – Forschung heute – Zukunft morgen. Georg Thieme Verlag KG, 2018. http://dx.doi.org/10.1055/s-0038-1641021.

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Hamza, Shaimaa, Ekaterina Evgenevna Garanina, Ekaterina Vladimirovna Martynova, Maria Ivanovna Markelova, Jurij Nikolaevich Davidyuk, Venera Gusmanovna Shakirova, and Svetlana Francevna Khaiboullina. "Antibody Immune Responses to SARS-CoV-2 Peptides in COVID-19 Convalescent Patients." In All-Russian scientific conference with International Participation. Publishing house Sreda, 2022. http://dx.doi.org/10.31483/r-102484.

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Identifying immunogenic targets of SARS-CoV-2 is essential to develop novel treatments. The authors of the article studied humoral immune responses to spike (S) and nucleocapsid (N) SARS-CoV-2 proteins in serum from convalescent COVID-19 patients from Tatarstan, Russia. Multiple SARS-CoV-2 peptides were identified as reacting with convalescent COVID-19 serum. In addition, age and gender associated differences in the reactivity to S and N protein peptides were identified. Changing pattern of immunogenic peptide reactivity in COVID-19 serum based on age and gender was demonstrated. These data highlight how humoral immune responses to some of these peptides could contribute to SARS-CoV-2 pathogenesis.
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Zhang, Shenghong, Li Li, Shanshan Huang, Ting Feng, Gaoshi Zhou, and Minhu Chen. "IDDF2018-ABS-0193 Cytokine IL9 mediates the pathogenesis of crohn’s disease through the MIR21-CLDN8 pathway." In International Digestive Disease Forum (IDDF) 2018, Hong Kong, 9–10 June 2018. BMJ Publishing Group Ltd and British Society of Gastroenterology, 2018. http://dx.doi.org/10.1136/gutjnl-2018-iddfabstracts.25.

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Lezhniova, Vera Runarovna, Ekaterina Vladimirovna Martynova, Timur Il'dusovich Khaibullin, Ilnur Il'dusovich Salafutdinov, Mariia Ivanovna Markelova, Aleksandr Vladimirovich Laikov, Leonid Valentinovich Lopukhov, and Svetlana Frantsevna Khaibullina. "Seasonal changes in serum metabolite and cytokine levels in Multiple Sclerosis." In All-Russian scientific conference with International Participation. Publishing house Sreda, 2022. http://dx.doi.org/10.31483/r-102302.

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Multiple sclerosis (MS) is a chronic debilitating disease of unknown etiology. The disease has a seasonal exacerbation of clinical symptoms, which are frequently described in spring and summer. However, the mechanisms of such seasonal exacerbations remain unknown. In this study, we used targeted metabolomics analysis of serum samples using LC-MC/MC to determine seasonal changes in metabolites. We have found changes in multiple metabolites which differed depending on season. The ceramides, belonging to the sphingolipid pathway, were found activated in spring-summer (SS) and fall-winter (FW) MS, suggesting their central role in disease pathogenesis. Our identification of ceramide activation suggests a mechanism of neuron damage in MS which could be further investigated as therapeutic targets.
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Scholtis, A., M. Haderer, E. Aschenbrenner, H. Gschwendtner, C. Kunst, K. Gülow, and M. Müller-Schilling. "Reduktion der p53-Familie und Zelltodinduktion durch E. coli in Darmepithelzellen als Mechanismus der Pathogenese der spontan bakteriellen Peritonitis." In 47. Jahrestagung der Gesellschaft für Gastroenterologie in Bayern e.V. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1688850.

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Reports on the topic "ALS pathogenesis"

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Rothstein, Jeffrey D., and Betty Diamond. The Role of NG2 Glial Cells in ALS Pathogenesis. Fort Belvoir, VA: Defense Technical Information Center, October 2013. http://dx.doi.org/10.21236/ada598910.

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Rothstein, Jeffrey D. The Role of NG2 Glial Cells in ALS Pathogenesis. Fort Belvoir, VA: Defense Technical Information Center, December 2014. http://dx.doi.org/10.21236/ada618869.

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Zhu, Qiaochu, Jin Zhou, Hai Huang, Jie Han, Biwei Cao, Dandan Xu, Yan Zhao, and Gang Chen. Risk factors associated with amyotrophic lateral sclerosis: a protocol for systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, September 2022. http://dx.doi.org/10.37766/inplasy2022.9.0118.

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Review question / Objective: To identify and list the risk factors associated with the onset and progression of ALS. Condition being studied: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting the upper and lower motor neurons in the spinal bulb, cerebral cortex, and spinal cord. The clinical processing symptoms accompany muscle atrophy, fasciculation, and fatigue of limbs, which can lead to general paralysis and death from respiratory failure within 3-5 years after the onset of this disease. Though the pathogenesis of ALS is still unclear, exploring the associations between risk factors and ALS can provide reliable evidence to find the pathogenesis in the future. This meta-analysis aims to synthesize all related risk factors on ALS, comprehensively understand this disease, and provide clues to mechanism research and clinicians.
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Splitter, Gary, and Menachem Banai. Microarray Analysis of Brucella melitensis Pathogenesis. United States Department of Agriculture, 2006. http://dx.doi.org/10.32747/2006.7709884.bard.

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Original Objectives 1. To determine the Brucella genes that lead to chronic macrophage infection. 2. To identify Brucella genes that contribute to infection. 3. To confirm the importance of Brucella genes in macrophages and placental cells by mutational analysis. Background Brucella spp. is a Gram-negative facultative intracellular bacterium that infects ruminants causing abortion or birth of severely debilitated animals. Brucellosis continues in Israel, caused by B. melitensis despite an intensive eradication campaign. Problems with the Rev1 vaccine emphasize the need for a greater understanding of Brucella pathogenesis that could improve vaccine designs. Virulent Brucella has developed a successful strategy for survival in its host and transmission to other hosts. To invade the host, virulent Brucella establishes an intracellular niche within macrophages avoiding macrophage killing, ensuring its long-term survival. Then, to exit the host, Brucella uses placenta where it replicates to high numbers resulting in abortion. Also, Brucella traffics to the mammary gland where it is secreted in milk. Missing from our understanding of brucellosis is the surprisingly lillie basic information detailing the mechanisms that permit bacterial persistence in infected macrophages (chronic infection) and dissemination to other animals from infected placental cells and milk (acute infection). Microarray analysis is a powerful approach to determine global gene expression in bacteria. The close genomic similarities of Brucella species and our recent comparative genomic studies of Brucella species using our B. melitensis microarray, suqqests that the data obtained from studying B. melitensis 16M would enable understanding the pathogenicity of other Brucella organisms, particularly the diverse B. melitensis variants that confound Brucella eradication in Israel. Conclusions Results from our BARD studies have identified previously unknown mechanisms of Brucella melitensis pathogenesis- i.e., response to blue light, quorum sensing, second messenger signaling by cyclic di-GMP, the importance of genomic island 2 for lipopolysaccharide in the outer bacterial membrane, and the role of a TIR domain containing protein that mimics a host intracellular signaling molecule. Each one of these pathogenic mechanisms offers major steps in our understanding of Brucella pathogenesis. Strikingly, our molecular results have correlated well to the pathognomonic profile of the disease. We have shown that infected cattle do not elicit antibodies to the organisms at the onset of infection, in correlation to the stealth pathogenesis shown by a molecular approach. Moreover, our field studies have shown that Brucella exploit this time frame to transmit in nature by synchronizing their life cycle to the gestation cycle of their host succumbing to abortion in the last trimester of pregnancy that spreads massive numbers of organisms in the environment. Knowing the bacterial mechanisms that contribute to the virulence of Brucella in its host has initiated the agricultural opportunities for developing new vaccines and diagnostic assays as well as improving control and eradication campaigns based on herd management and linking diagnosis to the pregnancy status of the animals. Scientific and Agricultural Implications Our BARD funded studies have revealed important Brucella virulence mechanisms of pathogenesis. Our publication in Science has identified a highly novel concept where Brucella utilizes blue light to increase its virulence similar to some plant bacterial pathogens. Further, our studies have revealed bacterial second messengers that regulate virulence, quorum sensing mechanisms permitting bacteria to evaluate their environment, and a genomic island that controls synthesis of its lipopolysaccharide surface. Discussions are ongoing with a vaccine company for application of this genomic island knowledge in a Brucella vaccine by the U.S. lab. Also, our new technology of bioengineering bioluminescent Brucella has resulted in a spin-off application for diagnosis of Brucella infected animals by the Israeli lab by prioritizing bacterial diagnosis over serological diagnosis.
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Gutnick, David, and David L. Coplin. Role of Exopolysaccharides in the Survival and Pathogenesis of the Fire Blight Bacterium, Erwinia amylovora. United States Department of Agriculture, September 1994. http://dx.doi.org/10.32747/1994.7568788.bard.

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Fireblight, a disease of apples and pears, is caused by Erwinia amylovora. Mutants of E. amylovora that do not produce the extreacellular polysaccharide (EPS), amylovoran, are avirulent. A similar EPS, stewartan, is produced by E. stewartii, which caused Stewart's wilt of corn, and which has also been implicated in the virulence of this strain. Both stewartan and amylovoran are type 1 capsular polysaccharides, typified by the colanic acid slime produced by Escherichia coli. Extracellular polysaccharide slime and capsules are important for the virulence of bacterial pathogens of plants and animals and to enhance their survival and dissemination outside of the host. The goals of this project were to examine the importance of polysaccharide structure on the pathogenicity and survival properties of three pathogenic bacteria: Erwinia amylovora, Erwinia stewartii and Escherichia coli. The project was a collaboration between the laboratories of Dr. Gutnick (PI, E. coli genetics and biochemistry), Dr. Coplin (co-PI, E. stewartii genetics) and Dr. Geider (unfunded collaborator, E. amylovora genetics and EPS analysis). Structural analysis of the EPSs, sequence analysis of the biosynthetic gene clusters and site-directed mutagenesis of individual cps and ams genes revealed that the three gene clusters shared common features for polysaccharide polymerization, translocation, and precursor synthesis as well as in the modes of transcriptional regulation. Early EPS production resulted in decreased virulence, indicating that EPS, although required for pathogenicity, is anot always advantageous and pathogens must regulate its production carefully.
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Xu, Jin-Rong, and Amir Sharon. Comparative studies of fungal pathogeneses in two hemibiotrophs: Magnaporthe grisea and Colletotrichum gloeosporioides. United States Department of Agriculture, May 2008. http://dx.doi.org/10.32747/2008.7695585.bard.

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Plant pathogenic fungi have various life styles and different plant infection strategies. Hemibiotrophs like Magnaporthe grisea and Colletotrichum species develop specialized structures during plant infection. The goal of this study was to identify, characterize, and compare genes required for plant infection in M. grisea and C. gloeosporioides. Specific objectives are to: 1) further characterize genes identified in the preliminary studies of C. gloeosporioides and M. grisea;2) identify and characterize additional fungal genes tagged by GFP; and 3) identify in planta growth and appressorium-specific genes by subtractive hybridization and transcript profiling by the LongSAGE method. In this study, the PI and Co-PI collaborated closely on studies in M. grisea and C. gloeosporioides. In M. grisea, REMI and ATMT were used to transform the wildtype with promoter-less EGFP constructs. A total of 28 mutants defective in different plant infection processes or expressing EGFP during plant infection were identified. Genes disrupted in five selected mutants have been identified, including MG03295 that encodes a putative Rho GTPase. In transformant L1320, the transforming vector was inserted in the MIRI gene that encodes a nuclear protein. The expression of MIRI was highly induced during infection. Deletion and site-directed mutagenesis analyses were used to identify the promoter regions and elements that were essential for induced in planta expression of MIRI. This was the first detailed characterization of the promoter of an in planta gene in M. grisea and the MIRI promoter can be used to monitor infectious growth. In addition, the Agilent whole-genome array of M. grisea was used for microarray analyses with RNA samples from appressoria formed by the wild-type shain and the pmkl and mstl2 mutants. Over 200 genes were downregulated in the mst I 2 and pmkl mutants. Some of them are putative transcription factors that may regulate appressorium formation and infectious hyphal growth. In C. gloeosporioides, various REMI mutants showing different pathogenic behavior were identified and characterized. Mutants N3736 had a single insertion and was hyper-virulent. The gene disrupted in mutant3736 (named CgFMOI) encodes a FAD-dependent monooxygenase. Expression analyses linked the expression of the CgFMOI gene with the necrotrophic phase of fungal infection, and also suggest that expression of CgFMOl is unnecessary for the first stages of infection and for biotrophy establishment. All CgFMOl-silenced mutants had reduced virulence. In REMI mutant N159, the tagged gene encodes a putative copper transporter that is homologue of S. cerevisiae CTR2. In yeast, Ctr2 is a vacuolar transporter for moving copper from the vacuole to the cytoplasm. The gene was therefore termed CgCTR2. In addition to characterization of CgCTR2, we also conducted comparative analyses in M. grisea. The M. grisea CgCTR-2 homolog was isolated, knockout strains were generated and characterized and the M. grisea was used to complement the Nl 59 C. gloeosporioides mutant. Overall, we have accomplished most of proposed experiments and are in the process of organizing and publishing other data generated in this project. For objective 3, we used the microarray analysis approach. Several genes identified in this study are novel fungal virulence factors. They have the potential to be used as targets for developing more specific or effective fungicides. In the long run, comparative studies of fungal genes, such as our CgCTR2 work, may lead to better disease control strategies.
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Yogev, David, Ricardo Rosenbusch, Sharon Levisohn, and Eitan Rapoport. Molecular Pathogenesis of Mycoplasma bovis and Mycoplasma agalactiae and its Application in Diagnosis and Control. United States Department of Agriculture, April 2000. http://dx.doi.org/10.32747/2000.7573073.bard.

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Mycoplasma bovis and M. agalactiae are two phylogenetically related mycoplasmas which cause economically significant diseases in their respective bovine or small ruminant hosts. These organisms cause persistent asymptomatic infections that can result in severe outbreaks upon introduction of carrier animals into susceptible herds. Little is known about the mechanisms underlying mycoplasma-host interaction, variation in virulence, or of the factors enabling avoidance of the host immune system. In recent years it has become apparent that the ability of pathogenic microorganisms to rapidly alter surface antigenic structures and to fine tune their antigenicity, a phenomena called antigenic variation, is one of the most effective strategies used to escape immune destruction and to establish chronic infections. Our discovery of a novel genetic system, mediating antigenic variation in M. bovis (vsp) as well as in M. agalactiae (avg) served as a starting point for our proposal which included the following objectives: (i) Molecular and functional characterization of the variable surface lipoproteins (Vsp) system of M. bovis and comparison with the Vsp-counterpart in M. agalactiae (ii) Determination of the role of Vsp proteins in the survival of M. bovis when confronted by host defense factors, (iii) Assessment of Vsp-based genetic and antigenic typing of M. bovis and M. agalactiae for epidemiology of infection and (iv) Improvement of diagnostic tests for M. bovis and M. agalactiae based on the vsp-and vsp-analogous systems. We have carried out an extensive molecular characterization of the vsp system and unravelled the precise molecular mechanism responsible for the generation of surface antigenic variation in M. bovis. Our data clearly demonstrated that the two pathogenic mycoplasma species possess large gene families encoding variable lipoprotein antigens that apparently play an important role in immune evasion and in pathogen-host interaction during infection. Phase variable production of these antigens was found to be mediated by a novel molecular mechanism utilizing double site-specific DNA inversions via an intermediate vsp configuration. Studies in model systems indicate that phase variation of VspA is relevant in interaction between M. bovis and macrophages or monocytes, a crucial stage in pathogenesis. Using an ELISA test with captured VspA as an antigen, phase variation was shown to occur in vivo and under field conditions. Genomic rearrangements in the avg gene family of M. agalactiae were shown to occur in vivo and may well have a role in evasion of host defences and establishment of chronic infection. An epidemiological study indicated that patterns of vsp-related antigenic variation diverge rapidly in an M. bovis infected herd. Marked divergence was also found with avg-based genomic typing of M. agalactiae in chronically infected sheep. However, avg-genomic fingerprints were found to be relatively homogeneous in different animals during acute stages of an outbreak of Contagious Agalactiae, and differ between unrelated outbreaks. These data support the concept of vsp-based genomic typing but indicate the necessity for further refinement of the methodology. The molecular knowledge on these surface antigens and their encoding genes provides the basis for generating specific recombinant tools and serological methods for serodiagnosis and epidemiological purposes. Utilization of these methods in the field may allow differentiating acutely infected herds from chronic herds and disease-free herds. In addition the highly immunogenic nature of these lipoproteins may facilitate the design of protective vaccine against mycoplasma infections.
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Mawassi, Munir, and Valerian Dolja. Role of RNA Silencing Suppression in the Pathogenicity and Host Specificity of the Grapevine Virus A. United States Department of Agriculture, January 2010. http://dx.doi.org/10.32747/2010.7592114.bard.

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RNA silencing is a defense mechanism that functions against virus infection and involves sequence-specific degradation of viral RNA. Diverse RNA and DNA viruses of plants encode RNA silencing suppressors (RSSs), which, in addition to their role in viral counterdefense, were implicated in the efficient accumulation of viral RNAs, virus transport, pathogenesis, and determination of the virus host range. Despite rapidly growing understanding of the mechanisms of RNA silencing suppression, systematic analysis of the roles played by diverse RSSs in virus biology and pathology is yet to be completed. Our research was aimed at conducting such analysis for two grapevine viruses, Grapevine virus A (GVA) and Grapevine leafroll-associated virus-2 (GLRaV- 2). Our major achievements on the previous cycle of BARD funding are as follows. 1. GVA and GLRaV-2 were engineered into efficient gene expression and silencing vectors for grapevine. The efficient techniques for grapevine infection resulting in systemic expression or silencing of the recombinant genes were developed. Therefore, GVA and GLRaV-2 were rendered into powerful tools of grapevine virology and functional genomics. 2. The GVA and GLRaV-2 RSSs, p10 and p24, respectively, were identified, and their roles in viral pathogenesis were determined. In particular, we found that p10 functions in suppression and pathogenesis are genetically separable. 3. We revealed that p10 is a self-interactive protein that is targeted to the nucleus. In contrast, p24 mechanism involves binding small interfering RNAs in the cytoplasm. We have also demonstrated that p10 is relatively weak, whereas p24 is extremely strong enhancer of the viral agroinfection. 4. We found that, in addition to the dedicated RSSs, GVA and GLRaV-2 counterdefenses involve ORF1 product and leader proteases, respectively. 5. We have teamed up with Dr. Koonin and Dr. Falnes groups to study the evolution and function of the AlkB domain presents in GVA and many other plant viruses. It was demonstrated that viral AlkBs are RNA-specific demethylases thus providing critical support for the biological relevance of the novel process of AlkB-mediated RNA repair.
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Sordillo, Lorraine, Don Wojchowski, Gary Perdew, Arthur Saran, and Gabriel Leitner. Identification of Staphylococcus aureaus Virulence Factors Associated with Bovine Mastitis. United States Department of Agriculture, February 2001. http://dx.doi.org/10.32747/2001.7574340.bard.

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Staphylococcus aureus is a major cause of mastitis in dairy cattle. The organism is able to adhere to and penetrate mammary epithelium, forming deep seated abscesses that result in chronic infections. This study was based on the observation that certain genotypes of S. aureus are isolated more frequently from field cases of bovine mastitis than others and the most prevalent genotypes of S. aureus have an increased ability to resist neutrophil phagocytosis and killing compared to the rare variants. It was hypothesized that these predominating genotypes differentially express virulence factors that allow them to overcome or suppress essential host defense mechanisms and successfully colonize mammary parenchyma. The overall objective of this study was to determine the mechanisms by which predominating S. aureus genotypes were able to resist mammary gland defense mechanisms. The following specific aims were accomplished to address the overall objectives of this project: 1. Analyze and compare cell surface and secreted protein profiles of common and rare S. aureus genotypes isolated from field cases of bovine mastitis. 2. Purify and sequence selectively synthesized proteins unique to the most prevalent genotypes of S. aureus . 3. Determine the in vitro effects of isolated proteins on essential host defense mechanisms. Results from each specific aim showed that these redominating genotypes differentially express factors that may allow them to overcome or suppress essential host defense mechanisms and successfully colonize mammary parenchyma. Using complementary approaches, both the US and Israeli teams identified differentially expressed S. aureus factors that were positively correlated with virulence as determined by the ability to modify host immune cell responses and increase disease pathogenesis. Several candidate virulence factors have ben identified at both the molecular (US team) and protein (Israeli team) levels. Components of the phosphotransferase system were shown to be differentially expressed in prevalent strains of S. aureus and to modify the growth potential of these strains in a milk microenvironment. Evidence provided by both the Israeli and US teams also demonstrated a potential role of Staphylococcal enterotoxins in the pathogenesis of mastitis. Certain enterotoxins were shown to directly affect neutrophil bactericidal activities which can profoundly affect the establishment of new intramammary infections. Other evidence suggests that S. aureus superantigens can suppress mammary defenses by enhancing lymphoid suppressor cell activity. Collectively, these data suggest that unique factors are associated with predominating S. aureus genotypes that can affect in vitro and in vivo virulence as related to the pathogenesis of bovine mastitis. The potential development of a subunit mastitis vaccine which incorporates only relevant antigenic determinants has not been investigated in depth. Experiments outlined in this proposal has identified putative virulence factors which contribute to the pathogenesis of S. aureus mastitis and which may be used to formulate an efficacious subunit mastitis vaccine. Results from these studies may lead to the development of new methods to prevent this costly disease, providing a viable alternative to less effective mastitis control procedures based on chemotherapy.
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Li, Ying-Sheng, Wei-Chih Yeh, and Chung-Yao Hsu. Association of low serum ferritin levels with augmentation in patients with restless legs syndrome: A systemic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, May 2023. http://dx.doi.org/10.37766/inplasy2023.5.0074.

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Review question / Objective: P: patients with restless legs syndrome under dopaminergic agents; I: survey the serum ferritin level; low serum ferritin level as the case group; C: survey the serum ferritin level; high serum ferritin level as the case group; O: the association between serum ferritin levels and the development of augmentation. Condition being studied: Although BID is the fundamental pathogenesis of RLS, the association of iron and augmentation has not been discussed in detail. Trenkwalder et al. stated that augmentation was associated with low serum ferrtin [1]. Frauscher et al reported a significant inverse correlation between serum ferrtin and augmentation [2]. To resolve the doubtful results, our meta-analysis aimed to to confirm the association between augmentation and ferritin. [1]. Frauscher et al reported a significant inverse correlation between serum ferrtin and augmentation; [2]. To resolve the doubtful results, our meta-analysis aimed to to confirm the association between augmentation and ferritin.
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