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1
Babu, Sajesh, and Nallur B. Ramachandra. "Screen for new mutations on the 2nd chromosome involved in indirect flight muscle development in Drosophila melanogaster." Genome 50, no. 4 (April 2007): 343–50. http://dx.doi.org/10.1139/g07-012.
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An extensive ethylmethanesulfonate mutagenesis of Drosophila melanogaster was undertaken to isolate the stronger alleles of 3 indirect flight-muscle mutations. We isolated 17 strong mutant lines, with nearly complete penetrance and expressivity, using direct screening under polarized light, from more than 1700 mutagenized chromosomes. On complementation, we found 11 of these 17 mutant lines to be alleles of 3 indirect flight-muscle mutations (Ifm(2)RU1, 3 noncomplementing lines; ifm(2)RU2, 6 alleles; ifm(2)RU3, 2 alleles) of the previously isolated 8 complementation groups (Ifm(2)RU1to ifm(2)RU8). In addition, we found 6 new complementation groups with strong defects in adult-muscle morphology; we named these ifm(2)RS1 to ifm(2)RS6. All mutant lines were mapped by meiotic recombination, and 5 of the 6 new complementation lines were mapped using chromosome deficiencies. ifm(2)RS1 maps to a region that harbors ifm(2)RU4 (a mutation that was isolated previously); however, theses are not alleles because each complements the other mutation, and the mutant-muscle phenotype is very different. We used direct screening under polarized light to find recessive mutations; although this method was labor intensive, it can be used to identify recessive genes involved in myogenesis, unlike screens for flightlessness or wing-position defects. This screen identifies regions on the second chromosome that harbor probable genes that are likely expressed in the mesoderm and are thought to be involved in myogenesis. This screen has generated valuable resources that will help us to understand the role of many molecular players involved in myogenesis.
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Haji, Mona, Laoucine Kerbache, and Tareq Al-Ansari. "Development of Risk Management Mitigation Plans for the Infant Formula Milk Supply Chain Using an AHP Model." Applied Sciences 13, no. 13 (June 29, 2023): 7686. http://dx.doi.org/10.3390/app13137686.
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Infant formula milk (IFM) is critical in the diet of many babies and must be of high-quality. Unfortunately, IFM has been a target of adulteration by those attempting to make illegal profits and has suffered from contamination-related issues. This study’s main objective was to identify the most critical risks affecting IFM quality in the supply chain and determine mitigation strategies to improve IFM performance measurement. We developed a model to reduce adulteration and contamination rates in the infant formula milk supply chains (IFMSCs) and maximize safety. The steps to achieve the study’s objectives included: (1) identifying the importance of IFMs for infant nutrition and their risks; (2) establishing mitigation criteria for evaluating IFMSC’s performance to maximize quality; and (3) analyzing each mitigation criterion to maximize IFM safety. Based on pairwise comparisons by professionals in the food supply chain (FSC) of decision-making, the Analytic Hierarchy Process (AHP) model was used to analyze and prioritize mitigation alternatives. According to the contamination quality risk agent, mitigation alternative (QR.M2) ranked highest. This study’s findings illustrate how vital avoiding risk is when dealing with public health, especially infants’ health, and how IFM must undergo precise testing and quality checks at every supply chain stage to ensure quality.
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Asemu, Girma, Kelly A. O'Connell, James W. Cox, Erinne R. Dabkowski, Wenhong Xu, Rogerio F. Ribeiro, Kadambari C. Shekar, et al. "Enhanced resistance to permeability transition in interfibrillar cardiac mitochondria in dogs: effects of aging and long-term aldosterone infusion." American Journal of Physiology-Heart and Circulatory Physiology 304, no. 4 (February 15, 2013): H514—H528. http://dx.doi.org/10.1152/ajpheart.00674.2012.
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Functional differences between subsarcolemmal and interfibrillar cardiac mitochondria (SSM and IFM) have been observed with aging and pathological conditions in rodents. Results are contradictory, and there is little information from large animal models. We assessed the respiratory function and resistance to mitochondrial permeability transition (MPT) in SSM and IFM from healthy young (1 yr) and old (8 yr) female beagles and in old beagles with hypertension and left ventricular (LV) wall thickening induced by 16 wk of aldosterone infusion. MPT was assessed in SSM and IFM by Ca2+ retention and swelling. Healthy young and old beagles had similar mitochondrial structure, respiratory function, and Ca2+-induced MPT within SSM and IFM subpopulations. On the other hand, oxidative capacity and resistance to Ca2+-induced MPT were significantly greater in IFM compared with SSM in all groups. Old beagles treated with aldosterone had greater LV wall thickness and worse diastolic filling but normal LV chamber volume and systolic function. Treatment with aldosterone did not alter mitochondrial respiratory function but accelerated Ca2+-induced MPT in SSM, but not IFM, compared with healthy old and young beagles. In conclusion, in a large animal model, oxidative capacity and resistance to MPT were greater in IFM than in SSM. Furthermore, aldosterone infusion increased susceptibility to MPT in SSM, but not IFM. Together this suggests that SSM are less resilient to acute stress than IFM in the healthy heart and are more susceptible to the development of pathology with chronic stress.
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Fujii, Masato, Susumu Ohya, Hisao Yamamura, and Yuji Imaizumi. "Development of Recombinant Cell Line Co-expressing Mutated Nav1.5, Kir2.1, and hERG for the Safety Assay of Drug Candidates." Journal of Biomolecular Screening 17, no. 6 (April 12, 2012): 773–84. http://dx.doi.org/10.1177/1087057112442102.
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To provide a high-throughput screening method for human ether-a-go-go-gene–related gene (hERG) K+ channel inhibition, a new recombinant cell line, in which single action potential (AP)–induced cell death was produced by gene transfection. Mutated human cardiac Na+ channel Nav1.5 (IFM/Q3), which shows extremely slow inactivation, and wild-type inward rectifier K+ channel, Kir2.1, were stably co-expressed in HEK293 cells (IFM/Q3+Kir2.1). In IFM/Q3+Kir2.1, application of single electrical stimulation (ES) elicited a long AP lasting more than 30 s and led cells to die by more than 70%, whereas HEK293 co-transfected with wild-type Nav1.5 and Kir2.1 fully survived. The additional expression of hERG K+ channels in IFM/Q3+Kir2.1 shortened the duration of evoked AP and thereby markedly reduced the cell death. The treatment of the cells with hERG channel inhibitors such as nifekalant, E-4031, cisapride, terfenadine, and verapamil, recovered the prolonged AP and dose-dependently facilitated cell death upon ES. The EC50 values to induce the cell death were 3 µM, 19 nM, 17 nM, 74 nM, and 3 µM, respectively, whereas 10 µM nifedipine did not induce cell death. Results indicate the high utility of this cell system for hERG K+ channel safety assay.
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Miramini, Saeed, Lihai Zhang, Martin Richardson, and Priyan Mendis. "The Role of Locking Plate Stiffness in Bone Fracture Healing Stabilized by Far Cortical Locking Technique." International Journal of Computational Methods 15, no. 04 (May 24, 2018): 1850024. http://dx.doi.org/10.1142/s021987621850024x.
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The locking plate fixations have been developed to enhance bone healing by wide bridging of the fracture and allowing some level of interfragmentary movement (IFM) at the fracture site. However, the IFM induced by conventional locking plate constructs is not uniform at the fracture site and so result in asymmetric callus formation, and ultimately delayed healing. The far cortical locking technique has been recently innovated to address this issue by inducing a uniform IFM. However, the far cortical locking technique is still in its infancy and more research efforts are required before its practical clinical application. Using the theory of porous media and computational methods, this study investigated the effectiveness of far cortical locking technique in presence of different mechanical stiffness of locking plate. The research outcomes indicate that the application of far cortical looking technique enhances IFM at near cortex, and so reduce the difference of IFM between near and far cortex. Further, it shows that, under far cortical locking technique, the bending stiffness of a locking plate plays an important role in bone healing. The use of a stiffer locking plate together with far cortical locking screws encourages more uniform tissue development across the fracture gap. The current research underlines the importance of the optimal selection of plate stiffness for application of far cortical locking technique.
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Neely, Andy. "Cambridge Service Alliance, Distributed Information and Automation Laboratory, Research Capability Development Programme." Global Journal of Enterprise Information System 9, no. 1 (May 5, 2017): 129. http://dx.doi.org/10.18311/gjeis/2017/15879.
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Professor Andy Neely is Pro-Vice-Chancellor: Enterprise and Business Relations at the University of Cambridge, Head of the Institute for Manufacturing (IfM) and Head of the Manufacturing and Management Division of Cambridge University Engineering Department. He is a Fellow of Sidney Sussex College and Founding Director of the Cambridge Service Alliance.
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Hamilton, Colin, Robert Phaal, Mita Brahmbhatt, Peter Jarritt, and Topun Austin. "Designing the landscape for technological development in neonatal neurocritical care." BMJ Innovations 4, no. 4 (August 29, 2018): 163–71. http://dx.doi.org/10.1136/bmjinnov-2018-000288.
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ObjectivesTo identify current ‘gaps’ in clinical practice or therapeutic knowledge of the care of neonatal neurointensive care patients and to determine the impact healthcare technologies can have on improving outcomes.DesignThe Cambridge Institute for Manufacturing’s (IfM) roadmapping methodology.SettingCambridge, UK.Participants16 delegates were selected through professional networks. They provided coverage of academia and clinical skills, as well as expertise in neonatology, engineering and technology development.Main outcome measuresA ‘strategic landscape’ has been developed with ‘landmarks’ identified as ‘trends or drivers’, ‘patient pathway experience and unmet needs’ and ‘enabling project or resources’. Priorities were voted on by delegates.Results26 strategic ‘landmarks’ were identified, and of these 8 were considered ‘trends or drivers’, 8 ‘patient pathway experience and unmet needs’ and 10 as ‘enabling project or resources’. Of these, five priorities for the future of neonatal neurocritical care were identified by a voting process: real-time video monitoring for parents; individualised management of preterm infants in neonatal neurocritical care based on real-time multimodal monitoring; continuous electroencephalogram monitoring for early seizure diagnosis; neuroprotection: understanding basic mechanisms; and sleep measurement.ConclusionsThrough the use of the IfM methodology, a list of priorities has been developed for future work into improving the experience and possible outcomes of newborn infants with brain injuries and their families. While not an exhaustive list, it provides the beginning for a national conversation on the topic.
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Cacheux, W., B. Gourmel, J. Alexandre, N. Germann, F. Rabillon, and F. Goldwasser. "Ifosfamide given once every other week: A clinical and pharmacological study." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 13008. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.13008.
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13008 Background. Ifosfamide (IFM) is a bi-functional alkylator with wide spectrum of activity in solid tumors and has an auto-inductive liver metabolism through P450 cytochromes. Auto-induction might permit a better therapeutic index for combination therapy. Methods. A phase I trial with interpatient dose escalation of a single dose of IFM given every 2 wks in advanced solid tumor pts. IFM, its dechloroethylated and active 4-hydroxy metabolites, were measured at cycle 1 & 2 at the end of infusion, 2 and 5h later, using gas chromatography. IFM elimination was considered as following a monocompartimental model kinetics. Results From January 2004 to June 2006; 20 pts of PS<2 were included :10 F, 10 M, median age 61 years (39–78), median previous chemotherapies: 2 (0–5). Primary tumor was most often ovarian (5), peritoneal (3), sarcoma (2), melanoma (2), or miscellaneous (8). 10 pts received 2.5g/m2 and other 10 pts received 3g/m2. A total of 79 cycles were evaluable for toxicity. median number of cycles: 4 (1–8). No Grade (Gr) 3–4 hematologic toxicity, no alopecia. Gr2 nausea and fatigue were the most common toxicities at 3g/m2. No toxicity-related fatal event was noted. One objective response was noted in pancreatic cancer pt and one sustained CA125 decline in a heavily pretreated ovarian cancer pt. A slight (7–10%) but reproducible decrease of AUC was detectable at cycle 2, at both dose levels, related to auto-inductive metabolism (see table below). The other PK results are available and will be presented (Table). Intra individual variations (large SD) were noticed for each pharmacokinetic (PK) parameter. Conclusions: A slight non dose- dependent but rather patient-dependent auto-induction of IFM metabolism was detected. The toxicity profile allows the development of every 2 wks IFM-based combination therapies. [Table: see text] No significant financial relationships to disclose.
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Trevino-Villarreal, Jose Humberto, Douglas A. Cotanche, Rosalinda Sepulveda, and Rick A. Rogers. "Effect of pericytes on melanoma development." Journal of Clinical Oncology 30, no. 30_suppl (October 20, 2012): 83. http://dx.doi.org/10.1200/jco.2012.30.30_suppl.83.
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83 Background: Melanoma-associated stroma cells regulate tumor establishment, invasion, and dissemination through paracrine and heterotypic cell-cell interactions with cancer cells. Pericytes constitute a major noninflammatory component of the melanoma-associated stroma. Our study is designed to evaluate the role of pericytes in melanoma development. Methods: Tumors induced in GFP+/SCID mice with GFP-B16 cells were harvested after 14 days, enzyme digested, labeled against mesenchymal markers, and analyzed by flow cytometry (FC). The distribution of stromal subpopulations in tumors was investigated by immunofluorescence microscopy (IFM). Stromal pericytes from tumors and adipose tissue were FACS sorted, mixed with B16 cells at a 3:1 ratio, and injected into SCID mice. Tumor diameters were taken periodically with a scientific caliper, and used to determine tumor volumes using the ellipsoid formula. Results: FC analysis showed that the melanoma stroma was composed of CD45+ inflammatory cells, CD31+ endothelial cells, FAP+ myofibroblasts and CD146+ cells. IFM analysis showed that the CD146+ cells are perivascular CD31-/CD34-/α-SMA+ stromal pericytes that associated with TGF-β immunoreactive CD271+/CD146+B16 cells in perivascular tumor niches. Co-induction experiments were performed to investigate the effect of pericytes on melanoma development. We observed faster growth rates in the size of tumors co-induced with pericytes, compared with tumors induced with B16 cells alone. These co-induced tumors had bigger masses, more volume, were hypercellular, and had increase vascularization compared with control tumors. In addition, pericytes increased the B16 cell proliferation rate, as determined by higher expression of Ki-67 in the tumor fraction of co-induced tumors. Conclusions: Pericytes promote melanoma development by inducing angiogenesis and melanoma cell proliferation. Our results suggest that pericytes could be utilized as a therapeutic target for melanoma treatment.
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Fernandes, J., M. Bate, and K. Vijayraghavan. "Development of the indirect flight muscles of Drosophila." Development 113, no. 1 (September 1, 1991): 67–77. http://dx.doi.org/10.1242/dev.113.1.67.
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We have followed the pupal development of the indirect flight muscles (IFMs) of Drosophila melanogaster. At the onset of metamorphosis larval muscles start to histolyze, with the exception of a specific set of thoracic muscles. Myoblasts surround these persisting larval muscles and begin the formation of one group of adult indirect flight muscles, the dorsal longitudinal muscles. We show that the other group of indirect flight muscles, the dorsoventral muscles, develops simultaneously but without the use of larval templates. By morphological criteria and by patterns of specific gene expression, our experiments define events in IFM development.
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Reedy, Mary C., Belinda Bullard, and Jim O. Vigoreaux. "Flightin Is Essential for Thick Filament Assembly and Sarcomere Stability in Drosophila Flight Muscles." Journal of Cell Biology 151, no. 7 (December 25, 2000): 1483–500. http://dx.doi.org/10.1083/jcb.151.7.1483.
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Flightin is a multiply phosphorylated, 20-kD myofibrillar protein found in Drosophila indirect flight muscles (IFM). Previous work suggests that flightin plays an essential, as yet undefined, role in normal sarcomere structure and contractile activity. Here we show that flightin is associated with thick filaments where it is likely to interact with the myosin rod. We have created a null mutation for flightin, fln0, that results in loss of flight ability but has no effect on fecundity or viability. Electron microscopy comparing pupa and adult fln0 IFM shows that sarcomeres, and thick and thin filaments in pupal IFM, are 25–30% longer than in wild type. fln0 fibers are abnormally wavy, but sarcomere and myotendon structure in pupa are otherwise normal. Within the first 5 h of adult life and beginning of contractile activity, IFM fibers become disrupted as thick filaments and sarcomeres are variably shortened, and myofibrils are ruptured at the myotendon junction. Unusual empty pockets and granular material interrupt the filament lattice of adult fln0 sarcomeres. Site-specific cleavage of myosin heavy chain occurs during this period. That myosin is cleaved in the absence of flightin is consistent with the immunolocalization of flightin on the thick filament and biochemical and genetic evidence suggesting it is associated with the myosin rod. Our results indicate that flightin is required for the establishment of normal thick filament length during late pupal development and thick filament stability in adult after initiation of contractile activity.
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Krüger, Merlin Frederik, Stefan Zorn, and Kilian Gericke. "COMBINING FUNCTION MODELLING AND REQUIREMENTS MODELLING WITH THE IFM FRAMEWORK." Proceedings of the Design Society 3 (June 19, 2023): 987–96. http://dx.doi.org/10.1017/pds.2023.99.
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AbstractThe transmission of information between requirements modelling and function modelling in the product development process often appears challenging because of multiple used models and different terminology of specific disciplines. The integrated function modelling (IFM) framework is used for functional analysis of technical moderate complex systems and supports cross-disciplinary modelling and communication in the design team. To improve the applicability of this method and its supporting purpose in the modelling process, the authors combined requirements as an additional entity with the existing entities of this method. Furthermore, the extended framework has been used to visualise the procedure with this approach as an example. The outlook provides the potential for further development of the method.
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Abed, Ahmed M., Ali AlArjani, Laila F. Seddek, and Samia ElAttar. "Modify the Injection Machine Mechanism to Enhance the Recycling of Plastic Waste Mixed with MHD Nanoparticles." Sustainability 15, no. 3 (February 1, 2023): 2641. http://dx.doi.org/10.3390/su15032641.
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Recycling plastic waste (RPW) benefits the ecological footprint. Therefore, the authors test its mixing by magnetic hydrodynamic MHD nanofluid materials such as alumina in two sizes (βcore, βskin) prepared into a new device called the incubator installed in the desktop injection machine to enhance its solubility by taking advantage of the mixture’s heat via defining the oblique stagnation-point slip flow (OSPSF) of a nanofluid in two dimensions. The paper has been innovative in mathematically identifying the operating parameters’ values for the injection flow mechanism (IFM) via controlling in Riga magnetic field and piston orifice pressure using a meta-heuristic algorithm called WSA. The proposed (IFM) is used to experimentally enhance the mixture properties via parameters’ control to meet the output quality and predict the control equation for the Riga plate. IFM controls the amount of pushed nanoparticles in the mixture with a ratio of plastic to aluminum approximate by 96.1%: 3.9%. The defects were reduced by approximately 23.21%, with an increasing system performance of 70.98%.
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Mansyur, Yusup, and Atik Aprianingsih. "Proposed Development Strategy for Green Diesel Product in Industrial Fuel Market." European Journal of Business and Management Research 7, no. 4 (July 21, 2022): 148–53. http://dx.doi.org/10.24018/ejbmr.2022.7.4.1527.
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PTM is one of Indonesia Energy Enterprise which is carried out integrated energy business by covering exploration & production, refinery, marketing & distribution, and new & renewable energy business based on strong commercial principles. Industrial Fuel Marketing (IFM) division is part of Company’s Commercial & Trading business, established to bring various of product into domestic industrial fuel market and marine sectors. Currently IFM as market leader which is hold the market more than 70% Share. PTM is assigned by shareholder to develop Biorefinery with capacity 20,000 Barrel/Day in 2019. Biorefinery will produce Green Diesel from Crude Palm Oil (CPO) as main product with catalytic processing. Shareholder willing to implement the Biorefinery for alternative fuel sources to reduce dependence on petroleum-based fuels, as well as to reduce climate change and reduce fossil fuel import. There are several issues regarding Biorefinery business in term of Green Diesel Market which are higher CPO price than crude oil price therefore the Green Diesel price will be higher than Petroleum Diesel. In accordance with those issues, it will need business strategic in Biorefinery implementation. In this case, Author will propose strategic marketing of Green Diesel to penetrate domestic Industrial Fuel Market. Unfortunately, In Industrial Fuel sector there is open competition among fuel suppliers which currently more than 230 suppliers. The object of this research is developing business strategy for Green Diesel product in Industrial Fuel Market (IFM). To develop business strategy, the conceptual framework is necessary to have right alternatives strategies that are appropriate for the company. This research will carry out the external and internal analysis, for external analysis using Market Analysis, Porter Five Forces Analysis, Competitor Analysis and Consumer Analysis. Whereas the internal analysis will use 4P Marketing Mix, Existing Business Model Canvas and VRIO Framework. The first stage will be internal external factor evaluation, then the matching stage will use TOWS (Threats, Opportunities, Weakness, Strengths) Matrix to develop alternative strategies, in the end of the stage the final analysis will use QSPM (Quantitative Strategic Planning Matrix) to evaluate the feasibility of each of these alternative strategies. Based on QSPM there are top five strategies feasible to be implemented which is Development of target market priority on SOE and government institution, coopetition strategy, development of digital marketing, development of employee capabilities on Green Diesel Business and development of flexibility term of Payment (TOP).
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Boine, Barbara, Richard L. Kingston, and Michael N. Pearson. "Recombinant expression of the coat protein of Botrytis virus X and development of an immunofluorescence detection method to study its intracellular distribution in Botrytis cinerea." Journal of General Virology 93, no. 11 (November 1, 2012): 2502–11. http://dx.doi.org/10.1099/vir.0.043869-0.
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Botrytis cinerea is infected by many mycoviruses with varying phenotypical effects on the fungal host, including Botrytis virus X (BVX), a mycovirus that has been found in several B. cinerea isolates worldwide with no obvious effects on growth. Here we present results from serological and immunofluorescence microscopy (IFM) studies using antiserum raised against the coat protein of BVX expressed in Escherichia coli fused to maltose-binding protein. Due to the high yield of recombinant protein it was possible to raise antibodies that recognized BVX particles. An indirect ELISA, using BVX antibodies, detected BVX in partially purified virus preparations from fungal isolates containing BVX alone and in mixed infection with Botrytis virus F. The BVX antiserum also proved suitable for IFM studies. Intensely fluorescing spots (presumed to be virus aggregates) were found to be localized in hyphal cell compartments and spores of natural and experimentally infected B. cinerea isolates using IFM. Immunofluorescently labelled sections through fungal tissue, as well as fixed mycelia grown on glass slides, showed aggregations of virions closely associated with fungal cell membranes and walls, next to septal pores, and in hyphal tips. Also, calcofluor white staining of mature cell walls of virus-transfected Botrytis clones revealed numerous cell wall areas with increased amounts of chitin/glycoproteins. Our results indicate that some BVX aggregates are closely associated with the fungal cell wall and raise the question of whether mycoviruses may be able to move through the wall and therefore not be totally dependent on intracellular routes of transmission.
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Grabs, W., A. C. Tyagi, and M. Hyodo. "Integrated flood management." Water Science and Technology 56, no. 4 (August 1, 2007): 97–103. http://dx.doi.org/10.2166/wst.2007.541.
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While there have been a number of international initiatives centred around hydrological sciences and technical approaches, the social, economic, environmental, and legal and institutional aspects of flood management have been dealt with sporadically and in a limited manner. WMO and the Global Water Partnership have established the Associated Programme on Flood Management (APFM) to address these issues and developed a concept of Integrated Flood Management (IFM) in 2002. This article is the result of the integrated flood management approaches through pilot projects and multi-disciplinary approaches launched by the initiative since the establishment of the IFM concept. This approach seeks to integrate land- and water-resources development in a river basin, within the context of Integrated Water Resources Management (IWRM) and aims at maximizing the benefits from floodplains and at the same time reducing loss of life from flooding. This approach identified the key elements of IFM and recommended that these can be put in place by: adopting a basin approach to flood management; adopting a multi-disciplinary approach in flood management; reducing vulnerability to and risks from flooding; enabling community participation; and preserving ecosystems; and addressing climate change and variability, supported by enabling mechanism through appropriate legislation and regulations.
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Hagve, Martin, Petter Fosse Gjessing, Ole Martin Fuskevåg, Terje S. Larsen, and Øivind Irtun. "Skeletal muscle mitochondria exhibit decreased pyruvate oxidation capacity and increased ROS emission during surgery-induced acute insulin resistance." American Journal of Physiology-Endocrinology and Metabolism 308, no. 8 (April 15, 2015): E613—E620. http://dx.doi.org/10.1152/ajpendo.00459.2014.
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Development of acute insulin resistance represents a negative factor after surgery, but the underlying mechanisms are not fully understood. We investigated the postoperative changes in insulin sensitivity, mitochondrial function, enzyme activities, and release of reactive oxygen species (ROS) in skeletal muscle and liver in pigs on the 2nd postoperative day after major abdominal surgery. Peripheral and hepatic insulin sensitivity were assessed by d-[6,6-2H2]glucose infusion and hyperinsulinemic euglycemic step clamping. Surgical trauma elicited a decline in peripheral insulin sensitivity (∼34%, P < 0.01), whereas hepatic insulin sensitivity remained unchanged. Intramyofibrillar (IFM) and subsarcolemma mitochondria (SSM) isolated from skeletal muscle showed a postoperative decline in ADP-stimulated respiration (VADP) for pyruvate (∼61%, P < 0.05, and ∼40%, P < 0.001, respectively), whereas VADP for glutamate and palmitoyl-l-carnitine (PC) was unchanged. Mitochondrial leak respiration with PC was increased in SSM (1.9-fold, P < 0.05) and IFM (2.5-fold, P < 0.05), indicating FFA-induced uncoupling. The activity of the pyruvate dehydrogenase complex (PDC) was reduced (∼32%, P < 0.01) and positively correlated to the decline in peripheral insulin sensitivity ( r = 0.748, P < 0.05). All other mitochondrial enzyme activities were unchanged. No changes in mitochondrial function in liver were observed. Mitochondrial H2O2 and O2·− emission was measured spectrofluorometrically, and H2O2 was increased in SSM, IFM, and liver mitochondria (∼2.3-, ∼2.5-, and ∼2.3-fold, respectively, all P < 0.05). We conclude that an impairment in skeletal muscle mitochondrial PDC activity and pyruvate oxidation capacity arises in the postoperative phase along with increased ROS emission, suggesting a link between mitochondrial function and development of acute postoperative insulin resistance.
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Albanova, V. I., V. V. Chikin, and R. V. Epishev. "Revisited diagnostics of hereditary epidermolysis bullosa." Vestnik dermatologii i venerologii 90, no. 3 (June 24, 2014): 53–59. http://dx.doi.org/10.25208/0042-4609-2014-90-3-53-59.
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Hereditary epidermolysis bullosa is a big group of hereditary diseases with the main manifestations in the form of blisters on the skin and mucous coat after slight mechanical injuries. It is not always possible to diagnose this disease based on the clinical picture. The article discusses current laboratory diagnostics methods for hereditary epidermolysis bullosa including immunofluorescence antigen mapping (IFM), transmission electron microscopy (TEM) and genetic analysis (molecular or DNA diagnostics) as well as their advantages and disadvantages. TEM determines the micro splitting level and nature of ultrafine changes in the area of the dermoepidermal junction; at the same time, such tests need special expensive equipment. Substantial experience is also needed to analyze the resulting submicroscopic images. IFM determines whether expression of the affected protein related to the disease development is reduced or absent; however, invalid (false positive or false negative) results can be obtained in patients with the reduced expression of the affected protein. Genetic analysis plays a key role for prenatal diagnostics. Therefore, to make an exact diagnosis of hereditary epidermolysis bullosa, it is expedient to apply IFM, TEM and genetic analysis. The need to set an exact diagnosis of the disease is related to the fact that the promising treatment methods being currently developed are aimed at treating patients with certain forms of the disease.
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Veith, Moritz, Andreas Zimmermann, Jonas Hillenbrand, and Jürgen Fleischer. "Detektion des Vorspannungsverlusts in Kugelgewindetrieben/Detection of preload loss in ball screw drives – Optimization of machine tool maintenance with the Guard Plus system." wt Werkstattstechnik online 110, no. 07-08 (2020): 485–90. http://dx.doi.org/10.37544/1436-4980-2020-07-08-29.
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Ziel der Instandhaltung von Werkzeugmaschinen ist die Verfügbarkeitsabsicherung, um hohe Bauteilqualität und Produktivität zu gewährleisten. Die Kenntnis des Vorschubachsenzustandes, im Besonderen des Kugelgewindetriebs, ist daher von enormer Wichtigkeit. Das „Guard-Plus“-System, eine Entwicklung der August Steinmeyer GmbH und der ifm diagnostics GmbH, ermöglicht dies durch Detektion des Vorspannungsverlustes aufgrund von Verschleiß. Untersuchungen zur Systemfunktion wurden in diesem Beitrag durch das wbk Institut für Produktionstechnik durchgeführt. The aim of machine tool maintenance is to ensure availability in order to guarantee high product quality and productivity. Knowledge of the wear condition of feed axes involved, especially the ball screw, is therefore of enormous importance. The Guard Plus system, a joint development of August Steinmeyer GmbH and ifm diagnostics GmbH, enables this by detecting the preload loss due to wear. Investigation of the system’s function are presented through wbk Institute of Production Science in the following article.
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Schmitz, Marissa Bongiovanni, and Erin Clover Kelly. "Ecosystem Service Commodification: Lessons from California." Global Environmental Politics 16, no. 4 (November 2016): 90–110. http://dx.doi.org/10.1162/glep_a_00374.
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In 2013 the state of California launched a cap-and-trade program with a groundbreaking protocol for improved forest management (IFM), providing a framework to monetize carbon sequestration in managed forests. Through in-depth interviews and document review, this research examines California's IFM program development as a case study in stakeholder-engaged ecosystem commodification. We consider how diverse, vested-interest actors contested rival program design options by using the familiar narratives of ecological modernization, green governmentality, and civic environmentalism. The results reveal the benefits and complexities of delegating methodological design to stakeholders who seek direct participation in the market, and highlight the challenges of balancing multiple program objectives, including environmental benefits, legitimacy and market reception, and landowner participation potential. This research provides a unique window into the complex process of forest-offset program design and offers broader lessons for ecosystem markets currently being designed and implemented globally.
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Islam, Serajul, and Tania Sultana. "Practice of Islamic Financial Management in Bangladesh: Evidence from Islamic Banks." International Journal of Islamic Banking and Finance Research 3, no. 1 (January 17, 2019): 1–12. http://dx.doi.org/10.46281/ijibfr.v3i1.227.
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The growing awareness of the systemic importance of Islamic banking and finance to the development has prepared the ground for the work of upgrading the existing Islamic banking practices. Hence, this study aims to evaluate the Islamic Financial Management (IFM) practices of Islamic banks in Bangladesh. In line with the objective of the study, several ratio analyses were conducted based on ANNOVA test and the sample size includes 8 Islamic banks from 2007 to 2013.The findings revealed that the Islamic banks in Bangladesh are homogenous; however, they are not financially healthy when liquidity measurements are concerned. Additionally, capital structure efficiency results revealed that most of the Islamic Banks in Bangladesh are practicing debt-based financing rather than equity. While the study has observed that the practices of IFM in Bangladesh are promising, however, there are numerous challenges encroaching the industry. Hence, immediate attention from the respective authorities, including practitioners and policy makers are indeed vital.
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Dhanyasi, Nagaraju, Dagan Segal, Eyal Shimoni, Vera Shinder, Ben-Zion Shilo, K. VijayRaghavan, and Eyal D. Schejter. "Surface apposition and multiple cell contacts promote myoblast fusion in Drosophila flight muscles." Journal of Cell Biology 211, no. 1 (October 12, 2015): 191–203. http://dx.doi.org/10.1083/jcb.201503005.
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Fusion of individual myoblasts to form multinucleated myofibers constitutes a widely conserved program for growth of the somatic musculature. We have used electron microscopy methods to study this key form of cell–cell fusion during development of the indirect flight muscles (IFMs) of Drosophila melanogaster. We find that IFM myoblast–myotube fusion proceeds in a stepwise fashion and is governed by apparent cross talk between transmembrane and cytoskeletal elements. Our analysis suggests that cell adhesion is necessary for bringing myoblasts to within a minimal distance from the myotubes. The branched actin polymerization machinery acts subsequently to promote tight apposition between the surfaces of the two cell types and formation of multiple sites of cell–cell contact, giving rise to nascent fusion pores whose expansion establishes full cytoplasmic continuity. Given the conserved features of IFM myogenesis, this sequence of cell interactions and membrane events and the mechanistic significance of cell adhesion elements and the actin-based cytoskeleton are likely to represent general principles of the myoblast fusion process.
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Miramini, Saeed, Li Hai Zhang, Martin Richardson, and Priyan Mendis. "Computational Simulation of Mechanical Microenvironment of Early Stage of Bone Healing under Locking Compression Plate with Dynamic Locking Screws." Applied Mechanics and Materials 553 (May 2014): 281–86. http://dx.doi.org/10.4028/www.scientific.net/amm.553.281.
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It is well known that bone healing outcomes highly depend on the mechanical microenvironment of the fracture site, and a certain degree of interfragmentary movement (IFM) is essential for indirect (i.e. natural) bone healing. The application of locking compression plate (LCP) internal fixation in the treatment of bone fracture is a common practice which leads to early mobility and full function of the fractured extremity. However should the fixation configuration be too stiff, it might result in delayed healing or asymmetric tissue development across the fracture site due to the fact that IFM in near cortex area is too small to promote healing. Dynamic locking screw (DLS) has been recently designed to tackle this problem by reducing the stiffness of LCP fixation. However, the actual mechano-regulation mechanisms in which DLS uses to regulate the healing process are still not fully understood. The objective of this paper is to develop a computational model to understand the change of mechanical microenvironment of fracture site under LCP with dynamic locking screw in comparison to standard locking screw, and how this change could potentially regulate tissue development within the fracture callus during the healing process.Keywords: bone healing, locking compression plate, dynamic locking screw, finite element modelling
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Malmgaard-Clausen, Nikolaj Moelkjaer, Michael Kjaer, and Stephanie G. Dakin. "Pathological Tendon Histology in Early and Chronic Human Patellar Tendinopathy." Translational Sports Medicine 2022 (October 4, 2022): 1–9. http://dx.doi.org/10.1155/2022/2799665.
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The present pilot study investigated the extent of histological tissue changes in both chronic tendinopathy and in individuals that display early clinical signs of tendinopathy. The study included 8 individuals of whom 3 were healthy without any tendon symptoms, 2 had early symptoms (1–2 months), and 3 had chronic symptoms (>3 months) from their patellar tendons. Percutaneous needle biopsy samples were obtained from the affected tendon tissue region. Biopsy samples were stained with Haematoxylin & Eosin, and multiplex immunofluorescence staining was performed for markers of inflammation and resolution. Both early and chronic stage patellar tendon biopsy samples from this small patient cohort exhibited expansion of the interfascicular matrix (IFM) and endotenon regions together with increased cellularity and vascularity. These histological observations were moderate in early tendinopathy, whereas they were more pronounced and associated with marked disruption of tissue architecture in chronic tendinopathy. Early stage tendinopathic patellar tendons expressed markers associated with an activated phenotype of fibroblasts (CD90, CD34), macrophages (S100A8), and endothelial cells (ICAM1, VCAM1). These tissues also expressed enzymes implicated in inflammation (PTGS2, 15PGDH) and resolution (ALOX12) and the proresolving receptor ERV1. Immunopositive staining for these markers was predominantly located in the IFM regions. These preliminary findings suggest that mild to moderate structural histological changes including expansion of IFM and endotenon regions are pathological features of early tendinopathy, and support inflammatory and resolving processes are active in early-stage disease. Further investigation of the cellular and molecular basis of early-stage tendinopathy is required to inform therapeutic strategies that prevent the development of irreversible chronic tendon disease.
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Ordoñez, Maria-Cristina, Leopoldo Galicia, and Karla Valladares-Samperio. "Carbon and Nitrogen Dynamics in Mexican Management Forest: Simulation of Biomass Harvesting and C and N Amendments." Forest Science 68, no. 2 (December 18, 2021): 172–83. http://dx.doi.org/10.1093/forsci/fxab059.
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Abstract Sustainable silvicultural management requires the maintenance of long-term ecosystem processes. We used the CENTURY model to simulate the impact of wood extraction and organic amendments on aboveground biomass, carbon (C) storage, and the availability of nitrogen (N) in the two dominant silvicultural methods in Mexico: the silvicultural development method (SDM) and irregular forest management (IFM). The values of the mean absolute percentage error for the SDM and IFM were 2.1% and 3.3% for C in aboveground biomass, 5.7% and 5.0% for soil organic carbon (SOC), and 14.9% and 21.6% for N, respectively. Simulation for the SDM (1967–2068) suggested a reduction of ~7% in C in soil, microbial biomass, and litter, 9% in aboveground biomass C, and ~20% in the mineral N available. For IFM, the simulation (2009–2019) suggested a reduction of 14% in the accumulation of aboveground biomass and 13% in the mineral N available. Simulation of the adoption of management practices suggested that N mineral availability would increase by 2%–3% without drastically reducing the SOC, improving aboveground biomass production by ~7%, in each management system. Study Implications In Mexico, current silvicultural management is causing alterations in the biological and chemical processes of the soil, but the future impacts on the production of forest wood and loss of fertility cannot be estimated by direct measurements. We simulated two silvicultural management alternatives with two rotation cycles and measured the response in terms of SOC, nitrogen availability, and aboveground biomass. The model shows that improving forest residue management by adding organic amendments to the soil would counteract changes in soil microbial activity, nitrogen availability, SOC, and aboveground biomass in the future. Managers should consider this information to reorient current crop residue management to achieve the objectives and the sustainability of forest management in Mexican temperate forests.
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Macedo, Taísa Gonçalves, Carlos Antônio Dos Santos, Antônio de Amorim Brandão, Evandro Silva Pereira Costa, and Margarida Goréte Ferreira do Carmo. "SINGLE-HEAD BROCCOLI PRODUCTION UNDER DIFFERENT SPACING AND CONDITIONS OF BAIXADA FLUMINENSE." REVISTA DE AGRICULTURA NEOTROPICAL 9, no. 3 (September 9, 2022): e6908. http://dx.doi.org/10.32404/rean.v9i3.6908.
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This study aimed to evaluate different spacings between rows on the development and yield of single-head broccoli under the soil and climate conditions of Seropédica, in the Baixada Fluminense region, the State of Rio de Janeiro (Brazil). Tests were carried out under field conditions using the Avenger hybrid. The experimental design adopted was randomized blocks with four treatments and four replications per treatment. Four spacings between rows were tested: 0.6 m, 0.7 m, 0.8 m, and 1.0 m. The spacing between plants in the rows was 0.6 m in all treatments. The number of leaves (NL), plant height (PHT), fresh leaf mass (FLM), stem fresh mass (SFM), inflorescence fresh mass (IFM), inflorescence longitudinal diameter (ILD), and estimated yield (YLD) were evaluated. Data were submitted to analysis of variance (ANOVA) and regression analysis (p<0.05). Spacing variations did not influence PHT and SFM. There was a linear increase in NL and FLM according to the increase in the spacing between rows. A quadratic effect of spacing was observed on ILD, IFM, and YLD. The spacing between the rows of 0.85 m ensured greater yield (6.97 Mg ha-1) and the production of inflorescences with characteristics compatible with those required by the consumer market (ILD = 9.83 cm; MFI = 347.15 g). It is concluded that the production of single-head broccoli under the conditions of Seropédica-RJ is possible, and the population density influences the development and yield of plants.
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Hamilton, Colin, Anna Maw, Andrew Gill, Mita Brahmbhatt, Robert Phaal, and John Pickard. "Paediatric neurorehabilitation: finding and filling the gaps through the use of the Institute for Manufacturing strategic roadmapping method." BMJ Innovations 3, no. 3 (July 2017): 137–43. http://dx.doi.org/10.1136/bmjinnov-2017-000202.
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IntroductionAcquired brain injury (ABI) is a major cause of morbidity and mortality in childhood. Specialist rehabilitation services are often situated far from families and local services may be non-standardised and fragmented. A strategic level of understanding is needed to improve patient care and outcomes. Roadmapping techniques are commonly used in industry settings to discover and present a systematic understanding of structures; however, they are rarely used in the healthcare setting. With continuing pressures on healthcare systems worldwide, they provide an effective method for examining services.MethodsThe Institute for Manufacturing (IfM) strategic roadmapping method was used to identify areas of difficulty and opportunities in paediatric neurorehabilitation. Participants included stakeholders from a wide range of professions and sectors who have input with children after ABI.ResultsDelegates identified a range of ‘layers’ covering trends, drivers, current experience and unmet needs. From these layers, four priorities were identified and further expanded.These included: ‘access to medical and therapy expertise close(r) to home’, ‘shared understanding across family, school and health’, ‘family and professional awareness of resources and support’ and ‘establishing a centre for rehabilitation technology evaluation, advice and co-ordination of services and research’.ConclusionThe IfM strategic roadmapping method identified and developed key areas for development in the field of paediatric neurological rehabilitation. Healthcare professionals looking at strategic level difficulties should strongly consider the use of such systematic tools when evaluating areas of practice.
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Driscoll, D. A. "How to find a metapopulationThis review is one of a series dealing with some aspects of the impact of habitat fragmentation on animals and plants. This series is one of several virtual symposia focussing on ecological topics that will be published in the Journal from time to time." Canadian Journal of Zoology 85, no. 10 (October 2007): 1031–48. http://dx.doi.org/10.1139/z07-096.
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Where habitat loss and fragmentation is severe, many native species are likely to have reduced levels of dispersal between remnant populations. For those species to avoid regional extinction in fragmented landscapes, they must undergo some kind of metapopulation dynamics so that local extinctions are countered by recolonisation. The importance of spatial dynamics for regional survival means that research into metapopulation dynamics is essential. In this review I explore the approaches taken to examine metapopulation dynamics, highlight the analytical methods used to get the most information out of field data, and discover some of the major research gaps. Statistical models, including Hanski’s incidence function model (IFM) are frequently applied to presence–absence data, an approach that is often strengthened using long-term data sets that document extinctions and colonisations. Recent developments are making the IFM more biologically realistic and expanding the range of situations for which the model is relevant. Although accurate predictions using the IFM seem unlikely, it may be useful for ranking management decisions. A key weakness of presence–absence modelling is that the mechanisms underlying spatial dynamics remain inferential, so combining modelling approaches with detailed demographic research is warranted. For species where very large data sets cannot be obtained to facilitate statistical modelling, a demographic approach alone or with stochastic modelling may be the only viable research angle to take. Dispersal is a central process in metapopulation dynamics. Research combining mark–recapture or telemetry methods with model-selection procedures demonstrate that dispersal is frequently oversimplified in conceptual and statistical metapopulation models. Dispersal models like the island model that underlies classic metapopulation theory do not approximate the behaviour of real species in fragmented landscapes. Nevertheless, it remains uncertain if additional biological realism will improve predictions of statistical metapopulation models. Genetic methods can give better estimates of dispersal than direct methods and take less effort, so they should be routinely explored alongside direct ecological methods. Recent development of metacommunity theory (communities connected by dispersal) emphasises a range of mechanisms that complement metapopulation theory. Taking both theories into account will enhance interpretation of field data. The extent of metapopulation dynamics in human modified landscapes remains uncertain, but we have a powerful array of field and analytical approaches for reducing this knowledge gap. The most informative way forward requires that many species are studied in the same fragmented landscape by applying a selection of approaches that reveal complementary aspects of spatial dynamics.
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Sheets, Michael F., John W. Kyle, and Dorothy A. Hanck. "The Role of the Putative Inactivation Lid in Sodium Channel Gating Current Immobilization." Journal of General Physiology 115, no. 5 (May 1, 2000): 609–20. http://dx.doi.org/10.1085/jgp.115.5.609.
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We investigated the contribution of the putative inactivation lid in voltage-gated sodium channels to gating charge immobilization (i.e., the slow return of gating charge during repolarization) by studying a lid-modified mutant of the human heart sodium channel (hH1a) that had the phenylalanine at position 1485 in the isoleucine, phenylalanine, and methionine (IFM) region of the domain III–IV linker mutated to a cysteine (ICM-hH1a). Residual fast inactivation of ICM-hH1a in fused tsA201 cells was abolished by intracellular perfusion with 2.5 mM 2-(trimethylammonium)ethyl methanethiosulfonate (MTSET). The time constants of gating current relaxations in response to step depolarizations and gating charge–voltage relationships were not different between wild-type hH1a and ICM-hH1aMTSET. The time constant of the development of charge immobilization assayed at −180 mV after depolarization to 0 mV was similar to the time constant of inactivation of INa at 0 mV for hH1a. By 44 ms, 53% of the gating charge during repolarization returned slowly; i.e., became immobilized. In ICM-hH1aMTSET, immobilization occurred with a similar time course, although only 31% of gating charge upon repolarization (OFF charge) immobilized. After modification of hH1a and ICM-hH1aMTSET with Anthopleurin-A toxin, a site-3 peptide toxin that inhibits movement of the domain IV-S4, charge immobilization did not occur for conditioning durations up to 44 ms. OFF charge for both hH1a and ICM-hH1aMTSET modified with Anthopleurin-A toxin were similar in time course and in magnitude to the fast component of OFF charge in ICM-hH1aMTSET in control. We conclude that movement of domain IV-S4 is the rate-limiting step during repolarization, and it contributes to charge immobilization regardless of whether the inactivation lid is bound. Taken together with previous reports, these data also suggest that S4 in domain III contributes to charge immobilization only after binding of the inactivation lid.
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Croston, Tara L., Dharendra Thapa, Anthony A. Holden, Kevin J. Tveter, Sara E. Lewis, Danielle L. Shepherd, Cody E. Nichols, et al. "Functional deficiencies of subsarcolemmal mitochondria in the type 2 diabetic human heart." American Journal of Physiology-Heart and Circulatory Physiology 307, no. 1 (July 1, 2014): H54—H65. http://dx.doi.org/10.1152/ajpheart.00845.2013.
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The mitochondrion has been implicated in the development of diabetic cardiomyopathy. Examination of cardiac mitochondria is complicated by the existence of spatially distinct subpopulations including subsarcolemmal (SSM) and interfibrillar (IFM). Dysfunction to cardiac SSM has been reported in murine models of type 2 diabetes mellitus; however, subpopulation-based mitochondrial analyses have not been explored in type 2 diabetic human heart. The goal of this study was to determine the impact of type 2 diabetes mellitus on cardiac mitochondrial function in the human patient. Mitochondrial subpopulations from atrial appendages of patients with and without type 2 diabetes were examined. Complex I- and fatty acid-mediated mitochondrial respiration rates were decreased in diabetic SSM compared with nondiabetic ( P ≤ 0.05 for both), with no change in IFM. Electron transport chain (ETC) complexes I and IV activities were decreased in diabetic SSM compared with nondiabetic ( P ≤ 0.05 for both), with a concomitant decline in their levels ( P ≤ 0.05 for both). Regression analyses comparing comorbidities determined that diabetes mellitus was the primary factor accounting for mitochondrial dysfunction. Linear spline models examining correlative risk for mitochondrial dysfunction indicated that patients with diabetes display the same degree of state 3 and electron transport chain complex I dysfunction in SSM regardless of the extent of glycated hemoglobin (HbA1c) and hyperglycemia. Overall, the results suggest that independent of other pathologies, mitochondrial dysfunction is present in cardiac SSM of patients with type 2 diabetes and the degree of dysfunction is consistent regardless of the extent of elevated HbA1c or blood glucose levels.
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Gilley, Ryan P., Norberto González-Juarbe, Anukul T. Shenoy, Luis F. Reyes, Peter H. Dube, Marcos I. Restrepo, and Carlos J. Orihuela. "Infiltrated Macrophages Die of Pneumolysin-Mediated Necroptosis following Pneumococcal Myocardial Invasion." Infection and Immunity 84, no. 5 (February 29, 2016): 1457–69. http://dx.doi.org/10.1128/iai.00007-16.
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Streptococcus pneumoniae(the pneumococcus) is capable of invading the heart. Herein we observed that pneumococcal invasion of the myocardium occurred soon after development of bacteremia and was continuous thereafter. Using immunofluorescence microscopy (IFM), we observed thatS. pneumoniaereplication within the heart preceded visual signs of tissue damage in cardiac tissue sections stained with hematoxylin and eosin. DifferentS. pneumoniaestrains caused distinct cardiac pathologies: strain TIGR4, a serotype 4 isolate, caused discrete pneumococcus-filled microscopic lesions (microlesions), whereas strain D39, a serotype 2 isolate, was, in most instances, detectable only using IFM and was associated with foci of cardiomyocyte hydropic degeneration and immune cell infiltration. Both strains efficiently invaded the myocardium, but cardiac damage was entirely dependent on the pore-forming toxin pneumolysin only for D39. Early microlesions caused by TIGR4 and microlesions formed by a TIGR4 pneumolysin-deficient mutant were infiltrated with CD11b+and Ly6G-positive neutrophils and CD11b+and F4/80-positive (F4/80+) macrophages. We subsequently demonstrated that macrophages in TIGR4-infected hearts died as a result of pneumolysin-induced necroptosis. The effector of necroptosis, phosphorylated mixed-lineage kinase domain-like protein (MLKL), was detected in CD11b+and F4/80+cells associated with microlesions. Likewise, treatment of infected mice and THP-1 macrophagesin vitrowith the receptor-interacting protein 1 kinase (RIP1) inhibitor necrostatin-5 promoted the formation of purulent microlesions and blocked cell death, respectively. We conclude that pneumococci that have invaded the myocardium are an important cause of cardiac damage, pneumolysin contributes to cardiac damage in a bacterial strain-specific manner, and pneumolysin kills infiltrated macrophages via necroptosis, which alters the immune response.
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Napper, Moira. "Finding the Evidence: Clinical Guidelines from Source to Practice. IFM Healthcare study day, Scottish Health Service Development Group, Edinburgh, 26th January 1998." Health Libraries Review 15, no. 3 (September 1998): 210–11. http://dx.doi.org/10.1046/j.1365-2532.1998.15302092.x.
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Vincent Mthembu, Andile, Unathi Kolanisi, Nothando Delight Qumbisa, and Thembekile Prudence Kheswa. "Indigenising Informal Financial Mechanism (IFM) of Rural Women in the Northern Region of Kwazulu-Natal, South Africa." African Journal of Gender, Society and Development (formerly Journal of Gender, Information and Development in Africa) 11, no. 3 (September 1, 2022): 125–44. http://dx.doi.org/10.31920/2634-3622/2022/v11n3a6.
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There is little documentation of umholiswano from local people’s perspective, as local knowledge has evolved with time. A phenomenology research design outlined the attributes and their meaningful value as perceived by local communities. 65 participants participated in a series of focus group discussions and complemented six key informant interviews. Umholiswano (stokvel) is an indigenous concept that has been part of the life of many indigenous communities before the money era. It was used as a mechanism to achieve social justice, establish peace and create socio-economic balance toward improved well-being. In this study, umholiswano is a household financial planning and management tool, saving/investment system, a social-cohesion-nurturing and therapeutic mechanism founded on six core value principles (6CVPs), such as ubuntu, trust, solidarity, dignity preservation of social wealth and ukudlala (fun). Most key players are women, and umholiswano is regarded as the 21st livestock for women. The majority are in the economically active age group but lack the skills to enter the formal economy. They rely on social grants and entrepreneurship activities. Umholiswano is undervalued as an economic strategy, nevertheless, its significant contribution to the quality of life of rural women is observable. But, there is an existing gap for a quantifiable tool to assess the umholiswano’s contribution, as the measurability should start by identifying indicators designed “with people and for the people” and the above six core value principles identified in the study could be set as a guiding framework towards indicators development.
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Lashayo, Deogratius Mathew, and Julius Raphael Athuman Mhina. "Towards Cash-Less Economy." International Journal of Mobile Devices, Wearable Technology, and Flexible Electronics 12, no. 1 (January 1, 2022): 1–24. http://dx.doi.org/10.4018/ijmdwtfe.311432.
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Recently, there has been speedy development of mobile technologies and an increase in diffusion of smartphones among young people. This has provided opportunities for innovative companies to create new payment solutions to their young customers. Although there has been a lot of coverage on consumer acceptance of mobile payments, only limited studies in Tanzania provide guidelines for NFC technology acceptance. This study aimed at examining factors influencing the acceptance of NFC technology in Tanzania using young customers (students). Current research modifies UTAUT framework based on existing literature to achieve the stated purpose. The snowball sampling technique was used to select 405 students from the IFM. SEM was employed in the analysis of collected data. The findings reveal that both security and trust are significant and positively affect adoption of NFC technology in Tanzania. Surprisingly, the results also indicated that the combination of social influence and security explains 84% of the trust. The implication, limitations, and future studies were also discussed.
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Iswanaji, Chairir, Aziz Muslim, and M. Zidny Nafi' Hasbi. "Ijarah Collaborative Service Model in Sharia Banking." Indonesian Interdisciplinary Journal of Sharia Economics (IIJSE) 5, no. 2 (July 31, 2022): 702–19. http://dx.doi.org/10.31538/iijse.v5i2.1778.
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Ijarah is a contract for the transfer of usufructuary rights over goods or services, through payment of rental wages, without being followed by a transfer of ownership of the goods themselves. The context of ijarah in Islamic banking is a lease contract in which a bank or financial institution leases equipment to one of its customers based on a definite predetermined cost. The research method is qualitative with a comparative study approach. Data collection techniques include observation, documentation, and deep interviews. The object of this research was carried out in the Yogyakarta area. The findings of the ijarah case presented in this study indicate that the services created jointly by customers, service organizations (Islamic banks), and assisting parties divide their roles into sub-roles assigned to individuals. This research provides a basic understanding of the development of a sharia service model, which can complement the current IFM to holistically capture both economic transactions and service elements, which are currently prevailing in the Islamic banking market.
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Jarausch, K. F., J. E. Houston, and P. E. Russell. "Correlation of film stress and the mechanical response of Au thin films." Proceedings, annual meeting, Electron Microscopy Society of America 54 (August 11, 1996): 856–57. http://dx.doi.org/10.1017/s0424820100166749.
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The investigation of the mechanical properties of nanostructured materials is critical to the continuing development of thin film technology. For example, the semiconductor industry must understand how stress and strain effect the electronic properties of superlattices and cause the delamination of metal interconnect films. A variety of nano-indentation techniques have been developed as tools to investigate the mechanical behavior of thin films. In a previous study the interfacial force microscope (IFM) was used to survey the mechanical response of 200nm thick Au films deposited on various substrates under various deposition conditions. By combining the methods of contact mechanics and classic indentation techniques, quantitative investigations of the effective elastic modulus and the maximum shear-stress at the plastic threshold were tabulated. The results indicated a large variation in these parameters for the various film/substrates, while the values were consistent over a single film/substrate. The observed variation could be explained by several factors: differences in the films morphology, adhesion to the substrate, or residual stress.
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Windlinger, Lukas, Susanne Hofer, Christian Coenen, Franziska Honegger, Daniel von Felten, Andrea Kofler, and Thomas Wehrmüller. "FM research in Switzerland." Facilities 32, no. 1/2 (January 28, 2014): 18–26. http://dx.doi.org/10.1108/f-09-2012-0074.
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Purpose – This paper aims to review FM research in Switzerland with a focus on recent research projects at the Institute of Facility Management of the Zurich University of Applied Sciences. Design/methodology/approach – The paper provides a summary and review of research projects. Findings – FM research in Switzerland has grown in the past few years and is now well rooted in the Swiss FM industry. The focus is on service management, workplace management and FM in health care. FM research in Switzerland has been driven collaboratively by the Institute of FM and the industry. Research limitations/implications – Research at the IFM is very much oriented towards application and many collaborative projects between industry, public administration and universities have been conducted. However, some fields of FM have received little attention yet. Practical implications – FM research in Switzerland has been driven collaboratively by the Institute of FM and the industry. The focus is on application, e.g. management tools, benchmarking systems or the relationship of FM services, organisational outcomes, and customer satisfaction. Many research results contribute to the development of Swiss FM industry. Originality/value – In this article the authors summarize FM research in Switzerland and their research approach. With this they contribute to transparency and further development of FM research.
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Editorial Team. "Research in the Workplace Award." Evidence Based Library and Information Practice 1, no. 4 (December 11, 2006): 84. http://dx.doi.org/10.18438/b87c7c.
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The Research in the Workplace Award (RIWA)* is a biennial grant that seeks to fund small LIS-led workplace research projects.
The award of £3000 GBP/$5900 USD/$6800 CAD aims to encourage and support those new to research. Projects can relate to any aspect of service provision, development or theory. Advice is available throughout the lifetime of your project, which should be achievable within 12 months. The award fund must constitute at least 55% of the overall project funding.
If you have an idea for a small work-based research project, why not consider applying for RIWA 2006/7?
A copy of the 2 page application form is available from:
http://ifmh.org.uk/RIWA.html
Submission deadline: 22nd December 2006.
For further details contact Maria on +44 (0) 161 295 6423 or email: m.j.grant@salford.ac.uk
* RIWA 2006/7 is sponsored by the National Library for Health CPD Forum, IFM Healthcare, the Health Libraries Group, the University Medical School Librarians Group, the University Health Sciences Libraries and Libraries for Nursing.
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Boivin, Teela, Cathie Elmgren, Brian W. Brooks, Hongsheng Huang, Franco Pagotto, and Min Lin. "Expression of Surface Protein LapB by a Wide Spectrum of Listeria monocytogenes Serotypes as Demonstrated with Anti-LapB Monoclonal Antibodies." Applied and Environmental Microbiology 82, no. 22 (September 9, 2016): 6768–78. http://dx.doi.org/10.1128/aem.01908-16.
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ABSTRACTProtein antigens expressed on the surface of all strains ofListeria monocytogenesand absent from nonpathogenicListeriaspp. are presumably useful targets for pathogen identification, detection, and isolation using specific antibodies (Abs). To seek such surface proteins expressed in various strains ofL. monocytogenesfor diagnostic applications, we focused on a set of surface proteins known to be involved or putatively involved inL. monocytogenesvirulence and identifiedListeriaadhesion protein B (LapB) as a candidate based on the bioinformatics analysis of whole-genome sequences showing that the gene coding for LapB was present inL. monocytogenesstrains and absent from strains of otherListeriaspp. Immunofluorescence microscopy (IFM), performed with rabbit polyclonal antibodies against the recombinant LapB protein (rLapB) ofL. monocytogenesserotype 4b strain L10521, confirmed expression of LapB on the surface. A panel of 48 mouse monoclonal antibodies (MAbs) to rLaB was generated, and 7 of them bound strongly to the surface ofL. monocytogenescells as demonstrated using IFM. Further characterization of these 7 anti-LapB MAbs, using an enzyme-linked immunosorbent assay (ELISA), revealed that 6 anti-LapB MAbs (M3484, M3495, M3500, M3509, M3517, and M3519) reacted strongly with 46 (86.8%) of 53 strains representing 10 of the 12 serotypes tested (1/2a, 1/2b, 1/2c, 3a, 3b, 3c, 4ab, 4b, 4d, and 4e). These results indicate that LapB, together with companion anti-LapB MAbs, can be targeted as a biomarker for the detection and isolation of variousL. monocytogenesstrains from contaminated foods.IMPORTANCEStrains ofL. monocytogenesare traditionally grouped into serotypes. Identification of a surface protein expressed in all or the majority of at least 12 serotypes would aid in the development of surface-binding monoclonal antibodies (MAbs) for detection and isolation ofL. monocytogenesfrom foods. Bioinformatics analysis revealed that the gene coding forListeriaadhesion protein B (LapB), a surface protein involved inL. monocytogenesvirulence, was present inL. monocytogenesstrains and absent from otherListeriaspp. Polyclonal antibodies against recombinant LapB (rLapB) detected the exposed epitopes on the surface ofL. monocytogenes. Production and extensive assessment of 48 MAbs to rLapB showed that 6 anti-LapB MAbs (M3484, M3495, M3500, M3509, M3517, and M3519) detected the expression of LapB in a wide range ofL. monocytogenesisolates representing 10 of 12 serotypes tested, suggesting that LapB, together with specific MAbs, can be targeted as a biomarker for pathogen detection and isolation.
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Rattan, Punam. "Cultivating Agricultural Evolution: Revolutionizing Farming Through The Power of AI And Technology." Review of Artificial Intelligence in Education 4, no. 00 (August 17, 2023): e010. http://dx.doi.org/10.37497/rev.artif.intell.educ.v4i00.10.
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Objective: The objective of this study is to explore the current and potential role of Artificial Intelligence (AI) in the agricultural sector. We aim to analyze the adoption and impact of AI solutions in farming, identify challenges, and discuss the prospects for its future integration.
Method: We conducted a comprehensive review of existing literature and ongoing research projects related to AI applications in agriculture. We also examined case studies, technological developments, and AI pioneers in the field.
Results: Our analysis reveals that while AI solutions are being researched and applied in agriculture, there is a gap in widespread industry adoption. Large-scale research projects are underway, and some AI applications are available in the market. However, the development of predictive solutions to address real farming challenges is in the early stages. AI's influence extends across various sectors, contributing to the advancement of technologies such as big data, robotics, and the Internet of Things.
An illustrative example is the styrofoam container device, which utilizes machine learning and computer vision to detect and categorize "safety occurrences." Although not all-encompassing, this technology gathers significant data, such as driver behavior, speed, and surroundings. IFM's system promptly alerts supervisors to safety breaches, enhancing both safety and productivity.
Conclusion: The future of AI in agriculture hinges on the widespread adoption of AI solutions. The agricultural industry remains underserved in terms of AI integration, and the development of predictive solutions is in its early stages. However, AI's impact across sectors underscores its importance. Pioneers like IFM and IBM's patent statistics demonstrate the expanding scope of AI innovation.
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Sanya, Ogunsakin. "Commodity Price Shocks And Macroeconomic Performance In Sub-Saharan Africa." Archives of Business Research 8, no. 5 (May 25, 2020): 169–82. http://dx.doi.org/10.14738/abr.85.7937.
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This study investigated the relationship between commodity price shocks and output growth in Sub-Saharan African countries using panel data which covered the period between 2005 and 2017. Data for the study were sourced from the World Development Indicators (WDI). Data base of the World Bank, The IMF’S International Financial Statistics (IFM) and Publications of Central Banks of various countries selected. The study employed Generalized Movement Average (GMM) as the estimation technique. Findings from the study showed that positive changes in the prices of export commodities has little positive impact on macroeconomic performance in Sub-Saharan Africa while negative price change has negative and significant impact on macroeconomic performance in Sub-Saharan African countries during study period. Based on these findings, the study therefore concludes that the relationship between commodity price shocks and macroeconomic performance in Sub-Saharan Africa is asymmetric. The study recommends that countries in Sub-Saharan Africa should introduce and implement policies to withstand shocks that may come from commodity price shocks such as economic diversification not only in area of agriculture but also in the area of industrialization and manufacturing.
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Cripps, R. M., E. Ball, M. Stark, A. Lawn, and J. C. Sparrow. "Recovery of dominant, autosomal flightless mutants of Drosophila melanogaster and identification of a new gene required for normal muscle structure and function." Genetics 137, no. 1 (May 1, 1994): 151–64. http://dx.doi.org/10.1093/genetics/137.1.151.
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Abstract To identify further mutations affecting muscle function and development in Drosophila melanogaster we recovered 22 autosomal dominant flightless mutations. From these we have isolated eight viable and lethal alleles of the muscle myosin heavy chain gene, and seven viable alleles of the indirect flight muscle (IFM)-specific Act88F actin gene. The Mhc mutations display a variety of phenotypic effects, ranging from reductions in myosin heavy chain content in the indirect flight muscles only, to reductions in the levels of this protein in other muscles. The Act88F mutations range from those which produce no stable actin and have severely abnormal myofibrillar structure, to those which accumulate apparently normal levels of actin in the flight muscles but which still have abnormal myofibrils and fly very poorly. We also recovered two recessive flightless mutants on the third chromosome. The remaining five dominant flightless mutations are all lethal alleles of a gene named lethal(3)Laker. The Laker alleles have been characterized and the gene located in polytene bands 62A10,B1-62B2,4. Laker is a previously unidentified locus which is haplo-insufficient for flight. In addition, adult wild-type heterozygotes and the lethal larval trans-heterozygotes show abnormalities of muscle structure indicating that the Laker gene product is an important component of muscle.
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Krishnan, Amrita Y., Matthew Mei, Canlan Sun, Jennifer Berano-Teh, Stephen J. Forman, Myo Htut, Tongjun Kang, et al. "Risk factors for development of second primary malignancies (SPM) after autologous stem cell transplant (ASCT) for multiple myeloma." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8038. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8038.
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8038 Background: Studies from the CALGB and IFM have suggested an increased incidence of SPM post ASCT in patients on lenalidomide maintenance. Patients with MM as well as patients post ASCT are inherently at higher risk of SPM. Therefore, assessment of risk factors associated with SPM would be useful in therapeutic decisions re preASCT therapy and post ASCTmaintenance. Methods: We conducted a retrospective cohort study of 841 consecutive MM patients who underwent at least one ASCT at City of Hope from 1989 to 2009. Sixty cases with 70 SPMs were identified. A nested case-control study was also conducted to understand the role of therapeutic exposures associated with SPMs. Controls were MM patients post ASCT matched by year of HCT (±5 years). Results: The median length of follow up was 3.3 yrs. (range 0.3-19.9). Median age at ASCT was 56 yrs (range 18-77). 62% had received a single autologous HCT, 27% tandem autologous HCT, 11% had received multiple HCTs (72 had a second allogeneic HCT)). The overall cumulative incidence of any SPM was 7.4% at 5 years and 15.9% at 10 years; the cumulative incidence of SPMs for patients >55 years approached 21.9% at 10 years. The cumulative incidence of MDS/AML was 1.8% and of solid tumors was 13.0%. Factors examined included age, race, sex, number and individual therapeutic exposures ( pre-ASCT, conditioning, and post-ASCT), disease status at ASCT. Multivariate Cox regression analysis revealed non-Hispanic whites (RR=2.4, 95% CI, 1.2-4.6, p=0.01) and older age (>55) at diagnosis of MM (RR=2.3, 95% CI, 1.3-4.1, p=0.004) to be associated with an increased risk of developing SPMs. Only cumulative thalidomide exposure (both pre-ASCT and post-ASCT) demonstrated a trend toward a positive association (OR=3.5, 95% CI, 0.6-19.4, p=0.15). Six patients (3 cases and 3 controls) were exposed to lenalidomide prior to development of SPM (OR=1.0, 95% CI, 0.14-7.10). Conclusions: This single institution analysis identified non-hispanic whites and older age to be associated with increased risk of developing SPM in pts post ASCT for MM. The trend towards increased risk with thalidomide exposure may be suggestive of a class effect from IMIDs that is not restricted to lenalidomide alone.
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AvetLoiseau, Herve, Jean-Luc Harousseau, Philippe Moreau, Claire Mathiot, Thierry Facon, Michel Attal, Arthur Bradwell, and Stephen Harding. "Heavy/Light Chain Specific Immunoglobulin Ratios at Presentation Are Prognostic for Progression Free Survival in the IFM 2005-01 Myeloma Trial." Blood 114, no. 22 (November 20, 2009): 1818. http://dx.doi.org/10.1182/blood.v114.22.1818.1818.
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Abstract Abstract 1818 Poster Board I-844 The current International staging system (ISS) for myeloma utilises the measurement of beta 2 microglobulin (B2M) and albumin, whilst total immunoglobulin or M-spike measurements are not generally considered to be prognostic. In contrast, some studies have reported that levels of serum free light chains, expressed as a k/l ratio, do provide prognostic information for myeloma patients. The development of antibodies which bind to conformational epitopes spanning the junctional regions between bound κ or λ light chains and their respective heavy chain partners has allowed the specific measurement of serum IgGκ, IgGλ, IgAκ and IgAλ concentrations. In turn, this has enabled the calculation of IgGκ/IgGλ and IgAκ/IgAλ ratios (heavy/light chain or HLC ratios) for individual patients. In this study, the prognostic value of HLC ratios was compared with the ISS. Archived, frozen presentation sera from 339 patients enrolled on the IFM 2005-01 trial were assayed. B2M and albumin were measured in all sera. In addition, IgGk & IgGl concentrations were measured in sera from the 245 IgG myeloma patients (166 IgGk, 79 IgGl). IgAk and IgAl concentrations were measured in the sera from the 94 IgA myeloma patients (60 IgAk, 34 IgAl). These measurements were made on a Siemens BNTMII nephelometer, using reagents from the Binding Site, UK. HLC ratios (IgGk/IgGl or IgAk/IgAl) were calculated for all patients. Association of the various serum markers with progression free survival (PFS) was assessed using Kaplan Meier and Cox regression analysis (SPSS v14.0). Kaplan Meier analysis indicated that more abnormal HLC ratios were associated with reduced PFS (>median for IgGk and IgAk patients, <median for IgGl and IgAl patients; P=0.007). Using more extreme ratios (>200 or <0.01), the significance was increased (P=0.002). Cox regression analysis, confirmed the association of the latter HLC ratios with reduced PFS (P<0.001) and indicated that the association was independent of and more significant than that of B2M or albumin. The combined use of the extreme HLC ratios, and B2M>3.5mg/L in a risk stratification model, showed significant differences in PFS for patients with 0,1 or 2 adverse risk factors (P=0.000013; Fig.1). A more complex risk stratification model combining HLC ratios with the ISS also showed significant differences in PFS according to the number of risk factors (P=0.0001). Prognosis for overall survival could not be examined meaningfully with these patients because of limited mortality (13.5%) at this time point. The use of HLC ratios provides a measure of tumour immunoglobulin production plus immunoparesis. It is probably the combination of these 2 factors which gives the prognostic value. HLC measurements were readily made on an automated nephelometer and they may form a useful addition to the current ISS assessments. Disclosures Bradwell: The Binding Site Group Ltd: Shareholder. Harding:The Binding Site Group Ltd: Employment.
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Aston, Judith. "Interactive Documentary." Interactive Film & Media Journal 2, no. 4 (December 30, 2022): 7–18. http://dx.doi.org/10.32920/ifmj.v2i4.1732.
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This article responds to the 4th Interactive Film and Media International Conference (IFM 2022) themes of eco-media, epistemologies and listening by focusing on the role that interactive documentary can play in addressing the existential and pressing issue of climate change. It re-visits the article Interactive Documentary: setting the field which I co-authored with Sandra Gaudenzi in 2012 in light of this now central concern and asks how the affordances of interactive documentary can be used to help re-frame our engagement with the human and the non-human. It places metamodern and polyphonic thinking at the centre of this discussion, as two key concepts that I consider to be particularly helpful when thinking about the contribution that interactive documentary can make to wider debates about eco-media. The paper argues that metamodernism and polyphony can contribute to the development of transformative approaches to interactive documentary and indeed to interactive narrative more generally. This is important as it offers us a set of cognitive tools through which to think about how to navigate the complexities and uncertainties of our collective futures which climate change is undoubtedly bringing. The paper engages with the theoretical arguments first and then applies these to a discussion of my work as a co-convenor of the Polyphonic Documentary project before bringing these thoughts together as tentative conclusions and unresolved issues.
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Hollander, John M., Dharendra Thapa, and Danielle L. Shepherd. "Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: influence of cardiac pathologies." American Journal of Physiology-Heart and Circulatory Physiology 307, no. 1 (July 1, 2014): H1—H14. http://dx.doi.org/10.1152/ajpheart.00747.2013.
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Cardiac tissue contains discrete pools of mitochondria that are characterized by their subcellular spatial arrangement. Subsarcolemmal mitochondria (SSM) exist below the cell membrane, interfibrillar mitochondria (IFM) reside in rows between the myofibrils, and perinuclear mitochondria are situated at the nuclear poles. Microstructural imaging of heart tissue coupled with the development of differential isolation techniques designed to sequentially separate spatially distinct mitochondrial subpopulations have revealed differences in morphological features including shape, absolute size, and internal cristae arrangement. These findings have been complemented by functional studies indicating differences in biochemical parameters and, potentially, functional roles for the ATP generated, based upon subcellular location. Consequently, mitochondrial subpopulations appear to be influenced differently during cardiac pathologies including ischemia/reperfusion, heart failure, aging, exercise, and diabetes mellitus. These influences may be the result of specific structural and functional disparities between mitochondrial subpopulations such that the stress elicited by a given cardiac insult differentially impacts subcellular locales and the mitochondria contained within. The goal of this review is to highlight some of the inherent structural and functional differences that exist between spatially distinct cardiac mitochondrial subpopulations as well as provide an overview of the differential impact of various cardiac pathologies on spatially distinct mitochondrial subpopulations. As an outcome, we will instill a basis for incorporating subcellular spatial location when evaluating the impact of cardiac pathologies on the mitochondrion. Incorporation of subcellular spatial location may offer the greatest potential for delineating the influence of cardiac pathology on this critical organelle.
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Xiao, Jinglei, Vasyl Bondarenko, Yali Wang, Antonio Suma, Marta Wells, Qiang Chen, Tommy Tillman, et al. "Regulation and drug modulation of a voltage-gated sodium channel: Pivotal role of the S4–S5 linker in activation and slow inactivation." Proceedings of the National Academy of Sciences 118, no. 28 (July 6, 2021): e2102285118. http://dx.doi.org/10.1073/pnas.2102285118.
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Voltage-gated sodium (NaV) channels control excitable cell functions. While structural investigations have revealed conformation details of different functional states, the mechanisms of both activation and slow inactivation remain unclear. Here, we identify residue T140 in the S4–S5 linker of the bacterial voltage-gated sodium channel NaChBac as critical for channel activation and drug effects on inactivation. Mutations at T140 either attenuate activation or render the channel nonfunctional. Propofol, a clinical anesthetic known to inhibit NaChBac by promoting slow inactivation, binds to a pocket between the S4–S5 linker and S6 helix in a conformation-dependent manner. Using 19F-NMR to quantify site-specific binding by saturation transfer differences (STDs), we found strong STDs in inactivated, but not activated, NaChBac. Molecular dynamics simulations show a highly dynamic pocket in the activated conformation, limiting STD buildup. In contrast, drug binding to this pocket promotes and stabilizes the inactivated states. Our results provide direct experimental evidence showing distinctly different associations between the S4–S5 linker and S6 helix in activated and inactivated states. Specifically, an exchange occurs between interaction partners T140 and N234 of the same subunit in activation, and T140 and N225 of the domain-swapped subunit in slow inactivation. The drug action on slow inactivation of prokaryotic NaV channels seems to have a mechanism similar to the recently proposed “door-wedge” action of the isoleucine-phenylalanine-methionine (IFM) motif on the fast inactivation of eukaryotic NaV channels. Elucidating this gating mechanism points to a possible direction for conformation-dependent drug development.
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Lai, Giacomo, Pierluigi Caboni, Cristina Piras, Massimo Pes, Maria Sitzia, Margherita Addis, Antonio Pirisi, and Paola Scano. "Development and Chemico-Physical Characterization of Ovine Milk-Based Ingredients for Infant Formulae." Applied Sciences 13, no. 1 (January 3, 2023): 653. http://dx.doi.org/10.3390/app13010653.
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The great majority of infant formula (FM) for neonate’s nutrition are produced using ingredients from cow milk. Recently, some countries, such as China and New Zealand, are turning their attention to the use of ovine milk ingredients for FM production. In this study, a pilot plant process has been set up to produce infant formula ingredients from Sarda sheep milk. To meet the nutritional needs of neonates (0–6 and 6–12 months of age) two different liquid milk-derived formulations (IF1 and IF2, respectively) obtained mixing whole milk, skimmed milk, and whey milk ultrafiltration concentrate (retentate) were produced. Compositional analysis of milk, retentate, and the final IFs showed that the two formulations contain elements of nutritional interest, such as well-balanced content of high biological value proteins (casein:whey proteins ratio of 30:70 and 60:40 for IF1 and IF2, respectively), vitamin A, E and B5, cholesterol, minerals, nucleotides, free amino acids and essential fatty acids (n–6:n–3 ~1), compatible with the growth and development needs of neonates. Therefore, the obtained IF1 and IF2 can be proposed as valuable ovine dairy ingredients for FM manufacturing. Further studies will be necessary to verify the adaptability of the developed process from laboratory to industrial scale application.
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Leleu, Xavier, Simona Iacobelli, Alain Barrois, Benjamin Pelle, Liz Clark, Eileen Boyle, Philippe Moreau, et al. "Risk Factors of Thromboembolic Events in Multiple Myeloma Treated with IMiDs-Based Therapy While on LMWH Prophylaxis,." Blood 118, no. 21 (November 18, 2011): 3340. http://dx.doi.org/10.1182/blood.v118.21.3340.3340.
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Abstract Abstract 3340 Background. Immunomodulator drugs (IMiDs) are promising oral agents in Multiple Myeloma (MM); and MM that cannot benefit from novel agents, including IMiDs, only have 9 months survival. On the other hand IMiDs are associated with an increased risk of thromboembolic events (TE) in MM, and must be stopped when TE occurs with a potential shortened life expectancy. Although DVT (Deep Venous Thrombosis), including PE (Pulmonary Embolism), was primarily observed, arterial events were also described. Guidelines have proposed LWMH for VTE prophylaxis for patients that displayed greater than 2 risk factors of VTE. Studies have showed a decrease incidence of TE since a prophylaxis was mandatory; however TE remained despite use of LMWH. We sought to characterize and study the incidence of TE in MM treated with an IMiDs-based regimen and having LMWH as TE prophylaxis, and to determine risk factors for patients to develop TE. Method. MMVAR/IFM 2005–04 is a large multicenter, prospective, randomized, open-label, phase 3, EBMT and IFM combined study that compared VTD to TD for MM patients in first progression after autologous transplantation. Treatment comprised 8 cycles of bortezomib 1.3 mg/m2 IV bolus on days 1, 4, 8 and 11 of a 21-days cycle and then on days 1, 8, 15 and 22 of a 42-days cycle for 4 more cycles. In both arms, oral thalidomide was administered at 200 mg/day for 1 year with dexamethasone at 40 mg/day for 4 days every 3 weeks for 1 year. A TE prophylaxis was mandatory in both arms using enoxaparin 40 mg/day during one year. TTP was the primary end point. Response was assessed by EBMT criteria. Adverse events were graded by the NCI-CTCAE, Version 3.0. Results. The MMVAR trial was stopped because of superiority of VTD over TD at first interim analysis, as 157 relapsed were recorded out of 267 patients randomized in arm VTD (n=135) and arm TD (n=132), respectively. With a median follow-up of 27 months, the probability of achieving CR and CR+PR during the first year, the median TTP and PFS were greater in the VTD arm, although it did not translate into a better OS, yet. In the VTD and TD arms, the mean number of treatment cycles for the 12 cycles was 7.56 vs 9.93, respectively. Treatment was discontinued due to toxicity in 48 patients, including 8 (17%) related to occurrence of TE, and 33 patients died during the treatment period. There were 24 (8.9%) TE recorded, 12 in either arm; we have then decided to pool the 2 groups for the subsequent analysis. The characteristics of the MM with TE were not different from the overall population, 14 male/10 female, median age (range) was 63 (42–76) with 25% patients older than 65. The median (min-max) time from start of MMVAR to occurrence of TE was 3.4 months (0.3–11.9), not different in either arm. TE occurred in 16 (66%) vs. 8 (33%) patients in the first 4 months and after 4 months, respectively. 15 (62.5%) pts had at least some tumor burden reduction (minor response and better) at time of occurrence of TE, while 12.5% had progression of MM, 12.5% stable disease, and 12.5% were non evaluable. All TE occurred while pts were on LMWH prophylaxis since the initiation of the study treatment but one. The occurrence of TE impacted the treatment of MM as 16 (67%) pts did stop their IMiDs-based treatment, either transiently for 8 (33%) pts or definitely for 8 (33%) pts. The doses of the IMiDs were reduced for 5 pts when IMiDs were reintroduced. Overall only 5 pts had no change applied to their MM treatment while TE occurred. The occurrence of TE might have impacted response rate, CR rate, and the survival end points, TTP, PFS and OS. An update of this sub analysis will be presented at ASH with multivariate analysis to determine risk factors for occurrence of TE while on LMWH prophylaxis. Conclusion. Although LMWH is recommended to patients with high risk of TE, the optimal dose and duration of LMWH remains to be determined. More studies are needed to determine risk factors of TE in MM patients treated with IMiDs-based regimen, and to guide physician in their routine practice with the optimal TE prophylaxis. On behalf of the Myeloma Subcommittee of the Chronic Leukemia Working Party of the EBMT (European Group for Blood and Marrow Transplantation) and the IFM (Intergroupe Francophone du Myélome). Disclosures: Leleu: Amgen: Honoraria; Roche: Research Funding; Janssen Cilag: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; LeoPharma: Honoraria, Research Funding; Novartis: Research Funding. Masszi:Centocor Ortho Biotech Research & Development: Research Funding. Hajek:Merck:; Janssen: Honoraria; Celgene: Honoraria.
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Fokkema, Cathelijne, Bronno Van Der Holt, Mark van Duin, Ruth Wester, Tom Cupedo, Philippe Moreau, Jessica Vermeulen, Annemiek Broyl, and Pieter Sonneveld. "Peripheral Neuropathy in the Cassiopeia Study." Blood 136, Supplement 1 (November 5, 2020): 48. http://dx.doi.org/10.1182/blood-2020-137400.
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Introduction Peripheral neuropathy (PNP) remains one of the most common adverse events during multiple myeloma (MM) treatment. The immunomodulatory agent thalidomide and proteasome inhibitor bortezomib are particularly prone to induce PNP (Dimopoulos MA et al., Leukemia., 2010). Both agents are part of standard treatment regimens for newly diagnosed transplant-eligible MM patients. PNP varies from mild symptoms to severe disability, depending on timely dose reduction or discontinuation of treatment. Currently, incidence or severity of PNP cannot be predicted. Therefore, it is of utmost importance to monitor incidence of PNP in different treatment combinations, and in order to identify risk factors for developing PNP. Aims To investigate the incidence of PNP in patients treated in the Cassiopeia trial, to evaluate the role of CD38 antibody (daratumumab) treatment in development of PNP, and to identify risk factors for the development of PNP. Methods We retrospectively analysed incidence of PNP grade 2 to 4, scored according to common terminology criteria for adverse events version 4 (CTCAE) in the Cassiopeia study, a phase III trial conducted by IFM/HOVON, investigating the efficacy of adding daratumumab to bortezomib, thalidomide and dexamethasone (VTD). 1074 newly diagnosed MM patients were randomised. Patients received 4 induction cycles and 2 post transplantation consolidation cycles of 28 days each. Cycles included subcutaneous bortezomib (1.3 mg/m2 days 1,4,8,11), oral thalidomide (100 mg daily), dexamethasone (20-40 mg) and daratumumab intravenously (16 mg/kg and weekly during induction cycles 1 and 2 and once every two weeks during induction cycles 3,4 and consolidation). This trial was registered as ClinicalTrials.gov NCT02541383 and was supported by the French IFM and Dutch HOVON groups (Moreau et al., Lancet, 2019). Multivariate analysis was performed including sex, age, arm, body mass index (BMI), cytogenetics, ISS stage, country, diabetes mellitus (DM), creatinine clearance, liver function, ECOG, baseline PNP and disease characteristics. Results Baseline characteristics in dara-VTD and VTD arms were similar. Overall, 380/1074 (35%) patients developed grade ≥2 PNP and 102/1074 (9%) patients developed grade ≥3 PNP. Multivariate analysis indicated that the cumulative incidence of PNP grade ≥2 was significantly lower in the dara-VTD arm (33%) when compared to the VTD arm (38%) (hazard ratio (HR)=0.73, 95% confidence interval (CI) 0.59-0.91, P=0.004). Furthermore, risk factors associated with a higher cumulative incidence of PNP grade ≥2 included older age (HR=1.03; P=0.020), grade 1 PNP at baseline (HR= 2.75; P= 0.002) and higher BMI (HR=1.46, P=0.003 for BMI 25-30 to HR=2.02, P=0.004 for BMI > 35). Progression free survival (PFS) from the end of induction was similar (86% vs 80% at 2 years, HR = 0.74, 95% CI 0.41-1.33, P=0.32) for patients developing grade ≥2 PNP during induction (179 pts, 17%). An unexpected finding was the difference in cumulative incidence between countries participating in this trial: in the Netherlands 68/141 (49%) of patients developed grade ≥2 PNP, while in France this was 280/846 (33%) and in Belgium 31/87 (36%) (p<0.001). The protocol of the Cassiopeia trial included instructions of discontinuation and dose modification, when PNP grade ≥2 was observed. However, in a subset of patients reaching PNP grade ≥ 2 the (temporary) discontinuation or adjustment of dose as described in the treatment protocol had not been applied (respectively in 148/352 (42%) with PNP ≥ 2 and in 39/97 (40%) with PNP ≥3). Conclusions Despite bortezomib being administered subcutaneously and clear instructions on discontinuation and dose modification, we observed a clinically relevant incidence of grade ≥2 PNP (35%) and grade ≥3 PNP (9%) in patients treated in the Cassiopeia trial. Patients in the dara-VTD arm showed less grade ≥2 PNP, suggesting a possible positive effect of daratumumab. Risk factors for the development of grade ≥2 PNP included older age, PNP at baseline and BMI > 25. Differences in incidence between countries were observed, however no clear explanation was found. Furthermore, standard measures for grading PNP, such as CTCAE criteria, are subject to interpretation bias of both the patient and the treating physician. Continuous screening and correct grading of PNP and strict compliance with guidelines is warranted. Disclosures Moreau: Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Honoraria. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Sonneveld:Sanofi: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.