1,425 research outputs found
A signaling role for dystrophin: Inhibiting skeletal muscle atrophy pathways
SummarySkeletal muscle atrophy is a common comorbidity of cancer. The cellular signaling mechanisms that regulate muscle size constitute a balance of the protein breakdown pathways upregulated during atrophy, and the protein synthesis pathways that are activated during skeletal muscle hypertrophy. In this issue of Cancer Cell, Acharyya et al. demonstrate a new and surprising regulatory axis that is centered around dystrophin, the protein that is mutated in settings of muscular dystrophy. These data reposition dystrophin as a signaling protein and connect an important cellular complex required for the structural integrity of muscle to the pathways that modulate muscle size
Treating cancer cachexia to treat cancer
Skeletal muscle wasting is a major component of cachectic states found in a variety of disease settings, including cancer. As increasing caloric intake often provides little benefit in combating muscle loss in cachectic patients, a major research focus has been to develop strategies stimulating muscle anabolic pathways - in an attempt to fight the catabolic pathways induced during cachexia. Two recent papers have reported the beneficial effects of blocking the myostatin/activin signalling pathway in mouse models of cancer cachexia. We discuss the implications of their findings both with respect to the role that this signalling pathway may play in the aetiology of cachexia and with respect to the prospects for targeting this pathway as a therapeutic strategy in patients with cachexia
Constant light exposure in mice potentiates ethanol consumption and preference and disrupts circadian locomotor activity rhythms
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Validation of machine learning models to detect amyloid pathologies across institutions.
Semi-quantitative scoring schemes like the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) are the most commonly used method in Alzheimer's disease (AD) neuropathology practice. Computational approaches based on machine learning have recently generated quantitative scores for whole slide images (WSIs) that are highly correlated with human derived semi-quantitative scores, such as those of CERAD, for Alzheimer's disease pathology. However, the robustness of such models have yet to be tested in different cohorts. To validate previously published machine learning algorithms using convolutional neural networks (CNNs) and determine if pathological heterogeneity may alter algorithm derived measures, 40 cases from the Goizueta Emory Alzheimer's Disease Center brain bank displaying an array of pathological diagnoses (including AD with and without Lewy body disease (LBD), and / or TDP-43-positive inclusions) and levels of Aβ pathologies were evaluated. Furthermore, to provide deeper phenotyping, amyloid burden in gray matter vs whole tissue were compared, and quantitative CNN scores for both correlated significantly to CERAD-like scores. Quantitative scores also show clear stratification based on AD pathologies with or without additional diagnoses (including LBD and TDP-43 inclusions) vs cases with no significant neurodegeneration (control cases) as well as NIA Reagan scoring criteria. Specifically, the concomitant diagnosis group of AD + TDP-43 showed significantly greater CNN-score for cored plaques than the AD group. Finally, we report that whole tissue computational scores correlate better with CERAD-like categories than focusing on computational scores from a field of view with densest pathology, which is the standard of practice in neuropathological assessment per CERAD guidelines. Together these findings validate and expand CNN models to be robust to cohort variations and provide additional proof-of-concept for future studies to incorporate machine learning algorithms into neuropathological practice
Evolution and Diversity of a Fungal Self/Nonself Recognition Locus
Self/nonself discrimination is an essential feature for pathogen recognition and graft rejection and is a ubiquitous phenomenon in many organisms. Filamentous fungi, such as Neurospora crassa, provide a model for analyses of population genetics/evolution of self/nonself recognition loci due to their haploid nature, small genomes and excellent genetic/genomic resources. In N. crassa, nonself discrimination during vegetative growth is determined by 11 heterokaryon incompatibility (het) loci. Cell fusion between strains that differ in allelic specificity at any of these het loci triggers a rapid programmed cell death response.In this study, we evaluated the evolution, population genetics and selective mechanisms operating at a nonself recognition complex consisting of two closely linked loci, het-c (NCU03493) and pin-c (NCU03494). The genomic position of pin-c next to het-c is unique to Neurospora/Sordaria species, and originated by gene duplication after divergence from other species within the Sordariaceae. The het-c pin-c alleles in N. crassa are in severe linkage disequilibrium and consist of three haplotypes, het-c1/pin-c1, het-c2/pin-c2 and het-c3/pin-c3, which are equally frequent in population samples and exhibit trans-species polymorphisms. The absence of recombinant haplotypes is correlated with divergence of the het-c/pin-c intergenic sequence. Tests for positive and balancing selection at het-c and pin-c support the conclusion that both of these loci are under non-neutral balancing selection; other regions of both genes appear to be under positive selection. Our data show that the het-c2/pin-c2 haplotype emerged by a recombination event between the het-c1/pin-c1 and het-c3/pin-c3 approximately 3-12 million years ago.These results support models by which loci that confer nonself discrimination form by the association of polymorphic genes with genes containing HET domains. Distinct allele classes can emerge by recombination and positive selection and are subsequently maintained by balancing selection and divergence of intergenic sequence resulting in recombination blocks between haplotypes
Start Up of a Nb-1%Zr Potassium Heat Pipe From the Frozen State
The start up of a liquid metal heat pipe from the frozen state was evaluated experimentally with a Nb-1%Zr heat pipe with potassium as the working fluid. The heat pipe was fabricated and tested at Los Alamos National Laboratory. RF induction heating was used to heat 13 cm of the 1-m-long heat pipe. The heat pipe and test conditions are well characterized so that the test data may be used for comparison with numerical analyses. An attempt was made during steady state tests to calibrate the heat input so that the heat input would be known during the transient cases. The heat pipe was heated to 675 C with a throughput of 600 W and an input heat flux of 6 W/cm(exp 2). Steady state tests, start up from the frozen state, and transient variations from steady state were performed
Fabrication and Testing of Mo-Re Heat Pipes Embedded in Carbon/Carbon
Refractory-composite/heat-pipe-cooled wing an tail leading edges are being considered for use on hypersonic vehicles to limit maximum temperatures to values below material reuse limits and to eliminate the need to actively cool the leading edges. The development of a refractory-composite/heat-pipe-cooled leading edge has evolved from the design stage to the fabrication and testing of heat pipes embedded in carbon/carbon (C/C). A three-foot-long, molybdenum-rhenium heat pipe with a lithium working fluid was fabricated and tested at an operating temperature of 2460 F to verify the individual heat-pipe design. Following the fabrication of this heat pipe, three additional heat pipes were fabricated and embedded in C/C. The C/C heat-pipe test article was successfully tested using quartz lamps in a vacuum chamber in both a horizontal and vertical orientation. Start up and steady state data are presented for the C/C heat-pipe test article. Radiography and eddy current evaluations were performed on the test article
Development and validation of a bovine macrophage specific cDNA microarray
BACKGROUND: The response of macrophages to danger signals is an important early stage in the immune response. Our understanding of this complex event has been furthered by microarray analysis, which allows the simultaneous investigation of the expression of large numbers of genes. However, the microarray resources available to study these events in livestock animals are limited. RESULTS: Here we report the development of a bovine macrophage specific (BoMP) cDNA microarray. The BoMP microarray contains 5026 sequence elements (printed in duplicate) and numerous controls. The majority of the clones incorporated on the microarray were derived from the BoMP cDNA library generated from bovine myeloid cells subjected to various stimuli, including over 900 sequences unique to the library. Additional clones representing immunologically important genes have been included on the BoMP microarray. The microarray was validated by investigating the response of bovine monocytes to stimulation with interferon-γ and lipopolysaccharide using amplified RNA. At 2 and 16 hours post stimulation 695 genes exhibited statistically significant differential expression, including; 26 sequences unique to the BoMP library, interleukin 6, prion protein and toll-like receptor 4. CONCLUSION: A 5 K cDNA microarray has been successfully developed to investigate gene expression in bovine myeloid cells. The BoMP microarray is available from the ARK-Genomics Centre for Functional Genomics in Farm Animals, UK
Transpiration-Cooled Spacecraft-Insulation-Repair Fasteners
Transpiration-cooled fasteners are proposed that operate like an open-loop heat pipe (self-tapping screws, bolts, and spikes) for use in on-orbit repair of thermal- insulation of a space shuttle or other spacecraft. By limiting the temperature rise of such a fastener and of the adjacent repair material and thermal protection system, the transpiration cooling would contribute to the ability of the repair to retain its strength and integrity in the high-heat-flux, oxidizing environment of reentry into the atmosphere of the Earth. A typical fastener according to the proposal would include a hollow refractory-metal, refractory-composite, or ceramic screw or bolt, the central cavity of which would be occupied by a porous refractory- metal or ceramic plug that would act as both a reservoir and a wick for a transpirant liquid. The plug dimensions, the plug material, and the sizes of the pores would be chosen in conjunction with the transpirant liquid so that (1) capillary pumping could be relied upon to transport the liquid to the heated surface, where the liquid would be vaporized, and (2) the amount of liquid would suffice for protecting against the anticipated heat flux and integrated heat load
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