To survive, cells must respond to changing environmental conditions. One way that eukaryotic cells react to harsh stimuli is by forming physiological, RNA-seeded subnuclear condensates, termed ...amyloid bodies (A-bodies). The molecular constituents of A-bodies induced by different stressors vary significantly, suggesting this pathway can tailor the cellular response by selectively aggregating a subset of proteins under a given condition. Here, we identify critical structural elements that regulate heat shock-specific amyloid aggregation. Our data demonstrates that manipulating structural pockets in constituent proteins can either induce or restrict their A-body targeting at elevated temperatures. We propose a model where selective aggregation within A-bodies is mediated by the thermal stability of a protein, with temperature-sensitive structural regions acting as an intrinsic form of post-translational regulation. This system would provide cells with a rapid and stress-specific response mechanism, to tightly control physiological amyloid aggregation or other cellular stress response pathways.
Peripheral nerves (PNs) are frequently injured as a result of trauma or disease. Development of therapies to regenerate PNs requires the use of animal models, typically beginning in rodents and ...progressing to larger species. There are several large animal models of PN regeneration that each has their benefits and drawbacks. Sheep have been used in PN studies due to their similarities in body weight to humans and the ease and lesser expense in their care and housing relative to other species. We have investigated the use of sheep for studies of PN regeneration and have developed and tested an injury model in the peroneal branch of the sciatic nerve. Three experimental groups were tested on mature sheep: a bisection; a 5‐cm reverse autograft; and sham surgery. Protocols were developed for the post‐operative care for animals with this injury, and regeneration was tracked for extended time points via compound muscle action potentials (CMAPs) and endpoint assessments of nerve morphometry, muscle mass and muscle fibrosis. Results indicate the practical viability of this PN injury model and show distinctions in the degree and rate of regeneration between bisection and reverse autograft that persisted 14 months. This long‐term study shows bisections lead to significantly improved CMAPS and muscle mass and lesser muscle fibrosis as compared to reverse autograft. The persistence of these discernable changes between two relatively similar experimental groups out to extended time points is an indication of the sensitivity of this nerve section and its potential applicability for comparative studies.
Development of therapies to regenerate peripheral nerves (PN) requires the use of animal models, typically beginning in rodents and progressing to larger species. In the present study, we have investigated the use of sheep for studies of PN regeneration and have developed and tested an injury model in the peroneal branch of the sciatic nerve in a long term study (14 months).
More than a quarter of a million individuals in the US live with spinal cord injury (SCI). SCI disrupts neural circuitry to vital organs in the body. Despite severe incidences of long-term peripheral ...complications from SCI, the cardio-metabolic consequences and divergences in sex-related responses are not well described. We examined the effects of SCI on functional recovery, cardiac structure and function, body composition, and glucose metabolism on adult female and male Sprague Dawley (SD) rats. SCI was induced at T10 via contusion. Measured outcomes include behavioral assessment, body weight, dual-energy X-ray absorptiometry (DEXA) for body composition, echocardiography for cardiac structure and function, intraperitoneal glucose tolerance test (IPGTT) for glucose metabolism, insulin tolerance test (ITT), and histology of cardiac structure at the endpoint. There was a decrease in body fat percentage in both sexes, with SCI females disproportionately affected in percent body fat change. Left ventricular internal diameter during systole (LVIDs) was decreased in SCI females more than in SCI males. No significant differences in glucose metabolism were observed up to 20 weeks post-injury (PI). These data show significant cardio-metabolic differences as a consequence of SCI and, furthermore, that sex is an underlying factor in these differences.
OBJECTIVE:To interrogate a poly-T variant (rs10524523, ′523) in TOMM40, a gene adjacent to the APOE gene on chromosome 19, in older persons with APOE ε3/3 homozygosity for association with cognitive ...decline, the clinical hallmark of Alzheimer disease (AD).
METHODS:Data came from participants in 2 cohort studies of aging and dementia who underwent annual clinical evaluations for up to 21 years. APOE and TOMM40′523 genotypes were determined from DNA from blood or brain samples. Linear mixed models compared the rates of decline in cognition among APOE ε3/3 carriers with different ′523 genotypes.
RESULTS:The 1,170 APOE ε3/3 homozygotes were of European ancestry, were free of dementia at baseline, and had an average age of 78.5 years at baseline. Three major genotypes at the ′523 variant were linked to APOE ε3/3; 26.5% had 2 short poly-Ts (S/S), 48.5% had 1 short and 1 very long poly-T (S/VL), and 24.0% had 2 very long poly-Ts (VL/VL). Participants with ʼ523-S/S had faster decline in global cognition than participants with ʼ523-S/VL or VL/VL (p = 0.002). The same association was observed for episodic memory (p < 0.001) and semantic memory (p = 0.003) but not for working memory, perceptual speed, or visuospatial ability.
CONCLUSIONS:Our data reveal an association of APOE ε3/3-TOMM40′523 haplotypes with cognitive decline in community-based older persons such that the S/S poly-T genotype is related to faster cognitive decline, primarily in the domains of episodic and semantic memory.
Abnormal coagulation and inflammation are hallmarks of SARs-COV-19. Stratifying affected patients on admission to hospital may help identify those who at are risk of developing severe disease early ...on. Rotational Thromboelastometry (ROTEM) is a point of care test that can be used to measure abnormal coagulation and calprotectin is a measure of inflammation.
Assess if ROTEM can measure hypercoagulability on admission and identify those who will develop severe disease early on. Assess if calprotectin can measure inflammation and if there is a correlation with ROTEM and calprotectin.
COVID-19 patients were recruited on admission and ROTEM testing was undertaken daily for a period of 7 days. Additionally inflammatory marker calprotectin was also tested for the same period.
33 patients were recruited to the study out of which 13 were admitted to ITU and 20 were treated on the ward. ROTEM detected a hypercoagulable state on admission but did not stratify between those admitted to a ward or escalated to ITU. Calprotectin levels were raised but there was no statistical difference (p = 0.73) between patients admitted to a ward or escalated to ITU. Significant correlations were observed between FIBA5 (r = 0.62; p<0.00), FIBCFT (r = -0.57; p<0.00), FIBMCF (r = 0.64; p<0.00) and INMCF (r = 0.57; p<0.00) and calprotectin.
COVID-19 patients were hypercoagulable on admission. The correlations between ROTEM and calprotectin underline the interactions between inflammation and coagulation.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Contemporary transcatheter and minimally invasive approaches allow for improved cosmesis and eliminate sternotomy; however, access to a 'Heart Team' approach to minimally invasive atrial septal ...defect (ASD) repair remains limited in Canada.
Retrospective chart review of all minimally invasive atrial septal defect repairs performed between 2009 and 2017 at a quaternary cardiac care centre were included. We compared residual shunt, functional status, periprocedural complications, and hospital lengths-of-stay between patients undergoing transcatheter and minimally invasive endoscopic ASD repair.
Between 2009 and 2017, 61 consecutive patients underwent ASD repair at a single centre: 28 patients underwent transcatheter closure (64.3% female; median age 57, interquartile range 43-70.5) and 33 patients underwent minimally invasive endoscopic repair (72.7% female; median age 37, interquartile range 24-50). Patient demographics were similar between the two groups with the exception of transcatheter patients having smaller defect size (1.65 cm versus 2.35 cm, p = 0.002). Procedural success was 93% (26/28) and 100% (33/33) for transcatheter and minimally invasive groups (p = 0.21), respectively. Periprocedural complications were similarly low between the two groups with the exception of longer hospital length-of-stay in the surgical patients (5 days vs 1 day, p < 0.0001). Over a follow-up period (transcatheter: 0.5-56.5 months, surgical: 0.25-89 months), there was no difference in residual shunt (14.3% versus 6.1%, p = 0.4) or NYHA I Functional Class (88.5% versus 96.9%, p = 0.21).
Transcatheter and minimally invasive approaches to ASD repair are safe and feasible in selected patients using a 'Heart Team' approach and represent attractive alternatives to median sternotomy.
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