Human coronaviruses (HCoVs) are recognized respiratory pathogens for which accumulating evidence indicates that in vulnerable patients the infection can cause more severe pathologies. HCoVs are not ...always confined to the upper respiratory tract and can invade the central nervous system (CNS) under still unclear circumstances. HCoV-induced neuropathologies in humans are difficult to diagnose early enough to allow therapeutic interventions. Making use of our already described animal model of HCoV neuropathogenesis, we describe the route of neuropropagation from the nasal cavity to the olfactory bulb and piriform cortex and then the brain stem. We identified neuron-to-neuron propagation as one underlying mode of virus spreading in cell culture. Our data demonstrate that both passive diffusion of released viral particles and axonal transport are valid propagation strategies used by the virus. We describe for the first time the presence along axons of viral platforms whose static dynamism is reminiscent of viral assembly sites. We further reveal that HCoV OC43 modes of propagation can be modulated by selected HCoV OC43 proteins and axonal transport. Our work, therefore, identifies processes that may govern the severity and nature of HCoV OC43 neuropathogenesis and will make possible the development of therapeutic strategies to prevent occurrences.
Coronaviruses may invade the CNS, disseminate, and participate in the induction of neurological diseases. Their neuropathogenicity is being increasingly recognized in humans, and the presence and persistence of human coronaviruses (HCoV) in human brains have been proposed to cause long-term sequelae. Using our mouse model relying on natural susceptibility to HCoV OC43 and neuronal cell cultures, we have defined the most relevant path taken by HCoV OC43 to access and spread to and within the CNS toward the brain stem and spinal cord and studied in cell culture the underlying modes of intercellular propagation to better understand its neuropathogenesis. Our data suggest that axonal transport governs HCoV OC43 egress in the CNS, leading to the exacerbation of neuropathogenesis. Exploiting knowledge on neuroinvasion and dissemination will enhance our ability to control viral infection within the CNS, as it will shed light on underlying mechanisms of neuropathogenesis and uncover potential druggable molecular virus-host interfaces.
There has been no subsequent meta-analysis examining the effects of long working hours on health or occupational health since 1997. Therefore, this paper aims to conduct a meta-analysis covering ...studies after 1997 for a comparison. A total of 243 published records were extracted from electronic databases. The effects were measured by five conditions, namely, physiological health (PH), mental health (MH), health behaviours (HB), related health (RH), and nonspecified health (NH). The overall odds ratio between long working hours and occupational health was 1.245 (95% confidence interval (CI): 1.195-1.298). The condition of related health constituted the highest odds ratio value (1.465, 95% CI: 1.332-1.611). The potential moderators were study method, cut-point for long weekly working hours, and country of origin. Long working hours were shown to adversely affect the occupational health of workers. The management on safeguarding the occupational health of workers working long hours should be reinforced.
The risk of osteoporotic fracture with dabigatran use in patients with nonvalvular atrial fibrillation (NVAF) is unknown.
To investigate the risk of osteoporotic fracture with dabigatran vs warfarin ...in patients with NVAF.
Retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with NVAF from 2010 through 2014 and prescribed dabigatran or warfarin were matched by propensity score at a 1:2 ratio with follow-up until July 31, 2016.
Dabigatran or warfarin use during the study period.
Risk of osteoporotic hip fracture and vertebral fracture was compared between dabigatran and warfarin users using Poisson regression. The corresponding incidence rate ratio (IRR) and absolute risk difference (ARD) with 95% CIs were calculated.
Among 51 496 patients newly diagnosed with NVAF, 8152 new users of dabigatran (n = 3268) and warfarin (n = 4884) were matched by propensity score (50% women; mean SD age, 74 11 years). Osteoporotic fracture developed in 104 (1.3%) patients during follow-up (32 dabigatran users 1.0%; 72 warfarin users 1.5%). Results of Poisson regression analysis showed that dabigatran use was associated with a significantly lower risk of osteoporotic fracture compared with warfarin (0.7 vs 1.1 per 100 person-years; ARD per 100 person-years, -0.68 95% CI, -0.38 to -0.86; IRR, 0.38 95% CI, 0.22 to 0.66). The association with lower risk was statistically significant in patients with a history of falls, fractures, or both (dabigatran vs warfarin, 1.6 vs 3.6 per 100 person-years; ARD per 100 person-years, -3.15 95% CI, -2.40 to -3.45; IRR, 0.12 95% CI, 0.04 to 0.33), but not in those without a history (0.6 vs 0.7 per 100 person-years; ARD per 100 person-years, -0.04 95% CI, 0.67 to -0.39; IRR, 0.95 95% CI, 0.45 to 1.96) (P value for interaction, <.001).
Among adults with NVAF receiving anticoagulation, the use of dabigatran compared with warfarin was associated with a lower risk of osteoporotic fracture. Additional study, perhaps including randomized clinical trials, may be warranted to further understand the relationship between use of dabigatran vs warfarin and risk of fracture.
RNA viruses are characterized by a high mutation rate, a buffer against environmental change. Nevertheless, the means by which random mutation improves viral fitness is not well characterized. Here ...we report the X-ray crystal structure of the receptor-binding domain (RBD) of the human coronavirus, HCoV-229E, in complex with the ectodomain of its receptor, aminopeptidase N (APN). Three extended loops are solely responsible for receptor binding and the evolution of HCoV-229E and its close relatives is accompanied by changing loop-receptor interactions. Phylogenetic analysis shows that the natural HCoV-229E receptor-binding loop variation observed defines six RBD classes whose viruses have successively replaced each other in the human population over the past 50 years. These RBD classes differ in their affinity for APN and their ability to bind an HCoV-229E neutralizing antibody. Together, our results provide a model for alphacoronavirus adaptation and evolution based on the use of extended loops for receptor binding.
Human aminopeptidase N (hAPN/hCD13) is a dimeric membrane protein and a member of the M1 family of zinc metallopeptidases. Within the rennin-angiotensin system, its enzymatic activity is responsible ...for processing peptide hormones angiotensin III and IV. In addition, hAPN is also involved in cell adhesion, endocytosis, and signal transduction and it is an important target for cancer therapy. Reported here are the high resolution x-ray crystal structures of the dimeric ectodomain of hAPN and its complexes with angiotensin IV and the peptidomimetic inhibitors, amastatin and bestatin. Each monomer of the dimer is found in what has been termed the closed form in other M1 enzymes and each monomer is characterized by an internal cavity surrounding the catalytic site as well as a unique substrate/inhibitor-dependent loop ordering, which in the case of the bestatin complex suggests a new route to inhibitor design. The hAPN structure provides the first example of a dimeric M1 family member and the observed structural features, in conjunction with a model for the open form, provide novel insights into the mechanism of peptide processing and signal transduction.
Background: Human aminopeptidase N (hAPN) is a dimeric cell surface protease involved in peptide processing, cell adhesion, endocytosis, and signal transduction.
Results: Crystal structures of peptide and inhibitor complexes were determined.
Conclusion: Unlike other family members, hAPN shows substrate-dependent loop ordering and a novel dimer structure.
Significance: A model for catalysis and conformational changes provides mechanistic insights into how hAPN mediates its functional roles.
The UK Biobank genotyped about 500k participants using Applied Biosystems Axiom microarrays. Participants were subsequently sequenced by the UK Biobank Exome Sequencing Consortium. Axiom genotyping ...was highly accurate in comparison to sequencing results, for almost 100,000 variants both directly genotyped on the UK Biobank Axiom array and via whole exome sequencing. However, in a study using the exome sequencing results of the first 50k individuals as reference (truth), it was observed that the positive predictive value (PPV) decreased along with the number of heterozygous array calls per variant. We developed a novel addition to the genotyping algorithm, Rare Heterozygous Adjusted (RHA), to significantly improve PPV in variants with minor allele frequency below 0.01%. The improvement in PPV was roughly equal when comparing to the exome sequencing of 50k individuals, or to the more recent ~200k individuals. Sensitivity was higher in the 200k data. The improved calling algorithm, along with enhanced quality control of array probesets, significantly improved the positive predictive value and the sensitivity of array data, making it suitable for the detection of ultra-rare variants.
The intracellular progesterone receptor links the reproductive and immune systems via regulation of CD4+ T cells.
Pg has distinct immunomodulatory properties involved in poorly understood immune ...phenomena, including maternal tolerance of the fetus, increased risk of certain infections during pregnancy or after Pg birth control, and pregnancy‐associated remission of autoimmune disease. Several potential mechanisms have been identified, including alteration of Th1 and Treg activity, but the precise cellular and molecular targets of Pg immunomodulation in vivo remain obscure, partly because Pg can signal through several different receptor types. One such receptor, the iPR, encoded by the pgr gene, is essential for reproduction in female mice and is expressed in the thymus and CD4+ T cells. We hypothesized that iPR regulates CD4+ T cell activity and adaptive immune responses in vivo. With the use of iPR KO mice, we demonstrate that iPR specifically suppresses TD antibody responses, primarily by dampening CD4+ Teff activity, likely via transcriptional repression of the IFN‐γ gene and modulation of other programs regulating CD4+ T cells. Our results highlight a novel mechanism linking the endocrine and immune systems, and they offer insight into important but poorly understood phenomena in womenˈs health and autoimmunity.
Lipid emulsion infusion reverses cardiac toxicity of local anesthetics. The predominant effect is likely creation of a "lipid sink." This in vitro study determined the extent to which Intralipid® ...(Fresenius Kabi, Uppsala, Sweden) and Lipofundin® (B. Braun Melsungen AG, Melsungen, Germany) sequester anesthetics from serum, and whether it varies with pH.
Bupivacaine, ropivacaine, and mepivacaine were added to human drug-free serum (pH 7.4) at 10 μg/ml. The lipid emulsions were added, and the mixture shaken and incubated at 37°C. Lipid was removed by ultracentrifugation and drug remaining in the serum measured. Additional experiments were performed using 100 μg/ml bupivacaine and at pH 6.9.
Lipofundin® extracted all three anesthetics to a greater extent than Intralipid® (34.7% vs..22.3% for bupivacaine, 25.8% vs..16.5% for ropivacaine, and 7.3% vs..4.7% for mepivacaine). By increasing either concentration of bupivacaine or lipid, there was an increase in drug extraction from serum. Adjusting the pH to 6.9 had no statistically significant effect on the percentage of bupivacaine sequestered.
Bupivacaine, ropivacaine, and mepivacaine were sequestered to an extent consistent with their octanol:water partition constants (logP). In contrast with previous studies of extraction of lipids from buffer solutions, an emulsion containing 50% each of medium- and long-chain triglycerides extracted local anesthetics to a greater extent from human serum than one containing exclusively long-chain triglycerides, calling into question recent advanced cardiac life support guidelines for resuscitation from anesthetic toxicity that specify use of a long-chain triglyceride. The current data also do not support recent recommendations to delay administration until pH is normalized.
•Factors that affect risk-taking behaviors of construction workers are identified.•A grounded theory model for risk-taking behaviors of construction workers is proposed.•Recommendations for reducing ...the risk-taking behaviors are provided.
A qualitative approach was employed to explore the attitudes and experiences of construction workers toward risk-taking behaviors and to identify the underlying reasons that may explain why construction workers take or do not take risks at work. Forty face-to-face individual interviews with construction workers were conducted. NVivo software was utilized to analyze the qualitative data. The data were categorized using grounded theory techniques and a three-stage coding approach. The grounded theory model that was established shows that risk-taking behavior was affected by factors in three contexts, namely, personal, behavioral, and environmental contexts. The findings of this study provide useful recommendations to reduce the risk-taking behaviors of construction workers, which include meeting the expectations of construction workers and optimizing benefits, such as convenience, work effectiveness, physical comfort, safety training that emphasizes on the unfavorable consequences of risk-taking behaviors, close safety supervision, safety fines, safety incentives, and time-sufficient work schedule.
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