Simian immunodeficiency viruses of sooty mangabeys (SIVsm) are the source of multiple, successful cross-species transmissions, having given rise to HIV-2 in humans, SIVmac in rhesus macaques, and ...SIVstm in stump-tailed macaques. Cellular assays and phylogenetic comparisons indirectly support a role for TRIM5alpha, the product of the TRIM5 gene, in suppressing interspecies transmission and emergence of retroviruses in nature. Here, we investigate the in vivo role of TRIM5 directly, focusing on transmission of primate immunodeficiency viruses between outbred primate hosts. Specifically, we retrospectively analyzed experimental cross-species transmission of SIVsm in two cohorts of rhesus macaques and found a significant effect of TRIM5 genotype on viral replication levels. The effect was especially pronounced in a cohort of animals infected with SIVsmE543-3, where TRIM5 genotype correlated with approximately 100-fold to 1,000-fold differences in viral replication levels. Surprisingly, transmission occurred even in individuals bearing restrictive TRIM5 genotypes, resulting in attenuation of replication rather than an outright block to infection. In cell-culture assays, the same TRIM5 alleles associated with viral suppression in vivo blocked infectivity of two SIVsm strains, but not the macaque-adapted strain SIVmac239. Adaptations appeared in the viral capsid in animals with restrictive TRIM5 genotypes, and similar adaptations coincide with emergence of SIVmac in captive macaques in the 1970s. Thus, host TRIM5 can suppress viral replication in vivo, exerting selective pressure during the initial stages of cross-species transmission.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Type-III CRISPR-Cas systems have recently been adopted for sequence-specific detection of SARS-CoV-2. Here, we repurpose the type III-A CRISPR complex from Thermus thermophilus (TtCsm) for ...programmable capture and concentration of specific RNAs from complex mixtures. The target bound TtCsm complex generates two cyclic oligoadenylates (i.e., cA
and cA
) that allosterically activate ancillary nucleases. We show that both Can1 and Can2 nucleases cleave single-stranded RNA, single-stranded DNA, and double-stranded DNA in the presence of cA
. We integrate the Can2 nuclease with type III-A RNA capture and concentration for direct detection of SARS-CoV-2 RNA in nasopharyngeal swabs with 15 fM sensitivity. Collectively, this work demonstrates how type-III CRISPR-based RNA capture and concentration simultaneously increases sensitivity, limits time to result, lowers cost of the assay, eliminates solvents used for RNA extraction, and reduces sample handling.
Long-standing clinical findings report a dramatic surge of vasopressin in umbilical cord blood of the human neonate, but the neural underpinnings and function(s) of this phenomenon remain obscure. We ...studied neural activation in perinatal mice and rats, and found that birth triggers activation of the suprachiasmatic, supraoptic, and paraventricular nuclei of the hypothalamus. This was seen whether mice were born vaginally or via Cesarean section (C-section), and when birth timing was experimentally manipulated. Neuronal phenotyping showed that the activated neurons were predominantly vasopressinergic, and vasopressin mRNA increased fivefold in the hypothalamus during the 2-3 days before birth. Copeptin, a surrogate marker of vasopressin, was elevated 30-to 50-fold in plasma of perinatal mice, with higher levels after a vaginal than a C-section birth. We also found an acute decrease in plasma osmolality after a vaginal, but not C-section birth, suggesting that the difference in vasopressin release between birth modes is functionally meaningful. When vasopressin was administered centrally to newborns, we found an ~ 50% reduction in neuronal cell death in specific brain areas. Collectively, our results identify a conserved neuroendocrine response to birth that is sensitive to birth mode, and influences peripheral physiology and neurodevelopment.
Neural plasticity plays a critical role in learning, memory, and recovery from injury to the nervous system. Although much is known about the physical and physiological determinants of plasticity, ...little is known about the influence of cognitive factors. In this study, we investigated whether selective attention plays a role in modifying changes in neural excitability reflecting long-term potentiation (LTP)-like plasticity. We induced LTP-like effects in the hand area of the human motor cortex using transcranial magnetic stimulation (TMS). During the induction of plasticity, participants engaged in a visual detection task with either low or high attentional demands. Changes in neural excitability were assessed by measuring motor-evoked potentials in a small hand muscle before and after the TMS procedures. In separate experiments plasticity was induced either by paired associative stimulation (PAS) or intermittent theta-burst stimulation (iTBS). Because these procedures induce different forms of LTP-like effects, they allowed us to investigate the generality of any attentional influence on plasticity. In both experiments reliable changes in motor cortex excitability were evident under low-load conditions, but this effect was eliminated under high-attentional load. In a third experiment we investigated whether the attentional task was associated with ongoing changes in the excitability of motor cortex, but found no difference in evoked potentials across the levels of attentional load. Our findings indicate that in addition to their role in modifying sensory processing, mechanisms of attention can also be a potent modulator of cortical plasticity.
Adaptive expertise represents the combination of both efficient problem-solving for clinical encounters with known solutions, as well as the ability to learn and innovate when faced with a novel ...challenge. Fostering adaptive expertise requires careful approaches to instructional design to emphasize deeper, more effortful learning. These teaching strategies are time-intensive, effortful, and challenging to implement in health professions education curricula. The authors are educators whose missions encompass the medical education continuum, from undergraduate through to organizational learning. Each has grappled with how to promote adaptive expertise development in their context. They describe themes drawn from educational experiences at these various learner levels to illustrate strategies that may be used to cultivate adaptive expertise.
At Vanderbilt University School of Medicine, a restructuring of the medical school curriculum provided multiple opportunities to use specific curricular strategies to foster adaptive expertise development. The advantage for students in terms of future learning had to be rationalized against assessments that are more short-term in nature. In a consortium of emergency medicine residency programs, a diversity of instructional approaches was deployed to foster adaptive expertise within complex clinical learning environments. Here the value of adaptive expertise approaches must be balanced with the efficiency imperative in clinical care. At Mayo Clinic, an existing continuous professional development program was used to orient the entire organization towards an adaptive expertise mindset, with each individual making a contribution to the shift.
The different contexts illustrate both the flexibility of the adaptive expertise conceptualization and the need to customize the educational approach to the developmental stage of the learner. In particular, an important benefit of teaching to adaptive expertise is the opportunity to influence individual professional identity formation to ensure that clinicians of the future value deeper, more effortful learning strategies throughout their careers.
Organisational scientists are paying increasing attention to humility, following a larger trend in scholarship highlighting the relational and interdependent nature of leadership and business. A ...growing body of evidence identifies humility as vital to effective organisational leadership, facilitating positive organisational outcomes, such as lower voluntary turnover and greater follower job satisfaction. To date, research on the subject has focused on certain specific organisational contexts, including businesses, hospitals, and schools. This paper reviews the existing literature and explores why humility may be an especially important leader trait in international humanitarian aid organisations and relief work—a context that is not only uniquely challenging, but also one that would seemingly stand to benefit keenly from the quality. It argues that humility is essential for effective leadership because it is normative of good character, it is predictive of positive outcomes, and it corresponds to a genuine representation of the nature of humanitarian aid.
Abstract Objective To estimate the prevalence of gestational diabetes mellitus (GDM) prevalence estimates for subgroups of US Asian and Pacific Islander (API) women by using data from 2005 and 2006 ...birth certificates. Methods Using 2005–2006 natality files from states that implemented the revised 2003 US birth certificate, which differentiates between GDM and preexisting diabetes (2005: 12 states; 2006: 19 states), we calculated age-adjusted GDM prevalence estimates for API mothers who delivered singleton infants. Results Among 3,108,877 births, US APIs had a substantially higher age-adjusted prevalence of GDM (6.3%) than whites (3.8%), blacks (3.5%), or Hispanics (3.6%). Among API subgroups, age-adjusted GDM prevalence varied significantly, from 3.7% among women of Japanese descent to 8.6% among women of Asian Indian descent. Foreign-born APIs had significantly higher GDM rates than US-born APIs except among women of Japanese and Korean ancestry. Conclusion Overall, US API women have the highest risk for GDM among all US racial/ethnic groups. However, APIs are a heterogeneous group by genetic background, culture, and diet and other lifestyle behaviors. Our findings imply that, whenever possible, API subgroups should be evaluated separately in health research.
Late Preterm Birth and Risk of Developing Asthma Abe, Karon, PhD; Shapiro-Mendoza, Carrie K., PhD, MPH; Hall, Laura R., MPH ...
The Journal of pediatrics,
07/2010, Letnik:
157, Številka:
1
Journal Article
Recenzirano
Objective To evaluate the association between gestational age at birth (late preterm vs term) and risk for physician-diagnosed asthma. Study design We conducted a retrospective cohort study using the ...Third National Health and Nutrition Examination Survey (1988-1994) linked natality files. The study included children age 2-83 months from singleton births, born late preterm (n = 537) or term (n = 5650). Using survival analysis, we modeled time to diagnosis of asthma; children with no asthma diagnosis were censored at the age of their survey interview. We used Cox proportional hazard regression to estimate hazard ratios and 95% confidence intervals for gestational age and asthma risk, adjusting for maternal age, maternal education, parental history of asthma/hay fever, maternal smoking history during pregnancy, race/ethnicity, and sex of the child. Results Adjusted analysis showed that physician-diagnosed asthma was modestly associated with late preterm birth (hazard ratio, 1.3; 95% confidence interval, 0.8-2.0), but this association was not statistically significant ( P = .30). Conclusions Our study found that late preterm birth was not associated with a diagnosis of asthma in early childhood.
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