Genetic Effects on Bone Loss in Peri- and Postmenopausal Women: A Longitudinal Twin Study

This longitudinal twin study was designed to assess the heritability of bone loss in peri- and postmenopausal women. A sample of 724 female twins was studied. Baseline and repeat BMD measurements were performed. Results of genetic model-fitting analysis indicated genetic effects on bone loss account for similar to 40% of the between-individual variation in bone loss at the lumbar spine, forearm, and whole body. Introduction: BMD and bone loss are important predictors of fracture risk. Although the heritability of peak BMD is well documented, it is not clear whether bone loss is also under genetic regulation. This study was designed to assess the heritability of bone loss in peri- and postmenopausal women. Materials and Methods: A sample of 724 female twins (177 monozygotic [MZ] and 185 dizygotic [DZ] pairs), 45-82 yr of age, was studied. Each individual had baseline BMD measurements at the lumbar spine, hip, forearm, and total body by DXA and at least one repeat measure, on average 4.9 yr later. Change in BMD (Delta BMD) was expressed as percent of gain or loss per year. Intraclass correlation coefficients for ABMD were calculated for MZ and DZ pairs. Genetic model-fitting analysis was conducted to partition the total variance of ABMD into three components: genetic (G), common environment (C), and specific environment, including measurement error (E). The index of heritability was estimated as the ratio of genetic variance over total variance. Results: The mean annual Delta BMD was -0.37 +/- 1.43% (SD) per year at the lumbar spine, -0.27 +/- 1.32% at the total hip, -0.77 +/- 1.66% at the total forearm, -0.36 +/- 56% at the femoral neck, and -0.16 +/- 0.81% at the whole body. Intraclass correlation coefficients were significantly higher in MZ than in DZ twins for all studied parameters, except at the hip sites. Results of genetic model-fitting analysis indicated that the indices of heritability for ABMD were 0.38, 0.49, and 0.44 for the lumbar spine, total forearm, and whole body, respectively. However, the genetic effect on ABMD at all hip sites was not significant. Conclusions: These data suggest that, although genetic effects on bone loss with aging are less pronounced than on peak bone mass, they still account for similar to 40% of the between-individual variation in bone loss for the lumbar spine, total forearm, and whole body in peri- and postmenopausal women. These findings are relevant for studies aimed at identification of genes that are involved in the regulation of bone loss

Magnetic torque anomaly in the quantum limit of Weyl semimetals

Electrons in materials with linear dispersion behave as massless Weyl- or Dirac-quasiparticles, and continue to intrigue due to their close resemblance to elusive ultra-relativistic particles as well as their potential for future electronics. Yet the experimental signatures of Weyl-fermions are often subtle and indirect, in particular if they coexist with conventional, massive quasiparticles. Here we show a pronounced anomaly in the magnetic torque of the Weyl semimetal NbAs upon entering the quantum limit state in high magnetic fields. The torque changes sign in the quantum limit, signalling a reversal of the magnetic anisotropy that can be directly attributed to the topological nature of the Weyl electrons. Our results establish that anomalous quantum limit torque measurements provide a direct experimental method to identify and distinguish Weyl and Dirac systems

Environmental and Demographic Determinants of Avian Influenza Viruses in Waterfowl across the Contiguous United States

Outbreaks of avian influenza in North American poultry have been linked to wild waterfowl. A first step towards understanding where and when avian influenza viruses might emerge from North American waterfowl is to identify environmental and demographic determinants of infection in their populations. Laboratory studies indicate water temperature as one determinant of environmental viral persistence and we explored this hypothesis at the landscape scale. We also hypothesized that the interval apparent prevalence in ducks within a local watershed during the overwintering season would influence infection probabilities during the following breeding season within the same local watershed. Using avian influenza virus surveillance data collected from 19,965 wild waterfowl across the contiguous United States between October 2006 and September 2009 We fit Logistic regression models relating the infection status of individual birds sampled on their breeding grounds to demographic characteristics, temperature, and interval apparent prevalence during the preceding overwintering season at the local watershed scale. We found strong support for sex, age, and species differences in the probability an individual duck tested positive for avian influenza virus. In addition, we found that for every seven days the local minimum temperature fell below zero, the chance an individual would test positive for avian influenza virus increased by 5.9 percent. We also found a twelve percent increase in the chance an individual would test positive during the breeding season for every ten percent increase in the interval apparent prevalence during the prior overwintering season. These results suggest that viral deposition in water and sub-freezing temperatures during the overwintering season may act as determinants of individual level infection risk during the subsequent breeding season. Our findings have implications for future surveillance activities in waterfowl and domestic poultry populations. Further study is needed to identify how these drivers might interact with other host-specific infection determinants, such as species phylogeny, immunological status, and behavioral characteristics

Differential Impact of Tetratricopeptide Repeat Proteins on the Steroid Hormone Receptors

Tetratricopeptide repeat (TPR) motif containing co-chaperones of the chaperone Hsp90 are considered control modules that govern activity and specificity of this central folding platform. Steroid receptors are paradigm clients of Hsp90. The influence of some TPR proteins on selected receptors has been described, but a comprehensive analysis of the effects of TPR proteins on all steroid receptors has not been accomplished yet.We compared the influence of the TPR proteins FK506 binding proteins 51 and 52, protein phosphatase-5, C-terminus of Hsp70 interacting protein, cyclophillin 40, hepatitis-virus-B X-associated protein-2, and tetratricopeptide repeat protein-2 on all six steroid hormone receptors in a homogeneous mammalian cell system. To be able to assess each cofactor's effect on the transcriptional activity of on each steroid receptor we employed transient transfection in a reporter gene assay. In addition, we evaluated the interactions of the TPR proteins with the receptors and components of the Hsp90 chaperone heterocomplex by coimmunoprecipitation. In the functional assays, corticosteroid and progesterone receptors displayed the most sensitive and distinct reaction to the TPR proteins. Androgen receptor's activity was moderately impaired by most cofactors, whereas the Estrogen receptors' activity was impaired by most cofactors only to a minor degree. Second, interaction studies revealed that the strongly receptor-interacting co-chaperones were all among the inhibitory proteins. Intriguingly, the TPR-proteins also differentially co-precipitated the heterochaperone complex components Hsp90, Hsp70, and p23, pointing to differences in their modes of action.The results of this comprehensive study provide important insight into chaperoning of diverse client proteins via the combinatorial action of (co)-chaperones. The differential effects of the TPR proteins on steroid receptors bear on all physiological processes related to steroid hormone activity

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Importance Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear. Objective To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19. Setting, Design, and Participants Case series of patients (age <21 years) hospitalized between March 15, 2020, and December 15, 2020, with positive severe acute respiratory syndrome coronavirus 2 test result (reverse transcriptase-polymerase chain reaction and/or antibody) at 61 US hospitals in the Overcoming COVID-19 public health registry, including 616 (36%) meeting criteria for multisystem inflammatory syndrome in children. Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening involvement was adjudicated by experts based on clinical and/or neuroradiologic features. Exposures Severe acute respiratory syndrome coronavirus 2. Main Outcomes and Measures Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge. Results Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19–related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died. Conclusions and Relevance In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown

Assessment of paper interstate certificates of veterinary inspection used to support disease tracing in cattle

Objective—To evaluate the differences among each state’s Interstate Certificate of Veterinary Inspection (ICVI) form and the legibility of data on paper ICVIs used to support disease tracing in cattle. Design—Descriptive retrospective cross-sectional study. Sample—Examples of ICVIs from 50 states and 7,630 randomly sampled completed paper ICVIs for cattle from 48 states. Procedures—Differences among paper ICVI forms from all 50 states were determined. Sixteen data elements were selected for further evaluation of their value in tracing cattle. Completed paper ICVIs for interstate cattle exports in 2009 were collected from 48 states. Each of the 16 data elements was recorded as legible, absent, or illegible on forms completed by accredited veterinarians, and results were summarized by state. Mean values for legibility at the state level were used to estimate legibility of data at the national level. Results—ICVIs were inconsistent among states in regard to data elements requested and availability of legible records. A mean ± SD of 70.0 ± 22.1% of ICVIs in each state had legible origin address information. Legible destination address information was less common, with 55.0 ± 21.4% of records complete. Incomplete address information was most often a result of the field having been left blank. Official animal identification was present on 33.1% of ICVIs. Conclusions and Clinical Relevance—The inconsistency among state ICVI forms and quality of information provided on paper ICVIs could lead to delays and the need for additional resources to trace cattle, which could result in continued spread of disease. Standardized ICVIs among states and more thorough recording of information by accredited veterinarians or expanded usage of electronic ICVIs could enhance traceability of cattle during an outbreak

The Ups and Downs of Repeated Cleavage and Internal Fragment Production in Top-Down Proteomics

Analysis of whole proteins by mass spectrometry, or top-down proteomics, has several advantages over methods relying on proteolysis. For example, proteoforms can be unambiguously identified and examined. However, from a gas-phase ion-chemistry perspective, proteins are enormous molecules that present novel challenges relative to peptide analysis. Herein, the statistics of cleaving the peptide backbone multiple times are examined to evaluate the inherent propensity for generating internal versus terminal ions. The raw statistics reveal an inherent bias favoring production of terminal ions, which holds true regardless of protein size. Importantly, even if the full suite of internal ions is generated by statistical dissociation, terminal ions are predicted to account for at least 50% of the total ion current, regardless of protein size, if there are three backbone dissociations or fewer. Top-down analysis should therefore be a viable approach for examining proteins of significant size. Comparison of the purely statistical analysis with actual top-down data derived from ultraviolet photodissociation (UVPD) and higher-energy collisional dissociation (HCD) reveals that terminal ions account for much of the total ion current in both experiments. Terminal ion production is more favored in UVPD relative to HCD, which is likely due to differences in the mechanisms controlling fragmentation. Importantly, internal ions are not found to dominate from either the theoretical or experimental point of view. Graphical abstract ᅟ