Genetic insight into the putative causal proteins and druggable targets of osteoporosis: a large-scale proteome-wide mendelian randomization study

Background: Osteoporosis is a major causative factor of the global burden of disease and disability, characterized by low bone mineral density (BMD) and high risks of fracture. We aimed to identify putative causal proteins and druggable targets of osteoporosis.Methods: This study utilized the largest GWAS summary statistics on plasma proteins and estimated heel BMD (eBMD) to identify causal proteins of osteoporosis by mendelian randomization (MR) analysis. Different GWAS datasets were used to validate the results. Multiple sensitivity analyses were conducted to evaluate the robustness of primary MR findings. We have also performed an enrichment analysis for the identified causal proteins and evaluated their druggability.Results: After Bonferroni correction, 67 proteins were identified to be causally associated with estimated BMD (eBMD) (p < 4 × 10−5). We further replicated 38 of the 67 proteins to be associated with total body BMD, lumbar spine BMD, femoral neck BMD as well as fractures, such as RSPO3, IDUA, SMOC2, and LRP4. The findings were supported by sensitivity analyses. Enrichment analysis identified multiple Gene Ontology items, including collagen-containing extracellular matrix (GO:0062023, p = 1.6 × 10−10), collagen binding (GO:0005518, p = 8.6 × 10−5), and extracellular matrix structural constituent (GO:0005201, p = 2.7 × 10−5).Conclusion: The study identified novel putative causal proteins for osteoporosis which may serve as potential early screening biomarkers and druggable targets. Furthermore, the role of plasma proteins involved in collagen binding and extracellular matrix in the development of osteoporosis was highlighted. Further studies are warranted to validate our findings and investigate the underlying mechanism

Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis

Advances in the field of cancer immunology, including studies on tumor-infiltrating CD8(+) cytotoxic T lymphocytes (CTLs), have led to new immunotherapeutics with proven efficacy against late-stage cancers. However, the antitumor potential of the immune system in targeting early-stage cancers remains uncertain. Here, we demonstrated that both genetic and chemical induction of thymic stromal lymphopoietin (TSLP) at a distant site leads to robust antitumor immunity against spontaneous breast carcinogenesis in mice. Breast tumors exposed to high circulating levels of TSLP were arrested at an early adenoma-like stage and were prevented from advancing to late carcinoma and metastasis. Additionally, CD4(+) Th2 cells mediated the antitumor effects of TSLP, challenging the notion that Th2 cells only promote cancer. We also discovered that TSLP is expressed by the breast tumor cells themselves and acts to block breast cancer promotion. Moreover, TSLP-induced immunity also blocked early stages of pancreatic cancer development. Together, our findings demonstrate that TSLP potently induces immunity directed against early stages of breast cancer development without causing inflammation in the normal breast tissue. Moreover, our results highlight a previously unappreciated function of the immune system in controlling the early development of cancer and establish a fundamental role for TSLP and Th2 cells in tumor immunity against early-stage cancers

The CSF in neurosarcoidosis contains consistent clonal expansion of CD8 T cells, but not CD4 T cells

The tissue-specific drivers of neurosarcoidosis remain poorly defined. To identify cerebrospinal fluid (CSF) specific, antigen-driven T and B cell responses, we performed single-cell RNA sequencing of CSF and blood cells from neurosarcoid participants coupled to T and B cell receptor sequencing. In contrast to pulmonary sarcoidosis, which is driven by CD4 T cells, we found CD8 T cell clonal expansion enriched in the neurosarcoid CSF. These CSF-enriched CD8 T cells were composed of two subsets with differential expression of EBI2, CXCR3, and CXCR4. Lastly, our data suggest that IFNγ signaling may distinguish neurosarcoidosis from other neurological disorders

Concussion in para sport:the first position statement of the Concussion in Para Sport (CIPS) Group

Concussion is a frequent injury in many sports and is also common in para athletes. However, there is a paucity of concussion research related to para sport, and prior International Concussion in Sport (CIS) consensus papers have not substantively addressed this population. To remedy this and to improve concussion care provided to para athletes, the concussion in para sport (CIPS) multidisciplinary expert group was created. This group analysed and discussed in-depth para athlete-specific issues within the established key clinical domains of the current (2017) consensus statement on CIS. Due to the onset of the COVID-19 pandemic, the group held all meetings by video conferencing. The existing Sport Concussion Assessment Tool 5 (SCAT5) for the immediate on-field and office-based off-field assessment of concussion was evaluated as part of this process, to identify any para athlete-specific concerns. Regular preparticipation and periodic health examinations are essential to determine a baseline reference point for concussion symptoms but pose additional challenges for the interpreting clinician. Further considerations for concussion management for the para athlete are required within the remove, rest, reconsider and refer consensus statement framework. Considering return to sport (RTS), the 2017 CIS consensus statement has limitations when considering the RTS of the para athlete. Case-by-case decision making related to RTS following concussion is imperative for para athletes. Additional challenges exist for the evaluation and management of concussion in para athletes. There is a need for greater understanding of existing knowledge gaps and attitudes towards concussion among athlete medical staff, coaches and para athletes. Future research should investigate the use and performance of common assessment tools in the para athlete population to better guide their clinical application and inform potential modifications. Concussion prevention strategies and sport-specific rule changes, such as in Para Alpine Skiing and Cerebral Palsy Football, also should be carefully considered to reduce the occurrence of concussion in para athletes

The Floor of Yellowstone Lake is Anything but Quiet—New Discoveries from High-Resolution Sonar Imaging, Seismic- Reflection Profiling, and Submersible Studies

Discoveries from multibeam sonar mapping and seis-mic-reflection surveys of Yellowstone Lake provide new insight into the recent geologic forces that have shaped a large lake at the active front of the Yellowstone hot spot, a region strongly affected by young (\u3c2 \u3em.y.), large-volume (\u3e100–1,000s km3) silicic volcanism, active tectonism, and accompanying uplift. Specifically, our mapping has identified the extent of postcaldera-collapse volcanism and active hydrothermal processes occurring above a large magma chamber beneath the lake floor. Multiple advances and recessions of thick glacial ice have overlapped volcanic and hydrothermal activity leaving a lake basin that has been shaped predominantly by fire and ice. Yellowstone Lake has an irregular bottom covered with dozens of features directly related to hydrothermal, tectonic, volcanic,and sedimentary processes. Detailed bathymetric, seismic-reflection, and magnetic evidence reveals that rhyolitic lava flows underlie much of Yellowstone Lake and exert fundamental control on lake morphology and localization of hydrothermal activity in the northern, West Thumb, and central basins. Many previously unknown features have been identified and include more than 660 hydrothermal vents, several very large (\u3e500-m diameter) hydrothermal-explosion craters, many small hydrothermal-vent craters (~1-to 200-m diameter), domed lacustrine sediments related to hydrothermal activity, elongate fissures cutting postglacial sediments, siliceous hydrothermal-spire structures, sublacustrine landslide deposits, submerged former shorelines, large glacial melting features, incipient faulting along the trace of the Eagle Bay fault zone, and a recently active graben. Sampling and observations with a submersible remotely operated vehicle confirm and extend our understanding of the identified features. Faults, fissures, hydrothermally inflated domal structures, hydrothermal-explosion craters, and sublacustrine landslides constitute potentially significant geologic hazards. Toxic elements derived from hydrothermal processes also may significantly affect the Yellowstone ecosystem

The Floor of Yellowstone Lake is Anything but Quiet—New Discoveries from High-Resolution Sonar Imaging, Seismic- Reflection Profiling, and Submersible Studies

Discoveries from multibeam sonar mapping and seis-mic-reflection surveys of Yellowstone Lake provide new insight into the recent geologic forces that have shaped a large lake at the active front of the Yellowstone hot spot, a region strongly affected by young (\u3c2 \u3em.y.), large-volume (\u3e100–1,000s km3) silicic volcanism, active tectonism, and accompanying uplift. Specifically, our mapping has identified the extent of postcaldera-collapse volcanism and active hydrothermal processes occurring above a large magma chamber beneath the lake floor. Multiple advances and recessions of thick glacial ice have overlapped volcanic and hydrothermal activity leaving a lake basin that has been shaped predominantly by fire and ice. Yellowstone Lake has an irregular bottom covered with dozens of features directly related to hydrothermal, tectonic, volcanic,and sedimentary processes. Detailed bathymetric, seismic-reflection, and magnetic evidence reveals that rhyolitic lava flows underlie much of Yellowstone Lake and exert fundamental control on lake morphology and localization of hydrothermal activity in the northern, West Thumb, and central basins. Many previously unknown features have been identified and include more than 660 hydrothermal vents, several very large (\u3e500-m diameter) hydrothermal-explosion craters, many small hydrothermal-vent craters (~1-to 200-m diameter), domed lacustrine sediments related to hydrothermal activity, elongate fissures cutting postglacial sediments, siliceous hydrothermal-spire structures, sublacustrine landslide deposits, submerged former shorelines, large glacial melting features, incipient faulting along the trace of the Eagle Bay fault zone, and a recently active graben. Sampling and observations with a submersible remotely operated vehicle confirm and extend our understanding of the identified features. Faults, fissures, hydrothermally inflated domal structures, hydrothermal-explosion craters, and sublacustrine landslides constitute potentially significant geologic hazards. Toxic elements derived from hydrothermal processes also may significantly affect the Yellowstone ecosystem

Optimization of the lead probe neutron detector.

The lead probe neutron detector was originally designed by Spencer and Jacobs in 1965. The detector is based on lead activation due to the following neutron scattering reactions: {sup 207}Pb(n, n'){sup 207m}Pb and {sup 208}Pb(n, 2n){sup 207m}Pb. Delayed gammas from the metastable state of {sup 207m}Pb are counted using a plastic scintillator. The half-life of {sup 207m}Pb is 0.8 seconds. In the work reported here, MCNP was used to optimize the efficiency of the lead probe by suitably modifying the original geometry. A prototype detector was then built and tested. A 'layer cake' design was investigated in which thin (< 5 mm) layers of lead were sandwiched between thicker ({approx} 1 - 2 cm) layers of scintillator. An optimized 'layer cake' design had Figures of Merit (derived from the code) which were a factor of 3 greater than the original lead probe for DD neutrons, and a factor of 4 greater for DT neutrons, while containing 30% less lead. A smaller scale, 'proof of principle' prototype was built by Bechtel/Nevada to verify the code results. Its response to DD neutrons was measured using the DD dense plasma focus at Texas A&M and it conformed to the predicted performance. A voltage and discriminator sweep was performed to determine optimum sensitivity settings. It was determined that a calibration operating point could be obtained using a {sup 133}Ba 'bolt' as is the case with the original lead probe

Neutron scattering effects on fusion ion temperature measurements.

To support the nuclear fusion program at Sandia National Laboratories (SNL), a consistent and verifiable method to determine fusion ion temperatures needs to be developed. Since the fusion temperature directly affects the width in the spread of neutron energies produced, a measurement of the neutron energy width can yield the fusion temperature. Traditionally, the spread in neutron energies is measured by using time-of-flight to convert a spread in neutron energies at the source to a spread in time at detector. One potential obstacle to using this technique at the Z facility at SNL is the need to shield the neutron detectors from the intense bremsstrahlung produced. The shielding consists of eight inches of lead and the concern is that neutrons will scatter in the lead, artificially broaden the neutron pulse width and lead to an erroneous measurement. To address this issue, experiments were performed at the University of Rochester's Laboratory for Laser Energetics, which demonstrated that a reliable ion temperature measurement can be achieved behind eight inches of lead shielding. To further expand upon this finding, Monte Carlo N-Particle eXtended (MCNPX) was used to simulate the experimental geometric conditions and perform the neutron transport. MCNPX was able to confidently estimate results observed at the University of Rochester

1964: Abilene Christian College Bible Lectures - Full Text

LEADERSHIP IN THE CHURCH” Being the Abilene Christian College Annual Bible Lectures 1964 Price: $3.95 Published by ABILENE CHRISTIAN COLLEGE STUDENTS EXCHANGE ACC Station Abilene, Texa