Defective cancellous bone structure and abnormal response to PTH in cortical bone of mice lacking Cx43 cytoplasmic C-terminus domain

Connexin 43 (Cx43) forms gap junction channels and hemichannels that allow the communication among osteocytes, osteoblasts, and osteoclasts. Cx43 carboxy-terminal (CT) domain regulates channel opening and intracellular signaling by acting as a scaffold for structural and signaling proteins. To determine the role of Cx43 CT domain in bone, mice in which one allele of full length Cx43 was replaced by a mutant lacking the CT domain (Cx43(ΔCT/fl)) were studied. Cx43(ΔCT/fl) mice exhibit lower cancellous bone volume but higher cortical thickness than Cx43(fl/fl) controls, indicating that the CT domain is involved in normal cancellous bone gain but opposes cortical bone acquisition. Further, Cx43(ΔCT) is able to exert the functions of full length osteocytic Cx43 on cortical bone geometry and mechanical properties, demonstrating that domains other than the CT are responsible for Cx43 function in cortical bone. In addition, parathyroid hormone (PTH) failed to increase endocortical bone formation or energy to failure, a mechanical property that indicates resistance to fracture, in cortical bone in Cx43(ΔCT) mice with or without osteocytic full length Cx43. On the other hand, bone mass and bone formation markers were increased by the hormone in all mouse models, regardless of whether full length or Cx43(ΔCT) were or not expressed. We conclude that Cx43 CT domain is involved in proper bone acquisition; and that Cx43 expression in osteocytes is dispensable for some but not all PTH anabolic actions

Critical animal and media studies: Expanding the understanding of oppression in communication research

Critical and communication studies have traditionally neglected the oppression conducted by humans towards other animals. However, our (mis)treatment of other animals is the result of public consent supported by a morally speciesist-anthropocentric system of values. Speciesism or anthroparchy, as much as any other mainstream ideologies, feeds the media and at the same time is perpetuated by them. The goal of this article is to remedy this neglect by introducing the subdiscipline of Critical Animal and Media Studies. Critical Animal and Media Studies takes inspiration both from critical animal studies – which is so far the most consolidated critical field of research in the social sciences addressing our exploitation of other animals – and from the normative-moral stance rooted in the cornerstones of traditional critical media studies. The authors argue that the Critical Animal and Media Studies approach is an unavoidable step forward for critical media and communication studies to engage with the expanded circle of concerns of contemporary ethical thinking

LOGISTICS IN CONTESTED ENVIRONMENTS

This report examines the transport and delivery of logistics in contested environments within the context of great-power competition (GPC). Across the Department of Defense (DOD), it is believed that GPC will strain our current supply lines beyond their capacity to maintain required warfighting capability. Current DOD efforts are underway to determine an appropriate range of platforms, platform quantities, and delivery tactics to meet the projected logistics demand in future conflicts. This report explores the effectiveness of various platforms and delivery methods through analysis in developed survivability, circulation, and network optimization models. Among other factors, platforms are discriminated by their radar cross-section (RCS), noise level, speed, cargo capacity, and self-defense capability. To maximize supply delivered and minimize the cost of losses, the results of this analysis indicate preference for utilization of well-defended convoys on supply routes where bulk supply is appropriate and smaller, and widely dispersed assets on shorter, more contested routes with less demand. Sensitivity analysis on these results indicates system survivability can be improved by applying RCS and noise-reduction measures to logistics assets.Director, Warfare Integration (OPNAV N9I)Major, Israel Defence ForcesCivilian, Singapore Technologies Engineering Ltd, SingaporeCommander, Republic of Singapore NavyCommander, United States NavyCaptain, Singapore ArmyLieutenant, United States NavyLieutenant, United States NavyMajor, Republic of Singapore Air ForceCaptain, United States Marine CorpsLieutenant, United States NavyLieutenant, United States NavyLieutenant, United States NavyLieutenant, United States NavyLieutenant, United States NavyCaptain, Singapore ArmyLieutenant Junior Grade, United States NavyCaptain, Singapore ArmyLieutenant Colonel, Republic of Singapore Air ForceApproved for public release. distribution is unlimite

Phylogeny of the Infraorder Pentatomomorpha Based on Fossil and Extant Morphology, with Description of a New Fossil Family from China

<div><h3>Background</h3><p>An extinct new family of Pentatomomorpha, Venicoridae Yao, Ren & Cai <b>fam. nov.</b>, with 2 new genera and 2 new species (<em>Venicoris solaris</em> Yao, Ren & Rider <b>gen. & sp. nov.</b> and <em>Clavaticoris zhengi</em> Yao, Ren & Cai <b>gen. & sp. nov.</b>) are described from the Early Cretaceous Yixian Formation in Northeast China.</p> <h3>Methodology/Principal Findings</h3><p>A cladistic analysis based on a combination of fossil and extant morphological characters clarified the phylogenetic status of the new family and has allowed the reconstruction of intersuperfamily and interfamily relationships within the Infraorder Pentatomomorpha. The fossil record and diversity of Pentatomomorpha during the Mesozoic is discussed.</p> <h3>Conclusions/Significance</h3><p>Pentatomomorpha is a monophyletic group; Aradoidea and the Trichophora are sister groups; these fossils belong to new family, treated as the sister group of remainder of Trichophora; Pentatomoidea is a monophyletic group; Piesmatidae should be separated as a superfamily, Piesmatoidea. Origin time of Pentatomomorpha should be tracked back to the Middle or Early Triassic.</p> </div

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Rare copy number variation in posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further

Phase 3, Randomized, 20-Month Study of the Efficacy and Safety of Bimatoprost Implant in Patients with Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 2)

Objective- To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10 and 15 µg bimatoprost implant in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods- This randomized, 20-month, multicenter, masked, parallel-group, phase 3 trial enrolled 528 patients with OAG or OHT and an open iridocorneal angle inferiorly in the study eye. Study eyes were administered 10 or 15 µg bimatoprost implant on day 1, week 16, and week 32, or twice-daily topical timolol maleate 0.5%. Primary endpoints were IOP and IOP change from baseline through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). Results- Both 10 and 15 µg bimatoprost implant met the primary endpoint of noninferiority to timolol in IOP lowering through 12 weeks. Mean IOP reductions from baseline ranged from 6.2–7.4, 6.5–7.8, and 6.1–6.7 mmHg through week 12 in the 10 µg implant, 15 µg implant, and timolol groups, respectively. IOP lowering was similar after the second and third implant administrations. Probabilities of requiring no IOP-lowering treatment for 1 year after the third administration were 77.5% (10 µg implant) and 79.0% (15 µg implant). The most common TEAE was conjunctival hyperemia, typically temporally associated with the administration procedure. Corneal TEAEs of interest (primarily corneal endothelial cell loss, corneal edema, and corneal touch) were more frequent with the 15 than the 10 µg implant and generally were reported after repeated administrations. Loss in mean CECD from baseline to month 20 was ~ 5% in 10 µg implant-treated eyes and ~ 1% in topical timolol-treated eyes. Visual field progression (change in the mean deviation from baseline) was reduced in the 10 µg implant group compared with the timolol group. Conclusions- The results corroborated the previous phase 3 study of the bimatoprost implant. The bimatoprost implant met the primary endpoint and effectively lowered IOP. The majority of patients required no additional treatment for 12 months after the third administration. The benefit-risk assessment favored the 10 over the 15 µg implant. Studies evaluating other administration regimens with reduced risk of corneal events are ongoing. The bimatoprost implant has the potential to improve adherence and reduce treatment burden in glaucoma

EPHEDRA USE IN A SELECT GROUP OF ADOLESCENT ATHLETES

Ephedra-containing dietary supplements are consumed to improve sports performace, but may carry risks of cardiac and neurological adverse events. Little is known of their use by young athletes. Our aim was to determine the prevalence and patterns of ephedra use among high school athletes. An anonymous survey was performed in Rochester, Minnesota on high school athletes who participated in fall sports during 2003-04. Parental consent was obtained for athletes under age 18 years. Surveys were distributed at preparticipation examinations and in- school survey stations. The response rate to the survey was 68.2%, or 311 respondents out of a possible 456 with consent (or 26% of all 1197 athletes eligible prior to the consent process). Seven of 311 (2.3%) respondents used dietary supplements containing ephedra. Only one of seven users (14.3%) knew that the supplements they used contained ephedra. Ephedra use was more common in boys (five) than girls (two). Ephedra use was only found in 17 and 18-year-olds. The most common sports among ephedra users were football, track and field, and weightlifting. This study suggests that Ephedra use was infrequent among the young athletes in this population. However, ephedra users were generally unaware that the dietary supplements they consumed contained ephedra. Users were more likely to participate in football, track and field, and weightlifting. Ephedra users were likely to obtain supplements from their peers, and were largely uninformed of the content of their supplement