Protein structure networks (PSNs) have long been used to provide a coarse yet meaningful representation of protein structure, dynamics, and internal communication pathways. An important question is what criteria should be applied to construct the network so that to include relevant interresidue contacts while avoiding unnecessary connections. To address this issue we systematically considered varying residue distance cutoff length and the probability threshold for contact formation to construct PSNs based on atomistic molecular dynamics in order to assess the amount of mutual information within the resulting representations. We found that the minimum in mutual information is universally achieved at the cutoff length of 5 Å, irrespective of the applied contact formation probability threshold in all considered, distinct proteins. Assuming that the optimal PSNs should be characterised by the least amount of redundancy, which corresponds to the minimum in mutual information, this finding suggests an objective criterion for cutoff distance and supports the existing preference towards its customary selection around 5 Å length, typically based to date on heuristic criteria.

The hyper-diverse order Coleoptera comprises a staggering ~25% of known species on Earth. Despite recent breakthroughs in next generation sequencing, there remains a limited representation of beetle diversity in assembled genomes. Most notably, the ground beetle family Carabidae, comprising more than 40,000 described species, has not been studied in a comparative genomics framework using whole genome data. Here we generate a high-quality genome assembly for Nebria riversi, to examine sources of novelty in the genome evolution of beetles, as well as genetic changes associated with specialization to high elevation alpine habitats. In particular, this genome resource provides a foundation for expanding comparative molecular research into mechanisms of insect cold adaptation. Comparison to other beetles shows a strong signature of genome compaction, with N. riversi possessing a relatively small genome (~147 Mb) compared to other beetles, with associated reductions in repeat element content and intron length. Small genome size is not, however, associated with fewer protein-coding genes, and an analysis of gene family diversity shows significant expansions of genes associated with cellular membranes and membrane transport, as well as protein phosphorylation and muscle filament structure. Finally, our genomic analyses show that these high elevation beetles have endosymbiotic Spiroplasma, with several metabolic pathways (e.g. propanoate biosynthesis) that might complement N. riversi, although its role as a beneficial symbiont or as a reproductive parasite remains equivocal.

To date, there is no report on the subsequent development of AITL in patients with EBV-positive DLBCL. We performed a rare case of EBV-positive AITL developing one year after initial diagnosis of EBV-positive DLBCL. The patient showed poor response to the chemotherapy regimen, and poor surviva

Research hypotheses have been a cornerstone of science since before Galileo. Many have argued that inclusion of multiple hypotheses (1) encourage discovery of mechanisms, and (2) reduce bias – both features that should increase transferability and reproducibility. However, we are entering a new era of big data and highly predictive models where some argue the hypothesis is outmoded. Indeed, using a detailed literature analysis, we found prevalence of hypotheses in eco-evo research is very low (6.7-26%) and static from 1990-2015, a pattern mirrored in an extensive literature search (N=302,558 articles). Our literature review also indicates that neither grant success or citation rates were related to the inclusion of hypotheses, which may provide disincentive for hypothesis formulation. Here we confront common justifications for avoiding hypotheses and present new arguments based on benefits to the individual. Although hypotheses are not always necessary, we expect their continued and increased use will help our fields move toward greater understanding, reproducibility, prediction, and effective conservation of nature.

COVID-19 is a complex disease and many difficulties are faced today especially in the proper choice of pharmacological treatments. The role of antiviral agents for COVID-19 is still being investigated. The evidence for immunomodulatory and anti-inflammatory drugs is quite conflicting, while the use of corticosteroids is supported by robust evidence. The use of heparins in hospitalized critically ill patients is preferred over other anticoagulants. Lastly, conflicting data were found regarding to the use of convalescent plasma and vitamin D. According to data shared by the WHO, many vaccines are under phase 3 clinical trials and some of them already received the marketing approval in EU countries and in the US. In conclusion, drugs repurposing has represented the main approach recently used in the treatment of patients with COVID-19. At this moment, the analysis of efficacy and safety data of drugs and vaccines used in real life context is strongly needed.

Background The maturation of innate immune responses in health and atopy is still incompletely understood. Methods We aimed to evaluate age-related trajectories of the TLR3 and TLR7/8 pathways across the lifespan and whether these differ between healthy and atopic individuals. Peripheral blood mononuclear cells (PBMCs) were isolated from 39 otherwise healthy atopic and 39 non-atopic subjects, aged 0-45 years. Selected cytokines involved in antiviral responses were measured by Luminex in culture supernatants of poly(I:C)- and R848-stimulated PBMCs. The non-parametric correlation between age and cytokine expression and differences in developmental trajectories between healthy and atopic were estimated. Patterns of cytokine development were identified with principal component analysis. Results Normal innate immune maturation entails significant and progressive age-related changes in the production of IL-1β, TNF-α, MIP-1β, MCP-3, IP-10, IL-10, IL-12p70 and IFN-γ upon TLR3 and/or TLR7/8 stimulation. Individual cytokines made small contributions to the observed variability; chemokines MCP-3 and IP-10 were key contributors. The development of these pathways deviated in atopic subjects with significant differences observed in the trajectories of IL-1β, MIP-1β and IL-10 synthesis. Conclusion TLR3 and TLR7/8 pathways mature during childhood, while atopy is associated with an abnormal maturation pattern. Suboptimal responses in Th1, inflammatory cytokine and chemokine production may be implicated in poor antiviral immunity in atopics, while deficient maturation of IL-10 producing capacity in the breaking of tolerance.

Background: This study evaluates the impact of peak preoperative troponin level on outcomes of coronary artery bypass grafting (CABG) for non-ST-elevation myocardial infarction (NSTEMI). Methods: This was a retrospective review of patients undergoing isolated CABG from 2011-2018 with presentation of NSTEMI. Patients were stratified into low- and high-risk groups based on median preoperative peak troponin (1.95ng/dL). Major cardiac and cerebrovascular events (MACCE) and mortality were compared. Multivariable analysis was performed to model risk factors for MACCE and mortality. Results: This study included 1,211 patients, 607 low- (≤1.95ng/dL) and 604 high-risk (>1.95ng/dL). Patients were well-matched with respect to age and comorbidity. High-risk patients had lower median preoperative ejection fraction (46.5% [IQR 35.0%-55.0%] vs 53.0% [IQR 40.0%-58.0%]) and higher incidence of preoperative intra-aortic balloon pump (15.9% vs 8.73%). Intensive care unit (47 hours [IQR 26-82] vs 43 hours [IQR 25-69]) and hospital lengths of stay (10 days [IQR 8-13] vs 9 days [IQR 8-12]) were longer in the high-risk group (each P<0.05). Postoperative complications and thirty-day, one- and five-year rates of both MACCE and survival were similar between groups. Peak troponin >1.95ng/dL was not associated with increased hazards for MACCE, mortality, or readmission in multivariable modeling. In sub-analyses, neither increasing troponin as a continuous variable nor peak troponin >10.00ng/mL were associated with increased hazards for these outcomes. Conclusions: Higher preoperative troponin levels are associated with longer lengths of stay but not MACCE or mortality following CABG. Dictating timing of CABG for NSTEMI based on peak troponin does not appear to be warranted.

The out-of-plane displacement (OPD) of a circular dielectric elastomer actuator (DEA) membrane has been explored in recent years for a variety of important applications. Circular DEAs consist of an elastomer membrane that is prestretched to a rigid frame and coated with compliant electrodes. Such a simple configuration has found many interesting applications such as in, pumps, pulse tracking, hopping search and rescue robots, dielectric elastomer (DE) generators for renewable energy harvesting, linear actuators, and many others. Here, we present an easy-to-follow implementation of the OPD equations for circular DEAs via a detailed numerical solution using the shooting method (SM) on a system of differential algebraic equations (DAE), based on previous theoretical work. The SM numerical solution to the system of DAEs is applied to a practical range of values based on the reported literature. Analysis of the results and comparison against other studies are provided. The current work provides a go-to framework for implementation in further research and development.

We report the case of sudden rupture of a radial artery small pseudoaneurysm (PSA) occurring in a 63-years-old patient who had been hospitalized for COVID-19 pneumonia.

There are various clinical presentations of inguinal hernia. Computed tomography is a well-known tool to help diagnose inguinal hernia; however, radiographs are rarely reported to be useful in this aspect. We present a rare case wherein radiographs helped in the diagnosis of inguinal hernia.

Background: Left ventricular (LV) outflow tract (LVOT) obstruction increases mortality in patients undergoing transcatheter mitral valve implantation (TMVI) in degenerated bioprostheses, annuloplasty rings, and native mitral valves. We aimed to evaluate the left ventricular outflow tract area after TMVI using 3-diensional (3D) transesophageal echocardiography (TEE) and to investigate the pre-procedural cardiac geometry affects the LVOT area after TMVI. Methods: We retrospectively reviewed echocardiography data in 43 patients who had TMVI. A change in pressure gradient across LVOT from before to after TMVI (∆PG) and post-procedure 3D cross sectional area (CSA) at the level of the most distal portion of the mitral valve stent that was closest to the LV apex were assessed as evidence of LVOT narrowing. Results: TMVI with the use of balloon-expandable valve system was performed for 24 bioprostheses, 7 annuloplasty rings, and 12 native valves. Compared to patients without increase in LVOT gradient (∆PG <10 mmHg; n=33), patients with increase in LVOT gradient (∆PG ≥10 mmHg; n=10) had smaller LV end-systolic volume (LVESV), greater LV ejection fraction (LVEF) and smaller aorto-mitral (AM) angle. CSA at the valve stent distal edge showed strong association with ∆PG (r=-0.68, P<0.0001). Only small AM angle was associated with small CSA at the valve stent ventricular edge on multivariable analysis, independent of LVESV and LVEF. Conclusion: Pre-procedural AM angle as well as LVESV and LVEF were associated with LVOT narrowing in patients undergoing transcatheter mitral valve-in-valve, valve-in-ring, and valve-in-native valve implantation. These data may be useful for preprocedural planning.

Purpose: To observe and describe the stiffness changes of the optic nerve in the patients with multiple sclerosis (MS) with or without optic neuritis and healthy adults via shear wave elastography (SWE). Methods: Seventy optic nerves from thirty-five patients with MS and sixty optic nerves from thirty healthy subjects were included prospectively in the study. The optic nerve (ON), optic disc (OD), and perineural area were evaluated with SWE and optic nerve sheat diameter (ONSD) was measured by ultrasound. Results The mean age of patients was 39.68 ± 9.99 years. There was no statistically significant difference between the groups in terms of ONSD, SWE ON, SWE OD, and SWE perineural area levels (p> 0.05). In the MS group; No statistically significant difference was found between patients with and without optic neuritis for the mean age, gender distribution, duration of MS, types of MS, ONSD, SWE ON, SWE OD, SWE perineural area, and Expanded Disability Status Scale (EDSS) scores (p> 0.05). No statistically significant difference in terms of ONSD, SWE ON, SWE OD, and SWE perineural area between the MS patients with or without optic neuritis and the control group (p> 0.05). Conclusion: Shear wave elastography measurements of the optic nerve, optic disc, and perineural area do not contribute to the evaluation of optic neuritis in a patient with MS.

A new perspective of localized shear strain accumulation was proposed to elucidate the formation mechanism of fine granular area (FGA) generated in a high strength steel under very-high-cycle fatigue (VHCF). On the one hand, experiments of VHCF under the negative stress ratio of -1 was carried out, and the microstructure of FGA was found and characterized by using Scanning Electron Microscope, Transmission Electron Microscopy, and Transmission Kikuchi Diffraction. The results show that the FGA consists of high-density dislocations, sub-grains, and fine grains with high angle grain boundaries. On the other hand, the evolution of shear strain and fatigue damage at the vicinity of an inclusion was modelled by using crystal plasticity finite element method at both positive and negative stress ratios. The results show that although the overall strain in VHCF is negligible, significant shear strain is accumulated at the vicinity of the inclusion. Such a large local strain is the driving force for the formation of FGA. The results also suggest that with the accumulation of shear strain and damage, the positive stress ratio is gradually evolved into negative. This may explain why FGA has also been reported at positive stress ratios in some literatures.

Both termites and large mammalian herbivores (LMH) are savanna ecosystem engineers that have profound impacts on ecosystem structure and function. Both of these savanna engineers modulate many common and shared dietary resources such as woody and herbaceous plant biomass, yet few studies have addressed how they impact one another. In particular, it is unclear how herbivores may influence the abundance of long-lived termite mounds via changes in termite dietary resources such as woody and herbaceous biomass. While it has long been assumed that abundance and areal cover of termite mounds in the landscape remains relatively stable, most data are observational, and few experiments have tested how termite mound patterns may respond to biotic factors such as changes in large herbivore communities. Here, we use a broad tree density gradient and two landscape-scale experimental manipulations—the first a multi-guild large herbivore exclosure experiment and the second a tree removal experiment– to demonstrate that patterns in termite mound abundance and cover are unexpectedly dynamic. Termite mound abundance, but not areal cover not significantly, is positively associated with experimentally controlled presence of cattle, but not wild mesoherbivores (15-1000 kg) or megaherbivores (elephants and giraffes). Herbaceous productivity and tree density, termite dietary resources that significantly affected by different LMH treatments, are both positive predictors of termite mound abundance. Experimental reductions of tree densities are associated with lower abundances of termite mounds. These results reveal a richly interacting web of relationships among multiple savanna ecosystem engineers and suggest that termite mound abundance and areal cover is intimately tied to herbivore-driven resource availability.

Abstract Background: Subcutaneous implantable cardioverter defibrillators (S-ICDs) avoid complications secondary to transvenous leads, but inappropriate shocks (ISs) are frequent. Furthermore, IS data from patients with Brugada syndrome (BrS) with an S-ICD are scarce. Objective: We aimed to establish the incidence, mechanisms, and predictors of S-ICD in this population. Methods: We analyzed the clinical and electrocardiographic characteristics, automated screening test data, device programming, and IS occurrence in adult patients with BrS with an S-ICD. Results: Thirty-nine patients were enrolled (69% male, mean age at diagnosis 46±13 years, mean age at implantation 48±13 years). During a mean follow-up of 26±21 months, 18% patients experienced IS. Patients with IS were younger at the time of diagnosis (36±8 versus 48±13 years, p=0.018) and S-ICD implantation (38±9 versus 50±23 years, p=0.019) and presented with spontaneous type 1 Brugada ECG pattern more frequently at diagnosis or during follow-up (71% versus 25%, p=0.018). During automated screening tests, patients with IS showed lower QRS voltage in the primary vector in the supine position (0.58±0.26 versus 1.10±0.35 mV, p=0.011) and lower defibrillator automated screening score (DASS) in the primary vector in the supine (123±165 versus 554±390 mV, p=0.005) and standing (162±179 versus 486±388 mV, p=0.038) positions. Age at diagnosis was the only independent predictor of IS (hazard ratio=0.873, 95% confidence interval: 0.767-0.992, p=0.037). Conclusion: IS was a frequent complication in patients with BrS with an S-ICD. Younger age was independently associated with IS. A more thorough screening process might help prevent IS in this population.

Imatinib is used as first-line treatment for chronic myeloid leukemia (CML) even in patients with impaired renal function. We successfully used therapeutic drug monitoring to determine the dose for re-administration of imatinib in a CML patient who initiated dialysis for acute renal dysfunction associated with the initial imatinib therapy.

Growth-differentiation factor 15 (GDF15) is an inflammatory cytokine involved in energy homeostasis. Its circulating levels are acutely increased by the type 2 diabetes medication metformin, resulting in reduced appetite and weight loss. We identified a genetic variant at the GDF15 gene to proxy a small, lifelong increase in circulating GDF15 levels, and leveraged it in colocalization and Mendelian randomization analyses to investigate the effects of chronically elevated GDF15 levels on body mass index (BMI) and type 2 diabetes liability. The results provide human genetic evidence supporting that chronically elevated GDF15 levels increase BMI. There was no genetic evidence to support bi-directional effects, or that chronically elevated GDF15 levels directly affect liability to type 2 diabetes. Our results contrast the BMI lowering effects of an acute increase in GDF15 levels observed after metformin use. These findings have direct implications for informing pharmacological strategies aimed at targeting GDF15 levels for weight loss.

The T-graft is a new tool in the armament of structural rhinoplasty. The graft makes it easy to create a well- balanced nasal framework both for beginners and more experienced rhinoplastic surgeons. Due to its multifunctional character the T-graft allows the surgeon to control nasal length as well as nasal tip projection and -rotation. The T-graft is indicated in many anatomical features like in patients with a short nose or heavy soft tissue envelope, but also in patients with under projection of the nasal tip, under- or over-rotation of the nasal tip and deviations of the caudal nasal septum.