Plasma Membrane-Associated Restriction Factors and Their Counteraction by HIV-1 Accessory Proteins.

The plasma membrane is a site of conflict between host defenses and many viruses. One aspect of this conflict is the host's attempt to eliminate infected cells using innate and adaptive cell-mediated immune mechanisms that recognize features of the plasma membrane characteristic of viral infection. Another is the expression of plasma membrane-associated proteins, so-called restriction factors, which inhibit enveloped virions directly. HIV-1 encodes two countermeasures to these host defenses: The membrane-associated accessory proteins Vpu and Nef. In addition to inhibiting cell-mediated immune-surveillance, Vpu and Nef counteract membrane-associated restriction factors. These include BST-2, which traps newly formed virions at the plasma membrane unless counteracted by Vpu, and SERINC5, which decreases the infectivity of virions unless counteracted by Nef. Here we review key features of these two antiviral proteins, and we review Vpu and Nef, which deplete them from the plasma membrane by co-opting specific cellular proteins and pathways of membrane trafficking and protein-degradation. We also discuss other plasma membrane proteins modulated by HIV-1, particularly CD4, which, if not opposed in infected cells by Vpu and Nef, inhibits viral infectivity and increases the sensitivity of the viral envelope glycoprotein to host immunity

AI-powered simulation-based inference of a genuinely spatial-stochastic model of early mouse embryogenesis

Understanding how multicellular organisms reliably orchestrate cell-fate decisions is a central challenge in developmental biology. This is particularly intriguing in early mammalian development, where early cell-lineage differentiation arises from processes that initially appear cell-autonomous but later materialize reliably at the tissue level. In this study, we develop a multi-scale, spatial-stochastic simulator of mouse embryogenesis, focusing on inner-cell mass (ICM) differentiation in the blastocyst stage. Our model features biophysically realistic regulatory interactions and accounts for the innate stochasticity of the biological processes driving cell-fate decisions at the cellular scale. We advance event-driven simulation techniques to incorporate relevant tissue-scale phenomena and integrate them with Simulation-Based Inference (SBI), building on a recent AI-based parameter learning method: the Sequential Neural Posterior Estimation (SNPE) algorithm. Using this framework, we carry out a large-scale Bayesian inferential analysis and determine parameter sets that reproduce the experimentally observed system behavior. We elucidate how autocrine and paracrine feedbacks via the signaling protein FGF4 orchestrate the inherently stochastic expression of fate-specifying genes at the cellular level into reproducible ICM patterning at the tissue scale. This mechanism is remarkably independent of the system size. FGF4 not only ensures correct cell lineage ratios in the ICM, but also enhances its resilience to perturbations. Intriguingly, we find that high variability in intracellular initial conditions does not compromise, but rather can enhance the accuracy and precision of tissue-level dynamics. Our work provides a genuinely spatial-stochastic description of the biochemical processes driving ICM differentiation and the necessary conditions under which it can proceed robustly.Comment: 62 pages, 15 figures, 4 tables, enhancement of Introduction and Discussion section

Guidelines for Permitting Overloads, Part 2: Statistical Analysis of Overload Vehicle Effects on Indiana Highway Bridges

This report summarizes an analytical investigation carried out to develop a set of guidelines for regulation of overload vehicles in Indiana. A formula based first phase evaluation of overload permit requests is developed through statistical study of the rating of a representative sample of the highway bridges in Indiana using a representative sample of overload vehicles observed in the state in 1990 and 1991 plus the HS 20 design vehicle and the two Indiana Toll Road loadings. A sample of 148 bridges is chosen from a total population of 3700 Indiana highway bridges using a proportionate stratified random sampling process. A sample of 25 trucks, with the truck parameters uniformly distributed over their ranges is compiled from the 1990 and 1991 truck population (permit vehicles obtained from INDOT and AASHTO HS Design Vehicle). The selected trucks are used to rate bridges in the selected sample using the Bridge Analysis and Rating System (BARS) program at the operating stress level. BARS is based on elastic line girder and truss analysis. The allowable load, W, is subjected to linear regression analysis with several bridge and truck parameters as regressor or independent variables

Antegrade common femoral artery closure device use is associated with decreased complications.

ObjectiveAntegrade femoral artery access is often used for ipsilateral infrainguinal peripheral vascular intervention. However, the use of closure devices (CD) for antegrade access (AA) is still considered outside the instructions for use for most devices. We hypothesized that CD use for antegrade femoral access would not be associated with an increased odds of access site complications.MethodsThe Vascular Quality Initiative was queried from 2010 to 2019 for infrainguinal peripheral vascular interventions performed via femoral AA. Patients who had a cutdown or multiple access sites were excluded. Cases were then stratified into whether a CD was used or not. Hierarchical multivariable logistic regressions controlling for hospital-level variation were used to examine the independent association between CD use and access site complications. A sensitivity analysis using coarsened exact matching was performed using factors different between treatment groups to reduce imbalance between the groups.ResultsOverall, 11,562 cases were identified and 5693 (49.2%) used a CD. Patients treated with a CD were less likely to be white (74.1% vs 75.2%), have coronary artery disease (29.7% vs 33.4%), use aspirin (68.7% vs 72.4%), and have heparin reversal with protamine (15.5% vs 25.6%; all P < .05). CD patients were more likely to be obese (31.6% vs 27.0%), have an elective operation (82.6% vs 80.1%), ultrasound-guided access (75.5% vs 60.6%), and a larger access sheath (6.0 ± 1.0 F vs 5.5 ± 1.0 F; P < .05 for all). CD cases were less likely to develop any access site hematoma (2.55% vs 3.53%; P < .01) or a hematoma requiring reintervention (0.63% vs 1.26%; P < .01) and had no difference in access site stenosis or occlusion (0.30% vs 0.22%; P = .47) compared with no CD. On multivariable analysis, CD cases had significantly decreased odds of developing any access site hematoma (odds ratio, 0.75; 95% confidence interval, 0.59-0.95) and a hematoma requiring intervention (odds ratio, 0.56; 95% confidence interval, 0.38-0.81). A sensitivity analysis after coarsened exact matching confirmed these findings.ConclusionsIn this nationally representative sample, CD use for AA was associated with a lower odds of hematoma in selected patients. Extending the instructions for use indications for CDs to include femoral AA may decrease the incidence of access site complications, patient exposure to reintervention, and costs to the health care system

Soil properties following reforestation or afforestation of marginal cropland

Aims Reforestation or afforestation of marginal agricultural lands offers opportunities to sequester soil organic carbon (SOC), improve the quality of degraded soils, and provide ecosystem services. The objectives of this study were to identify the extent and distribution of marginally productive cropland in the state of Iowa and to quantify the changes in SOC and relevant soil properties following tree planting. Methods A geographic information system (GIS) analysis was used to identify 1.05 million ha of marginal cropland within the state. Soil samples were collected from four locations with (\u3c51 yr-old) forest plantations and adjacent crop fields. Soil samples were analyzed for SOC, total nitrogen (TN), pH, cation exchange capacity (CEC), ammonium acetateextractable K, Ca, Mg, and Na, and particle size. Results The forested soils had 30.0±5.1 % (mean ±standard error) more SOC than the tilled cropland. The average annual change in SOC following tree planting was estimated to be 0.56±0.05 Mg C ha−1 yr−1. Differences were observed in several soil properties but strong correlations with SOC content were only observed for bulk density and extractable Ca. Conclusions These results indicate that within 5 decades of tree planting on former cropland or pasture there was consistently and significantly greater SOC in soil beneath the trees

Soil properties following reforestation or afforestation of marginal cropland

Aims Reforestation or afforestation of marginal agricultural lands offers opportunities to sequester soil organic carbon (SOC), improve the quality of degraded soils, and provide ecosystem services. The objectives of this study were to identify the extent and distribution of marginally productive cropland in the state of Iowa and to quantify the changes in SOC and relevant soil properties following tree planting. Methods A geographic information system (GIS) analysis was used to identify 1.05 million ha of marginal cropland within the state. Soil samples were collected from four locations with (\u3c51 yr-old) forest plantations and adjacent crop fields. Soil samples were analyzed for SOC, total nitrogen (TN), pH, cation exchange capacity (CEC), ammonium acetateextractable K, Ca, Mg, and Na, and particle size. Results The forested soils had 30.0±5.1 % (mean ±standard error) more SOC than the tilled cropland. The average annual change in SOC following tree planting was estimated to be 0.56±0.05 Mg C ha−1 yr−1. Differences were observed in several soil properties but strong correlations with SOC content were only observed for bulk density and extractable Ca. Conclusions These results indicate that within 5 decades of tree planting on former cropland or pasture there was consistently and significantly greater SOC in soil beneath the trees

Tweaking synchronization by connectivity modifications

ACKNOWLEDGMENTS The authors wish to thank the Nesin Foundation for an amazing working group activity in Nesin Math Village, and we wish to thank Tiago Pereira for fruitful discussions. P.S. and J.K. acknowledge gratefully the support of BMBF, CoNDyNet, FK. 03SF0472A. T.P. acknowledges FAPESP (No. 2012/22160-7 and No. 2015/02486-3) and IRTG 1740. D.E. acknowledge support by the Leibniz Association (WGL) under Grant No. SAW-2013-IZW-2542.Peer reviewedPublisher PD

Assessment of Pneumonia Severity Indices as Mortality Predictors

BACKGROUND The leading cause of infectious disease death in the United States is community-acquired pneumonia (CAP). Several pneumonia severity indices exist and are widely used as tools to assist physicians regarding site of care based on risk of death. However, limited data exists that discerns which of the most commonly used severity scores is the best predictor of mortality across multiple time points. The objective of this study is to determine the best mortality predictor at different time points between four of the most commonly used pneumonia severity scores. METHODS This was a secondary analysis of a prospective, multicenter, population-based, observational study of patients hospitalized with CAP in the city of Louisville, KY. The severity indices used were the American Thoracic Society (ATS) criteria, the Pneumonia Severity Index (PSI), the British Thoracic Society criteria (CURB-65), Quick Sepsis-Related Organ Failure Assessment (QSOFA), and direct ICU admission to represent physician discretion. The accuracy, kappa statistic, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the ability to predict in-hospital, 30-day, 6-month, and 1-year mortality. 95% confidence intervals for each variable were generated by bootstrapping with random sampling and resampling of the subjects 1000 times. In addition, the area under the curve (AUC) was calculated for each severity score and mortality time point. RESULTS There were 6013 eligible patients included in this analysis with data collected between the years 2014 and 2016. At each time point, the QSOFA had the highest sensitivity and NPV, while the PSI had the highest specificity and PPV. QSOFA had the highest accuracy for in-hospital mortality, 30-day mortality, and 6-month mortality, and the CURB-65 had highest mortality for 1-year mortality. The QSOFA had the highest kappa statistic for in-hospital mortality, the CURB-65 had the highest kappa statistic for 30-day mortality, and the PSI had the highest kappa statistic for 6-month and 1-year mortality. The AUC was highest for the ATS criteria for in-hospital mortality, and was highest for the PSI at the remaining time points. CONCLUSIONS The results of this study show that QSOFA and the PSI are the most reliable severity indices for mortality predictions based on these measures. QSOFA was found, on average, to have the highest accuracy, sensitivity, and NPV. Additionally, PSI was found, on average, to have the highest kappa statistic, specificity, and PPV. The AUC, on average, was best with PSI as the predictor. QSOFA is most capable of making true negative predictions and the PSI is the most capable of making true positive predictions across the four time points

Palliative Laparoscopic End Colostomy in a Nonagenarian

Patients with advanced gynecologic malignancy often require fecal diversion as a sole procedure in cases of obstruction or fistula formation. This unique patient population has a frequent history of advanced age, prior abdominal surgery, pelvic radiation, poor nutritional status and medical comorbidities. The use of laparoscopic colostomy for palliative fecal diversion in this context has not been well described in the gynecologic oncology literature. We present the first case of palliative laparoscopic end-colostomy in a nonagenarian as a sole procedure for fecal diversion in advanced gynecologic malignancy. Palliative laparoscopic end-colostomy is a safe, feasible, and effective method to optimize quality of life in select elderly women with advanced gynecologic malignancy