Miracle-dz/UniFAR-FTUs huggingface dataset:
A Single-Amino-Acid Substitution at Position 225 in Hemagglutinin Alters the Transmissibility of Eurasian Avian-Like H1N1 Swine Influenza Virus in Guinea Pigs

ABSTRACT Efficient transmission from human to human is the prerequisite for an influenza virus to cause a pandemic; however, the molecular determinants of influenza virus transmission are still largely unknown. In this study, we explored the molecular basis for transmission of Eurasian avian-like H1N1 (EAH1N1) swine influenza viruses by comparing two viruses that are genetically similar but differ in their transmissibility in guinea pigs: the A/swine/Guangxi/18/2011 virus (GX/18) is highly transmissible by respiratory droplet in guinea pigs, whereas the A/swine/Heilongjiang/27/2012 virus (HLJ/27) does not transmit in this animal model. We used reverse genetics to generate a series of reassortants and mutants in the GX/18 background and tested their transmissibility in guinea pigs. We found that a single-amino-acid substitution of glycine (G) for glutamic acid (E) at position 225 (E225G) in the HA1 protein completely abolished the respiratory droplet transmission of GX/18, whereas the substitution of E for G at the same position (G225E) in HA1 enabled HLJ/27 to transmit in guinea pigs. We investigated the underlying mechanism and found that viruses bearing 225E in HA1 replicated more rapidly than viruses bearing 225G due to differences in assembly and budding efficiencies. Our study indicates that the amino acid 225E in HA1 plays a key role in EAH1N1 swine influenza virus transmission and provides important information for evaluating the pandemic potential of field influenza virus strains. IMPORTANCE Efficient transmission among humans is a prerequisite for a novel influenza virus to cause a human pandemic. Transmissibility of influenza viruses is a polygenic trait, and understanding the genetic determinants for transmissibility will provide useful insights for evaluating the pandemic potential of influenza viruses in the field. Several amino acids in the hemagglutinin (HA) protein of influenza viruses have been shown to be important for transmissibility, usually by increasing virus affinity for human-type receptors. In this study, we explored the genetic basis of the transmissibility difference between two Eurasian avian-like H1N1 (EAH1N1) swine influenza viruses in guinea pigs and found that the amino acid glutamic acid at position 225 in the HA1 protein plays a critical role in the transmission of EAH1N1 virus by increasing the efficiency of viral assembly and budding.
Effects of Geometry of Ring Spinning Triangle on Yarn Torque: Part II: Distribution of Fiber Tension within a Yarn and Its Effects on Yarn Residual Torque

This paper presents a theoretical analysis of fiber tension distribution within a ring spun yarn without relaxation. Yarn residual torque is determined on the basis of the translation of fiber tension at the spinning triangle, as presented in the first part of this series of papers, into the fiber tension within the yarn. The results from numerical simulations indicate that, with fiber buckling, the yarn exhibits a lower average fiber tension and, thus, a much reduced yarn residual torque than that without fiber buckling. Comparison with experiments confirmed that fiber buckling exists in ring yarns while the assumption of no fiber buckling is not realistic. Generally, a low yarn twist results in low average fiber tension in the yarn and, thus, a reduced yarn residual torque. A symmetrical spinning triangle leads to a slightly higher yarn residual torque than a right-angle spinning triangle when the yarn counts and twists are identical and fiber buckling occurs.
Cooperation of Antiporter LAT2/CD98hc with Uniporter TAT1 for Renal Reabsorption of Neutral Amino Acids.

Background Reabsorption of amino acids (AAs) across the renal proximal tubule is crucial for intracellular and whole organism AA homeostasis. Although the luminal transport step is well understood, with several diseases caused by dysregulation of this process, the basolateral transport step is not understood. In humans, only cationic aminoaciduria due to malfunction of the basolateral transporter y+LAT1/CD98hc (SLC7A7/SLC3A2), which mediates the export of cationic AAs, has been described. Thus, the physiologic roles of basolateral transporters of neutral AAs, such as the antiporter LAT2/CD98hc (SLC7A8/SLC3A2), a heterodimer that exports most neutral AAs, and the uniporter TAT1 (SLC16A10), which exports only aromatic AAs, remain unclear. Functional cooperation between TAT1 and LAT2/CD98hc has been suggested by in vitro studies but has not been evaluated in vivoMethods To study the functional relationship of TAT1 and LAT2/CD98hc in vivo, we generated a double-knockout mouse model lacking TAT1 and LAT2, the catalytic subunit of LAT2/CD98hc (dKO LAT2-TAT1 mice). Results Compared with mice lacking only TAT1 or LAT2, dKO LAT2-TAT1 mice lost larger amounts of aromatic and other neutral AAs in their urine due to a tubular reabsorption defect. Notably, dKO mice also displayed decreased tubular reabsorption of cationic AAs and increased expression of y+LAT1/CD98hc.Conclusions The LAT2/CD98hc and TAT1 transporters functionally cooperate in vivo, and y+LAT1/CD98hc may compensate for the loss of LAT2/CD98hc and TAT1, functioning as a neutral AA exporter at the expense of some urinary loss of cationic AAs. Cooperative and compensatory mechanisms of AA transporters may explain the lack of basolateral neutral aminoacidurias in humans.
Cardiac Kir2.1 and NaV1.5 Channels Traffic Together to the Sarcolemma to Control Excitability

Rationale: In cardiomyocytes, NaV1.5 and Kir2.1 channels interact dynamically as part of membrane bound macromolecular complexes. Objective: The objective of this study was to test whether NaV1.5 and Kir2.1 preassemble during early forward trafficking and travel together to common membrane microdomains. Methods and Results: In patch-clamp experiments, coexpression of trafficking-deficient mutants Kir2.1&Dgr;314-315 or Kir2.1R44A/R46A with wild-type (WT) NaV1.5WT in heterologous cells reduced inward sodium current compared with NaV1.5WT alone or coexpressed with Kir2.1WT. In cell surface biotinylation experiments, expression of Kir2.1&Dgr;314-315 reduced NaV1.5 channel surface expression. Glycosylation analysis suggested that NaV1.5WT and Kir2.1WT channels associate early in their biosynthetic pathway, and fluorescence recovery after photobleaching experiments demonstrated that coexpression with Kir2.1 increased cytoplasmic mobility of NaV1.5WT, and vice versa, whereas coexpression with Kir2.1&Dgr;314-315 reduced mobility of both channels. Viral gene transfer of Kir2.1&Dgr;314-315 in adult rat ventricular myocytes and human induced pluripotent stem cell–derived cardiomyocytes reduced inward rectifier potassium current and inward sodium current, maximum diastolic potential and action potential depolarization rate, and increased action potential duration. On immunostaining, the AP1 (adaptor protein complex 1) colocalized with NaV1.5WT and Kir2.1WT within areas corresponding to t-tubules and intercalated discs. Like Kir2.1WT, NaV1.5WT coimmunoprecipitated with AP1. Site-directed mutagenesis revealed that NaV1.5WT channels interact with AP1 through the NaV1.5Y1810 residue, suggesting that, like for Kir2.1WT, AP1 can mark NaV1.5 channels for incorporation into clathrin-coated vesicles at the trans-Golgi. Silencing the AP1 υ-adaptin subunit in human induced pluripotent stem cell–derived cardiomyocytes reduced inward rectifier potassium current, inward sodium current, and maximum diastolic potential and impaired rate-dependent action potential duration adaptation. Conclusions: The NaV1.5-Kir2.1 macromolecular complex pre-assembles early in the forward trafficking pathway. Therefore, disruption of Kir2.1 trafficking in cardiomyocytes affects trafficking of NaV1.5, which may have important implications in the mechanisms of arrhythmias in inheritable cardiac diseases.
Dexmedetomidine During Noninvasive Ventilation: Different Acuity, Different Risks?

Steven L. Shein, MD Division of Pediatric Critical Care Medicine Department of Pediatrics Rainbow Babies and Children’s Hospital Cleveland, OH subsequent mini-bolus doses, if needed. Conversely, septic shock may be characterized by reduced α-adrenergic responsiveness so that higher epinephrine doses are needed. Genetically associated reduced α-adrenergic responsiveness may also partly explain the wide variation in response (11). Although pediatric intensivists have favored epinephrine over norepinephrine for vasoactive support of septic patients (12), epinephrine has more metabolic side effects, such as increasing lactate concentration, stimulating potassium movement into cells, and redirecting blood flow from the splanchnic circulation (13). Overall, the effectiveness of mini-bolus epinephrine is difficult to determine from this study (1). Three children (16%) progressed to cardiac arrest, and three other children required extracorporeal membrane oxygenation. Those children on vasoactive infusions had their overall vasoactive infusion score significantly increase as clinicians strove to stabilize the patient. Finally, it is important to recall that medication errors are common in children (14). Besides errors in prescribing, the use of mini-dose epinephrine requires preparing a dilute solution for injection at the bedside. This introduces risks related to errors in drug preparation and subsequent calculation of the correct dose and volume to use. If mini-bolus doses are contemplated in the PICU, the dose and dose volume should be precalculated on emergency drug sheets, and explicit instructions on dilution preparation should be included on the drug sheet or stored with the epinephrine on the code cart.
Prescription Drug Monitoring Programs Are Associated With Sustained Reductions In Opioid Prescribing By Physicians.

State prescription drug monitoring programs are promising tools to rein in the epidemic of prescription opioid overdose. We used data from a national survey to assess the effects of these programs on the prescribing of opioid analgesics and other pain medications in ambulatory care settings at the point of care in twenty-four states from 2001 to 2010. We found that the implementation of a prescription drug monitoring program was associated with more than a 30 percent reduction in the rate of prescribing of Schedule II opioids. This reduction was seen immediately following the launch of the program and was maintained in the second and third years afterward. Effects on overall opioid prescribing and prescribing of non-opioid analgesics were limited. Increased use of these programs and the adoption of new policies and practices governing their use may have contributed to sustained effectiveness. Future studies are needed to evaluate the policies' comparative effectiveness.
Unchanged Plasma Levels of the Soluble Urokinase Plasminogen Activator Receptor in Elective Coronary Artery Bypass Graft Surgery Patients and Cardiopulmonary Bypass Use

Objective and Design The soluble urokinase plasminogen activator receptor (suPAR) has been recently recognized as a potential biological marker of various disease states, but the impact of a major surgical intervention on the suPAR level has not yet been established. The aim of our study was to investigate if the induction of a systemic inflammatory reaction in response to cardiopulmonary bypass would be accompanied by an increase in the plasma suPAR level. Methods and Subjects Patients undergoing coronary artery bypass grafting under cardiopulmonary bypass (CPB) were added. Based on the baseline suPAR level, patients were divided into group 1 (suPAR within normal range) or group 2 (suPAR above range). Blood was collected before the induction of anesthesia and 6 and 24 hours after surgery. Plasma suPAR, IL-6, IL-8, TNF-α, troponin I, NT-proBNP, and NGAL were quantified to assess the impact of surgical trauma on these markers. Results The baseline suPAR level was within the normal range in 31 patients (3.3 ng/mL), and elevated in 29 (5.1 ng/mL) (p<0.001). Baseline mediators of systemic inflammatory reaction concentrations (IL-6, TNF-α, and IL-8) and organ injury indices (troponin I, NT-proBNP, and NGAL) were low and increased after surgery in all patients (p<0.05). The surgery did not cause significant changes in the suPAR level either at 6 or 24 hours after, however the difference between groups observed at baseline remained substantial during the postoperative period. Conclusions There was no change in the suPAR level observed in patients subjected to elective cardiac coronary artery bypass surgery and CPB, despite activation of a systemic inflammatory reaction.
Seed-Mediated Gene Flow Promotes Genetic Diversity of Weedy Rice within Populations: Implications for Weed Management

Increased infestation of weedy rice—a noxious agricultural pest has caused significant reduction of grain yield of cultivated rice (Oryza sativa) worldwide. Knowledge on genetic diversity and structure of weedy rice populations will facilitate the design of effective methods to control this weed by tracing its origins and dispersal patterns in a given region. To generate such knowledge, we studied genetic diversity and structure of 21 weedy rice populations from Sri Lanka based on 23 selected microsatellite (SSR) loci. Results indicated an exceptionally high level of within-population genetic diversity (He = 0.62) and limited among-population differentiation (Fst = 0.17) for this predominantly self-pollinating weed. UPGMA analysis showed a loose genetic affinity of the weedy rice populations in relation to their geographical locations, and no obvious genetic structure among populations across the country. This phenomenon was associated with the considerable amount of gene flow between populations. Limited admixture from STRUCTURE analyses suggested a very low level of hybridization (pollen-mediated gene flow) between populations. The abundant within-population genetic diversity coupled with limited population genetic structure and differentiation is likely caused by the considerable seed-mediated gene flow of weedy rice along with the long-distance exchange of farmer-saved rice seeds between weedy-rice contaminated regions in Sri Lanka. In addition to other effective weed management strategies, promoting the application of certified rice seeds with no weedy rice contamination should be the immediate action to significantly reduce the proliferation and infestation of this weed in rice ecosystems in countries with similar rice farming styles as in Sri Lanka.
The risk of violence associated with novel psychoactive substance misuse in patients presenting to acute mental health services

Novel psychoactive substance (NPS) availability is increasing at a phenomenal rate and so is their associated misuse. Currently, the harms associated with NPS misuse are unclear. This report presents the initial findings of a continuing study looking into the impact of NPS misuse on admissions to an acute mental health facility in London. Violence preadmission and violence during admission have been found to be significant in NPS misusers compared to non‐NPS substance misusers. Our findings have important consequences for acute mental health, emergency, and public health services. NPS misusers require specific assessment and risk management to reduce the risk of violence towards others.
Landscape controls on the timing of spring, autumn, and growing season length in mid‐Atlantic forests

The timing of spring leaf development, trajectories of summer leaf area, and the timing of autumn senescence have profound impacts to the water, carbon, and energy balance of ecosystems, and are likely influenced by global climate change. Limited field‐based and remote‐sensing observations have suggested complex spatial patterns related to geographic features that influence climate. However, much of this variability occurs at spatial scales that inhibit a detailed understanding of even the dominant drivers. Recognizing these limitations, we used nonlinear inverse modeling of medium‐resolution remote sensing data, organized by day of year, to explore the influence of climate‐related landscape factors on the timing of spring and autumn leaf‐area trajectories in mid‐Atlantic, USA forests. We also examined the extent to which declining summer greenness (greendown) degrades the precision and accuracy of observations of autumn offset of greenness. Of the dominant drivers of landscape phenology, elevation was the strongest, explaining up to 70% of the spatial variation in the onset of greenness. Urban land cover was second in importance, influencing spring onset and autumn offset to a distance of 32 km from large cities. Distance to tidal water also influenced phenological timing, but only within ~5 km of shorelines. Additionally, we observed that (i) growing season length unexpectedly increases with increasing elevation at elevations below 275 m; (ii) along gradients in urban land cover, timing of autumn offset has a stronger effect on growing season length than does timing of spring onset; and (iii) summer greendown introduces bias and uncertainty into observations of the autumn offset of greenness. These results demonstrate the power of medium grain analyses of landscape‐scale phenology for understanding environmental controls on growing season length, and predicting how these might be affected by climate change.
Impact of savings groups on the lives of the poor

Significance We conducted a large randomized evaluation of a savings-led microfinance program across three countries. This evaluation provides important evidence on the impact of a popular development intervention on the lives of low-income households in rural communities by looking at its effects on usage of financial services, microenterprise activity, income, female empowerment, consumption, and the ability to cope with shocks. Savings-led microfinance programs operate in poor rural communities in developing countries to establish groups that save and then lend out the accumulated savings to each other. Nonprofit organizations train villagers to create and lead these groups. In a clustered randomized evaluation spanning three African countries (Ghana, Malawi, and Uganda), we find that the promotion of these community-based microfinance groups leads to an improvement in household business outcomes and women’s empowerment. However, we do not find evidence of impacts on average consumption or other livelihoods.
Water Content Differences Have Stronger Effects than Plant Functional Groups on Soil Bacteria in a Steppe Ecosystem

Many investigations across natural and artificial plant diversity gradients have reported that both soil physicochemical factors and plant community composition affect soil microbial communities. To test the effect of plant diversity loss on soil bacterial communities, we conducted a five-year plant functional group removal experiment in a steppe ecosystem in Inner Mongolia (China). We found that the number and composition type of plant functional groups had no effect on bacterial diversity and community composition, or on the relative abundance of major taxa. In contrast, bacterial community patterns were significantly structured by soil water content differences among plots. Our results support researches that suggest that water availability is the key factor structuring soil bacterial communities in this semi-arid ecosystem.
Reliability and validity of measurements on digital study models and plaster models.

OBJECTIVE To compare manual plaster cast and digitized model analysis for accuracy and efficiency. MATERIAL AND METHODS Nineteen plaster models of orthodontic patients in permanent dentition were analyzed by two calibrated examiners. Analyses were performed with a diagnostic calliper and computer-assisted analysis after digitization of the plaster models. The reliability and efficiency of different examiners and methods were compared statistically using a mixed model. RESULTS Statistically significant differences were found for comparisons of all 28 teeth (P < 0.001), mandibular intermolar width (IMW, P = 0.0453), and overjet (P < 0.001 to P = 0.0329). Single-tooth measurements tended to have larger values when measured manually and the SD was between 0.06 and 1.33mm. Digital analyses gave significantly higher values for mandibular IMW and overjet. Less time was needed for digital measurements. CONCLUSION Clinical significance of the differences between the methods compared did not appear significant. 3D laser-scanned plaster model analysis appears to be an adequate, reliable, and time saving alternative to analogue model analysis using a calliper.
The Deterrence Effect of Prison: Dynamic Theory and Evidence

Using administrative, longitudinal data on felony arrests in Florida, we exploit the discontinuous increase in the punitiveness of criminal sanctions at 18 to estimate the deterrence effect of incarceration. Our analysis suggests a 2 percent decline in the log-odds of offending at 18, with standard errors ruling out declines of 11 percent or more. We interpret these magnitudes using a stochastic dynamic extension of Becker's (1968) model of criminal behavior. Calibrating the model to match key empirical moments, we conclude that deterrence elasticities with respect to sentence lengths are no more negative than -0.13 for young offenders.
Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy

Significance Ketamine is an NMDA receptor (NMDAR) antagonist that alleviates depressive symptoms in patients with treatment-resistant depression within hours of administering a single dose. However, psychoactive side effects limit its use. Understanding the mechanism underlying ketamine’s antidepressant effect is crucial in identifying targets for novel therapeutics with fewer side effects. Here, we report ketamine enhances excitability of pyramidal cells indirectly by reducing synaptic GABAergic inhibition, thus causing disinhibition. Additionally, we investigated whether other NMDAR antagonists and the muscarinic acetylcholine receptor antagonist scopolamine shared this disinhibition mechanism. Our results show that only those antagonists with antidepressant efficacy in humans disinhibit pyramidal cells at a clinically relevant concentration, supporting the concept that disinhibition is likely involved in the antidepressant effect of these antagonists. Low-dose ketamine, an open-channel N-methyl d-aspartate receptor (NMDAR) antagonist, mediates rapid antidepressant effects in humans that are mimicked in preclinical rodent models. Disinhibition of pyramidal cells via decreased output of fast-spiking GABAergic interneurons has been proposed as a key mechanism that triggers the antidepressant response. Unfortunately, to date, disinhibition has not been directly demonstrated. Furthermore, whether disinhibition is a common mechanism shared among other antagonists with rapid antidepressant properties in humans has not been investigated. Using in vitro electrophysiology in acute slices of dorsal hippocampus from adult male Sprague–Dawley rats, we examined the immediate effects of a clinically relevant concentration of ketamine to directly test the disinhibition hypothesis. As a mechanistic comparison, we also tested the effects of the glycine site NMDAR partial agonist/antagonist GLYX-13 (rapastinel), the GluN2B subunit-selective NMDAR antagonist Ro 25-6981, and the muscarinic acetylcholine receptor (mAChR) antagonist scopolamine. Low-dose ketamine, GLYX-13, and scopolamine reduced inhibitory input onto pyramidal cells and increased synaptically driven pyramidal cell excitability measured at the single-cell and population levels. Conversely, Ro 25-6981 increased the strength of inhibitory transmission and did not change pyramidal cell excitability. These results show a decrease in the inhibition/excitation balance that supports disinhibition as a common mechanism shared among those antagonists with rapid antidepressant properties. These data suggest that pyramidal cell disinhibition downstream of NMDAR antagonism could serve as a possible biomarker for the efficacy of rapid antidepressant therapy.