Miracle-dz/UniFAR-FTUs huggingface dataset:
Calcineurin Governs Thermotolerance and Virulence of Cryptococcus gattii

The pathogenic yeast Cryptococcus gattii, which is causing an outbreak in the Pacific Northwest region of North America, causes life-threatening pulmonary infections and meningoencephalitis in healthy individuals, unlike Cryptococcus neoformans, which commonly infects immunocompromised patients. In addition to a greater predilection for C. gattii to infect healthy hosts, the C. gattii genome sequence project revealed extensive chromosomal rearrangements compared with C. neoformans, showing genomic differences between the two Cryptococcus species. We investigated the roles of C. gattii calcineurin in three molecular types: VGIIa (R265), VGIIb (R272), and VGI (WM276). We found that calcineurin exhibits a differential requirement for growth on solid medium at 37°, as calcineurin mutants generated from R265 were more thermotolerant than mutants from R272 and WM276. We demonstrated that tolerance to calcineurin inhibitors (FK506, CsA) at 37° is linked with the VGIIa molecular type. The calcineurin mutants from the R272 background showed the most extensive growth and morphological defects (multivesicle and larger ring-like cells), as well as increased fluconazole susceptibility. Our cellular architecture examination showed that C. gattii and C. neoformans calcineurin mutants exhibit plasma membrane disruptions. Calcineurin in the C. gattii VGII molecular type plays a greater role in controlling cation homeostasis compared with that in C. gattii VGI and C. neoformans H99. Importantly, we demonstrate that C. gattii calcineurin is essential for virulence in a murine inhalation model, supporting C. gattii calcineurin as an attractive antifungal drug target.
Equivalence of dose response curves

This paper investigates the problem if the difference between two parametric models m1,m2 describing the relation between the response and covariates in two groups is of no practical significance, such that inference can be performed on the basis of the pooled sample. Statistical methodology is developed to test the hypotheses H0 : d(m1,m2) ≥ " versus H1 : d(m1,m2) < " of equivalence between the two regression curves m1,m2, where d denotes a metric measuring the distance between m1 and m2 and " is a pre specified constant. Our approach is based on an estimate d( ˆ m1, ˆ m2) of this distance and its asymptotic properties. In order to improve the approximation of the nominal level for small sample sizes a bootstrap test is developed, which addresses the specific form of the interval hypotheses. In particular, data has to be generated under the null hypothesis, which implicitly defines a manifold for the vector of parameters. The results are illustrated by means of a simulation study, and it is demonstrated that the new methods yield a substantial improvement with respect to power compared to all currently available tests for this problem.
Improved online algorithms for the sorting buffer problem on line metrics

An instance of the sorting buffer problem consists of a metric space and a server, equipped with a finite-capacity buffer capable of holding a limited number of requests. An additional ingredient of the input is an online sequence of requests, each of which is characterized by a destination in the given metric space; whenever a request arrives, it must be stored in the sorting buffer. At any point in time, a currently pending request can be served by drawing it out of the buffer and moving the server to its corresponding destination. The objective is to serve all input requests in a way that minimizes the total distance traveled by the server. In this article, we focus our attention on instances of the problem in which the underlying metric is either an evenly-spaced line metric or a continuous line metric. Our main findings can be briefly summarized as follows. (1) We present a deterministic O(log n)-competitive algorithm for n-point evenly-spaced line metrics. This result improves on a randomized O(log2 n)-competitive algorithm due to Khandekar and Pandit [2006b]. It also refutes their conjecture, stating that a deterministic strategy is unlikely to obtain a nontrivial competitive ratio. (2) We devise a deterministic O(log N log log N)-competitive algorithm for continuous line metrics, where N denotes the length of the input sequence. In this context, we introduce a novel discretization technique of independent interest. (3) We establish the first nontrivial lower bound for the evenly-spaced case, by proving that the competitive ratio of any deterministic algorithm is at least 2 + &sqrt;3/&sqrt;3 ≈ 2.154. This result settles, to some extent, an open question due to Khandekar and Pandit [2006b], who posed the task of attaining lower bounds on the achievable competitive ratio as a foundational objective for future research.
Innovation , Litigation , and New Drugs

A generic drug maker that has been sued for infringing a patent on a branded drug will sometimes promise, as part of an agreement settling the litigation, to delay selling its drug until as late as the expiration of the patent term. I adapt the standard optimal patent term model to determine whether the delay in competition caused by such agreements raises consumer welfare by increasing rewards for innovation. Calibrating the model with U.S. drug market data, I find that, for all but the patents with the greatest probability of surviving litigation, settlements that delay entry by more than fifteen months harm consumers. I find that generic drug makers are in some cases willing to agree to enough delay to harm consumers, even in the absence of a reverse payment, and that harm can reach $1.3 billion for the average drug. *Assistant Professor, Department of Risk Management and Insurance, Robinson College of Business, Secondary Appointment, College of Law, Georgia State University. Email: rwoodcock@gsu.edu. I am grateful to Kangoh Lee, F.M. Scherer, Glenn W. Harrison, Alan G. Isaac, Walter G. Park, Maria Arbatskaya, and participants at the 2015 Roundtable for Engineering Entrepreneurship Research (REER) at Georgia Tech for comments on this work.
Time-Varying Climate Sensitivity from Regional Feedbacks

AbstractThe sensitivity of global climate with respect to forcing is generally described in terms of the global climate feedback—the global radiative response per degree of global annual mean surface temperature change. While the global climate feedback is often assumed to be constant, its value—diagnosed from global climate models—shows substantial time variation under transient warming. Here a reformulation of the global climate feedback in terms of its contributions from regional climate feedbacks is proposed, providing a clear physical insight into this behavior. Using (i) a state-of-the-art global climate model and (ii) a low-order energy balance model, it is shown that the global climate feedback is fundamentally linked to the geographic pattern of regional climate feedbacks and the geographic pattern of surface warming at any given time. Time variation of the global climate feedback arises naturally when the pattern of surface warming evolves, actuating feedbacks of different strengths in different.
Independent associations between metabolic syndrome, diabetes mellitus and atherosclerosis: observations from the Dallas Heart Study

Diabetes mellitus (DM) has been termed a “coronary disease equivalent”, yet data suggest that only those DM subjects with metabolic syndrome (MetS) are at increased coronary risk. Using data from the Dallas Heart Study, a large, probability-based population study, we assessed the individual and joint associations between MetS, DM and atherosclerosis, defined as coronary artery calcium (CAC) detected by electron-beam computerised tomography (EBCT) and abdominal aortic plaque (AAP) detected by magnetic resonance imaging. Among 2,735 participants, the median age was 44 years; 1,863 (68%) were non-white; 1,509 (55%) were women; 697 (25.5%) had MetS without DM; 53 (1.9%) had DM without MetS; and 246 (9.0%) had both DM and MetS. The prevalence of CAC increased from those with neither MetS nor DM (16.6%) to MetS only (24.0%) to DM only (30.2%) to both MetS and DM (44.7%) (ptrend <0.0001). The prevalence of CAC was higher in those with both DM and MetS versus either alone (p<0.0001). After adjustment, MetS and DM were each independently associated with CAC (odds ratio [OR] 1.4, 95% confidence intervals [CI] 1.1–1.8; OR 1.8, 95% CI 1.3–2.5, respectively). Compared with the group without DM or MetS, those with both MetS and DM had the most CAC (adjusted OR 2.3; 95% CI 1.6–3.2). All analyses of AAP yielded qualitatively similar results. In conclusion, both MetS and DM are independently associated with an increased prevalence of atherosclerosis, with the highest observed prevalence in subjects with both DM and MetS.
Reliability and validity of Chinese version of the Addiction Severity Index among drug users in the community.

OBJECTIVE To assess the reliability and validity of a new Chinese version of the Addiction Severity Index (ASI-C) in drug users in the community. METHODS Three hundred and eighty-one drug users in the community in Chengdu, Sichuan province were recruited. They were interviewed with a questionnaire consisting of the ASI-C revised on the basis of the previous Chinese version and 38 were interviewed for the second time at an interval of 7 days to evaluate test-retest reliability. RESULTS Cronbach's α coefficients for the internal consistency of the scale varied from 0.49 to 0.86. Test-retest correlation coefficients ranged from 0.50 to 0.93. Criterion validity was found acceptable, as compared with the Symptom Checklist 90 (SCL-90). CONCLUSION The ASI-C presented acceptable reliability and validity in a sample of drug users in the community.
An architecture based FEM framework to bridge the subcellular scale to tissue scale mechanical properties

From subcellular to tissue scale, plant cells maintain a distinctive hierarchy in its structural organization. However, due to microscale size and the lack of knowledge of the mechanics of plant cell and how they adhere to each other, the bridging between subcellular and extracellular scale is yet to be understood sufficiently. In this study, we have taken an onion outer epidermal peel, which is an array of one side wall profile from many cells, as the representative of a plant tissue and developed a framework of structure-based multiscale finite element method (FEM) computational model to scale-up mechanical properties from subcellular to tissue scale. A 3D repetitive volume element (RVE), which includes both subcellular and extracellular parameters, was built with ABAQUS® (a finite element software). Two dimensionally arranged RVEs would make a tissue patch of multiple cells. A sensitivity analysis was performed to understand the contribution of intercellular interaction or middle lamella (ML) to overall mechanical responses. We found that a ML layer, which was stiffer than wall fragment, did not have a major contribution to tissue scale mechanical properties. Once validated with experimental results at the same scale and environmental condition, this model will be used as a framework to study the contribution of extracellular parameters to overall mechanical responses in a variety of model system manifesting multiscale characteristics.
Proacrosin activation and acrosin release during the guinea pig acrosome reaction

The kinetics of proacrosin activation and release from guine pig spermatozoa during the nonsynchronous acrosome reaction were studied. Epididymal spermatozoa were incubated at 37°C in a defined medium (pH 7.8) containing 1.7 mM Ca2+. After 195 min, 78% of the motile spermatozoa had undergone the acrosome reaction as determined by light microscopy. Acrosin and proacrosin levels in the spermatozoa and medium were measured at the beginning of the incubation period. Most of the total acrosin activity (78%) was associated with the spermatozoa, of which greater than 90% was in the form of proacrosin. Proacrosin represented a small, stable fraction (23%) of the total acrosin in the medium; it did not activate to acrosin while in the medium. After 195 min, a decrease in sperm‐associated total acrosin (42%; p < 0.05) was accompanied by an increase in the total acrosin level in the medium (115%; P < 0.05). No change in the relative proacrosin content (percent of total acrosin) was evident in either medium or spermatozoa. Additional experiments quantified acrosin and proacrosin during the progression of the acrosome reaction. Both the loss of sperm‐associated total acrosin and the increase in total acrosin levels in the medium were highly correlated with the fraction of acrosome‐reacted spermatozoa (r = 0.954 and 0.922, respectively; P < 0.001). However, the rate of acrosin appearance in the medium was only 60% (P < 0.001) of the rate of acrosin loss from the spermatozoa. The fractional proacrosin content of spermatozoa (94%) and medium (31%) remained unchanged during the acrosome reaction (r = 0.15 and 0.30, respectively; P > 0.1). From these data, it was possible to estimate the total acrosin content of acrosome‐intact spermatozoa (434 mlU/107 spermatozoa), and the fractions of the total sperm acrosin levels that are (1) released as active acrosin (37%), (2) released as proacrosin (17%), (3) inactivated (36%), and (4) associated with the spermatozoa (10%) during the acrosome reaction. The data suggest that proacrosin activation occurs within the spermatozoa, prior to distruption of the acrosome; this finding is consistent with the contention that acrosin is an active component of the mechanism underlying the acrosome reaction.
Toward a Model for the Progenitors of Gamma-Ray Bursts

We consider models for gamma-ray bursts in which a collimated jet expands either into a homogeneous medium or into a stellar wind environment, and we calculate the expected afterglow temporal behavior. We show that (1) following a break and a faster decay afterglows should exhibit a flattening, which may be detectable in both the radio and optical bands, and (2) only observations at times much shorter than a day can clearly distinguish between a fireball interacting with a homogeneous medium and one interacting with a stellar wind. Using our results, we demonstrate that constraints can be placed on progenitor models. In particular, existing data imply that while some long-duration bursts may be produced by collapses of massive stars, it is almost certain that not all long-duration bursts are produced by such progenitors.
Various Techniques for the Surgical Treatment of Common Bile Duct Stones: A Meta Review

Common bile duct stones (CBDSs) may occur in up to 3%–14.7% of all patients for whom cholecystectomy is preformed. Patients presenting with CBDS have symptoms including: biliary colic, jaundice, cholangitis, pancreatitis or may be asymptomatic. It is important to distinguish between primary and secondary stones, because the treatment approach varies. Stones found before, during, and after cholecystectomy had also differing treatments. Different methods have been used for the treatment of CBDS but the suitable therapy depends on conditions such as patient' satisfaction, number and size of stones, and the surgeons experience in laparoscopy. Endoscopic retrograde cholangiopancreatography with or without endoscopic biliary sphincterotomy, laparoscopic CBD exploration (transcystic or transcholedochal), or laparotomy with CBD exploration (by T-tube, C-tube insertion, or primary closure) are the most commonly used methods managing CBDS. We will review the pathophysiology of CBDS, diagnosis, and different techniques of treatment with especial focus on the various surgical modalities.
Post-exercise whey protein hydrolysate supplementation induces a greater increase in muscle protein synthesis than its constituent amino acid content

It is well known that ingestion of a protein source is effective in stimulating muscle protein synthesis after exercise. In addition, there are numerous reports on the impact of leucine and leucine-rich whey protein on muscle protein synthesis and mammalian target of rapamycin (mTOR) signalling. However, there is only limited information on the effects of whey protein hydrolysates (WPH) on muscle protein synthesis and mTOR signalling. The aim of the present study was to compare the effects of WPH and amino acids on muscle protein synthesis and the initiation of translation in skeletal muscle during the post-exercise phase. Male Sprague–Dawley rats swam for 2 h to depress muscle protein synthesis. Immediately after exercise, the animals were administered either carbohydrate (CHO), CHO plus an amino acid mixture (AA) or CHO plus WPH. At 1 h after exercise, the supplements containing whey-based protein (AA and WPH) caused a significant increase in the fractional rate of protein synthesis (FSR) compared with CHO. WPH also caused a significant increase in FSR compared with AA. Post-exercise ingestion of WPH caused a significant increase in the phosphorylation of mTOR levels compared with AA or CHO. In addition, WPH caused greater phosphorylation of ribosomal protein S6 kinase and eukaryotic initiation factor 4E-binding protein 1 than AA and CHO. In contrast, there was no difference in plasma amino acid levels following supplementation with either AA or WPH. These results indicate that WPH may include active components that are superior to amino acids for stimulating muscle protein synthesis and initiating translation.
WLC35-2: Hierarchical Location Management for Transport Layer Mobility

IP mobility can be handled at different layers of the protocol stack. Mobile IP has been developed to handle mobility of Internet hosts at the network layer. As an alternative solution, a number of transport layer mobility protocols have been proposed. However, the location management schemes used in these transport layer solutions are not suitable for frequent mobile handovers due to user's high mobility. In this paper, we propose HiSlGMA, a hierarchical location management scheme for transport layer mobility schemes. We used an analytical model to evaluate HiSlGMA using signaling cost as the performance measure, followed by comparison of the signalling cost of HiSlGMA and hierarchical mobile IPv6 (an enhancement of Mobile IP) and existing transport layer mobility solutions.
Using formal techniques to debug the AMBA system-on-chip bus protocol

System-on-chip (SoC) designs use bus protocols for high performance data transfer among the intellectual property (IP) cores. These protocols incorporate advanced features such as pipelining, burst and split transfers. In this paper, we describe a case study in formally verifying a widely used SoC bus protocol: the advanced micro-controller bus architecture (AMBA) protocol from ARM. In particular, we develop a formal specification of the AMBA protocol. We then employ model checking, a state space exploration based formal verification technique, to verify crucial design invariants. The presence of pipelining and split transfer in the AMBA protocol gives rise to interesting corner cases, which are hard to detect via informal reasoning. Using the SMV model checker, we have detected a potential bus starvation scenario in the AMBA protocol. Such scenarios demonstrate the inherent intricacies in designing pipelined bus protocols.
Mass Reduction and Functional Improvement of the Left Ventricle after Aortic Valve Replacement for Degenerative Aortic Stenosis

Background Left ventricular (LV) hypertrophy caused by aortic valve stenosis (AS) leads to cardiovascular morbidity and mortality. We sought to determine whether aortic valve replacement (AVR) decreases LV mass and improves LV function. Materials and Methods Retrospective review for 358 consecutive patients, who underwent aortic valve replacement for degenerative AS between January 1995 and December 2008, was performed. There were 230 men and 128 women, and their age at operation was 63.2±10 years (30~85 years). Results There was no in-hospital mortality, and mean follow-up duration after discharge was 48.9 months (2~167 months). Immediate postoperative echocardiography revealed that LV mass index and mean gradient across the aortic valve decreased significantly (p<0.001), and LV mass continued to decrease during the follow-up period (p<0.001). LV ejection fraction (EF) temporarily decreased postoperatively (p<0.001), but LV function recovered immediately and continued to improve with a significant difference between preoperative and postoperative EF (p<0.001). There were 15 late deaths during the follow-up period, and overall survival at 5 and 10 years were 94% and 90%, respectively. On multivariable analysis, age at operation (p=0.008), concomitant coronary bypass surgery (p<0.003), lower preoperative LVEF (<40%) (p=0.0018), and higher EUROScore (>7) (p=0.045) were risk factors for late death. Conclusion After AVR for degenerative AS, reduction of left ventricular mass and improvement of left ventricular function continue late after operation.
Urinary tract infection after stroke.

BACKGROUND Urinary tract infection (UTI) is a recognized complication of stroke. We aimed to determine the incidence of UTI after acute stroke, the risk factors associated with this complication, and its association with outcome. METHODS Prospective study of consecutive acute stroke patients admitted to an urban teaching hospital. Routine clinical assessment included the modified National Institutes of Health Stroke Scale (mNIHSS) and modified Rankin scale (mRS). Patients were followed up for 3 months, including recording of clinician diagnosis of UTI. RESULTS We studied 412 patients; 65 (15.8%) were diagnosed with UTI, at a median of 14 days (IQR = 4-39) post-stroke. In a binomial multivariate regression analysis, UTI was associated with urinary catheterization (OR = 3.03, 95% CI 1.41-6.52), higher mRS (OR = 1.85, 1.29-2.64) and increasing age (OR = 1.51, 1.13-2.00 for each decade). UTI was associated with death or disability at 3 months, however, this link was attenuated and became non-significant when measures of stroke severity and pre-stroke morbidity were included in a multivariate analysis. CONCLUSION UTI is common after acute stroke. It is associated with urinary catheterization, post-stroke disability and increasing age. Avoidance of catheterization might reduce the incidence of this common complication.
The broadly conserved regulator PhoP links pathogen virulence and membrane potential in Escherichia coli

PhoP is considered a virulence regulator despite being conserved in both pathogenic and non‐pathogenic Enterobacteriaceae. While Escherichia coli strains represent non‐pathogenic commensal isolates and numerous virulent pathotypes, the PhoP virulence regulator has only been studied in commensal E. coli. To better understand how conserved transcription factors contribute to virulence, we characterized PhoP in pathogenic E. coli. Deletion of phoP significantly attenuated E. coli during extraintestinal infection. This was not surprising since we demonstrated that PhoP differentially regulated the transcription of > 600 genes. In addition to survival at acidic pH and resistance to polymyxin, PhoP was required for repression of motility and oxygen‐independent changes in the expression of primary dehydrogenase and terminal reductase respiratory chain components. All phenotypes have in common a reliance on an energized membrane. Thus, we hypothesized that PhoP mediates these effects by regulating genes encoding proteins that generate proton motive force. Indeed, bacteria lacking PhoP exhibited a hyperpolarized membrane and dissipation of the transmembrane electrochemical gradient increased susceptibility of the phoP mutant to acidic pH, while inhibiting respiratory generation of the proton gradient restored resistance to antimicrobial peptides independent of lipopolysaccharide modification. These findings demonstrate a connection between PhoP, virulence and the energized state of the membrane.