Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives

Significance AcrB is one of the major multidrug resistance-conferring antibiotic efflux pumps from pathogenic bacteria. We have designed and produced the periplasmic, substrate binding domain of AcrB and solved its crystal structure in complex with multiple novel pyranopyridine inhibitors, as well as with drugs transported by AcrB. The structural data are corroborated by various cellular assays and molecular dynamics (MD) simulations, and allow us to propose a mechanism for AcrB efflux inhibition. Furthermore, the results provide a molecular platform for the development of combinational therapies against pathogenic Enterobacteriaceae. The Escherichia coli AcrAB-TolC efflux pump is the archetype of the resistance nodulation cell division (RND) exporters from Gram-negative bacteria. Overexpression of RND-type efflux pumps is a major factor in multidrug resistance (MDR), which makes these pumps important antibacterial drug discovery targets. We have recently developed novel pyranopyridine-based inhibitors of AcrB, which are orders of magnitude more powerful than the previously known inhibitors. However, further development of such inhibitors has been hindered by the lack of structural information for rational drug design. Although only the soluble, periplasmic part of AcrB binds and exports the ligands, the presence of the membrane-embedded domain in AcrB and its polyspecific binding behavior have made cocrystallization with drugs challenging. To overcome this obstacle, we have engineered and produced a soluble version of AcrB [AcrB periplasmic domain (AcrBper)], which is highly congruent in structure with the periplasmic part of the full-length protein, and is capable of binding substrates and potent inhibitors. Here, we describe the molecular basis for pyranopyridine-based inhibition of AcrB using a combination of cellular, X-ray crystallographic, and molecular dynamics (MD) simulations studies. The pyranopyridines bind within a phenylalanine-rich cage that branches from the deep binding pocket of AcrB, where they form extensive hydrophobic interactions. Moreover, the increasing potency of improved inhibitors correlates with the formation of a delicate protein- and water-mediated hydrogen bond network. These detailed insights provide a molecular platform for the development of novel combinational therapies using efflux pump inhibitors for combating multidrug resistant Gram-negative pathogens.
Multicenter Performance Evaluation of a New TaqMan PCR Assay for Monitoring Human Immunodeficiency Virus RNA Load

ABSTRACT A TaqMan real-time PCR assay, the COBAS TaqMan human immunodeficiency virus (HIV) (HPS-CTMHIV) PCR assay, recently developed for the quantification of HIV type 1 RNA in plasma, was evaluated in comparison with the licensed COBAS AMPLICOR HIV-1 MONITOR (CAHIM) assay. In this study, we have analyzed the tests' sensitivities, precisions, and linearities using multiple replicates of a standard panel of HIV RNA covering a 7-logarithm range of concentrations, as well as serial threefold dilutions of high-titer clinical samples. The subtype inclusivity was also investigated, using a panel of subtypes A to H, while a collection of 160 clinical samples was analyzed to assess the tests' specificities and the systems' similarities. The results of these experiments showed that the HPS-CTMHIV assay has a sensitivity of 53 copies/ml (95% hit rate), 100% specificity, and good intra- and interassay precision. The results of the HPS-CTMHIV assay were linear in the 50- to 107-copies/ml range, with a correlation coefficient (R) for expected versus observed results of 0.98. Compared to the CAHIM assay, the HPS-CTMHIV assay showed a high correlation (R = 0.99) across the dynamic range of RNA concentrations that, for the CAHIM assay, requires two different sample preparations. Equivalent performances were also observed for the two systems in the detection and quantification of HIV subtypes A to H. These data indicate that the HPS-CTMHIV assay may be one of the tests of choice for monitoring viral load throughout the course of HIV infection and during highly active antiretroviral therapy.
PIP2 hydrolysis underlies agonist‐induced inhibition and regulates voltage gating of two‐pore domain K+ channels

Two‐pore (2‐P) domain potassium channels are implicated in the control of the resting membrane potential, hormonal secretion, and the amplitude, frequency and duration of the action potential. These channels are strongly regulated by hormones and neurotransmitters. Little is known, however, about the mechanism underlying their regulation. Here we show that phosphatidylinositol 4,5‐bisphosphate (PIP2) gating underlies several aspects of 2‐P channel regulation. Our results demonstrate that all four 2‐P channels tested, TASK1, TASK3, TREK1 and TRAAK are activated by PIP2. We show that mechanical stimulation may promote PIP2 activation of TRAAK channels. For TREK1, TASK1 and TASK3 channels, PIP2 hydrolysis underlies inhibition by several agonists. The kinetics of inhibition by the PIP2 scavenger polylysine, and the inhibition by the phosphatidylinositol 4‐kinase inhibitor wortmannin correlated with the level of agonist‐induced inhibition. This finding suggests that the strength of channel PIP2 interactions determines the extent of PLC‐induced inhibition. Finally, we show that PIP2 hydrolysis modulates voltage dependence of TREK1 channels and the unrelated voltage‐dependent KCNQ1 channels. Our results suggest that PIP2 is a common gating molecule for K+ channel families despite their distinct structures and physiological properties.
Clinical characteristics of high-functioning youth with autism spectrum disorder and anxiety.

AIM & METHODS Clinical characteristics were examined in 108 high-functioning youth (children with a full IQ scale of at least 70) with an autism spectrum disorder (ASD; aged 7-15 years) who were presenting for inclusion in one of four clinical trials examining the efficacy of cognitive behavioral therapy in youth with ASD and anxiety. RESULTS We present baseline characteristics of this cohort, including prevalence rates of anxiety and comorbid disorders, and correlates of anxiety (e.g., comorbid diagnoses, impairment, anxiety severity and mental health services received) as a function of age and ASD diagnosis in treatment-seeking youth. Primary anxiety disorders were: 41.7% (n = 45) social phobia, 25.9% (n = 28) generalized anxiety disorder, 15.7% (n = 17) separation anxiety disorder, 12.0% (n = 13) obsessive-compulsive disorder and 4.6% (n = 5) specific phobia. Overall, 91.6% of participants (n = 99) met criteria for two or more anxiety disorders. Parents reported considerable functional impairment as measured by the Columbia Impairment Scale and anxiety severity as measured by the Pediatric Anxiety Rating Scale; this did not statistically differ as a function of ASD diagnosis or age. Anxiety severity, the number of comorbid anxiety diagnoses and total comorbid diagnoses were directly associated with parent-reported child impairment. Youth with ASD and anxiety present as a heterogeneous cohort with significant impairments and complex diagnostic presentations. CONCLUSION These data provide information about the nature of anxiety in youth with ASD, which may foster the development of tailored treatment protocols.
How the GCC Economic Crises Effect Labor Migration: Evidence from Pakistan

Migrant workers have participated in promoting economic growth and prosperity and the generation of wealth in countries of destination. The Gulf Cooperation Council (GCC) which is comprised of six countries such as Saudi Arabia, UAE, Qatar, Kuwait, Bahrain, and Oman have been historically and traditionally job market for Pakistani workers. Labor migration and its relationship to economic growth and employment have received increasing attention because of increasing demand for labor, higher salaries, economic and political stability. Using a case study, we focus on the impact and relationship of labor migration with macroeconomic indicators such as Gross Domestic Product (GDP), unemployment, and inflation rate. Limited employment opportunities, the weak economy, and political instability are the factors leading labor migration from Pakistan. Consequently, the government of Pakistan considered labor migration primarily as an employment sector and encourage labor migration to solve economic problems in the country. We analyze the impact of labor migration on (GDP), Inflation rate and unemployment in Pakistan with the help of time series data from 1971-2016. The result to have showed a positive and significant relationship between labor migration and GDP, while a negative but significant relationship with unemployment. On the other hand, there is no relationship between labor migration and inflation rate. we found that the GCC economic crises actually caused significant influence on labor migration in the case of Pakistan.
The Endocrine Regulation of Chicken Growth

The somatotropic axis plays a key role in proliferation and differentiation of avian organs during both pre- and post-hatching periods. This review discusses the complexity of regulation of the endocrine system for chicken development and growth by growth hormone (GH), insulin-like growth factor (IGF), and IGF binding protein (IGFBP). In addition, the thyrotropic axis, including thyrotropin-releasing hormone (TRH) and thyroid hormones (T 4 and T 3 ), is also involved in the GH-secreting pattern. In mammals, IGF-I and -II are always sequestered in a 150 kDa non-covalent ternary complex. This complex consists of one molecule each of IGF-I or IGF-II, IGFBP-3 or IGFBP-5 and an acid labile subunit (ALS). Chick ALS is identified in different strains for the first time, and further investigation of the expression of ALS on developmental stage and ALS effect on IGF bioavailability may be addressed in the future.
"Nonspecific" cholinesterase and acetylcholinesterase in rat tissues: molecular forms, structural and catalytic properties, and significance of the two enzyme systems.

"Nonspecific" cholinesterase (acylcholine acylhydrolase; EC 3.1.1.8) from various rat tissues has been found to exist in several stable molecular forms that appear as exact counterparts of molecular forms of acetylcholinesterase (acetylcholine hydrolase; EC 3.1.1.7). The sedimentation pattern of cholinesterase was similar to that of acetylcholinesterase with a small but significant shift between the sedimentation coefficients of the corresponding forms. Extraction yields in different media also demonstrated a close parallelism between the two enzyme systems. Other properties, such as thermal stability and catalytic characteristics, indicated both differences and similarities. In spite of the structural resemblance implied by their physicochemical properties, cholinesterase did not crossreact with antibodies against acetylcholinesterase. The nature of the relationships revealed by these studies and their bearing on the physiological significance of cholinesterases are discussed.
Recovery from psychotic illness: A 15- and 25-year international follow-up study

Background Poorly defined cohorts and weak study designs have hampered cross-cultural comparisons of course and outcome in schizophrenia. Aims To describe long-term outcome in 18 diverse treated incidence and prevalence cohorts. To compare mortality, 15- and 25-year illness trajectory and the predictive strength of selected baseline and short-term course variables. Method Historic prospective study. Standardised assessments of course and outcome. Results About 75% traced. About 50% of surviving cases had favourable outcomes, but there was marked heterogeneity across geographic centres. In regression models, early (2-year) course patterns were the strongest predictor of 15-year outcome, but recovery varied by location; 16% of early unremitting cases achieved late-phase recovery. Conclusions A significant proportion of treated incident cases of schizophrenia achieve favourable long-term outcome. Sociocultural conditions appear to modify long-term course. Early intervention programmes focused on social as well as pharmacological treatments may realise longer-term gains.
Direct and indirect effects of biological factors on extinction risk in fossil bivalves

Biological factors, such as abundance and body size, may contribute directly to extinction risk and indirectly through their influence on other biological characteristics, such as geographic range size. Paleontological data can be used to explicitly test many of these hypothesized relationships, and general patterns revealed through analysis of the fossil record can help refine predictive models of extinction risk developed for extant species. Here, I use structural equation modeling to tease apart the contributions of three canonical predictors of extinction—abundance, body size, and geographic range size—to the duration of bivalve species in the early Cenozoic marine fossil record of the eastern United States. I find that geographic range size has a strong direct effect on extinction risk and that an apparent direct effect of abundance can be explained entirely by its covariation with geographic range. The influence of geographic range on extinction risk is manifest across three ecologically disparate bivalve clades. Body size also has strong direct effects on extinction risk but operates in opposing directions in different clades, and thus, it seems to be decoupled from extinction risk in bivalves as a whole. Although abundance does not directly predict extinction risk, I reveal weak indirect effects of both abundance and body size through their positive influence on geographic range size. Multivariate models that account for the pervasive covariation between biological factors and extinction are necessary for assessing causality in evolutionary processes and making informed predictions in applied conservation efforts.
Circulating nucleic acids in plasma/serum

&NA; Since the discovery of circulating nucleic acids in plasma in 1948, many diagnostic applications have emerged. For example, diagnostic and prognostic potentials of circulating tumour‐derived DNA have been demonstrated for many types of cancer. The parallel development of fetal‐derived DNA detection in maternal plasma has opened up the possibility of non‐invasive prenatal diagnosis and monitoring of many pregnancy‐associated disorders. In this regard, non‐invasive fetal rhesus blood group genotyping has already been translated to clinical practice. Other applications of circulating DNA in traumatology and transplant monitoring have also been reported. The more recent discoveries of circulating tumour‐derived RNA and fetal‐derived RNA have proven to be equally important as their DNA counterparts. Successful prenatal diagnosis of Down's syndrome by fetal RNA analysis has recently been reported. However, the definite origin and release mechanisms of circulating nucleic acids have remained incompletely understood, with cell death being suggested to be associated with such nucleic acid release. Pre‐analytical standardisation will become increasingly relevant when comparing data from different laboratories. In conclusion, studies of circulating nucleic acids have promised exciting developments in molecular diagnostics in the years to come.
Uncertainty Times for Portfolio Selection at Financial Market

The financial market presents non-linearities for the behavior of stock returns for periods of high and low market. This article studies portfolios whose variance-covariance matrices are estimates using a multivariate model with regime change. Investment strategies for portfolios are presented in the presence of uncertainty as to the high or low state of the stock market. The portfolios were applied to the main Ibovespa shares. The proposed portfolios offered better performance for the period analyzed.
Impaired Visual Scanning and Memory for Faces in High-Functioning Autism Spectrum Disorders: It's Not Just the Eyes

Abstract Prior studies suggest that autism spectrum disorders (ASD) are associated with a domain-specific memory impairment for faces. The underlying cause of this problem and its relation to impaired visual scanning of faces—particularly of the eyes—remains to be determined. We recorded eye movements while 22 high-functioning ASD and 21 typically developing (TD) adolescents encoded and later recognized faces and objects from a single, nonsocial object category (electric fans). Relative to TD subjects, ASD individuals had poorer memory for faces, but not fans. Correlational analyses showed significant relationships between recognition memory and fixations. Eye tracking during encoding revealed that TD subjects made more fixations to faces than fans, whereas ASD individuals did not differ in number of fixations made to each stimulus type. Moreover, although both the TD and ASD groups showed a strong preference for fixating the eyes more than the mouth, the ASD subjects were less likely than TD subjects to scan regions of the face outside of the primary facial features (i.e., eyes, nose, and mouth). We concluded that ASD individuals have a domain-specific memory impairment for faces relative to mechanical objects and that this impairment may be related to abnormal scanning during encoding. (JINS, 2011, 17, 1021–1029)
Husbands' And Wives' Adjustment to Pregnancy And First Parenthood

There are conflicting reports regarding type and extent of the change in couples' lives due to the arrival of a first baby. The present short-term longitudinal study of 39 volunteer couples had two major objectives: (1) to examine changes in couples' division of labor during the transition to parenthood, and (2) to investigate husband-wife differences in the associations between indices of marital and parental adjustment during the early postpartum months. Individual questionnaires and interviews were administered in couples' homes on three occasions: early pregnancy, late pregnancy, and 3-4 months postpartum. Repeated measure analyses of changes in feminine and masculine household tasks did not confirm a linear shift toward more sex-typed arrangement but rather demonstrated a curvilinear pattern with the least sex-typed arrangements occurring in late pregnancy. These results indicate that the pregnancy period needs to be viewed as a time of changes in instrumental roles. There were several wife-husband differences in associations between marriage quality and parenting in the postpartum period. Notably, greater involvement with the baby was positively associated with paternal adjustment but negatively related to wives' marital adjustment. These findings underscore the complex associations among husbands' and wives' household roles, marital adjustment, involvement with baby, and adjustment to parenthood.
Patterns of Work and Poverty: Exploratory Profiles of Working-Poor Households

This study uses Survey of Income and Program Participation (SIPP) data to test one of the assumptions of the welfare reform efforts that produced the Family Support Act of 1988. Those efforts assumed that sustained labor-force participation enables the working poor to escape poverty. The results of the study question that assumption, indicating that most of those in a select group of working-poor households who were poor all the time or some of the time worked throughout the entire study period. Only some subgroups could benefit from increased labor-force participation. Expanding the use of the Earned Income Tax Credit is discussed in light of these findings.
Effects of temporomandibular joint stimulation on nociceptive and nonnociceptive neurons of the cat's trigeminal subnucleus caudalis (medullary dorsal horn).

1. The extracellular activity of 196 single neurons in subnucleus caudalis (medullary dorsal horn) of the trigeminal (V) spinal tract nucleus was examined in chloralose-anesthesized, paralyzed cats. Electrical, mechanical, and algesic chemical stimuli were applied to the exposed temporomandibular joint (TMJ) in order to activate TMJ afferents. Seventy-eight neurons were studied that responded to electrical stimulation of the TMJ at a mean latency of 9.9 +/- 4.8 (SD) ms. 2. All neurons with TMJ input received additional afferent input, predominantly from facial skin or intraoral sites. Caudalis neurons were classified on the basis of their cutaneous mechanoreceptive field properties as low-threshold mechanoreceptive (LTM), wide dynamic range (WDR), or nociceptive specific (NS); a few neurons unresponsive to cutaneous stimuli were responsive to manipulation of deep subcutaneous structures. A sample of caudalis neurons was tested for responsiveness to electrical TMJ stimulation after the mechanoreceptive field properties of the neurons were determined. In this sample, 24% of the LTM neurons, 29% of the WDR neurons, 36% of the NS neurons, and 57% of the neurons with input from deep structures were responsive to TMJ stimulation. The WDR and NS neurons with TMJ inputs had mechanoreceptive field properties and laminar locations in caudalis that were comparable to those previously described for cutaneous nociceptive neurons in caudalis; also in accordance with recent studies, 74% of the neurons tested showed convergence of tooth pulp and/or hypoglossal (XII) nerve afferent inputs. 3. In contrast to the LTM neurons, the WDR and NS neurons were especially responsive to intense mechanical and algesic chemical stimulation of the TMJ as well as to electrical stimulation of TMJ afferents. For example, 71% of the WDR and NS neurons excited by electrical stimulation of the TMJ afferents and tested for their responsiveness to injections of algesic chemicals (7% NaCl, KCl, bradykinin, histamine) into the TMJ responded to at least one of these chemicals. The temporal characteristics of these responses were quantified. 4. The TMJ afferent inputs to the WDR and NS neurons were considered to be predominantly of a nociceptive character because of (1) the long latency and high threshold of most TMJ-evoked responses, which are consistent with previous demonstrations that small-diameter afferents predominantly supply the TMJ and, (2) the preferential responsiveness to noxious mechanical and chemical stimulation of TMJ afferents of neurons which were functionally identified as cutaneous nociceptive neurons. (ABSTRACT TRUNCATED AT 400 WORDS)
A data-mining approach to the Parkour discipline

Parkour is a relatively new discipline. As an uncommon nexus between risk, resistance, and the philosophy of overcoming obstacles, it is continuously gaining interest and popularity. However, the “voice” of parkour practitioners has been explored only qualitatively, on small samples and from a phenomenological point of view. In this work, raw data from the official American Parkour forum (from 2005 to 2013) have been web-scraped and treated with the Meaning Extraction Method (MEM), a simple and flexible technique providing optimal dimension reduction and the identification of broader themes related to the parkour discipline, thus providing a broader vision of a phenomena which is configuring itself as a true life-style.