Miracle-dz/UniFAR-FTUs huggingface dataset:
Covalent Modification of Thr302 in Cytochrome P450 2B1 by the Mechanism-Based Inactivator 4-tert-Butylphenylacetylene

The mechanism of inactivation of cytochrome P450 2B1 (CYP2B1) by 4-tert-butylphenylacetylene (BPA) has been characterized previously to be caused by the covalent binding of a reactive intermediate to the apoprotein rather than heme destruction (J Pharmacol Exp Ther 331:392–403, 2009). The identification of a BPA-glutathione conjugate and the increase in the mass of the BPA-adducted apoprotein have indicated that the mass of adduct is 174 Da, equivalent to the mass of BPA plus one oxygen atom. To identify the adducted residue, BPA-inactivated CYP2B1 was digested with trypsin, and the digest was then analyzed by using capillary liquid chromatography with a LTQ linear ion trap mass spectrometer as the detector. A mass shift of 174 Da was used for a SEQUEST database search. The tandem mass spectrometry fragmentation of the modified peptide and the identity of modified residue were determined. The results revealed a mass increase of 174 Da for the peptide sequence 296FFAGTSSTTLR308 in the I-helix of CYP2B1 and that the site of adduction formation is Thr302. Homology modeling and ligand docking studies showed that BPA binds in close proximity to both the heme iron and Thr302 with the distances being 2.96 and 3.42 Å, respectively. The identification of Thr302 in the CYP2B1 active site as the site of covalent modification leading to inactivation by BPA supports previous hypotheses that this conserved Thr residue may play a crucial role for various functions in P450s.
Dimerization In Vivo and Inhibition of the Nonreceptor Form of Protein Tyrosine Phosphatase Epsilon

ABSTRACT cyt-PTPε is a naturally occurring nonreceptor form of the receptor-type protein tyrosine phosphatase (PTP) epsilon. As such, cyt-PTPε enables analysis of phosphatase regulation in the absence of extracellular domains, which participate in dimerization and inactivation of the receptor-type phosphatases receptor-type protein tyrosine phosphatase alpha (RPTPα) and CD45. Using immunoprecipitation and gel filtration, we show that cyt-PTPε forms dimers and higher-order associations in vivo, the first such demonstration among nonreceptor phosphatases. Although cyt-PTPε readily dimerizes in the absence of exogenous stabilization, dimerization is increased by oxidative stress. Epidermal growth factor receptor stimulation can affect cyt-PTPε dimerization and tyrosine phosphorylation in either direction, suggesting that cell surface receptors can relay extracellular signals to cyt-PTPε, which lacks extracellular domains of its own. The inactive, membrane-distal (D2) phosphatase domain of cyt-PTPε is a major contributor to intermolecular binding and strongly interacts in a homotypic manner; the presence of D2 and the interactions that it mediates inhibit cyt-PTPε activity. Intermolecular binding is inhibited by the extreme C and N termini of D2. cyt-PTPε lacking these regions constitutively dimerizes, and its activities in vitro towards para-nitrophenylphosphate and in vivo towards the Kv2.1 potassium channel are markedly reduced. We conclude that physiological signals can regulate dimerization and phosphorylation of cyt-PTPε in the absence of direct interaction between the PTP and extracellular molecules. Furthermore, dimerization can be mediated by the D2 domain and does not strictly require the presence of PTP extracellular domains.
Attitudes of respiratory therapists and nurses about measures to prevent ventilator-associated pneumonia: a multicenter, cross-sectional survey study.

OBJECTIVE To understand the reported practices of and adherence to evidence-based guidelines for the prevention of ventilator-associated pneumonia (VAP) among respiratory therapists (RTs) and registered nurses (RNs) in academic and nonacademic intensive care units. METHODS We conducted a multicenter, cross-sectional survey. We first obtained demographic information about health care professionals in a nonidentifiable method. We next questioned the practice patterns of RTs and RNs for preventing VAP based on evidence-supported guidelines. The participants were RTs and RNs working in academic and nonacademic intensive care units; 278 respondents participated in this study (172 RTs and 106 RNs). There were no interventions. RESULTS The 3 major findings were: (1) both the RTs and the RNs reported that they frequently practice VAP-prevention measures, (2) the rate of adherence to ineffective measures (eg, routine changes of the ventilator circuit, disposable catheters) is also relatively high, which suggests that the evidence is not translated into bedside practice, (3) a substantial proportion of participants did not know the VAP rate in their institution, which might make it difficult to convince bedside practitioners to apply evidence-based practice, and might reflect a lack of infection-control/surveillance programs at hospitals. CONCLUSION Consumers, the Centers for Disease Control and Prevention, and other organizations are currently trying to implement mandatory reporting of hospital infections, including VAP rate. Without a definition of VAP suited to individual institutions, an organized data-collection and reporting method, and team-based approaches to preventing and treating VAP, hospitals may not be able to meet these requests and track improvement efforts. Prevention measures need to be translated to bedside practice to improve the outcomes of critically ill patients.
Where are the Pink and White Terraces of Lake Rotomahana?

ABSTRACT In 2018, Bunn and Nolden published a paper purporting to have established the true position of the Pink and White Terraces of Lake Rotomahana using forensic cartography, ‘reverse engineering’ an 1859 compass survey of Ferdinand von Hochstetter. Their results suggest that the terraces are buried partly on land, near the present-day lake shore. Sightlines constructed using an 1881 Charles Spencer photograph overlooking the White Terraces towards distant Maungaongaonga and Maungakakaramea, and replicated by us, show the location of the White Terraces by Bunn and Nolden to be untenable. Fitting the pre-1886 eruption outline map of Lake Rotomahana of Keam (2016. The Tarawera eruption, Lake Rotomahana, and the origin of the Pink and White Terraces. Journal of Volcanology and Geothermal Research 314:10–38.) to our high-resolution bathymetry shows a remarkable fit of the shoreline around the Pink Terraces area to distinct bathymetric features. Side-scan sonar images of inferred tiers of Pink Terraces (de Ronde CEJ, Scott BJ, Leonard GS, Calvert AT. 2016a. Evolution of the sublacustrine geothermal system of Lake Rotomahana, New Zealand: effects of the 1886 Mt. Tarawera eruption—an introduction. Journal of Volcanology and Geothermal Research 314:1–9.) show they sit where the map of Keam would have them lie.
Blood pressure in early autosomal dominant polycystic kidney disease.

BACKGROUND Hypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin-angiotensin-aldosterone system, and progression of kidney disease. METHODS In this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m(2) of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting-enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume. RESULTS The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006), without significant differences between the lisinopril-telmisartan group and the lisinopril-placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P=0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (-1.17 vs. -0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P=0.002). CONCLUSIONS In early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume. As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study A] ClinicalTrials.gov number, NCT00283686.).
Prevalence and outcome of newly detected diabetes in patients who undergo percutaneous coronary intervention.

AIMS The beneficial effect of specific measures in patients with newly detected diabetes during percutaneous coronary intervention (PCI) has been poorly studied. Here, we determined the prevalence of newly detected diabetes in a cohort of patients who underwent PCI and analysed their clinical outcome. METHODS AND RESULTS A prospective study included patients without previous diagnosis of diabetes that were referred for PCI between November 2005 and May 2006. Major cardiac events were registered after admission and during 12 months of follow-up, and oral glucose tolerance was tested at 15 days after hospital discharge. Six hundred and sixty-two consecutive patients were referred to our hospital for PCI. The distribution of the glycometabolic state of the entire population was (95% CI): known diabetes 28.8% (25.2-32.6), newly detected diabetes 16.2% (13.1-19.8), impaired glucose tolerance 24.5% (20.8-28.5), impaired fasting glucose 1% (0.4-2.4), and normal glucose regulation 29.5% (25.5-33.7). In a multivariable analysis, the presence of newly detected diabetes was not an independent predictor of cardiac events after 1 year of follow-up. CONCLUSION The prevalence of diabetes in patients who underwent PCI was very high (45%), 35% of which was patients with newly detected diabetes. In our series newly detected diabetes was not an independent predictor of outcome at 12 months. Nevertheless, this finding requires independent confirmation in other series to draw general conclusions on the whole spectrum of percutaneous interventions.
Prenatal cocaine exposure adversely affects development of the primate cerebral cortex

This study was conducted to determine whether prenatal exposure to cocaine interferes with the development of the primate cerebral cortex. For this purpose, pregnant rhesus monkeys received cocaine orally (20 mg/kg/day in fruit or candy treats), twice a day from the 40th‐102nd days of pregnancy (E40‐E102), which is a period of corticogenesis in this species. The control group of pregnant animals received fruit or candy treats only. On E64 and E65, all animals received intravenous injections of [3H]thymidine. Monkeys were allowed to deliver at term. The offspring were sacrificed at age 2 months, and their brains were processed for histology and autoradiography. The analysis of cresyl violet‐stained sections showed that prenatal treatment with cocaine significantly altered lamination of the primate cerebral cortex, in some cases completely blending distinction between individual layers. In addition, autoradiographic analysis revealed that in the control animals, [3H]thymidine labeling concentrated in cortical layers V and/or IV depending on the cytoarchitectonic area observed. In contrast, drug‐ treated animals displayed labeled cells in the white matter and cortical layer VI in addition to layers V and IV, suggesting inability of cortical cells to reach proper cortical layers. The number of labeled cells was also much lower in these animals. Finally, immunocytochemical studies with antisera directed toward glial fibrillary acidic protein showed that prenatal exposure to cocaine had dramatic effect on the glial fibers normally observed in the upper cortical layers. In many cortical regions of cocaine‐treated animals, we observed practically no such fibers. This study demonstrates that cocaine administered during pregnancy can significantly affect the development of the primate cerebral cortex. © 1995 Wiley‐Liss, Inc.
Multi-decadal mass balance series of three Kyrgyz glaciers inferred from transient snowline observations

Glacier mass balance observations in the Tien Shan and Pamir mountains are sparse and often discontinuous. Nevertheless, glaciers are one of the most important components of the high-mountain cryosphere in the region; they strongly influence water availability in the arid, continental and intensely populated downstream areas. This study provides reliable and continuous mass balance series for selected glaciers located in the Tien Shan and Pamir-Alay. A combination of three independent methods was used to reconstruct for the past two decades the mass balance of the three benchmark glaciers, Abramov, Golubin and No. 354. By applying different approaches, it was possible to compensate for the limitations and shortcomings of each individual method. This study proposes the use of transient snowline observations throughout the melting season obtained from satellite imagery and terrestrial automatic cameras. By combining modelling with remotely acquired information on summer snow depletion, it was possible to infer glacier mass changes for unmeasured years. Multi-annual mass changes based on high accuracy digital elevation models and in situ glaciological surveys were used to validate the results for the investigated glaciers. Substantial mass loss was confirmed for the three studied glaciers by all three methods, ranging from −0.30 ± 0.19 m w. e. a −1 to −0.41 ± 0.33 m w. e. a −1 over the 2004–2016 period. Our results indicate that integration of snowline observations into mass balance modelling significantly narrows the uncertainty ranges of the estimates, and hence highlights the potential of the methodology for application to inaccessible glaciers at larger scales for which no direct measurements are available.
Reasoning about Data Repetitions with Counter Systems

We study linear-time temporal logics interpreted over data words with multiple attributes. We restrict the atomic formulas to equalities of attribute values in successive positions and to repetitions of attribute values in the future or past. We demonstrate correspondences between satisfiability problems for logics and reachability-like decision problems for counter systems. We show that allowing/disallowing atomic formulas expressing repetitions of values in the past corresponds to the reachability/coverability problem in Petri nets. This gives us 2EXPSPACE upper bounds for several satisfiability problems. We prove matching lower bounds by reduction from a reachability problem for a newly introduced class of counter systems. This new class is a succinct version of vector addition systems with states in which counters are accessed via pointers, a potentially useful feature in other contexts. We strengthen further the correspondences between data logics and counter systems by characterizing the complexity of fragments, extensions and variants of the logic. For instance, we precisely characterize the relationship between the number of attributes allowed in the logic and the number of counters needed in the counter system.
Molecular Subtyping of Bacillus anthracis and the 2001 Bioterrorism-Associated Anthrax Outbreak, United States

Molecular subtyping of Bacillus anthracis played an important role in differentiating and identifying anthrax strains during the 2001 bioterrorism-associated outbreak. Because B. anthracis has a low level of genetic variability, only a few subtyping methods, with varying reliability, exist. We initially used multiple-locus variable-number tandem repeat analysis (MLVA) to subtype 135 B. anthracis isolates associated with the outbreak. All isolates were determined to be of genotype 62, the same as the Ames strain used in laboratories. We sequenced the protective antigen gene (pagA) from 42 representative outbreak isolates and determined they all had a pagA sequence indistinguishable from the Ames strain (PA genotype I). MLVA and pagA sequencing were also used on DNA from clinical specimens, making subtyping B. anthracis possible without an isolate. Use of high-resolution molecular subtyping determined that all outbreak isolates were indistinguishable by the methods used and probably originated from a single source. In addition, subtyping rapidly identified laboratory contaminants and non-outbreak–related isolates.
Evaluation of set-based queries with aggregation constraints

Many applications often require finding a set of items of interest with respect to some aggregation constraints. For example, a tourist might want to find a set of places of interest to visit in a city such that the total expected duration is no more than six hours and the total cost is minimized. We refer to such queries as SAC queries for ``set-based with aggregation constraints'' queries. The usefulness of SAC queries is evidenced by the many variations of SAC queries that have been studied which differ in the number and types of constraints supported. In this paper, we make two contributions to SAC query evaluation. We first establish the hardness of evaluating SAC queries with multiple count constraints and presented a novel, pseudo-polynomial time algorithm for evaluating a non-trivial fragment of SAC queries with multiple sum constraints and at most one of either count, group-by, or content constraint. We also propose a heuristic approach for evaluating general SAC queries. The effectiveness of our proposed solutions is demonstrated by an experimental performance study.
Social-demographic and social-psychological perspectives of fear of crime in Slovenia, Croatia and Bosnia and Herzegovina

Researh and theorising about the fear of crime has, in the main, been dominated by researchers who have relied upon sociological or socio-demographic variables to account for variations in fear levels. Whilst this body of work has contributed greatly to our understanding of the fear of crime, we are still far from a full understanding of this important and most corrosive aspect of contemporary society. This paper first presents three independent evaluations of fear of crime. The data, collected in Slovenia, Scotland and Holland, sheds further light on both the social psychological model proposed and the wider study of fear of crime. These evaluations served as a background for the present study of fear of crime in Slovenia in 2001 and Croatia and Bosnia and Herzegovina in 2002. The results show high level of fear of crime in women, people who perceive themselves as less physically fit, the unemployed, those who expose themselves by walking alone in dark and those who perceive streets and woods as sources of danger. In addition, higher level of fear of crime can be attributed to respondents who consider themselves a potentional vicitm due to the jelousy ot others or being attractive to a potential criminal in other ways, incapable of chasing of a potential assailant, and perceiving places as dangerous (criminalisable space).
Probing Natural Killer Cell Education by Ly49 Receptor Expression Analysis and Computational Modelling in Single MHC Class I Mice

Murine natural killer (NK) cells express inhibitory Ly49 receptors for MHC class I molecules, which allows for “missing self” recognition of cells that downregulate MHC class I expression. During murine NK cell development, host MHC class I molecules impose an “educating impact” on the NK cell pool. As a result, mice with different MHC class I expression display different frequency distributions of Ly49 receptor combinations on NK cells. Two models have been put forward to explain this impact. The two-step selection model proposes a stochastic Ly49 receptor expression followed by selection for NK cells expressing appropriate receptor combinations. The sequential model, on the other hand, proposes that each NK cell sequentially expresses Ly49 receptors until an interaction of sufficient magnitude with self-class I MHC is reached for the NK cell to mature. With the aim to clarify which one of these models is most likely to reflect the actual biological process, we simulated the two educational schemes by mathematical modelling, and fitted the results to Ly49 expression patterns, which were analyzed in mice expressing single MHC class I molecules. Our results favour the two-step selection model over the sequential model. Furthermore, the MHC class I environment favoured maturation of NK cells expressing one or a few self receptors, suggesting a possible step of positive selection in NK cell education. Based on the predicted Ly49 binding preferences revealed by the model, we also propose, that Ly49 receptors are more promiscuous than previously thought in their interactions with MHC class I molecules, which was supported by functional studies of NK cell subsets expressing individual Ly49 receptors.
COEVOLUTION OF MALE MATING SIGNAL AND FEMALE PREFERENCE DURING EARLY LINEAGE DIVERGENCE OF THE HAWAIIAN CRICKET, LAUPALA CERASINA

Sexual selection is a powerful evolutionary force shaping mate choice phenotypes, initiating phenotypic shifts resulting in (or reinforcing) population divergence and speciation when such shifts reduce mating probabilities among divergent populations. In the Hawaiian cricket genus Laupala, pulse rate of male calling song, a conspicuous mating signal, differs among species, potentially behaving as a speciation phenotype. Populations of the widespread species Laupala cerasina show variation in pulse rate. We document the degree of population differentiation in three features of calling song: pulse rate, pulse duration, and carrier frequency. All show significant population differentiation, with pulse rate showing the greatest heterogeneity. A Mantel test found no relationship between geographic distance and pulse rate divergence, indicating that a simple model of greater divergence with increasing distance cannot explain the observed pattern of differentiation. We demonstrate that female preference functions for pulse rate are unimodal, and that preference means show significant differentiation among populations. Furthermore, estimates of pulse rate preference correlate significantly with mean pulse rates across populations, indicating song and preference coevolve in a stepwise manner. This correlated divergence between signal and preference suggests that sexual selection facilitates the establishment of sexual isolation, reduced gene flow, and population differentiation, prerequisites for speciation.
Globalization and Multiproduct Firms

We present an international trade model with multiproduct firms. Firms are heterogeneously endowed with two types of capabilities that jointly determine the trade-off within firms between managing a large portfolio of products and producing at low marginal cost. The model can explain many of the documented cross-sectional correlations in firm performance measures, including why larger firms are more productive and more diversified, and yet more diversified firms trade at a discount. Globalization is shown to induce heterogeneous responses across firms in terms of scope and productivity, some of which are consistent with existing empirical work, while others are potentially testable.