Miracle-dz/UniFAR-FTUs huggingface dataset:
How Are Substrate Binding and Catalysis Affected by Mutating Glu127 and Arg161 in Prolyl-4-hydroxylase? A QM/MM and MD Study

Prolyl-4-hydroxylase is a vital enzyme for human physiology involved in the biosynthesis of 4-hydroxyproline, an essential component for collagen formation. The enzyme performs a unique stereo- and regioselective hydroxylation at the C4 position of proline despite the fact that the C5 hydrogen atoms should be thermodynamically easier to abstract. To gain insight into the mechanism and find the origin of this regioselectivity, we have done a quantum mechanics/molecular mechanics (QM/MM) study on wildtype and mutant structures. In a previous study (Timmins et al., 2017) we identified several active site residues critical for substrate binding and positioning. In particular, the Glu127 and Arg161 were shown to form multiple hydrogen bonding and ion-dipole interactions with substrate and could thereby affect the regio- and stereoselectivity of the reaction. In this work, we decided to test that hypothesis and report a QM/MM and molecular dynamics (MD) study on prolyl-4-hydroxylase and several active site mutants where Glu127 or Arg161 are mutated for Asp, Gln, or Lys. Thus, the R161D and R161Q mutants give very high barriers for hydrogen atom abstraction from any proline C–H bond and therefore will be inactive. The R161K mutant, by contrast, sees the regio- and stereoselectivity of the reaction change but still is expected to hydroxylate proline at room temperature. By contrast, the Glu127 mutants E127D and E127Q show possible changes in regioselectivity with the former being more probable to react compared to the latter.
Parameter Selection for the Deep Q-Learning Algorithm

Over the last several years deep learning algorithms have met with dramatic successes across a wide range of application areas. The recently introduced deep Q-learning algorithm represents the first convincing combination of deep learning with reinforcement learning. The algorithm is able to learn policies for Atari 2600 games that approach or exceed human performance. The work presented here introduces an open-source implementation of the deep Q-learning algorithm and explores the impact of a number of key hyper-parameters on the algorithm’s success. The results suggest that, at least for some games, the algorithm is very sensitive to hyper-parameter selection. Within a narrow-window of values the algorithm reliably learns high-quality policies. Outside of that narrow window, learning is unsuccessful. This brittleness in the face of hyper-parameter selection may make it difficult to extend the use deep Q-learning beyond the Atari 2600 domain.
The plaque-removing effect of four toothbrushing methods.

abstract – Two experimental studies were carried out to compare the plaque-removing ability of three well-known tooth-brushing methods (the roll, the horizontal scrub, and Charters') and brushing with a singletufted brush, the interbrush method. After withdrawal of all oral hygiene measures for three days, the teeth were brushed by a dental hygienist employing one of the methods in each quadrant of the mouth. The brushing was performed with brushes recommended for the different methods. Immediately after the brushing, the remaining plaque was assessed according to the Plaque Index. The brushing methods tested showed negligible effect on interdental plaque accumulations. This was valid both in dental students with healthy periodontal conditions and in periodontally treated persons. Vestibularly and lingually more plaque was left after brushing with the roll method than after brushing with any of the other methods. The differences between the horizontal scrub, the Charters', and the interbrush methods were small. Time studies revealed that the horizontal scrub was the least time-consuming method. The roll method required a little more time, but less than Charters’method, whereas the interbrush method was more time-consuming than any of the other methods tested.
Micturition symptoms in frontal tumours

In a series of 50 consecutive tumours involving the frontal lobes, seven cases (14%) were found who exhibited the syndrome, first described by Andrew and Nathan in 1964, of frequency of micturition, urgency, and incontinence causing distress to the patient. This suggests that this syndrome may occur rather more commonly than those authors had indicated. In 100 consecutive intracranial tumours, no instances were found with non-frontal tumours, indicating that the syndrome may be of localizing value.
Cell Proliferation and the Action of Cytotoxic Agents on Haemopoietic Tissue

Summary. The effect of several cytotoxic agents on maturing erythroid cells and repopulating stem cells has been investigated. The results demonstrate the extent to which the effect of these agents depend on the rate at which the cells are proliferating. They also show the need to consider damage to the maturing cells as a possible critical factor when proliferation‐dependent agents are administered repeatedly.
Prospective randomized multicentre study comparing stapler haemorrhoidopexy with Doppler‐guided transanal haemorrhoid dearterialization for third‐degree haemorrhoids

Aim Doppler‐guided transanal haemorrhoid dearterialization (THD) and stapler haemorrhoidopexy (SH) have been demonstrated to be less painful than the Milligan–Morgan procedure. The aim of this study was to compare the effectiveness of THD vs SH in the treatment of third‐degree haemorrhoids in an equivalent trial.
Synergistic effect of the hydroalcoholic extract from Lepidium meyenii (Brassicaceae) and Fagara tessmannii (Rutaceae) on male sexual organs and hormone level in rats

Background: Lepidium meyenii is a plant, which has been used in folk medicine to treat infertility and to increase sexual desire. However, few reports have investigated the administration of this plant with other plants having the same properties. Objective: The present investigation was designed to evaluate whether the combination of Lepidium meyenii and Fagara tessmannii can improve spermatogenesis and testosterone level in rats. Materials and Method: Twenty male rats were treated daily for 2 weeks with the hydroalcoholic extract of Fagara tessmannii and Lepidium meyenii (Fag + MN) as follow: (vehicle), (0.01 g + 0.5 mg), (0.1 g + 5 mg) and (1 g+ 50 mg)/kg BW. Results: At doses Fag 0.01 g/MN 0.5 mg and Fag 0.1 g/MN 5 mg, the weight of seminal vesicle, prostate, and testis significantly decreased (P < 0.05) while at dose Fag 1 g/MN 50 mg, the weight of epididymis and testis significantly increased (P < 0.05) when compared to the control. We noticed a significant increase of the number of spermatids/test (P < 0.05), epididymis sperm count (P < 0.05), and DSP/test of the rats at dose Fag 1 g/MN 50 mg while at dose Fag 0.01 g/MN 0.5 mg and Fag 0.1 g/MN 5 mg, sperm count was reduced in male organs, particularly in vas deferens (P < 0.05) and epididymis (P < 0.001). The serum testosterone concentration significantly decreased (P < 0.05) at lowest dose Fag 0.01 g/MN 0.5 mg. However, at highest dose Fag 1 g/MN 50 mg, the serum testosterone concentration increased significantly (P < 0.05). The length of stage VII-VIII and IX-I of the seminiferous tubule significantly (P < 0.05) increased while the length of stage II-VI significantly (P < 0.05) decreased. Conclusion: The results indicated that the combination of Lepidium meyenii (Black Maca) with Fagara tessmannii can improve male reproductive organs activities.
Global and regional trends in particulate air pollution and attributable health burden over the past 50 years

Long-term exposure to ambient particulate matter (PM2.5, mass of particles with an aerodynamic dry diameter of < 2.5 μm) is a major risk factor to the global burden of disease. Previous studies have focussed on present day or future health burdens attributed to ambient PM2.5. Few studies have estimated changes in PM2.5 and attributable health burdens over the last few decades, a period where air quality has changed rapidly. Here we used the HadGEM3-UKCA coupled chemistry-climate model, integrated exposure-response relationships, demographic and background disease data to provide the first estimate of the changes in global and regional ambient PM2.5 concentrations and attributable health burdens over the period 1960 to 2009. Over this period, global mean population-weighted PM2.5 concentrations increased by 38%, dominated by increases in China and India. Global attributable deaths increased by 89% to 124% over the period 1960 to 2009, dominated by large increases in China and India. Population growth and ageing contributed mostly to the increases in attributable deaths in China and India, highlighting the importance of demographic trends. In contrast, decreasing PM2.5 concentrations and background disease dominated the reduction in attributable health burden in Europe and the United States. Our results shed light on how future projected trends in demographics and uncertainty in the exposure–response relationship may provide challenges for future air quality policy in Asia.
Cardiovascular Disease Risk Factors in Hispanic Adolescents in South Texas

Objectives Despite a national crisis of increased prevalence of obesity and type 2 diabetes mellitus in adolescents, especially among Hispanics, there is a paucity of data on health indicators among farmworker adolescents and their peers. The main aim of this study was to estimate the prevalence of cardiovascular disease risk factors in a population of Hispanic adolescent students in south Texas. The study also aimed to compare the prevalence of these risk factors between students enrolled in the Migrant Education Program (MEP) and other students, and between boys and girls. Methods In partnership with the Weslaco (Texas) Independent School District and the Migrant Education Department, a cohort study was conducted from 2007 to 2010 to estimate the prevalence of overall obesity (body mass index ≥85th percentile for age and sex), abdominal obesity (waist circumference ≥75th percentile for age, sex, and ethnicity), acanthosis nigricans (AN), and high blood pressure (HBP; ≥90th percentile for age, height, and sex or systolic/diastolic BP ≥120/80 mm Hg) among MEP students compared with other students from two south Texas high schools. Multilevel logistic regression was used to assess the relation between sex and our main outcomes of interest while accounting for within-school nesting of participants. Results Among 628 sampled students, 508 (80.9%) completed the consent procedure and participated in the study. Of these, 257 were MEP students and 251 were non-MEP peers. Approximately 96.7% of participants were Hispanic and 50.0% were boys. Analyses of data across the years comparing MEP students and non-MEP students show an average prevalence of 44.8% versus 47.7% for overall obesity, 43.2% versus 43.7% for abdominal obesity, 24.7% versus 24.7% for AN, and 29.2% versus 32.8% for HBP. Across recruitment and follow-up years, the prevalence of overall obesity, abdominal obesity, and HBP was 1.3 to 1.5, 1.2 to 1.8, and 2.9 to 4.6 times higher in boys than in girls, respectively. In contrast, the prevalence of AN varied little by sex. Conclusions The high prevalence of cardiovascular risk factors in both groups suggests a compelling need for comprehensive, culturally targeted interventions to prevent future cardiovascular diseases in these high-risk Hispanic adolescents, especially among boys. There were not, however, substantial differences between MEP students and other students. These findings also support the feasibility of conducting future epidemiologic studies among adolescent farmworkers and their families, as well as culturally appropriate school or community-based interventions.
Role of the conserved AAUAAA sequence: four AAUAAA point mutants prevent messenger RNA 3' end formation.

ARTICLES The 1984 Nobel Prize in Medicine: J. W. Uhr. Electron Transfer Between Metal Complexes: Retrospective: H. Taube. Calcium-Mediated Reduction of Ionic Currents: A Biophysical Memory Trace: D. L. Alkon . Role of the Conserved AAUAAA Sequence: Four AAUAAA Point Mutants Prevent Messenger RNA 3' End Formation: M. Wickens and P. Stephenson.
Mothers of disabled children: a study of parental stress.

INTRODUCTION Parents of a child with a disability have an expanded and exaggerated role. Both mother and father are expected to fulfill societal requirements in being parents, as well as being expected to meet the specific needs arising due to the disability. This child demands more time and attention. Acceptance of the child is difficult, being hindered by accompanying feelings of guilt, anger, depression, self-blame and/or blaming the spouse (Copel, 1973). Society expects the parents to cope with having a disabled child, holds the parents responsible for socializing a disabled child to be like other children and yet expects the child to know his place among the "not normal", the stigmatized (Goffman, 1963). The mother is the primary socializing agent of the child. She must help the child learn to conform in his social behavior and to learn the skills of daily living even when the child is handicapped. Yet she is not provided with supports when her child is not capable of achieving the same as the non-handicapped child. This study was designed to gain understanding into the mother's perception of her experience vis-a-vis her child, given that her perception determines her emotional state, her attitude toward her child, herself, and her family, and dictates her current intervention with this child.
Septic shock: a goal‐directed therapy using volume loading, dobutamine and/or norepinephrine

In patients with septic shock and acute respiratory failure, norepinephrine (NE) alone or in combination with dobutamine was used. The aim of therapy was to obtain or maintain Cl ≥ 4.5 1 · min‐1 · m‐2, SVR ≥ 700–800 dyn · s · cm‐5 and oxygen delivery (Do2) ≥ 550 ml · min‐1 · m‐2. Twenty‐three patients (58 ± 3 years) were studied. Initially patients were given intravenous fluid resuscitation to obtain optimal cardiac filling pressures. Eleven patients were considered to be in hyperdynamic septic shock (cardiac index (CI) > 4.5 1. min‐1 · m‐2, SVR ≤ 600 dyn · s · cm‐5 and oliguria) and were given NE as a single agent (0.9 ± 0.2 μg kg‐1 · min‐1). The other 12 patients had CI < 3.5 1 · min‐1 · m‐2 and were given a combination of dobutamine (12 ± 0.09 μg · kg‐1 · min‐1) and NE (1.1 ± 0.2 μg · kg‐1 · min‐1). The latter drug was added since systemic vascular resistance (SVR) was less than 600 and oliguria persisted while on dobutamine. In all patients, during NE infusion SVR was greater than 700 dyn · s · cm‐5, C1 ≥ 4.5 1 · min‐1 · m‐2 and Do2 > 550 ml · min‐1 · m‐2. Urine flow was significantly increased during NE infusion, and only four patients remained oliguric. Anion gap and oxygen consumption were not modified. A complete resolution of septic shock was seen in 16 out of 23 patients (70%). Hospital mortality was 56%.
Fundamentals of short-circuit protection for transformers

This paper reviews principles of protection against internal short circuits in transformers of various constructions. Transformer fundamentals are reviewed as pertaining to protection. In particular, the electromagnetic circuit of a transformer is reviewed that links the terminal currents, winding currents, fluxes, and ampere-turns (ATs) in a set of balance equations for a given transformer. These balance equations are used to explain the sensitivity of protection to various types of transformer faults. The paper shows that the classical transformer differential compensation rules have roots in the first principles — they reflect the AT balance of the protected transformer. The rule of building transformer differential protection equations following the AT balance is used in this paper to derive differential equations for autotransformers; power zig-zag, Scott-T, and Le-Blanc transformers; and phase shifters. The restricted earth fault (REF) and negative-sequence transformer differential (87TQ) functions are explained as a means to detect ground faults near the neutral and turn-to-turn faults, respectively.
Effect of Combined Fluoroquinolone and Azole Use on QT Prolongation in Hematology Patients

ABSTRACT QTc prolongation is a risk factor for development of torsades de pointes (TdP). Combination therapy with fluoroquinolones and azoles is used in patients with hematologic malignancies for prophylaxis and treatment of infection. Both drug classes are implicated as risk factors for QTc prolongation. The cumulative effect on and incidence of QTc prolongation for this combination have not been previously described. A retrospective chart review was performed with hospitalized inpatients from 1 September 2008 to 31 January 2010 comparing QTc interval data from electrocardiogram (ECG) assessment at baseline and after the initiation of combination therapy. Ninety-four patients were eligible for inclusion. The majority, 88 patients (93.6%), received quinolone therapy with levofloxacin. Fifty-three patients (56.4%) received voriconazole; 40 (42.6%) received fluconazole. The overall mean QTc change from baseline was 6.1 (95% confidence interval [CI], 0.2 to 11.9) ms. Twenty-one (22.3%) of the studied patients had clinically significant changes in the QTc while receiving combination fluoroquinolone-azole therapy. Statistically significant risk factors for clinically significant changes in QTc were hypokalemia (P = 0.03) and a left-ventricular ejection fraction of <55% (P = 0.02). Low magnesium (P = 0.11), exposure to 2 or more drugs with the potential to prolong the QTc interval (P = 0.17), and female sex (P = 0.21) trended toward significance. Combination therapy with fluoroquinolone and azole antifungals is associated with increased QTc from baseline in hospitalized patients with hematologic malignancies. One in five patients had a clinically significant change in the QTc, warranting close monitoring and risk factor modification to prevent the possibility of further QTc prolongation and risk of TdP.
Tobin's Q and the location of Foreign Direct Investment in China

The aim of this paper is to examine the effects of the Chinese and Hong Kong stock markets on the levels of foreign direct investment into China’s regions, utilising dynamic panel estimation techniques. Using a Tobin’s Q measure, the results indicate that the effect is significant for both the Chinese and Hong Kong stock markets, but negatively signed, suggesting that FDI into China acts as a substitute for domestic investment. In addition we show that the Arellano-Bovver approach to dynamic panels produces an improvement into the modelling of FDI in China.
The Effect of Chorionic Villus Sampling on Fetal Heart Rate

Objective: Fetal heart rate (FHR) variation during chorionic villus sampling (CVS) is a controversial topic. Limited studies have been published on this subject. Our study intended to evaluate the effects of CVS on the FHR. Method: One hundred and sixty-five patients undergoing first-trimester elective CVS for prenatal diagnosis of β-thalassemia were entered into a prospective study. M-mode FHR was obtained before and immediately after CVS in the patients. Potentially confounding variables also recorded included: gestational age, number of needle passes and placental location. Results: FHR values before and after CVS were compared using the paired t test and showed no statistically significant differences by 95% confidence. No differences were found in data analyzing gestational age, number of needle passes or placental location. Conclusion: We were unable to detect any significant change in FHR after performing CVS. It seems that FHR is generally not altered by CVS.
InverseNet: Solving Inverse Problems with Splitting Networks

We propose a new method that uses deep learning techniques to solve the inverse problems. The inverse problem is cast in the form of learning an end-to-end mapping from observed data to the ground-truth. Inspired by the splitting strategy widely used in regularized iterative algorithm to tackle inverse problems, the mapping is decomposed into two networks, with one handling the inversion of the physical forward model associated with the data term and one handling the denoising of the output from the former network, i.e., the inverted version, associated with the prior/regularization term. The two networks are trained jointly to learn the end-to-end mapping, getting rid of a two-step training. The training is annealing as the intermediate variable between these two networks bridges the gap between the input (the degraded version of output) and output and progressively approaches to the ground-truth. The proposed network, referred to as InverseNet, is flexible in the sense that most of the existing end-to-end network structure can be leveraged in the first network and most of the existing denoising network structure can be used in the second one. Extensive experiments on both synthetic data and real datasets on the tasks, motion deblurring, super-resolution, and colorization, demonstrate the efficiency and accuracy of the proposed method compared with other image processing algorithms.
Maintaining a healthy SPANC balance through regulatory and mutational adaptation

Stress protection is an important but costly contributor to bacterial survival. Two distinct forms of environmental protection share a common cost and a significant species‐wide variability. Porin‐mediated outer membrane permeability and the RpoS‐controlled general stress response both involve a trade‐off between self‐preservation and nutritional competence, called the SPANC balance. Interestingly, different Escherichia coli strains exhibit distinct settings of the SPANC balance. It is tilted towards high stress resistance and a restricted diet in some isolates whereas others have broader nutritional capability and better nutrient affinity but lower levels of resistance. Growth‐ or stress‐related selective pressures working in opposite directions (antagonistic pleiotropy) result in polymorphisms affecting porins and RpoS. Consequently, these important cellular components are present at distinct concentrations in different isolates. A generalized hypothesis to explain bacterial adaptation, based on the SPANC investigations, is offered. A holistic approach to bacterial adaptation, involving a gamut of regulation and mutation, is likely to be the norm in broadening the capabilities of a species. Indeed, there is unlikely to be a standard regulatory setting typical for all members of a species. Gene regulation provides a limited fine control for maintaining the right level of adaptation in a particular niche but mutational changes provide the coarse control for adaptation between the species‐wide environments of free‐living bacteria.
Can Supply Restrictions Lower Price? Violence, Drug Dealing and Positional Advantage

Abstract The standard model of markets for illicit drugs predicts that tougher enforcement against sellers will raise prices; yet cocaine and heroin prices have fallen substantially during a period of massive increases in enforcement. We present a model in which the basic mechanisms at work in the textbook model may be substantially altered by an important feature of illegal markets—violence that creates inheritable heterogeneity along a dimension that both determines relevant production cost and imposes externalities on other suppliers. Dealers frequently make use of violence and threat of violence in the normal course of trade. A seller who is particularly effective in the use of violence may face lower enforcement costs than other dealers and generate an external cost borne by those sellers. Together these features generate a number of counter-intuitive policy implications. For example the arrest of a particularly violent dealer reduces external costs borne by other dealers. The net effect is a possible reduction in costs for the marginal dealer and hence a reduction in price.