Miracle-dz/UniFAR-FTUs huggingface dataset:
Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response

Objective— Drug-eluting stent delivery of mTORC1 (mechanistic target of rapamycin complex 1) inhibitors is highly effective in preventing intimal hyperplasia after coronary revascularization, but adverse effects limit their use for systemic vascular disease. Understanding the mechanism of action may lead to new treatment strategies. We have shown that rapamycin promotes vascular smooth muscle cell differentiation in an AKT2-dependent manner in vitro. Here, we investigate the roles of AKT (protein kinase B) isoforms in intimal hyperplasia. Approach and Results— We found that germ-line–specific or smooth muscle–specific deletion of Akt2 resulted in more severe intimal hyperplasia compared with control mice after arterial denudation injury. Conversely, smooth muscle–specific Akt1 knockout prevented intimal hyperplasia, whereas germ-line Akt1 deletion caused severe thrombosis. Notably, rapamycin prevented intimal hyperplasia in wild-type mice but had no therapeutic benefit in Akt2 knockouts. We identified opposing roles for AKT1 and AKT2 isoforms in smooth muscle cell proliferation, migration, differentiation, and rapamycin response in vitro. Mechanistically, rapamycin induced MYOCD (myocardin) mRNA expression. This was mediated by AKT2 phosphorylation and nuclear exclusion of FOXO4 (forkhead box O4), inhibiting its binding to the MYOCD promoter. Conclusions— Our data reveal opposing roles for AKT isoforms in smooth muscle cell remodeling. AKT2 is required for rapamycin’s therapeutic inhibition of intimal hyperplasia, likely mediated in part through AKT2-specific regulation of MYOCD via FOXO4. Because AKT2 signaling is impaired in diabetes mellitus, this work has important implications for rapamycin therapy, particularly in diabetic patients.
Application of Fluoroquinolone Resistance Score in Management of Complicated Urinary Tract Infections

ABSTRACT The fluoroquinolone resistance score (FQRS) predicts the probability of fluoroquinolone resistance with good discrimination. The score has been derived from patients with bloodstream infections caused by Gram-negative bacteria and is based on fluoroquinolone use within the past 6 months, among other clinical and health care exposure criteria. This study aims to examine the utility of the FQRS in patients with complicated urinary tract infections (cUTI) and determine whether extension of prior fluoroquinolone use to 12 months improves model discrimination. Adults with cUTI at Palmetto Health in central South Carolina, USA, from 1 April 2015 through 31 July 2015 were prospectively identified. Multivariate logistic regression was used to examine the association between prior fluoroquinolone use and resistance. Among 238 patients, 54 (23%) had cUTI due to fluoroquinolone-resistant bacteria. Overall, the median age was 66 years, 162 (68%) patients were women, and 137 (58%) patients had cUTI due to Escherichia coli. Prior exposure to fluoroquinolones within 3 months (adjusted odds ratio [aOR], 23.4; 95% confidence interval [CI], 8.2 to 76.8; P < 0.001) and within 3 to 12 months (aOR, 13.2; 95% CI, 3.1 to 68.4; P < 0.001) was independently associated with fluoroquinolone resistance compared to no prior use. The area under the receiver operating characteristic curve for the FQRS increased from 0.73 to 0.80 when prior fluoroquinolone use was extended from 6 to 12 months. FQRSs of ≥2 and ≥3 had negative predictive values of 91% and 90%, respectively. The modified FQRS stratifies patients with cUTI on the basis of the predicted probability of fluoroquinolone resistance with very good discrimination. Application of the modified FQRS may improve antimicrobial utilization in patients with acute pyelonephritis.
In Vitro and In Vivo Activity of Omadacycline against Two Biothreat Pathogens, Bacillus anthracis and Yersinia pestis

ABSTRACT The in vitro activity and in vivo efficacy of omadacycline (OMC) were evaluated against the causative pathogens of anthrax and plague, Bacillus anthracis and Yersinia pestis, respectively. MICs of OMC were determined by broth microdilution according to CLSI guidelines for 30 isolates each of Y. pestis and B. anthracis. The in vivo efficacy of omadacycline was studied at a range of dosages in both a postexposure prophylaxis (PEP) murine model of anthrax and plague as well as in a delayed treatment model of inhalational anthrax. Omadacycline was active in vitro against Y. pestis (MIC90 of 1 μg/ml) and B. anthracis (MIC90 of 0.06 μg/ml). Omadacycline was less active in vitro than ciprofloxacin (CIP) against Y. pestis (CIP MIC90 of 0.03 μg/ml) but was more potent in vitro against B. anthracis (CIP MIC90 of 0.12 μg/ml). In the mouse model of infection, the survival curves for all treatment cohorts differed significantly from the vehicle control (P = 0.004). The median survival for the vehicle-treated controls was 6 days postchallenge, while all antibiotic-treated mice survived the entire study. Omadacycline treatment with 5, 10, or 20 mg/kg of body weight twice daily for 14 days had significant efficacy over the vehicle control in the treatment of aerosolized B. anthracis. Additionally, for postexposure prophylaxis treatment of mice infected with Y. pestis, the survival curves for omadacycline (40 mg/kg twice daily), ciprofloxacin, and doxycycline cohorts differed significantly from the vehicle control (P < 0.0001). Omadacycline is potent and demonstrates efficacy against both B. anthracis and Y. pestis. The well-characterized oral and intravenous pharmacokinetics, safety, and tolerability warrant further assessment of the potential utility of omadacycline in combating these serious biothreat organisms.
Influences of Age, Sex, and Moderate Alcohol Drinking on the Intrinsic Functional Architecture of Adolescent Brains

The transition from adolescent to adult cognition and emotional control requires neurodevelopmental maturation likely involving intrinsic functional networks (IFNs). Normal neurodevelopment may be vulnerable to disruption from environmental insult such as alcohol consumption commonly initiated during adolescence. To test potential disruption to IFN maturation, we used resting-state functional magnetic resonance imaging (rs-fMRI) in 581 no-to-low alcohol-consuming and 117 moderate-to-high-drinking youth. Functional seed-to-voxel connectivity analysis assessed age, sex, and moderate alcohol drinking on default-mode, executive-control, salience, reward, and emotion networks and tested cognitive and motor coordination correlates of network connectivity. Among no-to-low alcohol-consuming adolescents, executive-control frontolimbicstriatal connectivity was stronger in older than younger adolescents, particularly boys, and predicted better ability in balance, memory, and impulse control. Connectivity patterns in moderate-to-high-drinking youth were tested mainly in late adolescence when drinking was initiated. Implicated was the emotion network with attenuated connectivity to default-mode network regions. Our cross-sectional rs-fMRI findings from this large cohort of adolescents show sexual dimorphism in connectivity and suggest neurodevelopmental rewiring toward stronger and spatially more distributed executive-control networking in older than younger adolescents. Functional network rewiring in moderate-to-high-drinking adolescents may impede maturation of affective and self-reflection systems and obscure maturation of complex social and emotional behaviors.
Socioeconomic status and hippocampal volume in children and young adults.

An individual's socioeconomic status (SES) is often viewed as a proxy for a host of environmental influences. SES disparities have been linked to variance in brain structures particularly the hippocampus, a neural substrate of learning and memory. However, it is unclear whether the association between SES and hippocampal volume is similar in children and adults. We investigated the relationship between hippocampal volume and SES in a group of children (n = 31, age 8-12 years) and a group of young adults (n = 32, age 18-25 years). SES was assessed with four indicators that loaded on a single factor, therefore a composite SES scores was used in the main analyses. Hippocampal volume was measured using manual demarcation on high resolution structural images. SES was associated with hippocampal volume in the children, but not in adults, suggesting that in childhood, but not adulthood, SES-related environmental factors influence hippocampal volume. In addition, hippocampal volume, but not SES, was associated with scores on a memory task, suggesting that net effects of postnatal environmental factors, captured by SES, are more distal determinants of memory performance than hippocampal volume. Longitudinal investigation of the association between SES, hippocampal volume and cognitive functioning may further our understanding of the putative neural mechanisms underlying SES-related environmental effects on cognitive development.
Exploring the Dependence of QM/MM Calculations of Enzyme Catalysis on the Size of the QM Region

Although QM/MM calculations are the primary current tool for modeling enzymatic reactions, the reliability of such calculations can be limited by the size of the QM region. Thus, we examine in this work the dependence of QM/MM calculations on the size of the QM region, using the reaction of catechol-O-methyl transferase (COMT) as a test case. Our study focuses on the effect of adding residues to the QM region on the activation free energy, obtained with extensive QM/MM sampling. It is found that the sensitivity of the activation barrier to the size of the QM is rather limited, while the dependence of the reaction free energy is somewhat larger. Of course, the results depend on the inclusion of the first solvation shell in the QM regions. For example, the inclusion of the Mg2+ ion can change the activation barrier due to charge transfer effects. However, such effects can easily be included in semiempirical approaches by proper parametrization. Overall, we establish that QM/MM calculations of activation barriers of enzymatic reactions are not highly sensitive to the size of the QM region, beyond the immediate region that describes the reacting atoms.
Potential use of activated Algerian natural pozzolan powder as a cement replacement material

Abstract The purpose of this experimental work is to develop a suitable approach for an alkali-activated binder material to replace cement CEM-II/42.5 by 80% of natural pozzolan. The chemical activity of silica and alumina found in Algeria's natural pozzolan is improved using heat treatment and chemical curing, together with several alkali activators, including a 6-mole NaOH and a 6-mole KOH along with CaCl2, Na2SO4 and Na2SiO3. The chemical and morphological processes are monitored using X-ray diffraction, TGA and DTA, as well as particle size distribution analyses. Laboratory tests show that thermal pretreatment positively affects the compressive strength; moreover, the use of 6% Na2SiO3 and 6% Na2SO4 results in increased short-term and long-term compressive strength, respectively. Optimal compressive strength values are reached under chemical activation and thermal pretreatment processes. These combined processes also affect Young's modulus values and the relative deformations caused by ultimate stresses. This experimental work highlights the potential of natural pozzolan in producing an economical and environmentally-friendly sustainable material that can be substituted for Portland cements and used in multiple engineering applications.
Assessing the Introduction of Mobile Banking in Jordan Using Technology Acceptance Model

The continuously growing number of mobile users demonstrates that more and more users seek to benefit from the freedom afforded without the need for cables, time and place. The mobility is the driving force behind the new global economy, with mobile banking, banks offer a new revolutionize services and giving their consumers more options than ever before. This study aimed to: (1) Investigate consumers' expectations and attitudes towards mobile banking in Jordan. (2) Identify the problems that organizations and consumers encounter while adopting or using mobile banking. (3) Measure the level of consumersâ? perceived usefulness (PU), perceived ease of use (PEOU), attitude towards using (ATU), behavioral intention to use (BI), and the actual use (AU) of mobile banking. Data for this study have been collected using a questionnaire containing 44 questions. Out of 325 questionnaires that have been distributed, 275 are returned (84.6%). As a result of this study it appeared that if consumers have positive Attitudes towards mobile banking, they would rely on it to conduct their banking transactions. This study finds that Jordanian consumers rely on wireless devices (Mobile) for their banking transactions, which leads to the actual use of this new technology, taking into consideration trust as a factor that could affect the success of using mobile banking in Jordan. This study gives quantified indicators about mobile banking and a model that might help in understanding the mobile banking environment in Jordan.
Efficacy of Acupuncture for Health Conditions in Children: A Review

Acupuncture has been used to treat a variety of childhood problems; however, the efficacy and safety of pediatric acupuncture remains unclear. This article reviews the existing empirical literature relating to the use of acupuncture for medical conditions in children. A systematic search of the literature revealed that acupuncture has been used to treat five main conditions in children, including pain, nocturnal enuresis, postoperative nausea/vomiting, laryngospasm/stridor, and neurological disorders. Despite a number of methodological issues, including limited sample sizes, lack of randomization, and inappropriate control groups, it is concluded that acupuncture represents a promising intervention for a variety of pediatric health conditions. To further address the safety, effectiveness, and acceptability of acupuncture in children, large-scale randomized controlled trials are needed.
Learning with Augmented Features for Heterogeneous Domain Adaptation

We propose a new learning method for heterogeneous domain adaptation (HDA), in which the data from the source domain and the target domain are represented by heterogeneous features with different dimensions. Using two different projection matrices, we first transform the data from two domains into a common subspace in order to measure the similarity between the data from two domains. We then propose two new feature mapping functions to augment the transformed data with their original features and zeros. The existing learning methods (e.g., SVM and SVR) can be readily incorporated with our newly proposed augmented feature representations to effectively utilize the data from both domains for HDA. Using the hinge loss function in SVM as an example, we introduce the detailed objective function in our method called Heterogeneous Feature Augmentation (HFA) for a linear case and also describe its kernelization in order to efficiently cope with the data with very high dimensions. Moreover, we also develop an alternating optimization algorithm to effectively solve the nontrivial optimization problem in our HFA method. Comprehensive experiments on two benchmark datasets clearly demonstrate that HFA outperforms the existing HDA methods.
Glutaminase inhibitor CB-839 synergizes with carfilzomib in resistant multiple myeloma cells

Curative responses in the treatment of multiple myeloma (MM) are limited by the emergence of therapeutic resistance. To address this problem, we set out to identify druggable mechanisms that convey resistance to proteasome inhibitors (PIs; e.g., bortezomib), which are cornerstone agents in the treatment of MM. In isogenic pairs of PI sensitive and resistant cells, we observed stark differences in cellular bioenergetics between the divergent phenotypes. PI resistant cells exhibited increased mitochondrial respiration driven by glutamine as the principle fuel source. To target glutamine-induced respiration in PI resistant cells, we utilized the glutaminase-1 inhibitor, CB-839. CB-839 inhibited mitochondrial respiration and was more cytotoxic in PI resistant cells as a single agent. Furthermore, we found that CB-839 synergistically enhanced the activity of multiple PIs with the most dramatic synergy being observed with carfilzomib (Crflz), which was confirmed in a panel of genetically diverse PI sensitive and resistant MM cells. Mechanistically, CB-839 enhanced Crflz-induced ER stress and apoptosis, characterized by a robust induction of ATF4 and CHOP and the activation of caspases. Our findings suggest that the acquisition of PI resistance involves adaptations in cellular bioenergetics, supporting the combination of CB-839 with Crflz for the treatment of refractory MM.
Cavity hydration dynamics in cytochrome c oxidase and functional implications

Significance Cytochrome c oxidase (CcO) reduces molecular oxygen to generate the proton motive force across the membrane that drives ATP synthesis. Internal water molecules in and near a central cavity play important roles in mediating the proton transfers. Molecular simulations of CcO reveal reversible transitions between wet and dry configurations of this internal cavity in response to the charge state of key cofactors and residues. Quantitative analysis of the free energy change and timescale of the transition suggests that hydration-level change of the central cavity is an essential feature that contributes to the vectorial efficiency of proton pumping in CcO. Thus, wetting transition of protein internal cavities can be functionally significant, especially for the transport of charged species. Cytochrome c oxidase (CcO) is a transmembrane protein that uses the free energy of O2 reduction to generate the proton concentration gradient across the membrane. The regulation of competitive proton transfer pathways has been established to be essential to the vectorial transport efficiency of CcO, yet the underlying mechanism at the molecular level remains lacking. Recent studies have highlighted the potential importance of hydration-level change in an internal cavity that connects the proton entrance channel, the site of O2 reduction, and the putative proton exit route. In this work, we use atomistic molecular dynamics simulations to investigate the energetics and timescales associated with the volume fluctuation and hydration-level change in this central cavity. Extensive unrestrained molecular dynamics simulations (accumulatively ∼4 μs) and free energy computations for different chemical states of CcO support a model in which the volume and hydration level of the cavity are regulated by the protonation state of a propionate group of heme a3 and, to a lesser degree, the redox state of heme a and protonation state of Glu286. Markov-state model analysis of ∼2-μs trajectories suggests that hydration-level change occurs on the timescale of 100–200 ns before the proton-loading site is protonated. The computed energetic and kinetic features for the cavity wetting transition suggest that reversible hydration-level change of the cavity can indeed be a key factor that regulates the branching of proton transfer events and therefore contributes to the vectorial efficiency of proton transport.
Health-Related Quality of Life in Spanish Children With Coeliac Disease

Objectives: The aim of the study was to assess health-related quality of life (HRQOL) using the Coeliac Disease Dutch Questionnaire (CDDUX) in Spanish children with coeliac disease. Methods: The CDDUX was cross-culturally adapted according to international consensus guidelines. HRQOL was assessed in coeliac members of the Madrid Coeliac Association ages 8 to 18 years using the adapted CDDUX. Cronbach &agr; coefficient was determined as a measure of intraquestionnaire reliability and intraclass correlation coefficients as a measure of reliability between scores awarded by children and parents. Demographic and clinical variables associated with HRQOL were also assessed. Results: A total of 1602 children of 3122 registered Madrid Coeliac Association members ages 8 to 18 years were invited to participate. The questionnaire was completed by 480 families (30%): 214 only by parents, 214 by parents and their children, and 52 only by children. Cronbach &agr; coefficient for the total score for parents was 0.90, and for children 0.88 (0.75–0.90 by scales). Mean total (standard deviation [SD]) HRQOL scores in children and parents were 55.5 (SD 12.7) and 53.89 (SD 12.19), respectively, with no differences detected in paired comparisons between the 2 groups. Significantly worse HRQOL scores were recorded in children showing a nonclassical clinical presentation, in those not adhering to treatment and in those reporting difficulties in following the diet. Conclusions: The CDDUX questionnaire emerged as reliable for use in Spanish children with celiac disease. Overall, both children and parents felt the disease had no substantial negative impacts on patient HRQOL.
Metabolic syndrome among elderly care-home residents in southern India: A cross-sectional study

Background: The health of the elderly population and the emergence of noncommunicable diseases have become major public health issues in recent years. Metabolic syndrome is thought to be the main driving force for the global epidemic of cardiovascular diseases, as well as for type 2 diabetes. This cross-sectional study aimed to determine the prevalence of metabolic syndrome and its correlates among the residents of care homes for the elderly in Hyderabad city, India. Methods: A total 114 elderly persons (aged ≥60 years) were evaluated in a cross-sectional study. Metabolic syndrome was defined by the 2005 criteria of the International Diabetes Federation. Data were collected on selected sociodemographic, behavioural and nutritional variables and cardiometabolic risk factors. Blood pressure and anthropometric measurements were also recorded. Fasting blood samples were collected for measurement of blood glucose and serum lipid levels. Univariable logistic regression was applied to investigate the associations between metabolic syndrome and known risk factors; adjusted analysis was then done by multivariable logistic regression for significant variables. Results: The overall prevalence of metabolic syndrome was 42.1% (48/114) among the study population. A higher prevalence (50.9%; 27/53) was found among women. High blood pressure or taking antihypertensive medication was found to be the most common (95.8%; 46/48) cardiometabolic component. The risk of metabolic syndrome did not differ significantly by age group, sex, caste, religion, type of diet (vegetarian or non-vegetarian), educational status, behavioural factors such as tobacco use and alcohol intake, physical activity (assessed by modified Eastern Cooperative Oncology Group [ECOG] scale), or physical exercise. However, a body mass index ≥23 kg/m2 was associated with metabolic syndrome (unadjusted odds ratio [OR]: 8.97; 95% confidence interval [CI]: 3.78–21.28); adjusted OR: 9.31; 95% CI: 4.12–22.14) Conclusion: The overall prevalence of metabolic syndrome in this study population of elderly care-home residents in India was more than 40%. Further research on the burden of metabolic syndrome in the elderly population is warranted.