Miracle-dz/UniFAR-FTUs huggingface dataset:
Four-week Tai Chi intervention decreases attention bias to drug cues in individuals with methamphetamine use disorder

ABSTRACT Background: Mind-body exercise is used for the rehabilitation of individuals with methamphetamine use disorder (MUD). Attention bias to substances is an important index of MUD. However, whether a mind-body exercise intervention can decrease attention bias is unclear. Objective: This study aimed to test the effect of a four-week Tai Chi (a Chinese traditional mind-body exercise) exercise program on the attention bias of individuals with MUD. Methods: Thirty-two men with MUD and without Tai Chi practice experience were recruited and randomly assigned to either a Tai Chi exercise group or a control group. The Tai Chi group received four-week Tai Chi training, while the control group engaged in daily exercise (including radio gymnastics and Jianxincao, two kinds of free-hand exercises). During a drug-related Stroop task, participants were instructed to respond to the color of the word ignoring the word type (drug-related or neutral words). The reaction time and d’ (the index of sensitivity) were measured. Results: The participants showed attention bias to substance cues; the reaction time was slower for drug-related words than for neutral words (p < .05). After the Tai Chi intervention, the Tai Chi group showed a faster reaction time (ps < .05) and a smaller d’ (ps < .05) than the baseline across all the word types. In contrast, the control group showed no differences (ps > .05). Conclusion: Four-week Tai Chi intervention reduced sensitivity and attentional bias to drug-related cues in individuals with MUD, suggesting that mind-body exercise might enhance recovery from MUD via attention control.
Assessment of the safe and efficacious dose of the selective progesterone receptor modulator vilaprisan for the treatment of patients with uterine fibroids by exposure–response modelling and simulation

We report population pharmacokinetic (popPK) and exposure–response (E–R) analyses for efficacy (induced amenorrhoea [IA]) and safety (unbound oestradiol [E2] concentrations) of the selective progesterone receptor modulator vilaprisan. Results were used to inform the dose for the Phase 3 programme in patients with uterine fibroids.
Sentiment Classification Using Sentence-level Lexical Based Semantic Orientation of Online Reviews

Sentiment analysis is the process of extracting knowledge from the peoples’ opinions, appraisals and emotions toward entities, events and their attributes. These opinions greatly impact on customers to make their choices regarding online shopping, choosing events, products and entities. With the rapid growth of online resources, discussion groups, forums and blogs; people communicate through these means of internet on daily basis. As a result, the vast amount of new data in the form of customer reviews and opinions are being generated progressively. So it is desired to develop an efficient and effective sentiment analysis system for online customer reviews and comments. In this study, the rule based domain independent sentiment analysis method is proposed. The proposed method classifies subjective and objective sentences from reviews and blog comments. The semantic score of subjective sentences is extracted from SentiWordNet to calculate their polarity as positive, negative or neutral based on the contextual sentence structure. The results show the effectiveness of the proposed method and it outperforms the word level and machine learning methods. The proposed method achieves an accuracy of 97.8% at the feedback level and 86.6% at the sentence level.
Patterns of pretreatment drug resistance mutations of very early diagnosed and treated infants in Botswana

Supplemental Digital Content is available in the text Objective: To describe the occurrence of HIV drug resistance mutations (DRMs) in both intact and defective HIV-1 cell-associated DNA (HIV-1 CAD) among early-treated infants. Design: The Botswana EIT Study (ClinicalTrials.gov NCT02369406) initiated antiretroviral therapy (ART) in the first week of life and evaluated HIV-1 in plasma and peripheral blood mononuclear cells (PBMCs). Methodology: We analyzed 257 near-HIV-1 full-length sequences (nFLS) obtained by Illumina next-generation sequencing from infants near birth. Sanger sequencing of pol was performed for mothers at delivery and children with clinical failure through 96 weeks. DRMs were identified using the Stanford HIV Drug Resistance Database. Results: In 27 infants, median PBMC HIV-1 proviral load was 492 copies/ml [IQR: 78–1246 copies/ml] at a median of 2 days (range 1–32); 18 (66.7%) had no DRMs detected; six (22.2%) had DRMs detected in defective DNA only, and three (11.1%) had DRMs in both defective and intact DNA (P = 0.09). A total of 60 of 151 (37.7%) defective sequences had at least one DRM: 31.8% NNRTI, 15.2% NRTI, 5.3% protease inhibitor, and 15.5% INSTI-associated mutations. In intact sequences, 33 of 106 (31.1%) had at least 1 DRM: 29.2% NNRTI, 7.5% NRTI, 0.9% protease inhibitor, and no INSTI-associated mutations. For all three infants with intact sequence DRMs, corresponding DRMs occurred in maternal plasma at delivery. Archived DRMs were detectable at a later clinical rebound on only one occasion. Conclusion: Defective HIV-1 cell-associated DNA sequences may overestimate the prevalence of drug resistance among early-treated children. The impact of DRMs from intact proviruses on long-term treatment outcomes warrants further investigation.
High-mass MALDI-MS unravels ligand-mediated G protein–coupling selectivity to GPCRs

Significance G protein–coupled receptors (GPCRs) are important pharmaceutical targets for the treatment of a broad spectrum of diseases. Upon ligand binding, GPCRs initiate intracellular signaling pathways by interacting with partner proteins. Assays that quantify the interplay between ligand binding and initiation of downstream signaling cascades are critical in the early stages of drug development. We have developed a high-throughput mass spectrometry method to unravel GPCR–protein complex interplay and demonstrated its use with three GPCRs to provide quantitative information about ligand-modulated coupling selectivity. This method provides insights into the molecular details of GPCR interactions and could serve as an approach for discovery of drugs that initiate specific cell-signaling pathways. G protein–coupled receptors (GPCRs) are important pharmaceutical targets for the treatment of a broad spectrum of diseases. Although there are structures of GPCRs in their active conformation with bound ligands and G proteins, the detailed molecular interplay between the receptors and their signaling partners remains challenging to decipher. To address this, we developed a high-sensitivity, high-throughput matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) method to interrogate the first stage of signal transduction. GPCR–G protein complex formation is detected as a proxy for the effect of ligands on GPCR conformation and on coupling selectivity. Over 70 ligand–GPCR–partner protein combinations were studied using as little as 1.25 pmol protein per sample. We determined the selectivity profile and binding affinities of three GPCRs (rhodopsin, beta-1 adrenergic receptor [β1AR], and angiotensin II type 1 receptor) to engineered Gα-proteins (mGs, mGo, mGi, and mGq) and nanobody 80 (Nb80). We found that GPCRs in the absence of ligand can bind mGo, and that the role of the G protein C terminus in GPCR recognition is receptor-specific. We exemplified our quantification method using β1AR and demonstrated the allosteric effect of Nb80 binding in assisting displacement of nadolol to isoprenaline. We also quantified complex formation with wild-type heterotrimeric Gαiβγ and β-arrestin-1 and showed that carvedilol induces an increase in coupling of β-arrestin-1 and Gαiβγ to β1AR. A normalization strategy allows us to quantitatively measure the binding affinities of GPCRs to partner proteins. We anticipate that this methodology will find broad use in screening and characterization of GPCR-targeting drugs.
(–)‐Nomilin chloro­form solvate

The absolute stereochemistry of the title compound, C28H33O9·CHCl3, has been determined by single-crystal X-ray diffraction by incorporation of the heavy-atom-containing solvent chloro­form. The A/B, B/C and C/D ring junctions are all trans-fused. Five-membered ring E is equatorially attached to ring D. The crystal structure is stabilized by weak inter­molecular C—H⋯O inter­actions.
Influence of Renal Function on the Single‐Dose Pharmacokinetics of Besifovir, a Novel Antiviral Agent for theTreatment of Hepatitis B Virus Infection

Per the well‐known resistance of hepatitis B virus to nucleoside/nucleotide analogs, alternative treatment options with higher resistance barriers have been approved for use in both treatment‐naïve and lamivudine‐resistant hepatitis B virus infections. This phase I study was conducted in adults with normal and impaired renal function to evaluate the effect of renal impairment on the pharmacokinetics of besifovir, a prodrug of an acyclic nucleotide phosphonate, that is mainly cleared via renal excretion. An open‐label, single‐dose parallel‐group clinical study was conducted in subjects with normal renal function and mild, moderate, and severe renal impairment. Subjects received a single oral dose of besifovir dipivoxil 150 mg, and serial blood and urine samples were collected for up to 72 hours after dosing to assess the pharmacokinetic characteristics of besifovir. The extent of plasma exposure of besifovir, detected as its major and active metabolites, LB80331 and LB80317, respectively, increased with worsening renal function. Compared to the subjects with normal renal function, the mean areas under the concentration‐time curves of LB80331 increased by 1.5‐, 2.5‐, and 4.5‐fold in subjects with mild, moderate, and severe impairment, respectively. LB80317 showed a 1.8‐, 3.2‐, and 6.2‐fold increase in subjects with mild, moderate, and severe renal impairment compared to those with normal function. The ratios of LB80331 renal clearance and the average estimated glomerular filtration rate of each renal impairment group with respect to the normal group were similar. The increase in plasma exposure and decrease in renal clearance suggest the need to adjust dosage regimens in patients with moderate to severe renal impairment.
Altered neurodevelopmental DNA methylation status after fetal growth restriction with brain-sparing

Abstract It is under debate how preferential perfusion of the brain (brain-sparing) in fetal growth restriction (FGR) relates to long-term neurodevelopmental outcome. Epigenetic modification of neurotrophic genes by altered fetal oxygenation may be involved. To explore this theory, we performed a follow-up study of 21 FGR children, in whom we prospectively measured the prenatal cerebroplacental ratio (CPR) with Doppler sonography. At 4 years of age, we tested their neurodevelopmental outcome using the Wechsler Preschool and Primary Scale of Intelligence, the Child Behavior Checklist, and the Behavior Rating Inventory of Executive Function. In addition, we collected their buccal DNA to determine the methylation status at predefined genetic regions within the genes hypoxia-inducible factor-1 alpha (HIF1A), vascular endothelial growth factor A (VEGFA), erythropoietin (EPO), EPO-receptor (EPOR), brain-derived neurotrophic factor (BDNF), and neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) by pyrosequencing. We found that FGR children with fetal brain-sparing (CPR <1, n = 8) demonstrated a trend (0.05 < p < 0.1) toward hypermethylation of HIF1A and VEGFA at their hypoxia-response element (HRE) compared with FGR children without fetal brain-sparing. Moreover, in cases with fetal brain-sparing, we observed statistically significant hypermethylation at a binding site for cyclic adenosine monophophate response element binding protein (CREB) of BDNF promoter exon 4 and hypomethylation at an HRE located within the NTRK2 promoter (both p <0.05). Hypermethylation of VEGFA was associated with a poorer Performance Intelligence Quotient, while hypermethylation of BDNF was associated with better inhibitory self-control (both p <0.05). These results led us to formulate the hypothesis that early oxygen-dependent epigenetic alterations due to hemodynamic alterations in FGR may be associated with altered neurodevelopmental outcome in later life. We recommend further studies to test this hypothesis.
Study on processing technology of compound soymilk beverage with ginger juice

Using the soybean, milk powder and ginger as material, the processing technology and key procedure of soymilk powder with ginger juice were studied in this paper. The result showed that the perfect effects of eliminating the beans smell were obtained if combining traditional production technology with covering method of natural material. The perfect stabling effect was obtained if the proportion of ginger juice to soybean milk was 1∶50(v/v). The sugar content was 8%. The milk powder content was 25%. This was the best formula. It was a kind of natural beverage that had rich nutrition, new taste and health functions with compound aroma of soymilk and ginger.
Combined Effect of MTHFR C677T and PAI-1 4G/5G Polymorphisms on the Risk of Venous Thromboembolism in Chinese Lung Cancer Patients

Venous thromboembolism (VTE) is a common and potentially fatal complication in cancer patients. Although several genetic risk factors related to thrombophilia have been identified, their contributions for the occurrence of VTE in cancer patients have conflicting results. The aim of this study was to evaluated the gene polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and plasminogen activator inhibitor-1 (PAI-1) 4G/5G in lung cancer patients, with and without VTE, and the combined effect on the risk of VTE. 92 lung cancer patients diagnosed with VTE (VTE group) and 122 lung cancer patients without VTE (non-VTE group) were enrolled in the study. The gene polymorphisms were analyzed by the method of polymerase chain reaction-restriction fragment length polymorphism. Gene mutation of factor V Leiden was not detected both in non-VTE group and VTE group. The frequency of MTHFR C677T homozygous mutation in VTE group was 25.00%, higher than that in the non-VTE group without statistical difference. It was found that the PAI-1 4G4G genotype is associated with a higher risk of VTE (OR: 2.62, 95%CI: 1.19-5.75). Interestingly, the interaction between MTHFR C677T and PAI-1 4G/5G polymorphisms showed that the coexistence of the 2 homozygous mutation could further increase the risk of VTE. In conclusion, PAI-1 4G/5G polymorphism may be an increased risk factor for VTE among lung cancer patients in Chinese population. The homozygous MTHFR C677T mutation may be not a risk factor for VTE but increases the risk, accompanied with PAI-1 4G5G genotype.
Psychological factors for the onset of depression: a meta-analysis of prospective studies

Objectives A comprehensive overview of the evidence for factors derived from leading psychological theories of the onset of major depressive disorder (MDD) that underpin psychological interventions is scarce . We aimed to systematically investigate the prospective evidence for factors derived from the behavioural, cognitive, diathesis–stress, psychodynamic and personality-based theories for the first onset of MDD. Design Systematic review and meta-analysis. Methods Databases PubMed, PsycINFO, Cochrane and Embase and published articles were systematically searched from inception up to August 2019. Prospective, longitudinal studies that investigated theory-derived factors before the first onset of MDD, established by a clinical interview, were included. Screening, selection and data extraction of articles were conducted by two screeners. The Grading of Recommendations Assessment, Development and Evaluation criteria were used to estimate level of confidence and risk of bias. Meta-analysis was conducted using random-effects models and mixed-method subgroup analyses. Primary and secondary outcome measures Effect size of a factor predicting the onset of MDD (OR, risk ratio or HR). Results From 42 133 original records published to August 2019, 26 studies met the inclusion criteria. Data were only available for the cognitive (n=6585) and personality-based (n=14 394) theories. Factors derived from cognitive theories and personality-based theories were related to increased odds of MDD onset (pooled OR=2.12, 95% CI: 1.12 to 4.00; pooled OR=2.43, 95% CI: 1.41 to 4.19). Publication bias and considerable heterogeneity were observed. Conclusion There is some evidence that factors derived from cognitive and personality-based theories indeed predict the onset of MDD (ie, dysfunctional attitudes and negative emotionality). There were no studies that prospectively studied factors derived from psychodynamic theories and not enough studies to examine the robust evidence for behavioural and diathesis–stress theories. Overall, the prospective evidence for psychological factors of MDD is limited, and more research on the leading psychological theories is needed. PROSPERO registration number CRD42017073975.
Association between Vitamin D and Risk of Stroke: A PRISMA-Compliant Systematic Review and Meta-Analysis

Background: Previous studies have shown inconsistent results for associations between vitamin D and risk of stroke. We gathered the existing published articles and conducted this meta-analysis with the aim to explore the association between vitamin D and risk of stroke. Methods: We searched for articles exploring the association between vitamin D and risk of stroke and published before April 2021 in the following databases: PubMed, Web of Science, MEDLINE, EMBASE, and Google Scholar. All statistical analyses were made using STATA 12.0 software. Q test and I2 were applied to examine heterogeneities between studies. Results: For the association between serum levels of 25(OH) vitamin D and risks of stroke, the present analysis included 20 cohort studies (including 213,276 participants) and a case-control analysis (including 13,642 participants). Additionally, the analysis included 15 studies (including 41,146 participants given vitamin D supplementation and 41,163 participants given placebo) to evaluate the influence of vitamin D supplementation on risk of stroke. Higher circulating levels of 25(OH) vitamin D were associated with a reduced risk of stroke (odds ratio/relative risk = 0.78, 95% confidence interval [CI]: 0.70–0.86, I2 = 41.5%, p = 0.025). However, the present analysis showed that vitamin D supplementation did not influence the risk of stroke (hazard ratio = 1.05, 95% CI: 0.96–1.14, I2 = 2.3%, p = 0.425). Conclusions: Our analysis indicated that lower circulating level of vitamin D was associated with an elevated risk of stroke, but extra supplement of vitamin D failed to show benefit in decreasing the risk of stroke. Further research and study are also needed to show the role of vitamin D in relation to stroke.
Azole-resistant Aspergillus fumigatus in the environment: Identifying key reservoirs and hotspots of antifungal resistance

Aspergillus fumigatus is an opportunistic human pathogen that causes aspergillosis, a spectrum of environmentally acquired respiratory illnesses. It has a cosmopolitan distribution and exists in the environment as a saprotroph on decaying plant matter. Azoles, which target Cyp51A in the ergosterol synthesis pathway, are the primary class of drugs used to treat aspergillosis. Azoles are also used to combat plant pathogenic fungi. Recently, an increasing number of azole-naive patients have presented with pan-azole–resistant strains of A. fumigatus. The TR34/L98H and TR46/Y121F/T289A alleles in the cyp51A gene are the most common ones conferring pan-azole resistance. There is evidence that these mutations arose in agricultural settings; therefore, numerous studies have been conducted to identify azole resistance in environmental A. fumigatus and to determine where resistance is developing in the environment. Here, we summarize the global occurrence of azole-resistant A. fumigatus in the environment based on available literature. Additionally, we have created an interactive world map showing where resistant isolates have been detected and include information on the specific alleles identified, environmental settings, and azole fungicide use. Azole-resistant A. fumigatus has been found on every continent, except for Antarctica, with the highest number of reports from Europe. Developed environments, specifically hospitals and gardens, were the most common settings where azole-resistant A. fumigatus was detected, followed by soils sampled from agricultural settings. The TR34/L98H resistance allele was the most common in all regions except South America where the TR46/Y121F/T289A allele was the most common. A major consideration in interpreting this survey of the literature is sampling bias; regions and environments that have been extensively sampled are more likely to show greater azole resistance even though resistance could be more prevalent in areas that are under-sampled or not sampled at all. Increased surveillance to pinpoint reservoirs, as well as antifungal stewardship, is needed to preserve this class of antifungals for crop protection and human health.
Phytocannabinoids - An Overview of the Analytical Methodologies for Detection and Quantification of Therapeutically and Recreationally Relevant Cannabis Compounds

Abstract The legalization of the cultivation of low Δ9-tetrahydrocannabinol (Δ9-THC) and high cannabidiol (CBD) Cannabis Sativa plants is gaining momentum around the world due to increasing demand for CBD-containing products. In many countries where CBD oils, extracts and CBD-infused foods and beverages are being sold in health shops and supermarkets, appropriate testing of these products is a legal requirement. Normally this involves determining the total Δ9-THC and CBD and their precursor tetrahydrocannabinolic acids (THCA) and cannabidiolic acid (CBDA). As our knowledge of the other relevant cannabinoids expands, it is likely so too will the demand for them as additives in many consumer products ensuring a necessity for quantification methods and protocols for their identification. This paper discusses therapeutically relevant cannabinoids found in Cannabis plant, the applicability and efficiency of existing extraction and analytical techniques as well as the legal requirements for these analyses. Graphical Abstract
Contribution of NMDA Receptors to Synaptic Function in Rat Hippocampal Interneurons

Abstract The ability of neurons to produce behaviorally relevant activity in the absence of pathology relies on the fine balance of synaptic inhibition to excitation. In the hippocampal CA1 microcircuit, this balance is maintained by a diverse population of inhibitory interneurons that receive largely similar glutamatergic afferents as their target pyramidal cells, with EPSCs generated by both AMPA receptors (AMPARs) and NMDA receptors (NMDARs). In this study, we take advantage of a recently generated GluN2A-null rat model to assess the contribution of GluN2A subunits to glutamatergic synaptic currents in three subclasses of interneuron found in the CA1 region of the hippocampus. For both parvalbumin-positive and somatostatin-positive interneurons, the GluN2A subunit is expressed at glutamatergic synapses and contributes to the EPSC. In contrast, in cholecystokinin (CCK)-positive interneurons, the contribution of GluN2A to the EPSC is negligible. Furthermore, synaptic potentiation at glutamatergic synapses on CCK-positive interneurons does not require the activation of GluN2A-containing NMDARs but does rely on the activation of NMDARs containing GluN2B and GluN2D subunits.