Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular Basis of Alternating Access Membrane Transport by the Sodium-Hydantoin Transporter Mhp1

Triangulating to Mechanism Cellular uptake and release of a variety of substrates are mediated by secondary transporters, but no crystal structures are known for all three fundamental states of the transport cycle, which has limited explanations for their proposed mechanisms. Shimamura et al. (p. 470) report a 3.8-angstrom structure of the inward-facing conformation of the bacterial sodium-benzylhydantoin transport protein, Mhp1, complementing the other two available structures. Molecular modeling for the interconversions of these structures shows a simple rigid body rotation of four helices relative to the rest of the structure in which the protein switches reversibly from outward- to inward-facing. Three complementary crystal structures reveal the mechanism of a transport protein in molecular dynamics simulations. The structure of the sodium-benzylhydantoin transport protein Mhp1 from Microbacterium liquefaciens comprises a five-helix inverted repeat, which is widespread among secondary transporters. Here, we report the crystal structure of an inward-facing conformation of Mhp1 at 3.8 angstroms resolution, complementing its previously described structures in outward-facing and occluded states. From analyses of the three structures and molecular dynamics simulations, we propose a mechanism for the transport cycle in Mhp1. Switching from the outward- to the inward-facing state, to effect the inward release of sodium and benzylhydantoin, is primarily achieved by a rigid body movement of transmembrane helices 3, 4, 8, and 9 relative to the rest of the protein. This forms the basis of an alternating access mechanism applicable to many transporters of this emerging superfamily.
The Potential of Closed-Loop Endovascular Neurostimulation as a Viable Therapeutic Approach for Drug Resistant Epilepsy: A Critical Review.

Over the last few decades, biomedical implants have successfully delivered therapeutic electrical stimulation to reduce the frequency and severity of seizures in people with drug-resistant epilepsy. However, neurostimulation approaches require invasive surgery to implant stimulating electrodes, and surgical, medical and hardware complications are not uncommon. An endovascular approach provides a potentially safer and less invasive surgical alternative. This article critically evaluates the feasibility of endovascular closed-loop neuromodulation for the treatment of epilepsy. By reviewing literature that reported the impact of direct electrical stimulation to reduce the frequency of epileptic seizures, we identified clinically validated extracranial, cortical and deep-cortical neural targets. We identified veins in close proximity to these targets, and evaluated the potential of delivering an endovascular implant to these veins based on their diameter. We then compared the risks and benefits of existing technology to describe a benchmark of clinical safety and efficacy that would need to be achieved for endovascular neuromodulation to provide therapeutic benefit. For the majority of brain regions that have been clinically demonstrated to reduce seizure occurrence in response to delivered electrical stimulation, vessels of appropriate diameter for delivery of an endovascular electrode to these regions could be achieved. This includes: delivery to the vagus nerve via the 13.2±0.9mm diameter internal jugular vein, the motor cortex via the 6.5±1.7mm diameter superior sagittal sinus, and the cerebellum via the 7.7±1.4mm diameter sigmoid sinus or 6.2±1.4mm diameter transverse sinus. Deep cerebral targets can also be accessed with an endovascular approach, with the 1.9±0.5mm diameter internal cerebral vein and 1.2mm diameter thalamostriate vein lying in close proximity to the anterior and centromedian nuclei of the thalamus, respectively. This work identified numerous veins that are in close proximity to conventional stimulation targets that are of a diameter large enough for delivery and deployment of an endovascular electrode array, supporting future work to assess clinical efficacy and chronic safety of an endovascular approach to deliver therapeutic neurostimulation.
Mechanism of collagen folding propagation studied by Molecular Dynamics simulations

Collagen forms a characteristic triple helical structure and plays a central role for stabilizing the extra-cellular matrix. After a C-terminal nucleus formation folding proceeds to form long triple-helical fibers. The molecular details of triple helix folding process is of central importance for an understanding of several human diseases associated with misfolded or unstable collagen fibrils. However, the folding propagation is too rapid to be studied by experimental high resolution techniques. We employed multiple Molecular Dynamics simulations starting from unfolded peptides with an already formed nucleus to successfully follow the folding propagation in atomic detail. The triple helix folding was found to propagate involving first two chains forming a short transient template. Secondly, three residues of the third chain fold on this template with an overall mean propagation of ~75 ns per unit. The formation of loops with multiples of the repeating unit was found as a characteristic misfolding event especially when starting from an unstable nucleus. Central Gly→Ala or Gly→Thr substitutions resulted in reduced stability and folding rates due to structural deformations interfering with folding propagation.
Regenerative and stem cell-based techniques for facial rejuvenation

This review discusses the most novel ideas and modalities being incorporated into facial rejuvenation. Recent innovative techniques include the use of regenerative stem cell techniques and regeneration supportive modalities such as nano-technology or gene therapies. This review aims to investigate approaches that are less well known and lacking established evidence in order to proactively study these techniques prior to them becoming popularized. These applications and relevant research were reviewed in the context of both surgical and non-surgical modalities in clinical practice. Future directions include the concept of “precision cosmetic medicine” utilizing gene editing and cellular therapies to tailor rejuvenation techniques based on each individual’s genetic make-up and therefore needs.
Small molecule‐mediated modulation of ubiquitination and neddylation improves HSC function ex vivo

Hematopoietic stem cells (HSCs) are particularly characterized by their quiescence and self‐renewal. Cell cycle regulators tightly control quiescence and self‐renewal capacity. Studies suggest that modulation of ubiquitination and neddylation could contribute to HSC function via cyclin‐dependent kinase inhibitors (CDKIs). S‐phase kinase‐associated protein 2 (SKP2) is responsible for ubiquitin‐mediated proteolysis of CDKIs. Here, we modulated overall neddylation and SKP2‐associated ubiquitination in HSCs by using SKP2‐C25, an SKP2 inhibitor, and MLN4924 (Pevonedistat) as an inhibitor of the NEDD8 system. Treatments of SKP2‐C25 and MLN4924 increased both murine and human stem and progenitor cell (HSPC) compartments. This is associated with the improved quiescence of murine HSC by upregulation of p27 and p57 CDKIs. A colony‐forming unit assay showed an enhanced in vitro self‐renewal potential post inhibition of ubiquitination and neddylation. In addition, MLN4924 triggered the mobilization of bone marrow HSPCs to peripheral blood. Intriguingly, MLN4924 treatment could decrease the proliferation of murine bone marrow mesenchymal stem cells or endothelial cells. These findings shed light on the contribution of SKP2, and associated ubiquitination and neddylation in HSC maintenance, self‐renewal, and expansion.
Using Bilateral tDCS to Modulate EEG Amplitude and Coherence of Men With Opioid Use Disorder Under Methadone Therapy: A Sham-controlled Clinical Trial

Objective. This study aimed to investigate the effect of bilateral transcranial direct current stimulation (tDCS) on the electroencephalography (EEG) amplitude and coherence in male patients with opioid use disorder (OUD), who were under methadone therapy. It compares the effects of active versus sham tDCS. Methods. This is a double-blind sham-controlled clinical trial. Participants were 30 male patients with OUD; they were divided into 3 groups of left anode/right cathode tDCS, right anode/left cathode tDCS, and sham tDCS. Their brainwave activity was measured by quantitative EEG before study and then active groups underwent tDCS (2 mA, 20 min) applied over their right/left dorsolateral prefrontal cortex (DLPFC) for 10 consecutive days. After stimulation, they were re-assessed. The collected data were analyzed in SPSS, MATLAB, and NeuroGuide v.2 applications. Results. After active tDCS, a significant decrease in amplitude of slow brain waves (delta, theta, and alpha) in prefrontal, frontal, occipital, and parietal areas, and an increase in the coherence of beta, delta, and theta frequency bands in the parietal, central, and temporal regions of addicts were reported. In the sham group, there was a significant decrease in the amplitude of the alpha wave and in the coherence of delta and theta waves. Conclusion. The active tDCS over the right/left DLPFC, as a noninvasive and complementary treatment, can modulate the amplitude and coherence of brainwaves in patients with OUD.
Disruption of endothelial Pfkfb3 ameliorates diet-induced murine insulin resistance.

Overnutrition-induced endothelial inflammation plays a crucial role in high fat diet (HFD)-induced insulin resistance in animals. Endothelial glycolysis plays a critical role in endothelial inflammation and proliferation, but its role in diet-induced endothelial inflammation and subsequent insulin resistance has not been elucidated. PFKFB3 is a critical glycolytic regulator, and its increased expression has been observed in adipose vascular endothelium of C57BL/6J mice fed with HFD in vivo, and in palmitate (PA)-treated primary human adipose microvascular endothelial cells (HAMECs) in vitro. We generated mice with Pfkfb3 deficiency selective for endothelial cells to examine the effect of endothelial Pfkfb3 in endothelial inflammation in metabolic organs and in the development of HFD-induced insulin resistance. EC Pfkfb3-deficient mice exhibited mitigated HFD-induced insulin resistance, including decreased body weight and fat mass, improved glucose clearance and insulin sensitivity, and alleviated adiposity and hepatic steatosis. Mechanistically, cultured PFKFB3 knockdown HAMECs showed decreased NF-κB activation induced by PA, and consequent suppressed adhesion molecule expression and monocyte adhesion. Taken together, these results demonstrate that increased endothelial PFKFB3 expression promotes diet-induced inflammatory responses and subsequent insulin resistance, suggesting that endothelial metabolic alteration plays an important role in the development of insulin resistance.
Association between exercise habits and stroke, heart failure, and mortality in Korean patients with incident atrial fibrillation: A nationwide population-based cohort study

Background There is a paucity of information about cardiovascular outcomes related to exercise habit change after a new diagnosis of atrial fibrillation (AF). We investigated the association between exercise habits after a new AF diagnosis and ischemic stroke, heart failure (HF), and all-cause death. Methods and findings This is a nationwide population-based cohort study using data from the Korea National Health Insurance Service. A retrospective analysis was performed for 66,692 patients with newly diagnosed AF between 2010 and 2016 who underwent 2 serial health examinations within 2 years before and after their AF diagnosis. Individuals were divided into 4 categories according to performance of regular exercise, which was investigated by a self-reported questionnaire in each health examination, before and after their AF diagnosis: persistent non-exercisers (30.5%), new exercisers (17.8%), exercise dropouts (17.4%), and exercise maintainers (34.2%). The primary outcomes were incidence of ischemic stroke, HF, and all-cause death. Differences in baseline characteristics among groups were balanced considering demographics, comorbidities, medications, lifestyle behaviors, and income status. The risks of the outcomes were computed by weighted Cox proportional hazards models with inverse probability of treatment weighting (IPTW) during a mean follow-up of 3.4 ± 2.0 years. The new exerciser and exercise maintainer groups were associated with a lower risk of HF compared to the persistent non-exerciser group: the hazard ratios (HRs) (95% CIs) were 0.95 (0.90–0.99) and 0.92 (0.88–0.96), respectively (p < 0.001). Also, performing exercise any time before or after AF diagnosis was associated with a lower risk of mortality compared to persistent non-exercising: the HR (95% CI) was 0.82 (0.73–0.91) for new exercisers, 0.83 (0.74–0.93) for exercise dropouts, and 0.61 (0.55–0.67) for exercise maintainers (p < 0.001). For ischemic stroke, the estimates of HRs were 10%–14% lower in patients of the exercise groups, yet differences were statistically insignificant (p = 0.057). Energy expenditure of 1,000–1,499 MET-min/wk (regular moderate exercise 170–240 min/wk) was consistently associated with a lower risk of each outcome based on a subgroup analysis of the new exerciser group. Study limitations include recall bias introduced due to the nature of the self-reported questionnaire and restricted external generalizability to other ethnic groups. Conclusions Initiating or continuing regular exercise after AF diagnosis was associated with lower risks of HF and mortality. The promotion of exercise might reduce the future risk of adverse outcomes in patients with AF.
Improving physico-chemical and microbiological quality of compost tea using different treatments during extraction

Compost tea is gaining much interest due to its nutritional, biostimulation and disease suppression benefits to the plants. Four experiments were carried out to determine the effect of incubation temperature, incubation periods, dilution rate and nutritional sources on the microbial populations, physico-chemical properties and indole acetic acid (IAA) levels. Incubation at 28°C showed the highest number of bacteria and aerobic N2-fixing bacteria (ANFB), along with the highest levels of total nitrogen and IAA. All the microbial populations increased in proportion with increase in the incubation period; however, increasing the incubation more than 48 h did not show any significant improvement (P ≤ 0.05) in the physico-chemical properties or IAA levels. All microbial numbers and chemical properties decreased by increasing the dilution rate. Adding a mixture of the three used nutrients (molasses "0.5% v/v", ammonium nitrate "0.5 g/L" and di-potassium phosphate "0.5 g/L") resulted in the highest microbial populations (except for ANFB) as compared to the molasses, or double the amount of each other chemical alone. This study show the optimum conditions for preparing compost tea with high microbiological and physico-chemical properties. The study includes ANFB, important for soil application, and IAA, important for foliar application, which have not been studied before in compost tea. Key words: Compost tea extraction, factors, microbiology, physico-chemical, indole acetic acid (IAA), aerobic N2-fixing bacteria (ANFB).
Associations between sleep disturbances, diabetes and mortality in the UK Biobank cohort: A prospective population‐based study

Non‐communicable diseases, including diabetes, are partly responsible for the deceleration of improvements of life expectancy in many countries. Diabetes is also associated with sleep disturbances. Our aim was to determine whether sleep disturbances, particularly in people with diabetes, were associated with increased mortality risk. Data from the UK Biobank were analysed (n = 487,728, mean follow‐up time = 8.9 years). The primary exposure was sleep disturbances, assessed through the question: Do you have trouble falling asleep at night or do you wake up in the middle of the night? The primary outcome was mortality. We also dichotomized sleep disturbances into “never/sometimes” versus “usually” (frequently), and combined with the presence/absence of diabetes: 24.2% of participants reported “never/rarely” experiencing sleep disturbances, 47.8% “sometimes” and 28.0% “usually”. In age‐ and sex‐adjusted models, frequent sleep disturbances were associated with an increased risk of all‐cause mortality (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.26–1.37), which remained significant in the fully adjusted model (HR 1.13, 95% CI 1.09–1.18). The presence of both diabetes and frequent sleep disturbances was associated with greater risk of all‐cause mortality than either condition alone. In the fully adjusted model, the hazard ratio for all‐cause mortality was 1.11 (95% CI, 1.07–1.15) for frequent sleep disturbances alone, 1.67 (95% CI, 1.57–1.76) for diabetes alone and 1.87 for both (95% CI, 1.75–2.01). Frequent sleep disturbances (experienced by more than one quarter of the sample) were associated with increased risk of all‐cause mortality. Mortality risk was highest in those with both diabetes and frequent sleep disturbances. Complaints of difficulty falling or staying asleep merit attention by physicians.
The co-occurrence of overweight/obesity and anaemia among adult women, adolescent girls and children living in fifty-two low- and middle-income countries

Abstract Objective: To investigate the magnitude and distribution of concurrent overweight/obesity and anaemia among adult women, adolescent girls and children living in low- and middle-income countries (LMIC). Design: We selected the most recent Demographic and Health Surveys with anthropometric and Hb level measures. Prevalence estimates and 95 % CI of concurrent overweight/obesity and anaemia were calculated for every country, overall and stratified by household wealth quintile, education level, area of residence and sex (for children only). Regional and overall pooled prevalences were estimated using a random-effects model. We measured gaps, expressed in percentage points, to display inequalities in the distribution of the double burden of malnutrition (DBM). Setting: Nationally representative surveys from fifty-two LMIC. Participants: Adult women (n 825 769) aged 20–49 years, adolescent girls (n 192 631) aged 15–19 years and children (n 391 963) aged 6–59 months. Results: The pooled prevalence of concurrent overweight/obesity and anaemia was 12·4 % (95 % CI 11·1, 13·7) among adult women, 4·5 % (95 % CI 4·0, 5·0) among adolescent girls and 3·0 % (95 % CI 2·7, 3·3) among children. Overall, the DBM followed an inverse social gradient, with a higher prevalence among the richest quintile, most educated groups and in urban areas; however, important variations exist. The largest inequality gaps were observed among adult women in Yemen by household wealth (24·0 percentage-points) and in Niger by education level (19·6 percentage-points) and area of residence (11·9 percentage-points). Differences were predominantly significant among adult women, but less among girls and children. Conclusions: Context-specific, multifaceted, responses with an equity lens are needed to reduce all forms of malnutrition.
Marijuana use and sleep quality during pregnancy

Abstract Objective Marijuana use among pregnant women is on the rise in part due to the perception that marijuana may improve problems related to pregnancy such as poor sleep. This study’s objective was to examine associations between marijuana use and sleep quality among a sample of women during pregnancy. Material and methods The sample included women seeking prenatal care at The Ohio State University Wexner Medical Center (2010–2015). Intake assessments included medical, demographic, and socioeconomic domains, as well as the Pittsburgh Sleep Quality Index. Marijuana use during pregnancy was determined using urine screens, chart abstraction, and self-report. Women completed standardized questionnaires regarding sleep quality, depressive symptoms, anxiety, stress, and discrimination at enrollment and each subsequent trimester. A linear mixed-effect model was used to assess the relationship between sleep variables and marijuana use adjusted for maternal race, education, household income, age, marital status, depressive symptoms, anxiety, stress, discrimination, and use of tobacco and other substances during pregnancy. Women completed the sleep quality assessments for a total of 294 pregnancies, which comprise the study population. Results Among the study sample (n = 294), 93 women used marijuana and 201 women did not use marijuana during their pregnancies. Women who used marijuana (n = 93) were more likely to identify as African-American (73% vs 58%; p = .01), report government health insurance (98% vs 89%; p = .001), use tobacco during pregnancy (66% vs 33%; p < .001), report less household income (70% vs 43% < 10,000 annual household income; p < .001), and be unmarried (69% vs 49%; p < .001) compared to women who did not. Mean sleep quality was similar among women who did (µ = 7.6; SD = 4.0) and did not use marijuana during pregnancy (µ = 7.7; SD = 4.0), and both groups had a mean score worse than the conventional cutoff for poor sleep quality (>5). In fact, both groups reported worse sleep than is typically observed among cohorts reporting poor sleep, which have ranged from 5.3 to 6.3. Conclusions Current findings did not suggest differences in sleep quality between women who used and did not use marijuana during pregnancy. Findings are contrary to the perception that marijuana use alleviates sleep-related problems during pregnancy. Given well-documented adverse outcomes associated with prenatal marijuana exposure for children and the increase in women using marijuana during pregnancy, providers should be prepared to discuss possible harms associated with marijuana use during pregnancy as well as provide psychoeducational information and service referrals to those interested. Future studies could improve upon this design by assessing objective measures of sleep, such as actigraphy, as well as marijuana use repeatedly throughout pregnancy, which may be a more optimal strategy for illuminating potential relationships between marijuana use and sleep during pregnancy.
Management of children with glucose‐6‐phosphate dehydrogenase deficiency presenting with acute haemolytic crisis during the SARs‐COV‐2 pandemic

Shortage of blood during the severe acute respiratory syndrome‐COV‐2 (SARs‐COV‐2) pandemic impacted transfusion practice. The primary aim of the study is to assess management of acute haemolytic crisis (AHC) in glucose‐6‐phosphate dehydrogenase(G6PD)‐ deficient children during SARs‐COV‐2 pandemic, and then to assess blood donation situation and the role of telemedicine in management.