Miracle-dz/UniFAR-FTUs huggingface dataset:
Dual targeting of higher-order DNA structures by azacryptands induces DNA junction-mediated DNA damage in cancer cells

Abstract DNA is intrinsically dynamic and folds transiently into alternative higher-order structures such as G-quadruplexes (G4s) and three-way DNA junctions (TWJs). G4s and TWJs can be stabilised by small molecules (ligands) that have high chemotherapeutic potential, either as standalone DNA damaging agents or combined in synthetic lethality strategies. While previous approaches have claimed to use ligands that specifically target either G4s or TWJs, we report here on a new approach in which ligands targeting both TWJs and G4s in vitro demonstrate cellular effects distinct from that of G4 ligands, and attributable to TWJ targeting. The DNA binding modes of these new, dual TWJ-/G4-ligands were studied by a panel of in vitro methods and theoretical simulations, and their cellular properties by extensive cell-based assays. We show here that cytotoxic activity of TWJ-/G4-ligands is mitigated by the DNA damage response (DDR) and DNA topoisomerase 2 (TOP2), making them different from typical G4-ligands, and implying a pivotal role of TWJs in cells. We designed and used a clickable ligand, TrisNP-α, to provide unique insights into the TWJ landscape in cells and its modulation upon co-treatments. This wealth of data was exploited to design an efficient synthetic lethality strategy combining dual ligands with clinically relevant DDR inhibitors.
Decreased vitamin D levels in obsessive-compulsive disorder patients

Abstract Objective The present paper compared vitamin D levels in adult patients with obsessive-compulsive disorder (OCD) and explored possible correlations with patients’ characteristics. Methods Fifty outpatients with OCD, according to DSM-5 criteria, were included and assessed with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Hamilton Rating Scale for Depression (HRDS). Results All the patients except one showed lower vitamin D levels than normative values (>30 nm/L). Vitamin D values of the whole sample were negatively correlated with Y-BOCS total, compulsion subscale, and some items’ scores, specifically “interference from obsessions,” “distress associated with obsessions,” and “time spent on compulsions”. The same relationships were detected in men, while women showed negative correlations between vitamin D levels and Y-BOCS compulsion subscale and “resistance to compulsions,” “degree of control of compulsions,” “insight” item scores. Conclusions Our findings would indicate that vitamin D might be involved in the pathophysiology of OCD, and that it is possibly related to the severity of the disorder and to typical symptoms, with some sex-related peculiarities. Further studies are necessary to support or not our findings and to ascertain the effectiveness of vitamin D supplementation in patients with OCD.
Sources of Variability in the Prospective Relation of Language to Social, Emotional, and Behavior Problem Symptoms: Implications for Developmental Language Disorder

Children with developmental language disorder (DLD) are at risk for social, emotional, and behavioral (SEB) maladjustment throughout development, though it is unclear if poor language proficiency per se can account for this risk as associations between language and SEB appear more variable among typical-language children. This study investigated whether the relationship between language and SEB problems is stronger at very low levels of language and considered confounders including socioeconomic status, sex, and nonverbal intelligence. These were examined using a population-based survey design, including children with a wide range of language and cognitive profiles, and assessed using the Strengths and Difficulties Questionnaire and six standardized language measures (n = 363, weighted n = 6,451). Structural equation models adjusted for prior levels of SEB revealed that the relationship of language at age 5–6 years to SEB at 7–9 years was nonlinear. Language more strongly predicted all clusters of SEB at disordered language levels relative to typical language levels, with standardized betas of −. 25 versus . 03 for behavioral, −. 31 versus −. 04 for peer, and . 27 versus . 03 for prosocial problems. Wald tests between these pairs of betas yielded p values from . 049 to . 014. Sex moderated the nonlinear association between language and emotional symptoms. These findings indicate a clinical need to support language development in order to mitigate against problems of SEB and to carefully monitor the mental health needs of children with DLD, particularly in the context of multiple, and potentially sex-specific, risks.
Spatial anxiety and spatial ability: Mediators of gender differences in math anxiety.

Females tend to be more anxious than males while engaging in mathematics, which has been linked to lower math performance and higher math avoidance. A possible repercussion of this gender difference is the underrepresentation of females in STEM fields (science, technology, engineering, and math), as math competencies are an essential part of succeeding in such fields. A related, but distinct, area of research suggests that males tend to outperform females in tasks that require spatial processing (i.e., the ability to mentally visualize, rotate, and transform spatial and visual information). Interestingly, factors from the spatial processing domain (spatial ability and spatial anxiety) are important in explaining gender differences in math anxiety. Here, we examined three types of spatial anxiety and ability (imagery, navigation, and manipulation), as well as math ability, as mediators of gender differences in math anxiety. Undergraduate students (125 male; 286 female) completed assessments of their general level of anxiety, their math anxiety, and their spatial anxiety. They also completed a series of tasks measuring their mathematical skill, their spatial skills, and basic demographics. Results suggest that manipulation anxiety and ability, navigation anxiety, and math ability explained the gender difference in math anxiety, but manipulation anxiety was the strongest mediator of this relation. Conversely, all other measures did not explain the gender difference in math anxiety. These findings help us better understand the gender difference in mathematics, and this is important in reducing the gender gap in STEM fields. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
In silico and in vitro assays reveal potential inhibitors against 3CL pro main protease of SARS-CoV-2

Abstract The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not showing any sign of slowing down even after the ongoing efforts of vaccination. The threats of new strains are concerning, as some of them are more infectious than the original one. A therapeutic against the disease is, therefore, of urgent need. Here, we use the DrugBank database to screen for potential inhibitors against the 3CL pro main protease of SARS-CoV-2. Instead of using the traditional approach of computational screening by docking, we developed a kernel ridge regressor (using a part of the docking data) to predict the binding energy of ligands. We used this model to screen the DrugBank database and shortlist two lead candidates (bromocriptine and avoralstat) for in vitro enzymatic study. Our results show that the 3CL pro enzyme activity in presence of 100 μM concentration of bromocriptine and avoralstat is 9.9% and 15.9%, respectively. Remarkably, bromocriptine exhibited submicromolar IC50 of 130 nM (0.13 μM). Avoralstat showed an IC50 of 2.16 μM. Further, the interactions of both drugs with 3CL pro were analyzed using molecular dynamics simulations of 100 ns. Results indicate that both ligands are stable in the binding pocket of the 3CL pro receptor. In addition, the MM-PBSA analysis revealed that bromocriptine (-29.37 kcal/mol) has a lower binding free energy compared to avoralstat (-6.91 kcal/mol). Further, hydrogen bond analysis also showed that bromocriptine interacts with the two catalytic residues, His41 and Cys145, more frequently than avoralstat. Communicated by Ramaswamy H. Sarma
Food insecurity and patterns of dietary intake in a sample of UK adults

Abstract The aim of this study was to identify the dietary intake correlates of food insecurity (FI) in UK adults. We recruited groups of low-income participants who were classified as food insecure (n 196) or food secure (n 198). Participants completed up to five 24 h dietary recalls. There was no difference in total energy intake by FI status (β FI = −0·06, 95 % CI − 0·25, 0·13). Food insecure participants consumed a less diverse diet, as evidenced by fewer distinct foods per meal (β FI = −0·27, 95 % CI − 0·47, −0·07), and had more variable time gaps between meals (β FI = 0·21, 95 % CI 0·01, 0·41). These associations corresponded closely to those found in a recent US study using similar measures, suggesting that the dietary intake signature of FI generalises across populations. The findings suggest that the consequences of FI for weight gain and health are not due to increased energy intake. We suggest that there may be important health and metabolic effects of temporal irregularity in dietary intake, which appears to be an important component of FI.
Ventilatory performance of AMBU® AuraGain™ and LMA® Supreme™ in laparoscopic surgery: A randomised controlled trial

The Ambu® AuraGain™ (Ambu A/S, Ballerup, Denmark) is a newer phthalate-free, single-use supraglottic device with the advantage of a facility for tracheal intubation if necessary intraoperatively. We compared the oropharyngeal leak pressures and other performance variables between the AMBU AuraGain and the LMA® Supreme™ (Teleflex Medical, Athlone, Co. Westmeath, Ireland) in patients undergoing laparoscopic cholecystectomy and preperitoneoscopic inguinal herniorrhaphy with carbon dioxide insufflation under controlled ventilation. We recruited 120 American Society of Anesthesiologists physical status class I–3 patients between the ages of 21 and 80 years undergoing laparoscopic cholecystectomy or preperitoneoscopic inguinal herniorrhaphy into this single-centre randomised controlled trial. The primary outcome measure was the oropharyngeal leak pressures. Secondary outcomes included insertion parameters, ventilatory characteristics and postoperative sequelae. The AuraGain had slightly but significantly higher oropharyngeal leak pressures than the LMA Supreme (mean (standard deviation) 26.1 (6.9) versus 21.4 (4.7) cmH2O, P < 0.010). The overall insertion success of the AuraGain was comparable to the LMA Supreme (AuraGain 58/60 (96.7%); LMA Supreme 56/59 (94.9%), P = 0.679). The AuraGain was deemed more difficult to insert than the LMA Supreme, with 26/60 (43.3%) of AuraGain insertions graded easy versus 48/59 (81.4%) of LMA Supreme, P < 0.001. The mean time to insertion of the AuraGain was slightly longer than the LMA Supreme, 32.2 (10.5) versus 28.3 (12.0) s, P < 0.001. Intraoperative device failure occurred following carbon dioxide insufflation in one AuraGain and three LMA Supremes, bringing the perioperative success rate of AuraGain and LMA Supreme to 95% and 89.8%, respectively, P = 0.322. No cases of regurgitation and aspiration occurred, and minor postoperative complications were similar. The AuraGain exhibited higher oropharyngeal leak pressures than the LMA Supreme, but was slightly more difficult to insert. The higher oropharyngeal leak pressures suggest that ventilation might be less affected by high peak inspiratory pressures when using the AuraGain than the LMA Supreme.
Cost‑effectiveness of tiotropium versus omalizumab for uncontrolled allergic asthma

Abstract Objective In patients with uncontrolled asthma, despite management with high doses of inhaled corticosteroids, the additional use of omalizumab and tiotropium is recommended. Omalizumab is an expensive medication and doubts arise as to whether the benefit of this drug outweighs the additional expense of the drug. The purpose of this study was to assess the cost-effectiveness of tiotropium versus omalizumab as add-on therapies to ICS + LABA for patients with uncontrolled allergic asthma. Methods A probabilistic Markov model was created to estimate the cost and quality-adjusted life years (QALYs) of patients with uncontrolled allergic asthma in Colombia. Total costs and QALYs of three interventions including standard therapy (ICS + LABA), add-on therapy with tiotropium, and add-on therapy with omalizumab, were calculated over a 10-year time horizon. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $19,000. Results The model showed that tiotropium was associated with lower cost than standard therapy and omalizumab (US$5590 vs. US$5693 vs. U$18,154 average annual cost per patient), and higher QALYs (11.8 vs. 11.3 vs. 11.9) average per patient), showing dominance respect to standard therapy. The probability that tiotropium provides a more cost-effective use of resources compared with standard therapy exceeds 99% for willingness-to-pay threshold. Conclusion Add-on therapy with tiotropium was a cost-effective alternative to omalizumab and standard therapy for uncontrolled allergic asthma. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines and should be replicated to validate their results in other middle-income countries.
Supplemental Material for: Quantum fluids of light in all-optical scatterer lattices

S. Alyatkin,1, 2 H. Sigurdsson,1, 2, 3 A. Askitopoulos,1, 2 J. D. Töpfer,1, 2 and P. G. Lagoudakis1, 2, 3, ∗ 1Center for Photonics and Quantum Materials, Skolkovo Institute of Science and Technology, Moscow, Russia 2Laboratories for Hybrid Photonics, Skolkovo Institute of Science and Technology, Moscow, Russia 3School of Physics and Astronomy, University of Southampton, Southampton, SO17 1BJ, United Kingdom (Dated: August 24, 2021)
Evaluation of the key prescription sequence symmetry analysis assumption using the calcium channel blocker: Loop diuretic prescribing cascade

To evaluate the prescription sequence symmetry analysis assumption regarding balance between marker drug (i.e., medication used to treat a drug‐induced adverse event) initiation rates before and after initiation of an index drug (i.e., medication that is potentially associated with the drug‐induced adverse event) in the absence of prescribing cascades, we used a well‐described example of loop diuretic initiation to treat dihydropyridine calcium channel blockers (DH CCB)‐induced edema.
Efficacy and Safety of Lumateperone for Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder: A Phase 3 Randomized Placebo-Controlled Trial.

OBJECTIVE In a phase 3 randomized double-blind placebo-controlled study, the authors investigated the efficacy and safety of 42 mg/day of lumateperone in patients with bipolar I or bipolar II disorder experiencing a major depressive episode. METHODS Patients 18-75 years old with a clinical diagnosis of bipolar I or bipolar II disorder and experiencing a major depressive episode were eligible for the study. Patients were randomized in a 1:1 ratio to receive 42 mg/day of lumateperone (N=188) or placebo (N=189), administered orally once daily in the evening for 6 weeks. The primary and key secondary efficacy endpoints were change from baseline to day 43 in score on the Montgomery-Åsberg Depression Rating Scale (MADRS) and total score on the Clinical Global Impressions Scale-Bipolar Version severity scale (CGI-BP-S), respectively. Safety assessments included treatment-emergent adverse events, laboratory parameters, vital signs, extrapyramidal symptoms, and suicidality. RESULTS At day 43, lumateperone treatment was associated with significantly greater improvement from baseline in MADRS score compared with placebo (least squares mean difference compared with placebo, -4.6 points; effect size=-0.56) and CGI-BP-S total score (least squares mean difference compared with placebo, -0.9; effect size=-0.46). Significant MADRS superiority for lumateperone over placebo was observed both in patients with bipolar I and bipolar II disorders. Somnolence and nausea were the only treatment-emergent adverse events that occurred with lumateperone at a clinically meaningful greater rate than placebo. The incidence of extrapyramidal symptom-related treatment-emergent adverse events was low and similar to that for placebo. Minimal changes were observed in weight, vital signs, or metabolic or endocrine assessments. CONCLUSIONS Lumateperone at 42 mg/day significantly improved depression symptoms and was generally well tolerated in patients with major depressive episodes associated with both bipolar I and bipolar II disorders.
Parallel Suture: A Simple Approach to Enable Early Laser Suture Lysis and Prevent Hypotony after Trabeculectomy

ABSTRACT Purpose To define a modified flap suture approach and evaluate its effectiveness. Methods Clinical data of patients undergoing trabeculectomy with modified parallel suture technique (Group 1, N = 38 eyes) were compared to patients operated with classical flap suture technique (Group 2, N = 42 eyes). In the modified technique, two parallel sutures (one tight and one loose) are placed simultaneously in one of the flap corners with the aim of obtaining a safety stitch when the tight one needs to be cut. Data from preoperative and postoperative visits at day 1, week 1, months 1, 3, 6 and year 1 were recorded from patient charts and compared between the groups. Results In Group 1, seven eyes underwent laser suture lysis (LSL) between postoperative days 2 to 8 and in Group 2 two eyes at days 29 and 37. No complication related to LSL was observed. Rate of postoperative hypotony decreased with the parallel suture approach (P= .002). Number of eyes experiencing any of the complications related to hypotony was lower in Group 1 (P= .004). No significant difference was noted in the mean IOP between the groups (P> .05 for all). Conclusion The modified approach with parallel suture technique was found to be effective and safe. By enabling early LSL, it provided more precise IOP modulation in the early postoperative period. Thus, in our series, the rate of hypotony and hypotony-related complications decreased, while the success of the surgery was preserved.
The relevance of pedigrees in the conservation genomics era

Over the past 50 years conservation genetics has developed a substantive toolbox to inform species management. One of the most long‐standing tools available to manage genetics—the pedigree—has been widely used to characterize diversity and maximize evolutionary potential in threatened populations. Now, with the ability to use high throughput sequencing to estimate relatedness, inbreeding, and genome‐wide functional diversity, some have asked whether it is warranted for conservation biologists to continue collecting and collating pedigrees for species management. In this perspective, we argue that pedigrees remain a relevant tool, and when combined with genomic data, create an invaluable resource for conservation genomic management. Genomic data can address pedigree pitfalls (e.g., founder relatedness, missing data, uncertainty), and in return robust pedigrees allow for more nuanced research design, including well‐informed sampling strategies and quantitative analyses (e.g., heritability, linkage) to better inform genomic inquiry. We further contend that building and maintaining pedigrees provides an opportunity to strengthen trusted relationships among conservation researchers, practitioners, Indigenous Peoples, and Local Communities.
A pre-clinical animal study of a novel mechanical-only ablation device treatment for superficial venous disease

Objective Current minimally invasive techniques for ablation in superficial venous reflux are limited to thermal based systems requiring tumescent anesthesia, non-thermal chemical sclerosants and permanent glue implantation. The aim of this feasibility study was to determine the safety and efficacy of a novel mechanical-only ablation (MOA) device called EnVena, in a recognised large animal model with chronic follow up. Methods Venous ablation of six lateral saphenous veins in three sheep was performed using the EnVena device. Luminal patency and vein wall fibrosis were evaluated by histologic analysis at 51 and 89 days. Results All treated veins demonstrated fibrotic occlusion in contiguous segments at 51 and 89 days on histological analysis. From 45 consecutive segments spanning the treatment length across the six treated veins, 26 (57%) were fully occluded, 7 (16%) were impinged or partially occluded and 12 (27%) were open. There were no device related complications during the follow up period. Conclusions A purely mechanical approach to superficial venous ablation demonstrated safety and efficacy in a recognized large animal model based on histological findings.
Cerebral haemodynamic response to somatosensory stimulation in preterm lambs and 7–10-day old lambs born at term: Direct synchrotron microangiography assessment

Neurovascular coupling has been well-defined in the adult brain, but variable and inconsistent responses have been observed in the neonatal brain. The mechanisms that underlie functional haemodynamic responses in the developing brain are unknown. Synchrotron radiation (SR) microangiography enables in vivo high-resolution imaging of the cerebral vasculature. We exploited SR microangiography to investigate the microvascular changes underlying the cerebral haemodynamic response in preterm (n = 7) and 7–10-day old term lambs (n = 4), following median nerve stimulation of 1.8, 4.8 and 7.8 sec durations. Increasing durations of somatosensory stimulation significantly increased the number of cortical microvessels of ≤200 µm diameter in 7–10-day old term lambs (p < 0.05) but not preterm lambs where, in contrast, stimulation increased the diameter of cerebral microvessels with a baseline diameter of ≤200 µm. Preterm lambs demonstrated positive functional responses with increased oxyhaemoglobin measured by near infrared spectroscopy, while 7–10-day old term lambs demonstrated both positive and negative responses. Our findings suggest the vascular mechanisms underlying the functional haemodynamic response differ between the preterm and 7–10-day old term brain. The preterm brain depends on vasodilatation of microvessels without recruitment of additional vessels, suggesting a limited capacity to mount higher cerebral haemodynamic responses when faced with prolonged or stronger neural stimulation.
Missing puzzle pieces of time-restricted-eating (TRE) as a long-term weight-loss strategy in overweight and obese people? A systematic review and meta-analysis of randomized controlled trials

Abstract The efficacy of using time restricted eating (TRE) for weight management and to mitigate metabolic disorders in overweight and obese people remains debatable. This meta-analysis quantified the impact of TRE on weight loss and metabolic health in overweight and obese people. The pooled results were subjected to a random-effects modeling using Hartung-Knapp-Sidik-Jonkman (HKSJ) method. Additionally, subgroup analysis was conducted based on study types, randomized controlled trials (RCTs) vs. non-randomized studies of interventions (NRSIs). Pooled results showed that subjects on TRE regimen (> 4 weeks) achieved a significant weight loss in comparison with unrestricted time regimen (weighted mean difference: −2.32%; 95% CI: −3.50, −1.14%; p < 0.01); however, weight loss was mainly attributed to the loss of lean mass rather than fat mass. The magnitude of weight loss was inversely correlated with daily fasting duration in RCTs. TRE significantly decreased the diastolic blood pressure and fasting insulin. An increase of low-density lipoprotein cholesterol (LDL-C) was observed in the TRE group. Favorable effect of TRE was observed on glucose metabolism but not on lipid profiles independent of weight loss. Hence TRE shall be administered with caution to overweight and obese people who have comorbidities such as dyslipidemia and sarcopenia. Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021. 1974335