Miracle-dz/UniFAR-FTUs huggingface dataset:
Genome‐wide mutation analysis in precancerous lesions of endometrial carcinoma

Clinicopathological evidence supports endometrial atypical hyperplasia (AH) or endometrial intraepithelial neoplasia as the precursor of uterine endometrioid carcinoma (EC), the most common gynecologic malignancy. However, the pathogenic progression from AH to EC remains unclear. Here, we employed whole‐exome sequencing to identify somatic mutations and copy number changes in micro‐dissected lesions from 30 pairs of newly diagnosed AH and EC. We found that all but one pair of AHs shared the same DNA mismatch repair status as their corresponding ECs. The percentage of common mutations between AH lesions and corresponding ECs varied significantly, ranging from 0.1% to 82%. Microsatellite stable AHs had fewer cancer driver mutations than ECs (5 versus 7, p = 0.017), but among microsatellite unstable AHs and ECs there was no difference in mutational numbers (36 versus 38, p = 0.65). As compared to AH specimens, 19 (79%) of 24 microsatellite stable EC tumors gained new cancer driver mutations, most of which involved PTEN, ARID1A, PIK3CA, CTNNB1, or CHD4. Our results suggest that some AH lesions are the immediate precursor of ECs, and progression depends on acquisition of additional cancer driver mutations. However, a complex clonal relationship between AH and EC can also be appreciated, as in some cases both lesions diverge very early or arise independently, thus co‐developing with distinct genetic trajectories. Our genome‐wide profile of mutations in AH and EC shines new light on the molecular landscape of tumor progression. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
COVID-19 and Psychological Distress-Changes in Internet Searches for Mental Health Issues in New York During the Pandemic.

Author Affiliations: Yale School of Medicine, New Haven, Connecticut (Johnston); San Francisco Veterans Affairs Medical Center, San Francisco, California (Dhruva); Department of Medicine, University of California School of Medicine, San Francisco (Dhruva); Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, New Haven, Connecticut (Ross); Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut (Ross); Section of General Internal Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut (Ross); Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Boston (Rathi); Harvard Business School, Boston, Massachusetts (Rathi).
Coexistence of Competitors in Patchy Environment

There are two implicit assumptions in Levins' (1969) metaphorical model of regional distribution: movements by individuals are possible between any two patches in the region, and the local time scale is much faster than the regional one. These assumptions are frequently incompatible. Levins' model is modified to allow for a varying difference between the local and regional time scales, and regional competition between two species is analyzed with the new model. The main results are that two like species may or may not coexist regionally, depending on the difference between the time scales (a large difference facilitates coexistence) and on the intensity of competition; a species' precompetitive distribution is a good predictor of its competitive success, just as the carrying capacity in the Lotka-Volterra model is a good predictor of success in local competition. Regional priority effect is possible, though unlikely when the time scales are very different. The local time scale is slower than the regional one in some organisms (e.g., orchids, ferns), which may survive regionally, although they may succeed in breeding only seldom. Two possible outcomes of regional competition are (1) a decrease in the fraction of habitat patches occupied by the competing species and (2) an increase in the proportion of regionally rare species, some of which may ultimately go extinct. I ask which of the two outcomes is more frequent in nature and suggest that the answer may depend on the time scales of local and regional population dynamics.
Standard Evaporative Water Loss and Metabolism of Juvenile Varanus mertensi (Squamata: Varanidae)

Evaporative water loss (EWL) varies considerably both within and between reptile species (Dmi'el, 1985; Eynan and Dmi'el, 1993; Lahav and Dmi'el, 1996) and can also be affected by acclimation (Hillman et al., 1979; Kobayashi et al., 1983). EWL data are available for a wide variety of reptiles from various habitats (see review by Mautz, 1982) but are limited for goannas under controlled conditions (Warburg, 1965; Green, 1969; Thompson and Withers, 1997a). For lizards, such as goannas, body water is lost by evaporation from the skin (including the eyes) and the respiratory passages and as a mixture of urine and feces (and in some species from nasal salt glands; Green, 1969; Saint Girons et al., 1981). The rate of cutaneous evaporative water loss (CEWL) is largely determined by the exposed surface area of the skin and eyes, the resistance of these surfaces to evaporation, and the difference in water vapor concentrations across the surfaces. The respiratory evaporative water loss (REWL) is determined mainly by the lung ventilation rate and body temperature but may be reduced by nasal countercurrent heat and water exchange (Mautz, 1980). Environmental conditions such as ambient temperature, relative humidity, and wind velocity also affect EWL (Thorpe and Kontogiannis, 1977; Mautz, 1980, 1982). EWL is generally higher for mesic reptiles than arid species (Snyder, 1971; Dmi'el, 1972; Shoemaker and Nagy, 1977), and we would expect the EWL of a semiaquatic goanna to be higher than for comparable terrestrial species. However, there are no data for EWL of semiaquatic goannas under controlled conditions. The semiaquatic goanna Varanus mertensi has a much higher field water turnover (WTR) than predicted for lizards from arid and tropical zones (Christian et al., 1996), but it is not clear whether their high WTR is associated with a high cutaneous EWL, respiratory EWL, water excretion, or a combination thereof. This study examines the standard EWL (EWL,td) and standard metabolic rate (VO2std) for juvenile V mertensi. The primary objectives were to measure total evaporative water loss and calculate resistance to water evaporation under standardized laboratory conditions (TEWLtd, rstd), and to partition TEWLStd and rstd into its respiratory and cutaneous components. Thompson and Withers (1997a) report TEWL,td and resistance to total water loss (rtota) for a number of terrestrial and arboreal Western Australian
Development and Evaluation of Feline Tailored Amlodipine Besylate Mini-Tablets Using l-lysine as a Candidate Flavouring Agent

Felines may find orally administered medicines unpalatable, thus presenting a problem in the treatment of chronic conditions such as hypertension, a commonly diagnosed condition in felines requiring daily administration of medication. A pertinent example is amlodipine besylate, formulations of which are known to be poorly tolerated by cats. There is therefore a need to develop feline-specific delivery approaches that are both simple to administer and mask the taste of the drug, thereby enhancing the owner’s commitment to treatment and the associated therapeutic outcome for the companion animal. In addition, it is helpful to develop accessible and reproducible means of assessing taste for pre-clinical selection, hence the use of recently developed taste biosensor systems for veterinary applications is an area of interest. This study focuses on developing feline-specific amlodipine besylate formulations by improving the taste using a suitable flavouring agent while reducing dosage form size to a 2 mm diameter mini-tablet. The choice of l-lysine as a flavouring agent was based on the dietary and taste preference of cats. The impact of l-lysine on the taste perception of the formulation was evaluated using a biosensor system (E-tongue) fitted with sensors sensitive to bitter tastes. The results showed l-lysine successfully masked bitterness, while the drug release studies suggest that it has no impact on drug dissolution. In addition, tableting parameters such as tablet mass uniformity, content uniformity, tablet diameter, thickness and hardness were all satisfactory. The present study suggests that amlodipine besylate mini-tablets containing l-lysine could improve the palatability and in turn support product acceptability and ease of administration. These data could have an impact on orally administered medicines for cats and other veterinary species through product differentiation and competitive advantage in the companion animal market sector. The study also outlines the use of the electronic tongue as a tool for formulation selection in the veterinary field.
Retrotransposon Tto1:functional analysis and engineering for insertional mutagenesis

Retrotransposons are genomic parasites activated by stress conditions that can be seriously detrimental for their host. In this work I demonstrate that Tto1, a typical plant LTR retrotransposon with insertion preference into genes can be turned into a synthetic molecular tool for gene tagging in plants and can be used to predict models for its replication steps. Although retrotransposons have been already used in plant mutagenesis, such application always required establishing protocols for tissue cultures and regeneration in vitro. Here, I show that sequence engineering of Tto1 provides the possibility to obtain transposition in vivo, with a simple screening method based on PCR and with the advantage to skip all in vitro manipulations. An artificial -estradiol inducible promoter has been used to obtain transposition “on demand” in Arabidopsis plants, which generates stable unlinked insertions that follow mendelian segregation in the progeny. Comparing serial deletions of 3’ LTR of the engineered inducible Tto1 (iTto1), I have mapped its two natural terminators and identified the “minimal” R (redundant) region required to achieve the complete reverse transcription of the genomic mRNA into a new cDNA copy. Interestingly, the transcripts ending at the major “early” terminator cannot support reverse transcription, suggesting a mechanism of natural control on the expression. Transcripts with a more extended termination point contain 100 essential nucleotides that define the active nucleus of the R region. This sequence promotes the formation of a stable hairpin structure that “kisses” a complementary identical hairpin on the cDNA and determines the formation of the characteristic cDNA/mRNA heteroduplex. Since the LTR is a repeated sequence the definition of a minimal redundant region has also the important implication to reduce the only possible target for sequence-based gene silencing, which should lead to an increase of the mutagenic efficiency of iTto1. Additional investigations have been carried out in attempt to identify points of improvement of iTto1 performances. By sequence alignment I identified different versions of the integrase that might have influence on insertion efficiency. Furthermore I tested the pOp6/LhGR-N system that will provide higher expression levels in different host plants. The final goal of my work is to extend the application of iTto1 to crop mutagenesis, therefore a big part of my work has been spent to develop Tto1 constructs with activity in barley. Transgenic plants have been obtained, however the constructs still need further experimentation.
Characterization of Low Molecular Weight Sulfate Ulva Polysaccharide and its Protective Effect against IBD in Mice

Inflammatory bowel disease (IBD) has been gradually considered a public health challenge worldwide. Sulfated polysaccharides, extracted from seaweed, have been shown to have an anti-inflammatory effect on the disease. In this study, LMW-ulvan, a unique sulfate Ulva polysaccharide with low molecular weight, was prepared using the enzymatic method. The structural characterization of LMW-ulvan and its protective effect on colitis induced by dextran sulfate sodium (DSS) were studied. The results showed that LMW-ulvan with molecular weight of 2.56 kDa consists of 57.23% rhamnose (Rha), 28.76% xylose (Xyl), 7.42% glucuronic acid (GlcA), and 1.77% glucose (Glc). Its backbone contains (1→3,4)-linked Rha, (1→4)-linked Xyl, and (1→4)-linked GlcA with small amounts of (1→4)-linked Rha residues; sulfate substitution was at C-3 of Rha. LMW-ulvan was found to reduce DSS-induced disease activity index, colon shortening, and colonic tissue damage, which were associated with decreased oxidative stresses and inflammation, thus improving the expression of tight junction proteins. These results indicate that LMW-ulvan is able to improve colitis and may be a promising application for IBD.
Sex Steroids Induce Membrane Stress Responses and Virulence Properties in Pseudomonas aeruginosa

Molecular mechanisms by which sex steroids interact with P. aeruginosa to modulate its virulence have yet to be reported. Our work provides the first characterization of a steroid-induced membrane stress mechanism promoting P. aeruginosa virulence, which includes the release of proinflammatory outer membrane vesicles, resulting in inflammation, host tissue damage, and reduced bacterial clearance. We further demonstrate that at nanomolar (physiological) concentrations, male and female sex steroids promote virulence in clinical strains of P. aeruginosa based on their dynamic membrane fluidic properties. This work provides, for the first-time, mechanistic insight to better understand and predict the P. aeruginosa related response to sex steroids and explain the interindividual patient variability observed in respiratory diseases such as cystic fibrosis that are complicated by gender differences and chronic P. aeruginosa infection. ABSTRACT Estrogen, a major female sex steroid hormone, has been shown to promote the selection of mucoid Pseudomonas aeruginosa in the airways of patients with chronic respiratory diseases, including cystic fibrosis. This results in long-term persistence, poorer clinical outcomes, and limited therapeutic options. In this study, we demonstrate that at physiological concentrations, sex steroids, including testosterone and estriol, induce membrane stress responses in P. aeruginosa. This is characterized by increased virulence and consequent inflammation and release of proinflammatory outer membrane vesicles promoting in vivo persistence of the bacteria. The steroid-induced P. aeruginosa response correlates with the molecular polarity of the hormones and membrane fluidic properties of the bacteria. This novel mechanism of interaction between sex steroids and P. aeruginosa explicates the reported increased disease severity observed in females with cystic fibrosis and provides evidence for the therapeutic potential of the modulation of sex steroids to achieve better clinical outcomes in patients with hormone-responsive strains. IMPORTANCE Molecular mechanisms by which sex steroids interact with P. aeruginosa to modulate its virulence have yet to be reported. Our work provides the first characterization of a steroid-induced membrane stress mechanism promoting P. aeruginosa virulence, which includes the release of proinflammatory outer membrane vesicles, resulting in inflammation, host tissue damage, and reduced bacterial clearance. We further demonstrate that at nanomolar (physiological) concentrations, male and female sex steroids promote virulence in clinical strains of P. aeruginosa based on their dynamic membrane fluidic properties. This work provides, for the first-time, mechanistic insight to better understand and predict the P. aeruginosa related response to sex steroids and explain the interindividual patient variability observed in respiratory diseases such as cystic fibrosis that are complicated by gender differences and chronic P. aeruginosa infection.
Challenging mental illness stigma in healthcare professionals and students: a systematic review and network meta-analysis

Abstract Objective Stigma among healthcare professionals may lead to poor quality of healthcare services for patients with mental illness. This study conducts a network meta-analysis to estimate the relative efficacy between different types of anti-stigma interventions for healthcare professionals. Design Network meta-analysis. Main Outcome Measures The attitudes and behavior intension of healthcare professionals toward mental illness. Results A total of 18 studies (22 trials) from 9 countries are included in the analysis. In the network meta-analysis, rank probabilities show interventions with indirect contact plus lecture (SUCRA = 81.5%), direct contact plus problem-based learning workshop (SUCRA = 77.4%), and indirect contact (SUCRA = 72.2%) having the highest probability of being ranked first, second, and third, respectively. Conclusion Our findings suggest that education combining social contact is the most effective anti-stigma intervention, which can be implemented in clinical practices to help reduce this stigma and improve healthcare services for patients with mental illness.
Communicating evidence about the environment’s role in obesity and support for government policies to tackle obesity: a systematic review with meta-analysis

ABSTRACT Public support for many policies that tackle obesity by changing environments is low. This may reflect commonly held causal beliefs about obesity, namely that it is due to failures of self-control rather than environmental influences. Several studies have sought to increase public support by changing these and similar causal beliefs, with mixed results. The current review is the first systematic synthesis of these studies. Searches of PsycInfo, Medline, Web of Science, Scopus, and Open Grey yielded 20 eligible studies (N = 8977) from 11,776 abstracts. Eligible studies were controlled experiments with an intervention group that communicated information about the environment’s role in obesity, and a measure of support for environment-based obesity policies. The protocol was prospectively registered on PROSPERO. Meta-analyses showed no evidence that communicating information about the environment’s influence on obesity changed policy support or the belief that the environment influences obesity. A likely explanation for this null effect is the ineffectiveness of interventions that were designed to change the belief that the environment influences obesity. The possibility remains, however, that the association observed between beliefs about the causes of obesity and attitudes towards obesity policies is correlational and not causal.
Pigment Epithelium-Derived Factor (PEDF) Fragments Prevent Mouse Cone Photoreceptor Cell Loss Induced by Focal Phototoxicity In Vivo

Here, we evaluated the effects of PEDF (pigment epithelium-derived factor) and PEDF peptides on cone-photoreceptor cell damage in a mouse model of focal LED-induced phototoxicity (LIP) in vivo. Swiss mice were dark-adapted overnight, anesthetized, and their left eyes were exposed to a blue LED placed over the cornea. Immediately after, intravitreal injection of PEDF, PEDF-peptide fragments 17-mer, 17-mer[H105A] or 17-mer[R99A] (all at 10 pmol) were administered into the left eye of each animal. BDNF (92 pmol) and bFGF (27 pmol) injections were positive controls, and vehicle negative control. After 7 days, LIP resulted in a consistent circular lesion located in the supratemporal quadrant and the number of S-cones were counted within an area centered on the lesion. Retinas treated with effectors had significantly greater S-cone numbers (PEDF (60%), 17-mer (56%), 17-mer [H105A] (57%), BDNF (64%) or bFGF (60%)) relative to their corresponding vehicle groups (≈42%). The 17-mer[R99A] with no PEDF receptor binding and no neurotrophic activity, PEDF combined with a molar excess of the PEDF receptor blocker P1 peptide, or with a PEDF-R enzymatic inhibitor had undetectable effects in S-cone survival. The findings demonstrated that the cone survival effects were mediated via interactions between the 17-mer region of the PEDF molecule and its PEDF-R receptor.
Nutritional intervention strategies for the management of overweight and obesity in primary health care: A systematic review with meta‐analysis

A systematic review with meta‐analysis (MA) was conducted to synthesize the effectiveness of nutrition intervention strategies for managing overweight and obesity in the adult population attending primary health care. Relevant articles were searched in the PubMed, Embase, Web of Science, Cochrane and LILACS databases from inception to January 2020. Seventy studies were identified: 45 randomized controlled trials (RCTs) and 25 uncontrolled before‐after studies (UBAs). The MA of nutritional intervention revealed a reduced average estimate of the effect on weight in RCTs (weighted mean differences [WMD] = −1.80 kg, 95% confidence interval [CI], −2.40 to −1.19), BMI (WMD = −0.80 kg/m2, 95% CI, −1.11 to −0.49), and WC (WMD = −2.28 cm, 95% CI, −3.06 to −1.49); and for UBAs showed reductions in weight (WMD = −4.17 kg; 95% CI, −5.18 to −1.70), BMI (WMD = −1.26 kg/m2; 95% CI, −1.81 to −0.72) and (WMD = −2.90 cm; 95%CI, −4.21 to −1.59). There was no association between treatment effect and follow‐up for both designs. Nutritional interventions alone yielded a higher but nonsignificant average reduction on weight when compared with combined components intervention. Interventions delivered through individual or group sessions showed a similar positive effect on weight decrease. The dietary prescription approach yielded a greater effect on weight loss than did the behavioural approaches but only in UBA studies.
Outpatient health care utilization for sleep disorders in the Cerner Health Facts database.

STUDY OBJECTIVES Sleep disorders are common in the general population This study aimed to identify direct health care utilization for sleep disorders using big data through the Cerner Health Facts database. METHODS The Cerner Health Facts database has 68.7 million patients in the data warehouse, documenting approximately 506.9 million encounters from 100 non-affiliated health care systems. To identify sleep-related health care utilization, we examined the frequency of outpatient encounters related to sleep disorders between the years 2000 and 2017. Sleep disorders were grouped based on the International Classification of Sleep Disorders-Third Edition (ICSD-3). RESULTS Approximately 20.5 million patients were identified with a total of 127.4 million outpatient encounters. In pediatric patients (ages 0-18 years), healthcare utilization for major sleep diagnoses was measured per 100,000 encounters. Sleep-related breathing disorders ranked first among common sleep disorders for pediatric patients followed by parasomnia, insomnia, sleep movement disorders, hypersomnolence, then circadian rhythm disorders (820.1, 258.1, 181.6, 68.3, 48.1, and 16.2 per 100,000 encounters, respectively). However, in adult patients, the ranking was slightly different, with sleep-related breathing disorders ranked first, followed by insomnia, sleep-related movement disorders, hypersomnolence, parasomnia, then circadian rhythm disorders (1352.6, 511.6, 166.3, 79.1, 25.7, and 4.2 per 100,000 encounters, respectively). In general, there was a bimodal pattern with a clear dip in sleep-related health care utilization in young adults age (age 19-29 years), with the exception of insomnia. CONCLUSIONS Patients with sleep disorders show a relatively low health care utilization despite a known high prevalence of sleep disorders in the general population. This finding may highlight under-recognition of sleep problems or decreased access to health care for sleep disorders. In addition, this study highlights the effect of age-based variation on different sleep disorders, which may have an impact on allocating resources.