Miracle-dz/UniFAR-FTUs huggingface dataset:
Biomarkers of Endocannabinoid System Activation in Severe Obesity

Background Obesity is a worldwide epidemic, and severe obesity is a risk factor for many diseases, including diabetes, heart disease, stroke, and some cancers. Endocannabinoid system (ECS) signaling in the brain and peripheral tissues is activated in obesity and plays a role in the regulation of body weight. The main research question here was whether quantitative measurement of plasma endocannabinoids, anandamide, and related N-acylethanolamines (NAEs), combined with genotyping for mutations in fatty acid amide hydrolase (FAAH) would identify circulating biomarkers of ECS activation in severe obesity. Methodology/Principal Findings Plasma samples were obtained from 96 severely obese subjects with body mass index (BMI) of ≥40 kg/m2, and 48 normal weight subjects with BMI of ≤26 kg/m2. Triple-quadrupole mass spectroscopy methods were used to measure plasma ECS analogs. Subjects were genotyped for human FAAH gene mutations. The principal analysis focused on the FAAH 385 C→A (P129T) mutation by comparing plasma ECS metabolite levels in the FAAH 385 minor A allele carriers versus wild-type C/C carriers in both groups. The main finding was significantly elevated mean plasma levels of anandamide (15.1±1.4 pmol/ml) and related NAEs in study subjects that carried the FAAH 385 A mutant alleles versus normal subjects (13.3±1.0 pmol/ml) with wild-type FAAH genotype (p = 0.04), and significance was maintained after controlling for BMI. Conclusions/Significance Significantly increased levels of the endocannabinoid anandamide and related NAEs were found in carriers of the FAAH 385 A mutant alleles compared with wild-type FAAH controls. This evidence supports endocannabinoid system activation due to the effect of FAAH 385 mutant A genotype on plasma AEA and related NAE analogs. This is the first study to document that FAAH 385 A mutant alleles have a direct effect on elevated plasma levels of anandamide and related NAEs in humans. These biomarkers may indicate risk for severe obesity and may suggest novel ECS obesity treatment strategies.
Multi-Layered Network Embedding

Network embedding has gained more attentions in recent years. It has been shown that the learned low-dimensional node vector representations could advance a myriad of graph mining tasks such as node classiﬁ-cation, community detection, and link prediction. A vast majority of the existing eﬀorts are overwhelmingly devoted to single-layered networks or homogeneous networks with a single type of nodes and node interactions. However, in many real-world applications, a variety of networks could be abstracted and presented in a multi-layered fashion. Typical multi-layered networks include critical infrastructure systems, collaboration platforms, social recommender systems, to name a few. Despite the widespread use of multi-layered networks, it remains a daunting task to learn vector representations of diﬀerent types of nodes due to the bewildering combination of both within-layer connections and cross-layer network dependencies. In this paper, we study a novel problem of multi-layered network embedding. In particular, we propose a principled framework - MANE to model both within-layer connections and cross-layer network dependencies simultaneously in a uniﬁed optimization framework for embedding representation learning. Experiments on real-world multi-layered networks corroborate the eﬀectiveness of the proposed framework.
Mapping people’s views regarding the acceptability of surrogate motherhood

Abstract The aims of the present study were to map French laypersons’ views regarding the acceptability of maternal surrogacy and to delineate the circumstances under which surrogacy is considered, by different groups of people, as especially problematic. Participants (N = 236) were presented with a number of scenarios depicting the circumstances in which a couple has contracted with a surrogate mother and were asked to indicate the extent to which such a contract may present a moral problem. The scenarios were created by varying four factors: the type of surrogacy (traditional or gestational), the surrogate mother’s level of autonomy, the family context in which the surrogate mother lives, and whether surrogacy was commercial or altruistic. Three qualitatively different personal positions were found: (a) a majority group for which surrogacy always (30%) or often (34%) presents a moral problem, (b) a minority group (14%) for which maternal surrogacy does not systematically present a moral problem, and (c) another minority group (22%) for which circumstances – mainly the mother’s level of autonomy and the family context in which she lives – were completely determining.
Serum Nesfatin-1 Levels in Girls with Idiopathic Central Precocious Puberty

Objective: Nesfatin-1, an anorexigenic neuropeptide, is expressed mainly in the central nervous system and in some peripheral tissues. The role of nesfatin-1 in energy balance has been investigated. Despite the suggestion of a role for nesfatin-1 in reproductive function, data are limited on the role of nesfatin-1 in human puberty. Methods: The aim of this study was to investigate the following: i) the role of nesfatin-1 in puberty, and ii) relationship between nesfatin-1 and anthropometric measurements and gonadotropin levels in girls with idiopathic central precocious puberty (CPP). Twenty-four girls with CPP (7.68±1.02 years) and 20 female, prepubertal, healthy controls (7.48±0.88 years) were enrolled in the study. All patients with CPP were treated by the intramuscular administration of leuprolide acetate at a daily dose of 3.75 mg for 28 days. Nesfatin-1 was measured before and during treatment. Results: There was no difference in serum nesfatin-1 levels in girls with CPP and healthy controls [5.67 (2.5-20.6) mmol/L and 5.75 (2.51-9.64) mmol/L], respectively. There was a negative correlation between nesfatin-1 levels and body weight and body mass index-standard deviation score (p=0.01, r=-0.83; p=0.025, r=-0.81, respectively). No correlation was found between nesfatin-1 and gonadotropin, estradiol levels, uterine length or endometrial thickness. Conclusion: The results of this study suggest that there are no differences between girls with CPP and healthy, prepubertal girls regarding nesfatin-1 levels.
Progesterone-Mediated Inhibition of the GnRH Pulse Generator: Differential Sensitivity as a Function of Sleep Status

Context During normal, early puberty, luteinizing hormone (LH) pulse frequency is low while awake but increases during sleep. Mechanisms underlying such changes are unclear, but a small study in early pubertal girls suggested that differential wake-sleep sensitivity to progesterone negative feedback plays a role. Objective To test the hypothesis that progesterone acutely reduces waking LH pulse frequency more than sleep-associated pulse frequency in late pubertal girls. Design Randomized, placebo-controlled, double-blinded crossover study. Setting Academic clinical research unit. Participants Eleven normal, postmenarcheal girls, ages 12 to 15 years. Intervention Subjects completed two 18-hour admissions in separate menstrual cycles (cycle days 6 to 11). Frequent blood sampling for LH assessment was performed at 1800 to 1200 hours; sleep was encouraged at 2300 to 0700 hours. Either oral micronized progesterone (0.8 mg/kg/dose) or placebo was given at 0700, 1500, 2300, and 0700 hours, before and during the first admission. A second admission, performed at least 2 months later, was identical to the first except that placebo was exchanged for progesterone or vice versa (treatment crossover). Main Outcome Measures LH pulse frequency during waking and sleeping hours. Results Progesterone reduced waking LH pulse frequency by 26% (P = 0.019), with no change observed during sleep (P = 0.314). The interaction between treatment condition (progesterone vs placebo) and sleep status (wake vs sleep) was highly significant (P = 0.007). Conclusions In late pubertal girls, progesterone acutely reduced waking LH pulse frequency more than sleep-associated pulse frequency. Differential wake-sleep sensitivity to progesterone negative feedback may direct sleep-wake LH pulse frequency changes across puberty.
N-Myc Regulates Expression of Pluripotency Genes in Neuroblastoma Including lif, klf2, klf4, and lin28b

myc genes are best known for causing tumors when overexpressed, but recent studies suggest endogenous myc regulates pluripotency and self-renewal of stem cells. For example, N-myc is associated with a number of tumors including neuroblastoma, but also plays a central role in the function of normal neural stem and precursor cells (NSC). Both c- and N-myc also enhance the production of induced pluripotent stem cells (iPSC) and are linked to neural tumor stem cells. The mechanisms by which myc regulates normal and neoplastic stem-related functions remain largely open questions. Here from a global, unbiased search for N-Myc bound genes using ChIP-chip assays in neuroblastoma, we found lif as a putative N-Myc bound gene with a number of strong N-Myc binding peaks in the promoter region enriched for E-boxes. Amongst putative N-Myc target genes in expression microarray studies in neuroblastoma we also found lif and three additional important embryonic stem cell (ESC)-related factors that are linked to production of iPSC: klf2, klf4, and lin28b. To examine the regulation of these genes by N-Myc, we measured their expression using neuroblastoma cells that contain a Tet-regulatable N-myc transgene (TET21N) as well as NSC with a nestin-cre driven N-myc knockout. N-myc levels closely correlated with the expression of all of these genes in neuroblastoma and all but lif in NSC. Direct ChIP assays also indicate that N-Myc directly binds the lif promoter. N-Myc regulates trimethylation of lysine 4 of histone H3 in the promoter of lif and possibly in the promoters of several other stem-related genes. Together these findings indicate that N-Myc regulates overlapping stem-related gene expression programs in neuroblastoma and NSC, supporting a novel model by which amplification of the N-myc gene may drive formation of neuroblastoma. They also suggest mechanisms by which Myc proteins more generally contribute to maintenance of pluripotency and self-renewal of ESC as well as to iPSC formation.
Population Pharmacokinetics and Pharmacodynamics of Meropenem in Nonobese, Obese, and Morbidly Obese Patients

The study objective was to evaluate meropenem population pharmacokinetics and pharmacodynamics in nonobese, obese, and morbidly obese patients. Forty adult patients—11 nonobese (body mass index [BMI] < 30 kg/m2), 9 obese (30 kg/m2 ≤ BMI < 40 kg/m2), and 20 morbidly obese (BMI ≥ 40 kg/m2)—received meropenem 500 mg every 6 hours (q6h), q8h, or q12h or 1 g q6h or q8h, infused over 0.5 hour. Population pharmacokinetic modeling was performed using NONMEM, and 5000‐patient Monte‐Carlo simulations were performed to calculate probability of target attainment (PTA) for 5 dosing regimens, infused over 0.5 and 3 hours, using fT>MIC of 40%, 54%, and 100% of the dosing interval. A 2‐compartment linear‐elimination model best described the serum concentration‐time data, and creatinine clearance was significantly associated with systemic clearance. Pharmacokinetic parameters were not significantly different among patient groups. In patients with creatinine clearances ≥50 mL/min, all simulated dosing regimens achieved >90% PTA at 40% fT>MIC in all patient groups at MICs ≤2 mg/L. Only 500 mg q8h, infused over 0.5 hour, did not achieve >90% PTA at 54% fT>MIC in nonobese and morbidly obese patients. At 100% fT>MIC, 1 g q6h and 2 g q8h, infused over 3 hours, reliably achieved >90% PTA in all patient groups. Meropenem pharmacokinetics are comparable among nonobese, obese, and morbidly obese patients. Standard dosing regimens provide adequate pharmacodynamic exposures for susceptible pathogens at 40% and 54% fT>MIC, but prolonged infusions of larger doses are needed for adequate exposures at 100% fT>MIC. Dosage adjustments based solely on body weight are unnecessary.
Darmstadt University of Technology Admission Control based on Packet Marking and Feedback Signalling – Mechanisms , Implementation and Experiments

The abstract system design and a prototype implementation of an admission control sys described. The system exploits the load signal generated by low complexity active queue manag schemes at internal nodes to carry out flow admission control at edge gateways. The location of fun components is studied and appropriate signalling extensions to exchange load information are pre The suitability of such signalling extensions for admission control and traffic regulation are discussed context of RSVP signalling. A number of questions of detail which are usually ignored by existing th and simulation work, are examined and solutions are presented. Certain modifications to traffic cont gorithms at both internal packet marking nodes and edge gateways are proposed and discussed. T tionality and correct system operation are demonstrated by experiments using the software pro Further, a variety of marking algorithms is compared experimentally to assess the suitability of their re tive load signal for admission control of inelastic traffic and load-adaptive traffic regulation.
Self-reported Cognitive Biases Moderate the Associations Between Social Stress and Paranoid Ideation in a Virtual Reality Experimental Study

Introduction Cognitive biases are associated with psychosis liability and paranoid ideation. This study investigated the moderating relationship between pre-existing self-reported cognitive biases and the occurrence of paranoid ideation in response to different levels of social stress in a virtual reality environment. Methods This study included 170 participants with different levels of psychosis liability (55 recent onset psychosis, 20 ultrahigh risk for psychosis, 42 siblings of psychotic patients, and 53 controls). All participants were exposed to virtual environments with different levels of social stress. The level of experienced paranoia in the virtual environments was measured with the State Social Paranoia Scale. Cognitive biases were assessed with a self-report continuous measure. Also, cumulative number of cognitive biases was calculated using dichotomous measures of the separate biases, based on general population norm scores. Results Higher belief inflexibility bias (Z = 2.83, P < .001), attention to threat bias (Z = 3.40, P < .001), external attribution bias (Z = 2.60, P < .001), and data-gathering bias (Z = 2.07, P < .05) were all positively associated with reported paranoid ideation in the social virtual environments. Level of paranoid response increased with number of cognitive biases present (B = 1.73, P < .001). The effect of environmental stressors on paranoid ideation was moderated by attention to threat bias (Z = 2.78, P < .01) and external attribution bias (Z = 2.75, P < .01), whereas data-gathering bias and belief inflexibility did not moderate the relationship. Conclusion There is an additive effect of separate cognitive biases on paranoid response to social stress. The effect of social environmental stressors on paranoid ideation is further enhanced by attention to threat bias and external attribution bias.
Overlapping network meta-analyses on the same topic: survey of published studies.

Background To assess how common it is for a published network meta-analysis (NMA) to have other published overlapping NMAs, and to evaluate these overlaps. Methods A total of 88 NMAs of randomized controlled trials evaluating the comparative effectiveness of health interventions were randomly selected. For each of these, we searched for NMAs on the same topic. A random sample of 40 pairs (an index NMA and one of its overlapping NMAs) was selected to assess the overlap in terms of nodes, treatments and references. The topic with the largest number of overlapping NMAs was described in depth. Results In all, 68 of the 88 index NMAs had at least one overlapping NMA: 77% [95% confidence interval (CI), 69-86%]. We identified 515 pairs of overlapping NMAs. Among the 40 randomly selected pairs, 73% (95% CI, 58-88%) of nodes, 79% (95% CI, 72-86%) of treatments and 48% (95% CI, 37-59%) of references included in the index NMAs were also found in the respective overlapping NMAs. Efficacy of biologics in rheumatoid arthritis had the largest number of overlapping NMAs, with 28 NMAs published between 2003 and 2014. Differences in selection and definition of nodes of treatments resulted in different network geometries. There were also differences in both the direction and the statistical significance of effects. Conclusions Published NMAs exhibit extensive overlap and potential redundancy. Erratic retrieval of eligible trials, and lack of consensus on the range of interventions to be considered and how they might be merged or split in different nodes, may cause confusion.
Community knowledge, perceptions and attitudes regarding leprosy in rural Cameroon: The case of Ekondotiti and Mbonge health districts in the South-west Region

Background Although leprosy is one of the oldest diseases known to humanity, it remains largely misunderstood. Misconceptions about leprosy lead to stigma towards people with the disease. This study aimed at exploring the knowledge, perceptions and attitudes regarding leprosy in rural Cameroon. Methods We carried out a cross-sectional community survey of 233 respondents aged 15–75 years, free from leprosy, and living in two rural health districts of the South-west Region of Cameroon. A questionnaire designed to evaluate knowledge, perceptions and attitudes about leprosy was used. Binary logistic regression was used to determine independent predictors of negative attitudes. Results About 82% of respondents had heard about, and 64.4% knew someone with leprosy. Information on leprosy was mainly from community volunteers (40.6%), friends (38.0%), and the media (24%). Only 19.7% of respondents knew the cause of leprosy, and a considerable proportion linked it to a spell (25.3%), unclean blood (15.5%) and heredity (14.6%). About 72% knew that leprosy is curable and 86.3% would advise medical treatment. Attitudes towards leprosy patients were generally negative. Only 42% would shake hands, 32.6% would share the same plate, and 28.3% and 27% respectively, would allow their child to play or marry a person with leprosy. Furthermore, only 33.9% approved of participation of leprosy patients, and 42.9% of their employment. Independent predictors of negative attitudes were: the belief that leprosy is a curse; is caused by a germ; and having seen a leprosy patient. The negative attitudes were dampened by: the beliefs that leprosy is a punishment, is hereditary and is due to poor personal hygiene. Conclusion An awareness intervention using community volunteers and the media, with information on the cause of leprosy, its clinical manifestations and curability, and sensitization messages correcting the misconceptions and beliefs regarding leprosy, could improve the community knowledge and attitudes towards leprosy. This would ultimately contribute to the reduction of leprosy burden in the community.
Does the common sexually transmitted parasite Trichomonas vaginalis have sex?

Introduction The parasite Trichomonas vaginalis is a haploid, flagellated, eukaryotic microbe that adheres to the human urogenital tract and causes the most common sexually transmitted parasitic infection, trichomoniasis ("trich"), with around 250 million new cases reported annually worldwide and about 7 million cases in the United States [1]. Previously considered a female “nuisance disease,” T. vaginalis has now been associated with adverse pregnancy outcomes such as preterm delivery, low birth weight, increased risk of HIV infection, and cervical and prostate cancers [2]. In contrast to other parasitic protists that can encyst (e.g., Giardia), T. vaginalis appears to have only one morphological form, a sexually transmitted, mitotically dividing trophozoite. Besides its important role as the causative agent of trich, the parasite is of interest due to its unusually large genome size (around 160 Mb), of which 65% is made up of families of transposable elements (TEs), members of which are highly similar to each other [3]. The nature and size of the T. vaginalis genome raises questions about its evolution and, in particular, how this supposedly asexually reproducing organism survives the deleterious effects of so many active TE families. Indeed, several lines of evidence described below suggest that T. vaginalis may engage in genetic exchange or has done so in its recent evolutionary past. Elucidating a possible sexual cycle in T. vaginalis is crucial not only for learning about its biology and parasitism (e.g., virulence and spread of drug resistance), but also to provide generalizable models for the evolution of sex in other parasites.
Aryl Hydrocarbon Receptor Ablation in Cardiomyocytes Protects Male Mice From Heart Dysfunction Induced by NKX2.5 Haploinsufficiency

Epidemiological studies in humans and research in vertebrates indicates that developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ubiquitous and biopersistent environmental toxicant, is associated with incidence of early congenital heart disease in the embryo and later in the adult. TCDD-mediated toxicity depends on the aryl hydrocarbon receptor (AHR) but the role of the TCDD-activated AHR in cardiac function is not well-defined. To characterize the mechanisms responsible for AHR-mediated disruption of heart function, we generated several mouse strains with cardiomyocyte-specific Ahr gene knockout. Here, we report results on one of these strains in which the Ahr gene was deleted by cre recombinase regulated by the promoter of the cardiomyocyte-specific Nkx2.5 gene. We crossed mice with loxP-targeted Ahrfx/fx alleles with Nkx2.5+/cre mice bearing a "knock-in" cre recombinase gene integrated into one of the Nkx2.5 alleles. In these mice, loss of one Nkx2.5 allele is associated with disrupted cardiac development. In males, Nkx2.5 hemizygosity resulted in cardiac haploinsufficiency characterized by hypertrophy, dilated cardiomyopathy, and impaired ejection fraction. Ahr ablation protected Nkx2.5+/cre haploinsufficient males from cardiac dysfunction while inducing a significant increase in body weight. These effects were absent or largely blunted in females. Starting at 3 months of age, mice were exposed by oral gavage to 1 μg/kg/week of TCDD or control vehicle for an additional 2 months. TCDD exposure restored cardiac physiology in aging males, appearing to compensate for the heart dysfunction caused by Nkx2.5 hemizygosity. Our findings underscore the conclusion that deletion of the Ahr gene in cardiomyocytes protects males from heart dysfunction due to NKX2.5 haploinsufficiency.