Miracle-dz/UniFAR-FTUs huggingface dataset:
Identifying the binding mechanism of LEAP2 to receptor GHSR1a

Liver‐expressed antimicrobial peptide 2 (LEAP2) is a highly conserved secretory peptide first isolated in 2003. However, its exact biological functions remained elusive until a recent study identified it as an endogenous antagonist for the growth hormone secretagogue receptor (GHSR1a), a G protein‐coupled receptor for which the gastric peptide ghrelin is the endogenous agonist. By tuning the ghrelin–GHSR1a system, LEAP2 has an important function in energy metabolism. In the present study, we first demonstrated that LEAP2 and ghrelin actually bound to GHSR1a in a competitive manner, rather than in a non‐competitive manner as previously reported, by binding assays and activation assays. Subsequently, we demonstrated that the antagonistic function of LEAP2 was drastically affected by the manner of its addition. LEAP2 primarily affected the maximal activation effect when added before ghrelin, whereas it primarily affected half‐maximal effective concentration when added at the same time as ghrelin. Thus, LEAP2 behaved as a competitive antagonist if added at the same time as the agonist and a non‐competitive antagonist if added before the agonist. This unusual property of LEAP2 might be caused by its slow dissociation from receptor GHSR1a. We also found that the N‐terminal fragment of LEAP2 was important for receptor binding. Our present study revealed an antagonistic mechanism for LEAP2, and will facilitate the design of novel antagonists for receptor GHSR1a in future studies.
A bootstrap version of the Hausman test to assess the impact of cluster-level endogeneity beyond the random intercept model

Abstract In the random intercept model for clustered data, the random effect is typically assumed to be independent of predictors. Violation of this assumption due to unmeasured cluster-level confounding (endogeneity) induces bias in the estimates of effects of within-cluster predictors. Treating cluster-specific intercepts as fixed rather than random avoids this bias. The Hausman test contrasts the fixed effect estimator with the traditional random effect estimator in the random intercept model to test for the presence of cluster-level endogeneity and has a known asymptotic -distribution under correct model specification. Unmeasured cluster-level heterogeneity may, however, interact with predictors as well, necessitating random slope models. Relying on either cluster or residual resampling in a bootstrap procedure, we propose two extensions of the Hausman test that can easily be used beyond the random intercept model. We compare the original Hausman test and its robust version to the newly proposed bootstrap tests in terms of empirical type I error rate and power. Under additive unmeasured heterogeneity, all methods perform equally well, whereas the original and robust Hausman tests are too liberal or too conservative under additional slope heterogeneity, both bootstrap Hausman tests maintain appropriate performance. Moreover, both bootstrap tests show robustness against misspecification in the presence of unit-level heteroscedasticity and temporal correlation.
Translating GWAS findings into therapies for depression and anxiety disorders: gene-set analyses reveal enrichment of psychiatric drug classes and implications for drug repositioning

Abstract Background Depression and anxiety disorders (AD) are the first and sixth leading causes of disability worldwide. Despite their high prevalence and significant disability resulted, there are limited advances in new drug development. Recently, genome-wide association studies (GWAS) have greatly advanced our understanding of the genetic basis underlying psychiatric disorders. Methods Here we employed gene-set analyses of GWAS summary statistics for drug repositioning. We explored five related GWAS datasets, including two on major depressive disorder (MDD2018 and MDD-CONVERGE, with the latter focusing on severe melancholic depression), one on AD, and two on depressive symptoms and neuroticism in the population. We extracted gene-sets associated with each drug from DSigDB and examined their association with each GWAS phenotype. We also performed repositioning analyses on meta-analyzed GWAS data, integrating evidence from all related phenotypes. Results Importantly, we showed that the repositioning hits are generally enriched for known psychiatric medications or those considered in clinical trials. Enrichment was seen for antidepressants and anxiolytics but also for antipsychotics. We also revealed new candidates or drug classes for repositioning, some of which were supported by experimental or clinical studies. For example, the top repositioning hit using meta-analyzed p values was fendiline, which was shown to produce antidepressant-like effects in mouse models by inhibition of acid sphingomyelinase. Conclusion Taken together, our findings suggest that human genomic data such as GWAS are useful in guiding drug discoveries for depression and AD.
Pervasive Linked Selection and Intermediate-Frequency Alleles Are Implicated in an Evolve-and-Resequencing Experiment of Drosophila simulans

Evolve-and-Resequence (E&R) experiments, where researchers allow populations to evolve within one or more controlled environments and then whole-genome sequence the resultant populations, are increasingly important in evolutionary genetics methodology. Here, Kelly. We develop analytical and simulation tools for evolve-and-resequencing experiments and apply them to a new study of rapid evolution in Drosophila simulans. Likelihood test statistics applied to pooled population sequencing data suggest parallel evolution of 138 SNPs across the genome. This number is reduced by orders of magnitude from previous studies (thousands or tens of thousands), owing to differences in both experimental design and statistical analysis. Whole genome simulations calibrated from Drosophila genetic data sets indicate that major features of the genome-wide response could be explained by as few as 30 loci under strong directional selection with a corresponding hitchhiking effect. Smaller effect loci are likely also responding, but are below the detection limit of the experiment. Finally, SNPs showing strong parallel evolution in the experiment are intermediate in frequency in the natural population (usually 30–70%) indicative of balancing selection in nature. These loci also exhibit elevated differentiation among natural populations of D. simulans, suggesting environmental heterogeneity as a potential balancing mechanism.
Enhanced Message-Passing Based LEACH Protocol for Wireless Sensor Networks

This paper proposes a distributed energy-efficient clustering protocol for wireless sensor networks (WSNs). Based on low-energy adaptive clustering hierarchy (LEACH) protocol, the proposed LEACH-eXtended Message-Passing (LEACH-XMP) substantially improves a cluster formation algorithm, which is critical for WSN operations. Unlike the previous approaches, a realistic non-linear energy consumption model is considered, which renders the clustering optimization highly nonlinear and challenging. To this end, a state-of-the-art message-passing approach is introduced to develop an efficient distributed algorithm. The main benefits of the proposed technique are its inherent nature of a distributed algorithm and the saving of computational load imposed for each node. Thus, it proves useful for a practical deployment. In addition, the proposed algorithm rapidly converges to a very accurate solution within a few iterations. Simulation results ensure that the proposed LEACH-XMP maximizes the network lifetime and outperforms existing techniques consistently.
Circulating Tumor Cell-Derived Pre-Clinical Models for Personalized Medicine

The main cause of death from cancer is associated with the development of metastases, resulting from the inability of current therapies to cure patients at metastatic stages. Generating preclinical models to better characterize the evolution of the disease is thus of utmost importance, in order to implement effective new cancer biomarkers and therapies. Circulating Tumor Cells (CTCs) are good candidates for generating preclinical models, making it possible to follow up the spatial and temporal heterogeneity of tumor tissues. This method is a non-invasive liquid biopsy that can be obtained at any stage of the disease. It partially summarizes the molecular heterogeneity of the corresponding tumors at a given time. Here, we discuss the CTC-derived models that have been generated so far, from simplified 2D cultures to the most complex CTC-derived explants (CDX models). We highlight the challenges and strengths of these preclinical tools, as well as some of the recent studies published using these models.
Patterns of Prenatal Alcohol Use That Predict Infant Growth and Development

In this study, we use longitudinal trajectory methods to distinguish patterns of prenatal alcohol use and determine if patterns are used to predict deficits in growth or neurodevelopment in offspring. BACKGROUND: Previous studies have had inconsistent findings regarding the quantity and frequency of prenatal alcohol exposure (PAE) that lead to deficits in growth and neurodevelopment. This may be due to imprecise methods of exposure classification. Our objective in this study was to employ longitudinal trajectory modeling of maternal drinking patterns associated with infant growth or neurodevelopmental deficits to a homogenous sample of mothers and infants. METHODS: From a sample of 471 pregnant women prospectively enrolled in a longitudinal study in the Ukraine, we performed a longitudinal cluster analysis of drinking patterns across gestation. We employed multivariable regression analyses to determine if each trajectory group was associated with infant weight, length, or head circumference at birth or psychomotor or mental deficits in infancy. RESULTS: We identified 5 distinct PAE trajectory groups: minimal or no PAE throughout gestation, low-to-moderate PAE with discontinuation early in gestation, low-to-moderate PAE sustained across gestation, moderate-to-high PAE with reduction early in gestation, and high PAE sustained across gestation. The highest-trajectory group was associated with deficits in infant weight and length at birth and deficits in psychomotor and mental performance at 6 to 12 months of age. Although confidence intervals overlapped, low-to-moderate sustained use was more strongly associated with most negative infant outcomes than moderate-to-high PAE with early reduction. CONCLUSIONS: With these findings, we confirm that high, sustained PAE confers the highest risk for adverse infant outcomes but demonstrate that even low-to-moderate PAE continued across gestation is associated with certain deficits. This approach may be used to help clinicians identify high-risk infants for targeted early intervention.
Tibial Slope and Its Effect on Force in Anterior Cruciate Ligament Grafts: Anterior Cruciate Ligament Force Increases Linearly as Posterior Tibial Slope Increases

Background: Previous work has reported that increased tibial slope is directly correlated with increased anterior tibial translation, possibly predisposing patients to higher rates of anterior cruciate ligament (ACL) tears and causing higher rates of ACL graft failures over the long term. However, the effect of changes in sagittal plane tibial slope on ACL reconstruction (ACLR) graft force has not been well defined. Purpose/Hypothesis: The purpose of this study was to quantify the effect of changes in sagittal plane tibial slope on ACLR graft force at varying knee flexion angles. Our null hypothesis was that changing the sagittal plane tibial slope would not affect force on the ACL graft. Study Design: Controlled laboratory study. Methods: Ten male fresh-frozen cadaveric knees had a posterior tibial osteotomy performed and an external fixator placed for testing and accurate slope adjustment. Following ACLR, specimens were compressed with a 200-N axial load at flexion angles of 0°, 15°, 30°, 45°, and 60°, and the graft loads were recorded through a force transducer clamped to the graft. Tibial slope was varied between −2° and 20° of posterior slope at 2° increments under these test conditions. Results: ACL graft force in the loaded testing state increased linearly as slope increased. This effect was independent of flexion angle. The final model utilized a 2-factor linear mixed-effects regression model and noted a significant, highly positive, and linear relationship between tibial slope and ACL graft force in axially loaded knees at all flexion angles tested (slope coefficient = 0.92, SE = 0.08, P < .001). Significantly higher graft force was also observed at 0° of flexion as compared with all other flexion angles for the loaded condition (all P < .001). Conclusion: The authors found that tibial slope had a strong linear relationship to the amount of graft force experienced by an ACL graft in axially loaded knees. Thus, a flatter tibial slope had significantly less loading of ACL grafts, while steeper slopes increased ACL graft loading. Our biomechanical findings support recent clinical evidence of increased ACL graft failure with steeper tibial slope secondary to increased graft loading. Clinical Relevance: Evaluation of the effect of increasing tibial slope on ACL graft force can guide surgeons when deciding if a slope-decreasing proximal tibial osteotomy should be performed before a revision ACLR. Overall, as slope increases, ACL graft force increases, and in our study, flatter slopes had lower ACL graft forces and were protective of the ACLR graft.
Is it feasible to carry out active case finding for tuberculosis in community-based settings?

Introduction and Objective: To achieve elimination of tuberculosis by 2025, identifying the remaining 25% of missed cases would play a major role. But there is paucity of evidence on this statement. This study aimed to assess feasibility of active case finding for tuberculosis in selected region of Puducherry. Methods: Community based survey was conducted by groups of trained undergraduate medical students. During January 2018, all residents of study area were assessed for presence of presumptive symptoms related to tuberculosis. Presumptive cases of tuberculosis were identified as per the programme definition and the same were facilitated to undergo follow up necessary investigations to rule out tuberculosis through frequent domiciliary visits. The data collection was done using mobile based Epicollect open access app. Feasibility was assessed using indicators namely household coverage, proportions of presumptive cases identified and undergone follow up investigations, number needed to screen for presumptive and confirmed cases of tuberculosis and average time spent per person. Results: Of the 2252 houses, 1746 were covered resulting in a response rate of 77.5% and included 6606 residents. Of the 55 presumptive cases identified (55/6606) 51 underwent investigations (51/55). Two new cases of tuberculosis were diagnosed in this survey. To identify one presumptive and confirmed case 120, 3303 people need to be screened respectively. Conclusion: Active case finding for tuberculosis is feasible provided the health system is able to invest adequate human resources and referral linkages to support peripheral centres.
Impact of a student-driven wellness program for individuals with disabilities on caregivers and family members

Abstract Aim: Few studies have addressed impact of participation in exercise programs on caregivers or family members of individuals with disabilities. Purpose: To evaluate the impact of interaction rich wellness program on family members or caregivers of participants. Methods: Nine family members or caregivers were selected for interviews. Interviews were transcribed and analyzed using a thematic approach. Results: Five themes were constructed from analysis of the interview data: benefit of class to self, positive feelings about participation, relationship dynamic, importance of classroom interaction, and burden of class. The first four themes occurred in caregivers despite individual burden determined by self-reported interview scores on the Zarit Burden interview. Conclusion: This study demonstrated the impact of an interaction rich exercise program on wellness of participants with disabilities and respective caregivers or family members. Caregivers or family members do acknowledge benefits of the program to themselves. However, the program does not reduce caregiver burden. Implications for Rehabilitation Rehabilitation professionals should be cognizant of the potential for indirect benefit of rehabilitation or exercise programs on family members or caregivers of patients. Rehabilitation programs should consider the indirect benefit on the caregivers of patients when evaluating the burden of a program on caregivers. Rehabilitation professionals should focus on interpersonal interaction to aid in positive outcomes for both patients and caregivers.
Predictors of fatigue and severe fatigue in a large international cohort of patients with systemic lupus erythematosus and a systematic review of the literature.

OBJECTIVE Fatigue is reported in up to 90% of patients with SLE. This study was conducted to identify the determinants associated with fatigue in a large cohort of patients with SLE, as well as to provide a systematic review of the literature. METHODS Patients from the Lupus BioBank of the upper Rhein, a large German-French cohort of SLE patients, were included in the FATILUP study if they fulfilled the 1997 ACR criteria for SLE and had Fatigue Scale for Motor and Cognitive Functions scores collected. Multivariate logistic regression analyses were performed to assess the determinants of fatigue and severe fatigue. RESULTS A total of 570 patients were included (89.1% female). The median age was 42 years (interquartile range 25-75: 34-52). The median value of the SAfety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI was 2 (0-4). Fatigue was reported by 386 patients (67.7%) and severe fatigue by 209 (36.7%). In multivariate analyses, fatigue was associated with depression [odds ratio (OR): 4.72 (95% CI: 1.39-16.05), P = 0.01], anxiety [OR: 4.49 (95% CI: 2.60-7.77), P < 0.0001], glucocorticoid treatment [OR: 1.59 (95% CI 1.05-2.41), P = 0.04], SELENA-SLEDAI scores [OR: 1.05 (95% CI: 1.00-1.12) per 1 point increase, P = 0.043] and age at sampling [OR: 1.01 (95% CI: 1.00-1.03) per 1 year increase, P = 0.03]. Severe fatigue was independently associated with anxiety (P < 0.0001), depression (P < 0.0001), glucocorticoid treatment (P = 0.047) and age at sampling (P = 0.03). CONCLUSION Both fatigue and severe fatigue are common symptoms in SLE, and are strongly associated with depression and anxiety. Disease activity and the use of glucocorticoids were also independently associated with fatigue, although more weakly.
The Assessment of Sexual Dysfunction in Male Patients with Multiple Sclerosis.

Introduction To investigate the effects of multiple sclerosis (MS) on male sexuality. Methods While 61 men with MS were included into the study group, 60 healthy men constituted the control group in the study. In MS patients, such parameters as functional status and depression levels were assessed with the Expanded Disability Status Scala (EDSS) and the Beck Depression Scale (BDS), other parameters such as pain levels, sexual function and quality of life (QoL) were evaluated with the Visual Analog Scala (VAS), the International Index of Erectile Function (IIEF) and the short form-36 (SF-36), respectively. Results Patients with MS were classified as 45 with EDSS <5.5 and 19 with EDSS >5.5. Mean VAS and BDI scores patients with MS were found statistically significantly higher, compared with those of the controls (p<0.05). Mean IIEF and all sub-group scores of SF-36 of patients with MS were found to be statistically significantly lower, compared with those of the control group (p<0.05). Mean EDSS in patients with MS was 2.75±2.42. While there was a positive correlation between IIEF scores of patients with MS, and mean mental and physical components of SF-36, a negative correlation was found between IIEF scores in MS patients, and age, disease duration, number of attacks, number of marital years and scores of EDSS, VAS and BDI (p<0.00). When BDI ≥17 was accepted as the threshold for depression, the depression was detected in 62.5% of patients with MS and 11.7% of the controls (p<0.001). Conclusion Sexual functions are affected negatively in male patients with MS and seem to be associated with increased disability, pain and accompanying depression. Therefore, male patients with MS should also be evaluated with regard to sexual function, as well as disability during their follow-ups.
Container Size Alters the Outcome of Interspecific Competition Between Aedes aegypti (Diptera: Culicidae) and Aedes albopictus

Abstract Aedes aegypti L. and Aedes albopictus Skuse co-occur in a variety of water-filled containers where they compete for resources. Larvae of Ae. albopictus Skuse often outcompete those of Ae. aegypti L. , but variation in biotic and abiotic parameters can modify the outcome of this interspecific competition. We tested whether container size can alter the magnitude and direction of intra- and interspecific competition by rearing three Ae. aegypti and Ae. albopictus larval combinations (100:0, 50:50 and 0:100) in three container sizes (small, medium, and large). For both mosquito species, individuals raised in small- and medium-sized containers had shorter development time to adulthood, higher survival to adulthood, and larger adult body size compared to individuals from large containers. For Ae. aegypti but not Ae. albopictus, survival to adulthood was significantly influenced by a two-way interaction between container size and larval competition. The negative effect of interspecific competition was stronger in the small and medium containers and the negative effect of intraspecific competition was stronger in large containers. Our results show that container size can affect the outcome of intra- and interspecific competition between Ae. aegypti and Ae. albopictus and may help account for the observed patterns of both competitive exclusion and coexistence documented in the field for these two medically important mosquito species.
Rufomycin Targets ClpC1 Proteolysis in Mycobacterium tuberculosis and M. abscessus

ClpC1 is an emerging new target for the treatment of Mycobacterium tuberculosis infections, and several cyclic peptides (ecumicin, cyclomarin A, and lassomycin) are known to act on this target. This study identified another group of peptides, the rufomycins (RUFs), as bactericidal to M. tuberculosis through the inhibition of ClpC1 and subsequent modulation of protein degradation of intracellular proteins. ABSTRACT ClpC1 is an emerging new target for the treatment of Mycobacterium tuberculosis infections, and several cyclic peptides (ecumicin, cyclomarin A, and lassomycin) are known to act on this target. This study identified another group of peptides, the rufomycins (RUFs), as bactericidal to M. tuberculosis through the inhibition of ClpC1 and subsequent modulation of protein degradation of intracellular proteins. Rufomycin I (RUFI) was found to be a potent and selective lead compound for both M. tuberculosis (MIC, 0.02 μM) and Mycobacterium abscessus (MIC, 0.4 μM). Spontaneously generated mutants resistant to RUFI involved seven unique single nucleotide polymorphism (SNP) mutations at three distinct codons within the N-terminal domain of clpC1 (V13, H77, and F80). RUFI also significantly decreased the proteolytic capabilities of the ClpC1/P1/P2 complex to degrade casein, while having no significant effect on the ATPase activity of ClpC1. This represents a marked difference from ecumicin, which inhibits ClpC1 proteolysis but stimulates the ATPase activity, thereby providing evidence that although these peptides share ClpC1 as a macromolecular target, their downstream effects are distinct, likely due to differences in binding.