Miracle-dz/UniFAR-FTUs huggingface dataset:
Conditional Approximate Bayesian Computation: A New Approach for Across-Site Dependency in High-Dimensional Mutation–Selection Models

A key question in molecular evolutionary biology concerns the relative roles of mutation and selection in shaping genomic data. Moreover, features of mutation and selection are heterogeneous along the genome and over time. Mechanistic codon substitution models based on the mutation-selection framework are promising approaches to separating these effects. In practice, however, several complications arise, since accounting for such heterogeneities often implies handling models of high dimensionality (e.g., amino acid preferences), or leads to across-site dependence (e.g., CpG hypermutability), making the likelihood function intractable. Approximate Bayesian Computation (ABC) could address this latter issue. Here, we propose a new approach, named Conditional ABC (CABC), which combines the sampling efficiency of MCMC and the flexibility of ABC. To illustrate the potential of the CABC approach, we apply it to the study of mammalian CpG hypermutability based on a new mutation-level parameter implying dependence across adjacent sites, combined with site-specific purifying selection on amino-acids captured by a Dirichlet process. Our proof-of-concept of the CABC methodology opens new modeling perspectives. Our application of the method reveals a high level of heterogeneity of CpG hypermutability across loci and mild heterogeneity across taxonomic groups; and finally, we show that CpG hypermutability is an important evolutionary factor in rendering relative synonymous codon usage. All source code is available as a GitHub repository (https://github.com/Simonll/LikelihoodFreePhylogenetics.git).
Coexistence of TERT Promoter Mutations and the BRAF V600E Alteration and Its Impact on Histopathological Features of Papillary Thyroid Carcinoma in a Selected Series of Polish Patients

TERT promoter (TERTp) mutations are important factors in papillary thyroid carcinomas (PTCs). They are associated with tumor aggressiveness, recurrence, and disease-specific mortality and their use in risk stratification of PTC patients has been proposed. In this study we investigated the prevalence of TERTp mutations in a cohort of Polish patients with PTCs and the association of these mutations with histopathological factors, particularly in coexistence with the BRAF V600E mutation. A total of 189 consecutive PTC specimens with known BRAF mutational status were evaluated. TERTp mutations were detected in 8.5% of cases (16/189) with the C228T mutation being the most frequent. In six of the PTC specimens (3.2%), four additional TERTp alterations were found, which included one known polymorphism (rs2735943) and three previously unreported alterations. The association analysis revealed that the TERTp hotspot mutations were highly correlated with the presence of the BRAF V600E mutation and their coexistence was significantly associated with gender, advanced patient age, advanced disease stage, presence of lymph node metastases, larger tumor size, and tumor-capsule infiltration. While correlations were identified, the possibility of TERTp mutations being key molecular modulators responsible for PTC aggressiveness requires further studies.
Regulating nociceptive transmission by VGluT2‐expressing spinal dorsal horn neurons

Vesicular glutamate transporter‐2 (VGluT2) mediates the uptake of glutamate into synaptic vesicles in neurons. Spinal cord dorsal horn interneurons are highly heterogeneous and molecularly diverse. The functional significance of VGluT2‐expressing dorsal horn neurons in physiological and pathological pain conditions has not been explicitly demonstrated. Designer receptors exclusively activated by designer drugs (DREADDs) are a powerful chemogenetic tool to reversibly control neuronal excitability and behavior. Here, we used transgenic mice with Cre recombinase expression driven by the VGluT2 promoter, combined with the chemogenetic approach, to determine the contribution of VGluT2‐expressing dorsal horn neurons to nociceptive regulation. Adeno‐associated viral vectors expressing double‐floxed Cre‐dependent Gαq‐coupled human M3 muscarinic receptor DREADD (hM3D)‐mCherry or Gαi‐coupled κ‐opioid receptor DREADD (KORD)‐IRES‐mCitrine were microinjected into the superficial spinal dorsal horn of VGluT2‐Cre mice. Immunofluorescence labeling showed that VGluT2 was predominantly expressed in lamina II excitatory interneurons. Activation of excitatory hM3D in VGluT2‐expressing neurons with clozapine N‐oxide caused a profound increase in neuronal firing and synaptic glutamate release. Conversely, activation of inhibitory KORD in VGluT2‐expressing neurons with salvinorin B markedly inhibited neuronal activity and synaptic glutamate release. In addition, chemogenetic stimulation of VGluT2‐expressing neurons increased mechanical and thermal sensitivities in naive mice, whereas chemogenetic silencing of VGluT2‐expressing neurons reversed pain hypersensitivity induced by tissue inflammation and peripheral nerve injury. These findings indicate that VGluT2‐expressing excitatory neurons play a crucial role in mediating nociceptive transmission in the spinal dorsal horn. Targeting glutamatergic dorsal horn neurons with inhibitory DREADDs may be a new strategy for treating inflammatory pain and neuropathic pain.
Managing Medically Unexplained Symptoms in Primary Care

Medically unexplained symptoms (MUS) are persistent physical symptoms in the absence of identifiable disease. MUS present a major challenge for primary care providers (PCPs) because complex symptom presentations, strained patient-physician relationships, and treatment-resistant symptoms can challenge a PCP’s sense of competency. This review is intended to help PCPs understand the burden and theoretical context of MUS and to provide concise recommendations for managing MUS within primary care settings. Based on a narrative review of the literature, these recommendations emphasize in particular the importance of co-creating plausible explanations for MUS, understanding the pitfalls of consultations involving MUS, and developing multimodal treatment plans.
Understanding the endocannabinoid system as a modulator of the trigeminal pain response to concussion

Post-traumatic headache is the most common symptom of postconcussion syndrome and becomes a chronic neurological disorder in a substantial proportion of patients. This review provides a brief overview of the epidemiology of postconcussion headache, research models used to study this disorder, as well as the proposed mechanisms. An objective of this review is to enhance the understanding of how the endogenous cannabinoid system is essential for maintaining the balance of the CNS and regulating inflammation after injury, and in turn making the endocannabinoid system a potential modulator of the trigeminal response to concussion. The review describes the role of endocannabinoid modulation of pain and the potential for use of phytocannabinoids to treat pain, migraine and concussion.
Dietary Patterns and Breast Cancer Risk: A Multi-Centre Case Control Study among North Indian Women

Evidence from India, a country with unique and distinct food intake patterns often characterized by lifelong adherence, may offer important insight into the role of diet in breast cancer etiology. We evaluated the association between Indian dietary patterns and breast cancer risk in a multi-centre case-control study conducted in the North Indian states of Punjab and Haryana. Eligible cases were women 30–69 years of age, with newly diagnosed, biopsy-confirmed breast cancer recruited from hospitals or population-based cancer registries. Controls (hospital- or population-based) were frequency matched to the cases on age and region (Punjab or Haryana). Information about diet, lifestyle, reproductive and socio-demographic factors was collected using a structured interviewer-administered questionnaire. All participants were characterized as non-vegetarians, lacto-vegetarians (those who consumed no animal products except dairy) or lacto-ovo-vegetarians (persons whose diet also included eggs). The study population included 400 breast cancer cases and 354 controls. Most (62%) were lacto-ovo-vegetarians. Breast cancer risk was lower in lacto-ovo-vegetarians compared to both non-vegetarians and lacto-vegetarians with odds ratios (95% confidence intervals) of 0.6 (0.3–0.9) and 0.4 (0.3–0.7), respectively. The unexpected difference between lacto-ovo-vegetarian and lacto-vegetarian dietary patterns could be due to egg-consumption patterns which requires confirmation and further investigation.
Obesity in Inflammatory Bowel Disease: Gains in Adiposity despite High Prevalence of Myopenia and Osteopenia

Background: Rising rates of obesity have been reported in patients with inflammatory bowel disease (IBD); however, prospective data is lacking. The aim of this study is to prospectively evaluate body composition in adults with IBD over 24 months. Methods: Whole body dual energy X-ray absorptiometry (DXA) data was performed at 0 months, 12 months, and 24 months. Bone mineral density (BMD), fat mass index (FMI (kg)/height (m2)), appendicular skeletal muscle index (ASMI (kg)/height (m2)), visceral adipose tissue and the visceral adipose height index (VHI, VAT area (cm3)/height (m2)), and clinical and anthropometric assessments were performed at each time point. Multivariable linear mixed effects regression analyses were performed. Results: Initially, 154 participants were assessed at baseline (70% Crohn’s disease, 55% male, median age 31 years), of whom 129 underwent repeated DXA at 12 months, and 110 underwent repeated DXA at 24 months. Amongst those undergoing repeated DXA, their body mass index (BMI) significantly increased over time, such that by 24 months, 62% of patients were overweight or obese (annual change BMI β = 0.43, 95%CI = [0.18, 0.67], p = 0.0006). Gains in BMI related to increases in both FMI and VHI (β = 0.33, 95%CI = [0.14, 0.53], p = 0.0007; β = 0.08, 95%CI = [0.02, 0.13], p = 0.001; respectively), whereas ASMI decreased (β = −0.07, 95%CI = [−0.12, −0.01], p = 0.01) with a concordant rise in rates of myopenia (OR = 3.1 95%CI = [1.2, 7.7]; p = 0.01). Rates of osteopenia and osteoporosis were high (37%), but remained unchanged over time (p = 0.23). Conclusion: Increasing rates of obesity in patients with IBD coincide with decreases in lean muscle mass over time, while high rates of osteopenia remain stable. These previously undocumented issues warrant attention in routine care to prevent avoidable morbidity.
Correlations between invisibility and usability in ubicomp and IoT applications: partial results

Quality characteristics present several difficulties to be addressed. Negative correlations are one of these issues developers must deal during software development. These correlations mean that supporting a characteristic can negatively impact another one. A well-known solution to help developers identifying such correlations is through non-functional requirements (NFRs) catalogs. Although there are several correlations catalogs proposed in the literature, they do not take into account new characteristics that have arisen with the Ubiquitous Computing (UbiComp) and the Internet of Things (IoT) environment, such as Invisibility. In a previous study, a process for defining a catalog of correlations for quality characteristics was proposed. In this paper, we present partial results of the execution of this process for Invisibility and Usability. We also discuss some challenges regarding catalogs for quality characteristics.
Combined effects of workplace bullying and perceived organizational support on employee behaviors: does resource availability help?

ABSTRACT Background and Objective: This research examines the detrimental effects of workplace bullying as a social stressor on employees’ job performance, organizational retaliatory behaviors, and organizational citizenship behaviors and how the availability of support can reduce the negative impact of bullying. Using social exchange theory and the conservation of resources theory as theoretical frameworks, we propose that workplace bullying drains personal resources, leading to reduced job performance, low citizenship behaviors, and increased organizational retaliatory behaviors. We also propose that perceived organizational support acts as moderator, such that it reduces the detrimental effects of bullying on employee behaviors. Research Design and Methods: We tested our hypotheses in two field studies (N = 478 and N = 395) conducted in Pakistan. Results: The results of both studies supported the assertion that workplace bullying exacerbates employees’ job performance, reduces organizational citizenship behaviors and intensifies organizational retaliatory behaviors. The idea that perceived organizational support would moderate the bullying-work behavior relationships found mixed support. While perceptions of organizational support reinforced the bullying-job performance and bullying-retaliatory behaviors relationships, it did not moderate the bullying-citizenship behaviors relationship in the suggested direction. Conclusion: The findings show that workplace bullying leads to more organizational citizenship behaviors when employee’s perceptions of organizational support is high.
Lactobacillus acidophilus DDS-1 Modulates the Gut Microbiota and Improves Metabolic Profiles in Aging Mice

Recent evidence suggests that gut microbiota shifts can alter host metabolism even during healthy aging. Lactobacillus acidophilus DDS-1, a probiotic strain, has shown promising probiotic character in vitro, as well as in clinical studies. The present study was carried out to investigate whether DDS-1 can modulate the host metabolic phenotype under the condition of age-affected gut microbial shifts in young and aging C57BL/6J mice. Collected fecal samples were analyzed using 16S rRNA gene sequencing for identifying gut microbiota and untargeted gas chromatography-mass spectrometry (GC-MS) metabolomics analysis. Gut microbial shifts were observed in the control groups (young and aging), leading to an alteration in metabolism. Principal coordinate analysis (PCoA) of microbiota indicated distinct separation in both the DDS-1-treated groups. L. acidophilus DDS-1 increased the relative abundances of beneficial bacteria, such as Akkermansia muciniphila and Lactobacillus spp. , and reduced the relative levels of opportunistic bacteria such as Proteobacteria spp. Metabolic pathway analysis identified 10 key pathways involving amino acid metabolism, protein synthesis and metabolism, carbohydrate metabolism, and butanoate metabolism. These findings suggest that modulation of gut microbiota by DDS-1 results in improvement of metabolic phenotype in the aging mice.
Walnut Protein Hydrolysates Play a Protective Role on Neurotoxicity Induced by d-Galactose and Aluminum Chloride in Mice

In recent years, with an increase in the aging population, neurodegenerative diseases have attracted more and more attention. This study aimed to investigate the potential neuroprotective effect of defatted walnut meal protein hydrolysates (DWMPH) on neurotoxicity induced by d-galactose (d-gal) and aluminum chloride (AlCl3) in mice. The animal models were established by combining treatments with d-gal (200 mg/kg/day, subcutaneously) and AlCl3 (100 mg/kg in drinking water) for 90 days. During the 90 days, 1 g/kg of DWMPH was administrated orally every day. The results indicated that DWMPH treatment alleviated oxidative stress, reversed cholinergic dysfunction, and suppressed the release of proinflammatory cytokines in the brains of d-gal + AlCl3-treated mice, and thus improving the learning and memory functions of these mice, which was closely correlated with the strong antioxidant activity of DWMPH. This finding suggests that DWMPH might be a promising dietary supplement in improving neuronal dysfunctions of the brain.
Language Experience in the Second Year of Life and Language Outcomes in Late Childhood

In this 10-year study, we explore the relationship between early childhood language experience and language and cognitive skills in late childhood. OBJECTIVES: Quantity of talk and interaction in the home during early childhood is correlated with socioeconomic status (SES) and can be used to predict early language and cognitive outcomes. We tested the effectiveness of automated early language environment estimates for children 2 to 36 months old to predict cognitive and language skills 10 years later and examined effects for specific developmental age periods. METHODS: Daylong audio recordings for 146 infants and toddlers were completed monthly for 6 months, and the total number of daily adult words and adult-child conversational turnswere automatically estimated with Language Environment Analysis software. Follow-up evaluations at 9 to 14 years of age included language and cognitive testing. Language exposure for 3 age groups was assessed: 2 to 17 months, 18 to 24 months, and ≥25 months. Pearson correlations and multiple linear regression analyses were conducted. RESULTS: Conversational turn counts at 18 to 24 months of age accounted for 14% to 27% of the variance in IQ, verbal comprehension, and receptive and/or expressive vocabulary scores 10 years later after controlling for SES. Adult word counts between 18 and 24 months were correlated with language outcomes but were considerably weakened after controlling for SES. CONCLUSIONS: These data support the hypothesis that early talk and interaction, particularly during the relatively narrow developmental window of 18 to 24 months of age, can be used to predict school-age language and cognitive outcomes. With these findings, we underscore the need for effective early intervention programs that support parents in creating an optimal early language learning environment in the home.
Comparative Evaluation of Recombinant Human Bone Morphogenetic Protein-2/Hydroxyapatite and Bovine Bone for New Bone Formation in Alveolar Ridge Preservation

Purpose: Hydroxyapatite treated with recombinant human bone morphogenetic protein-2/Hydroxyapatite (rhBMP-2/HA) or bovine bone was applied on extraction sockets for alveolar ridge preservation, and the results were compared with respect to clinical and histological bone formation. Materials and Methods: This was a prospective, randomized controlled clinical trial performed on 20 implant placement sites (10 in the experimental and 10 in the control group). rhBMP-2/HA was applied on extraction sockets in the experimental group and bovine bone on those of the control group. The bone at the corresponding sites was biopsied 3 months later, and clinical, histological, and histomorphometric analyses were performed. Results: The alveolar bone height was well preserved in both groups with relatively less change in width in the experimental group compared with the control group. The percentage of new bone was 25.37% ± 17.23% in the experimental group and 6.13% ± 4.32% in the control group; the difference was statistically significant. Conclusions: The alveolar ridge was preserved clinically and histologically in both groups. rhBMP-2/HA resulted in greater new bone formation than bovine bone 3 months after the surgery.
NEAT1 contributes to ox‐LDL‐induced inflammation and oxidative stress in macrophages through inhibiting miR‐128

Long noncoding RNAs (lncRNA) have been recognized as significant regulators in the progression of atherosclerosis (AS). Oxidized low‐density lipoprotein (ox‐LDL) can induce macrophage inflammation and oxidative stress, that serves important roles in AS. However, the exact function of lncRNA NEAT1 and its possible molecular mechanism in AS remain unclear. Here, we concentrated on the roles and molecular mechanisms of NEAT1 in AS development. In our current study, we observed that NEAT1 was elevated by ox‐LDL in a dose‐dependent and time‐dependent manner. RAW264.7 cell survival was greatly enhanced, and cell apoptosis was significantly inhibited by LV‐shNEAT1 transfection. In addition, knockdown of NEAT1 in RAW264.7 cells repressed CD36 expression and foam cell formation while NEAT1 overexpression shown an opposite process. Moreover, NEAT1 downregulation inhibited inflammation molecules including IL‐6, IL‐1β, and TNF‐α. Meanwhile, silencing of NEAT1 can also suppress reactive oxygen species (ROS) and malondialdehyde (MDA) levels with an enhancement of superoxide dismutase (SOD) activity in RAW264.7 cells. MicroRNAs are some short RNAs, and they can regulate multiple biological functions in many diseases including AS. Here, we found that miR‐128 expression was remarkably decreased in ox‐LDL‐incubated RAW264.7 cells. Interestingly, miR‐128 mimics was able to reverse AS‐correlated events induced by overexpression of NEAT1. By using bioinformatics analysis, miR‐128 was predicted as a target of NEAT1 and the correlation between them was validated in our study. Taken these together, it was implied that NEAT1 participated in ox‐LDL‐induced inflammation and oxidative stress in AS development through sponging miR‐128.
Assessing Metagenomic Signals Recovered from Lyuba, a 42,000-Year-Old Permafrost-Preserved Woolly Mammoth Calf

The reconstruction of ancient metagenomes from archaeological material, and their implication in human health and evolution, is one of the most recent advances in paleomicrobiological studies. However, as for all ancient DNA (aDNA) studies, environmental and laboratory contamination need to be specifically addressed. Here we attempted to reconstruct the tissue-specific metagenomes of a 42,000-year-old, permafrost-preserved woolly mammoth calf through shotgun high-throughput sequencing. We analyzed the taxonomic composition of all tissue samples together with environmental and non-template experimental controls and compared them to metagenomes obtained from permafrost and elephant fecal samples. Preliminary results suggested the presence of tissue-specific metagenomic signals. We identified bacterial species that were present in only one experimental sample, absent from controls, and consistent with the nature of the samples. However, we failed to further authenticate any of these signals and conclude that, even when experimental samples are distinct from environmental and laboratory controls, this does not necessarily indicate endogenous presence of ancient host-associated microbiomic signals.