Miracle-dz/UniFAR-FTUs huggingface dataset:
Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance

Significance While human genes underlying monogenic disorders are expected to undergo negative selection, the factors that impact the intensity of negative selection remain unknown. We find pervasive negative selection at genes underlying both autosomal dominant and the most severe autosomal recessive inborn errors. Among genes underlying dominant disorders, we show that loss of function entails stronger selection than gain of function, and haploinsufficiency than negative dominance. We develop a method that predicts whether an autosomal gene is more likely to underlie a recessive or a dominant disease. These results have evolutionary implications for studies of the drivers of negative selection, and practical implications in the search for genes underlying life-threatening, heritable conditions. Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.
Direct Observation of Hydrogen Bonds in Nucleic Acid Base Pairs by Internucleotide 2JNN Couplings

Hydrogen bonds play a key role in the stabilization of protein and nucleic acid secondary structure. Currently, most of the experimental evidence for the interaction of hydrogen bond donor and acceptor atoms is indirect. Here we show that scalar couplings across the hydrogen bond are observable for Watson−Crick base pairs in 15N-labeled RNA. These scalar couplings correlate the imino donor 15N nucleus and the corresponding acceptor 15N nucleus on the complementary base. The two-bond JNN couplings between the N3 of uridine and the N1 of adenosine, and between the N1 of guanosine and the N3 of cytidine, have values of approximately 7 Hz as determined by a novel quantitative J-correlation experiment for the 69-nucleotide T1 domain of the potato spindle tuber viroid. In contrast, for non-Watson−Crick base pairs the hydrogen bond acceptor is usually not a nitrogen, but an oxygen atom, and thus, the two-bond JNN couplings are not observed.
Influence of morphometric parameters on the size of collateral ligaments of the distal interphalangeal joint of equines

The physiological measurements of collateral ligaments of distal interphalangeal joint (CL‐DIPJ) differ in the literature. The factors that influence these differences are not well described. The aims of this study are to compare CL‐DIPJ sizes in equines with different withers height, as well as to correlate body weight and hoof size to the size of these ligaments. In total, 52 horses were used in the study. They were divided into two groups according to wither height: Group 1 (G1) ‐ 21 animals with up to 147 cm ‐ and group 2 (G2) ‐ 21 animals with greater than 148 cm. CL‐DIPJ was ultrasonographically measured in order to find the mean of dorso‐palmar (DPD) and latero‐medial (LMD) diameters and the cross‐sectional area (CSA). Hoof width and length were measured, and the results were used to calculate the hoof surface area. Withers height and body weight were also measured. Groups were statistically compared by Student's t test and Pearson's correlation application to each group. Groups were different in body size, HS and CL‐DIPJ size when p < . 05, except for the LMD of the medial collateral ligament of left thoracic limb. Withers height and body weight did not show significant correlations to CL‐DIPJ size in G1, but they had little influence on the size of CL‐DIPJ on G2. No correlation between the hoof size and the CL‐DIPJ was noted in any of the two groups. In conclusion, the CL‐DIPJ were larger in taller horses and their sizes were correlated to their height and weight, but they were not correlated to hoof size.
Phenomenology, Epidemiology and Aetiology of Postpartum Psychosis: A Review

Postpartum psychoses are a severe form of postnatal mood disorders, affecting 1–2 in every 1000 deliveries. These episodes typically present as acute mania or depression with psychosis within the first few weeks of childbirth, which, as life-threatening psychiatric emergencies, can have a significant adverse impact on the mother, baby and wider family. The nosological status of postpartum psychosis remains contentious; however, evidence indicates most episodes to be manifestations of bipolar disorder and a vulnerability to a puerperal trigger. While childbirth appears to be a potent trigger of severe mood disorders, the precise mechanisms by which postpartum psychosis occurs are poorly understood. This review examines the current evidence with respect to potential aetiology and childbirth-related triggers of postpartum psychosis. Findings to date have implicated neurobiological factors, such as hormones, immunological dysregulation, circadian rhythm disruption and genetics, to be important in the pathogenesis of this disorder. Prediction models, informed by prospective cohort studies of high-risk women, are required to identify those at greatest risk of postpartum psychosis.
Vitamin D in the development and progression of alzheimer’s disease: implications for clinical management

ABSTRACT Introduction Although the pathophysiological bases of Alzheimer’s disease (AD) remain incompletely understood and disease-modifying therapies are not available, intervention on modifiable risk factors is warranted. Research on nutrition and dietary components is challenging and controversies still persist about the role of micro- and macronutrients and health outcomes in dementia. Importantly, results of preclinical investigations have shown that vitamin D triggers different neural pathways that may be protective against these neurodegenerative mechanisms, including the deposition of amyloid plaques, inflammatory processes, neurofibrillary degeneration, glutamatergic excitotoxicity, excessive intraneuronal calcium influx, and oxidative stress, although its relationship with AD still needs to be fully understood. Areas covered The authors analyzed the recent evidence about the effects of vitamin D insufficiency on AD and the role of supplementation. Expert opinion Both insufficient (25–49.9 ng/ml) and deficient levels (<25 ng/ml) of vitamin D may contribute to an increased susceptibility to AD. However, further well-designed prospective studies are needed for a better understanding of the involvement of low vitamin D concentrations in the AD natural history. Randomized clinical trials will also be necessary to address the issue of causality and determine whether vitamin D supplementation may be effective for the prevention or treatment of AD.
Towards deep phenotyping pregnancy: a systematic review on artificial intelligence and machine learning methods to improve pregnancy outcomes

Abstract Objective Development of novel informatics methods focused on improving pregnancy outcomes remains an active area of research. The purpose of this study is to systematically review the ways that artificial intelligence (AI) and machine learning (ML), including deep learning (DL), methodologies can inform patient care during pregnancy and improve outcomes. Materials and methods We searched English articles on EMBASE, PubMed and SCOPUS. Search terms included ML, AI, pregnancy and informatics. We included research articles and book chapters, excluding conference papers, editorials and notes. Results We identified 127 distinct studies from our queries that were relevant to our topic and included in the review. We found that supervised learning methods were more popular (n = 69) than unsupervised methods (n = 9). Popular methods included support vector machines (n = 30), artificial neural networks (n = 22), regression analysis (n = 17) and random forests (n = 16). Methods such as DL are beginning to gain traction (n = 13). Common areas within the pregnancy domain where AI and ML methods were used the most include prenatal care (e.g. fetal anomalies, placental functioning) (n = 73); perinatal care, birth and delivery (n = 20); and preterm birth (n = 13). Efforts to translate AI into clinical care include clinical decision support systems (n = 24) and mobile health applications (n = 9). Conclusions Overall, we found that ML and AI methods are being employed to optimize pregnancy outcomes, including modern DL methods (n = 13). Future research should focus on less-studied pregnancy domain areas, including postnatal and postpartum care (n = 2). Also, more work on clinical adoption of AI methods and the ethical implications of such adoption is needed.
Determination of Seven Antidepressants in Pericardial Fluid by Means of Dispersive Liquid–Liquid Microextraction and Gas Chromatography–Mass Spectrometry

Abstract Although blood is often used to detect and quantify the presence of drugs, there are some instances where samples obtained from other biological matrices, like pericardial fluid (PF), are necessary since adequate blood samples may not be available. PF is an epicardial transudate, which contains plasma components that include toxicological substances making this sample useful when blood samples are not available. This fluid is a well-preserved postmortem sample and can easily be collected in larger amounts without significant contamination, compared with other body fluids. Although studies involving PF began around the 1980s, the adequacy of such fluid as a biological matrix has been poorly investigated. Antidepressants are frequently detected in postmortem samples from forensic cases. Nowadays, they constitute some of the most commonly prescribed drugs worldwide. A total of seven antidepressants (venlafaxine, mirtazapine, olanzapine, paroxetine, sertraline, fluoxetine and citalopram) were evaluated in this study. A new extraction method involving dispersive liquid–liquid microextraction (DLLME) is presented in which chloroform and acetonitrile are determined to be the best extraction and dispersing solvents. The experimental design was achieved using StatGraphics 18. The response surface methodology enabled us to know the optimal volume for the two solvents used in the DLLME. The detection technique used was gas chromatography–mass spectrometry with electron impact ionization as ionization source. A temperature gradient has been used and the total chromatographic separation time was 19.43 min. Validation results met the international validation guidance (Food and Drug Administration (FDA)). Under the optimal condition, the method offered good validation parameters showing a new efficient, simple, rapid and sensitive method. The analytical method was applied to 31 PF samples. Twenty-one samples were positive with concentrations between 0.19 and 8.48 µg/mL. Venlafaxine and olanzapine were the antidepressants most frequently found.
The Hox transcription factor Ubx ensures somatic myogenesis by suppressing the mesodermal master regulator Twist

Early determination factors and lineage-specific master regulators are essential for the specification of cell and tissue types. However, once a cell has committed to a specific fate, it is equally critical to restrict the activity of such factors to enable proper differentiation. In many studies the functional network for master regulators are under constant investigations. Yet, how these factors are silenced remains unclear. Using the Drosophila mesoderm as a model and a comparative genomic approach, we identified the Hox transcription factor (TF) Ultrabithorax (Ubx) to be critical for the repression of the mesodermal master regulator Twist (Twi). Mesoderm-specific Ubx loss-of-function experiments using CRISPR/Cas9 as well as overexpression experiments demonstrated that Ubx majorly impacts twi transcription. A detailed mechanistic analysis revealed that Ubx requires the function of the NK-homeodomain protein Tinman (Tin) but not the muscle differentiation factor Myocyte enhancer factor 2 (Mef2) to bind to the twi promoter. Furthermore, we found these TF interactions to be critical for silencing of the twi promoter region by recruiting the Polycomb DNA binding protein Pleiohomeotic (Pho). In sum, our study demonstrates that the Hox TF Ubx is a critical player in mediating the silencing of the mesodermal master regulator Twi, which is crucial for coordinated muscle differentiation.
The potential impact of experiencing social inclusion in recreation for children with and without disabilities

Abstract Purpose Inclusive recreation programs can have individual and community impacts for children with and without disabilities. However, studies that explore the impact of such programs on children’s attitudes are mixed. The purpose of this study was to explore the perspectives of children with and without disabilities on the individual impact of an inclusive recreation program. Material and Method This study adopted a generic qualitative methodology. Interviews were conducted with participants between the ages of eight and 18 enrolled in the same program and each participant was interviewed twice. Inductive thematic analysis was used to analyze results. Results 17 participants were recruited for this study, which included nine children without disabilities (CWODs) and eight children with disabilities (CWDs). This study revealed five themes: a) CWODs have limited exposure to people with disabilities; b) CWODs and CWDs’ hopes of change; c) CWODs learned how to interact with people with disabilities; d) CWODs reported greater perceived similarity in functional ability and hobbies/interests between themselves and CWDs, and; e) CWODs become more comfortable being around people with disabilities. Conclusions This study helps broaden understandings of how inclusive experiences in recreation settings impact children with and without disability. IMPLICATIONS FOR REHABILITATION Children without disabilities can develop more positive attitudes toward children with disabilities in affective and cognitive domains after participating in an inclusive recreation program. Incorporating inclusive language into program design and implementation may promote positive attitudes toward diversity in recreation settings. Children without disabilities would benefit from more opportunities to interact with children with disabilities in unstructured, inclusive or integrated recreation settings.
Effect of cassava flour variety and concentration on bread loaf quality

Cassava flour from 12 clones was baked into bread loaves at 10, 20, 30, and 40% substitution. Loaves were rated according to volume, color and character of crust, texture and grain, crumb color, and taste. There was no correlation among various physicochemical properties of the cassava flour and bread quality. Cyanide concentration in the bread depended on the cassava variety and on the percentage substituted
Outcomes of COVID‐19 in hospitalized solid organ transplant recipients compared to a matched cohort of non‐transplant patients at a national healthcare system in the United States

Data describing outcomes of solid organ transplant (SOT) recipients with coronavirus disease 2019 (COVID‐19) are variable, and the association between SOT status and mortality remains unclear. In this study, we compare clinical outcomes of SOT recipients hospitalized with COVID‐19 between March 10, and September 1, 2020, to a matched cohort of non‐SOT recipients at a national healthcare system in the United States (US). From a population of 43 461 hospitalized COVID‐19‐positive patients, we created a coarsened exact matched cohort of 4035 patients including 128 SOT recipients and 3907 weighted matched non‐SOT controls. Multiple logistic regression was used to evaluate association between SOT status and clinical outcomes. Among the 4035 patients, median age was 60 years, 61.7% were male, 21.9% were Black/African American, and 50.8% identified as Hispanic/Latino ethnicity. Patients with a history of SOT were more likely to die within the study period when compared to matched non‐SOT recipients (21.9% and 14.9%, respectively; odds ratio [OR] 1.93; 95% confidence interval [CI]: 1.18–3.15). Moreover, SOT status was associated with increased odds of receiving invasive mechanical ventilation (OR [95% CI]: 2.34 [1.51–3.65]), developing acute kidney injury (OR [95% CI]: 2.41 [1.59–3.65]), and receiving vasopressor support during hospitalization (OR [95% CI]: 2.14 [1.31–3.48]).
When falls become fatal—Clinical care sequence

Objectives This study encompassed fall-related deaths, including those who died prior to medical care, that were admitted to multiple healthcare institutions, regardless of whether they died at home, in long-term care, or in hospice. The common element was that all deaths resulted directly or indirectly from injuries sustained during a fall, regardless of the temporal relationship. This comprehensive approach provides an unusual illustration of the clinical sequence of fall–related deaths. Understanding this pathway lays the groundwork for identification of gaps in healthcare needs. Design This is a retrospective study of 2014 fall-related deaths recorded by one medical examiner’s office (n = 511) within a larger dataset of all trauma related deaths (n = 1848). Decedent demographic characteristics and fall-related variables associated with the deaths were coded and described. Results Of those falling, 483 (94.5%) were from heights less than 10 feet and 394 (77.1%) were aged 65+. The largest proportion of deaths (n = 267, 52.3%) occurred post-discharge from an acute care setting. Of those who had a documented prior fall, 216 (42.3%) had a history of one fall while 31 (6.1%) had ≥2 falls prior to their fatal incident. For the 267 post-acute care deaths, 440 healthcare admissions were involved in their care. Of 267 deaths occurring post-acute care, 129 (48.3%) were readmitted within 30 days. Preventability, defined as opportunities for improvement in care that may have influenced the outcome, was assessed. Of the 1848 trauma deaths, 511 (27.7%) were due to falls of which 361 (70.6%) were determined to be preventable or potentially preventable. Conclusion Our data show that readmissions and repeated falls are frequent events in the clinical sequence of fall fatalities. Efforts to prevent fall-related readmissions should be a top priority for improving fall outcomes and increasing the quality of life among those at risk of falling.
Long-term depletion of cereblon induces mitochondrial dysfunction in cancer cells

Cereblon (CRBN) is a multi-functional protein that acts as a sub-strate receptor of the E3 ligase complex and a molecular chaperone. While CRBN is proposed to function in mitochondria, its specific roles are yet to be established. Here, we showed that knockdown of CRBN triggers oxidative stress and calcium overload in mitochondria, leading to disruption of mitochondrial membrane potential. Notably, long-term CRBN depletion using PROteolysis TArgeting Chimera (PROTAC) induced irreversible mitochondrial dysfunction, resulting in cell death. Our collective findings indicate that CRBN is required for mitochondrial homeostasis in cells.
Identification of a novel immune microenvironment signature predicting survival and therapeutic options for bladder cancer

Few studies have investigated the potential of tumor immune microenvironment genes as indicators of urinary bladder cancer. Here, we sought to establish an immune-related gene signature for determining prognosis and treatment options. We developed a ten-gene tumor immune microenvironment signature and evaluated its prognostic capacity on internal and external cohorts. Multivariate Cox regression and nomogram analyses revealed the prognostic risk model as an independent and effective indicator of prognosis. We observed lower proportions of CD8+ T cells, dendritic cells, regulatory T cells, higher proportions of macrophages and neutrophils in high UBC risk group. UBC tissues with high-risk score tend to exhibit high TP53 and RB1 mutation rates, high PD1/PD-L1 expression and poor-survival basal squamous subtypes, while those with low-risk score tend to have high FGFR3 mutation rates and luminal papillary subtypes. Unexpectedly, we found a highly significant positive correlation between glycolytic genes and risk score, highlighting metabolic competition in tumor ecosystem and potential therapeutic avenues. Our study thus revealed a tumor immune microenvironment signature for predicting prognostic and response to immune checkpoint inhibitors against bladder cancer. Prospective studies are required to further test the predictive capacity of this model.
Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance

Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.