Miracle-dz/UniFAR-FTUs huggingface dataset:
Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination

Based on its clinical benefits, Trikafta — the combination of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor), and the gating potentiator VX-770 (ivacaftor) — was FDA approved for treatment of patients with cystic fibrosis (CF) carrying deletion of phenylalanine at position 508 (F508del) of the CF transmembrane conductance regulator (CFTR) on at least 1 allele. Neither the mechanism of action of VX-445 nor the susceptibility of rare CF folding mutants to Trikafta are known. Here, we show that, in human bronchial epithelial cells, VX-445 synergistically restores F508del-CFTR processing in combination with type I or II correctors that target the nucleotide binding domain 1 (NBD1) membrane spanning domains (MSDs) interface and NBD2, respectively, consistent with a type III corrector mechanism. This inference was supported by the VX-445 binding to and unfolding suppression of the isolated F508del-NBD1 of CFTR. The VX-661 plus VX-445 treatment restored F508del-CFTR chloride channel function in the presence of VX-770 to approximately 62% of WT CFTR in homozygous nasal epithelia. Substantial rescue of rare misprocessing mutations (S13F, R31C, G85E, E92K, V520F, M1101K, and N1303K), confined to MSD1, MSD2, NBD1, and NBD2 of CFTR, was also observed in airway epithelia, suggesting an allosteric correction mechanism and the possible application of Trikafta for patients with rare misfolding mutants of CFTR.
Epidemiological insights from a large-scale investigation of intestinal helminths in Medieval Europe

Helminth infections are among the World Health Organization’s top neglected diseases with significant impact in many Less Economically Developed Countries. Despite no longer being endemic in Europe, the widespread presence of helminth eggs in archaeological deposits indicates that helminths represented a considerable burden in past European populations. Prevalence of infection is a key epidemiological feature that would influence the elimination of endemic intestinal helminths, for example, low prevalence rates may have made it easier to eliminate these infections in Europe without the use of modern anthelminthic drugs. To determine historical prevalence rates we analysed 589 grave samples from 7 European sites dated between 680 and 1700 CE, identifying two soil transmitted nematodes (Ascaris spp. and Trichuris trichiura) at all locations, and two food derived cestodes (Diphyllobothrium latum and Taenia spp.) at 4 sites. The rates of nematode infection in the medieval populations (1.5 to 25.6% for T. trichiura; 9.3–42.9% for Ascaris spp.) were comparable to those reported within modern endemically infected populations. There was some evidence of higher levels of nematode infection in younger individuals but not at all sites. The genetic diversity of T. trichiura ITS-1 in single graves was variable but much lower than with communal medieval latrine deposits. The prevalence of food derived cestodes was much lower (1.0–9.9%) than the prevalence of nematodes. Interestingly, sites that contained Taenia spp. eggs also contained D. latum which may reflect local culinary practices. These data demonstrate the importance of helminth infections in Medieval Europe and provide a baseline for studies on the epidemiology of infection in historical and modern contexts. Since the prevalence of medieval STH infections mirror those in modern endemic countries the factors affecting STH decline in Europe may also inform modern intervention campaigns.
Relation Extraction From Biomedical and Clinical Text: Unified Multitask Learning Framework

Motivation: To minimize the accelerating amount of time invested on the biomedical literature search, numerous approaches for automated knowledge extraction have been proposed. Relation extraction is one such task where semantic relations between the entities are identified from the free text. In the biomedical domain, extraction of regulatory pathways, metabolic processes, adverse drug reaction or disease models necessitates knowledge from the individual relations, for example, physical or regulatory interactions between genes, proteins, drugs, chemical, disease or phenotype. Results: In this paper, we study the relation extraction task from three major biomedical and clinical tasks, namely drug-drug interaction, protein-protein interaction, and medical concept relation extraction. Towards this, we model the relation extraction problem in a multi-task learning (MTL)framework, and introduce for the first time the concept of structured self-attentive network complemented with the adversarial learning approach for the prediction of relationships from the biomedical and clinical text. The fundamental notion of MTL is to simultaneously learn multiple problems together by utilizing the concepts of the shared representation. Additionally, we also generate the highly efficient single task model which exploits the shortest dependency path embedding learned over the attentive gated recurrent unit to compare our proposed MTL models. The framework we propose significantly improves over all the baselines (deep learning techniques)and single-task models for predicting the relationships, without compromising on the performance of all the tasks.
Analysis of genotype sequence data reveals the origin and evolutionary separation of Hawaiian hoary bat populations.

We examine the genetic history and population status of Hawaiian Hoary bats (Lasiurus semotus), the most isolated bats on Earth, and their relationship to Northern Hoary bats (L. cinereus), through whole-genome analysis of single-nucleotide polymorphisms (SNPs) mapped to a de novo-assembled reference genome. Profiles of genomic diversity and divergence indicate that Hawaiian Hoary bats are distinct from Northern Hoary bats, and form a monophyletic group, indicating a single ancestral colonization event 1.34 Mya, followed by substantial divergence between islands beginning 0.51 Mya. Phylogenetic analysis indicates Maui is central to the radiation across the archipelago, with the southward expansion to Hawai'i and westward to O'ahu and Kaua'i. Because this endangered species is of conservation concern, a clearer understanding of the population genetic structure of this bat in the Hawaiian Islands is of timely importance.
Functionally distinct roles for T and Tbx6 during mouse development

ABSTRACT The mouse T-box transcription factors T and Tbx6 are co-expressed in the primitive streak and have unique domains of expression; T is expressed in the notochord, while Tbx6 is expressed in the presomitic mesoderm. T-box factors are related through a shared DNA binding domain, the T-domain, and can therefore bind to similar DNA sequences at least in vitro. We investigated the functional similarities and differences of T and Tbx6 DNA binding and transcriptional activity in vitro and their interaction genetically in vivo. We show that at one target, Dll1, the T-domains of T and Tbx6 have different affinities for the binding sites present in the mesoderm enhancer. We further show using in vitro assays that T and Tbx6 differentially affect transcription with Tbx6 activating expression tenfold higher than T, that T and Tbx6 can compete at target gene enhancers, and that this competition requires a functional DNA binding domain. Next, we addressed whether T and Tbx6 can compete in vivo. First, we generated embryos that express Tbx6 at greater than wild-type levels embryos and show that these embryos have short tails, resembling the T heterozygous phenotype. Next, using the dominant-negative TWis allele, we show that Tbx6+/− TWis/+ embryos share similarities with embryos homozygous for the Tbx6 hypomorphic allele rib-vertebrae, specifically fusions of several ribs and malformation of some vertebrae. Finally, we tested whether Tbx6 can functionally replace T using a knockin approach, which resulted in severe T null-like phenotypes in chimeric embryos generated with ES cells heterozygous for a Tbx6 knockin at the T locus. Altogether, our results of differences in affinity for DNA binding sites and transcriptional activity for T and Tbx6 provide a potential mechanism for the failure of Tbx6 to functionally replace T and possible competition phenotypes in vivo. Summary: Mouse Tbx6 fails to compensate for heterozygous loss of T; instead ectopic Tbx6 in the T expression-domain in knockin embryos generates T null-like phenotypes suggestive of competition.
A Remote-Controlled Robotic System with Safety Protection Strategy Based on Force-Sensing and Bending Feedback for Transcatheter Arterial Chemoembolization

Transcatheter arterial chemoembolization (TACE) is the common choice of non-open surgery for hepatocellular carcinoma (HCC) now. In this study, a simple TACE robotic system of 4-degree-of-freedom is proposed to get higher accuracy and stability of the surgery operation and reduce X-ray exposure time of the surgeons. The master–slave control strategy is adopted in the robotic system and a customized sigmoid function is designed to optimize the joystick control of the master–slave robotic control system. A force-sensing module is developed to sense the resistance of the guide wire in linear delivery motion and an auxiliary bending feedback method based on constraint pipe with a film sensor is proposed. With two force-sensing methods, the safety strategy of robotic motion with 9 different motion constraint coefficients is given and a human–computer interface is developed. The TACE robot would monitor the value of the force sensor and the analog voltage of the film sensor to adopt the corresponding motion constraint coefficient in every 10 ms. Vascular model experiments were performed to validate the robotic system, and the results showed that the safety strategy could improve the reliability of the operation with immediate speed constraint and avoid potential aggressive delivery.
Connected Mental Health: Systematic Mapping Study

Background Although mental health issues constitute an increasing global burden affecting a large number of people, the mental health care industry is still facing several care delivery barriers such as stigma, education, and cost. Connected mental health (CMH), which refers to the use of information and communication technologies in mental health care, can assist in overcoming these barriers. Objective The aim of this systematic mapping study is to provide an overview and a structured understanding of CMH literature available in the Scopus database. Methods A total of 289 selected publications were analyzed based on 8 classification criteria: publication year, publication source, research type, contribution type, empirical type, mental health issues, targeted cohort groups, and countries where the empirically evaluated studies were conducted. Results The results showed that there was an increasing interest in CMH publications; journals were the main publication channels of the selected papers; exploratory research was the dominant research type; advantages and challenges of the use of technology for mental health care were the most investigated subjects; most of the selected studies had not been evaluated empirically; depression and anxiety were the most addressed mental disorders; young people were the most targeted cohort groups in the selected publications; and Australia, followed by the United States, was the country where most empirically evaluated studies were conducted. Conclusions CMH is a promising research field to present novel approaches to assist in the management, treatment, and diagnosis of mental health issues that can help overcome existing mental health care delivery barriers. Future research should be shifted toward providing evidence-based studies to examine the effectiveness of CMH solutions and identify related issues.
Salicylic Acid and its Role in Systemic Resistance Induced by Pseudomonas fluorescens to Early Blight Disease of Tomato

Seventeen isolates of Pseudomonas fluo-rescens (Pf) were examined for growth promotion and the induction of systemic resistance against early blight disease of tomato. A noticeable in-crease in shoot and root length was observed in plants treated with P. fluorescens. However, the root development was reduced by a combination of P. fluorescens and Alternaria alternata (A. alter-nata). P. fluorescens isolates systemically induced resistance against early blight of tomato caused by A. alternata and reduced (approx.18–42%) the dis-ease significantly. All the isolates of P. fluorescens produced salicylic acid (SA) in King's B (KB) broth and induced its accumulation in tomato leaf within 24 h of bacterial inoculation. SA levels were signifi-cantly increased in plants treated with bacteria compared to the split control from one to five days following inoculation. Low SA concentration (0.1–0.5 mg/ml) did not inhibit mycelial growth of A. alternata in vitro, contrary to inhibition at high concentrations. The exogenously applied SA first accumulates in host tissues and induces resistance, however, endogenous SA accumulation in plant tissue is considered to be involved in induced sys-temic resistance to early blight disease of tomato caused by A. alternata.
Phonological and surface dyslexia in individuals with brain tumors: Performance pre‐, intra‐, immediately post‐surgery and at follow‐up

We address existing controversies regarding neuroanatomical substrates of reading‐aloud processes according to the dual‐route processing models, in this particular instance in a series of 49 individuals with brain tumors who performed several reading tasks of real‐time neuropsychological testing during surgery (low‐ to high‐grade cerebral neoplasms involving the left hemisphere). We explored how reading abilities in individuals with brain tumors evolve during and after surgery for a brain tumor, and we studied the reading performance in a sample of 33 individuals in a 4‐month follow‐up after surgery. Impaired reading performance was seen pre‐surgery in 7 individuals with brain tumors, intra‐surgery in 18 individuals, at immediate post‐surgery testing in 26 individuals, and at follow‐up in 5 individuals. We classified their reading disorders according to operational criteria for either phonological or surface dyslexia. Neuroimaging results are discussed within the theoretical framework of the dual‐route model of reading. Lesion‐mask subtraction analyses revealed that areas selectively related with phonological dyslexia were located—along with the left hemisphere dorsal stream—in the Rolandic operculum, the inferior frontal gyrus, the precentral gyrus, the supramarginal gyrus, the insula (and/or the underlying external capsule), and parts of the superior longitudinal fasciculus, whereas lesions related to surface dyslexia involved the ventral stream, that is, the left middle and inferior temporal gyrus and parts of the left inferior longitudinal fasciculus.
Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts

TNFα is the main proinflammatory cytokine implicated in the pathogenesis of neurodegenerative disorders, but it also modulates physiological functions in both the developing and adult brain. In this study, we investigated a potential direct role of TNFα in determining phenotypic changes of a recently established cellular model of human basal forebrain cholinergic neuroblasts isolated from the nucleus basalis of Meynert (hfNBMs). Exposing hfNBMs to TNFα reduced the expression of immature markers, such as nestin and β-tubulin III, and inhibited primary cilium formation. On the contrary, TNFα increased the expression of TNFα receptor TNFR2 and the mature neuron marker MAP2, also promoting neurite elongation. Moreover, TNFα affected nerve growth factor receptor expression. We also found that TNFα induced the expression of DNA-methylation enzymes and, accordingly, downregulated genes involved in neuronal development through epigenetic mechanisms, as demonstrated by methylome analysis. In summary, TNFα showed a dual role on hfNBMs phenotypic plasticity, exerting a negative influence on neurogenesis despite a positive effect on differentiation, through mechanisms that remain to be elucidated. Our results help to clarify the complexity of TNFα effects in human neurons and suggest that manipulation of TNFα signaling could provide a potential therapeutic approach against neurodegenerative disorders.
Exploring the Regulatory Potential of Long Non-Coding RNA in Feed Efficiency of Indicine Cattle

Long non-coding RNA (lncRNA) can regulate several aspects of gene expression, being associated with complex phenotypes in humans and livestock species. In taurine beef cattle, recent evidence points to the involvement of lncRNA in feed efficiency (FE), a proxy for increased productivity and sustainability. Here, we hypothesized specific regulatory roles of lncRNA in FE of indicine cattle. Using RNA-Seq data from the liver, muscle, hypothalamus, pituitary gland and adrenal gland from Nellore bulls with divergent FE, we submitted new transcripts to a series of filters to confidently predict lncRNA. Then, we identified lncRNA that were differentially expressed (DE) and/or key regulators of FE. Finally, we explored lncRNA genomic location and interactions with miRNA and mRNA to infer potential function. We were able to identify 126 relevant lncRNA for FE in Bos indicus, some with high homology to previously identified lncRNA in Bos taurus and some possible specific regulators of FE in indicine cattle. Moreover, lncRNA identified here were linked to previously described mechanisms related to FE in hypothalamus-pituitary-adrenal axis and are expected to help elucidate this complex phenotype. This study contributes to expanding the catalogue of lncRNA, particularly in indicine cattle, and identifies candidates for further studies in animal selection and management.
Self-Healing EPDM Rubbers with Highly Stable and Mechanically-Enhanced Urea-Formaldehyde (UF) Microcapsules Prepared by Multi-Step In Situ Polymerization

The mechanically-enhanced urea-formaldehyde (UF) microcapsules are developed through a multi-step in situ polymerization method. Optical microscope (OM) and field emission scanning electron microscope (FE-SEM) prove that the microcapsules, 147.4 μm in diameter with a shell thickness of 600 nm, are well-formed. From 1H-nuclear magnetic resonance (1H-NMR) analysis, we found that dicyclopentadiene (DCPD), a self-healing agent encapsulated by the microcapsules, occupies ca. 40.3 %(v/v) of the internal volume of a single capsule. These microcapsules are mixed with EPDM (ethylene-propylene-diene-monomer) and Grubbs’ catalyst via a solution mixing method, and universal testing machine (UTM) tests show that the composites with mechanically-enhanced microcapsules has ca. 47% higher toughness than the composites with conventionally prepared UF microcapsules, which is attributed to the improved mechanical stability of the microcapsule. When the EPDM/microcapsule rubber composites are notched, Fourier-transform infrared (FT-IR) spectroscopy shows that DCPD leaks from the broken microcapsule to the damaged site and flows to fill the notched valley, and self-heals as it is cured by Grubbs’ catalyst. The self-healing efficiency depends on the capsule concentration in the EPDM matrix. However, the self-healed EPDM/microcapsule rubber composite with over 15 wt% microcapsule shows an almost full recovery of the mechanical strength and 100% healing efficiency.
Nanoscale Visualization of Phase Transition in Melting of Sn–Bi Particles by In situ Hard X-ray Ptychographic Coherent Diffraction Imaging

Abstract The phase transition in the melting of Sn–Bi eutectic solder alloy particles was observed by in situ hard X-ray ptychographic coherent diffraction imaging with a pin-point heating system. Ptychographic diffraction patterns of micrometer-sized Sn–Bi particles were collected at temperatures from room temperature to 540 K. The projection images of each particle were reconstructed at a spatial resolution of 25 nm, showing differences in the phase shifts due to two crystal phases in the Sn–Bi alloy system and the Sn/Bi oxides at the surface. By quantitatively evaluating the Bi content, it became clear that the nonuniformity of the composition of Sn and Bi at the single-particle level exists when the particles are synthesized by centrifugal atomization.
Cucurbituril-Based Biomacromolecular Assemblies.

The construction of controlled biomacromolecular assemblies has become a thriving area of supramolecular chemistry. In this respect, cucurbiturils (CBs), a class of macrocyclic receptors having robust skeletons, hydrophobic cavities, and carbonyl-laced portals, have been drawn into the limelight because of their advantageous molecular recognition characteristics with a variety of biomacromolecules, including peptides, nucleic acids, and proteins. In this minireview, we focus on the impressive advances in CB-based biomacromolecular assemblies, such as biosensors and assays, the regulation of biochemical reactions, and the treatment of serious diseases. CB-promoted subcellular bioimaging has also been demonstrated in different organelles. The case studies presented herein demonstrate the numerous applications, from fundamental research to translational applications, of diverse CB-based supra/biomacromolecular architectures.
Effect of Removing Chocolate Milk on Milk and Nutrient Intake Among Urban Secondary School Students

Introduction Schools across the United States have removed sweetened, flavored milk from cafeterias to reduce students’ sugar consumption and improve their health. However, evidence on the impact of the removal is limited. We examined the effect of a policy that removed chocolate milk from secondary schools on students’ milk consumption and estimated milk-related nutrient intake. Methods We collected data on milk selection and consumption during 1 lunch period in 24 California public secondary schools pre-policy (N = 3,158 students in 2016) and post-policy (N = 2,966 students in 2018). Schools had a student population that was 38% Asian and 29% Latino, with 63% qualifying for free or reduced-price meals. We used linear mixed effects models to assess changes in milk selection and waste, and we estimated related changes in added sugars, calcium, protein, and vitamin D consumed from milk. Results The proportion of students selecting milk declined 13.6%, from 89.5% pre-policy to 75.9% post-policy (95% CI for difference, 10.8% tο 16.4%), but the proportion of milk wasted remained stable (37.1% vs 39.3%; 95% CI for difference, −0.2% to 4.6%). Although average per-student milk consumption declined by less than 1 ounce per student (from 4.8 oz to 3.8 oz; 95% CI for difference, −1.1 oz to −0.7 oz), we observed no significant reductions in average per-student intake of calcium, protein, or vitamin D from milk. Estimated added sugars from milk declined significantly, by 3.1 grams per student (95% CI, −3.2 g to −2.9 g). Conclusion Removing chocolate milk modestly reduced student milk consumption without compromising average intake of key milk-related nutrients, and consumption of added sugars from milk declined significantly. Secondary schools should consider removing chocolate milk to support healthy beverage consumption.