Miracle-dz/UniFAR-FTUs huggingface dataset:
Prospective study reveals a microbiome signature that predicts the occurrence of post-operative enterocolitis in Hirschsprung disease (HSCR) patients

ABSTRACT Hirschsprung disease (HSCR) is a birth defect with an approximate incidence of 1/5,000 live births, and up to one-third of HSCR patients develop Hirschsprung-associated enterocolitis (HAEC), the leading cause of HSCR-related death. Very little is known about the pathogenesis, prevention, and early diagnosis of HAEC. Here, we used a prospective study to investigate the enteric microbiome composition at the time of surgery as a predictor for developing postoperative HAEC. We identified a microbiome signature containing 21 operational taxonomic units (OTUs) that can potentially predict postoperative HAEC with ~85% accuracy. Furthermore, we identified exclusive breastfeeding as a novel protective factor for total HAEC (i.e., preoperative and postoperative HAEC combined). In addition, we discovered that breastfeeding was associated with a lowered risk for HAEC potentially mediated by modulating the gut microbiome composition characterized by a lower abundance of Gram-negative bacteria and lower LPS concentrations. In conclusion, modulating the gut microbiome by encouraging breastfeeding might prevent HAEC progression in HSCR patients.
Extracellular Vesicle–Mediated In Vitro Transcribed mRNA Delivery for Treatment of HER2+ Breast Cancer Xenografts in Mice by Prodrug CB1954 without General Toxicity

Prodrugs are harmless until activated by a bacterial or viral gene product; they constitute the basis of gene-delivered prodrug therapies called GDEPT, which can kill tumors without major side effects. Previously, we utilized the prodrug CNOB (C16H7CIN2O4; not clinically tested) and enzyme HChrR6 in GDEPT to generate the drug MCHB (C16H9CIN2O2) in tumors. Extracellular vesicles (EVs) were used for directed gene delivery and HChrR6 mRNA as gene. Here, the clinical transfer of this approach is enhanced by: (i) use of CB1954 (tretazicar) for which safe human dose is established; HChrR6 can activate this prodrug. (ii) EVs delivered in vitro transcribed (IVT) HChrR6 mRNA, eliminating the potentially harmful plasmid transfection of EV producer cells we utilized previously; this has not been done before. IVT mRNA loading of EVs required several steps. Naked mRNA being unstable, we ensured its prodrug activating functionality at each step. This was not possible using tretazicar itself; we relied instead on HChrR6′s ability to convert CNOB into MCHB, whose fluorescence is easily visualizable. HChrR6 mRNA-translated product's ability to generate fluorescence from CNOB vicariously indicated its competence for tretazicar activation. (iii) Systemic IVT mRNA–loaded EVs displaying an anti-HER2 single-chain variable fragment (“IVT EXO-DEPTs”) and tretazicar caused growth arrest of human HER2+ breast cancer xenografts in athymic mice. As this occurred without injury to other tissues, absence of off-target mRNA delivery is strongly indicated. Many cancer sites are not amenable for direct gene injection, but current GDEPTs require this. In circumventing this need, a major advance in GDEPT applicability has been accomplished.
Enhancer–gene maps in the human and zebrafish genomes using evolutionary linkage conservation

The spatiotemporal expression of genes is controlled by enhancer sequences that bind transcription factors. Identifying the target genes of enhancers remains difficult because enhancers regulate gene expression over long genomic distances. To address this, we used an evolutionary approach to build two genome-wide maps of enhancer-gene associations in the human and zebrafish genomes. Enhancers were identified using sequence conservation, and linked to their predicted target genes using PEGASUS, a bioinformatics method that relies on evolutionary conservation of synteny. The analysis of these maps revealed that the number of enhancers linked to a gene correlate with its expression breadth. Comparison of both maps identified hundreds of vertebrate ancestral regulatory relationships from which we could determine that enhancer-gene distances scale with genome size despite strong positional conservation. The two maps represent a resource for further studies, including the prioritisation of sequence variants in whole genome sequence of patients affected by genetic diseases.
Global Variation in Education Outcomes at Ages 5 to 19

Education produces far-reaching benefits to populations by improving health, increasing individual productivity and earnings, enhancing civic engagement, and facilitating economic and social intergenerational mobility (Hannum and Xie 2016; Montenegro and Patrinos 2014; OECD 2013c; Schultz 1961). In the aggregate, it enhances economic growth by contributing to technological change and innovation (Becker 1964; Mankiw, Romer, and Weil 1992; Mincer 1974; Solow 1956; Pradham and others 2016, chapter 30 of this volume). Education outcomes are affected by a number of factors. At the child or student level, nutrition, health, and interactions with parents and other adults affect brain development, emotional and psychological well-being, and the capacity to learn (Crookston and others 2013). At the school level, education quality is enhanced by school leadership, an orderly and safe environment, high expectations, positive reinforcement, regular assessment, constructive school-home relations, and opportunity to learn (OTL) (Sammons, Hillman, and Mortimore 1995). Education, health, and social policies can create an enabling environment and equalize opportunities for all students through resource allocation, monitoring and supervision, curriculum improvement, teacher management, policy toward the language of instruction, and interventions targeted to disadvantaged groups. Chudgar and Luschei’s (2009) study of 25 participating systems in international studies found that although family background affects outcomes more, schools are an important source of variation in student achievement in poor countries and can bridge the achievement gap. Definitions of age groupings and age-specific terminology used in the volume can be found in chapter 1 (Bundy and others 2017).
Expression, Purification, and Characterization of Anti-Zika virus Envelope Protein: Polyclonal and Chicken-Derived Single Chain Variable Fragment Antibodies

Zika virus (ZIKV) is a new and emerging virus that has caused outbreaks worldwide. The virus has been linked to congenital neurological malformations in neonates and Guillain–Barré syndrome in adults. Currently there are no effective vaccines available. As a result, there is a great need for ZIKV treatment. In this study, we developed single chain variable fragment (scFv) antibodies that target the ZIKV envelope protein using phage display technology. We first induced an immune response in white leghorn laying hens against the ZIKV envelope (E) protein. Chickens were immunized and polyclonal immunoglobulin yolk (IgY) antibodies were extracted from egg yolks. A high-level titer of anti-ZIKV_E IgY antibodies was detected using enzyme-linked immunosorbent assay (ELISA) after the third immunization. The titer persisted for at least 9 weeks. We constructed two antibody libraries that contained 5.3 × 106 and 4.5 × 106 transformants. After biopanning, an ELISA phage assay confirmed the enrichment of specific clones. We randomly selected 26 clones that expressed ZIKV scFv antibodies and classified them into two groups, short-linker and long-linker. Of these, four showed specific binding activities toward ZIKV_E proteins. These data suggest that the polyclonal and monoclonal scFv antibodies have the diagnostic or therapeutic potential for ZIKV.
Short-Term Exposure to Waterpipe/Hookah Smoke Triggers a Hyperactive Platelet Activation State and Increases the Risk of Thrombogenesis

Supplemental Digital Content is available in the text. Objective: Cardiovascular disease is a major public health problem. Among cardiovascular disease’s risk factors, tobacco smoking is considered the single most preventable cause of death, with thrombosis being the main mechanism of cardiovascular disease mortality in smokers. While tobacco smoking has been on the decline, the use of waterpipes/hookah has been rising, mainly due to the perception that they are less harmful than regular cigarettes. Strikingly, there are few studies on the negative effects of waterpipes on the cardiovascular system, and none regarding their direct contribution to thrombus formation. Approach and Results: We used a waterpipe whole-body exposure protocol that mimics real-life human exposure scenarios and investigated its effects, relative to clean air, on platelet function, hemostasis, and thrombogenesis. We found that waterpipe smoke (WPS)–exposed mice exhibited both shortened thrombus occlusion and bleeding times. Further, our results show that platelets from WPS-exposed mice are hyperactive, with enhanced agonist-induced aggregation, dense and α-granule secretion, αIIbβ3 integrin activation, phosphatidylserine expression, and platelet spreading, when compared with clean air–exposed platelets. Finally, at the molecular level, it was found that Akt (protein kinase B) and ERK (extracellular signal-regulated kinases) phosphorylation are enhanced in the WPS and in nicotine-treated platelets. Conclusions: Our findings demonstrate that WPS exposure directly modulates hemostasis and increases the risk of thrombosis and that this is mediated, in part, via a state of platelet hyperactivity. The negative health impact of WPS/hookah, therefore, should not be underestimated. Moreover, this study should also help in raising public awareness of the toxic effects of waterpipe/hookah.
Sky islands as foci for divergence of fig trees and their pollinators in southwest China

The dynamics of populations and their divergence over time have shaped current levels of biodiversity and in the case of the “sky islands” of mountainous southwest (SW) China have resulted in an area of exceptional botanical diversity. Ficus tikoua is a prostrate fig tree subendemic to the area that displays unique intraspecific diversity, producing figs typical of different pollination modes in different parts of its range. By combining climate models, genetic variation in populations of the tree's obligate fig wasp pollinators and distributions of the different plant phenotypes, we examined how this unusual situation may have developed. We identified three genetically distinct groups of a single Ceratosolen pollinator species that have largely parapatric distributions. The complex topography of the region contributed to genetic divergence among the pollinators by facilitating geographical isolation and providing refugia. Migration along elevations in response to climate oscillations further enhanced genetic differentiation of the three pollinator groups. Their distributions loosely correspond to the distributions of the functionally significant morphological differences in the male figs of their host plants, but postglacial expansion of one group has not been matched by spread of its associated plant phenotype, possibly due to a major river barrier. The results highlight how interplay between the complex topography of the “sky island” complex and climate change has shaped intraspecies differentiation and relationships between the plant and its pollinator. Similar processes may explain the exceptional botanical diversity of SW China.
The 4th and 112th Residues of Viral Capsid Cooperatively Modulate Capsid-CPSF6 Interactions of HIV-1

Binding of HIV-1 capsid (CA) to cleavage and polyadenylation specificity factor 6 (CPSF6) is hypothesized to provide a significant fitness advantage to in vivo viral replication, explaining why CA-CPSF6 interactions are strictly conserved in primate lentiviruses. We recently identified a Q4R mutation in CA after propagation of an interferon (IFN)-β-hypersensitive CA mutant, RGDA/Q112D (H87R, A88G, P90D, P93A and Q112D) virus, in IFN-β-treated cells. The Q4R substitution conferred significant IFN-β resistance to the RGDA/Q112D virus by affecting several properties of the virus, including the sensitivity to myxovirus resistance protein B (MxB), the kinetics of reverse transcription, and the initiation of uncoating. Notably, the Q4R substitution restored the CPSF6 interaction of the RGDA/Q112D virus. To better understand how the Q4R substitution modulated the CA-CPSF6 interaction, we generated a series of CA mutants harboring substitutions at the 4th and 112th residues. In contrast to the effect in the RGDA/Q112D background, the Q4R substitution diminished CA-CPSF6 interaction in an otherwise wild-type virus. Our genetic and structural analyses revealed that while either the Q4R or Q112D substitution impaired CA-CPSF6 interaction, the combination of these substitutions restored this interaction. These results suggest that the 4th and 112th residues in HIV-1 CA cooperatively modulate CA-CPSF6 interactions, further highlighting the tremendous levels of plasticity in primate lentivirus CA, which is one of the barriers to antiretroviral therapy in HIV-1-infected individuals.
Problems in Colorectal Stapler Use

Introduction Pneumatosis intestinalis (PI) is a broad term that describes the presence of gas in the bowel walls. The colon is affected in 36% of cases. Eosinophilic colitis (EC) is a rare form of colitis that is characterized mainly by eosinophilia in blood and affected tissues. Although eosinophilic colitis responds well to conservative treatment, yet the association of PI could be an indication of emergent surgery. Case Presentation A 48-year-old female patient with a history of recurrent attacks of abdominal pain and distention that did not respond to conservative treatment, was hospitalized and investigated thoroughly. The result of abdominal computed tomography (CT) scan indicated the presence of pneumatosis coli. Based on the findings of the CT scan, colonoscopy was done revealing hyperemic and hypertrophied mucosa at the hepatic flexure, from which multiple punch biopsies were taken for histopathological assessment. The pathological examination of these biopsies detected a diffuse active colitis of moderate severity with excess eosinophils (10 - 15/HPF), which is consistent with the diagnosis of EC. The patient improved dramatically on fluid therapy and antibiotics with complete resolution of pneumatosis coli in the follow up CT scan. However, the patient developed a severe relapse of symptoms once oral intake was resumed and this time the conservative treatment failed to improve the condition. Surgery was indicated and laparoscopic right hemicolectomy with primary anastomosis and covering ileostomy was done. The patient was free of symptoms after the operation and her postoperative course was uneventful with no complications encountered. Conclusions Eosinophilic colitis usually has a good prognosis, however its association with pneumatosis coli could reflect a serious damage to the colonic mucosa. Although eosinophilic colitis responds well to medical treatment, yet in certain cases where clinical signs are evident and pneumatosis coli is present, surgical intervention is the treatment of choice.
Early-Life Intervention Using Fecal Microbiota Combined with Probiotics Promotes Gut Microbiota Maturation, Regulates Immune System Development, and Alleviates Weaning Stress in Piglets

Previous studies have suggested that immune system development and weaning stress are closely related to the maturation of gut microbiota. The early-life period is a “window of opportunity” for microbial colonization, which potentially has a critical impact on the development of the immune system. Fecal microbiota transplantation (FMT) and probiotics are often used to regulate gut microbial colonization. This study aims to test whether early intervention with FMT using fecal microbiota from gestation sows combined with Clostridium butyricum and Saccharomyces boulardii (FMT-CS) administration could promote the maturation of gut microbiota and development of immune system in piglets. Piglets were assigned to control (n = 84) and FMT-CS treatment (n = 106), which were treated with placebo and bacterial suspension during the first three days after birth, respectively. By 16S rRNA gene sequencing, we found that FMT-CS increased the α-diversity and reduced the unweighted UniFrac distances of the OTU community. Besides, FMT-CS increased the relative abundance of beneficial bacteria, while decreasing that of opportunistic pathogens. FMT-CS also enhanced the relative abundance of genes related to cofactors and vitamin, energy, and amino acid metabolisms during the early-life period. ELISA analysis revealed that FMT-CS gave rise to the plasma concentrations of IL-23, IL-17, and IL-22, as well as the plasma levels of anti-M.hyo and anti-PCV2 antibodies. Furthermore, the FMT-CS-treated piglets showed decreases in inflammation levels and oxidative stress injury, and improvement of intestinal barrier function after weaning as well. Taken together, our results suggest that early-life intervention with FMT-CS could promote the development of innate and adaptive immune system and vaccine efficacy, and subsequently alleviate weaning stress through promoting the maturation of gut microbiota in piglets.
Clinical state tracking in serious mental illness through computational analysis of speech

Individuals with serious mental illness experience changes in their clinical states over time that are difficult to assess and that result in increased disease burden and care utilization. It is not known if features derived from speech can serve as a transdiagnostic marker of these clinical states. This study evaluates the feasibility of collecting speech samples from people with serious mental illness and explores the potential utility for tracking changes in clinical state over time. Patients (n = 47) were recruited from a community-based mental health clinic with diagnoses of bipolar disorder, major depressive disorder, schizophrenia or schizoaffective disorder. Patients used an interactive voice response system for at least 4 months to provide speech samples. Clinic providers (n = 13) reviewed responses and provided global assessment ratings. We computed features of speech and used machine learning to create models of outcome measures trained using either population data or an individual’s own data over time. The system was feasible to use, recording 1101 phone calls and 117 hours of speech. Most (92%) of the patients agreed that it was easy to use. The individually-trained models demonstrated the highest correlation with provider ratings (rho = 0.78, p<0.001). Population-level models demonstrated statistically significant correlations with provider global assessment ratings (rho = 0.44, p<0.001), future provider ratings (rho = 0.33, p<0.05), BASIS-24 summary score, depression sub score, and self-harm sub score (rho = 0.25,0.25, and 0.28 respectively; p<0.05), and the SF-12 mental health sub score (rho = 0.25, p<0.05), but not with other BASIS-24 or SF-12 sub scores. This study brings together longitudinal collection of objective behavioral markers along with a transdiagnostic, personalized approach for tracking of mental health clinical state in a community-based clinical setting.
Molecular flexibility of DNA as a key determinant of RAD51 recruitment

The timely activation of homologous recombination is essential for the maintenance of genome stability, in which the RAD51 recombinase plays a central role. Biochemically, human RAD51 polymerises faster on single‐stranded DNA (ssDNA) compared to double‐stranded DNA (dsDNA), raising a key conceptual question: how does it discriminate between them? In this study, we tackled this problem by systematically assessing RAD51 binding kinetics on ssDNA and dsDNA differing in length and flexibility using surface plasmon resonance. By directly fitting a mechanistic model to our experimental data, we demonstrate that the RAD51 polymerisation rate positively correlates with the flexibility of DNA. Once the RAD51‐DNA complex is formed, however, RAD51 remains stably bound independent of DNA flexibility, but rapidly dissociates from flexible DNA when RAD51 self‐association is perturbed. This model presents a new general framework suggesting that the flexibility of DNA, which may increase locally as a result of DNA damage, plays an important role in rapidly recruiting repair factors that multimerise at sites of DNA damage.
Metoprolol joint Lingguizhugantang in treatment of coronary heart disease arrhythmias effect analysis

Objective To further analyze metoprolol Lingguizhugantang effect on coronary heart disease arrhythmias.Methods A total of 128 cases were selected from January 2011 to January 2012 in Quzhou city people's Hospital of coronary heart disease patients with cardiac arrhythmias,and these patients are numbered,singular in the observation group,double the number for the control group,each group of 64 patients.Control group were given using metoprolol as treatment drug,and the observation group in the control group based on the joint lingguizhu gantang for treatment,treatment for 4 weeks.And finally the curative effect were compared.Results Control group,the overall effective rate was 60.94%,and observe group's overall efficiency was up to 96.12%(P 0.05);observation group of patients in the treatment process,atrial premature beats,premature ventricular contractions and atrioventricular junctionthe num ber of premature beats,etc.to be significantly less than the control group(P 0.05),the results of these two sets of data are statistically significant.Conclusion The effect of metoprolol lingguizhu gantang in which the treatment of coronary heart disease arrhythmia was significantly higher than the simple use of metoprolol,which has a good refer ence for the clinical treatment of coronary heart disease,arrhythmia.
The Use of the Index of Ideality of Correlation to Build Up Models for Bioconcentration Factor

We establish a QSPR analysis for the bioconcentration factor of 851 heterogeneous structural compounds. Linear models are proposed via two different approaches: i. the optimal descriptor method implemented in CORAL, and ii. multivariable linear regressions on the best molecular descriptors found with the Replacement Method on 44,216 structural descriptors. Such variables are derived with different freely available softwares, such as PaDEL, PyDescriptor, Mold2, QuBiLs‐MAS and ISIDA/Fragmentor. The same validation set is employed in order to compare the predictive performance between the so‐obtained CORAL and RM based models. Finally, the comparison of several models for the bioconcentration factor confirms the ability of the so‐called index of ideality of correlation to be a criterion of predictive potential in Quantitative Structure‐Property Relationships.
A sensitive amperometric detection of neurotransmitter acetylcholine using carbon dot‐modified carbon paste electrode

Acetylcholine is a neurotransmitter, which is located at the intersections of the nerve and muscles in the lymph nodes of the internal organs motor systems and in various parts of the central nervous system. A decrease of acetylcholine in brain is associated with Alzheimer‘s disease. That is why it is an important agent for this disease. In this study, a bienzymatic biosensor system with acetylcholine esterase and choline oxidase was prepared with carbon paste electrode modified with carbon nano Dot‐(3‐Aminopropyl) triethoxysilane (CDs‐APTES) for determination of the amount of acetylcholine. Acetylcholine esterase and choline oxidase enzymes were immobilized onto a modified carbon paste electrode by cross‐linking with glutaraldehyde. Determination of acetylcholine was carried out by the oxidation of enzymatically produced H2O2 at 0.4 V versus Ag/AgCl. The effect of temperature, pH, and substrate concentration on the acetylcholine response of the prepared biosensor was investigated. In addition, the optimum CDs‐APTES amount, the linear operating range of the biosensor, and the interference effect were also investigated.