snu-aidas/HVMap-dataset huggingface dataset:
ALS-FUS pathology revisited: singleton FUS mutations and an unusual case with both a FUS and TARDBP mutation

INTRODUCTION Mutations in the FUS gene have been shown to be a rare cause of amyotrophic lateral sclerosis (ALS-FUS) and whilst well documented clinically and genetically there have been relatively few neuropathological studies. Recent work suggested a possible correlation between pathological features such as frequency of basophilic inclusions in neurons and rate of clinical decline, other studies have revealed a discrepancy between the upper motor neuron features detected clinically and the associated pathology. The purpose of this study was to describe the pathological features associated with more recently discovered FUS mutations and reinvestigate those with well recognised mutations in an attempt to correlate the pathology with mutation and/or clinical phenotype. The brains and spinal cords of seven cases of ALS-FUS were examined neuropathologically, including cases with the newly described p. K510E mutation and a case with both a known p. P525L mutation in the FUS gene and a truncating p. Y374X mutation in the TARDBP gene. RESULTS The neuropathology in all cases revealed basophilic and FUS inclusions in the cord. The density and type of inclusions varied markedly between cases, but did not allow a clear correlation with clinical progression. Only one case showed significant motor cortical pathology despite the upper motor neuron clinical features being evident in 4 patients. The case with both a FUS and TARDBP mutation revealed FUS positive inclusions but no TDP-43 pathology. Instead there were unusual p62 positive, FUS negative neuronal and glial inclusions as well as dot-like neurites. CONCLUSIONS The study confirms cases of ALS-FUS to be mainly a lower motor neuron disease and to have pathology that does not appear to neatly correlate with clinical features or genetics. Furthermore, the case with both a FUS and TARDBP mutation reveals an intriguing pathological profile which at least in part involves a very unusual staining pattern for the ubiquitin-binding protein p62.
A systematic review of parent and clinician views and perceptions that influence prescribing decisions in relation to acute childhood infections in primary care

OBJECTIVES To investigate the views of parents, clinicians, and children pertaining to prescribing decisions for acute childhood infection in primary care. METHODS A systematic review of qualitative studies. Meta-ethnographic methods were used, with data drawn from the primary studies in an interpretive analysis. RESULTS A total of 15 studies met the inclusion criteria. The literature was dominated by concerns about antibiotic over-prescription. Children's views were not reported. Clinicians prescribed antibiotics when they felt pressured by parents or others (e.g. employers) to do so, when they believed there was a clear clinical indication, but also when they felt uncertain of clinical or social outcomes they prescribed "just in case". Parents wanted antibiotics when they felt they would improve the current illness, and when they felt pressure from daycare providers or employers. Clinicians avoided antibiotics when they were concerned about adverse reactions or drug resistance, when certain they were not indicated, and when there was no perceived pressure from parents. Parents also wished to avoid adverse effects of antibiotics, and did not want antibiotics when they would not relieve current symptoms. Some parents preferred to avoid medication altogether. Within paediatric consultations, parents sought a medical evaluation and decision. Primary care clinicians want satisfied parents and short consultations. CONCLUSIONS Antibiotic prescriptions for childhood infections in primary care often result from "just in case" prescribing. These findings suggest that interventions which reduce clinician uncertainty regarding social or clinical outcomes and provide strategies to meet parents' needs within a short consultation are most likely to reduce antibiotic prescribing.
Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey

OBJECTIVES To carry out a further survey of archived appendix samples to understand better the differences between existing estimates of the prevalence of subclinical infection with prions after the bovine spongiform encephalopathy epizootic and to see whether a broader birth cohort was affected, and to understand better the implications for the management of blood and blood products and for the handling of surgical instruments. DESIGN Irreversibly unlinked and anonymised large scale survey of archived appendix samples. SETTING Archived appendix samples from the pathology departments of 41 UK hospitals participating in the earlier survey, and additional hospitals in regions with lower levels of participation in that survey. SAMPLE 32,441 archived appendix samples fixed in formalin and embedded in paraffin and tested for the presence of abnormal prion protein (PrP). RESULTS Of the 32,441 appendix samples 16 were positive for abnormal PrP, indicating an overall prevalence of 493 per million population (95% confidence interval 282 to 801 per million). The prevalence in those born in 1941-60 (733 per million, 269 to 1596 per million) did not differ significantly from those born between 1961 and 1985 (412 per million, 198 to 758 per million) and was similar in both sexes and across the three broad geographical areas sampled. Genetic testing of the positive specimens for the genotype at PRNP codon 129 revealed a high proportion that were valine homozygous compared with the frequency in the normal population, and in stark contrast with confirmed clinical cases of vCJD, all of which were methionine homozygous at PRNP codon 129. CONCLUSIONS This study corroborates previous studies and suggests a high prevalence of infection with abnormal PrP, indicating vCJD carrier status in the population compared with the 177 vCJD cases to date. These findings have important implications for the management of blood and blood products and for the handling of surgical instruments.
LincRNA-p21 suppresses target mRNA translation.

Mammalian long intergenic noncoding RNAs (lincRNAs) are best known for modulating transcription. Here we report a posttranscriptional function for lincRNA-p21 as a modulator of translation. Association of the RNA-binding protein HuR with lincRNA-p21 favored the recruitment of let-7/Ago2 to lincRNA-p21, leading to lower lincRNA-p21 stability. Under reduced HuR levels, lincRNA-p21 accumulated in human cervical carcinoma HeLa cells, increasing its association with JUNB and CTNNB1 mRNAs and selectively lowering their translation. With elevated HuR, lincRNA-p21 levels declined, which in turn derepressed JunB and β-catenin translation and increased the levels of these proteins. We propose that HuR controls translation of a subset of target mRNAs by influencing lincRNA-p21 levels. Our findings uncover a role for lincRNA as a posttranscriptional inhibitor of translation.
Large intestine-targeted nanoparticle-releasing oral vaccine to control genitorectal viral infection

Both rectal and vaginal mucosal surfaces serve as transmission routes for pathogenic microorganisms. Vaccination through large intestinal mucosa, previously proven protective for both of these mucosal sites in animal studies, can be achieved successfully by direct intracolorectal (i.c.r.) administration, but this route is clinically impractical. Oral vaccine delivery seems preferable but runs the risk of the vaccine's destruction in the upper gastrointestinal tract. Therefore, we designed a large intestine-targeted oral delivery with pH-dependent microparticles containing vaccine nanoparticles, which induced colorectal immunity in mice comparably to colorectal vaccination and protected against rectal and vaginal viral challenge. Conversely, vaccine targeted to the small intestine induced only small intestinal immunity and provided no rectal or vaginal protection, demonstrating functional compartmentalization within the gut mucosal immune system. Therefore, using this oral vaccine delivery system to target the large intestine, but not the small intestine, may represent a feasible new strategy for immune protection of rectal and vaginal mucosa.
Prognostic Value of Late Gadolinium Enhancement Cardiovascular Magnetic Resonance in Cardiac Amyloidosis

BACKGROUND The prognosis and treatment of the 2 main types of cardiac amyloidosis, immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis, are substantially influenced by cardiac involvement. Cardiovascular magnetic resonance with late gadolinium enhancement (LGE) is a reference standard for the diagnosis of cardiac amyloidosis, but its potential for stratifying risk is unknown. METHODS AND RESULTS Two hundred fifty prospectively recruited subjects, 122 patients with ATTR amyloid, 9 asymptomatic mutation carriers, and 119 patients with AL amyloidosis, underwent LGE cardiovascular magnetic resonance. Subjects were followed up for a mean of 24±13 months. LGE was performed with phase-sensitive inversion recovery (PSIR) and without (magnitude only). These were compared with extracellular volume measured with T1 mapping. PSIR was superior to magnitude-only inversion recovery LGE because PSIR always nulled the tissue (blood or myocardium) with the longest T1 (least gadolinium). LGE was classified into 3 patterns: none, subendocardial, and transmural, which were associated with increasing amyloid burden as defined by extracellular volume (P<0.0001), with transitions from none to subendocardial LGE at an extracellular volume of 0.40 to 0.43 (AL) and 0.39 to 0.40 (ATTR) and to transmural at 0.48 to 0.55 (AL) and 0.47 to 0.59 (ATTR). Sixty-seven patients (27%) died. Transmural LGE predicted death (hazard ratio, 5.4; 95% confidence interval, 2.1-13.7; P<0.0001) and remained independent after adjustment for N-terminal pro-brain natriuretic peptide, ejection fraction, stroke volume index, E/E', and left ventricular mass index (hazard ratio, 4.1; 95% confidence interval, 1.3-13.1; P<0.05). CONCLUSIONS There is a continuum of cardiac involvement in systemic AL and ATTR amyloidosis. Transmural LGE is determined reliably by PSIR and represents advanced cardiac amyloidosis. The PSIR technique provides incremental information on outcome even after adjustment for known prognostic factors.
Metabolomics study of the therapeutic mechanism of Schisandra Chinensis lignans in diet-induced hyperlipidemia mice

BACKGROUND Schisandra, a globally distributed plant, has been widely applied for the treatment of diseases such as hyperlipidemia, fatty liver and obesity in China. In the present work, a rapid resolution liquid chromatography coupled with quadruple-time-of-flight mass spectrometry (RRLC-Q-TOF-MS)-based metabolomics was conducted to investigate the intervention effect of Schisandra chinensis lignans (SCL) on hyperlipidemia mice induced by high-fat diet (HFD). METHODS Hyperlipidemia mice were orally administered with SCL (100 mg/kg) once a day for 4 weeks. Serum biochemistry assay of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) was conducted to confirm the treatment of SCL on lipid regulation. Metabolomics analysis on serum samples was carried out, and principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were carried out for the pattern recognition and characteristic metabolites identification. The relative levels of critical regulatory factors of liver lipid metabolism, sterol regulatory element-binding proteins (SREBPs) and its related gene expressions were measured by quantitative real-time polymerase chain reaction (RT-PCR) for investigating the underlying mechanism. RESULTS Oral administration of SCL significantly decreased the serum levels of TC, TG and LDL-c and increased the serum level of HDL-c in the hyperlipidemia mice, and no effect of SCL on blood lipid levels was observed in control mice. Serum samples were scattered in the PCA scores plots in response to the control, HFD and SCL group. Totally, thirteen biomarkers were identified and nine of them were recovered to the normal levels after SCL treatment. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, the anti-hyperlipidemia mechanisms of SCL may be involved in the following metabolic pathways: tricarboxylic acid (TCA) cycle, synthesis of ketone body and cholesterol, choline metabolism and fatty acid metabolism. Meanwhile, SCL significantly inhibited the mRNA expression level of hepatic lipogenesis genes such as SREBP-1c, fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), and decreased the mRNA expression of liver X receptor α (LXRα). Moreover, SCL also significantly decreased the expression level of SREBP-2 and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in the liver of hyperlipidemia mice. CONCLUSION Anti-hyperlipidemia effect of SCL was confirmed by both serum biochemistry and metabolomics analysis. The mechanism may be related to the down-regulation of LXRα/SREBP-1c/FAS/ACC and SREBP2/HMGCR signaling pathways.
Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells.

TET family enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. Here, we show that Tet1 and Tet2 are Oct4-regulated enzymes that together sustain 5hmC in mouse embryonic stem cells (ESCs) and are induced concomitantly with 5hmC during reprogramming of fibroblasts to induced pluripotent stem cells. ESCs depleted of Tet1 by RNAi show diminished expression of the Nodal antagonist Lefty1 and display hyperactive Nodal signaling and skewed differentiation into the endoderm-mesoderm lineage in embryoid bodies in vitro. In Fgf4- and heparin-supplemented culture conditions, Tet1-depleted ESCs activate the trophoblast stem cell lineage determinant Elf5 and can colonize the placenta in midgestation embryo chimeras. Consistent with these findings, Tet1-depleted ESCs form aggressive hemorrhagic teratomas with increased endoderm, reduced neuroectoderm, and ectopic appearance of trophoblastic giant cells. Thus, 5hmC is an epigenetic modification associated with the pluripotent state, and Tet1 functions to regulate the lineage differentiation potential of ESCs.
Polycomb Associates Genome-wide with a Specific RNA Polymerase II Variant, and Regulates Metabolic Genes in ESCs

Polycomb repressor complexes (PRCs) are important chromatin modifiers fundamentally implicated in pluripotency and cancer. Polycomb silencing in embryonic stem cells (ESCs) can be accompanied by active chromatin and primed RNA polymerase II (RNAPII), but the relationship between PRCs and RNAPII remains unclear genome-wide. We mapped PRC repression markers and four RNAPII states in ESCs using ChIP-seq, and found that PRC targets exhibit a range of RNAPII variants. First, developmental PRC targets are bound by unproductive RNAPII (S5p(+)S7p(-)S2p(-)) genome-wide. Sequential ChIP, Ring1B depletion, and genome-wide correlations show that PRCs and RNAPII-S5p physically bind to the same chromatin and functionally synergize. Second, we identify a cohort of genes marked by PRC and elongating RNAPII (S5p(+)S7p(+)S2p(+)); they produce mRNA and protein, and their expression increases upon PRC1 knockdown. We show that this group of PRC targets switches between active and PRC-repressed states within the ESC population, and that many have roles in metabolism.
Cerebral palsy among term and postterm births.

CONTEXT Although preterm delivery is a well-established risk factor for cerebral palsy (CP), preterm deliveries contribute only a minority of affected infants. There is little information on the relation of CP risk to gestational age in the term range, where most CP occurs. OBJECTIVE To determine whether timing of birth in the term and postterm period is associated with risk of CP. DESIGN, SETTING, AND PARTICIPANTS Population-based follow-up study using the Medical Birth Registry of Norway to identify 1,682,441 singleton children born in the years 1967-2001 with a gestational age of 37 through 44 weeks and no congenital anomalies. The cohort was followed up through 2005 by linkage to other national registries. MAIN OUTCOME MEASURES Absolute and relative risk of CP for children surviving to at least 4 years of age. RESULTS Of the cohort of term and postterm children, 1938 were registered with CP in the National Insurance Scheme. Infants born at 40 weeks had the lowest risk of CP, with a prevalence of 0.99/1000 (95% confidence interval [CI], 0.90-1.08). Risk for CP was higher with earlier or later delivery, with a prevalence at 37 weeks of 1.91/1000 (95% CI, 1.58-2.25) and a relative risk (RR) of 1.9 (95% CI, 1.6-2.4), a prevalence at 38 weeks of 1.25/1000 (95% CI, 1.07-1.42) and an RR of 1.3 (95% CI, 1.1-1.6), a prevalence at 42 weeks of 1.36/1000 (95% CI, 1.19-1.53) and an RR of 1.4 (95% CI, 1.2-1.6), and a prevalence after 42 weeks of 1.44 (95% CI, 1.15-1.72) and an RR of 1.4 (95% CI, 1.1-1.8). These associations were even stronger in a subset with gestational age based on ultrasound measurements: at 37 weeks the prevalence was 1.17/1000 (95% CI, 0.30-2.04) and the relative risk was 3.7 (95% CI, 1.5-9.1). At 42 weeks the prevalence was 0.85/1000 (95% CI, 0.33-1.38) and the relative risk was 2.4 (95% CI, 1.1-5.3). Adjustment for infant sex, maternal age, and various socioeconomic measures had little effect. CONCLUSION Compared with delivery at 40 weeks' gestation, delivery at 37 or 38 weeks or at 42 weeks or later was associated with an increased risk of CP.
53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks

Defective DNA repair by homologous recombination (HR) is thought to be a major contributor to tumorigenesis in individuals carrying Brca1 mutations. Here, we show that DNA breaks in Brca1-deficient cells are aberrantly joined into complex chromosome rearrangements by a process dependent on the nonhomologous end-joining (NHEJ) factors 53BP1 and DNA ligase 4. Loss of 53BP1 alleviates hypersensitivity of Brca1 mutant cells to PARP inhibition and restores error-free repair by HR. Mechanistically, 53BP1 deletion promotes ATM-dependent processing of broken DNA ends to produce recombinogenic single-stranded DNA competent for HR. In contrast, Lig4 deficiency does not rescue the HR defect in Brca1 mutant cells but prevents the joining of chromatid breaks into chromosome rearrangements. Our results illustrate that HR and NHEJ compete to process DNA breaks that arise during DNA replication and that shifting the balance between these pathways can be exploited to selectively protect or kill cells harboring Brca1 mutations.
The genetics of Mexico recapitulates Native American substructure and affects biomedical traits

Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide.
Induced pluripotent stem cells in Alzheimer’s disease: applications for disease modeling and cell-replacement therapy

Alzheimer's disease (AD) is the most common cause of dementia in those over the age of 65. While a numerous of disease-causing genes and risk factors have been identified, the exact etiological mechanisms of AD are not yet completely understood, due to the inability to test theoretical hypotheses on non-postmortem and patient-specific research systems. The use of recently developed and optimized induced pluripotent stem cells (iPSCs) technology may provide a promising platform to create reliable models, not only for better understanding the etiopathological process of AD, but also for efficient anti-AD drugs screening. More importantly, human-sourced iPSCs may also provide a beneficial tool for cell-replacement therapy against AD. Although considerable progress has been achieved, a number of key challenges still require to be addressed in iPSCs research, including the identification of robust disease phenotypes in AD modeling and the clinical availabilities of iPSCs-based cell-replacement therapy in human. In this review, we highlight recent progresses of iPSCs research and discuss the translational challenges of AD patients-derived iPSCs in disease modeling and cell-replacement therapy.
Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase–dependent manner

Nitrite (NO(2)(-)), previously viewed as a physiologically inert metabolite and biomarker of the endogenous vasodilator NO, was recently identified as an important biological NO reservoir in vasculature and tissues, where it contributes to hypoxic signaling, vasodilation, and cytoprotection after ischemia-reperfusion injury. Reduction of nitrite to NO may occur enzymatically at low pH and oxygen tension by deoxyhemoglobin, deoxymyoglobin, xanthine oxidase, mitochondrial complexes, or NO synthase (NOS). We show that nitrite treatment, in sharp contrast with the worsening effect of NOS inhibition, significantly attenuates hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction, and mortality in a mouse shock model induced by a lethal tumor necrosis factor challenge. Mechanistically, nitrite-dependent protection was not associated with inhibition of mitochondrial complex I activity, as previously demonstrated for ischemia-reperfusion, but was largely abolished in mice deficient for the soluble guanylate cyclase (sGC) alpha1 subunit, one of the principal intracellular NO receptors and signal transducers in the cardiovasculature. Nitrite could also provide protection against toxicity induced by Gram-negative lipopolysaccharide, although higher doses were required. In conclusion, we show that nitrite can protect against toxicity in shock via sGC-dependent signaling, which may include hypoxic vasodilation necessary to maintain microcirculation and organ function, and cardioprotection.