Phospho-regulation of ASCL1-mediated chromatin opening during cellular reprogramming.

The proneural transcription factor ASCL1 regulates neurogenesis and drives somatic cell reprogramming into neurons. However, not all cell types can be reprogrammed by ASCL1, raising the questions of what provides competence and how we can overcome barriers to enable directed differentiation. Here, we investigate how levels of ASCL1 and its phosphorylation modulate its activity over progressive lineage restriction of mouse embryonic stem cells.

Strand-resolved mutagenicity of DNA damage and repair.

DNA base damage is a major source of oncogenic mutations. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair.

Cows' Milk Allergy-Associated Constipation: When to Look for It? A Narrative Review.

Constipation is a very common disorder, mostly functional in nature, that may persist for years in up to 35-52% of children. Food allergy prevalence, severity and persistence are increasing over time, and cows' milk protein is the commonest food allergen recognised to affect gastrointestinal motility in children. There is mounting evidence of the role of cows' milk (CM) allergy (CMA) in children with constipation.

Pervasive lesion segregation shapes cancer genome evolution.

Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion. Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations.

Evidence-based systematic review of cognitive rehabilitation, emotional, and family treatment studies for children with acquired brain injury literature: From 2006 to 2017.

This paper updates guidelines for effective treatments of children with specific types of acquired brain injury (ABI) published in 2007 with more recent evidence. A systematic search was conducted for articles published from 2006 to 2017. Full manuscripts describing treatments of children (post-birth to 18) with acquired brain injury were included if study was published in peer-reviewed journals and written in English.

Revisiting the mystery of recent stratospheric temperature trends.

Simulated stratospheric temperatures over the period 1979-2016 in models from the Chemistry-Climate Model Initiative (CCMI) are compared with recently updated and extended satellite observations. The multi-model mean global temperature trends over 1979- 2005 are -0.88 ± 0.

A study of dysphagia symptoms and esophageal body function in children undergoing anti-reflux surgery.

Background: The role of high-resolution esophageal impedance manometry (HRIM) for establishing risk for dysphagia after anti-reflux surgery is unclear. We conducted a prospective study of children with primary gastroesophageal reflux (GER) disease, for whom symptoms of dysphagia were determined pre-operatively and then post-operatively and we examined for features that may predict post-operative dysphagia.

Methods: Thirteen children (aged 6.

Mutational landscape of a chemically-induced mouse model of liver cancer.

Background & Aims: Carcinogen-induced mouse models of liver cancer are used extensively to study the pathogenesis of the disease and are critical for validating candidate therapeutics. These models can recapitulate molecular and histological features of human disease. However, it is not known if the genomic alterations driving these mouse tumour genomes are comparable to those found in human tumours.

Paediatric constipation: An approach and evidence-based treatment regimen.

Background: Constipation affects 5-30% of children and is responsible for 3% of primary care visits. General practitioners (GPs) are frequently the first medical encounter for concerned parents regarding their child's bowel habit.

Objective: The aim of this article is to review the assessment and management of children with constipation to empower GPs to initiate treatment and know when to refer to a paediatrician.

Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution.

Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution. Here we measure allele-specific transcription factor binding occupancy of three liver-specific transcription factors between crosses of two inbred mouse strains to elucidate the regulatory mechanisms underlying transcription factor binding variations in mammals. Our results highlight the pre-eminence of cis-acting variants on transcription factor occupancy divergence.

Aging increases cell-to-cell transcriptional variability upon immune stimulation.

Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated naïve and effector memory CD4 T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong up-regulation of a core activation program, coupled with a decrease in cell-to-cell variability.

Successful transmission and transcriptional deployment of a human chromosome via mouse male meiosis.

Most human aneuploidies originate maternally, due in part to the presence of highly stringent checkpoints during male meiosis. Indeed, male sterility is common among aneuploid mice used to study chromosomal abnormalities, and male germline transmission of exogenous DNA has been rarely reported. Here we show that, despite aberrant testis architecture, males of the aneuploid Tc1 mouse strain produce viable sperm and transmit human chromosome 21 to create aneuploid offspring.

DMP1-CDG (CDG1e) with Significant Gastrointestinal Manifestations; Phenotype and Genotype Expansion.

The literature describes eight cases of mutations in the DPM1 gene generating DMP1-CDG, causing similar phenotype of early onset seizures, microcephaly and developmental delay. Investigations of these patients revealed associated abnormal findings on brain imaging, elevated CK, abnormal clotting factors and mildly deranged serum transaminases. We describe the ninth case of DMP1-CDG, whose clinical presentation includes severe gastrointestinal involvement, i.

Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy.

The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma.

Prolonged colonic manometry in children with defecatory disorders.

Objectives: Colonic manometry is a test used in the evaluation of children with defecation disorders unresponsive to conventional treatment. The most commonly reported protocol in pediatrics consists of a study that lasts approximately 4 hours. Given the wide physiological variations in colonic motility throughout the day, longer observation may detect clinically relevant information.

Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma.

The c-Jun N-terminal protein kinase (JNK) and its two direct activators, namely the mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) and MKK7, constitute a signaling node frequently mutated in human pancreatic ductal adenocarcinoma (PDAC). Here we demonstrate the cooperative interaction of endogenous expression of Kras(G12D) with loss-of-function mutations in mkk4 or both, mkk4 and mkk7 genes in the pancreas. More specifically, impaired JNK signaling in a subpopulation of Pdx1-expressing cells dramatically accelerated the appearance of Kras(G12D)-induced acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasias, which rapidly progressed to invasive PDAC within 10 weeks of age.

Solid-state vs water-perfused catheters to measure colonic high-amplitude propagating contractions.

Background:   Solid-state (SS) manometry catheters with portable data loggers offer many potential advantages over traditional water-perfused (WP) systems, such as prolonged recordings in a more physiologic ambulatory setting and the lack of risk for water overload. The use of SS catheters has not been evaluated in comparison with perfused catheters in children. This study aims to compare data provided by SS and WP catheters in children undergoing colonic manometry studies.

Ability of commonly used prediction equations to predict resting energy expenditure in children with inflammatory bowel disease.

Background: Paediatric onset inflammatory bowel disease (IBD) may cause alterations in energy requirements and invalidate the use of standard prediction equations. Our aim was to evaluate four commonly used prediction equations for resting energy expenditure (REE) in children with IBD.

Methods: Sixty-three children had repeated measurements of REE as part of a longitudinal research study yielding a total of 243 measurements.

Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults.

Background: Gastroesophageal reflux disease (GORD) is said to be the causative factor in up to 41% of adults with chronic cough. Treatment for GORD includes conservative measures (diet manipulation), pharmaceutical therapy (motility or prokinetic agents, H(2)-antagonist and proton pump inhibitors (PPI)) and fundoplication.

Objectives: To evaluate the efficacy of GORD treatment on chronic cough in children and adults with GORD and prolonged cough that is not related to an underlying respiratory disease, i.

Colonic hyperactivity results in frequent fecal soiling in a subset of children after surgery for Hirschsprung disease.

Background And Aim: Fecal soiling is a challenging problem in some children after pull-through surgery for Hirschsprung disease (HSCR). The prevailing perception is that soiling results from overflow incontinence; however, its treatment with laxatives yields mixed results. Colonic manometry studies are reported to be normal in most patients in this population.

An objective study of acid reflux and cough in children using an ambulatory pHmetry-cough logger.

Objective: There are no objective ambulatory studies on the temporal relationship between reflux and cough in children. Commercial pHmetry loggers have slow capture rates (0.25 Hz) that limit objective quantification of reflux and cough.

Quality of life in children with Crohn disease.

Objectives: : Quality of life (QOL) is reportedly poor in children with Crohn disease (CD) but improves with increasing disease duration. This article aims to detail QOL in a cohort of Australian children with CD in relation to disease duration, disease activity, and treatment.

Materials And Methods: : QOL, assessed using the IMPACT-III questionnaire, and disease activity measures, assessed using the Pediatric Crohn's Disease Activity Index (PCDAI), were available in 41 children with CD.

Bone health in children with inflammatory bowel disease: adjusting for bone age.

Objectives: Clinical results of bone mineral density for children with inflammatory bowel disease are commonly reported using reference data for chronological age. It is known that these children, particularly those with Crohn disease, experience delayed growth and maturation. Therefore, it is more appropriate to compare clinical results with bone age rather than chronological age.

Interobserver variability in antroduodenal manometry.

Interobserver variability affects investigations involving assessment of complex visual data, such as histopathology, radiology and motility. This study assessed interobserver variation for interpretation of antroduodenal manometry (ADM), as this has not been previously investigated. Thirty-five ADM recordings from children aged 0.

Resting energy expenditure in children with inflammatory bowel disease.

Objectives: There is controversy in the literature regarding the effect of inflammatory bowel disease (IBD) on resting energy expenditure (REE). In many cases this may have resulted from inappropriate adjustment of REE measurements to account for differences in body composition. This article considers how to appropriately adjust measurements of REE for differences in body composition between individuals with IBD.