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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. Transcription factor binding differences linked to cis -acting variants generally exhibit additive inheritance, while those linked to trans -acting variants are most often dominantly inherited. Cis -acting variants lead to local coordination of transcription factor occupancies that decay with distance; distal coordination is also observed and may be modulated by long-range chromatin contacts. Our results reveal the regulatory mechanisms that interplay to drive transcription factor occupancy, chromatin state, and gene expression in complex mammalian cell states. “Variation in the noncoding regulatory sequences in the genome plays important roles in human disease and evolution. Here, the authors use F1 mouse hybrids to shed light on the regulatory mechanisms mediating transcription factor binding, chromatin state and gene expression in mammalian cells.”

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. Discussion: In the absence of organic aetiology, childhood constipation is almost always functional and often due to painful bowel movements that prompt the child to withhold stool. It is important to initiate a clear management plan for the family, as what is an easily treatable condition can escalate into a vicious cycle of pain if not addressed early. The medical approach should consider organic disease, the use of appropriate toileting habits, and dietary modifications. Laxatives are often required to re-establish regular, painless defaecation.

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. In these offspring, we mapped transcription, transcriptional initiation, enhancer activity, non-methylated DNA, and transcription factor binding in adult tissues. Remarkably, when compared with mice derived from female passage of human chromosome 21, the chromatin condensation during spermatogenesis and the extensive epigenetic reprogramming specific to male germline transmission resulted in almost indistinguishable patterns of transcriptional deployment. Our results reveal an unexpected tolerance of aneuploidy during mammalian spermatogenesis, and the surprisingly robust ability of mouse developmental machinery to accurately deploy an exogenous chromosome, regardless of germline transmission.

IN Western Europe and the United States approximately 1 in 12 women develop breast cancer. A small proportion of breast cancer cases, in particular those arising at a young age, are attributable to a highly penetrant, autosomal dominant predisposition to the disease. The breast cancer susceptibility gene, BRCA2 , was recently localized to chromosome 13q12-q13. Here we report the identification of a gene in which we have detected six different germline mutations in breast cancer families that are likely to be due to BRCA2 . Each mutation causes serious disruption to the open reading frame of the transcriptional unit. The results indicate that this is the BRCA2 gene.

BackgroundPaediatric 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.MethodsSixty-three children had repeated measurements of REE as part of a longitudinal research study yielding a total of 243 measurements. These were compared with predicted REE from Schofield, Oxford, FAO/WHO/UNU, and Harris-Benedict equations using the Bland-Altman method.ResultsMean (±SD) age of the patients was 14.2 (2.4) years. Mean measured REE was 1566 (336) kcal per day compared with 1491 (236), 1441 (255), 1481 (232), and 1435 (212) kcal per day calculated from Schofield, Oxford, FAO/WHO/UNU, and Harris-Benedict, respectively. While the Schofield equation demonstrated the least difference between measured and predicted REE, it, along with the other equations tested, did not perform uniformly across all subjects, indicating greater errors at either end of the spectrum of energy expenditure. Smaller differences were found for all prediction equations for Crohn's disease compared with ulcerative colitis.ConclusionsOf the commonly used equations, the equation of Schofield should be used in pediatric patients with IBD when measured values are not able to be obtained. (Inflamm Bowel Dis 2010;)

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. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues.

DNA base damage is a major source of oncogenic mutations 1 . Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation 2 . Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication 3 , 4 , we observe identical fidelity and damage tolerance for both strands. For small alkylation adducts of DNA, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky UV-induced adducts 5 . The accumulation of multiple distinct mutations at the site of persistent lesions provides the means to quantify the relative efficiency of repair processes genome wide and at single-base resolution. At multiple scales, we show DNA damage-induced mutations are largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can actively drive oncogenic mutagenesis by corrupting the fidelity of nucleotide excision repair. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance and repair of DNA damage, thereby shaping cancer genome evolution. How strand-asymmetric processes such as replication and transcription interact with DNA damage to drive mechanisms of repair and mutagenesis is explored.

Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion 1 , 2 . 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. We characterize this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multiallelic and combinatorial genetic diversity. The phasing of lesions enables accurate measurement of strand-biased repair processes, quantification of oncogenic selection and fine mapping of sister-chromatid-exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes. Mutagenic lesions such as those that give rise to cancer frequently segregate—unrepaired—during cell division, resulting in phasing of multiple alleles across generations of daughter cells and consequent tumour heterogeneity.

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. With this narrative review, we aim to provide clinicians with an updated and critical overview of food allergy-associated constipation. We searched Embase, Medline and the Cochrane Library, using keywords related to the topic. Only reviews and studies including children aged 0–17 years that were published in English were considered. Constipation has been reported in 4.6% of infants with CMA; the prevalence of food allergy underlying chronic constipation in children resistant to conventional treatment and presenting to tertiary clinics ranges between 28% and 78%. The identification of predisposing risk factors and of a specific phenotype of food allergy-induced constipation remains elusive. No allergic tests, radiological or motility investigations achieve sufficient sensitivity and specificity to screen children for CMA-related constipation. A 4-week cows’ milk protein (CMP) elimination diet may be considered for children with chronic constipation resistant to conventional treatment and who lack alarm sign/symptoms of organic diseases. In subjects with ameliorated symptoms on CMP elimination, the diagnosis of CMA should be confirmed by a food challenge to avoid an unnecessary protracted diet.

Abstract Disclosure: F.N. Connor-Recio: None. J. Colón Castellano: None. Immunoglobulin-G4-related thyroid disease (IgG4-RTD) is a medically treatable disease and quick diagnosis is imperative as rapid progression of the disease can result in unnecessary surgery. IgG4-RTD is a condition that associates thyroid diseases with a spectrum of IgG4-related disease (IgG4-RD). Four subcategories of IgG4-RTD have so far been identified: Riedel thyroiditis (RT), fibrosing variant of Hashimoto thyroiditis (FVHT), IgG4-related Hashimoto thyroiditis, and Graves’ disease with elevated IgG4 levels. The pathogenesis of IgG4-RTD involves genetic factors, antigen-antibody reactions, and allergic phenomena, but remains poorly understood. Due to insufficient awareness of this clinical entity, the prevalence of IgG4-RTD is likely to be underestimated. This is a 47-year-old male with history of recurrent Graves’ disease that has reached remission twice with methimazole, Hepatitis C infection s/p 8 weeks of ledipasvir/sofosbuvir, chronic uncomplicated pancreatitis of unknown etiology. The patient presented to endocrine clinics as follow up referring pressure-like chest pain associated with palpitations mostly at rest of 1-2 min duration that self-resolved and started around one month ago. While physically active, felt more agitated but denied chest pain. Also reported dry and itchy eyes that had been worsening and unintentional weight loss. The patient described these symptoms like when he was first diagnosed with Graves’ disease. Vital signs were essentially normal except for tachycardia. Physical exam remarkable for goiter without tenderness to palpation, bilateral gynecomastia, adequate hair distribution, no peripheral edema, deep tendon reflexes with normal relaxation phase, no exophthalmos nor conjunctival injection or stare. Pertinent laboratories included elevated IgG4 of 154.3 mg/dL (normal 4-86 mg/dL), suppressed TSH of <0.005 uIU/mL (normal 0.460-4.980 uIU/mL) and elevated TSI at 416% (normal <=140%). Patient was subsequently oriented about definitive treatment alternatives such as thyroidectomy and radioblation but opted for medical therapy. In addition, he was oriented about the use of Rituximab together with methimazole to increase the probability of remission in context of IgG4-RTD, however he refused.This case further illustrates an association between IgG4-RTD with Graves’ disease. The pathogenesis is still unclear, and precise diagnostic criteria are not yet defined. Studies have shown a higher prevalence of thyroid eye disease in these patients. Physicians should consider the possibility of IgG4-RTD in a patient with recurrent Graves’ disease as recognizing it promptly can be crucial in evaluation and management for other IgG4-RTD. Furthermore, recognition of this association might lead to development of new therapeutic approaches for example use of Rituximab in combination with anti-thyroid drugs to induce remission. Presentation: Monday, July 14, 2025