Epigenetics and the timing of neuronal differentiation.

Epigenetic regulation of the genome is required for cell-type differentiation during organismal development and is especially important to generate the panoply of specialized cell types that comprise the brain. Here, we review how progressive changes in the chromatin landscape, both in neural progenitors and in postmitotic neurons, orchestrate the timing of gene expression programs that underlie first neurogenesis and then functional neuronal maturation. We discuss how disease-associated mutations in chromatin regulators can change brain composition by impairing the timing of neurogenesis.

Brain-wide correspondence of neuronal epigenomics and distant projections.

Single-cell analyses parse the brain's billions of neurons into thousands of 'cell-type' clusters residing in different brain structures. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain.

Single-cell DNA methylation and 3D genome architecture in the human brain.

Delineating the gene-regulatory programs underlying complex cell types is fundamental for understanding brain function in health and disease. Here, we comprehensively examined human brain cell epigenomes by probing DNA methylation and chromatin conformation at single-cell resolution in 517 thousand cells (399 thousand neurons and 118 thousand non-neurons) from 46 regions of three adult male brains. We identified 188 cell types and characterized their molecular signatures.

Human Immune Cell Epigenomic Signatures in Response to Infectious Diseases and Chemical Exposures.

Variations in DNA methylation patterns in human tissues have been linked to various environmental exposures and infections. Here, we identified the DNA methylation signatures associated with multiple exposures in nine major immune cell types derived from peripheral blood mononuclear cells (PBMCs) at single-cell resolution. We performed methylome sequencing on 111,180 immune cells obtained from 112 individuals who were exposed to different viruses, bacteria, or chemicals.

Mutations of the histone linker H1-4 in neurodevelopmental disorders and functional characterization of neurons expressing C-terminus frameshift mutant H1.4.

Rahman syndrome (RMNS) is a rare genetic disorder characterized by mild to severe intellectual disability, hypotonia, anxiety, autism spectrum disorder, vision problems, bone abnormalities and dysmorphic facies. RMNS is caused by de novo heterozygous mutations in the histone linker gene H1-4; however, mechanisms underlying impaired neurodevelopment in RMNS are not understood. All reported mutations associated with RMNS in H1-4 are small insertions or deletions that create a shared frameshift, resulting in a H1.

A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex.

Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain. With the proliferation of multi-omics datasets, a major challenge is to validate and integrate results into a biological understanding of cell-type organization. Here we generated transcriptomes and epigenomes from more than 500,000 individual cells in the mouse primary motor cortex, a structure that has an evolutionarily conserved role in locomotion.

Epigenomic diversity of cortical projection neurons in the mouse brain.

Neuronal cell types are classically defined by their molecular properties, anatomy and functions. Although recent advances in single-cell genomics have led to high-resolution molecular characterization of cell type diversity in the brain, neuronal cell types are often studied out of the context of their anatomical properties. To improve our understanding of the relationship between molecular and anatomical features that define cortical neurons, here we combined retrograde labelling with single-nucleus DNA methylation sequencing to link neural epigenomic properties to projections.

Comparative cellular analysis of motor cortex in human, marmoset and mouse.

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species.

DNA methylation atlas of the mouse brain at single-cell resolution.

Mammalian brain cells show remarkable diversity in gene expression, anatomy and function, yet the regulatory DNA landscape underlying this extensive heterogeneity is poorly understood. Here we carry out a comprehensive assessment of the epigenomes of mouse brain cell types by applying single-nucleus DNA methylation sequencing to profile 103,982 nuclei (including 95,815 neurons and 8,167 non-neuronal cells) from 45 regions of the mouse cortex, hippocampus, striatum, pallidum and olfactory areas. We identified 161 cell clusters with distinct spatial locations and projection targets.

Single nucleus multi-omics regulatory landscape of the murine pituitary.

To provide a multi-omics resource and investigate transcriptional regulatory mechanisms, we profile the transcriptome, chromatin accessibility, and methylation status of over 70,000 single nuclei (sn) from adult mouse pituitaries. Paired snRNAseq and snATACseq datasets from individual animals highlight a continuum between developmental epigenetically-encoded cell types and transcriptionally-determined transient cell states. Co-accessibility analysis-based identification of a putative Fshb cis-regulatory domain that overlaps the fertility-linked rs11031006 human polymorphism, followed by experimental validation illustrate the use of this resource for hypothesis generation.

Cinacalcet: A Viable Therapeutic Option for Primary Hyperparathyroidism in the Elderly.

Objective: Parathyroidectomy is usually curative in primary hyperparathyroidism (PHPT), but its utility would be limited if patients are elderly who may either refuse surgery or may have advanced frailty and multimorbidity. We evaluated the effectiveness of cinacalcet, an allosteric modulator of calcium-sensing receptor in PHPT in an elderly cohort of patients.

Methods: A prospective analysis of 29 patients who had PHPT and despite fulfilling criteria for surgery were unable to undergo parathyroidectomy either due to self-refusal ( = 12) or due to advanced multimorbidity ( = 17).

SEASONAL VARIATION OF VITAMIN D AND SERUM THYROTROPIN LEVELS AND ITS RELATIONSHIP IN A EUTHYROID CAUCASIAN POPULATION.

Objective: It is unclear whether seasonal variations in vitamin D concentrations affect the hypothalamo-pituitary-thyroid axis. We investigated the seasonal variability of vitamin D and serum thyrotropin (TSH) levels and their interrelationship.

Methods: Analysis of 401 patients referred with nonspecific symptoms of tiredness who had simultaneous measurements of 25-hydroxyvitamin D3 (25[OH]D3) and thyroid function.

Weekly Intramuscular Injection of Levothyroxine following Myxoedema: A Practical Solution to an Old Crisis.

An 82-year-old female with known hypothyroidism was admitted to hospital after being found on the floor. On examination, she was unkempt, confused, bradycardic, hypothermic, and barely arousable. Initial biochemistry revealed a thyroid stimulating hormone (TSH) of >100 mU/L and free thyroxine (FT4) level of 1.

Assay validation for the assessment of adipogenesis of multipotential stromal cells--a direct comparison of four different methods.

Background Aims: Mesenchymal stromal cells (MSCs) are regenerative and immuno-privileged cells that are used for both tissue regeneration and treatment of severe inflammation-related disease. For quality control of manufactured MSC batches in regard to mature fat cell contamination, a quantitative method for measuring adipogenesis is needed.

Methods: Four previously proposed methods were validated with the use of bone marrow (BM) MSCs during a 21-day in vitro assay.

A case of traumatic rupture of the distal oesophagus: the importance of early diagnosis.

We present a case of blunt traumatic rupture of the distal oesophagus successfully managed following early diagnosis and treatment. This is a rare cause of oesophageal perforation. We present the evidence that early diagnosis of ruptured oesophagus leads to reduced mortality and fewer complications.

Radiotherapy for rectal carcinoma: an unusual cause of foreskin phimosis.

Phimosis of the foreskin secondary to radiotherapy for a pelvic malignancy has not been previously described in the world literature. However, as radiotherapy is ever more widely used in the treatment of various pelvic malignancies, it is important to ensure that this complication is prevented by the use of appropriate penile shielding.

Surgery results in significant improvement in growth in children with Crohn's disease refractory to medical therapy.

Inflammatory bowel disease (IBD) in children can cause significant impairment in linear growth, and delay in pubertal onset. The aim of this study was to assess the impact of surgery on linear growth in children with Crohn's disease (CD) who were resistant to medical therapy, and had documented evidence of growth impairment. We performed a retrospective study on eight consecutive patients with refractory disease who had attended the paediatric IBD clinic.

Role of the neutrophil in septic shock and the adult respiratory distress syndrome.

The adult respiratory distress syndrome (ARDS) is a serious complication of many medical and surgical conditions, most of which do not involve direct pulmonary injury. In surgical practice, septic shock has long been recognised as an important cause of ARDS and it presents many management challenges. Endotoxin released from dead and dying Gram-negative bacteria induces a generalised inflammatory response that results in multiple organ dysfunction, the lung being just one target of this injurious process.