Interplay between CTCF-binding and CTCF-lacking regulatory elements in generating an architectural stripe at the Igh locus.

Three-dimensional genome organization orchestrates recombination and transcription of immunoglobulin heavy chain (Igh) genes. The structure of wild-type (WT) alleles includes a prominent architectural stripe that extends from a cluster of CTCF binding elements at the 3' end of the locus (3'CBE), suggesting interactions of this end with sequences throughout the 2 Mb Igh TAD. Here we elucidate interplay between regulatory elements located in the 3'Igh domain (260 kb) that impact the stripe.

Studying Mitogen-Independent Proliferation in Murine B Cells.

The prevailing dogma of the cell cycle posits that a mitogenic signal is required at the end of each mitosis for cells to progress through the next G1. This textbook model is based mostly on experiments with fibroblast cultures. Burnet's clonal selection theory states that selected B and T cells expand rapidly to initiate immune response.

The Psu protein of phage satellite P4 inhibits transcription termination factor ρ by forced hyper-oligomerization.

Many bacteriophages modulate host transcription to favor expression of their own genomes. Phage satellite P4 polarity suppression protein, Psu, a building block of the viral capsid, inhibits hexameric transcription termination factor, ρ, by presently unknown mechanisms. Our cryogenic electron microscopy structures of ρ-Psu complexes show that Psu dimers clamp two inactive, open ρ rings and promote their expansion to higher-oligomeric states.

DNA binding of an RNA helicase bacterial transcription terminator.

The bacterial transcription terminator Rho is a hexameric ATP-dependent RNA helicase that dislodges elongating RNA polymerases.  It has an N-terminal primary RNA binding site (PBS) on each subunit and a C-terminal secondary RNA binding site at the central channel. Here, we show that Rho also binds to linear longer double-stranded DNAs (dsDNA) and the circular plasmids non-specifically using its PBS.

Functionally important components of the transcription elongation complex involved in Rho-dependent termination.

Bacterial transcription terminator, Rho is an RNA (Ribonucleic Acid)-dependent ATPase that terminates transcription. Several structures of pretermination complexes of the Rho-transcription elongation complex (EC) revealed a static picture of components of the EC that come close to the nascent RNA-bound Rho, where many of the residues of EC reside ≤10 Å from the Rho residues. However, the in vitro-formed Rho-EC complexes do not reveal the in vivo Rho-EC dynamic interaction patterns during the termination process.

Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study.

Background: Physical activity is essential for maintaining muscle mitochondrial function and aerobic capacity. The molecular mechanisms underlying such protective effects are incompletely understood, in part because it is difficult to separate the effects of disease status and physical activity. We explored the association of human skeletal muscle transcriptomic with four measures of energetics and mitochondria oxidative capacity in healthy individuals.

YY1-mediated enhancer-promoter communication in the immunoglobulin μ locus is regulated by MSL/MOF recruitment.

The rearrangement and expression of the immunoglobulin μ heavy chain (Igh) gene require communication of the intragenic Eμ and 3' regulatory region (RR) enhancers with the variable (V) gene promoter. Eμ binding of the transcription factor YY1 has been implicated in enhancer-promoter communication, but the YY1 protein network remains obscure. By analyzing the comprehensive proteome of the 1-kb Eμ wild-type enhancer and that of Eμ lacking the YY1 binding site, we identified the male-specific lethal (MSL)/MOF complex as a component of the YY1 protein network.

A Cross-Sectional Study on Motor and Sensory Nerve Functions in Women Newly Diagnosed and Untreated for Hypothyroidism in a Tribal Area of Odisha, India.

Altered levels of thyroid hormones can impact various body systems, including the nervous system. Hypothyroidism may disrupt nerve conduction due to pathophysiological changes associated with hormone deficiency. The tribal population, characterized by distinct lifestyles and dietary habits, may experience unique influences on their growth and development.

RelA-mediated signaling connects adaptation to chronic cardiomyocyte stress with myocardial and systemic inflammation in the ADCY8 model of accelerated aging.

Mice with cardiac-specific overexpression of adenylyl cyclase (AC) type 8 (TG) are under a constant state of severe myocardial stress. They have a remarkable ability to adapt to this stress, but they eventually develop accelerated cardiac aging and experience reduced longevity. We have previously demonstrated through bioinformatics that constitutive adenylyl cyclase activation in TG mice is associated with the activation of inflammation-related signaling pathways.

Unraveling the Tcrb interactome.

In this issue of JEM, Allyn et al. (https://doi.org/10.

Aging and Inflammation.

Aging can be conceptualized as the progressive disequilibrium between stochastic damage accumulation and resilience mechanisms that continuously repair that damage, which eventually cause the development of chronic disease, frailty, and death. The immune system is at the forefront of these resilience mechanisms. Indeed, aging is associated with persistent activation of the immune system, witnessed by a high circulating level of inflammatory markers and activation of immune cells in the circulation and in tissue, a condition called "inflammaging.

Peptides designed from a bacteriophage capsid protein function as synthetic transcription repressors.

The bacteriophage capsid protein, Psu (polarity suppression), inhibits the bacterial transcription terminator, Rho. In an effort to find nontraditional antibacterial agents, we previously designed peptides from the Psu C terminus that function as inhibitors of Rho. Here, we demonstrated that these peptides have positive surface-charge densities, and they downregulate many genes in Escherichia coli.

Cardiomyocyte-specific adenylyl cyclase type-8 overexpression induces activation of RelA together with myocardial and systemic inflammation.

Background: Mice with cardiac-specific overexpression of adenylyl cyclase (AC) type 8 (TG ) are under a constant state of severe myocardial stress. They have a remarkable ability to adapt to this stress, but they eventually develop accelerated cardiac aging and experience reduced longevity.

Results: Here we demonstrate that activation of ACVIII in cardiomyocytes results in cell-autonomous RelA-mediated NF-κB signaling.

Epigenetic signature of human immune aging in the GESTALT study.

Age-associated DNA methylation in blood cells convey information on health status. However, the mechanisms that drive these changes in circulating cells and their relationships to gene regulation are unknown. We identified age-associated DNA methylation sites in six purified blood-borne immune cell types (naive B, naive CD4 and CD8 T cells, granulocytes, monocytes, and NK cells) collected from healthy individuals interspersed over a wide age range.

NF-κB subunits direct kinetically distinct transcriptional cascades in antigen receptor-activated B cells.

The nuclear factor kappa B (NF-κB) family of transcription factors orchestrates signal-induced gene expression in diverse cell types. Cellular responses to NF-κB activation are regulated at the level of cell and signal specificity, as well as differential use of family members (subunit specificity). Here we used time-dependent multi-omics to investigate the selective functions of Rel and RelA, two closely related NF-κB proteins, in primary B lymphocytes activated via the B cell receptor.

Cross-sectional analysis of healthy individuals across decades: Aging signatures across multiple physiological compartments.

The study of age-related biomarkers from different biofluids and tissues within the same individual might provide a more comprehensive understanding of age-related changes within and between compartments as these changes are likely highly interconnected. Understanding age-related differences by compartments may shed light on the mechanism of their reciprocal interactions, which may contribute to the phenotypic manifestations of aging. To study such possible interactions, we carried out a targeted metabolomic analysis of plasma, skeletal muscle, and urine collected from healthy participants, age 22-92 years, and identified 92, 34, and 35 age-associated metabolites, respectively.

Whole-genome methylation analysis of aging human tissues identifies age-related changes in developmental and neurological pathways.

Age-associated changes in the DNA methylation state can be used to assess the pace of aging. However, it is not understood what mechanisms drive these changes and whether these changes affect the development of aging phenotypes and the aging process in general. This study was aimed at gaining a more comprehensive understanding of aging-related methylation changes across the whole genome, and relating these changes to biological functions.

A novel nucleic acid-binding protein, Gp49, from mycobacteriophage with mycobactericidal activity has the potential to be a therapeutic agent.

The mycobacteriophages encode unique proteins that are potent to be therapeutic agents. We screened several clones with mycobactericidal properties from a genomic library of mycobacteriophages. Here we report the properties of one such clone coding the gene product, Gp49, of the phage Che12.

Transcription factor TFII-I fine tunes innate properties of B lymphocytes.

The ubiquitously expressed transcription factor TFII-I is a multifunctional protein with pleiotropic roles in gene regulation. TFII-I associated polymorphisms are implicated in Sjögren's syndrome and Lupus in humans and, germline deletion of the gene in mice leads to embryonic lethality. Here we report a unique role for TFII-I in homeostasis of innate properties of B lymphocytes.

Aging exacerbates the brain inflammatory micro-environment contributing to α-synuclein pathology and functional deficits in a mouse model of DLB/PD.

Background: Although ɑ-synuclein (ɑ-syn) spreading in age-related neurodegenerative diseases such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) has been extensively investigated, the role of aging in the manifestation of disease remains unclear.

Methods: We explored the role of aging and inflammation in the pathogenesis of synucleinopathies in a mouse model of DLB/PD initiated by intrastriatal injection of ɑ-syn preformed fibrils (pff).

Results: We found that aged mice showed more extensive accumulation of ɑ-syn in selected brain regions and behavioral deficits that were associated with greater infiltration of T cells and microgliosis.