Coexpression of Nuclear Receptors and Histone Methylation Modifying Genes in the Testis: Implications for Endocrine Disruptor Modes of Action

BACKGROUND: Endocrine disruptor chemicals elicit adverse health effects by perturbing nuclear receptor signalling systems. It has been speculated that these compounds may also perturb epigenetic mechanisms and thus contribute to the early origin of adult onset disease. We hypothesised that histone methylation may be a component of the epigenome that is susceptible to perturbation. We used coexpression analysis of publicly available data to investigate the combinatorial actions of nuclear receptors and genes involved in histone methylation in normal testis and when faced with endocrine disruptor compounds. METHODOLOGY/PRINCIPAL FINDINGS: The expression patterns of a set of genes were profiled across testis tissue in human, rat and mouse, plus control and exposed samples from four toxicity experiments in the rat. Our results indicate that histone methylation events are a more general component of nuclear receptor mediated transcriptional regulation in the testis than previously appreciated. Coexpression patterns support the role of a gatekeeper mechanism involving the histone methylation modifiers Kdm1, Prdm2, and Ehmt1 and indicate that this mechanism is a common determinant of transcriptional integrity for genes critical to diverse physiological endpoints relevant to endocrine disruption. Coexpression patterns following exposure to vinclozolin and dibutyl phthalate suggest that coactivity of the demethylase Kdm1 in particular warrants further investigation in relation to endocrine disruptor mode of action. CONCLUSIONS/SIGNIFICANCE: This study provides proof of concept that a bioinformatics approach that profiles genes related to a specific hypothesis across multiple biological settings can provide powerful insight into coregulatory activity that would be difficult to discern at an individual experiment level or by traditional differential expression analysis methods

Structural basis for the recognition and cleavage of histone H3 by cathepsin L

Proteolysis of eukaryotic histone tails has emerged as an important factor in the modulation of cell-cycle progression and cellular differentiation. The recruitment of lysosomal cathepsin L to the nucleus where it mediates proteolysis of the mouse histone H3 tail has been described recently. Here, we report the three-dimensional crystal structures of a mature, inactive mutant of human cathepsin L alone and in complex with a peptide derived from histone H3. Canonical substrate–cathepsin L interactions are observed in the complex between the protease and the histone H3 peptide. Systematic analysis of the impact of posttranslational modifications at histone H3 on substrate selectivity suggests cathepsin L to be highly accommodating of all modified peptides. This is the first report of cathepsin L–histone H3 interaction and the first structural description of cathepsin L in complex with a substrate

Differential diagnosis of parapharyngeal abscess with multisystem inflammatory syndrome in children associated with COVID-19

The pandemic of the new coronavirus infection (COVID-19) has identified new diagnostic and medical tasks before different doc-tors. As observations show, children have the flow of infection easier than adults. However, in some cases, COVID-19 in children proceeds extremely difficult, with fever and multisystem inflammation, possibly requiring treatment in the resuscitation depart-ment. In domestic practice, the term “Multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19” is used to indicate the disease. Among the local symptoms of MIS are inflammations of the skin and mucous membranes, as well as var-ious lymphadenopathy. The article presents the results of our clinic’s observation of 205 patients with MIS for the period from May 2020 to May 2021. In some patients, the clinical manifestations of MIS-C required differential diagnosis with parapharyngeal abscesses (PPA). For this purpose, the children were consulted by an otorhinolaryngologist and a CT scan of the neck with contrast enhancement was performed. Despite the striking clinical manifestations similar to PPA, in no case was a pharyngeal abscess re-vealed. Both of these diseases are potentially fatal if treatment is not started on time, and therefore we believe that the awareness of otorhinolaryngologists about the manifestations of MIS-C will be useful in modern clinical practice. © 2022, Media Sphera Publishing Group. All rights reserved

Interdisciplinary Personalized Approach in Rehabilitation of Children with Voice Disorders

В статье рассматривается междисциплинарность как специфическая форма организации научного знания, базирующаяся на связях между различными дисциплинами, позволяющими обеспечить повышение эффективности медико-психолого-педагогического воздействия в процессе восстановления голоса у детей.The study of a child's voice from the perspective of the interdisciplinary and personalized approach (PP) in the system of complex rehabilitation is one of the urgent problems of modern logopedics and otorhinolaryngology. The article presents data on the prevalence of voice disorders among children, their diagnosis and treatment. The interdisciplinary approach is interpreted as a specific form of organization of scientific knowledge, based on the links between various disciplines and technologies that make it possible to increase the effectiveness of medico-psycho-pedagogical intervention in the process of voice restoration

Streamlined analysis schema for high-throughput identification of endogenous protein complexes

Immunoprecipitation followed by mass spectrometry (IP/MS) has recently emerged as a preferred method in the analysis of protein complex components and cellular protein networks. Targeting endogenous protein complexes of higher eukaryotes, particularly in large-scale efforts, has been challenging due to cellular heterogeneity, high proteome complexity, and, compared to lower organisms, lack of efficient in-locus epitope-tagging techniques. It is further complicated by variability in nonspecific identifications and cross-reactivity of primary antibodies. Still, the study of endogenous human protein networks is highly desired despite its challenges. Here we describe a streamlined IP/MS protocol for the purification and identification of extended endogenous protein complexes. We investigate the sources of nonspecific protein binding and develop semiquantitative specificity filters that are based on peptide spectral count measurements. We also outline logical constraints for the derivation of accurate complex composition from IP/MS data and demonstrate the effectiveness of this approach by presenting our analyses of different transcriptional coregulator complexes. We show consistent purification of novel components for the Integrator complex, analyze the composition of the Mediator complex solely from our data to demonstrate the wide usability of spectral counts, and deconvolute heterogeneous HDAC1/2 networks into core complex modules and several novel subcomplex interactions

X-ray crystal structure of MENT: evidence for functional loop–sheet polymers in chromatin condensation

Most serpins are associated with protease inhibition, and their ability to form loop–sheet polymers is linked to conformational disease and the human serpinopathies. Here we describe the structural and functional dissection of how a unique serpin, the non-histone architectural protein, MENT (Myeloid and Erythroid Nuclear Termination stage-specific protein), participates in DNA and chromatin condensation. Our data suggest that MENT contains at least two distinct DNA-binding sites, consistent with its simultaneous binding to the two closely juxtaposed linker DNA segments on a nucleosome. Remarkably, our studies suggest that the reactive centre loop, a region of the MENT molecule essential for chromatin bridging in vivo and in vitro, is able to mediate formation of a loop–sheet oligomer. These data provide mechanistic insight into chromatin compaction by a non-histone architectural protein and suggest how the structural plasticity of serpins has adapted to mediate physiological, rather than pathogenic, loop–sheet linkages