-
Indian Journal of Pediatrics Oct 2023Enlargement of breasts among boys is termed gynecomastia. This could be due to an alteration in the androgen-estrogen ratio along with the effects of other hormones... (Review)
Review
Enlargement of breasts among boys is termed gynecomastia. This could be due to an alteration in the androgen-estrogen ratio along with the effects of other hormones including growth hormone, insulin like growth factor 1, prolactin, and other factors affecting aromatase enzyme. The common causes of gynecomastia are pubertal gynecomastia, obesity, drugs and hypogonadism. Several other diseases including liver or renal failure, thyrotoxicosis, Klinefelter syndrome, tumors and environmental pollutants can cause gynecomastia. History and clinical examination will help formulate targeted investigations and management. The factors to be evaluated in these include examination of breasts and testes, in addition to other parts of systemic examination. Treatment of underlying disorders can improve gynecomastia, such as use of testosterone in hypogonadism. Some boys may not need any intervention as gynecomastia may resolve on its own. Medical management is useful in simple gynecomastia. Tamoxifen has been tried successfully in adolescents with gynecomastia. Other drugs including clomiphene, danazol, letrozole and anastrozole have not been consistently useful in this age group. In severe chronic gynecomastia, surgery is the treatment of choice.
Topics: Adolescent; Male; Humans; Gynecomastia; Hypertrophy; Tamoxifen; Growth Hormone; Hypogonadism
PubMed: 37592101
DOI: 10.1007/s12098-023-04810-7 -
Nature Communications Oct 2023Alteration of the size and stiffness of the nucleus triggered by environmental cues are thought to be important for eukaryotic cell fate and function. However, it...
Alteration of the size and stiffness of the nucleus triggered by environmental cues are thought to be important for eukaryotic cell fate and function. However, it remains unclear how context-dependent nuclear remodeling occurs and reprograms gene expression. Here we identify the nuclear envelope proteins SUN1/2 as mechano-regulators of the nucleus during M1 polarization of the macrophage. Specifically, we show that LPS treatment decreases the protein levels of SUN1/2 in a CK2-βTrCP-dependent manner to shrink and soften the nucleus, therefore altering the chromatin accessibility for M1-associated gene expression. Notably, the transmembrane helix of SUN1/2 is solely required and sufficient for the nuclear mechano-remodeling. Consistently, SUN1/2 depletion in macrophages facilitates their phagocytosis, tissue infiltration, and proinflammatory cytokine production, thereby boosting the antitumor immunity in mice. Thus, our study demonstrates that, in response to inflammatory cues, SUN1/2 proteins act as mechano-regulators to remodel the nucleus and chromatin for M1 polarization of the macrophage.
Topics: Animals; Mice; Cell Nucleus; Microtubule-Associated Proteins; Nuclear Proteins; Chromatin
PubMed: 37828059
DOI: 10.1038/s41467-023-42187-5 -
The Journal of Clinical Investigation Jul 2023Epigenetic status-altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. However, the functional outcomes and...
Epigenetic status-altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. However, the functional outcomes and cellular dependencies arising from these mutations remain unresolved. In this study, we investigated cellular dependencies, or vulnerabilities, that arise when enhancer function is compromised by loss of the frequently mutated COMPASS family members MLL3 and MLL4. CRISPR dropout screens in MLL3/4-depleted mouse embryonic stem cells (mESCs) revealed synthetic lethality upon suppression of purine and pyrimidine nucleotide synthesis pathways. Consistently, we observed a shift in metabolic activity toward increased purine synthesis in MLL3/4-KO mESCs. These cells also exhibited enhanced sensitivity to the purine synthesis inhibitor lometrexol, which induced a unique gene expression signature. RNA-Seq identified the top MLL3/4 target genes coinciding with suppression of purine metabolism, and tandem mass tag proteomic profiling further confirmed upregulation of purine synthesis in MLL3/4-KO cells. Mechanistically, we demonstrated that compensation by MLL1/COMPASS was underlying these effects. Finally, we demonstrated that tumors with MLL3 and/or MLL4 mutations were highly sensitive to lometrexol in vitro and in vivo, both in culture and in animal models of cancer. Our results depicted a targetable metabolic dependency arising from epigenetic factor deficiency, providing molecular insight to inform therapy for cancers with epigenetic alterations secondary to MLL3/4 COMPASS dysfunction.
Topics: Humans; Animals; Mice; Proteomics; Histone-Lysine N-Methyltransferase; Mutation; Neoplasms; Epigenesis, Genetic
PubMed: 37252797
DOI: 10.1172/JCI169993 -
Neuroscience and Biobehavioral Reviews Jul 2023Animal personality, consistent individual differences in behaviour, is an important concept for understanding how individuals vary in how they cope with environmental... (Review)
Review
Animal personality, consistent individual differences in behaviour, is an important concept for understanding how individuals vary in how they cope with environmental challenges. In order to understand the evolutionary significance of animal personality, it is crucial to understand the underlying regulatory mechanisms. Epigenetic marks such as DNA methylation are hypothesised to play a major role in explaining variation in phenotypic changes in response to environmental alterations. Several characteristics of DNA methylation also align well with the concept of animal personality. In this review paper, we summarise the current literature on the role that molecular epigenetic mechanisms may have in explaining personality variation. We elaborate on the potential for epigenetic mechanisms to explain behavioural variation, behavioural development and temporal consistency in behaviour. We then suggest future routes for this emerging field and point to potential pitfalls that may be encountered. We conclude that a more inclusive approach is needed for studying the epigenetics of animal personality and that epigenetic mechanisms cannot be studied without considering the genetic background.
Topics: Animals; Behavior, Animal; Personality; Individuality; Epigenesis, Genetic; Biological Evolution
PubMed: 37094740
DOI: 10.1016/j.neubiorev.2023.105194 -
Advanced Biology Jan 2024Although a large amount of data consistently shows that genes affect immunometabolic characteristics and outcomes, epigenetic mechanisms are also heavily implicated.... (Review)
Review
Although a large amount of data consistently shows that genes affect immunometabolic characteristics and outcomes, epigenetic mechanisms are also heavily implicated. Epigenetic changes, including DNA methylation, histone modification, and noncoding RNA, determine gene activity by altering the accessibility of chromatin to transcription factors. Various factors influence these alterations, including genetics, lifestyle, and environmental cues. Moreover, acquired epigenetic signals can be transmitted across generations, thus contributing to early disease traits in the offspring. A closer investigation is critical in this aspect as it can help to understand the underlying molecular mechanisms further and gain insights into potential therapeutic targets for preventing and treating diseases arising from immuno-metabolic dysregulation. In this review, the role of chromatin alterations in the transcriptional modulation of genes involved in insulin resistance, systemic inflammation, macrophage polarization, endothelial dysfunction, metabolic cardiomyopathy, and nonalcoholic fatty liver disease (NAFLD), is discussed. An overview of emerging chromatin-modifying drugs and the importance of the individual epigenetic profile for personalized therapeutic approaches in patients with immuno-metabolic disorders is also presented.
Topics: Humans; DNA Methylation; Epigenesis, Genetic; Non-alcoholic Fatty Liver Disease; Chromatin; Inflammation
PubMed: 37794610
DOI: 10.1002/adbi.202300211 -
Frontiers in Cellular and Infection... 2023Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected a substantial portion of the world's population, and novel consequences of COVID-19 on the... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected a substantial portion of the world's population, and novel consequences of COVID-19 on the human body are continuously being uncovered. The human microbiome plays an essential role in host health and well-being, and multiple studies targeting specific populations have reported altered microbiomes in patients infected with SARS-CoV-2. Given the global scale and massive incidence of COVID on the global population, determining whether the effects of COVID-19 on the human microbiome are consistent and generalizable across populations is essential.
METHODS
We performed a synthesis of human microbiome responses to COVID-19. We collected 16S rRNA gene amplicon sequence data from 11 studies sampling the oral and nasopharyngeal or gut microbiome of COVID-19-infected and uninfected subjects. Our synthesis included 1,159 respiratory (oral and nasopharyngeal) microbiome samples and 267 gut microbiome samples from patients in 11 cities across four countries.
RESULTS
Our reanalyses revealed communitywide alterations in the respiratory and gut microbiomes across human populations. We found significant overall reductions in the gut microbial diversity of COVID-19-infected patients, but not in the respiratory microbiome. Furthermore, we found more consistent community shifts in the gut microbiomes of infected patients than in the respiratory microbiomes, although the microbiomes in both sites exhibited higher host-to-host variation in infected patients. In respiratory microbiomes, COVID-19 infection resulted in an increase in the relative abundance of potentially pathogenic bacteria, including .
DISCUSSION
Our findings shed light on the impact of COVID-19 on the human-associated microbiome across populations, and highlight the need for further research into the relationship between long-term effects of COVID-19 and altered microbiota.
Topics: Humans; COVID-19; SARS-CoV-2; RNA, Ribosomal, 16S; Microbiota; Gastrointestinal Microbiome
PubMed: 37600938
DOI: 10.3389/fcimb.2023.1211348 -
BioRxiv : the Preprint Server For... Nov 2023Despite Alzheimer's disease (AD) disproportionately affecting women, the mechanisms remain elusive. In AD, microglia undergo 'metabolic reprogramming', which contributes...
Despite Alzheimer's disease (AD) disproportionately affecting women, the mechanisms remain elusive. In AD, microglia undergo 'metabolic reprogramming', which contributes to microglial dysfunction and AD pathology. However, how sex and age contribute to metabolic reprogramming in microglia is understudied. Here, we use metabolic imaging, transcriptomics, and metabolic assays to probe age-and sex-associated changes in brain and microglial metabolism. Glycolytic and oxidative metabolism in the whole brain was determined using Fluorescence Lifetime Imaging Microscopy (FLIM). Young female brains appeared less glycolytic than male brains, but with aging, the female brain became 'male-like.' Transcriptomic analysis revealed increased expression of disease-associated microglia (DAM) genes (e.g., , , ), and genes involved in glycolysis and oxidative metabolism in microglia from aged females compared to males. To determine whether estrogen can alter the expression of these genes, BV-2 microglia-like cell lines, which abundantly express DAM genes, were supplemented with 17β-estradiol (E2). E2 supplementation resulted in reduced expression of DAM genes, reduced lipid and cholesterol transport, and substrate-dependent changes in glycolysis and oxidative metabolism. Consistent with the notion that E2 may suppress DAM-associated factors, LPL activity was elevated in the brains of aged female mice. Similarly, DAM gene and protein expression was higher in monocyte-derived microglia-like (MDMi) cells derived from middle-aged females compared to age-matched males and was responsive to E2 supplementation. FLIM analysis of MDMi from young and middle-aged females revealed reduced oxidative metabolism and FAD+ with age. Overall, our findings show that altered metabolism defines age-associated changes in female microglia and suggest that estrogen may inhibit the expression and activity of DAM-associated factors, which may contribute to increased AD risk, especially in post-menopausal women.
PubMed: 38076915
DOI: 10.1101/2023.11.28.569104 -
Proceedings of the National Academy of... Sep 2023Protein synthesis is a fundamental cellular process in neurons that is essential for synaptic plasticity and memory consolidation. Here, we describe our investigations...
Protein synthesis is a fundamental cellular process in neurons that is essential for synaptic plasticity and memory consolidation. Here, we describe our investigations of a neuron- and muscle-specific translation factor, ukaryotic longation actor (eEF1A2), which when mutated in patients results in autism, epilepsy, and intellectual disability. We characterize three patient mutations, G70S, E122K, and D252H, and demonstrate that all three mutations decrease de novo protein synthesis and elongation rates in HEK293 cells. In mouse cortical neurons, the mutations not only decrease de novo protein synthesis but also alter neuronal morphology, regardless of endogenous levels of eEF1A2, indicating that the mutations act via a toxic gain of function. We also show that eEF1A2 mutant proteins display increased tRNA binding and decreased actin-bundling activity, suggesting that these mutations disrupt neuronal function by decreasing tRNA availability and altering the actin cytoskeleton. More broadly, our findings are consistent with the idea that eEF1A2 acts as a bridge between translation and the actin cytoskeleton, which is essential for proper neuron development and function.
Topics: Animals; Humans; Mice; Actins; Autistic Disorder; Epilepsy; HEK293 Cells; Mutation; Peptide Elongation Factor 1
PubMed: 37695913
DOI: 10.1073/pnas.2307704120 -
Journal of Nuclear Cardiology :... Aug 2023Coronary flow reserve (CFR) values measured by dynamic SPECT systems are typically consistent with other modalities (e.g., PET). However, large discrepancies are often...
BACKGROUND
Coronary flow reserve (CFR) values measured by dynamic SPECT systems are typically consistent with other modalities (e.g., PET). However, large discrepancies are often observed for individual patients. Positioning of the region-of-interest (ROI), representing the arterial input function (AIF) could explain some of these discrepancies. We explored the possibility of positioning the ROI in a manner that evaluates its consistency with patient-based injected radiotracer doses.
METHODS
Dose-consistent dynamic SPECT methodology was introduced, and its application was demonstrated in a twenty-patient clinical study. The effect of various ROI positions was investigated and comparison to myocardial perfusion imaging was performed.
RESULTS
Mean AIF ratios were consistent with the injected dose ratios for all examined ROI positions. Good agreement (> 80%) between total perfusion deficit and CFR was found in the detection of obstructive CAD patients for all ROIs considered. However, for individual patients, significant dependence on ROI position was observed (altering CFR by typically 30%). The proposed methodology's uncertainty was evaluated (~ 7%) and found to be smaller than the variability due to choice of ROI position.
CONCLUSION
Dose-consistent dynamic SPECT may contribute to evaluating uncertainty of CFR measurements and may potentially decrease uncertainty by allowing improved ROI positioning for individual patients.
Topics: Humans; Coronary Artery Disease; Coronary Circulation; Tomography, Emission-Computed, Single-Photon; Myocardial Perfusion Imaging; Fractional Flow Reserve, Myocardial
PubMed: 36477896
DOI: 10.1007/s12350-022-03160-9 -
Clinical Journal of Oncology Nursing Sep 2023Taste alteration is a common side effect of chemotherapy and can have a direct impact on patients' quality of life. Consistent evaluation of alteration in taste is...
Taste alteration is a common side effect of chemotherapy and can have a direct impact on patients' quality of life. Consistent evaluation of alteration in taste is lacking in clinical practice. The literature strongly suppo.
Topics: Humans; Quality of Life; Taste; Drug-Related Side Effects and Adverse Reactions; Antineoplastic Agents
PubMed: 37729452
DOI: 10.1188/23.CJON.479-485