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The HIV/AIDS epidemic has driven the rise in cases of Kaposi sarcoma (KS) among children and adolescents living with HIV in countries with high Human gammaherpesvirus 8 (HHV-8) seroprevalence, such as Tanzania, where specialized oncology programs are sparse. Consequently, descriptions of successful treatment of KS in children and adolescents by general pediatricians are important. A retrospective analysis was performed of children and adolescents diagnosed with KS and treated with chemotherapy and combination antiretroviral therapy (cART) at the Baylor College of Medicine Children's Foundation Tanzania Center of Excellence – Mbeya between 2011 and 2017. Sixty-one patients were diagnosed with KS with a median age of 12.6 years (interquartile range (IQR) 9.4 − 15.5). Diagnosis was confirmed by histopathology in 36% (22/61). Among HIV positive patients (59/61), 78% (46/59) were on cART at KS diagnosis. Severe immunosuppression was present in 63% (35/56) of those with CD4 data and 44% (27/61) had SAM. Advanced-stage T1 disease was present in 64% (39/61), including 28% (17/61) with visceral/disseminated KS. Two-year estimated overall survival (OS) was 72% (95% Confidence Interval (CI): 58%–82%) and median follow up for survivors was 25.7 months (IQR 14.2–53.8). No patients were lost to follow up. Two-year OS was 63% (95% CI: 44%–77%) in patients with severe immune suppression and 60% (95% CI: 37%–76%) in patients with SAM. Among patients with visceral/disseminated KS, 53% (9/17) survived. This retrospective analysis demonstrated favorable outcomes in a complex cohort of children and adolescents with KS treated with chemotherapy by general pediatricians in Tanzania. [ABSTRACT FROM AUTHOR]

The current fuel system icing inhibitor (FSII) additives used for commercial and military aircraft are ethylene glycol mono methyl ether (EGME) and diethylene glycol mono methyl ether (DiEGME). Propylene glycol is used for wing deicing. Fuel deicing additives are required inmilitary fuels an optional in commercial fuels with wing deicing being weather dependent. The acetals and ketals of reduced sugars are being synthesized and modeled computationally because they are less toxic and more environmentally benign than EGME and DiEGME. Each compound is being studied with an emphasis on deicing effectiveness, human toxicity, and environmental hazard. This paper reports on three compounds derived from the sugar mannose. [ABSTRACT FROM AUTHOR]

A 3-year study of indoor radon in more than 1000 homes in northern Virginia and southern Maryland was conducted using 3-month exposure alpha-track monitors. In a study set of 200 homes, first-floor indoor radon concentrations, which most closely approximates home exposure levels, averaged slightly more than 3 pCi/l. In a study set of 100 homes, sub-slab ventilation was used to reduce indoor radon concentrations. Interest in remediation was related to public perception of the hazardous nature of radon; people living in homes with indoor radon measurements of more than 4 pCi/l were more likely to participate in theremediation phase of the project. Sub-slab ventilation was successful in more than 90% of the homes in reducing indoor radon from concentrations as high as 30 pCi/ to less than 4 pCi/l, at least for the entire year of post-remediation radon measurements. [ABSTRACT FROM AUTHOR]

Genetic defects affecting steroid biosynthesis cause cortisol deficiency and differences of sex development; among these defects are recessive mutations in the steroidogenic enzymes CYP11A1 and CYP11B, whose function is supported by reducing equivalents donated by ferredoxin reductase (FDXR) and ferredoxin. So far, mutations in the mitochondrial flavoprotein FDXR have been associated with a progressive neuropathic mitochondriopathy named FDXR-related mitochondriopathy (FRM), but cortisol insufficiency has not been documented. However, patients with FRM often experience worsening or demise following stress associated with infections. We investigated 2 female patients with FRM carrying the potentially novel homozygous FDXR mutation p.G437R with ambiguous genitalia at birth and sudden death in the first year of life; they presented with cortisol deficiency and androgen excess compatible with 11-hydroxylase deficiency. In addition, steroidogenic FDXR-variant cell lines reprogrammed from 3 patients with FRM fibroblasts displayed deficient mineralocorticoid and glucocorticoid production. Finally, Fdxr-mutant mice allelic to the severe p.R386W human variant showed reduced progesterone and corticosterone production. Therefore, our comprehensive studies show that human FDXR variants may cause compensated but possibly life-threatening adrenocortical insufficiency in stress by affecting adrenal glucocorticoid and mineralocorticoid synthesis through direct enzyme inhibition, most likely in combination with disturbed mitochondrial redox balance.

This study evaluated workers' exposures to flame retardants, including polybrominated diphenyl ethers (PBDEs), organophosphate esters (OPEs), and other brominated flame retardants (BFRs), in various industries. The study aimed to characterize OPE metabolite urinary concentrations and PBDE serum concentrations among workers from different industries, compare these concentrations between industries and the general population, and evaluate the likely route of exposure (dermal or inhalation). The results showed that workers from chemical manufacturing had significantly higher ( p <0.05) urinary concentrations of OPE metabolites compared to other industries. Spray polyurethane foam workers had significantly higher ( p <0.05) urinary concentrations of bis(1-chloro-2-propyl) phosphate (BCPP) compared to other industries. Electronic scrap workers had higher serum concentrations of certain PBDE congeners compared to the general population. Correlations were observed between hand wipe samples and air samples containing specific flame-retardant parent chemicals and urinary metabolite concentrations for some industries, suggesting both dermal absorption and inhalation as primary routes of exposure for OPEs. Overall, this study provides insights into occupational exposure to flame retardants in different industries and highlights the need for further research on emerging flame retardants and exposure reduction interventions.

Mitochondria, the organelles responsible for generating ATP in eukaryotic cells, have been previously implicated as a contributor to diabetes. However, mitochondrial proteins are encoded by both nuclear DNA (nDNA) and mtDNA. In order to better understand the relative contribution of each of these genomes to diabetes, a chimeric mitochondrial-nuclear exchange (MNX) mouse was created via pronuclear transfer carrying nDNA from a strain susceptible to type 1 diabetes (NOD/ShiLtJ) and mtDNA from nondiabetic C57BL/6J mice. Inheritance of the resulting heteroplasmic mtDNA mixture was then tracked across multiple generations, showing that offspring heteroplasmy generally followed that of the mother, with occasional large shifts consistent with an mtDNA bottleneck in the germ line. In addition, survival and incidence of diabetes in MNX mice were tracked and compared with those in unaltered NOD/ShiLtJ control mice. The results indicated improved survival and a delay in diabetes onset in the MNX mice, demonstrating that mtDNA has a critical influence on disease phenotype. Finally, enzyme activity assays showed that the NOD/ShiLtJ mice had significant hyperactivity of complex I of the electron transport chain relative to MNX mice, suggesting that a particular mtDNA variant (m.9461T>C) may be responsible for disease causation in the original NOD/ShiLtJ strain., Article Highlights: Mitochondria have been previously implicated in diabetes, but the specific genetic factors remain unclear. To better understand the contributions of mitochondrial genes in nuclear DNA (nDNA) versus mtDNA, we created mitochondrial-nuclear exchange (MNX) mice carrying nDNA from a diabetic strain and mtDNA from nondiabetic mice. Long-term tracking of MNX mice showed occasional large shifts in heteroplasmy consistent with an mtDNA bottleneck in the germ line. In addition, the MNX mice showed improved survival and delayed incidence of diabetes relative to the unaltered diabetic mice, which appeared to be linked to the activity of respiratory complex I., (© 2023 by the American Diabetes Association.)

Limited by spatial and temporal resolution, traditional optical microscopy cannot image the delicate ultra-structure organelles and sub-organelles. The emergence of super-resolution microscopy makes it possible. In this review, we focus on mitochondria. We summarize the process of mitochondrial dynamics, the primary proteins that regulate mitochondrial morphology, the diseases related to mitochondrial dynamics. The purpose is to apply super-resolution microscopy developed during recent years to the mitochondrial research. By providing the right research tools, we will help to promote the application of this technique to the in-depth elucidation of the pathogenesis of diseases related to mitochondrial dynamics, assistdiagnosis and develop the therapeutic treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Using DNA methylation profiles ( n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.

Introduction: Peptide-HLA class I (pHLA) complexes on the surface of tumor cells can be targeted by cytotoxic T-cells to eliminate tumors, and this is one of the bases for T-cell-based immunotherapies. However, there exist cases where therapeutic T-cells directed towards tumor pHLA complexes may also recognize pHLAs from healthy normal cells. The process where the same T-cell clone recognizes more than one pHLA is referred to as T-cell cross-reactivity and this process is driven mainly by features that make pHLAs similar to each other. T-cell cross-reactivity prediction is critical for designing T-cell-based cancer immunotherapies that are both effective and safe., Methods: Here we present PepSim, a novel score to predict T-cell cross-reactivity based on the structural and biochemical similarity of pHLAs., Results and Discussion: We show our method can accurately separate cross-reactive from non-crossreactive pHLAs in a diverse set of datasets including cancer, viral, and self-peptides. PepSim can be generalized to work on any dataset of class I peptide-HLAs and is freely available as a web server at pepsim.kavrakilab.org., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Details on the datasets used in this study are available in the supplementary file Datasets.xls., (Copyright © 2023 Hall-Swan, Slone, Rigo, Antunes, Lizée and Kavraki.)

Mitochondria are small double-membraned organelles responsible for the generation of energy used in the body in the form of ATP. Mitochondria are unique in that they contain their own circular mitochondrial genome termed mtDNA. mtDNA codes for 37 genes, and together with the nuclear genome (nDNA), dictate mitochondrial structure and function. Not surprisingly, pathogenic variants in the mtDNA or nDNA can result in mitochondrial disease. Mitochondrial disease primarily impacts tissues with high energy demands, including the heart. Mitochondrial cardiomyopathy is characterized by the abnormal structure or function of the myocardium secondary to genetic defects in either the nDNA or mtDNA. Mitochondrial cardiomyopathy can be isolated or part of a syndromic mitochondrial disease. Common manifestations of mitochondrial cardiomyopathy are a phenocopy of hypertrophic cardiomyopathy, dilated cardiomyopathy, and cardiac conduction defects. The underlying pathophysiology of mitochondrial cardiomyopathy is complex and likely involves multiple abnormal processes in the cell, stemming from deficient oxidative phosphorylation and ATP depletion. Possible pathophysiology includes the activation of alternative metabolic pathways, the accumulation of reactive oxygen species, dysfunctional mitochondrial dynamics, abnormal calcium homeostasis, and mitochondrial iron overload. Here, we highlight the clinical assessment of mtDNA-related mitochondrial cardiomyopathy and offer a novel hypothesis of a possible integrated, multivariable pathophysiology of disease.

Mitochondrial dysfunction plays an important role in the aging process. However, the mechanism by which this dysfunction causes aging is not fully understood. The accumulation of mutations in the mitochondrial genome (or "mtDNA") has been proposed as a contributor. One compelling piece of evidence in support of this hypothesis comes from the Polg D257A/D257A mutator mouse (Polg mut/mut ). These mice express an error-prone mitochondrial DNA polymerase that results in the accumulation of mtDNA mutations, accelerated aging, and premature death. In this paper, we have used the Polg mut/mut model to investigate whether the age-related biological effects observed in these mice are triggered by oxidative damage to the DNA that compromises the integrity of the genome. Our results show that mutator mouse has significantly higher levels of 8-oxoguanine (8-oxoGua) that are correlated with increased nuclear DNA (nDNA) strand breakage and oxidative nDNA damage, shorter average telomere length, and reduced mtDNA integrity. Based on these results, we propose a model whereby the increased level of reactive oxygen species (ROS) associated with the accumulation of mtDNA mutations in Polg mut/mut mice results in higher levels of 8-oxoGua, which in turn lead to compromised DNA integrity and accelerated aging via increased DNA fragmentation and telomere shortening. These results suggest that mitochondrial play a central role in aging and may guide future research to develop potential therapeutics for mitigating aging process., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Mitochondria play a very important role in many crucial cellular functions. Each eukaryotic cell contains hundreds of mitochondria with hundreds of mitochondrial genomes. Mutant and wild-type mitochondrial DNA (mtDNA) may co-exist as heteroplasmy and cause human disease. The purpose of the protocols in this article is to simultaneously determine the mtDNA sequence and quantify the heteroplasmy level using parallel sequencing. The protocols include mitochondrial genomic DNA PCR amplification of two full-length products using two distinct sets of PCR primers. The PCR products are mixed at an equimolar ratio, and the samples are then barcoded and sequenced with high-throughput next-generation sequencing technology. This technology is highly sensitive, specific, and accurate in determining mtDNA mutations and the degree/level of heteroplasmy. © 2022 Wiley Periodicals LLC. Basic Protocol 1: PCR amplification of mitochondrial DNA Basic Protocol 2: Analysis of next-generation sequencing of mitochondrial DNA Basic Protocol 3: Mutect2 pipeline for automated sample processing and large-scale data analysis., (© 2022 Wiley Periodicals LLC.)

Background: Refined coal tar sealant (RCTS) emulsions are used to seal the surface of asphalt pavement. Nine of the 22 polycyclic aromatic hydrocarbons (PAHs) evaluated in this study are classified as known, probable, or possible human carcinogens. Exposure assessment research for RCTS workers has not been published previously., Objectives: The overall objective of this study was to develop a representative occupational exposure assessment of PAH exposure for RCTS workers based on worksite surveys. The specific aims were to: 1) quantify full-shift airborne occupational exposures to PAHs among RCTS workers; 2) quantify workers' dermal exposures to PAHs; 3) quantify biomarkers of PAH exposure in workers' urine; 4) identify specific job titles associated with RCTS exposure; and 5) apply these results to a biological exposure index to assess risk of potential genotoxicity from occupational exposures., Methods: A total of twenty-one RCTS workers were recruited from three companies. Personal and area air samples were collected using a modification of NIOSH Method 5515. Dermal exposure was assessed by hand and neck wipes before and after shifts. Twenty-two PAHs were quantified via gas chromatography-mass spectrometry selected ion monitoring. Internal dose was estimated by quantifying select PAH metabolites in pre- and post-shift urine samples using on-line solid phase extraction-high performance liquid chromatography-tandem mass spectrometry., Results: PAH levels in the worker breathing zones were highest for naphthalene, acenaphthene, and phenanthrene, with geometric means of 52.1, 11.4, and 9.8 μg/m 3 , respectively. Hand wipe levels of phenanthrene, fluoranthene and pyrene were the highest among the 22 PAHs with geometric means of 7.9, 7.7, and 5.5 μg/cm 2 , respectively. Urinary PAH biomarkers for naphthalene, fluorene, phenanthrene, and pyrene were detected in all workers and were higher for post-shift samples than those collected pre-shift. Urinary concentrations of the metabolite 1-hydroxypyrene were greater than the American Conference of Governmental Industrial Hygienists (ACGIH) Biological Exposure Index (BEI) for this metabolite in 89 percent of post-shift samples collected on the final day of the work week or field survey. Statistically significances were found between concentrations of fluorene, naphthalene, and phenanthrene in the breathing zone of workers and their corresponding urinary PAH biomarkers. Workers were placed in two work place exposure groups: applicators and non-applicators. Applicators had higher total PAH concentrations in personal breathing zone (PBZ) air samples than non-applicators and were more likely to have post-shift hand wipe concentrations significantly higher than pre-shift concentrations. Concentrations of post-shift urinary biomarkers were higher, albeit not significantly, for applicators than non-applicators., Conclusions: The exposure results from RCTS worker samples cannot be explained by proximal factors such as nearby restaurants or construction. Air and skin concentration levels were substantially higher for RCTS workers than previously published levels among asphalt workers for all PAHs. PAH profiles on skin wipes were more consistent with RCTS sealant product than air samples. Last day post-shift urinary concentrations of 1-hydroxypyrene greatly exceeded the ACGIH BEI benchmark of 2.5 μg/L in 25 of 26 samples, which suggests occupational exposure and risk of genotoxicity. When pyrene and benzo[a]pyrene were both detected, concentration ratios from personal exposure samples were used to calculate the adjusted BEI. Concentrations of 1-hydroxypyrene exceeded the adjusted BEIs for air, hand wipes, and neck wipes in most cases. These results indicate the need to increase safety controls and exposure mitigation for RCTS workers., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy. However, the underlying mechanism remains elusive. We show here that Pink1 knockout (KO) mice display defective dendritic spine maturation, reduced axonal synaptic vesicles, abnormal synaptic connection, and attenuated long-term synaptic potentiation (LTP). Drp1 activation via S616 phosphorylation rescues deficits of spine maturation in Pink1 KO neurons. Notably, mice harboring a knockin (KI) phosphor-null Drp1 S616A recapitulate spine immaturity and synaptic abnormality identified in Pink1 KO mice. Chemical LTP (cLTP) induces Drp1 S616 phosphorylation in a PINK1-dependent manner. Moreover, phosphor-mimetic Drp1 S616D restores reduced dendritic spine localization of mitochondria in Pink1 KO neurons. Together, this study provides the first in vivo evidence of functional regulation of Drp1 by phosphorylation and suggests that PINK1-Drp1 S616 phosphorylation coupling is essential for convergence between mitochondrial dynamics and neural circuitry formation and refinement., (© 2022. The Author(s).)

Background: In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31., Objective: The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia., Methods: Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the "GeneMatcher" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function., Results: Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM&#95;001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility., Conclusion: A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity., (© 2021 International Parkinson and Movement Disorder Society.)

Preterm birth (PTB), or birth that occurs earlier than 37 weeks of gestational age, is a major contributor to infant mortality and neonatal hospitalization. Mutations in the mitochondrial genome (mtDNA) have been linked to various rare mitochondrial disorders and may be a contributing factor in PTB given that maternal genetic factors have been strongly linked to PTB. However, to date, no study has found a conclusive connection between a particular mtDNA variant and PTB. Given the high mtDNA copy number per cell, an automated pipeline was developed for detecting mtDNA variants using low-coverage whole-genome sequencing (lcWGS) data. The pipeline was first validated against samples of known heteroplasmy, and then applied to 929 samples from a PTB cohort from diverse ethnic backgrounds with an average gestational age of 27.18 weeks (range: 21-30). Our new pipeline successfully identified haplogroups and a large number of mtDNA variants in this large PTB cohort, including 8 samples carrying known pathogenic variants and 47 samples carrying rare mtDNA variants. These results confirm that lcWGS can be utilized to reliably identify mtDNA variants. These mtDNA variants may make a contribution toward preterm birth in a small proportion of live births., (© 2021 The Authors. Human Mutation Published by Wiley Periodicals LLC.)

Mitochondrial disorders affect at least 1 in 5,000 individuals worldwide and are often incurable and fatal. Mitochondrial replacement therapy (MRT) is an in vitro fertilization technique used to prevent the transmission of mitochondrial disorders. Currently, MRT is the only approach that provides mothers who carry a pathogenic variant in their mitochondrial DNA (mtDNA), the opportunity to have a biological child without a mitochondrial disease. MRT involves the combination of nuclear DNA from the egg of the carrier mother and the cytoplasm from an oocyte donor, which contains healthy mitochondria. While MRT was approved for use in the UK in 2015, the ban on congressional funding for research on 'heritable genetic modification' has made MRT unavailable within the US borders. This survey-based study aimed to describe genetic counselors' experience, knowledge, and opinions about MRT. Additionally, we also assessed whether genetic counselors' comfort discussing MRT with patients, and feelings about clinical use of MRT in the United States changed after providing information about MRT compared with baseline. Responses were received from 139 genetic counselors in North America. Findings indicate low awareness and knowledge about MRT among participants. However, more participants expressed comfort with discussing MRT with patients and more participants were able to form opinions about statements about MRT after they were provided with information about MRT. This study is the first to assess genetic counselors' opinions toward MRT and suggests the need for more education about novel technologies such as MRT among genetic counselors., (© 2021 National Society of Genetic Counselors.)