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We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene mt-COX1 and influence obesity-induced cardiac dysfunction through the mitochondrial pathway. Because liver plays a pivotal role during obesity, we hypothesized that miR-181c might contribute to the pathophysiological complications associated with obesity. Therefore, we used miR-181c/d -/- mice to study the role of miR-181c in hepatocyte lipogenesis during diet-induced obesity. The mice were fed a high-fat (HF) diet for 26 weeks, during which indirect calorimetric measurements were made. Quantitative PCR (qPCR) was used to examine the expression of genes involved in lipid synthesis. We found that miR-181c/d -/- mice were not protected against all metabolic consequences of HF exposure. After 26 weeks, the miR-181c/d -/- mice had a significantly higher body fat percentage than did wild-type (WT) mice. Glucose tolerance tests showed hyperinsulinemia and hyperglycemia, indicative of insulin insensitivity in the miR-181c/d -/- mice. miR-181c/d -/- mice fed the HF diet had higher serum and liver triglyceride levels than did WT mice fed the same diet. qPCR data showed that several genes regulated by isocitrate dehydrogenase 1 (IDH1) were more upregulated in miR-181c/d -/- liver than in WT liver. Furthermore, miR-181c delivered in vivo via adeno-associated virus attenuated the lipogenesis by downregulating these same lipid synthesis genes in the liver. In hepatocytes, miR-181c regulates lipid biosynthesis by targeting IDH1. Taken together, the data indicate that overexpression of miR-181c can be beneficial for various lipid metabolism disorders.

ObjectiveTranslin knockout (KO) mice display robust adiposity. Recent studies indicate that translin and its partner protein, trax, regulate the microRNA and ATM kinase signaling pathways, both of which have been implicated in regulating metabolism. In the course of characterizing the metabolic profile of these mice, we found that they display normal glucose tolerance despite their elevated adiposity. Accordingly, we investigated why translin KO mice display this paradoxical phenotype.MethodsTo help distinguish between the metabolic effects of increased adiposity and those of translin deletion per se, we compared three groups: (1) wild-type (WT), (2) translin KO mice on a standard chow diet, and (3) adiposity-matched WT mice that were placed on a high-fat diet until they matched translin KO adiposity levels. All groups were scanned to determine their body composition and tested to evaluate their glucose and insulin tolerance. Plasma, hepatic, and adipose tissue samples were collected and used for histological and molecular analyses.ResultsTranslin KO mice show normal glucose tolerance whereas adiposity-matched WT mice, placed on a high-fat diet, do not. In addition, translin KO mice display prominent hepatic steatosis that is more severe than that of adiposity-matched WT mice. Unlike adiposity-matched WT mice, translin KO mice display three key features that have been shown to reduce susceptibility to insulin resistance: increased accumulation of subcutaneous fat, increased levels of circulating adiponectin, and decreased Tnfα expression in hepatic and adipose tissue.ConclusionsThe ability of translin KO mice to retain normal glucose tolerance in the face of marked adipose tissue expansion may be due to the three protective factors noted above. Further studies aimed at defining the molecular bases for this combination of protective phenotypes may yield new approaches to limit the adverse metabolic consequences of obesity.

We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene mt-COX1 and influence obesity-induced cardiac dysfunction through the mitochondrial pathway. Because liver plays a pivotal role during obesity, we hypothesized that miR-181c might contribute to the pathophysiological complications associated with obesity. Therefore, we used miR-181c/d-/- mice to study the role of miR-181c in hepatocyte lipogenesis during diet-induced obesity. The mice were fed a high-fat (HF) diet for 26 weeks, during which indirect calorimetric measurements were made. Quantitative PCR (qPCR) was used to examine the expression of genes involved in lipid synthesis. We found that miR-181c/d-/- mice were not protected against all metabolic consequences of HF exposure. After 26 weeks, the miR-181c/d-/- mice had a significantly higher body fat percentage than did wild-type (WT) mice. Glucose tolerance tests showed hyperinsulinemia and hyperglycemia, indicative of insulin insensitivity in the miR-181c/d-/- mice. miR-181c/d-/- mice fed the HF diet had higher serum and liver triglyceride levels than did WT mice fed the same diet. qPCR data showed that several genes regulated by isocitrate dehydrogenase 1 (IDH1) were more upregulated in miR-181c/d-/- liver than in WT liver. Furthermore, miR-181c delivered in vivo via adeno-associated virus attenuated the lipogenesis by downregulating these same lipid synthesis genes in the liver. In hepatocytes, miR-181c regulates lipid biosynthesis by targeting IDH1. Taken together, the data indicate that overexpression of miR-181c can be beneficial for various lipid metabolism disorders.

Abstract We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene (mt-COX1), and influence obesity-induced cardiac dysfunction through mitochondrial pathway. Liver plays a pivotal role during obesity. Therefore, we hypothesized that miR-181c plays an important role in pathophysiological complications associated with obesity. We used miR-181c/d-/- mice to study the miR-181c role in lipogenesis in hepatocytes during diet-induced obesity (DIO). Indirect calorimetric measurements were made during the 26 weeks high fat diet (HFD) exposure. qPCR was performed to examine the gene expression involved in lipid synthesis. Here, we show that miR-181c/d-/- mice are not protected against all metabolic consequences of HFD exposure. After 26 weeks of the HFD, miR-181c/d-/- mice had a significantly higher body fat (%) compared to WT. Glucose tolerance tests showed hyperinsulinemia and hyperglycemia, indicative of insulin insensitivity in the miR-181c/d-/- mice. HFD-fed miR-181c/d-/- mice had higher serum and liver triglyceride levels compared to HFD-fed WT mice. qPCR data demonstrated that several genes which are regulated by isocitrate dehydrogenase 1 (IDH1) were upregulated in miR-181c/d-/- liver compared to WT liver. Furthermore, an AAV-8 was used to deliver miR-181c, in vivo, to validate the potential role of miR-181c in the liver. miR-181c delivery attenuate the lipogenesis by downregulating the same lipid synthesis genes in the liver. In hepatocytes, miR-181c regulates lipid biosynthesis by targeting IDH1. Taken together, the data indicate that overexpression of miR-181c can be beneficial for various lipid metabolism disorders. Competing Interest Statement The authors have declared no competing interest. Footnotes * Lead contact: Samarjit Das, Ph.D., Department of Anesthesiology & Critical Care Medicine, Dept. of Pathology, Cardiovascular Division, Johns Hopkins University, 720 Rutland Avenue, Ross 632, Baltimore, MD 21205, Tel: +1 (443) 287- 0168, Fax: +1 (410) 502-5862 * Non-Standard Abbreviations and Acronyms miRNA microRNA miR-181c/d-/- mice miR-181c and d knock-out mice IDH 1 Isocitrate Dehydrogenase 1 HFD 60% High fat diet DIO Diet-Induced Obesity ABCA1 ATP-binding cassette, subfamily A, member 1 ABCG1 ATP-binding cassette, subfamily G, member 1 ACLY ATP citrate lyase APOE Apolipoprotein E CPT1A Carnitine Palmitoyltransferase 1A FASN Fatty Acid Synthase GAPDH Glyceraldehyde-3-Phosphate Dehydrogenase HADHB Hydroxyacyl-Coenzyme A Dehydrogenase Trifunctional Multienzyme Complex, β subunit SREBP1 Sterol Regulatory Element Binding Transcription Factor 1 SNORD6 Small Nucleolar RNA, C/D Box 6

Globally, nearly 3 billion people rely on solid fuels for cooking and heating, the vast majority residing in low- and middle-income countries (LMICs). The resulting household air pollution (HAP) is a leading environmental risk factor, accounting for an estimated 1.6 million premature deaths annually. Previous interventions of cleaner stoves have often failed to reduce exposure to levels that produce meaningful health improvements. There have been no multicountry field trials with liquefied petroleum gas (LPG) stoves, likely the cleanest scalable intervention. This paper describes the design and methods of an ongoing randomized controlled trial (RCT) of LPG stove and fuel distribution in 3,200 households in 4 LMICs (India, Guatemala, Peru, and Rwanda). We are enrolling 800 pregnant women at each of the 4 international research centers from households using biomass fuels. We are randomly assigning households to receive LPG stoves, an 18-month supply of free LPG, and behavioral reinforcements to the control arm. The mother is being followed along with her child until the child is 1 year old. Older adult women (40 to of age) living in the same households are also enrolled and followed during the same period. Primary health outcomes are low birth weight, severe pneumonia incidence, stunting in the child, and high blood pressure (BP) in the older adult woman. Secondary health outcomes are also being assessed. We are assessing stove and fuel use, conducting repeated personal and kitchen exposure assessments of fine particulate matter with aerodynamic diameter ( ), carbon monoxide (CO), and black carbon (BC), and collecting dried blood spots (DBS) and urinary samples for biomarker analysis. Enrollment and data collection began in May 2018 and will continue through August 2021. The trial is registered with ClinicalTrials.gov (NCT02944682). This study will provide evidence to inform national and global policies on scaling up LPG stove use among vulnerable populations. https://doi.org/10.1289/EHP6407.

Despite advances in breast cancer treatment, residual disease driven by dormant tumor cells continues to be a significant clinical problem. Leukemia inhibitory factor receptor (LIFR) promotes a dormancy phenotype in breast cancer cells and LIFR loss is correlated with poor patient survival. Herein, we demonstrate that histone deacetylase inhibitors (HDACi), which are in phase III clinical trials for breast cancer, epigenetically induced LIFR and activated a pro-dormancy program in breast cancer cells. HDACi slowed breast cancer cell proliferation and reduced primary tumor growth. Primary breast tumors from HDACi-treated patients had increased LIFR levels and reduced proliferation rates compared to pre-treatment levels. Recent Phase II clinical trial data studying entinostat and azacitidine in metastatic breast cancer revealed that induction of several pro-dormancy genes post-treatment was associated with prolonged patient survival. Together, these findings suggest HDACi as a potential therapeutic avenue to promote dormancy, prevent recurrence, and improve patient outcomes in breast cancer.

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

Two years after the emergence of SARS-CoV-2, there is still a need for better ways to assess the risk of transmission in congregate spaces. We deployed active air samplers to monitor the presence of SARS-CoV-2 in real-world settings across communities in the Upper Midwestern states of Wisconsin and Minnesota. Over 29 weeks, we collected 527 air samples from 15 congregate settings. We detected 106 samples that were positive for SARS-CoV-2 viral RNA, demonstrating that SARS-CoV-2 can be detected in continuous air samples collected from a variety of real-world settings. We expanded the utility of air surveillance to test for 40 other respiratory pathogens. Surveillance data revealed differences in timing and location of SARS-CoV-2 and influenza A virus detection. In addition, we obtained SARS-CoV-2 genome sequences from air samples to identify variant lineages. Collectively, this shows air sampling is a scalable, high throughput surveillance tool that could be used in conjunction with other methods for detecting respiratory pathogens in congregate settings. Air surveillance offers a potential means of monitoring airborne pathogens without the need for individual sampling. Here, the authors perform continuous air sampling in 15 community settings in the US for 29 weeks and demonstrate its feasibility for routine detection of SARS-CoV-2 and other respiratory pathogens.

Reactive oxygen species (ROS) accumulation is a cardinal feature of skeletal muscle atrophy. ROS refers to a collection of radical molecules whose cellular signals are vast, and it is unclear which downstream consequences of ROS are responsible for the loss of muscle mass and strength. Here, we show that lipid hydroperoxides (LOOH) are increased with age and disuse, and the accumulation of LOOH by deletion of glutathione peroxidase 4 (GPx4) is sufficient to augment muscle atrophy. LOOH promoted atrophy in a lysosomal-dependent, proteasomal-independent manner. In young and old mice, genetic and pharmacological neutralization of LOOH or their secondary reactive lipid aldehydes robustly prevented muscle atrophy and weakness, indicating that LOOH-derived carbonyl stress mediates age- and disuse-induced muscle dysfunction. Our findings provide novel insights for the role of LOOH in sarcopenia including a therapeutic implication by pharmacological suppression.

The adjuvanted varicella-zoster virus (VZV) glycoprotein E (gE) subunit herpes zoster vaccine (HZ/su) confers higher protection against HZ than the live attenuated zoster vaccine (ZV). To understand the immunologic basis for the different efficacies of the vaccines, we compared immune responses to the vaccines in adults 50 to 85 years old. gE-specific T cells were very low/undetectable before vaccination when analyzed by FluoroSpot and flow cytometry. Both ZV and HZ/su increased gE-specific responses, but at peak memory response (PMR) after vaccination (30 days after ZV or after the second dose of HZ/su), gE-specific CD4+ and CD8+ T cell responses were 10-fold or more higher in HZ/su compared with ZV recipients. Comparing the vaccines, T cell memory responses, including gE-IL-2+ and VZV-IL-2+ spot-forming cells (SFCs), were higher in HZ/su recipients and cytotoxic and effector responses were lower. At 1 year after vaccination, all gE-Th1 and VZV-IL-2+ SFCs remained higher in HZ/su compared with ZV recipients. Mediation analyses showed that IL-2+ PMR were necessary for the persistence of Th1 responses to either vaccine and VZV-IL-2+ PMR explained 73% of the total effect of HZ/su on persistence. This emphasizes the biological importance of the memory responses, which were clearly superior in HZ/su compared with ZV participants.