The ability to identify a specific type of leukemia using minimally invasive biopsies holds great promise to improve the diagnosis, treatment selection, and prognosis prediction of patients. Using genome-wide methylation profiling and machine learning methods, we investigated the utility of CpG methylation status to differentiate blood from patients with acute lymphocytic leukemia (ALL) or acute myelogenous leukemia (AML) from normal blood. We established a CpG methylation panel that can distinguish ALL and AML blood from normal blood as well as ALL blood from AML blood with high sensitivity and specificity. We then developed a methylation-based survival classifier with 23 CpGs for ALL and 20 CpGs for AML that could successfully divide patients into high-risk and low-risk groups, with significant differences in clinical outcome in each leukemia type. Together, these findings demonstrate that methylation profiles can be highly sensitive and specific in the accurate diagnosis of ALL and AML, with implications for the prediction of prognosis and treatment selection.

We investigate the phased evolution and variation of the South Asian monsoon and resulting weathering intensity and physical erosion in the Himalaya–Karakoram Mountains since late Pliocene time (c. 3.4 Ma) using a comprehensive approach. Neodymium and strontium isotopic compositions and single-grain zircon U–Pb age spectra reveal the sources of the deposits in the east Arabian Sea, and show a combination of sources from the Himalaya and the Karakoram–Kohistan–Ladakh Mountains, with sediments from the Indian Peninsula such as the Deccan Traps or Craton. We interpret shifts in the sediment sources to have been forced by sea-level changes that correlate with South Asian monsoon rainfall variation since late Pliocene time. We collected 908 samples from the International Ocean Discovery Program Hole U1456A, which was drilled in the east Arabian Sea. Time series of hematite content and grain size of the sediments were examined downcore. We found South Asian monsoon precipitation and weathering intensity experienced three phases from late Pliocene time. Lower monsoon precipitation, with a lower variability and strong weathering intensity, occurred during 3.4–2.4 Ma; an increased and more variable South Asian monsoon rainfall, along with strengthened but fluctuating weathering intensity, occurred at 1.8–1.1 Ma; and a reduced rainfall with lower South Asian monsoon precipitation variability and moderate weathering intensity marked the period 1.1–0.1 Ma. Maximum entropy spectral analysis and wavelet transform show that there were orbital-dominated cycles of periods c. 100 and c. 41 ka in these proxy-based time series. We propose that the monsoon, sea level, global temperature and insolation together forced the weathering and erosion in SW Asia.

This scoping review synthesizes the existing research on the use of very low‐calorie diets (VLCDs) in subjects with nonalcoholic fatty liver disease (NAFLD) and end‐stage liver disease (ESLD). 19 studies were included, of which 5 were clinical trials, 11 were cohort studies, 1 was a case‐control study, and 2 were case series totaling 968 subjects. About 17 studies were focused on patients with NAFLD while the two case series described in patients with ESLD on the transplant list or post‐liver transplant. Six studies included subjects managed with VLCDs prior bariatric surgery. Most studies were short term and demonstrated acute improvement of diverse liver biomarkers including liver function tests, indices of hepatosteatosis and reduction in liver size. Adherence rates in these studies were between 69% and 93%. Eight studies did not report any adverse events and four subjects were reported to have discontinued VLCD due to adverse effects in two different studies. Aggregated adverse events were mild. Treatments based on VLCD in subjects with NAFLD seem to be safe and tolerable but can result in mild adverse effects. The findings of this scoping review suggest that the use of VLCD in patients with obesity complicated with NAFLD and potentially in ESLD appear to be effective to induce weight loss and to acutely reduce hepatosteatosis.

Resumo Fundamento Os bloqueadores dos receptores da angiotensina (BRA) e os inibidores da enzima conversora da angiotensina (IECA) aumentam a expressão de ACE2, que é um receptor para entrada de SARS-CoV-2 nas células. Embora as evidências sugiram que os IECA/BRA são seguros entre a população geral com COVID-19, sua segurança em pacientes com hipertensão relacionada ao sobrepeso/obesidade merece uma avaliação mais aprofundada. Objetivo Avaliamos a associação entre o uso de IECA/BRA e a gravidade da COVID-19 em pacientes com hipertensão relacionada ao sobrepeso/obesidade. Métodos O presente estudo incluiu 439 pacientes adultos com sobrepeso/obesidade (índice de massa corporal ≥ 25 kg/m 2 ) e hipertensão, diagnosticados com COVID-19 e internados no University of Iowa Hospitals and Clinic entre 1º de março e 7 de dezembro de 2020. Foram avaliadas a mortalidade e a gravidade da COVID-19 com base no tempo de internação hospitalar, internação em unidade de terapia intensiva, uso de oxigênio suplementar, ventilação mecânica e uso de vasopressores. A regressão logística multivariável foi usada para examinar as associações do uso de IECA/BRA com a mortalidade e outros marcadores de gravidade de COVID-19, com um alfa bilateral definido em 0,05. Resultados A exposição aos BRA (n = 91) e IECA (n = 149) antes da hospitalização foi significativamente associada a menor mortalidade ( odds ratio [OR] = 0,362, intervalo de confiança [IC] de 95% 0,149 a 0,880, p = 0,025) e menor tempo de internação hospitalar (IC 95% −0,217 a −0,025, p = 0,015). Adicionalmente, os pacientes em uso de IECA/BRA apresentaram uma tendência não significativa de menor internação em unidade de terapia intensiva (OR = 0,727, IC 95% 0,485 a 1,090, p = 0,123), uso de oxigênio suplementar (OR = 0,929, IC 95% 0,608 a 1,421,p = 0,734), ventilação mecânica (OR = 0,728, IC 95% 0,457 a 1,161, p = 0,182) e vasopressores (OR = 0,677, IC 95% 0,430 a 1,067, p = 0,093). Conclusão Os resultados sugerem que pacientes internados com COVID-19 e hipertensão relacionada ao sobrepeso/obesidade que receberam IECA/BRA antes da internação apresentam menor mortalidade e COVID-19 menos grave do que aqueles que não estavam tomando IECA/BRA. Os resultados também sugerem que a exposição aos IECA/BRA pode proteger pacientes com hipertensão relacionada ao sobrepeso/obesidade de COVID-19 grave e morte.

The skeletal muscle of type 2 diabetics exhibits mitochondrial dysfunction associated with increased mitochondrial fission. Dynamin-related protein 1 (DRP1) is responsible for mitochondrial division, whereas mitochondrial-endoplasmic reticulum contacts (MERCs) mark mitochondrial sites where fission occurs. Here, we have shown that skeletal muscle-specific DRP1 knock out (KO) mice are partly protected from high fat diet-induced obesity and diabetes, and exhibit increased insulin and glucose tolerance along with lower insulinemia. We also found that KO mice exhibit increased energy expenditure per unit of lean mass. Isolated DRP1-deficient skeletal muscle fibers from KO mice fed high fat diet have reduced respiratory capacity when exposed to ADP and palmitoyl-carnitine, but not when exposed to ADP, pyruvate, and malate. Additionally, the skeletal muscle of KO mice fed normal chow exhibited altered expression of genes associated with MERCs and increased expression of genes linked to ER stress. We observed substantial increases in gene expression of FGF21, a downstream signal of the ER stress response, in KO mice. However, FGF21 plasma concentration in KO mice was not elevated. Additionally, changes in MERC gene expression could potentially alter calcium signaling between the mitochondria and endoplasmic reticulum, changing insulin sensitivity in KO mice. In conclusion, we have shown that skeletal muscle-specific DRP1 KO mice are resistant to high fat diet-induced obesity and diabetes, perhaps due to elevated energy expenditure and differential mitochondrial respiratory adaptations to different substrates. Although FGF21 does not appear to contribute to this effect, it is possible that other ER-stress signals might help explain the observed phenotype in KO mice.