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Skeletal muscle serves fundamental roles in organismal health. Gene expression fluctuations are critical for muscle homeostasis and the response to environmental insults. Yet, little is known about post-transcriptional mechanisms regulating such fluctuations while impacting muscle proteome. Here we report genome-wide analysis of mRNA methyladenosine (m 6 A) dynamics of skeletal muscle hypertrophic growth following overload-induced stress. We show that increases in METTL3 (the m 6 A enzyme), and concomitantly m 6 A, control skeletal muscle size during hypertrophy; exogenous delivery of METTL3 induces skeletal muscle growth, even without external triggers. We also show that METTL3 represses activin type 2 A receptors (ACVR2A) synthesis, blunting activation of anti-hypertrophic signaling. Notably, myofiber-specific conditional genetic deletion of METTL3 caused spontaneous muscle wasting over time and abrogated overload-induced hypertrophy; a phenotype reverted by co-administration of a myostatin inhibitor. These studies identify a previously unrecognized post-transcriptional mechanism promoting the hypertrophic response of skeletal muscle via control of myostatin signaling. Muscle undergoes hypertrophy and atrophy in response to physiological stimuli or in pathological conditions, which is partially controlled through altered gene expression. Here the authors report that m 6 A methyltransferase METTL3 and mRNA m 6 A post-transcriptional modifications as a mechanism that regulates muscle hypertrophy and atrophy via myostatin signalling in mice.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Thus, a better understanding of molecular aberrations involved in HCC pathogenesis is necessary for developing effective therapy. It is well established that cancer cells metabolize energy sources differently to rapidly generate biomass. Glucose-6-phosphate-dehydrogenase (G6PD), the rate-limiting enzyme of the Pentose Phosphate Pathway (PPP), is often activated in human malignancies to generate precursors for nucleotide and lipid synthesis. Here, we determined the clinical significance of G6PD in primary human HCC by analyzing RNA-seq and clinical data in The Cancer Genome Atlas. We found that the upregulation of G6PD correlates with higher tumor grade, increased tumor recurrence, and poor patient survival. Notably, liver-specific miR-122, which is essential for metabolic homeostasis, suppresses G6PD expression by directly interacting with its 3′UTR. Luciferase reporter assay confirmed two conserved functional miR-122 binding sites located in the 3′-UTR of G6PD. Furthermore, we show that ectopic expression of miR-122 and miR-1, a known regulator of G6PD expression coordinately repress G6PD expression in HCC cells. These miRNAs also reduced G6PD activity in HepG2 cells that express relatively high activity of this enzyme. Collectively, this study provides evidence that anti-HCC efficacy of miR122 and miR-1 could be mediated, at least in part, through inhibition of PPP by suppressing the expression of G6PD.

Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-informed exploration of structure activity relationship (SAR) around this small molecule we develop SJ3149, a selective and potent degrader of CK1α protein in vitro and in vivo. The structure of SJ3149 co-crystalized in complex with CK1α + CRBN + DDB1 provides a rationale for the improved degradation properties of this compound. In a panel of 115 cancer cell lines SJ3149 displays a broad antiproliferative activity profile, which shows statistically significant correlation with MDM2 inhibitor Nutlin-3a. These findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors. Here, the authors describe a potent and selective CK1a molecular glue degrader with a broad antiproliferative potency. Crystallographic data provide rationale for the high degradation efficacy displayed by this compound.

MicroRNA-122 (miR-122) has been identified as a marker of various liver injuries, including hepatitis- virus-infection-, alcoholic-, and non-alcoholic steatohepatitis (NASH)-induced liver fibrosis. Here, we report that the extracellular miR-122 from hepatic cells can be delivered to hepatic stellate cells (HSCs) to modulate their proliferation and gene expression. Our published Argonaute crosslinking immunoprecipitation (Ago-CLIP) data identified several pro-fibrotic genes, including Ctgf, as miR-122 targets in mice livers. However, treating Ctgf as a therapeutic target failed to rescue the fibrosis developed in the miR-122 knockout livers. Alternatively, we compared the published datasets of human cirrhotic livers and miR-122 KO livers, which revealed upregulation of BCL2, suggesting its potential role in regulating fibrosis. Notably, ectopic miR-122 expression inhibited BCL2 expression in human HSC (LX-2) cells). Publicly available ChIP-seq data in human hepatocellular cancer (HepG2) cells and mice livers suggested miR-122 could regulate BCL2 expression indirectly through c-MYC, which was confirmed by siRNA-mediated depletion of c-MYC in Hepatocellular Carcinoma (HCC) cell lines. Importantly, Venetoclax, a potent BCL2 inhibitor approved for the treatment of leukemia, showed promising anti-fibrotic effects in miR-122 knockout mice. Collectively, our data demonstrate that miR-122 suppresses liver fibrosis and implicates anti-fibrotic potential of Venetoclax.

We aimed to assess the resistance rates of antimicrobial-resistant, in bacterial pathogens of epidemiological importance in 47 Mexican centers. In this retrospective study, we included a stratified sample of 47 centers, covering 20 Mexican states. Selected isolates considered as potential causatives of disease collected over a 6-month period were included. Laboratories employed their usual methods to perform microbiological studies. The results were deposited into a database and analyzed with the WHONET 5.6 software. In this 6-month study, a total of 22,943 strains were included. Regarding Gram-negatives, carbapenem resistance was detected in ≤ 3% in Escherichia coli, 12.5% in Klebsiella sp. and Enterobacter sp., and up to 40% in Pseudomonas aeruginosa; in the latter, the resistance rate for piperacillin-tazobactam (TZP) was as high as 19.1%. In Acinetobacter sp., resistance rates for cefepime, ciprofloxacin, meropenem, and TZP were higher than 50%. Regarding Gram-positives, methicillin resistance in Staphylococcus aureus (MRSA) was as high as 21.4%, and vancomycin (VAN) resistance reached up to 21% in Enterococcus faecium. Acinetobacter sp. presented the highest multidrug resistance (53%) followed by Klebsiella sp. (22.6%) and E. coli (19.4%). The multidrug resistance of Acinetobacter sp., Klebsiella sp. and E. coli and the carbapenem resistance in specific groups of enterobacteria deserve special attention in Mexico. Vancomycin-resistant enterococci (VRE) and MRSA are common in our hospitals. Our results present valuable information for the implementation of measures to control drug resistance.

Skeletal muscle serves fundamental roles in organismal health. Gene expression fluctuations are critical for muscle homeostasis and the response to environmental insults. Yet, little is known about post-transcriptional mechanisms regulating such fluctuations while impacting muscle proteome. Here we report genome-wide analysis of mRNA methyladenosine (m A) dynamics of skeletal muscle hypertrophic growth following overload-induced stress. We show that increases in METTL3 (the m A enzyme), and concomitantly m A, control skeletal muscle size during hypertrophy; exogenous delivery of METTL3 induces skeletal muscle growth, even without external triggers. We also show that METTL3 represses activin type 2 A receptors (ACVR2A) synthesis, blunting activation of anti-hypertrophic signaling. Notably, myofiber-specific conditional genetic deletion of METTL3 caused spontaneous muscle wasting over time and abrogated overload-induced hypertrophy; a phenotype reverted by co-administration of a myostatin inhibitor. These studies identify a previously unrecognized post-transcriptional mechanism promoting the hypertrophic response of skeletal muscle via control of myostatin signaling.

IntroductionAgeing entails a variety of physiological changes that increase the risk of chronic non-communicable diseases. The prevalence of these diseases leads to an increase in the use of health services. The care models implemented by health systems should provide comprehensive long-term healthcare. We conducted this systematic review to determine whether any model of care for older persons have proven to be effective.MethodsA systematic review of literature was carried out to identify randomised clinical trials that have assessed how effective a care model for older patients with chronic diseases. A searches electronic databases such as MEDLINE, Turning Research Into Practice Database, Cochrane Library and Cochrane Central Register of controlled Trials was conducted from January 1966 to January 2021. Two independent reviewers assessed the eligibility of the studies. Interventions were identified and classified according to the taxonomies developed by the Cochrane Effective Practice and Organisation of Care and Cochrane Consumers and Communication groups.ResultsOf the 4952 bibliographic references that were screened, 577 were potentially eligible and the final sample included 25 studies that evaluated healthcare models in older people with chronic diseases. In the 25 care models, the most frequently implemented interventions were educational, and those based on the provision of healthcare. Only 22% of the outcomes of interventions were identified as being effective, whereas 21% were identified as being partially effective; thus, more than 50% of the outcomes were identified as being ineffective.ConclusionsIt was not possible to determine a care model as effective. The interventions implemented in the models are variable. The most effective outcomes were focused on improving the patient–healthcare professional relationship in the early stages of the intervention. The interventions addressed in the studies were similar to public health interventions as their main objectives focused on promoting health. Most studies were of low methodological quality.

BackgroundMedian arcuate ligament syndrome is a rare disease with overlapping symptoms of broad foregut pathology. Appropriately selected patients can benefit from a laparoscopic or open median arcuate ligament release. Institutional series have reported the outcomes of open and laparoscopic techniques but there are no nationwide analysis comparing both techniques and overall trends in treatment.MethodsCross-sectional study using the American College of Surgeons-National Surgical Quality Improvement Project from 2010 to 2020. Celiac artery compression syndrome cases were identified by International Classification of Diseases (ICD) codes and categorized as open or laparoscopic. Trends in the use of each technique and 30-day complications were compared between the groups.ResultsA total of 578 open cases (76%) and 185 laparoscopic cases (24%) were identified. There was an increase adoption of the laparoscopic approach, with 22% of the cases employing this technique at the end of the study period, compared to 7% at the beginning of the study period. The open group had a higher prevalence of hypertension (26% vs 18%, p = 0.04) and bleeding disorders (5% vs 2%, p 0.03). Laparoscopic approach had a shorter length of stay (2.3 days vs 5.2 days, p < 0.0001), lower major complication rates (0.5% vs 4.0%, p = 0.02) and lower reoperation rates (0% vs 2.6%, p = 0.03). Overall mortality was 0.1%.ConclusionOverall numbers of surgical intervention for treatment of median arcuate ligament increased during this timeframe, as well as increased utilization of the laparoscopic approach. It appears to be an overall safe procedure, offering lower rates of complications and shorter length of stay.

A reduction in platelet count in critically ill patients is a marker of severity of the clinical condition. However, whether this association holds true in acute kidney injury (AKI) is unknown. We analyzed the association between platelet reduction in patients with AKI and major adverse kidney events (MAKE). In this retrospective cohort, we included AKI patients at the Hospital Civil of Guadalajara, in Jalisco, Mexico. Patients were divided according to whether their platelet count fell >21% during the first 10 days. Our objectives were to analyze the associations between a platelet reduction >21% and MAKE at 10 days (MAKE10) or at 30-90 days (MAKE30-90) and death. From 2017 to 2023, 400 AKI patients were included, 134 of whom had  > 21% reduction in platelet count. The mean age was 54 years, 60% were male, and 44% had sepsis. The mean baseline platelet count was 194 x 103 cells/µL, and 65% of the KDIGO3 patients met these criteria. Those who underwent hemodialysis (HD) had lower platelet counts. After multiple adjustments, a platelet reduction >21% was associated with MAKE10 (OR 4.2, CI 2.1-8.5) but not with MAKE30-90. The mortality risk increased 3-fold (OR 2.9, CI 1.1-7.7,  = 0.02) with a greater decrease in the platelets (<90 x 103 cells/µL). As the platelets decreased, the incidence of MAKE was more likely to increase. These associations lost significance when accounting for starting HD. In our retrospective cohort of patients with AKI,  > 21% reduction in platelet count was associated with MAKE. Our results are useful for generating hypotheses and motivating us to continue studying this association with a more robust design.

This study examined the toxicity of anethole and that of the essential oils of lemongrass (Cymbopogon citratus) and sweet marigold (Tagetes lucida) to the mite Varroa destructor and to honey bee workers and larvae. Anethole was the most toxic compound to V. destructor (LC50: 304.9 μg/ml), whereas Tagetes oil was the least toxic (LC50: 1256.27 μg/ml). The most and least toxic compounds to worker bees were anethole and Tagetes oil with LD50s of 35942 and 85381 μg/ml, respectively. For larvae, Tagetes oil was the most toxic compound (LD50: 9580.7 μg/ml) and anethole the least toxic (LD50: 14518.0 μg/ml). Anethole and Cymbopogon oil had the highest selectivity ratios. The expression of AChE, a gene that regulates the production of acetyl cholinesterase, a detoxifying enzyme, was not altered in bees treated with the plant compounds at 48 h post-treatment. This study showed that anethole and Cymbopogon oil have potential for controlling Varroa mites and seem to be relatively safe for larvae and adult honey bees.