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Toxin-antitoxin (TA) systems are widespread in bacteria and implicated in genome stability, virulence, phage defense, and persistence. TA systems have diverse activities and cellular targets, but their physiological roles and regulatory mechanisms are often unclear. Here, we show that the NatR-NatT TA system, which is part of the core genome of the human pathogen Pseudomonas aeruginosa, generates drug-tolerant persisters by specifically depleting nicotinamide dinucleotides. While actively growing P. aeruginosa cells compensate for NatT-mediated NAD + deficiency by inducing the NAD + salvage pathway, NAD depletion generates drug-tolerant persisters under nutrient-limited conditions. Our structural and biochemical analyses propose a model for NatT toxin activation and autoregulation and indicate that NatT activity is subject to powerful metabolic feedback control by the NAD + precursor nicotinamide. Based on the identification of natT gain-of-function alleles in patient isolates and on the observation that NatT increases P. aeruginosa virulence, we postulate that NatT modulates pathogen fitness during infections. These findings pave the way for detailed investigations into how a toxin-antitoxin system can promote pathogen persistence by disrupting essential metabolic pathways., (© 2024. The Author(s).)

An important epigenetic component of tyrosine kinase signaling is the phosphorylation of histones, and epigenetic readers, writers, and erasers. Phosphorylation of protein arginine methyltransferases (PRMTs), have been shown to enhance and impair their enzymatic activity. In this study, we show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates tyrosine residues (Y149 and Y334) in coactivator-associated arginine methyltransferase 1 (CARM1), an important target in hematologic malignancies, increasing its methyltransferase activity and altering its target specificity. While non-phosphorylatable CARM1 methylates some established substrates (e.g. BAF155 and PABP1), only phospho-CARM1 methylates the RUNX1 transcription factor, on R223 and R319. Furthermore, cells expressing non-phosphorylatable CARM1 have impaired cell-cycle progression and increased apoptosis, compared to cells expressing phosphorylatable, wild-type CARM1, with reduced expression of genes associated with G2/M cell cycle progression and anti-apoptosis. The presence of the JAK2-V617F mutant kinase renders acute myeloid leukemia (AML) cells less sensitive to CARM1 inhibition, and we show that the dual targeting of JAK2 and CARM1 is more effective than monotherapy in AML cells expressing phospho-CARM1. Thus, the phosphorylation of CARM1 by hyperactivated JAK2 regulates its methyltransferase activity, helps select its substrates, and is required for the maximal proliferation of malignant myeloid cells., (© 2024. The Author(s).)

Objective: We implemented a chatbot consent tool to shift the time burden from study staff in support of a national genomics research study., Materials and Methods: We created an Institutional Review Board-approved script for automated chat-based consent. We compared data from prospective participants who used the tool or had traditional consent conversations with study staff., Results: Chat-based consent, completed on a user's schedule, was shorter than the traditional conversation. This did not lead to a significant change in affirmative consents. Within affirmative consents and declines, more prospective participants completed the chat-based process. A quiz to assess chat-based consent user understanding had a high pass rate with no reported negative experiences., Conclusion: Our report shows that a structured script can convey important information while realizing the benefits of automation and burden shifting. Analysis suggests that it may be advantageous to use chatbots to scale this rate-limiting step in large research projects., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

In this study, we tested the effects of mechanical leaf removal, insecticide application, and their interaction on leafhoppers and phytophagous and predatory mites occurring in two vineyards over three growing seasons. Leaf removal was performed in the fruit zone using a two-head pulsed air leaf remover, while insecticides were applied with a tunnel air-assisted sprayer at the maximum dose/ha recommended on the product label. Results demonstrated the efficacy of insecticide application in reducing the population densities of leafhoppers but also their detrimental effects on predatory mites. In a number of case studies, leaf removal reduced leafhopper and predatory mite densities. In one vineyard, phytophagous mite populations increased some weeks after leaf removal and insecticide application, highlighting the need to carefully consider the potential impact of vineyard management practices on non-target arthropods in the IPM framework.

Robotic rehabilitation has emerged as a promising approach to enhance motor recovery after stroke, but there is limited knowledge about its efficacy in individuals who have experienced severe stroke. The study presented in this paper aims to analyze the effect of robotic therapy on the recovery of patients with severe stroke when combined with conventional rehabilitation therapies, and we want to observe whether there is a relationship between the clinical assessment provided by the therapist and the data recorded by the robotic device. Participants were divided into an experimental group and a control group, both receiving 15 sessions of conventional therapy in three consecutive weeks, but the experimental group underwent three out of five sessions per week with a robotic device. Both groups were evaluated using clinical scales, and in addition the experimental group was evaluated using an assessment game incorporated in the robotic device that provides session data such as the level of assistance needed by each user to complete the activity, or the score obtained in the game. These preliminary results showed that patients who received robot-assisted therapy had better motor function recovery compared to those who only received conventional therapy. In addition, it is also observed that the robot assistance needed by patients in the experimental group decreased as the sessions progressed, suggesting that robot-assisted therapy could be an effective tool for severe stroke patients.

During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation. DPF2 is a defining subunit of the hematopoiesis-specific BAF (SWI/SNF) chromatin-remodeling complex, and it is mutated in multiple cancers and neurological disorders. We uncovered that hematopoiesis-specific Dpf2-KO mice developed leukopenia, severe anemia, and lethal systemic inflammation characterized by histiocytic and fibrotic tissue infiltration resembling a clinical hyperinflammatory state. Dpf2 loss impaired the polarization of macrophages responsible for tissue repair, induced the unrestrained activation of Th cells, and generated an emergency-like state of HSC hyperproliferation and myeloid cell-biased differentiation. Mechanistically, Dpf2 deficiency resulted in the loss of the BAF catalytic subunit BRG1 from nuclear factor erythroid 2-like 2-controlled (NRF2-controlled) enhancers, impairing the antioxidant and antiinflammatory transcriptional response needed to modulate inflammation. Finally, pharmacological reactivation of NRF2 suppressed the inflammation-mediated phenotypes and lethality of Dpf2Δ/Δ mice. Our work establishes an essential role of the DPF2-BAF complex in licensing NRF2-dependent gene expression in HSCs and immune effector cells to prevent chronic inflammation.

Objectives: We aimed to investigate the frequency of probable sarcopenia and to compare the performance of SARC-F and SARC-CalF for detecting this condition in outpatient older adults from a low-resource setting., Methods: We conducted a retrospective, cross-sectional study in outpatient older adults aged ≥60 years attending a hospital in Peru, between August 2019 and February 2020. Probable sarcopenia was defined as low handgrip strength (<27 kg in men and <16 in women). We used SARC-F and SARC-CalF with their standard cut-off points (≥4 and ≥11, respectively). Low calf circumference was defined as ≤33 cm in women and ≤34 cm in men. We performed sensitivity and specificity analyses., Results: We included 206 older adults, 102 (49.5%) aged ≥75 years old and 140 (67.9%) females. Probable sarcopenia was present in 36.40% of the participants. SARC-F ≥4 was observed in 29.61% and SARC-CalF ≥11 in 41.26% of the population. SARC-F≥4 showed 41.33% sensitivity and 77.10% specificity, whereas SARC-Calf ≥11 had 50.67% sensitivity and 64.12% specificity., Conclusion: We found that one out of three of the population had probable sarcopenia. SARC-Calf showed superior but still low sensitivity than SARC-F, while both had moderate specificity and thus may be useful for ruling out the disease in clinical practice., (Copyright: © 2022 Hylonome Publications.)

Genome organization plays a pivotal role in transcription, but how transcription factors (TFs) rewire the structure of the genome to initiate and maintain the programs that lead to oncogenic transformation remains poorly understood. Acute promyelocytic leukemia (APL) is a fatal subtype of leukemia driven by a chromosomal translocation between the promyelocytic leukemia (PML) and retinoic acid receptor α (RARα) genes. We used primary hematopoietic stem and progenitor cells (HSPCs) and leukemic blasts that express the fusion protein PML-RARα as a paradigm to temporally dissect the dynamic changes in the epigenome, transcriptome, and genome architecture induced during oncogenic transformation. We found that PML-RARα initiates a continuum of topologic alterations, including switches from A to B compartments, transcriptional repression, loss of active histone marks, and gain of repressive histone marks. Our multiomics-integrated analysis identifies Klf4 as an early down-regulated gene in PML-RARα-driven leukemogenesis. Furthermore, we characterized the dynamic alterations in the Klf4 cis -regulatory network during APL progression and demonstrated that ectopic Klf4 overexpression can suppress self-renewal and reverse the differentiation block induced by PML-RARα. Our study provides a comprehensive in vivo temporal dissection of the epigenomic and topological reprogramming induced by an oncogenic TF and illustrates how topological architecture can be used to identify new drivers of malignant transformation., (© 2022 Mas et al.; Published by Cold Spring Harbor Laboratory Press.)

This study aimed to describe the perception about vaccines and the level of knowledge, attitudes and practices towards COVID-19 in older adults from a hospital in Lima, Peru. Descriptive and cross-sectional study carried out from March to November 2021. An instrument was adapted and validated to measure the level of knowledge, attitudes and practices; the perception about vaccines was evaluated with an exploratory questionnaire. Eighty-three older adults were surveyed, the mean age was 74.0 years and 62.7% were women. Most of the participants knew the cause and symptoms, and 50.6% believed that it could be transmitted by contaminated food. Additionally, 61.7% used traditional medicine to prevent it, and 65.4% considered that the level of social awareness was insufficient; 91.5% were vaccinated against COVID-19, and 65.4% considered these vaccines to be safe. In conclusion, most older adults showed a high level of knowledge, attitudes and practices and a positive perception about the vaccine against COVID-19.