The autophagy-targeting compound V46 enhances antimicrobial responses to Mycobacteroides abscessus by activating transcription factor EB.

Mycobacteroides abscessus (Mabc) is a rapidly growing nontuberculous mycobacterium that poses a considerable challenge as a multidrug-resistant pathogen causing chronic human infection. Effective therapeutics that enhance protective immune responses to Mabc are urgently needed. This study introduces trans-3,5,4'-trimethoxystilbene (V46), a novel resveratrol analogue with autophagy-activating properties and antimicrobial activity against Mabc infection, including multidrug-resistant strains.

pHeeling the pHorce.

In this issue of Neuron, Yamada et al. show that fast excitatory neurotransmission by protons acting at acid-sensing ion channels (ASICs) mediates mechanical force-evoked signaling at the Merkel cell-neurite complex, contributing to mammalian tactile discrimination.

Skin Reinnervation by Collateral Sprouting Following Spared Nerve Injury in Mice.

Following peripheral nerve injury, denervated tissues can be reinnervated via regeneration of injured neurons or collateral sprouting of neighboring uninjured afferents into denervated territory. While there has been substantial focus on mechanisms underlying regeneration, collateral sprouting has received less attention. Here, we used immunohistochemistry and genetic neuronal labeling to define the subtype specificity of sprouting-mediated reinnervation of plantar hindpaw skin in the mouse spared nerve injury (SNI) model, in which productive regeneration cannot occur.

Deep Learning-based Assessment of Facial Asymmetry Using U-Net Deep Convolutional Neural Network Algorithm.

Objectives: This study aimed to evaluate the diagnostic performance of a deep convolutional neural network (DCNN)-based computer-assisted diagnosis (CAD) system to detect facial asymmetry on posteroanterior (PA) cephalograms and compare the results of the DCNN with those made by the orthodontist.

Materials And Methods: PA cephalograms of 1020 patients with orthodontics were used to train the DCNN-based CAD systems for autoassessment of facial asymmetry, the degree of menton deviation, and the coordinates of its regarding landmarks. Twenty-five PA cephalograms were used to test the performance of the DCNN in analyzing facial asymmetry.

Lactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolism.

Histone acetylation involves the transfer of two-carbon units to the nucleus that are embedded in low-concentration metabolites. We found that lactate, a high-concentration metabolic byproduct, can be a major carbon source for histone acetylation through oxidation-dependent metabolism. Both in cells and in purified nuclei, C-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%).

Thromboembolic events in patients who received adjuvant chemotherapy for gastric cancer: a single-center retrospective study.

Background: Thromboembolic events (TEEs) are significant adverse events that can cause serious morbidities and mortality in cancer patients receiving chemotherapy. Patients with gastric cancer (GC) treated with palliative chemotherapy have been reported to experience a TEE incidence of 5-27%. However, very few reports have addressed TEEs in adjuvant chemotherapy (AC) for GC.

Chemical mimetics of the N-degron pathway alleviate systemic inflammation by activating mitophagy and immunometabolic remodeling.

The Arg/N-degron pathway, which is involved in the degradation of proteins bearing an N-terminal signal peptide, is connected to p62/SQSTM1-mediated autophagy. However, the impact of the molecular link between the N-degron and autophagy pathways is largely unknown in the context of systemic inflammation. Here, we show that chemical mimetics of the N-degron Nt-Arg pathway (p62 ligands) decreased mortality in sepsis and inhibited pathological inflammation by activating mitophagy and immunometabolic remodeling.

Targeting ERRα promotes cytotoxic effects against acute myeloid leukemia through suppressing mitochondrial oxidative phosphorylation.

Acute myeloid leukemia (AML) is an aggressive blood cancer with poor clinical outcomes. Emerging data suggest that mitochondrial oxidative phosphorylation (mtOXPHOS) plays a significant role in AML tumorigenesis, progression, and resistance to chemotherapies. However, how the mtOXPHOS is regulated in AML cells is not well understood.

Ohmyungsamycin promotes M1-like inflammatory responses to enhance host defence against infections.

Ohmyungsamycin A (OMS) is a newly identified cyclic peptide that exerts antimicrobial effects against . However, its role in nontuberculous mycobacteria (NTMs) infections has not been clarified. (Mabc) is a rapidly growing NTM that has emerged as a human pathogen in both immunocompetent and immunosuppressed individuals.

Arginine-mediated gut microbiome remodeling promotes host pulmonary immune defense against nontuberculous mycobacterial infection.

Nontuberculous mycobacterial pulmonary diseases (NTM-PDs) are emerging as global health threats with issues of antibiotic resistance. Accumulating evidence suggests that the gut-lung axis may provide novel candidates for host-directed therapeutics against various infectious diseases. However, little is known about the gut-lung axis in the context of host protective immunity to identify new therapeutics for NTM-PDs.

Chemical modulation of SQSTM1/p62-mediated xenophagy that targets a broad range of pathogenic bacteria.

The N-degron pathway is a proteolytic system in which the N-terminal degrons (N-degrons) of proteins, such as arginine (Nt-Arg), induce the degradation of proteins and subcellular organelles via the ubiquitin-proteasome system (UPS) or macroautophagy/autophagy-lysosome system (hereafter autophagy). Here, we developed the chemical mimics of the N-degron Nt-Arg as a pharmaceutical means to induce targeted degradation of intracellular bacteria via autophagy, such as serovar Typhimurium (. Typhimurium), , and as well as (Mtb).

A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis.

Hexokinase 2 (HK2), which catalyzes the first committed step in glucose metabolism, is induced in cancer cells. HK2's role in tumorigenesis has been attributed to its glucose kinase activity. Here, we describe a kinase independent HK2 activity, which contributes to metastasis.

miR-544-3p mediates arthritis pain through regulation of FcγRI.

Chronic joint pain is a major symptom in rheumatoid arthritis (RA) and its adequate treatment represents an unmet medical need. Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of RA as negative regulators of specific target mRNAs. Yet, their significance in RA pain is still not well defined.

Rufomycin Exhibits Dual Effects Against Infection by Inducing Host Defense and Antimicrobial Activities.

Nontuberculous mycobacterial pulmonary infection is often aggravated due to antibiotic resistance issues. There is a need for development of new drugs inducing both host immune responses and antimicrobial activities. This study shows that the rufomycins 4/5/6/7 (Rufomycin 4-7), which targets ClpC1 as a subunit of caseinolytic protein complex ClpC1/ClpP1/ClpP2 of mycobacteria, exhibits a dual effect in host innate defense and antimicrobial activities against a rough morphotype of (Mabs-R), a clinically severe morphotype that causes hyperinflammation.

Sex-Dependent Reduction in Mechanical Allodynia in the Sural-Sparing Nerve Injury Model in Mice Lacking Merkel Cells.

Innocuous touch sensation is mediated by cutaneous low-threshold mechanoreceptors (LTMRs). Aβ slowly adapting type I (SAI) neurons constitute one LTMR subtype that forms synapse-like complexes with associated Merkel cells in the basal skin epidermis. Under healthy conditions, these complexes transduce indentation and pressure stimuli into Aβ SAI LTMR action potentials that are transmitted to the CNS, thereby contributing to tactile sensation.

Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice.

Mitochondrial function and innate immunity are intimately linked; however, the mechanisms how mitochondrion-shaping proteins regulate innate host defense remains largely unknown. Herein we show that mitofusin-2 (MFN2), a mitochondrial fusion protein, promotes innate host defense through the maintenance of aerobic glycolysis and xenophagy via hypoxia-inducible factor (HIF)-1α during intracellular bacterial infection. Myeloid-specific MFN2 deficiency in mice impaired the antimicrobial and inflammatory responses against mycobacterial and listerial infection.

NRF2 Activation Promotes Aggressive Lung Cancer and Associates with Poor Clinical Outcomes.

Purpose: Stabilization of the transcription factor NRF2 through genomic alterations in and occurs in a quarter of patients with lung adenocarcinoma and a third of patients with lung squamous cell carcinoma. In lung adenocarcinoma, loss often co-occurs with loss and -activating alterations. Despite its prevalence, the impact of NRF2 activation on tumor progression and patient outcomes is not fully defined.

Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics.

Autophagy is an intracellular process that targets intracellular pathogens for lysosomal degradation. Autophagy is tightly controlled at transcriptional and post-translational levels. Nuclear receptors (NRs) are a family of transcriptional factors that regulate the expression of gene sets involved in, for example, metabolic and immune homeostasis.

Sirtuin 3 is essential for host defense against infection through regulation of mitochondrial homeostasis.

The global incidence of (Mabc), a rapidly growing nontuberculous mycobacterial strain that causes treatment-refractory pulmonary diseases, is increasing. Despite this, the host factors that allow for protection against infection are largely unknown. In this study, we found that sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, plays a critical role in host defense against Mabc infection.

Impact of a Ketogenic Diet on Metabolic Parameters in Patients with Obesity or Overweight and with or without Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials.

The aim of this meta-analysis was to explore the efficacy of a ketogenic diet in metabolic control in patients with overweight or obesity and with or without type 2 diabetes. Embase, PubMed, and Cochrane Library were searched for randomized controlled trials that enrolled patients with overweight or obesity on a ketogenic diet for metabolic control. Fourteen studies were included in meta-analysis.

Vancomycin Dosage and Its Association with Clinical Outcomes in Pediatric Patients with Gram-Positive Bacterial Infections.

Aim: The aim of this study was to evaluate whether vancomycin trough concentrations at initial steady state are associated with clinical and microbiological outcomes along with vancomycin-related nephrotoxicity in pediatric patients with Gram-positive bacterial (GPB) infections.

Methods: A retrospective cohort study of pediatric patients who received vancomycin for ≥72 hours during 2008-2016 was conducted. Study patients were divided into three cohorts in accordance with their first trough levels at steady state: <5 mg/L (lower-trough), 5-10 mg/L (low-trough), and >10 mg/L (high-trough; reference) cohorts.

Diol-ginsenosides from Korean Red Ginseng delay the development of type 1 diabetes in diabetes-prone biobreeding rats.

Background: The effects of diol-ginsenoside fraction (Diol-GF) and triol-ginsenoside fraction (Triol-GF) from Korean Red Ginseng on the development of type 1 diabetes (T1D) were examined in diabetes-prone biobreeding (DP-BB) rats that spontaneously develop T1D through an autoimmune process.

Methods: DP-BB female rats were treated with Diol-GF or Triol-GF daily from the age of 3-4 weeks up to 11-12 weeks (1 mg/g body weight).

Results: Diol-GF delayed the onset, and reduced the incidence, of T1D.