Vagal-α7 nicotinic acetylcholine receptor signaling exacerbates influenza severity by promoting lung epithelial cell infection.

The vagus nerve circuit, operating through the alpha-7 nicotinic acetylcholine receptor (α7 nAChR), regulates the inflammatory response by influencing immune cells. However, the role of vagal-α7 nAChR signaling in influenza virus infection is unclear. In particular, does vagal-α7 nAChR signaling impact the infection of alveolar epithelial cells (AECs), the primary target cells of influenza virus? Here, we demonstrated a distinct role of α7 nAChR in type II AECs compared to its role in immune cells during influenza infection. We found that deletion of Chrna7 (encoding gene of α7 nAChR) in type II AECs or disruption of vagal circuits reduced lung influenza infection and protected mice from influenza-induced lung injury. We further unveiled that activation of α7 nAChR enhanced influenza infection through PTP1B-NEDD4L-ASK1-p38MAPK pathway. Mechanistically, activation of α7 nAChR signaling decreased p38MAPK phosphorylation during infection, facilitating the nuclear export of influenza viral ribonucleoproteins and thereby promoting infection. Taken together, our findings reveal a mechanism mediated by vagal-α7 nAChR signaling that promotes influenza viral infection and exacerbates disease severity. Targeting vagal-α7 nAChR signaling may offer novel strategies for combating influenza virus infections.

Identification of pancreatic adenocarcinoma immune subtype associated with tumor neoantigen from aberrant alternative splicing.

Background: Pancreatic adenocarcinoma (PAAD) is referred to as an immunologically "cold" tumor that responds poorly to immunotherapy. A fundamental theory that explains the low immunogenicity of PAAD is the dramatically low tumor mutation burden (TMB) of PAAD tumors, which fails to induce sufficient immune response. Alternative splicing of pre-mRNA, which could alter the proteomic diversity of many cancers, has been reported to be involved in neoantigen production. Therefore, we aim to identify novel PAAD antigens and immune subtypes through systematic bioinformatics research. Methods: Data for splicing analysis were downloaded from The Cancer Genome Atlas (TCGA) SpliceSeq database. Among the available algorithms, we chose CIBERSORT to evaluate the immune cell distribution among PAADs. The TCGA-PAAD expression matrix was used to construct a co-expression network. Single-cell analysis was performed based on the Seurat workflow. Results: Integrated analysis of aberrantly upregulated genes, alternatively spliced genes, genes associated with nonsense-mediated RNA decay (NMD) factors, antigen presentation and overall survival (OS) in TCGA-PAAD revealed that PLEC is a promising neoantigen for PAAD-targeted therapy. We identified a C2 TCGA-PAAD subtype that had better prognosis and more CD8+ T-cell infiltration. We propose a novel immune subtyping system for PAAD to indicate patient prognosis and opportunities for immunotherapy, such as immune checkpoint (ICP) inhibitors. Conclusions: In conclusion, the present study used a transcriptome-guided approach to screen neoantigen candidates based on alternative splicing, NMD factors, and antigen-presenting signatures for PAAD. A prognosis model with guidance of immunotherapy will aid in patient selection for appropriate treatment.

The effect of coffee consumption on three main bone disorders: a Mendelian randomization trial.

INTRODUCTION: Despite a large number of observational studies examining the effect of coffee consumption(CC) on bone disorders(BDs), particularly, osteoarthritis(OA), osteoportic fracture(OF), and rheumatoid arthritis(RA), the conclusions are highly controversial. Thus, it is essential to examine the causal association between CC and BDs. MATERIALS AND METHODS: Mendelian randomization (MR) analysis was performed to assess the causal influence of CC on OF, RA, and OA. The main endpoint was the odds ratio (OR) of the inverse variance weighted (IVW) approach. In addition, the weighted median (WM), MR-Egger regressions, MR-pleiotropy residual sum and outlier (MR-PRESSO) and multivariable MR (MVMR) were included in sensitivity analyses. Furthermore, the function of causal SNPs was evaluated by gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction networks. RESULTS: Primary MR analysis based on the IVW method suggested that changes in CC alter risk of OF (OR = 1.383, 95%CI 1.079-1.853, P = 0.039), RA(OR: 1.623, 95%CI 1.042-2.527, P = 0.032) and HOA (hip osteoarthritis, OR = 1.536, 95% CI 1.044-2.259, P = 0.021). However, these causal relationships were not robust in sensitivity analyses. In contrast, there is a positive causal relationship between increased CC and the risk of KOA (knee osteoarthritis, OR: 2.094, 95%CI: 1.592-2.754, P = 1.41 × 10-7), as evidenced by the IVW using random effect. A similar effect size was observed across all MR sensitivity analyses, with no evidence of horizontal pleiotropy. CONCLUSION: Based on our MR analysis, increased CC was causally linked to an increase in the risk of KOA. Genetic predictions suggested that CC reduction may have benefits for bone health.

Inulin-gel-based oral immunotherapy remodels the small intestinal microbiome and suppresses food allergy.

Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells in the small intestine, suppressed pathogenic type 2 immune responses, increased interferon-γ+ and interleukin-10+ regulatory T cell populations, and restored ileal abundances of Eggerthellaceae and Enterorhabdus in allergic mice. Overall, our findings underscore the therapeutic potential of the engineered allergen gel as a suitable microbiome-modulating platform for food allergy and other allergic diseases.

Correction: Fundamental and practical approaches for single-cell ATAC-seq analysis.

[This corrects the article DOI: 10.1007/s42994-022-00082-5.].

Inhibitor of cardiolipin biosynthesis-related enzyme MoGep4 confers broad-spectrum anti-fungal activity.

Plant pathogens cause devastating diseases, leading to serious losses to agriculture. Mechanistic understanding of pathogenesis of plant pathogens lays the foundation for the development of fungicides for disease control. Mitophagy, a specific form of autophagy, is important for fungal virulence. The role of cardiolipin, mitochondrial signature phospholipid, in mitophagy and pathogenesis is largely unknown in plant pathogenic fungi. The functions of enzymes involved in cardiolipin biosynthesis and relevant inhibitors were assessed using a set of assays, including genetic deletion, plant infection, lipidomics, chemical-protein interaction, chemical inhibition, and field trials. Our results showed that the cardiolipin biosynthesis-related gene MoGEP4 of the rice blast fungus Magnaporthe oryzae regulates growth, conidiation, cardiolipin biosynthesis, and virulence. Mechanistically, MoGep4 regulated mitophagy and Mps1-MAPK phosphorylation, which are required for virulence. Chemical alexidine dihydrochloride (AXD) inhibited the enzyme activity of MoGep4, cardiolipin biosynthesis and mitophagy. Importantly, AXD efficiently inhibited the growth of 10 plant pathogens and controlled rice blast and Fusarium head blight in the field. Our study demonstrated that MoGep4 regulates mitophagy, Mps1 phosphorylation and pathogenesis in M. oryzae. In addition, we found that the MoGep4 inhibitor, AXD, displays broad-spectrum antifungal activity and is a promising candidate for fungicide development.

A novel compound alleviates oxidative stress via PKA/CREB1-mediated DJ-1 upregulation.

Oxidative stress is one of the major culprits causing dopaminergic neuron loss in Parkinson's disease (PD). DJ-1 is a protein with multiple actions against oxidative stress, apoptosis, neuroinflammation, etc. DJ-1 expression is decreased in sporadic PD, therefore increasing DJ-1 expression might be beneficial in PD treatment. However, drugs known to upregulate DJ-1 are still lacking. In this study, we identified a novel DJ-1-elevating compound called ChemJ through luciferase assay-based high-throughput compound screening in SH-SY5Y cells and confirmed that ChemJ upregulated DJ-1 in SH-SY5Y cell line and primary cortical neurons. DJ-1 upregulation by ChemJ alleviated MPP+-induced oxidative stress. In exploring the underlying mechanisms, we found that the transcription factor CREB1 bound to DJ-1 promoter and positively regulated its expression under both unstressed and 1-methyl-4-phenylpyridinium-induced oxidative stress conditions and that ChemJ promoted DJ-1 expression via activating PKA/CREB1 pathway in SH-SY5Y cells. Our results demonstrated that ChemJ alleviated the MPP+-induced oxidative stress through a PKA/CREB1-mediated regulation of DJ-1 expression, thus offering a novel and promising avenue for PD treatment.

ROR2 promotes invasion and chemoresistance of triple-negative breast cancer cells by activating PI3K/AKT/mTOR signaling.

Objective: This study aimed to investigate the role of receptor tyrosine kinase-like orphan receptor 2 (ROR2) in triple-negative breast cancer (TNBC). Methods: ROR2 expression in primary TNBC and metastatic TNBC tissues was analyzed by immunohistochemical staining and PCR. ROR2 expression in TNBC cell lines was detected by PCR and Western blot analysis. The migration, invasion and chemosensitivity of TNBC cells with overexpression or knockdown of ROR2 were examined. Results: ROR2 expression was high in metastatic TNBC tissues. ROR2 knockdown suppressed the migration, invasion and chemoresistance of TNBC cells. ROR2 overexpression in MDA-MB-435 cells promoted the migration, invasion, and chemoresistance. Moreover, ROR2 knockdown in HC1599 and MDA-MB-435 adriamycin-resistant cells enhanced chemosensitivity to adriamycin. ROR2 could activate PI3K/AKT/mTOR signaling in TNBC cells. Conclusion: ROR2 is upregulated and promotes metastatic phenotypes of TNBC by activating PI3K/AKT/mTOR signaling.

Hydrazone-functionalized nanoscale covalent organic frameworks as a nanocarrier for pH-responsive drug delivery enhanced anticancer activity.

Nanoscale covalent organic frameworks (NCOFs) as emerging drug-delivery nanocarriers have received much attention in biomedicine in recent years. However, there are few reports on the application of pH-responsive NCOFs for drug delivery nanosystems. In this work, hydrazone-decorated NCOFs as pH-triggered molecular switches are designed for efficient cancer therapy. These functionalized NCOFs with hydrazone groups on the channel walls (named NCOFs-NHNH2) are obtained via a post-synthetic modification strategy. Subsequently, the anticancer drug doxorubicin (DOX) as the model molecule is loaded through covalent linkage to yield NCOFs-NN-DOX. Finally, soybean phospholipid (SP) is coated on the surface of HNTs-NN-DOX, named NCOFs-NN-DOX@SP, to further enhance the dispersibility, stability and biocompatibility of HNTs in physiological solution. NCOFs-NN-DOX@SP showed an excellent and intelligent sustained-release effect with an almost sixfold increase at pH = 5.2 than at pH = 7.4. In vitro cell toxicity and imaging assays of NCOFs-NN-DOX@SP exhibited an enhanced therapeutic effect on Lewis lung carcinoma (LLC) cells, demonstrating that the fabricated NCOFs have a great potential in cancer therapy. Thus, this work provides a new way toward designing stimulus-responsive functionalized NCOFs and promotes their potential application as an on-demand drug delivery system in the field of cancer treatment.

A highly sensitive luminescent aptasensor utilizing MOF-74-co encapsulation of luminol in a 'turn-on' mode for streptomycin detection.

This study focused on detecting streptomycin (STR) residues using a luminescent aptasensor encapsulated with aptamer. Utilizing MOF-74-Co with peroxidase-like activity, luminol was enclosed in its pores. The specific STR aptamer acted as a gatekeeper, ensuring excellent performance. Upon exposure to STR, the aptamers detached, releasing luminol and amplifying the luminescent signal through MOF-74-Co catalytic activity. A linear relationship between fluorescence intensity and STR concentration (50 nM âˆ¼ 5 × 106 nM) was established, with a limit of detection of 0.065 nM. The sensor exhibited high selectivity for STR even in the presence of other aminoglycoside antibiotics. Applied to tea, egg, and honey samples, the sensor showed recovery rates of 91.38-100.2%, meeting safety standards. This MOF-based aptasensor shows promise for detecting harmful residues.

Mammary Paget's Disease as a Sign of Local Recurrence Two Decades Following Breast Conservation and Adjuvant Therapy for Early Stage Breast Cancer.

Reports of mammary Paget's disease (MPD) as a manifestation of breast cancer recurrence are rare. MPD presents a particular challenge when emerging more than two decades after a breast cancer treated with evidence-based therapy. There is a broad spectrum of non-malignant causes for dermatitis of the nipple during the initial presentation that may delay cancer work-up. This case highlights the MPD work-up and management in the context of a personal history of breast cancer. This unique clinical presentation emphasizes the importance of vigilant cancer surveillance for timely intervention, especially for a presumed cured cancer.

Ectopic parathyroid adenoma on sternocleidomastoid muscle: a case report.

A 54-year-old woman was admitted to the hospital with a left neck mass. Enhanced CT and ultrasound examinations revealed a lesion in the left sternocleidomastoid muscle. The patient undergone right thyroid lobe resection 8 years ago. Interestingly, the lesion on the sternocleidomastoid muscle, along with the left lobe of the patient's thyroid, visually appears to form a displaced and complete thyroid in the early Tc-99m-MIBI parathyroid scintigraphy. Combined with Tc-99m-MIBI scintigraphy and abnormal PTH and blood calcium levels, the consideration was given to the lesion in the sternocleidomastoid muscle as an ectopic parathyroid adenoma. Subsequent surgical pathology confirmed this suspicion.

Role of acupuncture in improving the outcome of sepsis-induced lung injury.

OBJECTIVE: The purpose of this study was to investigate the effect of serum exosomes of mice after acupuncture (acu-exo) on acute lung injury (ALI) in sepsis in vitro and in vivo. METHODS: Serum exosomes (acu-exo) of normal mice were prepared after acupuncture. Lipopolysaccharide (LPS) was used to establish the model of ALI in vivo and in vitro. Immunohistochemistry, western blot, and immunofluorescence were used to evaluate the mechanism of acu-exo on ALI. P2X7 knockout mice and P2X7 siRNA were used to verify the mechanism. RESULTS: Compared with normal mice, serum exosomes were significantly increased in normal mice after acupuncture. The results showed that P2X7 was increased in the lung of septic mice as compared with the WT group. It was also found that the increase in NLRP3 and NF-κB was accompanied by the activation of P2X7. Increased P2X7 led to activation of the P2X7 receptor causing mitochondrial dysfunctions in lung tissue of septic mice. Knockout of P2X7 or silenced P2X7 markedly decreased NLRP3 and NF-κB and led to mitochondrial function recovery in lung tissue of sepsis. At the same time, acu-exo significantly restored the above changes in the lung tissue of septic mice. CONCLUSIONS: Inhibition of P2X7 led to mitochondrial function recovery of lung tissue by inhibiting NLRP3 and NF-κB. At the same time, acu-exo could improve ALI by decreasing NLRP3 and NF-κB activation.

Rapid Mass Spectrometry-Based Multiattribute Method for Glycation Analysis with Integrated Afucosylation Detection Capability.

The multiattribute method (MAM) has emerged as a powerful tool for simultaneously screening multiple product quality attributes of therapeutic antibodies. One such potential critical quality attribute (CQA) is glycation, a common modification that can impact the heterogeneity, functional activity, and immunogenicity of therapeutic antibodies. However, current methods for monitoring glycation levels in MAM are rare and not sufficiently rapid and accurate. In this study, an improved mass spectrometry (MS)-based MAM was developed to simultaneously monitor glycation and other quality attributes including afucosylation. The method was evaluated using two therapeutic antibodies with different glycosylation site numbers. Treatment with IdeS, Endo F2, and dithiothreitol generated three distinct subunits, and the glycation results obtained were similar to those treated with PNGase F, which is routinely used to release glycans; the sample processing time was greatly reduced while providing additional quality attribute information. The MS-based MAM was also employed to assess the glycation progression following forced glycation in various buffer solutions. A significant increase in oxidation was observed when forced glycation was conducted in an ammonium bicarbonate buffer solution, and a total of 23 potential glycation sites and 4 significantly oxidized sites were identified. Notably, we found that ammonium bicarbonate was found to specifically stimulate oxidation, while glycation had a synergistic effect on oxidation. These findings establish this study as a novel methodology for achieving a technologically advanced platform and concept that enhances the efficacy of product development and quality control, characterized by its broad-spectrum, rapid, and accurate nature.

[Hydrochemical and Stable Isotopic Characteristics and Transformation Relationship of Water Bodies in the Guohe River Basin, Anhui Province].

The Guohe River Basin in Anhui Province was selected as the research area for this study. By collecting surface water, shallow groundwater, and middle-deep groundwater samples, various hydrochemical parameters and stable isotopes of water in different water bodies were analyzed using methods such as the Gibbs diagram, ion ratios, and MixSIAR model to reveal and quantify the transformation relationships between these water bodies. The results indicated that both surface water and groundwater in the study area were predominantly neutral to weakly alkaline. The hydrochemical types of surface water were mainly characterized by Cl·SO4·HCO3-Na and Cl·SO4-Na types, whereas the shallow groundwater exhibited HCO3-Ca·Mg and HCO3-Mg·Na types, and the middle-deep groundwater was of the Cl·HCO3-Na type. The hydrochemical characteristics of various water bodies were influenced by multiple factors such as rock weathering, evaporation concentration, and positive cation exchange. The distribution characteristics of δ18O and δ2H values in surface water and groundwater indicated that atmospheric precipitation was the main water source. The δ18O and δ2H in groundwater were significantly correlated with K+, Na+, Cl-, SO42-, and NO3-. According to the analysis using the MixSIAR model, the contribution of atmospheric precipitation to surface water was 46.5 %, whereas the contribution from shallow groundwater was 53.5 %. The sources of shallow groundwater were identified as atmospheric precipitation (57.4 %) and surface water (42.6 %), and the main source of supply for middle-deep groundwater was lateral flow from upstream groundwater.

Decay and Termite Resistance of Wood Modified by High-Temperature Vapour-Phase Acetylation (HTVPA), a Simultaneous Acetylation and Heat Treatment Modification Process.

High-temperature vapour-phase acetylation (HTVPA) is a simultaneous acetylation and heat treatment process for wood modification. This study was the first investigation into the impact of HTVPA treatment on the resistance of wood to biological degradation. In the termite resistance test, untreated wood exhibited a mass loss (MLt) of 20.3%, while HTVPA-modified wood showed a reduced MLt of 6.6-3.2%, which decreased with an increase in weight percent gain (WPG), and the termite mortality reached 95-100%. Furthermore, after a 12-week decay resistance test against brown-rot fungi (Laetiporus sulfureus and Fomitopsis pinicola), untreated wood exhibited mass loss (MLd) values of 39.6% and 54.5%, respectively, while HTVPA-modified wood exhibited MLd values of 0.2-0.9% and -0.2-0.3%, respectively, with no significant influence from WPG. Similar results were observed in decay resistance tests against white-rot fungi (Lenzites betulina and Trametes versicolor). The results of this study demonstrated that HTVPA treatment not only effectively enhanced the decay resistance of wood but also offered superior enhancement relative to separate heat treatment or acetylation processes. In addition, all the HTVPA-modified wood specimens prepared in this study met the requirements of the CNS 6717 wood preservative standard, with an MLd of less than 3% for decay-resistant materials.

Machine learning constructs a diagnostic prediction model for calculous pyonephrosis.

In order to provide decision-making support for the auxiliary diagnosis and individualized treatment of calculous pyonephrosis, the study aims to analyze the clinical features of the condition, investigate its risk factors, and develop a prediction model of the condition using machine learning techniques. A retrospective analysis was conducted on the clinical data of 268 patients with calculous renal pelvic effusion who underwent ultrasonography-guided percutaneous renal puncture and drainage in our hospital during January 2018 to December 2022. The patients were included into two groups, one for pyonephrosis and the other for hydronephrosis. At a random ratio of 7:3, the research cohort was split into training and testing data sets. Single factor analysis was utilized to examine the 43 characteristics of the hydronephrosis group and the pyonephrosis group using the T test, Spearman rank correlation test and chi-square test. Disparities in the characteristic distributions between the two groups in the training and test sets were noted. The features were filtered using the minimal absolute value shrinkage and selection operator on the training set of data. Auxiliary diagnostic prediction models were established using the following five machine learning (ML) algorithms: random forest (RF), xtreme gradient boosting (XGBoost), support vector machines (SVM), gradient boosting decision trees (GBDT) and logistic regression (LR). The area under the curve (AUC) was used to compare the performance, and the best model was chosen. The decision curve was used to evaluate the clinical practicability of the models. The models with the greatest AUC in the training dataset were RF (1.000), followed by XGBoost (0.999), GBDT (0.977), and SVM (0.971). The lowest AUC was obtained by LR (0.938). With the greatest AUC in the test dataset going to GBDT (0.967), followed by LR (0.957), XGBoost (0.950), SVM (0.939) and RF (0.924). LR, GBDT and RF models had the highest accuracy were 0.873, followed by SVM, and the lowest was XGBoost. Out of the five models, the LR model had the best sensitivity and specificity is 0.923 and 0.887. The GBDT model had the highest AUC among the five models of calculous pyonephrosis developed using the ML, followed by the LR model. The LR model was considered be the best prediction model when combined with clinical operability. As it comes to diagnosing pyonephrosis, the LR model was more credible and had better prediction accuracy than common analysis approaches. Its nomogram can be used as an additional non-invasive diagnostic technique.

Seasonal and Genetic Characteristics of Human Metapneumovirus Circulating - Henan Province, China, 2017-2023.

Introduction: This study examines the seasonal and genetic characteristics of human metapneumovirus (HMPV) in Henan from 2017 to 2023. Methods: Samples from patients with acute respiratory infection (ARI) testing positive for HMPV were subjected to real-time reverse transcription polymerase chain reaction The G gene was amplified and sequenced from these samples for epidemiological and phylogenetic analysis. Results: We enrolled 2,707 ARI patients from October 2017 to March 2023, finding an HMPV positivity rate of 6.17% (167/2,707). Children under five exhibited the highest infection rate at 7.78% (138/1,774). The 2018 and 2019 HMPV outbreaks predominantly occurred in spring (March to May), with peak positivity rates of 31.11% in May 2018 and 19.57% in May 2019. A notable increase occurred in November 2020, when positivity reached a historic high of 42.11%, continuing until January 2021. From February 2021 through March 2023, no significant seasonal peaks were observed, with rates ranging from 0% to 8.70%. Out of 81 G gene sequences analyzed, 46.91% (38/81) were identified as subtype A (A2c: 45.67%, 37/81; A2b: 1.23%, 1/81) and 53.09% (43/81) as subtype B (B1: 9.88%, 8/81; B2: 43.21%, 35/81). Notably, an AAABBA switch pattern was observed in HMPV subtypes. The dominant strains were A2c111nt-dup in subtype A and B2 in subtype B. Conclusions: Six years of surveillance in Henan Province has detailed the seasonal and genetic dynamics of HMPV, contributing valuable insights for the control and prevention of HMPV infections in China. These findings support the development of targeted HMPV vaccines and immunization strategies.

Target Recognition Triggered Split DNAzyme based Colorimetric Assay for Direct and Sensitive Methicillin-Resistance Analysis of Staphylococcus aureus.

The accurate and rapid detection of methicillin-resistant Staphylococcus aureus (MRSA) holds significant clinical importance. This work presents a new method for detecting methicillin-resistant Staphylococcus aureus (S. aureus) in clinical samples. The method uses an aptamer-based colorimetric assay that combines a recognizing probe to identify the target and split DNAzyme to amplify the signal, resulting in a highly sensitive and direct analysis of methicillin-resistance. The identification of the PBP2a protein on the membrane of S. aureus in clinical samples leads to the allosterism of the recognizing probe, and thus provides a template for the proximity ligation of split DNAzyme. The proximity ligation of split DNAzyme forms an intact DNAzyme to identify the loop section in the L probe and generates a nicking site to release the loop sequence ("3" and "4" fragments). The "3" and "4" fragments forms an intact sequence to induce the catalytic hairpin assembly, exposing the G-rich section. The released the G-rich sequence of LR probe induces the formation of G-quadruplex-hemin DNAzyme as a colorimetric signal readout. The absorption intensity demonstrated a strong linear association with the logarithm of the S. aureus concentration across a wide range of 5 orders of magnitude dynamic range under the optimized experimental parameters. The limit of detection was calculated to be 23 CFU/ml and the method showed high selectivity for MRSA.

Styxl2 regulates de novo sarcomere assembly by binding to non-muscle myosin IIs and promoting their degradation.

Styxl2, a poorly characterized pseudophosphatase, was identified as a transcriptional target of the Jak1-Stat1 pathway during myoblast differentiation in culture. Styxl2 is specifically expressed in vertebrate striated muscles. By gene knockdown in zebrafish or genetic knockout in mice, we found that Styxl2 plays an essential role in maintaining sarcomere integrity in developing muscles. To further reveal the functions of Styxl2 in adult muscles, we generated two inducible knockout mouse models: one with Styxl2 being deleted in mature myofibers to assess its role in sarcomere maintenance, and the other in adult muscle satellite cells (MuSCs) to assess its role in de novo sarcomere assembly. We find that Styxl2 is not required for sarcomere maintenance but functions in de novo sarcomere assembly during injury-induced muscle regeneration. Mechanistically, Styxl2 interacts with non-muscle myosin IIs, enhances their ubiquitination, and targets them for autophagy-dependent degradation. Without Styxl2, the degradation of non-muscle myosin IIs is delayed, which leads to defective sarcomere assembly and force generation. Thus, Styxl2 promotes de novo sarcomere assembly by interacting with non-muscle myosin IIs and facilitating their autophagic degradation.