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Yu Jiang,1,* Miao Yu,1,* Zhi-Feng Song,1,* Zhi-Yao Wei,1 Ji Huang,2 Hai-Yan Qian1 1Center for Coronary Heart Disease, Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Center for Coronary Artery Disease, Division of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, National Clinical Research Center for Cardiovascular Diseases, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ji Huang, Center for Coronary Artery Disease, Division of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, National Clinical Research Center for Cardiovascular Diseases, Beijing, 100029, People’s Republic of China, Email drjihuang@163.com Hai-Yan Qian, Center for Coronary Heart Disease, Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, People’s Republic of China, Email ahqhy712@163.comPurpose: Accumulating evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes hold significant potential for the treatment of atherosclerosis. However, large-scale production and organ-specific targeting of exosomes are still challenges for further clinical applications. This study aims to explore the targeted efficiency and therapeutic potential of biomimetic platelet membrane-coated exosome-mimetic nanovesicles (P-ENVs) in atherosclerosis.Methods: To produce exosome-mimetic nanovesicles (ENVs), MSCs were successively extruded through polycarbonate porous membranes. P-ENVs were engineered by fusing MSC-derived ENVs with platelet membranes and characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. The stability and safety of P-ENVs were also assessed. The targeted efficacy of P-ENVs was evaluated using an in vivo imaging system (IVIS) spectrum imaging system and immunofluorescence. Histological analyses, Oil Red O (ORO) staining, and Western blot were used to investigate the anti-atherosclerotic effectiveness of P-ENVs.Results: Both ENVs and P-ENVs exhibited similar characteristics to exosomes. Subsequent miRNA sequencing of P-ENVs revealed their potential to mitigate atherosclerosis by influencing biological processes related to cholesterol metabolism. In an ApoE−/− mice model, the intravenous administration of P-ENVs exhibited enhanced targeting of atherosclerotic plaques, resulting in a significant reduction in lipid deposition and necrotic core area. Our in vitro experiments showed that P-ENVs promoted cholesterol efflux and reduced total cholesterol content in foam cells. Further analysis revealed that P-ENVs attenuated intracellular cholesterol accumulation by upregulating the expression of the critical cholesterol transporters ABCA1 and ABCG1.Conclusion: This study highlighted the potential of P-ENVs as a novel nano-drug delivery platform for enhancing drug delivery efficiency while concurrently mitigating adverse reactions in atherosclerotic therapy.Keywords: exosome-mimetic nanovesicles, platelet membrane-coated nanovesicles, biomimicry, targeted delivery, atherosclerosis

Leucine-rich repeat kinase 2 (LRRK2, PARK8) gene has attracted considerable attention since the variants in this gene are recognized as the most common cause of Parkinson's disease (PD) so far. A number of association studies concerning variants of LRRK2 gene and PD susceptibility have been conducted in various populations. However, some results were inconclusive. To derive a more precise estimation of the relationship between LRRK2 and genetic risk of PD, we performed a comprehensive meta-analysis which included 27,363 cases and 29,741 controls from 61 published case-control studies. Totally, the effect of five LRRK2 variants all within the coding regions, i.e. G2019S, G2385R, R1628P, P755L and A419V, were evaluated in the meta-analysis using fixed effect model or random effects model if heterogeneity existed. There were genetic associations between four variants (G2019S, G2385R, R1628P and A419V) and increased PD risk, while there was no evidence of statistically significant association between P755L and PD. Publication bias and heterogeneity were absent in most analyses. Within its limitations, this meta-analysis demonstrated that the G2019S, G2385R, R1628P and A419V variations are risk factors associated with increased PD susceptibility. However, these associations vary in different ethnicities. [ABSTRACT FROM AUTHOR]

The F11 receptor (F11R) gene encoding junctional adhesion molecule A has been associated with gastric cancer (GC) and colorectal cancer (CRC), in which its role and regulation remain to be further elucidated. Recently F11R was also identified as a potential target of adenosine-to-inosine (A-to-I) mediated by the adenosine deaminases acting on RNA (ADARs). Herein, using RNA-Seq and experimental validation, our current study revealed an F11R RNA trinucleotide over-edited by ADAR, with its regulation of gene expression and clinical significance in four GC and three CRC cohorts. Our results found an over-edited AAA trinucleotide in an AluSg located in the F11R 3'-untranslated region (3'-UTR), which showed editing levels correlated with elevated ADAR expression across all GC and CRC cohorts in our study. Overexpression and knockdown of ADAR in GC and CRC cells, followed by RNA-Seq and Sanger sequencing, confirmed the ADAR-mediated F11R 3'-UTR trinucleotide editing, which potentially disrupted an RBM45 binding site identified by crosslinking immunoprecipitation sequencing (CLIP-seq) and regulated F11R expression in luciferase reporter assays. Moreover, the F11R trinucleotide editing showed promising predictive performance for diagnosing GC and CRC across GC and CRC cohorts. Our findings thus highlight both the potential biological and clinical significance of an ADAR-edited F11R trinucleotide in GC and CRC, providing new insights into its application as a novel diagnostic biomarker for both cancers., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

By analyzing the of genetic testing data of patients with renal polycystic kidney disease and their relatives, this study aims to identify unreported novel gene mutation sites associated with autosomal dominant polycystic kidney disease (ADPKD). Structural prediction software was employed to investigate protein structural changes before and after mutations, explore genotype-phenotype correlations, and enrich the ADPKD gene database. In this single-center retrospective study, patients with multiple renal cysts diagnosed from January 2019 to February 2023 at the Zhong Da Hospital Southeast University were included. Genetic and clinical data of patients and their families were collected. Unreported novel gene mutation sites associated with ADPKD were identified. The AlphaFold v2.3.1 software was used to predict protein structures. Changes in protein structure before and after mutations were compared to explore genotype-phenotype correlations and enrich the ADPKD gene database. Twelve mutated genes associated with renal cysts were detected in 52 families. Nineteen novel gene mutation sites associated with ADPKD were identified, including 17 mutations in the PKD1 gene (one splicing mutation, seven frameshift mutations, four nonsense mutations, one whole-codon insertion, and four missense mutations); one ALG9 missense mutation; and one chromosomal structural variation. Truncating mutations in the PKD1 gene were correlated with a more severe clinical phenotype, while non-truncating mutations were associated with greater clinical heterogeneity. Numerous novel gene mutation sites associated with ADPKD remain unreported. Therefore, it is essential to analyze the pathogenicity of these novel mutation sites, establish genotype-phenotype correlations, and enrich the ADPKD gene database.

Background: Hydrogen sulfide (H 2 S), the third gasotransmitter discovered, regulates a variety of physiological functions. Whether H 2 S alleviates skeletal muscle ageing by regulating autophagy has not been reported., Methods: Mice were administered 150 mg/kg/day of D-galactose ( D-gal), and C2C12 myotubes were cultured in 20 g/L D-gal to induce ageing. Sodium hydrosulfide (NaHS) was employed as an exogenous donor in the treatment group. The intracellular concentration of H 2 S was quantified by the 7-azido-4-methylcoumarin fluorescence probe. The proteins involved in the ubiquitin-mediated degradation of AMPKα1 were detected by liquid chromatography tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (Co-IP). S-sulfhydration of USP5 was tested by a biotin-switch assay. Associated proteins were analysed by western blot., Results: NaHS was found to effectively restore the H 2 S content in both ageing gastrocnemius (+91.89%, P < 0.001) and C2C12 myotubes (+27.55%, P < 0.001). In comparison to the D-gal group, NaHS was observed to increase the mean cross-sectional area of muscle fibres (+44.91%, P < 0.001), to decrease the collagen volume fraction of gastrocnemius (-81.32%, P = 0.001) and to reduce the β-galactosidase-positive area of C2C12 myotubes (-28.74%, P < 0.001). NaHS was also found to reverse the expression of muscle atrophy F box protein (MAFbx), muscle-specific RING finger protein 1 (MuRF1), Cyclin D1 and p21 in the ageing gastrocnemius tissue (MAFbx: -31.73%, P = 0.008; MuRF1: -32.37%, P = 0.003; Cyclin D1: +45.34%, P = 0.010; p21: -25.53%, P = 0.022) and C2C12 myotubes (MAFbx: -16.38%, P < 0.001; MuRF1: -16.45%, P = 0.003; Cyclin D1: +40.23%, P < 0.001; p21: -35.85%, P = 0.026). The AMPKα1-ULK1 pathway was activated and autophagy was up-regulated in NaHS-treated gastrocnemius tissue (p-AMPKα1: +61.61%, P = 0.018; AMPKα1: +30.64%, P = 0.010; p-ULK1/ULK1: +85.87%, P = 0.005; p62: -29.07%, P < 0.001; Beclin1: +24.75%, P = 0.007; light chain 3 II/I [LC3 II/I]: +55.78%, P = 0.004) and C2C12 myotubes (p-AMPKα1: +77.49%, P = 0.018; AMPKα1: +26.18%, P = 0.022; p-ULK1/ULK1: +38.34%, P = 0.012; p62: -9.02%, P = 0.014; Beclin1: +13.36%, P < 0.001; LC3 II/I: +79.38%, P = 0.017; autophagy flux: +24.88%, P = 0.034) compared with the D-gal group. The effects of NaHS on autophagy were comparable to those of acadesine and LYN-1604, and chloroquine could reverse its effects on ageing. LC-MS/MS and Co-IP experiments demonstrated that USP5 is a deubiquitinating enzyme of AMPKα1. Following the knockdown of USP5, the activation of AMPKα1 was decreased (p-AMPKα1: -42.10%, P < 0.001; AMPKα1: -43.93%, P < 0.001), autophagy was inhibited (p-ULK1/ULK1: -27.51, P = 0.001; p62: +36.00, P < 0.001; Beclin1: -22.15%, P < 0.001) and NaHS lost its ability to up-regulate autophagy. NaHS was observed to restore the expression (gastrocnemius: +62.17%, P < 0.001; C2C12 myotubes: +37.51%, P = 0.003) and S-sulfhydration (+53.07%, P = 0.009) of USP5 and reduce the ubiquitination of AMPKα1., Conclusions: H 2 S promotes the deubiquitination of AMPKα1 by increasing the expression and S-sulfhydration of USP5, thereby up-regulating autophagy and alleviating skeletal muscle ageing., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Sepsis-associated encephalopathy is a diffuse brain dysfunction secondary to infection. It has been established that factors such as age and sex can significantly contribute to the development of sepsis-associated encephalopathy. Our recent study implicated a possible link between adenosine-to-inosine RNA editing and sepsis-associated encephalopathy, yet the dynamics of adenosine-to-inosine RNA editing during sepsis-associated encephalopathy and how it could be influenced by factors such as age, sex and antidepressants remain uninvestigated. Our current study analysed and validated transcriptome-wide changes in adenosine-to-inosine RNA editing in the hippocampus of different septic mouse models. Seventy-four sites in 64 genes showed significant differential RNA editing over time in septic mice induced by caecal ligation and perforation. The differential RNA editing might contribute to the RNA expression regulation of the edited genes, with 42.2% differentially expressed. These differentially edited genes, especially those with missense editing, such as glutamate receptor, ionotropic, kainate 2 ( Grik2 , p.M620V), filamin A ( Flna , p.S2331G) and capicua transcriptional repressor ( Cic , p.E2270G), were mainly involved in abnormal social behaviour and neurodevelopmental and psychiatric disorders. Significant effects of age and sex were also observed on sepsis-associated RNA editing. Further comparison highlighted 40 common differential RNA editing sites that caecal ligation and perforation-induced and lipopolysaccharide-induced septic mouse models shared. Interestingly, these findings demonstrate temporal dynamics of adenosine-to-inosine RNA editing in the mouse hippocampus during sepsis, add to the understanding of age and sex differences in the disease and underscore the role of the epigenetic process in sepsis-associated encephalopathy., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To explore the surgical efficacy of conductive deafness caused by otosclerosis and ossicular malformation with 980 nm fiber laser stapedial floor fenestration. Methods: Data of 58 patients (ears) who were diagnosed with conductive deafness caused by otosclerosis (49 ears) and ossicular malformation (9 ears) treated by 980 nm Diode laser small-fenestra stapedotomy were retrospectively analyzed. Air conduction (AC) thresholds, bone conduction (BC) thresholds, and air-bone gap (ABG) at 0.5, 1, 2, 4 kHz pure tone frequencies were compared before and 3 months after surgery, and the advantages and precautions of 980 nm fiber laser were summarized. Paired t -test (SPSS 26.0 software) was use to analyze the listening data. Results: Fiber optic laser stapes fenestration and artificial stapes implantation were successfully completed in all 57 cases (ears), the hearing of another one patient (ear) with floating malformation of detachment of stapedial floor was lower than that before surgery. Preoperative at 0.5, 1, 2, 4 kHz frequencies of AC thresholds, BC thresholds, and ABG were (65.4±9.7) dB, (27.2±8.9) dB, and (38.2±9.8) dB respectively. Postoperative 3 months at the same frequency of AC thresholds, BC thresholds, and ABG were (42.1±11.3) dB, (26.9±6.6) dB, and (15.2±9.1) dB. Preoperative and postoperative of AC threshold and ABG were statistically significant at 0.5, 1, 2, 4 kHz ( t value was 13.270 and13.948, both P <0.01), and yet the BC threshold was not statistically significant before and after surgery at the same frequency ( t =0.418, P >0.05). Conclusions: 980 nm fiber laser stapes floor fenestration is an effective treatment for conductive deafness caused by otosclerosis and ossicular malformation.

Introduction: The activation of cerebral endothelial cells (CECs) has recently been reported to be the earliest acute neuroinflammation event in the CNS during sepsis-associated encephalopathy (SAE). Importantly, adenosine-to-inosine (A-to-I) RNA editing mediated by ADARs has been associated with SAE, yet its role in acute neuroinflammation in SAE remains unclear., Methods: Our current study systematically analyzed A-to-I RNA editing in cerebral vessels, cerebral endothelial cells (CECs), and microglia sampled during acute neuroinflammation after treatment in a lipopolysaccharide (LPS)-induced SAE mouse model., Results: Our results showed dynamic A-to-I RNA editing activity changes in cerebral vessels during acute neuroinflammation. Differential A-to-I RNA editing (DRE) associated with acute neuroinflammation were identified in these tissue or cells, especially missense editing events such as S367G in antizyme inhibitor 1 ( Azin1 ) and editing events in lincRNAs such as maternally expressed gene 3 ( Meg3 ), AW112010 , and macrophage M2 polarization regulator ( Mm2pr ). Importantly, geranylgeranyl diphosphate synthase 1 ( Ggps1 ) and another three genes were differentially edited across cerebral vessels, CECs, and microglia. Notably, Spearman correlation analysis also revealed dramatic time-dependent DRE during acute neuroinflammation, especially in GTP cyclohydrolase1 ( Gch1 ) and non-coding RNA activated by DNA damage ( Norad ), both with the editing level positively correlated with both post-LPS treatment time and edited gene expression in cerebral vessels and CECs., Discussion: The findings in our current study demonstrate substantial A-to-I RNA editing changes during acute neuroinflammation in SAE, underlining its potential role in the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer QL declared a past co-authorship with the author J-HC to the handling editor. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Li, Liang, Zhang, Li, Wei, Rao, Chen and Jin.)

The gut microbiota has been demonstrated to play a significant role in the pathogenesis of Parkinson's disease (PD). However, conflicting findings regarding specific microbial species have been reported, possibly due to confounding factors within human populations. Herein, our current study investigated the interaction between the gut microbiota and host in a non-human primate (NHP) PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using a multi-omic approach and a self-controlled design. Our transcriptomic sequencing of peripheral blood leukocytes (PBL) identified key genes involved in pro-inflammatory cytokine dysregulation, mitochondrial function regulation, neuroprotection activation, and neurogenesis associated with PD, such as IL1B, ATP1A3, and SLC5A3. The metabolomic profiles in serum and feces consistently exhibited significant alterations, particularly those closely associated with inflammation, mitochondrial dysfunctions and neurodegeneration in PD, such as TUDCA, ethylmalonic acid, and L-homophenylalanine. Furthermore, fecal metagenome analysis revealed gut dysbiosis associated with PD, characterized by a significant decrease in alpha diversity and altered commensals, particularly species such as Streptococcus, Butyrivibrio, and Clostridium. Additionally, significant correlations were observed between PD-associated microbes and metabolites, such as sphingomyelin and phospholipids. Importantly, PDPC significantly reduced in both PD monkey feces and serum, exhibiting strong correlation with PD-associated genes and microbes, such as SLC5A3 and Butyrivibrio species. Moreover, such multi-omic differential biomarkers were linked to the clinical rating scales of PD monkeys. Our findings provided novel insights into understanding the potential role of key metabolites in the host-microbiota interaction involved in PD pathogenesis., (© 2024. The Author(s).)

An inverse sandwich structure has been computationally predicted for uranium boride and extended to the series of actinide elements (An) from Th to Cm. The electronic structure and chemical bonding of these novel compounds have been analyzed using density functional theory and multireference wave-function based methods. We report the trends in electronic structure and bonding for An 2 B 8 , and found that (d-π)π and (d-p)δ are the most important factors in the stability of An 2 B 8 . The (f-p)δ bond provides extra stabilization for Pa 2 B 8 and U 2 B 8 , owing to the extensive interactions of An-B 8 -An, resulting in a short distance for the Pa-Pa and U-U bonds.

Background: Chronic total occlusions (CTO) occur in about 20% of patients referred for coronary angiography, and right coronary artery (RCA) CTO has been reported in 38-50% of the entire CTO population. Limited data on angiographic and procedural characteristics of RCA-CTO and the risk of adverse cardiac events asks for a detailed study., Methods: From 2010 to 2013, patients with attempted revascularization of at least one CTO lesion were included and followed up to 5 years after PCI. Eligible patients are assigned to RCA-CTO and non-RCA-CTO groups based on their target vessels. The primary endpoint was major adverse cardiovascular events (MACEs; a composite of all-cause death, myocardial infarction (MI) or rehospitalization for heart failure), and secondary endpoints were cardiac death, target lesion revascularization (TLR) and target vessel revascularization (TVR)., Results: The present study included 2659 eligible patients, among which 1285 patients were assigned to the RCA-CTO group, whereas 1374 patients were assigned to the non-RCA-CTO group. Lesions in RCA had longer lesion length, higher J-CTO score, higher rates of severe vessel tortuosity, a higher percentage of Rentrop grade 2-3, and more likely to be re-try lesion than those in LAD or LCX (all P < 0.01). CTO lesions in RCA reached less successful recanalization and post-procedural TIMI 3 flow (all <0.01). Multivariate Cox analysis revealed that RCA-CTO was not associated with primary outcome MACEs. Besides MACEs, RCA-CTO was also not associated with cardiac death, but was significantly associated with TLR and TVR (adjusted HR: 1.37 [95% CI:1.07-1.76], P = 0.01; adjusted HR: 1.43 [95% CI:1.13-1.82], P = 0.003)., Conclusion: RCA-CTO lesions, which had more complex angiographic features, independently contributed to TLR and TVR but not to MACEs or cardiac death in the 5 years of follow-up., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Metastatic castration-resistant prostate cancer (CRPC), the most refractory prostate cancer, inevitably progresses and becomes unresponsive to hormone therapy, revealing a pressing unmet need for this disease. Novel agents targeting HDAC6 and microtubule dynamics can be a potential anti-CRPC strategy., Methods: Cell proliferation was examined in CRPC PC-3 and DU-145 cells using sulforhodamine B assay and anchorage-dependent colony formation assay. Flow cytometric analysis of propidium iodide staining was used to determine cell-cycle progression. Cell-based tubulin polymerization assay and confocal immunofluorescence microscopic examination determine microtubule assembly/disassembly status. Protein expressions were determined using Western blot analysis., Results: A total of 82 novel derivatives targeting HDAC6 were designed and synthesized, and Compound 25202 stood out, showing the highest efficacy in blocking HDAC6 (IC 50 , 3.5 nM in enzyme assay; IC 50 , 1.0 μM in antiproliferative assay in CRPC cells), superior to tubastatin A (IC 50 , 5.4 μM in antiproliferative assay). The selectivity and superiority of 25202 were validated by examining the acetylation of both α-tubulin and histone H3, detecting cell apoptosis and HDACs enzyme activity assessment. Notably, 25202 but not tubastatin A significantly decreased HDAC6 protein expression. 25202 prolonged mitotic arrest through the detection of cyclin B1 upregulation, Cdk1 activation, mitotic phosphoprotein levels, and Bcl-2 phosphorylation. Compound 25202 did not mimic docetaxel in inducing tubulin polymerization but disrupted microtubule organization. Compound 25202 also increased the phosphorylation of CDC20, BUB1, and BUBR1, indicating the activation of the spindle assembly checkpoint (SAC). Moreover, 25202 profoundly sensitized cisplatin-induced cell death through impairment of cisplatin-evoked DNA damage response and DNA repair in both ATR-Chk1 and ATM-Chk2 pathways., Conclusion: The data suggest that 25202 is a novel selective and potent HDAC6 inhibitor. Compound 25202 blocks HDAC6 activity and interferes microtubule dynamics, leading to SAC activation and mitotic arrest prolongation that eventually cause apoptosis of CRPC cells. Furthermore, 25202 sensitizes cisplatin-induced cell apoptosis through impeding DNA damage repair pathways., (© 2024 Wiley Periodicals LLC.)

Background: Tissue-engineered heart valves (TEHVs) are promising new heart valve substitutes for valvular heart disease. The Notch signaling pathway plays a critical role in the development of congenital heart valves. Objective: To investigate the role of the Notch signaling pathway in the construction of TEHVs. Methods: The induced endothelial cells, which act as seed cells, were differentiated from adipose-derived stem cells and were treated with Jagged-1 (JAG-1) protein and γ-secretase inhibitor (DAPT, N -[ N -(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycine t-butyl ester), respectively. Cell phenotypic changes, the expression of proteins relating to the epithelial-mesenchymal transition (EMT), and changes in paxillin expression were detected. Decellularized valve scaffolds were produced from decellularized porcine aortic valves. The seed cells were them inoculated into Matrigel-coated flap scaffolds for complex culture and characterization. Results: JAG-1 significantly reduced apoptosis and promoted the seeded cells' proliferation and migration ability, in contrast to the treatment of DAPT. In addition, the expression of EMT-related proteins, E-cadherin and N-cadherin, was significantly increased after treatment with JAG-1 and was reduced after the application of DAPT. Meanwhile, the adhesive-related expression of paxillin and fibronectin proteins was increased after the activation of Notch1 signaling and vice versa. Of interest, activation of the Notch1 signaling pathway resulted in more closely arranged cells on the valve surface after recellularization. Conclusion: Activation of the JAG-1/Notch1 signaling pathway increased seeded cells' proliferation and migratory ability and promoted the EMT and adhesion of seed cells, which was conducive to binding to the matrix, facilitating accelerated endothelialization of TEHVs.

Reactivation and infection with cytomegalovirus (CMV) are frequently observed in recipients of solid organ transplants, bone marrow transplants, and individuals with HIV infection. This presents an increasing risk of allograft rejection, opportunistic infection, graft failure, and patient mortality. Among immunocompromised hosts, interstitial pneumonia is the most critical clinical manifestation of CMV infection. Recent studies have demonstrated the potential therapeutic benefits of exosomes derived from mesenchymal stem cells (MSC-exos) in preclinical models of acute lung injury, including pneumonia, ARDS, and sepsis. However, the role of MSC-exos in the pathogenesis of infectious viral diseases, such as CMV pneumonia, remains unclear. In a mouse model of murine CMV-induced pneumonia, we observed that intravenous administration of mouse MSC (mMSC)-exos reduced lung damage, decreased the hyperinflammatory response, and shifted macrophage polarization from the M1 to the M2 phenotype. Treatment with mMSC-exos also significantly reduced the infiltration of inflammatory cells and pulmonary fibrosis. Furthermore, in vitro studies revealed that mMSC-exos reversed the hyperinflammatory phenotype of bone marrow-derived macrophages infected with murine CMV. Mechanistically, mMSC-exos treatment decreased activation of the NF-κB/NLRP3 signaling pathway both in vivo and in vitro. In summary, our findings indicate that mMSC-exo treatment is effective in severe CMV pneumonia by reducing lung inflammation and fibrosis through the NF-κB/NLRP3 signaling pathway, thus providing promising therapeutic potential for clinical CMV infection.

Nonalcoholic fatty liver disease (NAFLD) is one of the common causes of chronic liver disease in the world. The problem of NAFLD had become increasingly prominent. However, its pathogenesis is still indistinct. As we all know, NAFLD begins with the accumulation of triglyceride (TG), leading to fatty degeneration, inflammation and other liver tissues damage. Notably, structure of nucleoporin 85 (NUP85) is related to lipid metabolism and inflammation of liver diseases. In this study, the results of researches indicated that NUP85 played a critical role in NAFLD. Firstly, the expression level of NUP85 in methionine-choline-deficient (MCD)-induced mice increased distinctly, as well as the levels of fat disorder and inflammation. On the contrary, knockdown of NUP85 had the opposite effects. In vitro , AML-12 cells were stimulated with 2 mm free fatty acids (FFA) for 24 h. Results also proved that NUP85 significantly increased in model group, and increased lipid accumulation and inflammation level. Besides, NUP85 protein could interact with C-C motif chemokine receptor 2 (CCR2). Furthermore, when NUP85 protein expressed at an extremely low level, the expression level of CCR2 protein also decreased, accompanied with an inhibition of phosphorylation of phosphoinositol-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway. What is more, trans isomer (ISRIB), a targeted inhibitor of NUP85, could alleviate NAFLD. In summary, our findings suggested that NUP85 functions as an important regulator in NAFLD through modulation of CCR2., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Herbivorous insects employ an array of salivary proteins to aid feeding. However, the mechanisms behind the recruitment and evolution of these genes to mediate plant-insect interactions remain poorly understood. Here, we report a potential horizontal gene transfer (HGT) event from bacteria to an ancestral bug of Eutrichophora. The acquired genes subsequently underwent duplications and evolved through co-option. We annotated them as horizontal-transferred, Eutrichophora-specific salivary protein (HESPs) according to their origin and function. In Riptortus pedestris (Coreoidea), all nine HESPs are secreted into plants during feeding. The RpHESP4 to RpHESP8 are recently duplicated and found to be indispensable for salivary sheath formation. Silencing of RpHESP4-8 increases the difficulty of R. pedestris in probing the soybean, and the treated insects display a decreased survivability. Although silencing the other RpHESPs does not affect the salivary sheath formation, negative effects are also observed. In Pyrrhocoris apterus (Pyrrhocoroidea), five out of six PaHESPs are secretory salivary proteins, with PaHESP3 being critical for insect survival. The PaHESP5, while important for insects, no longer functions as a salivary protein. Our results provide insight into the potential origin of insect saliva and shed light on the evolution of salivary proteins., (© 2024. The Author(s).)

Platelets play a pivotal role in many physiological and pathological processes, with their special targeting/adhering properties towards infarcted myocardium, injured or dysfunctional endothelium, and growing thrombus. Leveraging the site-targeting/adhering property, a variety of platelet-inspired targeting delivery（PITD）designs have been developed, the majority of which are reached by hitchhiking live platelets, cloaking nanoparticles with platelet membranes and mimicking platelet functions. With PITD, drugs or regenerative cells can directly reach targeted sites with minimized systematical distribution thus being of great clinical benefits. Coronary heart disease (CHD) is a major health burden worldwide. Plenty of PITD designs have shown promising outcomes for the treatment of CHD in preclinical models, especially in thrombolysis and post-percutaneous coronary intervention (post-PCI) anti-restenosis. Besides, PITD applications in cardiac protection and atherosclerotic plaque imaging are also under investigation. What's more, the potential benefits of PITD in the field of cell-based therapy are also attracting growing attention since it may resolve the problem of low arriving and retention efficiency, which are also particularly discussed in this review. In brief, our focus is putting on PITD strategies designed for the treatment of CHD, which hopefully can facilitate further optimization of this direction., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Recent studies have revealed that tumor immunotherapy resistance is influenced by ADAR-mediated RNA editing, but its targets remain unelucidated. Our current study identified the poliovirus receptor (PVR) oncogene, which encodes an immune checkpoint in colorectal cancer (CRC), as a potential target for RNA editing. We performed transcriptome sequencing analysis and experimental validation in two Chinese CRC cohorts. PVR and ADAR expressions significantly increased in CRC tumors and showed positive correlations in both cohorts, coupled with upregulated PVR RNA editing in CRC tumors. Manipulation of ADAR expression by over-expression or knockdown substantially changed PVR expression and RNA editing in HTC116 CRC cells. Luciferase reporter and actinomycin D assays further revealed that RNA editing in PVR 3'-UTR could upregulate PVR RNA expression, probably by increasing the RNA stability. By increasing PVR expression, ADAR-mediate RNA editing might contribute to tumor- and immune-related gene functions and pathways in CRC. Moreover, a signature combining PVR RNA editing and expression showed promising predictive performance in CRC diagnosis in both Chinese CRC cohorts. Our findings thus highlight the importance of ADAR-mediated RNA editing in PVR up-regulation in CRC tumors and provide new insight into the application of PVR RNA editing as a novel diagnostic biomarker for CRC., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We consider the preparation of matrix product states (MPS) on quantum devices via quantum circuits of local gates. We first prove that faithfully preparing translation-invariant normal MPS of N sites requires a circuit depth T=Ω(logN). We then introduce an algorithm based on the renormalization-group transformation to prepare normal MPS with an error ε in depth T=O[log(N/ε)], which is optimal. We also show that measurement and feedback leads to an exponential speedup of the algorithm to T=O[loglog(N/ε)]. Measurements also allow one to prepare arbitrary translation-invariant MPS, including long-range non-normal ones, in the same depth. Finally, the algorithm naturally extends to inhomogeneous MPS.

Background: In this study, we compared the clinical efficacy of endoscope-assisted anterior cervical discectomy and fusion (ACDF) with open ACDF in the treatment of single-segment cervical spondylotic myelopathy., Methods: A retrospective analysis was performed on 52 patients with single-segment cervical spondylotic myelopathy between June 2021 and February 2022, including 33 males and 19 females, with a mean age of 58.42 ± 9.26) years. Among them, 28 patients were treated with endoscope-assisted ACDF (Group A), including 2 cases of C4/5 segment, 16 cases of C5/6 segment, and 10 cases of C6/7 segment; 24 patients were treated with open ACDF (Group B), including 4 cases of C4/5 segment, 11 cases of C5/6 segment, and 9 cases of C6/7 segment. The operation time, intraoperative blood loss, hospital stay, and complications were recorded and compared between the two groups. The Visual Analogue Scale (VAS) and the Japanese Orthopaedic Association (JOA) score were used for clinical evaluation during the follow-up in the 1st month and 3rd month after surgery, and at the final follow-up., Results: The 52 patients were followed up on average for 13.04 months (12-17 months). The operation time in Group A and Group B was (105.18 + 8.66) minutes and (81.88 + 6.05) minutes, the intraoperative blood loss was (84.29 + 13.45) mL and (112.92 + 17.81) mL, and the hospital stay was (6.75 + 1.29) days and (7.63 + 1.41) days, respectively. The difference between the two groups was statistically significant (P < 0.05). The VAS and JOA scores in the 1st month and the 3rd month after surgery and the last follow-up significantly improved in both groups compared with those before surgery (P < 0.05). The VAS and JOA scores of Group A in the 1st month, 3rd month after surgery, and the last follow-up were better than those in Group B (P < 0.05). The complication rate in Group A was 7% (2/28), which was not significantly different from the 17% (4/24) in Group B (P > 0.05)., Conclusion: Both endoscope-assisted ACDF and open ACDF can achieve satisfactory clinical efficacy in the treatment of single-segment cervical spondylotic myelopathy. Although the operation time of endoscope-assisted ACDF is prolonged, it has the advantages of clear vision, thorough decompression, less blood loss, and reduced risk of nerve damage, and is worthy of clinical promotion and application., (© 2024. The Author(s).)

Purpose: The purpose of this study was to identify key genes and their regulatory networks that are conserved in mouse models of age-related macular degeneration (AMD) and human AMD., Methods: Retinal RNA-Seq was performed in laser-induced choroidal neovascularization (CNV) mice at day 3 and day 7 after photocoagulation. Mass spectrometry-based proteomic analysis was performed with retinas collected at day 3. Retinal RNA-Seq data was further compared among mouse models of laser-induced CNV and NaIO3-induced retinal degeneration (RD) and a large AMD cohort., Results: Retinal RNA-Seq revealed upregulated genes and pathways related to innate immunity and inflammation in mice with CNV, with more profound changes at the early stage (day 3). Proteomic analysis further validated these differentially expressed genes and their networks in retinal inflammation during CNV. Notably, the most evident overlap in the retina of mice with laser-induced CNV and NaIO3-induced RD was the upregulation of inflammation-related genes, pointing to a common vital role of retinal inflammation in the early stage for both mouse AMD models. Further comparative transcriptomic analysis of the mouse AMD models and human AMD identified 48 conserved genes mainly involved in inflammation response. Among them, B2M, C3, and SERPING1 were upregulated in all stages of human AMD and the mouse AMD models compared to controls., Conclusions: Our study demonstrates conserved molecular changes related to retinal inflammation in mouse AMD models and human AMD and provides new insight into the translational application of these mouse models in studying AMD mechanisms and treatments.

This study systematically combed the existing evidence of Houyanqing Oral Liquid in the treatment of acute pharyngitis from the &quot;6+1&quot; dimensions of safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine(TCM) and carried out qualitative and quantitative analysis of the data from each dimension. The multi-criteria decision analysis(MCDA) model and CSC v2.0 were used to evaluate the clinical value of this drug, so as to provide evidence for the selection of essential drugs in the department of otolaryngology and for medical and health decision-making. The dimensions are graded A, B, C, or D. The adverse reactions of Houyanqing Oral Liquid in the treatment of acute pharyngitis were mainly manifested as abdominal pain, diarrhea, rash, etc., which were relieved after drug withdrawal. In terms of safety, it was considered that Houyanqing Oral Liquid had controllable risk and high safety, which was rated as grade B. Compared with ribavirin aerosol alone, Houyanqing Oral Liquid combined with ribavirin aerosol can significantly improve the total response rate, shorten the time to abatement of fever and di-sappearance of throat pain and mucosal congestion, and alleviate mucosal congestion and cough with sputum. With medium-quality evidence, the effectiveness was rated as grade B. Compared with ribavirin aerosol alone, Houyanqing Oral Liquid combined with ribavirin aerosol had cost-effectiveness advantages in the treatment of acute pharyngitis, and its economy was rated as grade C with the evidence of general quality. For acute pharyngitis, Houyanqing Oral Liquid can shorten the disease course and obviously relieve sore throat. Moreover, it can be used for the treatment of radioactive pharyngitis and oral ulcer, and thus its innovation was rated as grade B. With convenient and simple administration and standard and complete drug information, the suitability of this drug was rated as grade B. Houyanqing Oral Liquid is derived from the folk prescription in Hunan province and has been subjected to real-world studies, and thus the TCM characteristics was rated as grade B. According to the ratings of all the dimensions, the comprehensive value of Houyanqing Oral Liquid in the clinical treatment of acute pharyngitis was determined as grade B, with sufficient evidence and clear results. It is suggested that the results should be conditionally converted into relevant policy of clinical basic drug management according to procedures.

Docosahexaenoic acid (DHA) as one of ω-3 polyunsaturated fatty acids (PUFAs), plays a key role in brain development, and is widely used in food additives and the pharmaceutical industry. Schizochytrium sp. is often considered as a satisfactory strain for DHA industrialization. The aim of this study was to assess the feasibility of phosphopantetheinyl transferase (PPTase) and ω-3 fatty acid desaturase (FAD) for regulating DHA content in Schizochytrium sp. PPTase is essential to activate the polyketide-like synthase (PKS) pathway, which can transfer apo-acyl-carrier protein (apo-ACP) into holo-ACP, and plays a key role in DHA synthesis. Moreover, DHA and docosapentaenoic acid (DPA) are synthesized by the PKS pathway simultaneously, so high DPA synthesis limits the increase of DHA content. In addition, the detailed mechanisms of PKS pathway have not been fully elucidated, so it is difficult to improve DHA content by modifying PKS. However, ω-3 FAD can convert DPA into DHA, and it is the most direct and effective way to increase DHA content and reduce DPA content. Based on this, PPTase was overexpressed to enhance the synthesis of DHA by the PKS pathway, overexpressed ω-3 FAD to convert the co-product of the PKS pathway into DHA, and co-overexpressed PPTase and ω-3 FAD. With these strategies, compared with wild type, the final lipid, and DHA titer were 92.5 and 51.5 g L -1 , which increased by 46.4% and 78.1%, respectively. This study established an efficient DHA production strain, and provided some feasible strategies for industrial DHA production in Schizochytrium sp., (© 2023 Wiley-VCH GmbH.)

Inflammation is implicated in the development of diabetic complications including vascular pathology. Centrosome is known to play a role in cell secretion. We have reported that diabetes can trigger centrosome amplification (CA). Thus, in the present study, we investigated the relationship between CA and the release of proinflammatory cytokines interleukin-1β, tumor necrosis factor-α and interleukin-6 in hCMEC/D3 human endothelial cells treated with advanced glycation end products (AGEs). We found that AGEs induced CA via PLK4 and increased the biosynthesis of the three cytokines via NF-κB. Importantly, treatment of the cells with AGEs also increased the release of the three cytokines. Inhibiting CA by knockdown of polo like kinase 4 (PLK4) attenuated the cytokine release but not their biosynthesis. Knockdown of the cytokines inhibited the CA, while addition of the cytokines individually to the cell culture increased the protein level of PLK4 and CA to a moderate level. Addition of the three cytokines together into the cell culture markedly enhanced the CA, to a level higher than that in the AGEs-treated group. In conclusion, our results provide the direct evidence that the cytokines can induce CA, and suggest that there is a mutual promoting cycle between CA and cytokine release in the treated samples. It is proposed that the cycle of CA-cytokine release is a candidate biological link between diabetes and its complications such as vascular pathologies., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Amnestic mild cognitive impairment (aMCI) is a stage between normal aging and Alzheimer disease (AD) where individuals experience a noticeable decline in memory that is greater than what is expected with normal aging, but dose not meet the clinical criteria for AD. This stage is considered a transitional phase that puts individuals at a high risk for developing AD. It is crucial to intervene during this stage to reduce the changes of AD development. Recently, advanced multimodal magnetic resonance imaging techniques have been used to study the brain structure and functional networks in individuals with aMCI. Through the use of structural magnetic resonance imaging, diffusion tensor imaging, and functional magnetic resonance imaging, abnormalities in certain brain regions have been observed in individuals with aMCI. Specifically, the default mode network, salience network, and executive control network have been found to show abnormalities in both structure and function. This review aims to provide a comprehensive understanding of the brain structure and functional networks associated with aMCI. By analyzing the existing literature on multimodal magnetic resonance imaging and aMCI, this study seeks to uncover potential biomarkers and gain insight into the underlying pathogenesis of aMCI. This knowledge can then guide the development of future treatments and interventions to delay or prevent the progression of aMCI to AD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Over the years, it has been found that colchicine offers substantial benefits in secondary prevention in patients with coronary artery disease (CAD). We studied the effects of colchicine timing because there are no guidelines about when to provide it during the perioperative period for patients with CAD., Methods: Up to January 1, 2023, seven electronic literature databases were screened (including three English databases and four Chinese databases). Randomized controlled trials included only treatment with colchicine in the perioperative period of CAD. The Cochrane Evaluation Tool was used to judge the risk of bias in research. Statistical analysis was performed by Stata 16.0 software., Results: We evaluated twelve studies that found colchicine to be effective in decreasing the occurrence of major adverse cardiac events (MACEs) ( p  < 0.00001), but it also raised the rate of adverse events ( p  = 0.001). Subgroup analysis showed the same benefit in lowering the incidence of MACE with continuous administration of a total daily dose of 0.5 mg postoperatively while minimizing drug-related side effects in the patients ( p  = 0.03). When it comes to preventing surgical stroke occurrences, postoperative administration is more effective ( p  = 0.006). While the effect of simultaneous preoperative and postoperative administration was marginally greater than other periods in reducing postoperative hs-CRP levels ( p  = 0.02)., Conclusion: Colchicine, a traditional anti-inflammatory drug, also reduces the risk of MACE by reducing inflammation after PCI. Administration at different periods had no significant effect on decreasing the occurrence of MACE, but when administered postoperatively, we advise continuous administration with a total daily dose of 0.5 mg to obtain the same benefit while minimizing the drug's side effects. Postoperative administration is the better measure to prevent postoperative stroke events. Due to the effective anti-inflammatory effect of colchicine, we recommend its use as early as possible in the perioperative period and its continued use at low doses in the postoperative period., Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display&#95;record.php?RecordID=316751, identifier CRD42022316751., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Wei, Lai, Li, Yu, Liu, Hu, Gao and Wu.)

Thoracic aortic aneurysms (TAAs) develop asymptomatically and are characterized by dilatation of the aorta. This is considered a life-threating vascular disease due to the risk of aortic rupture and without effective treatments. The current understanding of the pathogenesis of TAA is still limited, especially for sporadic TAAs without known genetic mutation. Sirtuin 6 (SIRT6) expression was significantly decreased in the tunica media of sporadic human TAA tissues. Genetic knockout of Sirt6 in mouse vascular smooth muscle cells accelerated TAA formation and rupture, reduced survival, and increased vascular inflammation and senescence after angiotensin II infusion. Transcriptome analysis identified interleukin (IL)-1β as a pivotal target of SIRT6, and increased IL-1β levels correlated with vascular inflammation and senescence in human and mouse TAA samples. Chromatin immunoprecipitation revealed that SIRT6 bound to the Il1b promoter to repress expression partly by reducing the H3K9 and H3K56 acetylation. Genetic knockout of Il1b or pharmacological inhibition of IL-1β signaling with the receptor antagonist anakinra rescued Sirt6 deficiency mediated aggravation of vascular inflammation, senescence, TAA formation and survival in mice. The findings reveal that SIRT6 protects against TAA by epigenetically inhibiting vascular inflammation and senescence, providing insight into potential epigenetic strategies for TAA treatment., (© 2023. The Author(s).)

Myopia is one of the most common causes of vision loss globally and is significantly affected by epigenetics. Adenosine-to-inosine (A-to-I RNA) editing is an epigenetic process involved in neurological disorders, yet its role in myopia remains undetermined. We performed a transcriptome-wide analysis of A-to-I RNA editing in the retina of form-deprivation myopia mice. Our study identified 91 A-to-I RNA editing sites in 84 genes associated with myopia. Notably, at least 27 (32.1%) of these genes with myopia-associated RNA editing showed existing evidence to be associated with myopia or related ocular phenotypes in humans or animal models, such as very low-density lipoprotein receptor ( Vldlr ) in retinal neovascularization and hypoxia-induced factor 1 alpha ( Hif1a ). Moreover, functional enrichment showed that RNA editing enriched in FDM was primarily involved in response to fungicides, a potentially druggable process for myopia prevention, and epigenetic regulation. In contrast, RNA editing enriched in controls was mostly involved in post-embryonic eye morphogenesis. Our results demonstrate altered A-to-I RNA editing associated with myopia in an experimental mouse model and warrant further study on its role in myopia development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pan, He, Lu, Pan, Wei, Jin, Wang and Chen.)

Background: Alzheimer's disease (AD) is a common, progressive, irreversible, and fatal neurodegenerative disorder with rapidly increasing worldwide incidence. Although much research on magnetic resonance imaging (MRI) of the white matter (WM) in AD has been published, no bibliometric analysis study has investigated this issue. Thus, this study aimed to provide an overview of the current status, hotspots, and trends in MRI of WM in AD., Methods: We searched for records related to MRI studies of WM in AD from 1990 to 2022 in the Web of Science Core Collection (WOSCC) database. CiteSpace (version 5.1.R8) and VOSviewer (version 1.6.19) software were used for bibliometric analyses., Results: A total of 2,199 articles were obtained from this study. From 1990 to 2022, the number of published articles showed exponential growth of y = 4.1374e 0.1294x , with an average of 17.9 articles per year. The top country and institutions were the United States and the University of California Davis, accounting for 44.52 and 5.32% of the total studies, respectively. The most productive journal was Neurology, and the most co-cited journal was Lancet Neurology. Decarli C was the most productive author. The current research frontier trend focuses on the association between small vessel disease and AD, the clinical application and exploration of diffusion MRI, and related markers., Conclusion: This study provides an in-depth overview of publications on MRI of WM in AD, identifying the current research status, hotspots, and frontier trends in the field., Competing Interests: AL was employed by the Sanofi-Aventis China Investment Co., Ltd. W-WZ was employed by the MSD R&D (China) Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yue, Zhang, Yang, Wang, Sun, Yan, Li, Zhao, Cao, Wang, Wei, Li, Zhu, Yang and Mah.)

Zoledronic acid (ZOL) is a potent antiresorptive agent that increases bone mineral density (BMD) and reduces fracture risk in postmenopausal osteoporosis (PMOP). The anti-osteoporotic effect of ZOL is determined by annual BMD measurement. In most cases, bone turnover markers function as early indicators of therapeutic response, but they fail to reflect long-term effects. We used untargeted metabolomics to characterize time-dependent metabolic shifts in response to ZOL and to screen potential therapeutic markers. In addition, bone marrow RNA-seq was performed to support plasma metabolic profiling. Sixty rats were assigned to sham-operated group (SHAM, n = 21) and ovariectomy group (OVX, n = 39) and received sham operation or bilateral ovariectomy, respectively. After modeling and verification, rats in the OVX group were further divided into normal saline group (NS, n = 15) and ZOL group (ZA, n = 18). Three doses of 100 μg/kg ZOL were administrated to the ZA group every 2 weeks to simulate 3-year ZOL therapy in PMOP. An equal volume of saline was administered to the SHAM and NS groups. Plasma samples were collected at five time points for metabolic profiling. At the end of the study, selected rats were euthanatized for bone marrow RNA-seq. A total number of 163 compound were identified as differential metabolites between the ZA and NS groups, including mevalonate, a critical molecule in target pathway of ZOL. In addition, prolyl hydroxyproline (PHP), leucyl hydroxyproline (LHP), 4-vinylphenol sulfate (4-VPS) were identified as differential metabolites throughout the study. Moreover, 4-VPS negatively correlated with increased vertebral BMD after ZOL administration as time-series analysis revealed. Bone marrow RNA-seq showed that the PI3K-AKT signaling pathway was significantly associated with ZOL-mediated changes in expression (adjusted-p = 0.018). In conclusion, mevalonate, PHP, LHP, and 4-VPS are candidate therapeutic markers of ZOL. The pharmacological effect of ZOL likely occurs through inhibition of the PI3K-AKT signaling pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Wang, Ren, Wei, Hu, Gu, Zhang, Yu and Wang.)

Purpose: Helicobacter pylori (HP) infection is an identified risk factor for pediatric chronic gastritis (PCG), but its impact on gastric juice microbiota (GJM) remains to be further elucidated in PCG. This study aimed to analyze and compare the microbial communities and microbial interactive networks of GJM in PCG that clinically tested positive and negative for HP (HP+ and HP-, respectively)., Methods: A total of 45 PCG patients aged from 6 to 16 years were recruited, including 20 HP+ and 25 HP- patients tested by culture and rapid urease test. Gastric juice samples were collected from these PCG patients and subjected to high-throughput amplicon sequencing and subsequent analysis of 16S rRNA genes., Results: While no significant change in alpha diversity, significant differences in beta diversity were observed between HP+ and HP- PCG. At the genus level, Streptococcus, Helicobacter , and Granulicatella were significantly enriched in HP+ PCG, whereas Campylobacter and Absconditabacteriales (SR1) were significantly enriched in HP - PCG. Network analysis showed that Streptococcus was the only genus positively correlated with Helicobacter ( r  = 0.497) in the GJM net work of overall PCG. Moreover, compared to HP- PCG, HP+ PCG showed a reduction in microbial network connectivity in GJM. Netshift analysis identified driver microbes including Streptococcus and other four genera, which substantially contributed to the GJM network transition from HP- PCG to HP+ PCG. Furthermore, Predicted GJM function analysis indicated up-regulated pathways related to the metabolism of nucleotides, carbohydrates, and L-Lysine, the urea cycle, as well as endotoxin peptidoglycan biosynthesis and maturation in HP+ PCG., Conclusion: GJM in HP+ PCG exhibited dramatically altered beta diversity, taxonomic structure, and function, with reduced microbial network connectivity, which could be involved in the disease etiology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Xia, Ru, Feng, Tao, Wei, Li, Qian, Lin and Chen.)

Diabetic wound healing has become a serious healthcare challenge. The high-glucose environment leads to persistent bacterial infection and mitochondrial dysfunction, resulting in chronic inflammation, abnormal vascular function, and tissue necrosis. To solve these issues, we developed a double-network hydrogel, constructed with pluronic F127 diacrylate (F127DA) and hyaluronic acid methacrylate (HAMA), and enhanced by SS31-loaded mesoporous polydopamine nanoparticles (MPDA NPs). As components, SS31, a mitochondria-targeted peptide, maintains mitochondrial function, reduces mitochondrial reactive oxygen species (ROS) and thus regulates macrophage polarization, as well as promoting cell proliferation and migration, while MPDA NPs not only scavenge ROS and exert an anti-bacterial effect by photothermal treatment under near-infrared light irradiation, but also control release of SS31 in response to ROS. This F127DA/HAMA-MPDA@SS31 (FH-M@S) hydrogel has characteristics of adhesion, superior biocompatibility and mechanical properties which can adapt to irregular wounds at different body sites and provide sustained release of MPDA@SS31 (M@S) NPs. In addition, in a diabetic rat full thickness skin defect model, the FH-M@S hydrogel promoted macrophage M2 polarization, collagen deposition, neovascularization and wound healing. Therefore, the FH-M@S hydrogel exhibits promising therapeutic potential for skin regeneration., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

The structures and bonding properties of several lithium polysulfide clusters LiS n -/0 ( n = 3-5) and Li 2 S 4 -/0 were investigated by size-selected anion photoelectron spectroscopy coupled with quantum chemistry calculations. The vertical detachment energies of LiS 3 - , LiS 4 - , and LiS 5 - were estimated to be 2.17 ± 0.08, 3.30 ± 0.08 and 3.66 ± 0.08 eV, respectively, and that of Li 2 S 4 - was estimated to be 3.21 ± 0.08 eV. It is found that LiS 3 - and LiS 3 have planar quadrilateral structures, and LiS 4 - and LiS 4 have distorted five-membered ring structures. LiS 5 - has a distorted six-membered ring structure while neutral LiS 5 has a book-shaped structure. The lowest-lying structure of Li 2 S 4 - can be viewed as a S 2 unit connecting to the Li-Li edge of a Li 2 S 2 tetrahedron. The lowest-lying structure of neutral Li 2 S 4 can be viewed as a S 2 unit connecting to the S atoms of a Li 2 S 2 quadrilateral. The natural population analysis (NPA) and electron localization function (ELF) analyses show that the excess electron of LiS n - is mainly localized over the sulfur chains, especially on the S atoms interacting with Li, thus, the most stable structures of LiS n - can be regarded as a Li + cation interacting with a S n 2- dianion. The results may be useful for understanding the formation of lithium polysulfides in lithium sulfur batteries.

Objective: To analyze the clinical manifestations and imaging characteristics of in vivo confocal microscopy (IVCM) for Nocardia keratitis. Methods: It was a retrospective case series study. Medical records of 16 consecutive patients (16 eyes) with Nocardia keratitis were collected from the Department of Ophthalmology at Beijing Tongren Hospital, Capital Medical University between 2018 and 2022. The group consisted of 11 males and 5 females. The inclusion criteria for the study were the presence of typical clinical manifestations of Nocardia keratitis and at least one positive pathogenic test (corneal scraping or microbial culture) indicating Nocardia infection. The medical history, clinical and microbiological examination data of the patients were analyzed, including risk factors, diagnosis time, clinical manifestations, diagnostic methods, strain isolation, cure time, and best corrected visual acuity before and after treatment. This study utilized techniques such as slit lamp microscopy, in vivo confocal microscopy (IVCM), scraping cytology, microbial culture, and mass spectrometry identification. Results: The main risk factors for Nocardia keratitis included plant or foreign body injuries (5 out of 16 cases), contact lens use (4 out of 16 cases), and surgery (2 out of 16 cases). The average time to diagnosis was (20.8±11.8) days, with the shortest time being 8 days and the longest being 60 days. The best corrected visual acuity was less than 0.05 in 7 patients, between 0.05 to 0.3 in 7 patients, and greater than or equal to 0.3 in 2 patients. The typical symptoms included superficial gray-white infiltration in a wreath-like pattern on the cornea, corneal ulcers with dry and gray-white necrotic tissue coverage, and in severe cases, corneal ulcer perforation. Nocardia corneal infection was identified in 12 out of 16 cases by scraping cytology, 9 out of 16 cases by mass spectrometry, and 8 out of 16 cases by both methods. IVCM showed the presence of fine and moderately reflective filamentous hyphae in the subepithelial and superficial stromal layer of the cornea, arranged in elongated, beaded, and branched structures. Infiltration of many hyper-reflective round inflammatory cells was also seen around the hyphae. Fourteen cases were treated with medication and 2 cases were treated with corneal transplantation. The average cure time was (37.5±25.2) days and there were no cases of recurrence during the follow-up period (all greater than 6 months). Conclusions: Nocardia keratitis is primarily characterized by dense, round, or wreath-like infiltration in the early stage, and by gray-white dry necrotic secretion and hypopyon on the surface of corneal ulcers in the middle and late stages. Fine, branched or beaded, and moderately reflective filamentous structures are the hallmark of the corneal lesion on the IVCM images.

Background: Microbial infection is accompanied by remodeling of the host transcriptome. Involvement of A-to-I RNA editing has been reported during viral infection but remains to be elucidated during intracellular bacterial infections., Results: Herein we analyzed A-to-I RNA editing during intracellular bacterial infections based on 18 RNA-Seq datasets of 210 mouse samples involving 7 tissue types and 8 intracellular bacterial pathogens (IBPs), and identified a consensus signature of RNA editing for IBP infections, mainly involving neutrophil-mediated innate immunity and lipid metabolism. Further comparison of host RNA editing patterns revealed remarkable similarities between pneumonia caused by IBPs and single-strand RNA (ssRNA) viruses, such as altered editing enzyme expression, editing site numbers, and levels. In addition, functional enrichment analysis of genes with RNA editing highlighted that the Rab GTPase family played a common and vital role in the host immune response to IBP and ssRNA viral infections, which was indicated by the consistent up-regulated RNA editing of Ras-related protein Rab27a. Nevertheless, dramatic differences between IBP and viral infections were also observed, and clearly distinguished the two types of intracellular infections., Conclusion: Our study showed transcriptome-wide host A-to-I RNA editing alteration during IBP and ssRNA viral infections. By identifying and comparing consensus signatures of host A-to-I RNA editing, our analysis implicates the importance of host A-to-I RNA editing during these infections and provides new insights into the diagnosis and treatment of infectious diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wei, Wang, Li, Wen, Gao, Xia, Li, Pan, Liu, Jin and Chen.)

The patient is a 73-year-old female who developed bilateral corneal ulcers one month after cataract surgery in her left eye. The diagnosis is bilateral conjunctival pemphigoid. She underwent a left-eye amniotic membrane transplant and a right-eye lamellar corneal transplant, and was treated with oral immunosuppressants. The patient's condition is stable.

Background Acute myocardial infarction (AMI) is one of the leading causes of mortality worldwide, whereas social support is a known predictor of the prognosis after AMI. As a common factor influencing social support, the impact of marital status on care quality, in-hospital mortality, and long-term prognosis of patients with AMI remains largely unknown. Methods and Results The present study analyzed data from the CAMI (China Acute Myocardial Infarction) registry involving 19 912 patients with AMI admitted at 108 hospitals in China between January 2013 and September 2014 and aimed to evaluate marital status-based differences in acute management, medical therapies, and short-term and long-term outcomes. The primary end point was 2-year all-cause death. The secondary end points included in-hospital death and 2-year major adverse cardiac and cerebrovascular events (a composite of all-cause death, myocardial infarction, or stroke). After multivariable adjustment, 1210 (6.1%) unmarried patients received less reperfusion treatment in patients with both ST-segment-elevation myocardial infarction and non-ST-segment-elevation myocardial infarction (adjusted odds ratio [OR], 0.520 [95% CI, 0.437-0.618]; P <0.0001; adjusted OR, 0.489 [95% CI, 0.364-0.656]; P <0.0001). Being unmarried was not associated with poorer in-hospital outcome but with long-term all-cause mortality and major adverse cardiac and cerebrovascular events in both ST-segment-elevation myocardial infarction (adjusted hazard ratio [HR], 1.225 [95% CI, 1.031-1.456]; P =0.0209; adjusted HR, 1.277 [95% CI, 1.089-1.498]; P =0.0027) and non-ST-segment-elevation myocardial infarction (adjusted HR, 1.302 [95% CI, 1.036-1.638]; P =0.0239; adjusted HR, 1.368 [95% CI, 1.105-1.694]; P =0.0040) populations. Conclusions The present study suggests that being unmarried is independently related to less reperfusion received, but could not explain the higher in-hospital mortality rate after covariate adjustment. Being unmarried is associated with a substantially increased risk of adverse events over at least the first 24 months after AMI. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01874691.

An 8-year-old male patient was admitted to ophthalmology for bilateral progressive blurred vision for 5 years. He had a history of multiple spontaneous fractures. Ocular examination revealed best-corrected visual acuity (BCVA) of 0.5 in the right eye and 0.6 in the left eye. Slitlamp examination showed bilateral blue sclerae, thining of the entire cornea and corneal ectasia. General physical examination demonstrated multi-site ligamentous laxity. The diagnosis of osteogenesis imperfacta was made. The patient was advised to wear rigid gas permeable contact lens with large diameter and stabilized peripheral curve, and the BCVA achieved 0.8 for both eyes.

A 48-year-old man presented to Beijing Tongren Hospital Ophthalmology Department with redness, increased secretions and vision loss in his right eye. He had been treated with pterygium excision and lamellar keratoplasty due to recurrent pterygium in the right eye. After corneal scraping and microbial culture, he was diagnosed as bacterial keratitis after pterygium lamellar keratoplasty in the right eye. After applying topical antibiotic eye drops, removing corneal graft and conducting amniotic membrane transplantation, corneal infection was controlled and his vision was recovered.

Background: Neuropathic pain is still a challenge for clinical treatment as a result of the comprehensive pathogenesis. Although emerging evidence demonstrates the pivotal role of glial cells in regulating neuropathic pain, the role of Schwann cells and their underlying mechanisms still need to be uncovered. Pannexin 1 (Panx 1), an important membrane channel for the release of ATP and inflammatory cytokines, as well as its activation in central glial cells, contributes to pain development. Here, we hypothesized that Schwann cell Panx 1 participates in the regulation of neuroinflammation and contributes to neuropathic pain., Methods: A mouse model of chronic constriction injury (CCI) in CD1 adult mice or P0-Cre transgenic mice, and in vitro cultured Schwann cells were used. Intrasciatic injection with Panx 1 blockers or the desired virus was used to knock down the expression of Panx 1. Mechanical and thermal sensitivity was assessed using Von Frey and a hot plate assay. The expression of Panx 1 was measured using qPCR, western blotting, and immunofluorescence. The production of cytokines was monitored through qPCR and enzyme-linked immunosorbent assay (ELISA). Panx1 channel activity was detected by ethidium bromide (EB) uptake., Results: CCI induced persistent neuroinflammatory responses and upregulation of Panx 1 in Schwann cells. Intrasciatic injection of Panx 1 blockers, carbenoxolone (CBX), probenecid, and Panx 1 mimetic peptide ( 10 Panx) effectively reduced mechanical and heat hyperalgesia. Probenecid treatment of CCI-induced mice significantly reduced Panx 1 expression in Schwann cells, but not in dorsal root ganglion (DRG). In addition, Panx 1 knockdown in Schwann cells with Panx 1 shRNA-AAV in P0-Cre mice significantly reduced CCI-induced neuropathic pain. To determine whether Schwann cell Panx 1 participates in the regulation of neuroinflammation and contributes to neuropathic pain, we evaluated its effect in LPS-treated Schwann cells. We found that inhibition of Panx 1 via CBX and Panx 1-siRNA effectively attenuated the production of selective cytokines, as well as its mechanism of action being dependent on both Panx 1 channel activity and its expression., Conclusion: In this study, we found that CCI-related neuroinflammation correlates with Panx 1 activation in Schwann cells, indicating that inhibition of Panx 1 channels in Schwann cells reduces neuropathic pain through the suppression of neuroinflammatory responses., (© 2022. The Author(s).)

Porcine circovirus 4 (PCV4), a novel porcine circovirus identified in pigs, has recently been proved to be pathogenic to piglets. However, little is known about its cross-species transmission, and demonstration of PCV4 in dairy cows is lacking. To explore whether the PCV4 genome exists in dairy cows, 1170 fecal samples were collected from dairy farms in 7 cities in Henan Province of China during 2012-2021, and screened by qPCR for the presence of PCVs (PCV2-PCV4). The detection results showed that the positive rate of PCV4 in dairy cows was 2.22 % (26/1170), but all fecal samples were negative for PCV2 and PCV3. Three full-length and five partial genomes of PCV4 strains were acquired, of which two PCV4 strains (NY2012-DC and XC2013-DC) were achieved from 2012 and 2013, indicating that PCV4 has been circulating in dairy cows in Henan Province of China for at least 10 years. The three PCV4 strains sequenced in this study shared high identity (97.5-99.5 %) with reference strains at the genome level. In phylogenetic analysis, three genotypes (PCV4a, PCV4b and PCV4c) were temporarily confirmed by analyzing 44 strains, and one amino acid variation in Rep (V239L) and three amino acid variations in Cap (N27S, R28G and M212L) were considered as a conserved genotype specific molecular marker. Analyzed from three perspectives (cross-time, cross-species and transboundary), the high nucleotide homology of PCV4 strains indicated the PCV4 evolutionary rate might be slow. Overall, this study was the first to report the detection of PCV4 in dairy cows and conducted a long-term retrospective investigation of PCV4 in Henan Province of China, which has important implications for understanding the genetic diversity and cross-species transmission of the ongoing PCV4 cases., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Understanding the ultrafine substructure in freshly formed Fe-C martensite is the key point to reveal the real martensitic transformation mechanism. As-quenched martensite, whose transformation temperature is close to room temperature, has been investigated in detail by means of transmission electron microscopy (TEM) in this study. The observation results revealed that the freshly formed martensite after quenching is actually composed of ultrafine crystallites with a grain size of 1−2 nm. The present observation result matches well with the suggestion based on X-ray studies carried out one hundred years ago. Such nanocrystals are distributed throughout the entire martensite. The whole martensite shows a uniform contrast under both bright and dark field observation modes, irrespective of what observation directions are chosen. No defect contrast can be observed inside each nanocrystal. However, a body-centered cubic {112}<111>-type twinning relationship exists among the ultrafine α-Fe grains. Such ultrafine α-Fe grains or crystallites are the root cause of the fine microstructure formed in martensitic steels and high hardness after martensitic transformation. The formation mechanism of the ultrafine α-Fe grains in the freshly formed martensite will be discussed based on a new γ → α phase transformation mechanism.

Background: Multimodality magnetic resonance imaging (MRI) is widely used to detect vascular cognitive impairment (VCI). However, a bibliometric analysis of this issue remains unknown. Therefore, this study aimed to explore the research hotspots and trends of multimodality MRI on VCI over the past 12 years based on the Web of Science core collection using CiteSpace Software (6.1R2)., Methods: Literature related to multimodality MRI for VCI from 2010 to 2021 was identified and analyzed from the Web of Science core collection database. We analyzed the countries, institutions, authors, cited journals, references, keyword bursts, and clusters using CiteSpace., Results: In total, 587 peer-reviewed documents were retrieved, and the annual number of publications showed an exponential growth trend over the past 12 years. The most productive country was the USA, with 182 articles, followed by China with 134 papers. The top 3 active academic institutions were Capital Medical University, Radboud UNIV Nijmegen, and UNIV Toronto. The most productive journal was the Journal of Alzheimer's Disease (33 articles). The most co-cited journal was Neurology, with the highest citations (492) and the highest intermediary centrality (0.14). The top-ranked publishing author was De Leeuw FE (17 articles) with the highest intermediary centrality of 0.04. Ward Law JM was the most cited author (123 citations) and Salat Dh was the most centrally cited author (0.24). The research hotspots of multimodal MRI for VCI include Alzheimer disease, vascular cognitive impairment, white matter intensity, cerebrovascular disease, dementia, mild cognitive impairment, neurovascular coupling, acute ischemic stroke, depression, and cerebral ischemic stroke. The main frontiers in the keywords are fMRI, vascular coupling, and cerebral ischemic stroke, and current research trends include impact, decline, and classification., Conclusions: The findings from this bibliometric study provide research hotspots and trends for multimodality MRI for VCI over the past 12 years, which may help researchers identify hotspots and explore cutting-edge trends in this field., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Quercetin ( 1 ) was converted into quercetin 7- O -succinyl glucoside ( 2 ) by used Bacillus amyloliquefaciens FJ18 as a solvent-resistant whole-cell biocatalyst. The structure of the new compound was confirmed by LC-MS analysis and NMR spectroscopy. The water-solubility of this novel quercetin 7- O -succinyl glucoside ( 2 ) was approximately 1000 times higher than that of native quercetin ( 2 ). Quercetin ( 1 ) and quercetin 7- O -succinyl glucoside ( 2 ) exhibited significant DPPH scavenging capacity with IC 50 values of 23.55 and 36.05 µM, respectively. Both compounds showed moderate cytotoxic effects against the two human cancer cell lines (MCF-7 and HepG2) with IC 50 values ranging from 39.45-63.38 µM.

Objective: To investigate the protective effects of Schisandra chinensis oil (SCEO) against aristolochic acid I (AA I)-induced nephrotoxicity in vivo and in vitro and elucidate the underlying mechanism., Methods: C57BL/6 mice were randomly divided into 5 groups according to a random number table, including control group, AA I group, and AA I +SCEO (0.25, 0.5 and 1 g/kg) groups (n=5 per group). Pretreatment with SCEO was done for 2 days by oral administration, while the control and AA I groups were treated with sodium carboxymethyl cellulose. Mice of all groups except for the control group were injected intraperitoneally with AA I (5 mg/kg) from day 3 until day 7. Histopathological examination and apoptosis of kidney tissue were observed by hematoxylin and eosin and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatinine (SCr), as well as renal malondialdehyde (MDA), glutathione, r-glutamyl cysteingl+glycine (GSH), and superoxide dismutase (SOD) were analyzed using enzyme-linked immunosorbent assay (ELISA). Expressions of hepatic cytochrome P450 1A1 (CYP1A1), CYP1A2, and nad(p)hquinonedehydrogenase1 (NQO1) were analyzed using ELISA, quantitative real-time polymerase chain reaction (qPCR) and Western blot, respectively. In vitro, SCEO (40 µ g/mL) was added 12 h before treatment with AA I (40 µ mol/mL for 48 h) in human renal proximal tubule cell line (HK-2), then apoptosis and reactive oxygen species (ROS) were analyzed by flow cytometry., Results: SCEO 0.5 and 1 g/kg ameliorated histopathological changes and TUNEL + staining in the kidney tissues of mice with AA I-induced nephrotoxicity, and reduced serum levels of ALT, AST, BUN and SCr (P<0.01 or P<0.05). SCEO 0.5 and 1 g/kg alleviated the ROS generation in kidney, containing MDA, GSH and SOD (P<0.01 or P<0.05). SCEO 1 g/kg increased the expressions of CYP1A1 and CYP1A2 and decreased NQO1 level in the liver tissues (P<0.01 or P<0.05). Besides, in vitro studies also demonstrated that SCEO 40 µ g/mL inhibited apoptosis and ROS generation (P<0.05 or P<0.01)., Conclusions: SCEO can alleviate AA I-induced kidney damage both in vivo and in vitro. The protective mechanism may be closely related to the regulation of metabolic enzymes, thereby inhibiting apoptosis and ROS production., (© 2022. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Acetaminophen (APAP) is one of the major causes of drug-induced acute liver injury, and ethanol may aggravate APAP-induced liver injury. The problem of ethanol- and APAP-induced liver injury becomes increasingly prominent, but the mechanism of ethanol- and APAP-induced liver injury remains ambiguous. p38γ is one of the four isoforms of P38 mitogen activated protein kinases, that contributes to inflammation in different diseases. In this study we investigated the role of p38γ in ethanol- and APAP-induced liver injury. Liver injury was induced in male C57BL/6 J mice by giving liquid diet containing 5% ethanol (v/v) for 10 days, followed by gavage of ethanol (25% (v/v), 6 g/kg) once or injecting APAP (200 mg/kg, ip), or combined the both treatments. We showed that ethanol significantly aggravated APAP-induced liver injury in C57BL/6 J mice. Moreover, the expression level of p38γ was up-regulated in the liver of ethanol-, APAP- and ethanol+APAP-treated mice. Knockdown of p38γ markedly attenuated liver injury, inflammation, and steatosis in ethanol+APAP-treated mice. Liver sections of p38γ-knockdown mice displayed lower levels of Oil Red O stained dots and small leaky shapes. AML-12 cells were exposed to APAP (5 mM), ethanol (100 mM) or combined treatments. We showed that P38γ was markedly increased in ethanol+APAP-treated AML-12 cells, whereas knockdown of p38γ significantly inhibited inflammation, lipid accumulation and oxidative stress in ethanol+APAP-treated AML-12 cells. Furthermore, we revealed that p38γ could combine with Dlg1, a member of membrane-associated guanylate kinase family. Deletion of p38γ up-regulated the expression level of Dlg1 in ethanol+APAP-treated AML-12 cells. In summary, our results suggest that p38γ functions as an important regulator in ethanol- and APAP-induced liver injury through modulation of Dlg1., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Heat stress is one of the major environmental stressors challenging the global poultry industry. Identifying the genes responsible for heat tolerance is fundamentally important for direct breeding programs. To uncover the genetic basis underlying the ambient temperature adaptation of chickens, we analyzed a total of 59 whole genomes from indigenous chickens that inhabit South Asian tropical regions and temperate regions from Northern China. We applied F ST and π-ratio to scan selective sweeps and identified 34 genes with a signature of positive selection in chickens from tropical regions. Several of these genes are functionally implicated in metabolism (FABP2, RAMP3, SUGCT, and TSHR) and vascular smooth muscle contractility (CAMK2), and they may be associated with adaptation to tropical regions. In particular, we found a missense mutation in thyroid-stimulating hormone receptor (41020238:G>A) that shows significant differences in allele frequency between the chicken populations of the two regions. To evaluate whether the missense mutation in TSHR could enhance the heat tolerance of chickens, we constructed segregated chicken populations and conducted heat stress experiments using homozygous mutations (AA) and wild-type (GG) chickens. We found that GG chickens exhibited significantly higher concentrations of alanine aminotransferase, lactate dehydrogenase, and creatine kinase than AA chickens under heat stress (35 ± 1°C) conditions (P < 0.05). These results suggest that TSHR (41020238:G>A) can facilitate heat tolerance and adaptation to higher ambient temperature conditions in tropical climates. Overall, our results provide potential candidate genes for molecular breeding of heat-tolerant chickens., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)