Implications of intestinal microecology and immune function alterations for immunotherapy outcomes in advanced unresectable lung adenocarcinoma.

OBJECTIVE: This investigation aims to explore alterations in intestinal microecology and immune function among patients with advanced, unresectable lung adenocarcinoma undergoing different outcomes from immunotherapy. METHODS: A cohort of 30 patients diagnosed with advanced unresectable lung adenocarcinoma received sintilimab immunotherapy as a monotherapy. Post four treatment cycles, efficacy was assessed, leading to the segregation of patients into two distinct cohorts: those responsive to treatment and those nonresponsive. Analysis involved observing variations in the abundance, distribution, and composition of fecal intestinal microorganisms pretreatment and posttreatment via 16S rRNA gene sequencing. RESULTS: In this study involving 30 advanced lung adenocarcinoma patients, significant observations were made regarding the impact of immunotherapy on immune function and the gut microbiome composition. Patients were divided into treatment and control groups, revealing that immunotherapy led to a significant increase in CD4+ T cells and a decrease in CD8+ T cells among the treatment-responsive individuals, indicating an enhanced immune response. Furthermore, an in-depth analysis of the gut microbiome showed an increase in diversity and abundance of beneficial bacteria such as Faecalibacterium and Subdoligranulum in the treatment group. These findings highlight the dual effect of immunotherapy on modulating immune function and altering gut microbiome diversity, suggesting its potential therapeutic benefits in improving the health status of patients with advanced lung adenocarcinoma. CONCLUSION: The structuring of gut flora plays a pivotal role in augmenting the efficacy of anti-tumor immunotherapy, underscoring the interplay between intestinal microecology and immune response in cancer treatment outcomes.

Antibacterial Activity of Plants in Cirsium: A Comprehensive Review.

As ethnic medicine, the whole grass of plants in Cirsium was used as antimicrobial. This review focuses on the antimicrobial activity of plants in Cirsium, including antimicrobial components, against different types of microbes and bacteriostatic mechanism. The results showed that the main antimicrobial activity components in Cirsium plants were flavonoids, triterpenoids and phenolic acids, and the antimicrobial ability varied according to the species and the content of chemicals. Among them, phenolic acids showed a strong antibacterial ability against Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococcus faecium. The antibacterial mechanisms include: (1) damaging the cell membrane, cell walls, mitochondria and nucleus of bacteria; (2) inhibiting the synthesis of proteins and nucleic acids; (3) suppressing the synthesis of enzymes for tricarboxylic acid cycle pathways and glycolysis, and then killing the bacteria via inhibition of energy production. Totally, most research results on antimicrobial activity of Cirsium plants are reported based on in vitro assays. The evidence from clinical data and comprehensive evaluation are needed.

Predictors and outcomes of withholding and withdrawal of life-sustaining treatments in intensive care units in Singapore: a multicentre observational study.

BACKGROUND: Clinical practice guidelines on limitation of life-sustaining treatments (LST) in the intensive care unit (ICU), in the form of withholding or withdrawal of LST, state that there is no ethical difference between the two. Such statements are not uniformly accepted worldwide, and there are few studies on LST limitation in Asia. This study aimed to evaluate the predictors and outcomes of withholding and withdrawal of LST in Singapore, focusing on the similarities and differences between the two approaches. METHODS: This was a multicentre observational study of patients admitted to 21 adult ICUs across 9 public hospitals in Singapore over an average of three months per year from 2014 to 2019. The primary outcome measures were withholding and withdrawal of LST (cardiopulmonary resuscitation, invasive mechanical ventilation, and vasopressors/inotropes). The secondary outcome measure was hospital mortality. Multivariable generalised mixed model analysis was used to identify independent predictors for withdrawal and withholding of LST and if LST limitation predicts hospital mortality. RESULTS: There were 8907 patients and 9723 admissions. Of the former, 80.8% had no limitation of LST, 13.0% had LST withheld, and 6.2% had LST withdrawn. Common independent predictors for withholding and withdrawal were increasing age, absence of chronic kidney dialysis, greater dependence in activities of daily living, cardiopulmonary resuscitation before ICU admission, higher Acute Physiology and Chronic Health Evaluation (APACHE) II score, and higher level of care in the first 24 h of ICU admission. Additional predictors for withholding included being of Chinese race, the religions of Hinduism and Islam, malignancy, and chronic liver failure. The additional predictor for withdrawal was lower hospital paying class (with greater government subsidy for hospital bills). Hospital mortality in patients without LST limitation, with LST withholding, and with LST withdrawal was 10.6%, 82.1%, and 91.8%, respectively (p < 0.001). Withholding (odds ratio 13.822, 95% confidence interval 9.987-19.132) and withdrawal (odds ratio 38.319, 95% confidence interval 24.351-60.298) were both found to be independent predictors of hospital mortality on multivariable analysis. CONCLUSIONS: Differences in the independent predictors of withholding and withdrawal of LST exist. Even after accounting for baseline characteristics, both withholding and withdrawal of LST independently predict hospital mortality. Later mortality in patients who had LST withdrawn compared to withholding suggests that the decision to withdraw may be at the point when medical futility is recognised.

Rotavirus infection inhibits SLA-I expression on the cell surface by degrading ß2 M via ERAD-proteasome pathway.

Group A Rotavirus (RVA) is a major cause of diarrhea in infants and piglets. ß2-microglobulin (ß2 M), encoded by the B2M gene, serves as a crucial subunit of the major histocompatibility complex class I (MHC-I) molecules. ß2 M is indispensable for the transport of MHC-I to the cell membrane. MHC-I, also known as swine leukocyte antigen class I (SLA-I) in pigs, presents viral antigens to the cell surface. In this study, RVA infection down-regulated ß2 M expression in both porcine intestinal epithelial cells-J2 (IPEC-J2) and MA-104 cells. RVA infection did not down-regulate the mRNA level of the B2M gene, indicating that the down-regulation of ß2 M occurred on the protein level. Mechanismly, RVA infection triggered ß2 M aggregation in the endoplasmic reticulum (ER) and enhanced the Lys48 (K48)-linked ubiquitination of ß2 M, leading to the degradation of ß2 M through ERAD-proteasome pathway. Furthermore, we found that RVA infection significantly impeded the level of SLA-I on the surface, and the overexpression of ß2 M could recover its expression. In this study, our study demonstrated that RVA infection degrades ß2 M via ERAD-proteasome pathway, consequently hampering SLA-I expression on the cell surface. This study would enhance the understanding of the mechanism of how RVA infection induces immune escape.

Neoadjuvant immunotherapy based on PD-1/L1 Inhibitors for gastrointestinal tumor: a review of rationale and clinical advances.

The landscape of current tumor treatment has been revolutionized by the advent of immunotherapy based on PD-1/PD-L1 inhibitors. Leveraging its capacity to mobilize systemic anti-tumor immunity, which is primarily mediated by T cells, there is growing exploration and expansion of its potential value in various stages of clinical tumor treatment. Neoadjuvant immunotherapy induces a robust immune response against tumors prior to surgery, effectively facilitating tumor volume reduction, early eradication or suppression of tumor cell activity, and control of potential metastatic spread, to improve curative surgical resection rates and prevent tumor recurrence. This review delineates the theoretical basis of neoadjuvant immunotherapy from preclinical research evidence, discusses specific challenges in clinical application, and provides a comprehensive overview of clinical research progress in neoadjuvant immunotherapy for gastrointestinal tumors. These findings suggest that neoadjuvant immunotherapy has the potential to ameliorate immunosuppressive states and enhance cytotoxic T cell function while preserving lymphatic drainage in the preoperative period. However, further investigations are needed on specific treatment regimens, suitable patient populations, and measurable endpoints. Despite numerous studies demonstrating the promising efficacy and manageable adverse events of neoadjuvant immunotherapy in gastrointestinal tumors, the availability of high-quality randomized controlled trials is limited, which highlights the necessity for further research.

Value of neutrophil-to-lymphocyte ratio in neuronal intranuclear inclusion disease.

Background and objectives: The neutrophil-to-lymphocyte ratio (NLR) is a widely recognized marker of inflammation in peripheral blood. However, its specific role in neuronal intranuclear inclusion disease (NIID) has not been reported. This study aims to investigate the relationship between NIID and NLR. Methods: A multicenter database was collected, including 157 NIID patients from seven hospitals (The Affiliated Hospital of Xuzhou Medical University, Yantai Yuhuangding Hospital, Tengzhou Central People's Hospital,The Affiliated Brain Hospital of Nanjing Medical University, Liaocheng People's Hospital,The Second Hospital of Shandong University, Inner Mongolia People's Hospital, Xuanwu Hospital Capital Medical University,The First Affiliated Hospital of USTC), along with 157 age- and gender-matched healthy control subjects. White blood cell counts (including neutrophils, lymphocytes, monocytes, eosinophils, and basophils) were obtained, and the NLR was calculated. Additionally, cognitive impairment was assessed using clinical evaluation scores. Results: NIID patients exhibited significantly higher NLR values compared to the healthy control group (p < 0.001). The plasma NLR levels in NIID patients showed a weak positive correlation with disease duration (r = 0.219, p = 0.016). However, no significant correlations were found between NLR and age of onset or cognitive impairment (p > 0.05). Conclusion: There is a significant association between NLR and NIID, suggesting a potential role of peripheral blood inflammation in the pathogenesis of NIID.

Mutation status of the KMT2 family associated with immune checkpoint inhibitors (ICIs) therapy and implicating diverse tumor microenvironments.

Mounting evidence suggests a strong association between tumor immunity and epigenetic regulation. The histone-lysine N-methyltransferase 2 (KMT2) family plays a crucial role in the methylation of histone H3 at lysine 4. By influencing chromatin structure and DNA accessibility, this modification serves as a key regulator of tumor progression and immune tolerance across various tumors. These findings highlight the potential significance of the KMT2 family in determining response to immune checkpoint inhibitor (ICI) therapy, which warrants further exploration. In this study, we integrated four ICI-treated cohorts (n = 2069) across 10 cancer types and The Cancer Genome Atlas pan-cancer cohort and conducted a comprehensive clinical and bioinformatic analysis. Our study indicated that patients with KMT2 family gene mutations benefited more from ICI therapy in terms of overall survival (P < 0.001, hazard ratio [HR] = 0.733 [95% confidence interval (CI): 0.632-0.850]), progression-free survival (P = 0.002, HR = 0.669 [95% CI: 0.518-0.864]), durable clinical benefit (P < 0.001, 54.1% vs. 32.6%), and objective response rate (P < 0.001, 40.6% vs. 22.0%). Through a comprehensive analysis of the tumor microenvironment across different KMT2 mutation statuses, we observed that tumors harboring the KMT2 mutation exhibited enhanced immunogenicity, increased infiltration of immune cells, and higher levels of immune cell cytotoxicity, suggesting a propensity towards a "hot tumor" phenotype. Therefore, our study indicates a potential association between KMT2 mutations and a more favorable response to ICI therapy and implicates different tumor microenvironments associated with ICI therapy response.

Synthesis of Chiral Sulfoxides by A Cyclic Oxidation-Reduction Multi-Enzymatic Cascade Biocatalysis.

Optically pure sulfoxides are valuable organosulfur compounds extensively employed in medicinal and organic synthesis. In this study, we present a biocatalytic oxidation-reduction cascade system designed for the preparation of enantiopure sulfoxides. The system involves the cooperation of a low-enantioselective chimeric oxidase SMO (styrene monooxygenase) with a high-enantioselective reductase MsrA (methionine sulfoxide reductase A), facilitating "non-selective oxidation and selective reduction" cycles for prochiral sulfide oxidation. The regeneration of requisite cofactors for MsrA and SMO was achieved via a cascade catalysis process involving three auxiliary enzymes, sustained by cost-effective D-glucose. Under the optimal reaction conditions, a series of heteroaryl alkyl, aryl alkyl and dialkyl sulfoxides in R configuration were synthesized through this "one-pot, one step" cascade reaction. The obtained compounds exhibited high yields of >90 % and demonstrated enantiomeric excess (ee) values exceeding 90 %. This study represents an unconventional and efficient biocatalytic way in utilizing the low-enantioselective oxidase for the synthesis of enantiopure sulfoxides.

Engineering of methionine sulfoxide reductase A with simultaneously improved stability and activity for kinetic resolution of chiral sulfoxides.

Methionine sulfoxide reductase A (MsrA) has emerged as promising biocatalysts in the enantioselective kinetic resolution of racemic (rac) sulfoxides. In this study, we engineered robust MsrA variants through directed evolution, demonstrating substantial improvements of thermostability. Mechanism analysis reveals that the enhanced thermostability results from the strengthening of intracellular interactions and increase in molecular compactness. Moreover, these variants demonstrated concurrent improvements in catalytic activities, and notably, these enhancements in stability and activity collectively contributed to a significant improvement in enzyme substrate tolerance. We achieved kinetic resolution on a series of rac-sulfoxides with high enantioselectivity under initial substrate concentrations reaching up to 93.0 g/L, representing a great improvement in the aspect of the substrate concentration for biocatalytic preparation of chiral sulfoxide. Hence, the simultaneously improved thermostability, activity and substrate tolerance of MsrA represent an excellent biocatalyst for the green synthesis of optically pure sulfoxides.

Exploration of kiwi root on non-small cell lung cancer based on network pharmacology and molecular docking.

BACKGROUND: Kiwi root is a Chinese herb clinically used in the treatment of lung neoplasm; however, the multi-target mechanism of kiwi root in the treatment of non-small cell lung cancer (NSCLC) remains to be elucidated. Thus, this study aimed to investigate the molecular mechanisms of kiwi root in the treatment of NSCLC through network pharmacology and molecular docking techniques. METHODS: The active components and targets of kiwi root were obtained from the TCMSP database, and NSCLC-related targets were obtained from the GeneCards, OMIM, and DrugBank databases. The intersection targets of NSCLC and kiwi root were obtained from VENNY 2.1.0. Then, the common targets were imported into the STRING database, and by using the Cytoscape 3.7.1 software, drug-disease network diagrams were created. Afterwards, the DAVID database was utilized to perform bioinformatic annotation. Finally, molecular docking of key components and key targets was performed by Autodock Tools. RESULTS: A total of 4083 NSCLC-related disease genes were collected from the GeneCards, OMIM,and DrugBank databases, and 177 non-duplicated drug targets were acquired from the TCMSP database. A total of 138 intersection target genes were obtained, in which TP53, AKT1, and TNF were the key targets. CONCLUSION: Through network pharmacology techniques, the mechanism of kiwi root in the treatment of NSCLC has been uncovered and provides a theoretical basis for the clinical treatment of NSCLC with kiwi root, which requires further experimental validation.

Chiral separation and bioactivities of six pairs of enantiomeric dilignans from Magnolia officinalis var. biloba.

Six pairs of enantiomeric dilignans, (+)/(-)-magdiligols A-F, have been isolated from an ethanolic extract of the barks of Magnolia officinalis var. biloba. Their chemical structures were elucidated by extensive spectroscopic analyses, NMR calculation with DP4+ analysis, and the electronic circular dichroism spectra calculation. (+)/(-)-1-3 possessed a dihydrobenzopyran ring, while a propyl chain of 1 was linked via ether bond. (+)/(-)-Magdiligols D and E ((+)/(-)-4 and 5) were dilignans possessing a furan ring. (+)-Magdiligol B ((+)/(-)-2), (+)/(-)-magdiligol C ((+)/(-)-3), and racemes 2, 3, and 5 showed potential hepatoprotective effects against APAP-induced HepG2 cell damage, increased the cell viability from 65.4% to 72.7, 78.7.76.6, 73.9, 77.9 and 73.2%, via decreasing the level of the live enzymes ALH and LDH consistently. (+)/(-)-Magdiligols B-D ((+)/(-)-2-4) and (+)/(-)-magdiligol F ((+)/(-)-6) exhibited significant antioxidative activity. (+)/(-)-Magdiligols B-C ((+)/(-)-2 and 3), (-)-magdiligol D ((-)-4), and (+)-magdiligol E ((+)-5) displayed significant PTP1B inhibitory activity with IC50 values 1.41-3.42 µM. (+)/(-)-Magdiligol B ((+)/(-)-2), and its raceme (2) demonstrated α-glucosidase inhibitory activity with the IC50 values 1.47, 2.88 and 1.85 µM, respectively.

Percutaneous nephrolithotomy guided by 5G-powered robot-assisted teleultrasound diagnosis system: first clinical experience with a novel tele-assistance approach (IDEAL stage 1).

BACKGROUND: To demonstrate the technical feasibility of percutaneous nephrolithotomy (PCNL) guided by 5G-powered robot-assisted teleultrasound diagnosis system (RTDS) in a complex kidney-stone (CKS) cohort and present our preliminary outcomes. PCNL is highly skill-required, which hinders it popularization in primary medical units of remote regions. We designed an innovative tele-assistance approach to make PCNL easy to be operated by inexperienced surgeons. METHODS: This was a prospective proof-of-concept study (IDEAL phase 1) on intraoperative tele-assistance provided by online urological experts via a 5G-powered RTDS. Total 15 CKS patients accepted this technology. Online experts manipulated a simulated probe to assist unskilled local operators by driving a patient-side robot-probe to guide and monitor the steps of access establishment and finding residual stones. RESULTS: Median total delay was 177ms despite one-way network-connecting distance > 5,800 km. No perceptible delay of audio-visual communication, driving robot-arm or dynamic ultrasound images was fed back. Successful tele-assistance was obtained in all cases. The first-puncture access-success rate was 78.6% with a one-session SF rate of 71.3% and without complications of grade III-V. CONCLUSIONS: The current technology based on 5G-powered RTDS can provide high-quality intraoperative tele-assistance, which has preliminarily shown satisfactory outcomes and reliable safety. It will break down a personal competence-based barrier to endow PCNL with more popular utilization. TRIAL REGISTRATION: The study was approved by ethics committee of the Xinjiang Kezhou People's Hospital and ethics committee of the First Affiliated Hospital of Nanjing Medical University and was registered on http://www.chictr.org.cn (ChiCTR2200065849, 16/11/2022).

[Systematic review and Meta-analysis of efficacy and safety of Shufeng Jiedu Capsules in treatment of influenza].

This study aims to systematically review the efficacy and safety of Shufeng Jiedu Capsules in the treatment of influenza. The randomized controlled trial(RCT) of Shufeng Jiedu Capsules alone or in combination with conventional western medicine for treating influenza were retrieved from PubMed, EMbase, Cochrane Library, Web of Science, SinoMed, CNKI, VIP, Wanfang, and ClinicalTrails.gov. The data analysis was performed in RevMan 5.4.1. The Cochrane risk of bias assessment tool was used to evaluate the quality of the involved RCT, and GRADEpro GDT to assess the quality of the evidence. A total of 11 RCTs involving 1 836 patients were included in this study. Compared with conventional western medicine, Shufeng Jiedu Capsules/Shufeng Jiedu Capsules + conventional western medicine improved the response rate(RR=1.09, 95%CI[1.03, 1.15], P=0.002), shortened the time to relief of cough, and increased the 3-day sore throat relief rate, whereas there was no significant difference in the time to fever abatement, the time to relief of sore throat, 3-day cough relief rate, or 3-day runny nose relief rate. Subgroup-analysis showed that Shufeng Jiedu Capsules + conventional western medicine improved the response rate(RR=1.11, 95%CI[1.08, 1.15], P<0.000 01), shortened the time to relief of cough, and increased the 3-day relief rate of symptoms(cough, sore throat, and runny nose) compared with conventional western medicine alone, while there was no significant difference in the time to fever abatement or the time to relief of sore throat. Shufeng Jiedu Capsules alone could not improve the response rate(RR=0.97, 95%CI[0.93, 1.02], P=0.19). In addition, Shufeng Jiedu Capsules/Shufeng Jiedu Capsules + conventional western medicine vs conventional western medicine were no significant difference in adverse reactions(RR=0.98, 95%CI[0.57, 1.69], P=0.95). The available evidence suggests that Shufeng Jiedu Capsules is effective and safe in the treatment of influenza, and the combination of Shufeng Jiedu Capsules with conventional western medicine can accelerate the relief of symptoms. However, since the number and quality of the included studies were low, the above findings remained to be further verified by multicenter RCT with large sample sizes.

Catalytic Asymmetric Polycyclization of Tertiary Enamides with Silyl Enol Ethers: Total Synthesis of (-)-Cephalocyclidin A.

A catalytic enantioselective polycyclization of tertiary enamides with terminal silyl enol ethers has been developed by virtue of Cu(OTf)2 catalysis with a novel spiropyrroline-derived oxazole (SPDO) ligand. This tandem reaction offers an effective approach to assemble bicyclic and tricyclic N-heterocycles bearing both aza- and oxa-quaternary stereogenic centers, which are primal subunits in a range of natural alkaloids. Strategic application of this methodology and a late-stage radical cyclization as key steps have been showcased in the concise total synthesis of (-)-cephalocyclidin A.

Glutathione-dependent redox homeostasis is critical for chlorothalonil detoxification in tomato leaves.

Glutathione plays a critical role in plant growth, development and response to stress. It is a major cellular antioxidant and is involved in the detoxification of xenobiotics in many organisms, including plants. However, the role of glutathione-dependent redox homeostasis and associated molecular mechanisms regulating the antioxidant system and pesticide metabolism remains unclear. In this study, endogenous glutathione levels were manipulated by pharmacological treatments with glutathione synthesis inhibitors and oxidized glutathione. The application of oxidized glutathione enriched the cellular oxidation state, reduced the activity and transcript levels of antioxidant enzymes, upregulated the expression level of nitric oxide and Ca2+ related genes and the content, and increased the residue of chlorothalonil in tomato leaves. Further experiments confirmed that glutathione-induced redox homeostasis is critical for the reduction of pesticide residues. RNA sequencing analysis revealed that miRNA156 and miRNA169 that target transcription factor SQUAMOSA-Promoter Binding Proteins (SBP) and NUCLEAR FACTOR Y (NFY) potentially participate in glutathione-mediated pesticide degradation in tomato plants. Our study provides important clues for further dissection of pesticide degradation mechanisms via miRNAs in plants.

Enantioselective Synthesis of 2,3,3a,8a-Tetrahydrofuro[2,3-b]benzofuran Scaffolds Enabled by Cu(II)/SPDO-Catalyzed [3+2] Cycloaddition of 2,3-Dihydrofuran and Quinone Esters.

An asymmetric [3+2] cycloaddition of quinone esters with 2,3-dihydrofuran has been realized via a newly developed Cu(II)/SPDO complex. It provides straightforward access to 2,3,3a,8a-tetrahydrofuro[2,3-b]benzofurans (TFB) with high enantioselectivity (up to 97.5:2.5 er) and diastereoselectivity (all >20:1 dr). The resulting adducts contain two adjacent stereocenters and a continuously functionalized benzene ring. Additionally, this transformation could be easily performed on a gram scale, allowing for expedient synthesis of natural dihydroaflatoxin D2 and aflatoxin B2.

The effective doses of remimazolam besylate in the procedural sedation of endoscopic retrograde cholangiopancreatography.

This study aimed to determine the values of the half-effective dose (ED50) and 95% effective dose (ED95) of remimazolam besylate used in the procedural sedation of endoscopic retrograde cholangiopancreatography (ERCP). Sixty patients who fulfilled the inclusion and exclusion criteria of this study were selected. Sufentanil was administered intravenously and remimazolam besylate was administered 2 min later. ERCP treatment was feasible when the modified alertness/sedation (MOAA/S) score was ≤2. If choking or movement occurred during duodenoscope placement, it was considered as a positive reaction. The dose was increased in the next patient; otherwise, it was considered as a negative reaction, and the dose was reduced in the next patient. The ED50 and ED95 values and 95% confidence interval (CI) of remimazolam besylate were calculated by Probit regression analysis. All 60 patients completed the trial. The ED50 and ED95 values of remimazolam besylate were 0.196 and 0.239 mg/kg, respectively, for the procedural sedation of ERCP. The time of MOAA/S score ≤ 2 was (82.58 ± 21.70) s, and the mean time of awakening was (9.03 ± 5.64) min. Transient hypotension was observed in two patients without medical intervention. The ED50 and ED95 values of remimazolam besylate used in the procedural sedation of ERCP were 0.196 and 0.239 mg/kg, and the dose of the medications has definite efficacy and good safety.

HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m5 C Methylation of Atf7 mRNA.

PIWI-interacting RNAs (piRNAs) are highly expressed in various cardiovascular diseases. However, their role in cardiomyocyte death caused by ischemia/reperfusion (I/R) injury, especially necroptosis, remains elusive. In this study, a heart necroptosis-associated piRNA (HNEAP) is found that regulates cardiomyocyte necroptosis by targeting DNA methyltransferase 1 (DNMT1)-mediated 5-methylcytosine (m5 C) methylation of the activating transcription factor 7 (Atf7) mRNA transcript. HNEAP expression level is significantly elevated in hypoxia/reoxygenation (H/R)-exposed cardiomyocytes and I/R-injured mouse hearts. Loss of HNEAP inhibited cardiomyocyte necroptosis and ameliorated cardiac function in mice. Mechanistically, HNEAP directly interacts with DNMT1 and attenuates m5 C methylation of the Atf7 mRNA transcript, which increases Atf7 expression level. ATF7 can further downregulate the transcription of Chmp2a, an inhibitor of necroptosis, resulting in the reduction of Chmp2a level and the progression of cardiomyocyte necroptosis. The findings reveal that piRNA-mediated m5 C methylation is involved in the regulation of cardiomyocyte necroptosis. Thus, the HNEAP-DNMT1-ATF7-CHMP2A axis may be a potential target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.

Compact multipass-laser-beam antenna for NV sensor sensitivity enhancement.

Large-area, highly uniform microwave field radiation and efficient excitation of fluorescence are the key to achieving high sensitivity sensing of the NV (nitrogen-vacancy) magnetometer. In this paper, we report a compact multipass-laser-beam antenna for NV ensemble color centers sensing. The antenna not only provides a tridimensional uniform magnetic field, but also can be used for efficient excitation of the NV fluorescence. The optimal size of the antenna and the angle of laser incidence are determined by the multi-physics field simulation software COMSOL. For an equivalent excitation power, the designed structure increases the path length of the excitation beam by up to three orders of magnitude, up to the level of m, compared to the conventional direct beam mode. Finally, this method increased the sensitivity by a factor of 60 realized a magnetic field sensitivity of 2.8 nT/√Hz in the range of 10-100 Hz. This work provides an experimental method for the design of integrated NV magnetometers.

Broad antagonism of coronaviruses nsp5 to evade the host antiviral responses by cleaving POLDIP3.

Coronaviruses (CoVs) are a family of the largest RNA viruses that typically cause respiratory, enteric, and hepatic diseases in animals and humans, imposing great threats to the public safety and animal health. Porcine deltacoronavirus (PDCoV), a newly emerging enteropathogenic coronavirus, causes severe diarrhea in suckling piglets all over the world and poses potential risks of cross-species transmission. Here, we use PDCoV as a model of CoVs to illustrate the reciprocal regulation between CoVs infection and host antiviral responses. In this study, downregulation of DNA polymerase delta interacting protein 3 (POLDIP3) was confirmed in PDCoV infected IPEC-J2 cells by isobaric tags for relative and absolute quantification (iTRAQ) and Western blotting analysis. Overexpression of POLDIP3 inhibits PDCoV infection, whereas POLDIP3 knockout (POLDIP3-/-) by CRISPR-Cas9 editing significantly promotes PDCoV infection, indicating POLDIP3 as a novel antiviral regulator against PDCoV infection. Surprisingly, an antagonistic strategy was revealed that PDCoV encoded nonstructural protein 5 (nsp5) was responsible for POLDIP3 reduction via its 3C-like protease cleavage of POLDIP3 at the glutamine acid 176 (Q176), facilitating PDCoV infection due to the loss of antiviral effects of the cleaved fragments. Consistent with the obtained data in IPEC-J2 cell model in vitro, POLDIP3 reduction by cleavage was also corroborated in PDCoV infected-SPF piglets in vivo. Collectively, we unveiled a new antagonistic strategy evolved by PDCoV to counteract antiviral innate immunity by nsp5-mediated POLDIP3 cleavage, eventually ensuring productive virus replication. Importantly, we further demonstrated that nsp5s from PEDV and TGEV harbor the conserved function to cleave porcine POLDIP3 at the Q176 to despair POLDIP3-mediated antiviral effects. In addition, nsp5 from SARS-CoV-2 also cleaves human POLDIP3. Therefore, we speculate that coronaviruses employ similar POLDIP3 cleavage mechanisms mediated by nsp5 to antagonize the host antiviral responses to sustain efficient virus infection.