Relationship between methylenetetrahydrofolate reductase C677T gene polymorphism and neutrophil gelatinase-associated lipocalin in early renal injury in H-type hypertension.

OBJECTIVE: To analyse the relationship between the polymorphisms of the H-type hypertensive methylenetetrahydrofolate reductase (MTHFR) C677T gene and neutrophil gelatinase-associated lipocalin (NGAL) in early kidney injury. METHOD: A total of 279 hospitalised patients with hypertension were selected and grouped according to their homocysteine (Hcy) level. If their blood Hcy level was ≥ 10 µmol/L they were assigned to the H-type hypertensive group, and if it was < 10 µmol/L they were assigned to the non-H-type hypertensive group. Blood lipid indexes, renal function indexes and blood glucose indexes were collected, and the differences between the two groups were compared. Furthermore, MTHFR C677T genotype distribution and allele frequency and Hcy level of MTHFR C677T genotype were compared, and logistic multiple regression analysis was conducted for the correlation of different genotypes of MTHFR C677T and the early kidney injury marker NGAL. RESULTS: In the non-H-type hypertensive group, the levels of Hcy and NGAL, cystatin, blood urea nitrogen, serum creatinine, uric acid, serum ß2-microglobulin and urinary microalbumin-to-creatinine ratio increased significantly, and the glomerular filtration rate level decreased significantly, when compared with the H-type hypertensive group, with statistical differences (p < 0.05). The H-type hypertensive group and the non-H-type hypertensive group had significant differences in the CC, CT and TT genotypes and allele frequencies at the MTHFR C677T locus. The MTHFR C677T gene mutation rate of the H-type hypertensive group was significantly higher than that of the non-H-type hypertensive group. The H-type hypertensive group had higher levels of the TT genotype and CT genotype Hcy. There was a statistical difference (p < 0.05). CONCLUSION: Methylenetetrahydrofolate reductase C677T polymorphism is correlated with the Hcy level, and its gene polymorphism will affect the Hcy level. Methylenetetrahydrofolate reductase C677T polymorphism has an interactive effect with NGAL. Screening NGAL and reducing Hcy levels are valuable methods for the prevention and treatment of early renal injury in patients with H-type hypertension and help improve the prognosis of patients and their quality of life.

Prognostic value of circulating tumor DNA in operable non-small cell lung cancer: a systematic review and reconstructed individual patient-data based meta-analysis.

BACKGROUND: This reconstructed individual patient data (IPD)-based meta-analysis is aimed to summarize the current findings and comprehensively investigate the predictive value of circulating tumor DNA (ctDNA) in operable non-small cell lung cancer (NSCLC). METHODS: PubMed, Cochrane and Embase were searched to include potentially eligible studies. The primary outcomes included progression-free survival (DFS) by ctDNA status at baseline, postoperative, and longitudinal timepoints. The IPD-based survival data was retracted and used in reconstructed IPD-based meta-analysis. Subgroup analysis was implemented based on the baseline characteristics. RESULTS: Totally, 28 studies were involved, including 15 full-length articles (1686 patients) for IPD-based synthesis and 20 studies for conventional meta-analysis. The IPD-based meta-analysis discovered that patients with positive ctDNA status at the baseline (hazard ratio, HR = 3.73, 95% confidential interval, CI: 2.95-4.72), postoperative (3.96, 2.19-7.16), or longitudinal timepoints (12.33, 8.72-17.43) showed significantly higher risk of recurrence. Patients with persistent ctDNA-negative status had the lowest recurrence rate, and the negative conversion of ctDNA from baseline to postoperative timepoints was correlated with elevated DFS. Subgroup analyses suggested that stage II-III patients with ctDNA-positive status may achieve preferable therapeutic outcomes. CONCLUSIONS: Plasm ctDNA monitoring shows excellent clinical significance at the tested timepoints. Perioperative conversion of ctDNA status may indicate the therapeutic effect of radical surgery. Postoperative adjuvant therapy may be determined according to the ctDNA status. TRAIL REGISTRATION: CRD42022304445.

Relationship between morning peak phenomenon and early renal injury NGAL in H-type hypertension.

PURPOSE: To investigate the relationship between morning blood pressure surge (MBPS) and neutrophilgelatinase associated lipocalin (NGAL) in patients with H-type hypertension. MATERIALS AND METHODS: A total of 224 patients with diagnosed H-type hypertension [homocysteine (Hcy)≧10umol/L] were selected and underwent 24-hour ambulatory blood pressure monitoring (ABPM). In the morning peak group (115 cases), NGAL and serum cystatin C levels, ß2-microglobulin levels were detected in each group, and general biochemical indicators were also detected. RESULTS: There was no significant difference in the course of hypertension, age, blood glucose, blood lipids, Hcy, BUN, Cr, and UA between the two groups (p > 0.05). CysC, ß2-MG were higher than those in the nonmorning peak group, and the difference was statistically significant (p < 0.05).; Pearson correlation analysis showed that NGAL was moderately and highly correlated with CysC, systolic blood pressure morning peak, ß2-MG, and high (p < 0.05), low-density lipoprotein (LDL-C), and Hcy were lowly correlated (p < 0.05).) and morning peak diastolic blood pressure (p > 0.05); multiple linear stepwise regression analysis indicated that morning peak systolic blood pressure, CysC,ß2-MG, and FBG were the risk factors for NGAL. CONCLUSION: The morning peak of systolic blood pressure in H-type hypertension is an important factor causing kidney injury. Paying attention to the ambulatory blood pressure monitoring and the control of morning peak blood pressure in patients with H-type hypertension, and early screening of NGAL has important clinical significance for the early prevention and treatment of renal injury in patients with H-type hypertension. PLAIN LANGUAGE SUMMARYThe morning peak of blood pressure is closely related to target organ damage.There are few studies on the relationship between morning peak phenomenon and renal damage in patients with H-type hypertension at home and abroad.We investigated the relationship between MBPS and NGAL in H-type hypertensive patients with BUN, Cr and UA in the normal range to provide a clinical basis for early renal protection in hypertensive patients.

Identification of Cyclic Dipeptides and a New Compound (6-(5-Hydroxy-6-methylheptyl)-5,6-dihydro-2H-pyran-2-one) Produced by Streptomyces fungicidicus against Alternaria solani.

As an important microbial resource, Actinomycetes, especially Streptomyces, have important application values in medicine and biotechnology. Streptomyces fungicidicus SYH3 was isolated from soil samples in tomato-growing areas and showed good inhibitory effects on Alternaria solani in tomato. To obtain pure active compounds, SYH3 fermentation broth was subjected to XAD-16 macroporous resin and silica gel column chromatography. Combined with the repeated preparation and separation of preparative high-performance liquid chromatography (HPLC), a total of four monomer compounds were obtained after activity tracking. Compound 4 was identified as a new six-membered lactone ring compound named 6-(5-hydroxy-6-methylheptyl)-5,6-dihydro-2H-pyran-2-one by 1D and 2D nuclear magnetic resonance (NMR) data and mass spectrometry (MS). The other three active compounds belong to the cyclodipeptide, and their half maximal inhibitory concentration (IC50) values against A. solani were 43.4, 42.9, and 30.6 µg/mL, respectively. Compound 4 significantly inhibited the spore germination and induced swollen and deformed local hyphae of A. solani with an IC50 value of 24.9 µg/mL. Compound 4 also had broad-spectrum antifungal activity and had a good antifungal effect on the tested plant-pathogenic fungi. The modes of action of new compound (4) still require further investigation, representing a novel and effective anti-fungal agent for future application.

Characterization and a RT-RPA assay for rapid detection of Chilli Veinal mottle virus (ChiVMV) in tobacco.

BACKGROUND: Chilli veinal mottle virus (ChiVMV), which belongs to the genus Potyvirus of the family Potyviridae, mainly infects solanaceous plants and has caused serious economic losses in Asia and Africa. Tobacco plants infected with ChiVMV suffered from punctate necrosis of leaves, leaf deformation, systemic necrosis of leaves and stems, and eventually plant death. However, ChiVMV infection could not usually be identified given the lack of rapid and efficient detection assays in tobacco plants. Therefore, an isolate of tobacco-infecting ChiVMV (ChiVMV-LZ) was obtained, and a novel isothermal amplification and detection technique, reverse transcription-recombinase polymerase amplification (RT-RPA), was established to detect ChiVMV in tobacco plants. METHODS: In this study, the full-length genome of ChiVMV-LZ was obtained using reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE) assays. The genome sequence of ChiVMV-LZ was characterized by sequence alignment and phylogenetic analysis. Then, a RT-RPA assay was established for rapid and sensitive detection of ChiVMV-LZ in tobacco. Additionally, the established RT-RPA assay was compared to the RT-PCR assay in aspect of sensitivity and application in field-collected tobacco samples. RESULTS: ChiVMV-LZ was isolated from diseased tobacco in Luzhou, Sichuan, China. The tobacco plants inoculated with ChiVMV-LZ showed typical symptoms of yellow and round spots on the leaves, and curled and folded leaf margin, similar to those observed on naturally ChiVMV-infected tobacco in the field. The full-length genomic sequence of ChiVMV-LZ was determined to be 9742 nucleotides. Sequence alignment and phylogenetic analysis showed that ChiVMV-LZ was most closely related to ChiVMV-Yp8 isolated from pepper plants in Sichuan province while distantly related to ChiVMV-YN from tobacco in Yunnan province, indicating a possibly geographical differentiation of ChiVMV isolates. Additionally, a RT-RPA assay was established for rapid detection of ChiVMV in tobacco. The RT-RPA has no cross-reaction with other related tobacco viruses and is about 10-fold more sensitive than conventional RT-PCR method. CONCLUSION: The characterization of ChiVMV-LZ infecting tobacco was determined, and the established RT-RPA assay provides a reliable and effective method for rapid detection of ChiVMV in tobacco.

Novel combined biological antiviral agents Cytosinpeptidemycin and Chitosan oligosaccharide induced host resistance and changed movement protein subcellular localization of tobacco mosaic virus.

Plant viral diseases cause severe economic losses in agricultural production. Development of microorganism-derived antiviral agents provides an alternative strategy to efficiently control plant viral diseases. In this study, the antiviral effect and mechanism of a combined biological agent Cytosinpeptidemycin and Chitosan oligosaccharide (CytPM-COS) were investigated. CytPM-COS effectively inhibited tobacco mosaic virus (TMV) in Nicotiana glutinosa, suppressed viral RNA and CP accumulation in BY-2 protoplast and affected the subcellular localization as well as punctate formation of TMV MP in N. benthamiana leaves. In addition, CytPM-COS triggered reactive oxygen species (ROS) production and induced up-regulation of various defense responsive genes including PR-1, PR-5, FLS2, Hsp70. Our results indicated that CytPM-COS can potentially act as a pesticide for integrated control of plant viruses in the future.

[Clinical application of whole exome sequencing in monogenic hereditary disorders in critically ill newborns].

OBJECTIVE: To explore the value and significance of the clinical application of whole exome sequencing (WES) in monogenic hereditary disorders in critically ill newborns. METHODS: The critically ill newborns in the neonatal intensive care unit with suspected hereditary diseases or unclear clinical diagnosis from June 2016 to December 2018 were enrolled. The whole blood samples from both newborns and parents were collected for WES. The detected genetic mutations were classified, the mutations associated with clinical phenotypes were searched for, and Sanger sequencing was performed to verify the mutations. RESULTS: A total of 45 newborns were enrolled, including 22 males and 23 females, and the median age of onset was 2.0 days. Of the 45 newborns, 12 (27%) were confirmed with monogenic hereditary disorders by molecular diagnostics, and the median age at diagnosis was 31.5 days. Of the 12 newborns with monogenic hereditary disorders, 5 (42%) were partially associated with clinical phenotypes but confirmed with monogenic hereditary disorders by additional information supplement and analysis. The improvement rate of newborns with monogenic hereditary disorders was 67% (8/12) after treatment. CONCLUSIONS: WES technology is a powerful tool for finding genetic mutations in monogenic hereditary disorders in critically ill newborns and can play a crucial role in clinical decision-making. However, a comprehensive interpretation of sequence data requires physicians to take the clinical phenotypes and the results of WES into consideration simultaneously.

Non-coding RNAs and exosomal non-coding RNAs in lung cancer: insights into their functions.

Lung cancer is the second most common form of cancer worldwide Research points to the pivotal role of non-coding RNAs (ncRNAs) in controlling and managing the pathology by controlling essential pathways. ncRNAs have all been identified as being either up- or downregulated among individuals suffering from lung cancer thus hinting that they may play a role in either promoting or suppressing the spread of the disease. Several ncRNAs could be effective non-invasive biomarkers to diagnose or even serve as effective treatment options for those with lung cancer, and several molecules have emerged as potential targets of interest. Given that ncRNAs are contained in exosomes and are implicated in the development and progression of the malady. Herein, we have summarized the role of ncRNAs in lung cancer. Moreover, we highlight the role of exosomal ncRNAs in lung cancer.

Severe disseminated Nocardia brasiliensis pneumonia with normal immune function: A case report.

RATIONALE: Members of the genus Nocardia brasiliensis are Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In recent years, the incidence of Nocardia brasiliensis has increased significantly and become a global concern. It may be predominantly caused pulmonary infections in immunocompromised hosts. Interestingly, however, we found that it can be present not only on immunocompromised hosts, but also to infect patients with a normal immune system. PATIENT CONCERNS: We report a very rare case of a 49-year-old immunocompetent man with disseminated Nocardia brasensis pneumonia. He had a fever for 14 days (maximum temperature about 38°C) and a history of mass rupture. DIAGNOSES: Severe Disseminated Nocardia brasiliensis pneumonia with normal immune function. INTERVENTIONS: No. OUTCOMES: The patient was finally diagnosed with Severe Disseminated Nocardia brasiliensis pneumonia and received compound sulfamethoxazole treatment for 4 months. LESSONS SUBSECTIONS: Our report highlights when cold pus appears in soft tissues such as the lower limbs, neck, nose, scalp, etc, should prompt timely evaluation and biopsy for definitive diagnosis. Be alert to a normally immunocompetent, disseminated Nocardia brasiliensis infection. Early recognition and effective treatment are necessary conditions for successful results. This would allow for better disease prognostication while enabling physicians to develop more effective treatment strategies.

Human umbilical cord mesenchymal stem cell transplantation for the treatment of acute-on-chronic liver failure: protocol for a multicentre random double-blind placebo-controlled trial.

INTRODUCTION: Acute-on-chronic liver failure (ACLF) is a prevalent and life-threatening liver disease with high short-term mortality. Although recent clinical trials on the use of mesenchymal stem cells (MSCs) for ACLF treatment have shown promising results, multicentre randomised controlled phase II clinical trials remain uncommon. The primary aim of this trial is to assess the safety and efficacy of different MSCs treatment courses for ACLF. METHODS AND ANALYSIS: This is a multicentre, double-blind, two-stage, randomised and placebo-controlled clinical trial. In the first stage, 150 patients with ACLF will be enrolled and randomly assigned to either a control group (50 cases) or an MSCs treatment group (100 cases). They will receive either a placebo or umbilical cord-derived MSCs (UC-MSCs) treatment three times (at weeks 0, 1 and 2). In the second stage, 28 days after the first UC-MSCs infusion, surviving patients in the MSCs treatment group will be further randomly divided into MSCs-short and MSCs-prolonged groups at a 1:1 ratio. They will receive two additional rounds of placebo or UC-MSCs treatment at weeks 4 and 5. The primary endpoints are the transplant-free survival rate and the incidence of treatment-related adverse events. Secondary endpoints include international normalised ratio, total bilirubin, serum albumin, blood urea nitrogen, model for end-stage liver disease score and Child-Turcotte-Pugh score. ETHICS AND DISSEMINATION: Ethical approval of this study has been obtained from the Fifth Medical Center of the Chinese PLA General Hospital (KY-2023-3-19-1). All results of the study will be submitted to international journals and international conferences for publication on completion of the study. TRIAL REGISTRATION NUMBER: NCT05985863.

Safety, immunogenicity and protective effect of sequential vaccination with inactivated and recombinant protein COVID-19 vaccine in the elderly: a prospective longitudinal study.

The safety and efficacy of COVID-19 vaccines in the elderly, a high-risk group for severe COVID-19 infection, have not been fully understood. To clarify these issues, this prospective study followed up 157 elderly and 73 young participants for 16 months and compared the safety, immunogenicity, and efficacy of two doses of the inactivated vaccine BBIBP-CorV followed by a booster dose of the recombinant protein vaccine ZF2001. The results showed that this vaccination protocol was safe and tolerable in the elderly. After administering two doses of the BBIBP-CorV, the positivity rates and titers of neutralizing and anti-RBD antibodies in the elderly were significantly lower than those in the young individuals. After the ZF2001 booster dose, the antibody-positive rates in the elderly were comparable to those in the young; however, the antibody titers remained lower. Gender, age, and underlying diseases were independently associated with vaccine immunogenicity in elderly individuals. The pseudovirus neutralization assay showed that, compared with those after receiving two doses of BBIBP-CorV priming, some participants obtained immunological protection against BA.5 and BF.7 after receiving the ZF2001 booster. Breakthrough infection symptoms last longer in the infected elderly and pre-infection antibody titers were negatively associated with the severity of post-infection symptoms. The antibody levels in the elderly increased significantly after breakthrough infection but were still lower than those in the young. Our data suggest that multiple booster vaccinations at short intervals to maintain high antibody levels may be an effective strategy for protecting the elderly against COVID-19.

Hydrogen inhalation ameliorates hepatic inflammation and modulates gut microbiota in rats with high-fat diet-induced non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a multisystem metabolic disease associated with gut microflora dysbiosis and inflammation. Hydrogen (H2) is a novel and effective antiinflammatory agent. The present study was aimed to clarify the effects of 4% H2 inhalation on NAFLD and its mechanism of action. Sprague-Dawley rats were fed a high-fat diet for 10 weeks to induce NAFLD. Rats in treatment group inhaled 4% H2 each day for 2 h. The protective effects on hepatic histopathology, glucose tolerance, inflammatory markers, and intestinal epithelial tight junctions were assessed. Transcriptome sequencing of liver and 16 S-seq of cecal contents were also performed to explore the related mechanisms of H2 inhalation. H2 improved the hepatic histological changes and glucose tolerance, decreased the liver function parameters of plasma alanine aminotransferase and aspartate aminotransferase, and relieved liver inflammation. Liver transcriptomic data suggested that H2 treatment significantly downregulated inflammatory response genes, and the lipopolysaccharide (LPS)/Toll-like receptor (TLR) 4/nuclear transcription factor kappa B (NF-κB) signaling pathway might be involved, and the expressions of critical proteins were further validated. Meanwhile, the plasma LPS level was significantly decreased by the H2 intervention. H2 also improved the intestinal tight junction barrier by enhancing the expressions of zonula occludens-1 and occluding. Based on 16S rRNA sequencing, H2 altered the composition of gut microbiota, improving the relative abundance of Bacteroidetes-to-Firmicutes. Collectively, our data show that H2 could prevent NAFLD induced by high-fat diet, and the anti-NAFLD effect is associated with the modulation of gut microbiota and inhibition of LPS/TLR4/NF-κB inflammatory pathway.

Identification and physiological activity of (methoxymethyl)triphenylphosphonium chloride as a new phytotoxin isolated from Rhizoctonia solani AG-3 TB.

Rhizoctonia solani as a cosmopolitan fungus is the causative agent of many crop diseases and leads to significant economic losses in crop production. To explore the toxin structure and physiological activity of R. solani AG-3 TB, high-performance liquid chromatography (HPLC), infrared absorption spectrum (IR), and nuclear magnetic resonance spectrum (NMR) were required. Here, the compound (methoxymethyl)triphenylphosphonium chloride (MMC) with the molecular formula C20H20ClOP was purified and identified from R. solani AG-3 TB. The pure compound MMC treated at 20 µg/mL, 50 µg/mL, and 100 µg/mL can cause obvious necrosis on leaves, increase active oxygen species (AOS), decrease chlorophyll content, and damage cellular structure. The results enrich the understanding of toxin compounds for R. solani and provide valuable insights into the toxicology of R. solani AG-3 TB.

Genomic characteristics and prognosis of lung cancer patients with MSI-H: A cohort study.

BACKGROUND: Microsatellite instability (MSI) is the first pan-cancer biomarker approved to guide immune checkpoint inhibitor therapy for MSI-high (MSI-H) solid tumors. In lung cancer, the MSI-H frequency is very low, and the genetic characteristics and prognosis of lung cancer with MSI-H were rarely reported. METHODS: Next-generation sequencing and immunohistochemistry were used detect MSI status, tumor mutation burden (TMB) and PD-L1 expression. RESULTS: Among 12,484 lung cancer patients screened, 66 were found with MSI-H, the proportion was as low as 0.5%. Compared with Microsatellite stability (MSS), TMB was higher in MSI-H lung cancer patients, while PD-L1 expression showed no considerable difference between MSI-H and MSS. After propensity score matching, compared with MSS, the most common companion mutations in MSI-H were TP53, BRCA2, TGFBR2, PTEN and KMT2C. In MSI-H lung adenocarcinoma with EGFR mutation, TGFBR2 and ERBB2 had higher mutation frequency than in MSS. CONCLUSION: The current study reveals the genetic characteristics of MSI-H lung cancer, which advanced our understanding of MSI-H lung cancer.

The effect of a low dose hydrogen-oxygen mixture inhalation in midlife/older adults with hypertension: A randomized, placebo-controlled trial.

Objective: To explore the effect of a low-dose hydrogen-oxygen (H2-O2) mixture inhalation in midlife/older adults with hypertension. Methods: This randomized, placebo-controlled trial included 60 participants with hypertension aged 50-70 years who were randomly divided into Air group (inhaled placebo air) or H2-O2 group [inhaled H2-O2 mixture (66% H2/33% O2)]. Participants in both groups were treated 4 h per day for 2 weeks. Four-limb blood pressure and 24-h ambulatory blood pressure were monitored before and after the intervention, and levels of plasma hormones related to hypertension were determined. Results: A total of 56 patients completed the study (27 in the Air group and 29 in the H2-O2 group). The right and left arm systolic blood pressure (SBP) were significantly decreased in H2-O2 group compared with the baseline levels (151.9 ± 12.7 mmHg to 147.1 ± 12.0 mmHg, and 150.7 ± 13.3 mmHg to 145.7 ± 13.0 mmHg, respectively; all p < 0.05). Meanwhile, the H2-O2 intervention significantly decreased diastolic nighttime ambulatory blood pressure by 2.7 ± 6.5 mmHg (p < 0.05). All blood pressures were unaffected in placebo group (all p > 0.05). When stratified by age (aged 50-59 years versus aged 60-70 years), participants in the older H2-O2 group showed a larger reduction in right arm SBP compared with that in the younger group (p < 0.05). In addition, the angiotensin II, aldosterone, and cortisol levels as well as the aldosterone-to-renin ratio in plasma were significantly lower in H2-O2 group compared with baseline (p < 0.05). No significant differences were observed in the Air group before and after the intervention. Conclusion: Inhalation of a low-dose H2-O2 mixture exerts a favorable effect on blood pressure, and reduces the plasma levels of hormones associated with hypertension on renin-angiotensin-aldosterone system and stress in midlife/older adults with hypertension.

Analysis of the Correlation between the Distribution of MTHFR Gene and the Severity and Renal Function of Elderly Patients with H-Type Hypertension.

In order to investigate the correlation between the distribution of methylenetetrahydrofolate reductase (MTHFR, MR) C677T gene and the severity of disease and renal function in elderly patients with H-type hypertension, a total of 170 patients with H-type hypertension admitted to our hospital from September 2020 to February 2021 and 173 elderly patients with non-H-type hypertension during the same period are selected as the research objects and are respectively included in the observation group and control group. Baseline data and distribution of MR C677T genotype are compared between the two groups, influencing factors of H-type hypertension are analyzed by logistic regression analysis, and differences and correlation of homocysteine (Hcy) and estimated glomerular filtration rate (eGFR) levels in different MR C677T genotypes are compared. The influence of MR C677T genotype on the severity and renal function of patients with H-type hypertension is further analyzed. There are many influencing factors for H-type hypertension, including advanced age, high-sodium diet, and MR TT genotype. Patients with hypertension with these risk factors should be monitored. H-type hypertension has a high frequency of carrying TT genotype and T allele, and the TT genotype in H-type hypertension will affect the Hcy and eGFR levels. Therefore, Hcy level of H-type hypertension patients with TT genotype should be actively controlled to help control the disease and reduce kidney damage. MR TT genotype can be used as a reference index in the early screening of H-type hypertension.

Bacillus velezensis SYL-3 suppresses Alternaria alternata and tobacco mosaic virus infecting Nicotiana tabacum by regulating the phyllosphere microbial community.

The occurrence of plant diseases is closely associated with the imbalance of plant tissue microecological environment. The regulation of the phyllosphere microbial communities has become a new and alternative approach to the biological control of foliar diseases. In this study, Bacillus velezensis SYL-3 isolated from Luzhou exhibited an effective inhibitory effect against Alternaria alternata and tobacco mosaic virus (TMV). The analysis of phyllosphere microbiome by PacBio sequencing indicated that SYL-3 treatment significantly altered fungal and bacterial communities on the leaves of Nicotiana tabacum plants and reduced the disease index caused by A. alternata and TMV. Specifically, the abundance of P. seudomo, Sphingomonas, Massilia, and Cladosporium in the SYL-3 treatment group increased by 19.00, 9.49, 3.34, and 12.29%, respectively, while the abundances of Pantoea, Enterobacter, Sampaiozyma, and Rachicladosporium were reduced. Moreover, the abundance of beneficial bacteria, such as Pseudomonas and Sphingomonas, was negatively correlated with the disease indexes of A. alternata and TMV. The PICRUSt data also predicted the composition of functional genes, with significant differences being apparent between SYL-3 and the control treatment group. Further functional analysis of the microbiome also showed that SYL-3 may induce host disease resistance by motivating host defense-related pathways. These results collectively indicate that SYL-3 may suppress disease progression caused by A. alternata or TMV by improving the microbial community composition on tobacco leaves.

Immunological alterations after immunotherapy with short lived HBV-TCR T cells associates with long-term treatment response in HBV-HCC.

The application of hepatitis B virus (HBV)-T-cell receptor (TCR) T-cell immunotherapy in patients with HBV-related hepatocellular carcinoma (HBV-HCC) has been apathetic, as the expression of HBV antigens by both normal HBV-infected hepatocytes and HCC cells with HBV-DNA integration increases the risk of on-target off-tumor severe liver inflammatory events. To increase the safety of this immunotherapeutic approach, we developed messenger RNA (mRNA) HBV-TCR-redirected T cells that-due to the transient nature of mRNA-are functionally short lived and can be infused in escalating doses. The safety of this approach and its clinical potential against primary HBV-HCC have never been analyzed in human trials; thus, we studied the clinical and immunological parameters of 8 patients with chronic HBV infection and diffuse nonoperable HBV-HCC treated at weekly intervals with escalating doses (1 × 104 , 1 × 105 , 1 × 106 , and 5 × 106 TCR+ T cells/kg body weight) of T cells modified with HBV-TCR encoding mRNA. The treatment was well tolerated with no severe systemic inflammatory events, cytokine storm, or neurotoxicity observed in any of these patients throughout treatment. Instead, we observed a destruction of the tumor lesion or a prolonged stable disease in 3 of 8 patients. Importantly, the patients without clinically relevant reductions of HCC did not display any detectable peripheral blood immunological alterations. In contrast, signs of transient localized liver inflammation, activation of the T-cell compartment, and/or elevations of serum chemokine (C-X-C motif) ligand (CXCL) 9 and CXCL10 levels were detected in patients with long-term clinical benefit. Conclusion: We show that despite the reduced in vivo half-life (3-4 days), adoptive transfer of mRNA HBV-TCR T cells into patients with HBV-HCC show long-term clinical benefit that was associated with transient immunological alterations.

Human mesenchymal stem cells treatment for severe COVID-19: 1-year follow-up results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial. METHODS: In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6 min walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102). FINDINGS: MSC administration improved in whole-lung lesion volume compared with the placebo with a difference of -10.8% (95% CI: -20.7%, -1.5%, p = 0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point. More interestingly, 17.9% (10/56) of patients in the MSC group had normal CT images at month 12, but none in the placebo group (p = 0.013). The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time. Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.6%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups. INTERPRETATION: UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients. FUNDING: The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.

Application of weighted gene co-expression network analysis to identify the hub genes in H1N1.

OBJECTIVE: Identifying the disease-associated interactions between different genes helps us to find novel therapeutic targets and predictive biomarkers. METHODS: Gene expression data GSE82050 from H1N1 and control human samples were acquired from the NCBI GEO database. Highly co-expressed genes were grouped into modules. Through Person's correlation coefficient calculation between the module and clinical phenotype, notable modules were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted, and the hub genes within the module of interest were identified. Also, gene expression data GSE27131 were acquired from the GEO database to verify differential key gene expression analysis. The CIBERSORT was used to evaluate the immune cells infiltration and the GSVA was performed to identify the differentially regulated pathways in H1N1. The receiver operating characteristic (ROC) curves were used to assess the diagnostic values of the hub genes. RESULT: The black module was shown to have the highest correlation with the clinical phenotype, mainly functioning in the signaling pathways such as the mitochondrial inner membrane, DNA conformation change, DNA repair, and cell cycle phase transition. Through analysis of the black module, we found 5 genes that were highly correlated with the H1N1 phenotype. The H1N1 project from GSE27131 confirmed an increased expression of these genes. CONCLUSION: By using the WGCNA we analyzed and predicted the key genes in H1N1. BRCA1, CDC20, MAD2L1, MCM2, and UBE2C were found to be the most relevant genes, which may be therapeutic targets and predictive biomarkers for H1N1 therapy.