Abnormal trial-to-trial variability in P300 time-varying directed eeg network of schizophrenia.

Cognitive disturbance in identifying, processing, and responding to salient or novel stimuli are typical attributes of schizophrenia (SCH), and P300 has been proven to serve as a reliable psychosis endophenotype. The instability of neural processing across trials, i.e., trial-to-trial variability (TTV), is getting increasing attention in uncovering how the SCH "noisy" brain organizes during cognition processes. Nevertheless, the TTV in the brain network remains unrevealed, notably how it varies in different task stages. In this study, resorting to the time-varying directed electroencephalogram (EEG) network, we investigated the time-resolved TTV of the functional organizations subserving the evoking of P300. Results revealed anomalous TTV in time-varying networks across the delta, theta, alpha, beta1, and beta2 bands of SCH. The TTV of cross-band time-varying network properties can efficiently recognize SCH (accuracy: 83.39%, sensitivity: 89.22%, and specificity: 74.55%) and evaluate the psychiatric symptoms (i.e., Hamilton's depression scale-24, r = 0.430, p = 0.022, RMSE = 4.891; Hamilton's anxiety scale-14, r = 0.377, p = 0.048, RMSE = 4.575). Our study brings new insights into probing the time-resolved functional organization of the brain, and TTV in time-varying networks may provide a powerful tool for mining the substrates accounting for SCH and diagnostic evaluation of SCH.

Impact of metabolic dysfunction-associated steatotic liver disease on the efficacy of immunotherapy in patients with chronic hepatitis B-related hepatocellular carcinoma.

OBJECTIVE: To investigate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on the efficacy of immune checkpoint inhibitor (ICI)-based therapy in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). METHODS: A total of 155 patients with CHB-related HCC who received ICI-based therapy (in the Department of Hepatology, Tianjin Second People's Hospital and Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute & Hospital) between April 2021 and December 2023 were evaluated. Patients were divided into two groups: MASLD concurrent with CHB [MASLD-CHB] (n = 38), and CHB (n = 117). RESULTS: The median progression-free survival (PFS, 6.9 months vs. 9.3 months; P = 0.001), progressive disease (57.89% vs. 37.61%; P = 0.028), and disease control rate (42.11% vs. 62.39%; P = 0. 028) in the MASLD-CHB group were significantly worse than the CHB group. The median overall survival was not attained. The percentage of CD4+PD1+ (17. 56% vs. 8.89%; P < 0.001) and CD8+PD1+ T cells (10.50% vs. 7.42%; P = 0.005) in patient samples from the MASLD-CHB group were significantly higher than the CHB group. Concurrent MASLD [hazard ratio (HR) = 1.921; 95% CI, 1.138-3.245; P = 0.015] and alpha-fetoprotein levels after 3 months of treatment (HR = 2.412; 95% CI, 1.360-4.279; P = 0.003) were independent risk factors for PFS in all patients. CONCLUSIONS: ICI-based therapy in patients with CHB-related HCC and concurrent MASLD resulted in poorer efficacy and shorter PFS compared to patients with CHB-related HCC alone.

Oxidative balance score: a potential tool for reducing the risk of colorectal cancer and its subsites incidences.

Background: The Oxidative Balance Score (OBS) is commonly used to assess oxidative stress and provides a comprehensive evaluation of dietary and lifestyle-related exposures. However, there is limited research on the association between OBS and colorectal cancer (CRC), its subsites, and complications. The objective of this study was to assess the relationship between OBS and the risk of CRC, its subsites, and common complications in a large prospective cohort study. Methods: We included data from 175,808 participants in the UK Biobank data sample repository from 2006 to 2010. We evaluated OBS using a scoring system based on 22 dietary and lifestyle factors. Multiple adjustments, including multivariate Cox proportional hazard regression, gender stratification, subgroup analysis, and sensitivity analysis, were performed to fully explore the relationship between OBS and CRC, its subsites, and complications. The mediation analysis was conducted to investigate whether serum albumin, uric acid, and neutrophil levels mediate the relationship between OBS and CRC. Results: After adjusting for potential confounding factors, a significant negative correlation was found between OBS and the risk of CRC and its subsites (proximal colon cancer, distal colon cancer, and rectal cancer). This correlation was particularly pronounced in male CRC patients. Serum albumin, uric acid, and neutrophil count, which are biomarkers, were found to have a significant mediating effect between OBS and CRC. Conclusion: Our study suggests that higher exposure to antioxidants assessed through OBS (diet and lifestyle rich in antioxidants) may decrease the occurrence of CRC and its subsites.

Noninvasive tests maintain high accuracy for advanced fibrosis in chronic hepatitis B patients with different nomenclatures of steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a new nomenclature proposed in 2023. We aimed to compare the diagnostic efficacy of noninvasive tests (NITs) for advanced fibrosis under different nomenclatures in patients with chronic hepatitis B (CHB). A total of 844 patients diagnosed with CHB and concurrent steatotic liver disease (SLD) by liver biopsy were retrospectively enrolled and divided into four groups. The performances of fibrosis-4 (FIB-4), gamma-glutamyl transpeptidase to platelet ratio index (GPRI), aspartate aminotransferase to platelet ratio index (APRI), and liver stiffness measurement (LSM) were compared among the four groups. The four NITs showed similar diagnostic efficacy for nonalcoholic fatty liver disease (NAFLD), MASLD, and metabolic dysfunction-associated fatty liver disease (MAFLD) in patients with CHB with advanced fibrosis. LSM showed the most stable accuracy for NAFLD (AUC = 0.842), MASLD (AUC = 0.846), and MAFLD (AUC = 0.863) compared with other NITs (p < 0.05). Among the four NITs, APRI (AUC = 0.841) and GPRI (AUC = 0.844) performed best in patients with CHB & MetALD (p < 0.05). The cutoff value for GPRI in patients with CHB & MetALD was higher than that in the other three groups, while further comparisons of NITs at different fibrosis stages showed that the median GPRI of CHB & MetALD (1.113) at F3-4 was higher than that in the CHB & MASLD group (0.508) (p < 0.05). Current NITs perform adequately in patients with CHB and SLD; however, alterations in cutoff values for CHB & MetALD need to be noted.

Advances in molecular mechanisms of inflammatory bowel disease­associated colorectal cancer (Review).

The link between inflammation and cancer is well documented and colonic inflammation caused by inflammatory bowel disease (IBD) is thought to be a high-risk factor for the development of colorectal cancer (CRC). The complex crosstalk between epithelial and inflammatory cells is thought to underlie the progression from inflammation to cancer. The present review collates and summarises recent advances in the understanding of the pathogenesis of IBD-associated CRC (IBD-CRC), including the oncogenic mechanisms of the main inflammatory signalling pathways and genetic alterations induced by oxidative stress during colonic inflammation, and discusses the crosstalk between the tumour microenvironment, intestinal flora and host immune factors during inflammatory oncogenesis in colitis-associated CRC. In addition, the therapeutic implications of anti-inflammatory therapy for IBD-CRC were discussed, intending to provide new insight into improve clinical practice.

Characterization and Mapping of a Rolling Leaf Mutant Allele rlT73 on Chromosome 1BL of Wheat.

Leaf rolling is regarded as an important morphological trait in wheat breeding. Moderate leaf rolling is helpful to keep leaves upright and improve the photosynthesis of plants, leading to increased yield. However, studies on the identification of genomic regions/genes associated with rolling leaf have been reported less frequently in wheat. In this study, a rolling leaf mutant, T73, which has paired spikelets, dwarfism, and delayed heading traits, was obtained from a common wheat landrace through ethyl methanesulfonate mutagenesis. The rlT73 mutation caused an increase in the number of epidermal cells on the abaxial side and the shrinkage of bulliform cells on the adaxial side, leading to an adaxially rolling leaf phenotype. Genetic analysis showed that the rolling leaf phenotype was controlled by a single recessive gene. Further Wheat55K single nucleotide polymorphism array-based bulked segregant analysis and molecular marker mapping delimited rlT73 to a physical interval of 300.29-318.33 Mb on the chromosome arm 1BL in the Chinese Spring genome. We show that a point mutation at the miRNA165/166 binding site of the HD zipper class III transcription factor on 1BL altered its transcriptional level, which may be responsible for the rolling leaf phenotype. Our results suggest the important role of rlT73 in regulating wheat leaf development and the potential of miRNA-based gene regulation for crop trait improvement.

Brain imaging derived phenotypes: a biomarker for the onset of inflammatory bowel disease and a potential mediator of mental complications.

Background and aims: Inflammatory bowel disease (IBD), mainly categorized into Crohn's disease (CD) and ulcerative colitis (UC), is a chronic relapsing gastrointestinal disorder that significantly impairs patients' quality of life. IBD patients often experience comorbidities such as anxiety and depression, and the underlying mechanisms and treatment strategies remain areas of investigation. Methods: We conducted a Mendelian randomization(MR) analysis utilizing brain image derived phenotypes (IDP) from the UK Biobank database to investigate the causal relationships between IBD and alterations in brain structural morphology and connectivity of neural tracts. This study aimed to identify biological evidence linking IBD to psychiatric disorders such as anxiety and depression. Results: Specifically, the volume of grey matter in the Left Frontal Orbital Cortex exhibited a negative association with the onset of Crohn's disease (odds ratio (OR) [95% confidence interval (CI)]: 0.315[0.180~0.551], adjusted P=0.001), while the volume of the superior frontal cortex in the right hemisphere showed a positive correlation with the development of Ulcerative colitis (OR [95% CI]: 2.285[1.793~2.911], adjusted P<0.001), and the volume of lateral occipital cortex in the left hemisphere demonstrated a positive relationship with Crohn's disease onset (OR [95% CI]: 1.709[1.671~1.747], adjusted P<0.001). In the context of reverse causality, the onset of UC or CD has led to alterations in imaging derived phenotypes associated with five disorders (anxiety, depression, schizophrenia, bipolar disorder, pain) and three functions (memory, emotion, language). Conclusion: Our study has demonstrated a causal relationship between IBD and IDPs. IDPs may serve as potential biomarkers for the progression of IBD and as predictive intermediaries for the development of neurological diseases in IBD patients.

Evaluation of compliance of CONSORT-CHM formula 2017 in randomized controlled trials of Chinese herbal medicine formulas: protocol of a five-year review.

Background: The CONSORT Extension for Chinese Herbal Medicine Formula 2017 (CONSORT-CHM Formula 2017) has established a reporting standard for randomized controlled trials (RCTs) of Chinese Herbal Medicine Formula (CHMF) interventions; however, its adherence and implications for the design and execution of study design remain ambiguous. It is necessary to evaluate the level of compliance with the CONSORT-CHM Formula 2017 in RCTs conducted over the past 5 years, and to determine the reporting quality of clinical trials in this field. Methods: First, a systematic search is conducted for RCTs on CHMF in EBM Reviews, Allied and Complementary Medicine (AMED), Embase, Ovid-MEDLINE(R), Wanfang data, China National Knowledge Infrastructure (CNKI), VIP Chinese Medical Journal Database (VIP) and Chinese Biomedical Literature (CBM) database, that encompassed CHMF interventional RCTs published from 1 January 2018 to 8 June 2022, with language restriction to English or Chinese. Second, a descriptive analysis will be performed regarding the study design and general characteristics of the included trials. Third, for the quality assessment, we have subdivided the CONSORT-CHM Formula 2017 checklist (consisting of 22 extended items) into a total of 42 sub-questions to facilitate scoring, with a specific focus on the description, quality control, and safety assessment of CHMF interventions. Professional training and a pilot test on 100 randomly selected articles will be provided for all reviewers. Throughout this process, a standard operating procedure (SOP) for quality assessment will be developed to ensure consistency. Each item will be assessed by two reviewers in a paired back-to-back manner, and the compliance rate will be calculated to assess inter-rater agreement. Discussion: This review will identify the current reporting characteristics and quality of CHMF interventional studies and further evaluate the impact of CONSORT-CHM Formula 2017. The results may provide suggestions for future application or promotion of the guideline. Registration: The study has been registered on Open Science Framework (https://osf.io/xpn7f).

Preparation and characterization of aspirin-fucoidan complex and its admirable antitumor activity on human non-small cell lung cancer cells.

The purpose of this work is to prepare a novel acetylated derivative of Undaria pinnatifida fucoidan (UPFUC) with admirable antitumor activity. Fucoidan was first acetylated by acetylsalicylic acid (aspirin, ASA) to form the ASA-UPFUC complex. The antitumor efficacy results stated that ASA-UPFUC inhibited the proliferation of human non-small cell lung cancer A549 cells in a dose-dependent manner, with an IC50 value of 49.09 µg/mL, 50.20 % lower than that of UPFUC. Importantly, the acetylation process had no adverse effects on the backbone structure of UPFUC. Simultaneously, ASA-UPFUC demonstrated a larger charge density than UPFUC, leading to enhanced solubility, improved surface charge effects, and a greater potential for exerting biological activity. Consequently, ASA-UPFUC increased the formation of alkyl and hydrogen bonds with tumor necrosis factor related apoptosis-inducing ligand receptors DR4 and DR5, thereby effectively stimulating the generation of cellular reactive oxygen species, diminishing mitochondrial membrane potential, suppressing nuclear factor κB (NFκB) p65 phosphorylation, enhancing the contents of Bax and cleaved caspase 3, and reducing the level of Bcl-2. The collective effects ultimately triggered the mitochondrial apoptotic pathway, leading to apoptosis in A549 cells. The findings support the potential utilization of ASA-UPFUC as a novel dietary additive for human lung cancer chemoprevention.

Purification and Identification of Peptides from Hydrilla verticillata (Linn. f.) Royle with Cytoprotective and Antioxidative Effect against H2O2-Treated HepG2 Cells.

Antioxidant peptides were purified from Hydrilla verticillata (Linn. f.) Royle (HVR) protein hydrolysate by ultrafiltration, gel filtration chromatography, and semipreparative reversed-phase HPLC and identified by UPLC-ESI-MS/MS. Therein, TCLGPK and TCLGER were selected to be synthesized, and they displayed desirable radical-scavenging activity to ABTS (99.20 ± 0.56-99.20 ± 0.43%), DPPH (97.32 ± 0.59-97.56 ± 0.97%), hydroxyl radical (54.32 ± 1.27-70.42 ± 2.01%), and superoxide anion (42.93 ± 1.46-52.62 ± 1.11%) at a concentration of 0.96 µmol/mL. They possessed a cytoprotective effect against H2O2-induced oxidative stress in HepG2 cells in a dose-dependent manner. 1.6 µmol/mL of the two peptides could perfectly protect HepG2 cells from H2O2-induced injury. The TCLGPK exhibited higher antioxidant activity and cytoprotective effect than TCLGER. Western blot and molecular docking results indicated that the two peptides achieved antioxidant ability and cytoprotective effect by combining with Kelch-like ECH-associated protein 1 (Keap1) to activate the Keap1-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response elements signaling pathway, leading to the activity and expression of the related antioxidases in the pathway significantly up-regulating and the intracellular reactive oxygen species level, lipid peroxidation, and cell apoptosis rate significantly down-regulating.

EEG brain network variability is correlated with other pathophysiological indicators of critical patients in neurology intensive care unit.

Continuous electroencephalogram (cEEG) plays a crucial role in monitoring and postoperative evaluation of critical patients with extensive EEG abnormalities. Recently, the temporal variability of dynamic resting-state functional connectivity has emerged as a novel approach to understanding the pathophysiological mechanisms underlying diseases. However, little is known about the underlying temporal variability of functional connections in critical patients admitted to neurology intensive care unit (NICU). Furthermore, considering the emerging field of network physiology that emphasizes the integrated nature of human organisms, we hypothesize that this temporal variability in brain activity may be potentially linked to other physiological functions. Therefore, this study aimed to investigate network variability using fuzzy entropy in 24-hour dynamic resting-state networks of critical patients in NICU, with an emphasis on exploring spatial topology changes over time. Our findings revealed both atypical flexible and robust architectures in critical patients. Specifically, the former exhibited denser functional connectivity across the left frontal and left parietal lobes, while the latter showed predominantly short-range connections within anterior regions. These patterns of network variability deviating from normality may underlie the altered network integrity leading to loss of consciousness and cognitive impairment observed in these patients. Additionally, we explored changes in 24-hour network properties and found simultaneous decreases in brain efficiency, heart rate, and blood pressure between approximately 1 pm and 5 pm. Moreover, we observed a close relationship between temporal variability of resting-state network properties and other physiological indicators including heart rate as well as liver and kidney function. These findings suggest that the application of a temporal variability-based cEEG analysis method offers valuable insights into underlying pathophysiological mechanisms of critical patients in NICU, and may present novel avenues for their condition monitoring, intervention, and treatment.

The dynamic causality brain network reflects whether the working memory is solidified.

Working memory, which is foundational to higher cognitive function, is the "sketchpad of volitional control." Successful working memory is the inevitable outcome of the individual's active control and manipulation of thoughts and turning them into internal goals during which the causal brain processes information in real time. However, little is known about the dynamic causality among distributed brain regions behind thought control that underpins successful working memory. In our present study, given that correct responses and incorrect ones did not differ in either contralateral delay activity or alpha suppression, further rooting on the high-temporal-resolution EEG time-varying directed network analysis, we revealed that successful working memory depended on both much stronger top-down connections from the frontal to the temporal lobe and bottom-up linkages from the occipital to the temporal lobe, during the early maintenance period, as well as top-down flows from the frontal lobe to the central areas as the delay behavior approached. Additionally, the correlation between behavioral performance and casual interactions increased over time, especially as memory-guided delayed behavior approached. Notably, when using the network metrics as features, time-resolved multiple linear regression of overall behavioral accuracy was exactly achieved as delayed behavior approached. These results indicate that accurate memory depends on dynamic switching of causal network connections and shifting to more task-related patterns during which the appropriate intervention may help enhance memory.

Clinical significance of serum microRNA-146a and inflammatory factors in children with Mycoplasma pneumoniae pneumonia after azithromycin treatment.

OBJECTIVE: This study aimed to investigate the clinical significance of serum microRNA-146a and pro-inflammatory factors in children with Mycoplasma pneumoniae pneumonia after azithromycin treatment. microRNA-146a is known to regulate inflammatory responses, and excessive inflammation is a primary characteristic of MPP. METHODS: Children with MPP received conventional symptomatic therapy along with intravenous administration of azithromycin for one week. Serum levels of microRNA-146a and pro-inflammatory factors were measured using RT-qPCR and ELISA kits, respectively. The correlation between microRNA-146a and pro-inflammatory factors was analyzed by the Pearson method. Pulmonary function indexes were assessed using a pulmonary function analyzer, and their correlation with microRNA-146a and pro-inflammatory factors after treatment was evaluated. Children with MPP were divided into effective and ineffective treatment groups, and the clinical significance of microRNA-146a and pro-inflammatory factors was evaluated using receiver operating characteristic curves and logistic multivariate regression analysis. RESULTS: Serum microRNA-146a was downregulated in children with MPP but upregulated after azithromycin treatment, contrasting with the trend observed for pro-inflammatory factors. MicroRNA-146a showed a negative correlation with pro-inflammatory cytokines. Pulmonary function parameters were initially reduced in children with MPP, but increased after treatment, showing positive/inverse associations with microRNA-146a and pro-inflammatory factors. Higher microRNA-146a and lower pro-inflammatory factors predicted better efficacy of azithromycin treatment. MicroRNA-146a, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) were identified as independent factors influencing treatment efficacy. CONCLUSION: Azithromycin treatment in children with MPP upregulates microRNA-146a, downregulates pro-inflammatory factors, and effectively improves pulmonary function.

Identification of SGMS2 as a molecule involved in natural killer cell recruitment and its in-deep analysis in the liver cancer microenvironment: Evidence from large populations cohort.

BACKGROUND: Liver cancer, a common malignancy within the digestive system, presents with a particularly grim prognosis. Within the immune microenvironment, the role of natural killer (NK) cells in liver cancer remains unclear. METHODS: We sourced data on clinical parameters and gene expressions for liver cancer patients from The Cancer Genome Atlas Program database and carried out all analyses using R software and its relevant codes. RESULTS: In our research, we delved into the genes intertwined with NK cells in hepatocellular carcinoma (HCC). Leveraging the QUANTISEQ and MCPCOUNTER algorithms to quantify NK cells, we spotlighted genes vital to the recruitment of NK cells. Among these genes, GDE1, WDFY3, DNAJB14, PKD2, DGAT2, SGMS2 and MKNK2 showed a strong correlation with patient outcomes. We also mapped out the single-cell expression trajectories of these genes within the HCC milieu. From our findings, SGMS2 emerged as a key gene warranting further scrutiny. Our in-depth analysis of SGMS2 shed light on its influence over specific biological pathways, its contribution to the immune landscape and its role in genomic instability within HCC. Drawing from this, we formulated a predictive model rooted in SGMS2-associated genes. This model showcased remarkable precision across both training and validation cohorts. CONCLUSIONS: Overall, our investigation underscored the profound implications of SGMS2, a gene pivotal to NK cell infiltration, in the landscape of HCC, thereby positioning it as a potential linchpin in oncological strategies.

Inactivated vaccines reduce the risk of liver function abnormality in NAFLD patients with COVID-19: a multi-center retrospective study.

BACKGROUND: Abnormal liver function was frequently observed in nonalcoholic fatty liver disease (NAFLD) patients infected with SARS-CoV-2. Our aim was to explore the effect of SARS-CoV-2 inactivated vaccines on liver function abnormality among NAFLD patients with COVID-19. METHODS: The multi-center retrospective cohort included 517 NAFLD patients with COVID-19 from 1 April to 30 June 2022. Participants who received 2 doses of the vaccine (n = 274) were propensity score matched (PSM) with 243 unvaccinated controls. The primary outcome was liver function abnormality and the secondary outcome was viral shedding duration. Logistic and Cox regression models were used to calculate the odds ratio (OR) and hazard ratio (HR) for the outcomes. Sensitivity analysis was conducted to assess robustness. FINDINGS: PSM identified 171 pairs of vaccinated and unvaccinated patients. Liver function abnormality was less frequent in the vaccinated group (adjusted OR, 0.556 [95% CI (confidence interval), 0.356-0.869], p = 0.010). Additionally, the vaccinated group demonstrated a lower incidence of abnormal bilirubin levels (total bilirubin: adjusted OR, 0.223 [95% CI, 0.072-0.690], p = 0.009; direct bilirubin: adjusted OR, 0.175 [95% CI, 0.080-0.384], p < 0.001) and shorter viral shedding duration (adjusted HR, 0.798 [95% CI, 0.641-0.994], p = 0.044) than the unvaccinated group. Further subgroup analysis revealed similar results, while the sensitivity analyses indicated consistent findings. INTERPRETATION: SARS-CoV-2 vaccination in patients with NAFLD may reduce the risk of liver dysfunction during COVID-19. Furthermore, vaccination demonstrated beneficial effects on viral shedding in the NAFLD population. FUNDING: 23XD1422700, Tszb2023-01, Zdzk2020-10, Zdxk2020-01, 2308085J27 and JLY20180124.

Clinical significance of serum microRNA-146a and inflammatory factors in children with Mycoplasma pneumoniae pneumonia after azithromycin treatment

Abstract Objective This study aimed to investigate the clinical significance of serum microRNA-146a and pro-inflammatory factors in children with Mycoplasma pneumoniae pneumonia after azithromycin treatment. microRNA-146a is known to regulate inflammatory responses, and excessive inflammation is a primary characteristic of MPP. Methods Children with MPP received conventional symptomatic therapy along with intravenous administration of azithromycin for one week. Serum levels of microRNA-146a and pro-inflammatory factors were measured using RT-qPCR and ELISA kits, respectively. The correlation between microRNA-146a and pro-inflammatory factors was analyzed by the Pearson method. Pulmonary function indexes were assessed using a pulmonary function analyzer, and their correlation with microRNA-146a and pro-inflammatory factors after treatment was evaluated. Children with MPP were divided into effective and ineffective treatment groups, and the clinical significance of microRNA-146a and pro-inflammatory factors was evaluated using receiver operating characteristic curves and logistic multivariate regression analysis. Results Serum microRNA-146a was downregulated in children with MPP but upregulated after azithromycin treatment, contrasting with the trend observed for pro-inflammatory factors. MicroRNA-146a showed a negative correlation with pro-inflammatory cytokines. Pulmonary function parameters were initially reduced in children with MPP, but increased after treatment, showing positive/inverse associations with microRNA-146a and pro-inflammatory factors. Higher microRNA-146a and lower pro-inflammatory factors predicted better efficacy of azithromycin treatment. MicroRNA-146a, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) were identified as independent factors influencing treatment efficacy. Conclusion Azithromycin treatment in children with MPP upregulates microRNA-146a, downregulates pro-inflammatory factors, and effectively improves pulmonary function.

Identification and fine-mapping of QYrAS286-2BL conferring adult-plant resistance to stripe rust in cultivated emmer wheat.

KEY MESSAGE: A novel major adult-plant stripe rust resistance QTL derived from cultivated emmer wheat was mapped to a 123.6-kb region on wheat chromosome 2BL. Stripe rust, caused by the fungal pathogen Puccinia striiformis f. sp. tritici (Pst), is one of the most devastating diseases of wheat. Identification of new sources of resistance and their utilization in breeding programs is the effectively control strategy. The objective of this study was to identify and genetically characterize the stripe rust resistance derived from the cultivated emmer accession AS286. A recombinant inbred line population, developed from a cross between the susceptible durum wheat line langdon and AS286, was genotyped using the Wheat55K single nucleotide polymorphism array and evaluated in field conditions with a mixture of the prevalent Chinese Pst races (CYR32, CYR33, CYR34, Zhong4, and HY46) and in growth chamber with race CYR34. Three QTLs conferring resistance were mapped on chromosomes 1BS, 2BL, and 5BL, respectively. The QYrAS286-1BS and QYrAS286-2BL were stable with major effects, explaining 12.91% to 18.82% and 11.31% to 31.43% of phenotypic variation, respectively. QYrAS286-5BL was only detected based on growth chamber seedling data. RILs harboring both QYrAS286-1BS and QYrAS286-2BL showed high levels of stripe rust resistance equal to the parent AS286. The QYrAS286-2BL was only detected at the adult-plant stage, which is different from previously named Yr genes and inherited as a single gene. It was further mapped to a 123.6-kb region using KASP markers derived from SNPs identified by bulked segregant RNA sequencing (BSR-Seq). The identified loci enrich our stripe rust resistance gene pool, and the flanking markers developed here could be useful in marker-assisted selection for incorporating QYrAS286-2BL into wheat cultivars.

Comprehensive treatment and a rare presentation of Cronkhite-Canada syndrome: Two case reports and review of literature.

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare sporadic polyposis syndrome that presents with gastrointestinal and ectodermal symptoms in addition to nutritional deficiencies. CCS combined with hypothyroidism is an even rarer condition, with no standard treatment guidelines. CASE SUMMARY: The present study described 2 patients with CCS: A 67-year-old woman with concomitant hypothyroidism and 68-year-old man treated with endoscopic mucosal resection (EMR). Both patients had multiple gastrointestinal symptoms and ectodermal changes, along with multiple gastrointestinal polyps. Microscopic examination showed that the mucosa in both patients was hyperemic and edematous, with pathologic examination showing distorted, atrophic, and dilated glands. Patient 1 had concomitant hypothyroidism and was treated with levothyroxine. Due to her self-reduction of hormone dose, her disease relapsed. Patient 2 underwent EMR, but refused further hormonal or biological treatments. Subsequently, he was treated with an oral Chinese medical preparation. CONCLUSION: Pharmacotherapy can induce and maintain remission in CCS patients, with adjuvant EMR, long-term follow-up, and endoscopic surveillance being necessary.

Integrated multi-omics analysis reveals the positive leverage of citrus flavonoids on hindgut microbiota and host homeostasis by modulating sphingolipid metabolism in mid-lactation dairy cows consuming a high-starch diet.

BACKGROUND: Modern dairy diets have shifted from being forage-based to grain and energy dense. However, feeding high-starch diets can lead to a metabolic disturbance that is linked to dysregulation of the gastrointestinal microbiome and systemic inflammatory response. Plant flavonoids have recently attracted extensive interest due to their anti-inflammatory effects in humans and ruminants. Here, multi-omics analysis was conducted to characterize the biological function and mechanisms of citrus flavonoids in modulating the hindgut microbiome of dairy cows fed a high-starch diet. RESULTS: Citrus flavonoid extract (CFE) significantly lowered serum concentrations of lipopolysaccharide (LPS) proinflammatory cytokines (TNF-α and IL-6), acute phase proteins (LPS-binding protein and haptoglobin) in dairy cows fed a high-starch diet. Dietary CFE supplementation increased fecal butyrate production and decreased fecal LPS. In addition, dietary CFE influenced the overall hindgut microbiota's structure and composition. Notably, potentially beneficial bacteria, including Bacteroides, Bifidobacterium, Alistipes, and Akkermansia, were enriched in CFE and were found to be positively correlated with fecal metabolites and host metabolites. Fecal and serum untargeted metabolomics indicated that CFE supplementation mainly emphasized the metabolic feature "sphingolipid metabolism." Metabolites associated with the sphingolipid metabolism pathway were positively associated with increased microorganisms in dairy cows fed CFE, particularly Bacteroides. Serum lipidomics analysis showed that the total contents of ceramide and sphingomyelin were decreased by CFE addition. Some differentially abundant sphingolipid species were markedly associated with serum IL-6, TNF-α, LPS, and fecal Bacteroides. Metaproteomics revealed that dietary supplementation with CFE strongly impacted the overall fecal bacterial protein profile and function. In CFE cows, enzymes involved in carbon metabolism, sphingolipid metabolism, and valine, leucine, and isoleucine biosynthesis were upregulated. CONCLUSIONS: Our research indicates the importance of bacterial sphingolipids in maintaining hindgut symbiosis and homeostasis. Dietary supplementation with CFE can decrease systemic inflammation by maintaining hindgut microbiota homeostasis and regulating sphingolipid metabolism in dairy cows fed a high-starch diet. Video Abstract.

Targeting VCP potentiates immune checkpoint therapy for colorectal cancer.

Immune checkpoint blockade therapies are still ineffective for most patients with colorectal cancer (CRC). Immunogenic cell death (ICD) enables the release of key immunostimulatory signals to drive efficient anti-tumor immunity, which could be used to potentiate the effects of immune checkpoint inhibitors. Here, we showed that inhibition of valosin-containing protein (VCP) elicits ICD in CRC. Meanwhile, VCP inhibitor upregulates PD-L1 expression and compromises anti-tumor immunity in vivo. Mechanistically, VCP transcriptionally regulates PD-L1 expression in a JAK1-dependent manner. Combining VCP inhibitor with anti-PD1 remodels tumor immune microenvironment and reduces tumor growth in mouse models of CRC. Addition of oncolytic virus further augments the therapeutic activity of the combination regimen. Our study shows the molecular mechanism for regulating PD-L1 expression by VCP and suggests that inhibition of VCP has the potential to increase the efficacy of immunotherapy in CRC.