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IntroductionEmerging evidences suggests that the disrupted branched-chain amino acids (BCAAs) homeostasis and elevated BCAAs promote obesity-related insulin resistance (IR). Exercise improves insulin sensitivity. However, whether BCAAs plays a role in the exercise-attenuated IR remains to be fully investigated.MethodsIn this study, male C57BL/6J mice were induced to become diet-induced obese (DIO) and served as subjects. The initial investigation focused on the impact of exercise on IR and BCAAs. The DIO mice were randomly assigned to either a sedentary group (CON, n = 16) or an exercise group (EX, n = 16). The EX group underwent a 12-week aerobic exercise regimen on a treadmill. After 12-week, plasma BCAAs and branched-chain keto acids (BCKAs) were measured by liquid chromatography-mass spectrometry, glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed, and the expression and phosphorylation of BCAAs catabolic proteins, as well as AKT T308 in gastrocnemius muscle and liver tissues, were evaluated using western blotting. Subsequently, the study explored the role of BCAAs in enhancing IR through exercise. Mice were randomly allocated into 4 groups: sedentary group (CON, n = 8), sedentary with BCAAs supplementation group (CON+BCAA, n = 8), exercise group (EX, n = 16), and exercise with BCAAs supplementation group (EX+BCAA, n = 16). The exercise protocol was as above. Mice in the BCAAs supplemented groups received drinking water containing 2% BCAAs. After 12-week, plasma BCAAs and BCKAs were measured, GTT and ITT tests were performed, and the phosphorylation of AKT T308, as well as p70S6K T389 in gastrocnemius muscle and liver, were compared between the EX group and the EX+BCAA group. Additionally, the phosphorylation of AMPKα T172 in both tissues was measured across all four groups.Results12-week aerobic exercise improved insulin sensitivity in DIO mice while inducing BCAAs catabolic protein expression in skeletal muscle and liver, and reducing the plasma BCAAs level. Importantly, BCAAs supplementation elevated the plasma level of BCAAs and counteracted the exercise-attenuated IR. In skeletal muscle and liver tissues, BCAAs supplementation impaired the exercise-improved insulin signaling without enhancing mammalian target of rapamycin activity. AMPK activity was enhanced by aerobic exercise, which was abolished by BCAAs supplementation.ConclusionAerobic exercise attenuated insulin resistance via restoring BCAAs homeostasis and AMPK activity. The impacts of BCAAs intake on the metabolic effects of exercise sheds light on the combined exercise and nutrition intervention strategy for diabetes management.

ObjectiveTo explore the diagnostic value of glycated CD59 (gCD59) in gestational diabetes mellitus (GDM).MethodsA total of 707 pregnant women who underwent the first visit in the obstetric outpatient clinic of the Affliated Suqian Hospital of Xuzhou Medical University from January 2022 to July 2023 were included, and were grouped according to the International Association of the Diabetes and Pregnancy Study Groups(IADPSG) diagnostic criteria, and finally 113 cases in the GDM group and 559 cases in the normal glucose tolerance (NGT) group were included, and the concentration of gCD59 was determined by enzyme-linked immunosorbent assay (ELISA). The baseline data characteristics of the two groups were compared, the risk factors for GDM were explored by multivariate binary logistic analysis, and the diagnostic value of gCD59 in predicting GDM was explored by receiver operating characteristic (ROC) curve analysis.ResultsThe level of gCD59 in the GDM group was significantly higher than that in the NGT group (1.49 SPU vs 0.87 SPU). Multivariate regression analysis showed that gCD59, diastolic blood pressure (DBP) and thyroid stimulating hormone (TSH) were independent risk factors for GDM.The area under the curve (AUC) of gCD59 for the diagnosis of GDM was 0.681 (95% CI: 0.583-0.717), with a sensitivity of 71.7% and a specificity of 58.3%. In combination with fasting glucose, gCD59 effectively diagnosed GDM with higher AUC of 0.871 (95% CI: 0.708-1.000).ConclusiongCD59 is an independent risk factor for GDM and a good biomarker for the diagnosis of GDM.

BackgroundThe evidence supporting a connection between elevated serum uric acid (SUA) levels and diabetic peripheral neuropathy (DPN) is controversial. The present study performed a comprehensive evaluation of this correlation by conducting a systematic review and meta-analysis of relevant research.MethodPubMed, Web of Science (WOS), Embase, and the Cochrane Library were searched for published literature from the establishment of each database to January 8, 2024. In total, 5 cohort studies and 15 cross-sectional studies were included, and 2 researchers independently screened and extracted relevant data. R 4.3.0 was used to evaluate the included literature. The present meta-analysis evaluated the relationship between SUA levels and the risk of DPN in type 2 diabetes (T2DM) by calculating the ratio of means (RoM) and 95% confidence intervals (CIs) using the method reported by JO Friedrich, and it also analyzed continuous outcome measures using standardized mean differences (SMDs) and 95% CIs to compare SUA levels between DPN and non-DPN groups. Funnel plot and Egger’s test were used to assess publication bias. Sensitivity analysis was conducted by sequentially removing each study one-by-one.ResultsThe meta-analysis included 20 studies, with 12,952 T2DM patients with DPN and 16,246 T2DM patients without DPN. There was a significant correlation between SUA levels and the risk of developing DPN [odds ratio (OR) = 1.23; 95% CI: 1.07-1.41; p = 0.001]. Additionally, individuals with DPN had higher levels of SUA compared to those without DPN (SMD = 0.4; 95% CI: -0.11-0.91; p < 0.01).ConclusionT2DM patients with DPN have significantly elevated SUA levels, which correlate with a heightened risk of peripheral neuropathy. Hyperuricemia (HUA) may be a risk indicator for assessing the risk of developing DPN in T2DM patients.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO, identifier CRD42024500373.

BackgroundUnbalanced inflammatory response is a critical feature of sepsis, a life-threatening condition with significant global health burdens. Immune dysfunction, particularly that involving different immune cells in peripheral blood, plays a crucial pathophysiological role and shows early warning signs in sepsis. The objective is to explore the relationship between sepsis and immune subpopulations in peripheral blood, and to identify patients with a higher risk of 28-day mortality based on immunological subtypes with machine-learning (ML) model.MethodsPatients were enrolled according to the sepsis-3 criteria in this retrospective observational study, along with age- and sex-matched healthy controls (HCs). Data on clinical characteristics, laboratory tests, and lymphocyte immunophenotyping were collected. XGBoost and k-means clustering as ML approaches, were employed to analyze the immune profiles and stratify septic patients based on their immunological subtypes. Cox regression survival analysis was used to identify potential biomarkers and to assess their association with 28-day mortality. The accuracy of biomarkers for mortality was determined by the area under the receiver operating characteristic (ROC) curve (AUC) analysis.ResultsThe study enrolled 100 septic patients and 89 HCs, revealing distinct lymphocyte profiles between the two groups. The XGBoost model discriminated sepsis from HCs with an area under the receiver operating characteristic curve of 1.0 and 0.99 in the training and testing set, respectively. Within the model, the top three highest important contributions were the percentage of CD38+CD8+T cells, PD-1+NK cells, HLA-DR+CD8+T cells. Two clusters of peripheral immunophenotyping of septic patients by k-means clustering were conducted. Cluster 1 featured higher proportions of PD1+ NK cells, while cluster 2 featured higher proportions of naïve CD4+T cells. Furthermore, the level of PD-1+NK cells was significantly higher in the non-survivors than the survivors (15.1% vs 8.6%, P

Type I interferons (IFN-I) represent a group of pleiotropic cytokines renowned for their antiviral activity and immune regulatory functions. A multitude of studies have unveiled a critical role of IFN-I in the brain, influencing various neurological processes and diseases. In this mini-review, I highlight recent findings on IFN-I’s effects on brain aging, Alzheimer’s disease (AD) progression, and central nervous system (CNS) homeostasis. The multifaceted influence of IFN-I on brain health and disease sheds light on the complex interplay between immune responses and neurological processes. Of particular interest is the cGAS-STING-IFN-I axis, which extensively participates in brain aging and various forms of neurodegeneration. Understanding the intricate role of IFN-I and its associated pathways in the CNS not only advances our comprehension of brain health and disease but also presents opportunities for developing interventions to modify the process of neurodegeneration and prevent age-related cognitive decline.

Effective industrial policies need to be implemented, particularly aligning with environmental protection goals to drive the high-quality growth of China’s economy in the new era. Setting up national high-tech zones falls under the purview of both regional and industrial policies. Using panel data from 163 prefecture-level cities in China from 2007 to 2019, this paper empirically analyzes the impact of national high-tech zones on the level of urban green innovation and its underlying mechanisms. It utilizes the national high-tech zones as a quasi-natural experiment and employs a double machine learning model. The study findings reveal that the policy for national high-tech zones greatly enhances urban green innovation. This conclusion remains consistent even after adjusting the measurement method, empirical samples, and controlling for other policy interferences. The findings from the heterogeneity analysis reveal that the impact of the national high-tech zone policy on green innovation exhibits significant regional heterogeneity, with a particularly significant effect in the central and western regions. Among cities, there is a notable push for green innovation levels in second-tier, third-tier, and fourth-tier cities. The moderating effect results indicate that, at the current stage of development, transportation infrastructure primarily exerts a negative moderating effect on how the national high-tech zone policy impacts the level of urban green innovation. This research provides robust empirical evidence for informing the optimization of the industrial policy of China and the establishment of a future ecological civilization system.

ObjectiveThis study aims to analyze the efficacy of anti-syphilis treatment and the impact of syphilis events on HIV virology and immunology in HIV/syphilis co-infected patients on long-term antiretroviral therapy (ART) and to investigate the incidence and factors of syphilis recurrence/re-infection/serofast state. The insights derived from this investigation can potentially guide strategies for preventing and managing syphilis and AIDS.MethodsA retrospective case–control study was conducted at the AIDS clinic of Peking Union Medical College Hospital from January 2003 to December 2022. The study involved 86 HIV/syphilis co-infected patients and 86 HIV mono-infected patients matched based on age, baseline CD4 + T cell counts, and viral load. We examined the clinical characteristics of HIV/syphilis co-infected patients, evaluated the efficacy of anti-syphilis treatment, and analyzed the dynamic changes in HIV virology and immunology. The Generalized Estimating Equations (GEE) model investigated the factors associated with HIV/syphilis co-infection and syphilis recurrence/reinfection/serofast state.ResultsSyphilis serofast state was observed in 11.6% (10/86) of HIV/syphilis co-infected patients after treatment, and 33.7% (29/86) had syphilis recurrence or re-infection. The overall effectiveness of syphilis treatment stood at 76.8% (63/82). Notably, the effectiveness of syphilis treatment displayed a significant correlation with baseline syphilis titers exceeding 1:128 (p = 0.003). Over the 10-year follow-up period on ART, the HLA-DR + CD8+/CD8 + % levels in the HIV/syphilis co-infected group were markedly higher than those in the HIV mono-infected group (p 0.05). GEE analysis model revealed that elevated HLA-DR + CD8+/CD8 + % levels were associated with HIV/syphilis co-infection (OR = 1.026, 95% CI = 1.007–1.046; p = 0.007) and syphilis recurrence/reinfection/serofast state (OR = 1.036, 95% CI = 1.008–1.065; p = 0.012).ConclusionWhile HIV/syphilis co-infected patients typically receive adequate treatment, the incidence of syphilis recurrence and reinfection remain notably elevated. A heightened HLA-DR + CD8+/CD8+ % is a notable risk factor for HIV/syphilis co-infection and syphilis recurrence/reinfection/serofast state. Therefore, it is advisable to reinforce health education efforts and ensure regular follow-ups for people living with HIV undergoing ART to monitor syphilis infection or increased risk of syphilis infection.

Nuclear protein of the testis (NUT) midline carcinoma (NMC) is a rare tumor, with particularly low incidence in the lungs, and a correspondingly poor prognosis. To determine the clinicopathological characteristics, outcomes, and prognostic factors of primary pulmonary NMC, a case was reported and a systematic review was performed. Twenty-nine records, including ours, involving 62 cases, were finally included. The median age at diagnosis was 29.5 years. At presentation, the most common symptoms at presentation were cough (47.50%) and chest/back pain (37.50%). In terms of diagnosis, 32.14% of NMC cases were identified through immunohistochemistry (IHC); However, a greater number of cases may be misdiagnosed initially, and ultimately, the diagnosis of NMC was confirmed through a combination of IHC and fluorescence in situ hybridization (FISH). Despite the clinical application of various chemotherapy-based treatments, the actual effectiveness remains unsatisfactory. Furthermore, Cox regression analysis of multiple factors identified male gender and concurrent presence of pleural effusion as indicators of shorter survival time in patients. These results emphasize the importance of increased diagnostic awareness among clinical and pathology practitioners concerning NMC. While there is currently no established standard for treating NMC, a treatment approach combining multiple methods shows promise for future research. Concurrently, clinical and foundational investigations addressing variables such as gender and the presence of pleural effusion may yield valuable insights into the diagnosis and treatment of NMC.

Neoadjuvant chemoimmunotherapy has demonstrated significant benefit for resectable non-small-cell lung cancer (NSCLC) excluding known EGFR/ALK genetic alterations. Recent evidence has shown that neoadjuvant chemoimmunotherapy could be clinically valuable in resectable localized driver gene-mutant NSCLC, though the data still lack robust support, especially for rare oncogenic mutations. Here, we report a patient with stage IIIA lung adenocarcinoma with a RET fusion gene and high expression of PD-L1 who underwent neoadjuvant chemoimmunotherapy and successfully attained a pathologic complete response. The patient has survived for 12 months with no recurrence or metastases after surgery. Our case suggests that this treatment strategy may be an alternative therapeutic option for resectable RET fusion-positive NSCLC patients.

BackgroundChronic metabolic changes relevant to human immunodeficiency virus type 1 (HIV-1) infection and in response to antiretroviral therapy (ART) remain undetermined. Moreover, links between metabolic dysfunction caused by HIV and immunological inflammation in long-term treated individuals have been poorly studied.MethodsUntargeted metabolomics and inflammatory cytokine levels were assessed in 47 HIV-infected individuals including 22 immunological responders (IRs) and 25 non-responders (INRs) before and after ART. The IRs and INRs were matched by age, gender, baseline viral load, and baseline CD4+T cell counts. Another 25 age-matched uninfected healthy individuals were also included as controls.ResultsAmong the 770 plasma compounds detected in the current study, significant changes were identified in lipids, nucleotides, and biogenic amino acids between HIV-infected patients and healthy controls. Principal Component Analysis (PCA) and the Random Forest (RF) model suggested that levels of selected metabolites could differentiate HIV-infected patients clearly from healthy controls. However, the metabolite profiles identified in our patients were similar, and only three metabolites, maltotetraose, N, N-dimethyl-5-aminovalerate, and decadienedioic acid (C10:2-DC), were different between IRs and INRs following long-term ART. The pathway enrichment analysis results revealed that disturbances in pyrimidine metabolism, sphingolipid metabolism, and purine metabolism after HIV infection and these changes did not recover to normal levels in healthy controls even with suppressive ART. Correlation analysis of the metabolism-immune network indicated that interleukin (IL)-10, D-dimer, vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and TNF-RII were positively correlated with most of the significantly changed lipid and amino acid metabolites but negatively correlated with metabolites in nucleotide metabolism.ConclusionsSignificant changes in many metabolites were observed in HIV-infected individuals before and after ART regardless of their immunological recovery status. The disturbed metabolic profiles of lipids and nucleotides in HIV infection did not recover to normal levels even after long-term ART. These changes are correlated with modified cytokines and biomarkers of chronic non-AIDS events, warranting tryout of interventions other than ART.

Hearing impairment is a global health problem. Stem cell therapy has become a cutting-edge approach to tissue regeneration. In this review, the recent advances in stem cell therapy for hearing loss have been discussed. Nanomaterials can modulate the stem cell microenvironment to augment the therapeutic effects further. The potential of combining nanomaterials with stem cells for repairing and regenerating damaged inner ear hair cells (HCs) and spiral ganglion neurons (SGNs) has also been discussed. Stem cell-derived exosomes can contribute to the repair and regeneration of damaged tissue, and the research progress on exosome-based hearing loss treatment has been summarized as well. Despite stem cell therapy’s technical and practical limitations, the findings reported so far are promising and warrant further investigation for eventual clinical translation.

BackgroundIn patients with invasive fungal infection (IFI), the steady-state serum trough concentration (Cmin) of voriconazole (VCZ) is highly variable and can lead to treatment failure (Cmin < 0.5 mg/L) and toxicity (Cmin ≥ 5.0 mg/L). However, It remains challenging to determine the ideal maintenance dose to achieve the desired Cmin level quickly.AimsThis randomized, prospective observational single-center study aimed to identify factors affecting VCZ-Cmin and maintenance dose and create an algorithmic model to predict the necessary maintenance dose. MeThe study enrolled 306 adult IFI patients, split into two groups: non-gene-directed (A) (where CYP2C19 phenotype is not involved in determining VCZ dose) and gene-directed (B) (where CYP2C19 phenotype is involved in determining VCZ dose).ResultsResults indicated that CYP2C19 genetic polymorphisms might significantly impact VCZ loading and maintenance dose selection. CYP2C19 phenotype, C-reaction protein (CRP), and average daily dose/body weight were significant influencers on VCZ-Cmin, while CYP2C19 phenotype, CRP, and body weight significantly impacted VCZ maintenance dose. A feasible predictive formula for VCZ stable maintenance dose was derived from the regression equation as a maintenance dose (mg) =282.774-0.735×age (year)+2.946×body weight(Kg)-19.402×CYP2C19 phenotype (UM/RM/NM:0, IM:1, PM:2)-0.316×CRP (mg/L) (p < 0.001).DiscussionDiThis formula may serve as a valuable supplement to the Clinical Pharmacogenetics Implementation Consortium (CPIC®) guideline for CYP2C19 and VCZ therapy, especially for IFI patients with highly variable inflammatory cytokines during VCZ therapy.

BackgroundPatients with gastric cancer have a poor prognosis. Currently, intraperitoneal chemotherapy has been considered a therapeutic option to improve prognosis due to its appealing theoretical rationales. But there is no consensus on the choice of chemotherapeutic agents used in intraperitoneal chemotherapy for gastric cancer. The real-world efficacy of applying intraoperative chemotherapy in gastric cancer still remains undefined.MethodsPatients with gastric cancer who underwent radical gastrectomy at the Gastrointestinal Department of The First Affiliated Hospital of Anhui Medical University between 2012 and 2019 were enrolled in this study. Patients were divided into two groups based on whether they received intraperitoneal chemotherapy. The t-test (mean of two samples) was conducted to compare the difference in measurement data between the two groups, and the chi-square test was used to compare the difference in count data. Kaplan-Meier method with log-rank test was performed to analyze the overall survival of patients. Kaplan-Meier method with log-rank test was also performed in various subgroups to respectively compare the survival of patients. Multivariate Cox analysis was performed to analyze the prognosis factors of these patients.ResultsA total of 1253 patients were included in the final analysis, in which 861 patients received intraperitoneal chemotherapy and 352 not received intraperitoneal chemotherapy. The clinicopathological features of the participants in the two groups were comparable. There was no significant difference between the two groups in overall survival (P > 0.05). Consistently, no significant difference was found between the two groups in each subgroup (P > 0.05). The multivariate Cox analysis demonstrated that only age, BMI, pathological type, TNM stage, and differentiation grade were independent risk factors of survival.ConclusionIntraoperative intraperitoneal chemotherapy usage did not improve survival in patients with gastric cancer undergoing radical gastrectomy.

Selective electrochemical hydrogenation (ECH) of biomass-derived unsaturated organic molecules has enormous potential for sustainable chemical production. However, an efficient catalyst is essential to perform an ECH reaction consisting of superior product selectivity and a higher conversion rate. Here, we examined the ECH performance of reduced metal nanostructures, i.e., reduced Ag (rAg) and reduced copper (rCu) prepared via electrochemical or thermal oxidation and electrochemical reduction process, respectively. Surface morphological analysis suggests the formation of nanocoral and entangled nanowire structure formation for rAg and rCu catalysts. rCu exhibits a slight enhancement in ECH reaction performance in comparison to the pristine Cu. However, the rAg exhibits more than two times higher ECH performance without compromising the selectivity for 5-(HydroxyMethyl) Furfural (HMF) to 2,5-bis(HydroxyMethyl)-Furan (BHMF) formation in comparison to the Ag film. Moreover, a similar ECH current density was recorded at a reduced working potential of 220 mV for rAg. This high performance of rAg is attributed to the formation of new catalytically active sites during the Ag oxidation and reduction processes. This study demonstrates that rAg can potentially be used for the ECH process with minimum energy consumption and a higher production rate.

IntroductionVibriosis causes enormous economic losses of marine fish. The present study investigated the intestinal microbial response to acute infection of half-smooth tongue sole with different-dose Vibrio alginolyticus within 72 h by metagenomic sequencing.MethodsThe inoculation amount of V. alginolyticus for the control, low-dose, moderate-dose, and high-dose groups were 0, 8.5 × 101, 8.5 × 104, and 8.5 × 107 cells/g respectively, the infected fish were farmed in an automatic seawater circulation system under a relatively stable temperature, dissolved oxygen and photoperiod, and 3 ~ 6 intestinal samples per group with high-quality DNA assay were used for metagenomics analysis.ResultsThe acute infections with V. alginolyticus at high, medium, and low doses caused the change of different-type leukocytes at 24 h, whereas the joint action of monocytes and neutrophils to cope with the pathogen infection only occurred in the high-dose group at 72 h. The metagenomic results suggest that a high-dose V. alginolyticus infection can significantly alter the intestinal microbiota, decrease the microbial α-diversity, and increase the bacteria from Vibrio and Shewanella, including various potential pathogens at 24 h. High-abundance species of potential pathogens such as V. harveyii, V. parahaemolyticus, V. cholerae, V. vulnificus, and V. scophthalmi exhibited significant positive correlations with V. alginolyticus. The function analysis revealed that the high-dose inflection group could increase the genes closely related to pathogen infection, involved in cell motility, cell wall/ membrane/envelope biogenesis, material transport and metabolism, and the pathways of quorum sensing, biofilm formation, flagellar assembly, bacterial chemotaxis, virulence factors and antibiotic resistances mainly from Vibrios within 72 h.DiscussionIt indicates that the half-smooth tongue sole is highly likely to be a secondary infection with intestinal potential pathogens, especially species from Vibrio and that the disease could become even more complicated because of the accumulation and transfer of antibiotic-resistance genes in intestinal bacteria during the process of V. alginolyticus intensified infection.

BackgroundSeveral studies have described the rapid decline and clearance of hepatitis B surface antigen (HBsAg) in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfection after initiating combined antiretroviral therapy (cART). Early decline of HBsAg levels is associated with HBsAg seroclearance in the treatment of chronic HBV infection. This study aims to evaluate the HBsAg kinetics and the determinants of early HBsAg decline in patients with HIV/HBV coinfection during cART.MethodsA total of 51 patients with HIV/HBV coinfection were enrolled from a previously established HIV/AIDS cohort and followed for a median of 59.5 months after cART initiation. Biochemical tests, virology and immunology assessments were measured longitudinally. The kinetics of HBsAg during cART were analyzed. Soluble programmed death-1 (sPD-1) levels and immune activation markers (CD38 and HLA-DR) were measured at baseline, 1-year and 3-year during treatment. HBsAg response was defined as a decline of more than 0.5 log10 IU/ml at 6 months from the baseline after initiation of cART.ResultsHBsAg declined faster (0.47 log10 IU/mL) in the first six months and attained a decrease of 1.39 log10 IU/mL after 5-year therapy. Seventeen (33.3%) participants achieved a decline of more than 0.5 log10 IU/ml at the first 6 months of cART(HBsAg response) of which five patients achieved HBsAg clearance at a median of 11 months (range: 6-51 months). Multivariate logistic analysis showed the lower baseline CD4+ T cell levels (OR=6.633, P=0.012) and sPD-1 level (OR=5.389, P=0.038) were independently associated with HBsAg response after cART initiation. The alanine aminotransferase abnormality rate and HLA-DR expression were significantly higher in patients who achieved HBsAg response than in those who did not achieve HBsAg response after cART initiation.ConclusionLower CD4 + T cells, sPD-1, and immune activation were related to a rapid HBsAg decline in patients with HIV/HBV-coinfection after the initiation of cART. These findings imply that immune disorders induced by HIV infection may disrupt immune tolerance to HBV, leading to a faster decline in HBsAg levels during coinfection.

Purpose/backgroundMicrosatellite instability (MSI) status is a significant biomarker for the response to immune checkpoint inhibitors, response to 5-fluorouracil-based adjuvant chemotherapy, and prognosis in colorectal carcinoma (CRC). This study investigated the predictive value of intratumoral-metabolic heterogeneity (IMH) and conventional metabolic parameters derived from 18F-FDG PET/CT for MSI in patients with stage I–III CRC.MethodsThis study was a retrospective analysis of 152 CRC patients with pathologically proven MSI who underwent 18F-FDG PET/CT examination from January 2016 to May 2022. Intratumoral-metabolic heterogeneity (including heterogeneity index [HI] and heterogeneity factor [HF]) and conventional metabolic parameters (standardized uptake value [SUV], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) of the primary lesions were determined. MTV and SUVmean were calculated on the basis of the percentage threshold of SUVs at 30%–70%. TLG, HI, and HF were obtained on the basis of the above corresponding thresholds. MSI was determined by immunohistochemical evaluation. Differences in clinicopathologic and various metabolic parameters between MSI-High (MSI-H) and microsatellite stability (MSS) groups were assessed. Potential risk factors for MSI were assessed by logistic regression analyses and used for construction of the mathematical model. Area under the curve (AUC) were used to evaluate the predictive ability of factors for MSI.ResultsThis study included 88 patients with CRC in stages I–III, including 19 (21.6%) patients with MSI-H and 69 (78.4%) patients with MSS. Poor differentiation, mucinous component, and various metabolic parameters including MTV30%, MTV40%, MTV50%, and MTV60%, as well as HI50%, HI60%, HI70%, and HF in the MSI-H group were significantly higher than those in the MSS group (all P < 0.05). In multivariate logistic regression analyses, post-standardized HI60% by Z-score (P = 0.037, OR: 2.107) and mucinous component (P < 0.001, OR:11.394) were independently correlated with MSI. AUC of HI60% and our model of the HI60% + mucinous component was 0.685 and 0.850, respectively (P = 0.019), and the AUC of HI30% in predicting the mucinous component was 0.663.ConclusionsIntratumoral-metabolic heterogeneity derived from 18F-FDG PET/CT was higher in MSI-H CRC and predicted MSI in stage I–III CRC patients preoperatively. HI60% and mucinous component were independent risk factors for MSI. These findings provide new methods to predict the MSI and mucinous component for patients with CRC.

Twenty-one novel ester tethered artemisinin-isatin hybrids were designed, synthesized and screened against human myeloid leukemia cell lines (K562 and K562/ADR), human acute lymphoblastic leukemia cell line (CCRF-CEM) as well as normal human peripheral blood mononuclear cells (PBMCs) for their cytotoxicity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The structure-activity relationships (SARs) were also discussed to facilitate further rational design of more effective candidates. The preliminary results showed that most of the ester tethered artemisinin-isatin hybrids (IC50: 0.32-29.35 µM) exhibited promising activity against CCRF-CEM cells, and some of them (IC50: 1.23-49.84 µM) were also active against K562 and K562/ADR human myeloid leukemia cell lines. Among them, hybrid 7d (IC50: 0.32, 2.67 and 1.23 µM) not only possessed profound activity against the three tested leukemia cell lines and excellent safety and selectivity profiles, but also showed promising pharmacokinetic properties. Accordingly, hybrid 7d could be considered as a potential lead molecule for the development of novel anti-leukemic agents with minimal untoward events to normal human cells.

BackgroundEarly detection of kidney diseases can be challenging as conventional methods such as blood tests or imaging techniques (computed tomography (CT), magnetic resonance imaging (MRI), or ultrasonography) may be insufficient to assess renal function. A single-photon emission CT (SPECT) renal scan provides a means of measuring glomerular filtration rates (GFRs), but its diagnostic accuracy is limited due to its planar imaging modality and semi-quantification property. In this study, we aimed to improve the accuracy of GFR measurement by preparing a positron emission tonometry (PET) tracer 68Ga-Ethylenediaminetetraacetic acid (68Ga-EDTA) and comprehensively evaluating its performance in healthy mice and murine models of renal dysfunction.MethodsDynamic PET scans were performed in healthy C57BL/6 mice and in models of renal injury, including acute kidney injury (AKI) and unilateral ureter obstruction (UUO) using 68Ga-EDTA. In a 30-min dynamic scan, PET images and time-activity curves (TACs) were acquired. Renal function and GFR values were measured using renograms and validated through serum renal function parameters, biodistribution results, and pathological staining.Results68Ga-EDTA dynamic PET imaging quantitatively captured the tracer elimination process. The calculated GFR values were 0.25 ± 0.02 ml/min in healthy mice, 0.01 ± 0.00 ml/min in AKI mice, and 0.25 ± 0.04, 0.29 ± 0.03 and 0.24 ± 0.01 ml/min in UUO mice, respectively. Furthermore, 68Ga-EDTA dynamic PET imaging and GFRPET were able to differentiate mild renal impairment before serum parameters indicated any changes.ConclusionsOur findings demonstrate that 68Ga-EDTA dynamic PET provides a reliable and precise means of evaluating renal function in two murine models of renal injury. These results hold promise for the widespread clinical application of 68Ga-EDTA dynamic PET in the near future.

BackgroundSeminal plasma plays a pivotal role in modulating sperm viability and function. However, the underlying mechanisms have not been fully elucidated.MethodIn this study, the bull semen production records of core breeding farms and bull stations in the past 10 years were analyzed.ResultsWe found that the semen of 5-year-old bulls collected for the first time is of the best quality (p < 0.05). Despite the bull semen collected under the above conditions, low-quality sperm is still obtained from part of bulls due to individual differences. Interestingly, seminal plasma from normal semen is capable of improving low-quality semen motility. To identify the potential key factors in seminal plasma, the differences in miRNA and metabolite profiles between normal and low-quality seminal plasma were analyzed. We found that 59 miRNAs were differently expressed, including 38 up-regulated and 21 down-regulated miRNAs. Three hundred and ninety-one and 327 significantly different metabolites were identified from the positive and negative ion models, respectively. These multiple miRNAs and metabolites collectively contribute to the motility of sperm, subsequently, affect semen quality.DiscussionTogether, these results not only revealed the critical factors of seminal plasma improving sperm quality but also provided potential miRNA- or metabolite-based biomarkers to identify the high semen quality.

PurposeTo evaluate the correlation between microvascular density (MVD) and intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) parameters and the effect of glycolytic flux after transarterial chemoembolization (TACE) in a rabbit VX2 liver tumor.Materials and methodsVX2 liver tumor allografts in 15 New Zealand white rabbits were treated with sterile saline (control group, n = 5) or lipiodol-doxorubicin emulsion (experimental group, n = 10). MRI was performed 2 weeks after the procedure to evaluate IVIM parameters, including apparent diffusion coefficient (ADC), pure diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (PF). All animal samples were taken of the tumor and surrounding liver. Immunostaining for CD31, CD34, CD105, and VEGF was used to evaluate MVD. The protein expression of Glut4, HK2, PKM2, LDHA, and MCT1 was determined using western blotting. Pearson correlation tests were used to analyze the relationship between MVD and IVIM parameters.ResultsD* value in the peritumoral region was negatively correlated with CD34 (r = –0.71, P = 0.01). PF value positively correlated with CD34 (r = 0.68, P = 0.015), CD105 (r = 0.76, P = 0.004) and VEGF (r = 0.72, P = 0.008) in the peritumoral region. Glut4, HK2, PKM2, and MCT1 in the peritumoral regions were higher in the experimental group than in the control group (all P < 0.05).ConclusionIVIM parameters were correlated with MVD in the intratumoral and peritumoral regions after TACE in a rabbit liver tumor model. The angiogenesis reflected by MVD may be related to changes of glycolytic flux.

Thrombocytopenia following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a common and life-threatening complication. Thus, new prevention and treatment strategies for post-HSCT thrombocytopenia are urgently required. In recent studies, thrombopoietin receptor agonists (TPO-RA) for treating post-HSCT thrombocytopenia indicated efficiency and safety. The improved effect of post-HSCT thrombocytopenia in adults was found in the administration of avatrombopag which was a new TPO-RA. However, there was no relevant study in the children's cohort. Herein, we retrospectively analyzed the effect of avatrombopag in post-HSCT thrombocytopenia in children. As a result, the overall response rate (ORR) and complete response rate (CRR) were 91% and 78%, respectively. Furthermore, both cumulative ORR and CRR were significantly lower in the poor graft function (PGF)/secondary failure of platelet recovery (SFPR) group compared to the engraftment-promotion group (86.7% vs. 100%, p = 0.002 and 65.0% vs. 100%, p

Short-chain fatty acids (SCFAs) are metabolites of gut microbes that can modulate the host inflammatory response, and contribute to health and homeostasis. Since the introduction of the gut-skin axis concept, the link between SCFAs and inflammatory skin diseases has attracted considerable attention. In this review, we have summarized the literature on the role of SCFAs in skin inflammation, and the correlation between SCFAs and inflammatory skin diseases, especially atopic dermatitis, urticaria, and psoriasis. Studies show that SCFAs are signaling factors in the gut-skin axis and can alleviate skin inflammation. The information presented in this review provides new insights into the molecular mechanisms driving gut-skin axis regulation, along with possible pathways that can be targeted for the treatment and prevention of inflammatory skin diseases.

BackgroundThe clinical benefits of high-dose intravenous immunoglobulin (IVIg) in treating COVID-19 remained controversial.MethodsWe systematically searched databases up to February 17, 2022, for studies examining the efficacy of IVIg compared to routine care. Meta-analyses were conducted using the random-effects model. Subgroup analysis, meta-regression, and trial series analysis w ere performed to explore heterogeneity and statistical significance.ResultsA total of 4,711 hospitalized COVID-19 patients (1,925 IVIg treated and 2786 control) were collected from 17 studies, including five randomized controlled trials (RCTs) and 12 cohort studies. The application of IVIg was not associated with all-cause mortality (RR= 0.89 [0.63, 1.26], P= 0.53; I2 = 75%), the length of hospital stays (MD= 0.29 [-3.40, 6.44] days, P= 0.88; I2 = 96%), the needs for mechanical ventilation (RR= 0.93 ([0.73, 1.19], P= 0.31; I2 = 56%), or the incidence of adverse events (RR= 1.15 [0.99, 1.33], P= 0.06; I2 = 20%). Subgroup analyses showed that overall mortality among patients with severe COVID-19 was reduced in the high-dose IVIg subgroup (RR= 0.33 [0.13, 0.86], P= 0.02, I2 = 68%; very low certainty).ConclusionsResults of this study suggest that severe hospitalized COVID-19 patients treated with high-dose IVIg would have a lower risk of death than patients with routine care.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021231040, identifier CRD42021231040.

The repair of exercise-induced muscle damage (EIMD) is closely related with inflammation. Branched-chain amino acids (BCAAs), as a nutritional supplement, promote EIMD repair; however, the underlying mechanism remains unclear. In vivo, Sprague–Dawley rats were subjected to Armstrong’s eccentric exercise (a 120-min downhill run with a slope of −16° and a speed of 16 m min−1) to induce EIMD and BCAA supplement was administered by oral gavage. Protein expression of macrophages (CD68 and CD163) and myogenic regulatory factors (MYOD and MYOG) in gastrocnemius was analyzed. Inflammatory cytokines and creatine kinase (CK) levels in serum was also measured. In vitro, peritoneal macrophages from mice were incubated with lipopolysaccharide (LPS) or IL-4 with or without BCAAs in culture medium. For co-culture experiment, C2C12 cells were cultured with the conditioned medium from macrophages prestimulated with LPS or IL-4 in the presence or absence of BCAAs. The current study indicated BCAA supplementation enhanced the M1/M2 polarization of macrophages in skeletal muscle during EIMD repair, and BCAAs promoted M1 polarization through enhancing mTORC1-HIF1α-glycolysis pathway, and promoted M2 polarization independently of mTORC1. In addition, BCAA-promoted M1 macrophages further stimulated the proliferation of muscle satellite cells, whereas BCAA-promoted M2 macrophages stimulated their differentiation. Together, these results show macrophages mediate the BCAAs’ beneficial impacts on EIMD repair via stimulating the proliferation and differentiation of muscle satellite cells, shedding light on the critical role of inflammation in EIMD repair and the potential nutritional strategies to ameliorate muscle damage.

BackgroundAt present, there is increasing evidence that both competitive endogenous RNAs (ceRNAs) and immune status in the tumor microenvironment (TME) can affect the progression of gastric cancer (GC), and are closely related to the prognosis of patients. However, few studies have linked the two to jointly determine the prognosis of patients with GC. This study aimed to develop a combined prognostic model based on ceRNAs and immune biomarkers.MethodsFirst, the gene expression profiles and clinical information were downloaded from TCGA and GEO databases. Then two ceRNA networks were constructed on the basis of circRNA. Afterwards, the key genes were screened by univariate Cox regression analysis and Lasso regression analysis, and the ceRNA-related prognostic model was constructed by multivariate Cox regression analysis. Next, CIBERSORT and ESTIMATE algorithms were utilized to obtain the immune cell infiltration abundance and stromal/immune score in TME. Furthermore, the correlation between ceRNAs and immunity was found out through co-expression analysis, and another immune-related prognosis model was established. Finally, combining these two models, a comprehensive prognostic model was built and visualized with a nomogram.ResultsThe (circRNA, lncRNA)-miRNA-mRNA regulatory network of GC was constructed. The predictive power of ceRNA-related and immune-related prognosis models was moderate. Co-expression analysis showed that the ceRNA network was correlated with immunity. The integrated model of combined ceRNAs and immunity in the TCGA training set, the AUC values of 1, 3, and 5-year survival rates were 0.78, 0.76, and 0.78, respectively; in the independent external validation set GSE62254, they were 0.81, 0.79, and 0.78 respectively; in GSE15459, they were 0.84, 0.88 and 0.89 respectively. Besides, the prognostic score of the comprehensive model can predict chemotherapeutic drug resistance. Moreover, we found that plasma variant translocation 1 (PVT1) and infiltrating immune cells (mast cells) are worthy of further investigation as independent prognostic factors.ConclusionsTwo ceRNA regulatory networks were constructed based on circRNA. At the same time, a comprehensive prognosis model was established, which has a high clinical significance for prognosis prediction and chemotherapy drug selection of GC patients.

ObjectiveThe purpose of this study was to assess the short-term and long-term outcomes of ventriculoperitoneal shunt (VPS) placement in patients with cryptococcal meningitis (CM).MethodsWe performed a retrospective analysis of all patients with CM admitted to the Peking Union Medical College Hospital from September 1990 to January 2021. We collected related clinical features to analyze the short- and long-term outcomes of VPS at 1 month and 1 year at least the following therapy, respectively. Overall survival (OS) was compared with all patients and a subgroup of critically ill cases by the Kaplan–Meier method with the log-rank test. Univariable and multivariable analyses were also performed using the Cox proportional hazard model to identify statistically significant prognostic factors.ResultsWe enrolled 98 patients, fifteen of whom underwent VPS. Those who received VPS had a lower cerebrospinal fluid (CSF) Cryptococcus burden (1:1 vs. 1:16; p = 0.046), lower opening pressures (173.3 mmH2 O vs. 224 mmH2O; p = 0.009) at lumbar punctures, and a lower incidence of critical cases (6.7 vs. 31.3%; p = 0.049). According to our long-term follow-up, no significant difference was shown in the Barthel Index (BI) between the two groups. Two patients in the VPS group suffered postoperative complications and had to go through another revision surgery. According to survival analysis, overall survival (OS) between the VPS and non-VPS groups was not significantly different. However, the Kaplan–Meier plots showed that critical patients with VPS had better survival in OS (p < 0.009). Multivariable analyses for critical patients showed VPS was an independent prognostic factor.ConclusionA VPS could reduce the intracranial pressure (ICP), decrease the counts of Cryptococcus neoformans by a faster rate and reduce the number of critical cases. The VPS used in critical patients with CM has a significant impact on survival, but it showed no improvement in the long-term Barthel Index (BI) vs. the conservative treatment and could lead to postoperative complications.

Candida haemulonii var. vulnera is a rare variant of C. haemulonii, which has been previously reported to cause human infections. Owing to the close kinship between C. haemulonii sensu stricto and C. haemulonii var. vulnera, accurate identification of C. haemulonii var. vulnera relied on DNA sequencing assay targeting, for example, rDNA internal transcribed spacer (ITS) region. In this work, two strains of C. haemulonii var. vulnera were collected from the China Hospital Invasive Fungal Surveillance Net (CHIF-NET). The identification capacity of three matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and VITEK 2 YST ID biochemical methods were evaluated against ITS sequencing. In addition, antifungal susceptibility testing was performed using Sensititre YeastOne. Moreover, we comprehensively screened drug-resistant related genes by whole-genome sequencing. The two strains were not correctly identified to species variant level using MALDI-TOF MS and YST ID cards. Both strains were resistant to amphotericin B (minimum inhibitory concentration [MIC] > 2 μg/ml). Moreover, strain F4564 and F4584 exhibited high MIC to fluconazole (>256 μg/ml) and 5-flucytosine (>64 μg/ml), respectively, which were supposed to result from key amino acid substitutions Y132F and G307A in Erg11p and V58fs and G60K substitutions in Fur1p. The rare species C. haemulonii var. vulnera has emerged in China, and such drug-resistant fungal species that can cause invasive diseases require further close attention.

Structures containing galactose and GalNAc residues are specifically recognized by asialoglycoprotein receptors, allowing them to selectively internalize by hepatocytes for drug-targeting delivery. However, methods for direct synthesis of GalNAc glycosides are still challenging due to the poor participating group of 2-acetamido. Here, we develop a facile strategy to synthesize various GalNAc glycosides by employing a series of rare earth metal triflates, and the results demonstrate that both α-glycosides and β-glycosides of GalNAc can be obtained by conducting with Hf(OTf)4 and Sc(OTf)3, respectively. These applicable results indicate that any interested GalNAc-containing substrates could be prepared by this simple strategy.

Bioactive coatings are promising for improving osseointegration and the long-term success of titanium dental or orthopaedic implants. Biomimetic octacalcium phosphate (OCP) coating can be used as a carrier for osteoinductive agents. κ-Carrageenan, a highly hydrophilic and biocompatible seaweed-derived sulfated-polysaccharide, promotes pre-osteoblast activity required for bone regeneration. Whether κ-carrageenan can functionalize OCP-coating to enhance osseointegration of titanium implants is unclear. This study aimed to analyze carrageenan-functionalized biomimetic OCP-coated titanium structure, and effects of carrageenan functionalization on pre-osteoblast behavior and osteogenic differentiation. Titanium discs were coated with OCP/κ-carrageenan at 0.125–2 mg/ml OCP solution, and physicochemical and biological properties were investigated. κ-Carrageenan (2 mg/ml) in the OCP coating of titanium discs decreased the pore size in the sheet-like OCP crystal by 41.32%. None of the κ-carrageenan concentrations tested in the OCP-coating did affect hydrophilicity. However, κ-carrageenan (2 mg/ml) increased (1.26-fold) MC3T3-E1 pre-osteoblast spreading at 1 h i.e., κ-Carrageenan in the OCP-coating increased pre-osteoblast proliferation (max. 1.92-fold at 2 mg/ml, day 1), metabolic activity (max. 1.50-fold at 2 mg/ml, day 3), and alkaline phosphatase protein (max. 4.21-fold at 2 mg/ml, day 3), as well as matrix mineralization (max. 5.45-fold at 2 mg/ml, day 21). κ-Carrageenan (2 mg/ml) in the OCP-coating increased gene expression of Mepe (4.93-fold) at day 14, and Runx2 (2.94-fold), Opn (3.59-fold), Fgf2 (3.47-fold), Ocn (3.88-fold), and Dmp1 (4.59-fold) at day 21 in pre-osteoblasts. In conclusion, κ-carrageenan modified the morphology and microstructure of OCP-coating on titanium discs, and enhanced pre-osteoblast metabolic activity, proliferation, and osteogenic differentiation. This suggests that κ-carrageenan-functionalized OCP coating may be promising for in vivo improvement of titanium implant osseointegration.

Pruritus of chronic spontaneous urticaria (CSU) is one of the most common and irritating sensations that severely affects the quality of life. However, the changes in the functional connectivity (FC) between thalamic subregions and other brain regions have not been fully elucidated. This study aimed to explore the potential changes in brain neural circuits by focusing on various subregions of the thalamus in patients with CSU pruritus to contribute to the understanding of chronic pruritus from the perspective of central mechanisms. A total of 56 patients with CSU and 30 healthy controls (HCs) completed the data analysis. Urticaria Activity Score 7 (UAS7), pruritus visual analog score (VAS-P), Dermatological Life Quality Index (DLQI), and immunoglobulin E (IgE) values were collected to assess clinical symptoms. Seed-based resting-state functional connectivity (rs-FC) analysis was used to assess relevant changes in the neural circuits of the brain. Compared to HCs, seeds within the caudal temporal thalamus (cTtha) on the right side of patients with CSU showed increased rs-FC with the cerebellum anterior lobe (CAL). Seeds within the lateral prefrontal thalamus (lPFtha) on the right side showed increased rs-FC with both CAL and pons, while those within the medial prefrontal thalamus (mPFtha) on the right side showed increased rs-FC with both CAL and the dorsal lateral prefrontal cortex (dlPFC) on the right side. Seeds within the posterior parietal thalamus (PPtha) on the right side showed increased rs-FC with the cerebellum posterior lobe (CPL) on the left side. The UAS7 values and IgE levels were positively correlated with the rs-FC of the right dlPFC. Our results suggest that patients with CSU may exhibit stronger rs-FC alterations between certain thalamic subregions and other brain regions. These changes affect areas of the brain involved in sensorimotor and scratching.Trial registration number[http://www.chictr.org.cn], identifier [ChiCTR1900022994].

Background: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory arthropathy. Recommendations for RA, specifically on pharmacotherapy, are essential in clinical practice. However, the direction and strength of recommendations are controversial across current clinical practice guidelines (CPGs) of RA.Objective: To systematically analyze the consistency of recommendations regarding pharmacotherapy of RA across CPGs.Methods: 11 electronic databases and websites were comprehensively searched from inception to 14 March 2022, to identify CPGs for diagnosis, therapy, and management of RA. Unambiguous and discrete specifications of the population-intervention-comparison (PIC) framework were used to classify the recommendations. Based on the PIC framework, consistency analyses across CPGs on pharmacotherapy of RA were performed. Two researchers reached a consensus on coding the direction and strength of each recommendation.Results: Finally, 26 CPGs were included in this study, and 14 of them, which included pharmacotherapy, were performed consistency analysis. 1) 64 recommendations from 14 CPGs were classified into 18 PICs. 2) Seven PICs (38%) were consistent in direction and strength, 10 PICs (56%) were consistent in direction but inconsistent in strength, and one PIC (6%) was inconsistent in direction (hydroxychloroquine, HCQ). 3) Sensitivity analysis tested the robustness, and the inconsistency remained high.Conclusion: The direction was highly consistent among the recommendations of pharmacotherapy for RA, but the strength was highly inconsistent. Reasons for the inconsistency need to be further investigated, and consistent recommendations could guide the pharmacotherapy of RA in clinical practice.

Image processing and analysis based on deep learning are becoming mainstream and increasingly accessible for solving various scientific problems in diverse fields. However, it requires advanced computer programming skills and a basic familiarity with character user interfaces (CUIs). Consequently, programming beginners face a considerable technical hurdle. Because potential users of image analysis are experimentalists, who often use graphical user interfaces (GUIs) in their daily work, there is a need to develop GUI-based easy-to-use deep learning software to support their work. Here, we introduce JustDeepIt, a software written in Python, to simplify object detection and instance segmentation using deep learning. JustDeepIt provides both a GUI and a CUI. It contains various functional modules for model building and inference, and it is built upon the popular PyTorch, MMDetection, and Detectron2 libraries. The GUI is implemented using the Python library FastAPI, simplifying model building for various deep learning approaches for beginners. As practical examples of JustDeepIt, we prepared four case studies that cover critical issues in plant science: (1) wheat head detection with Faster R-CNN, YOLOv3, SSD, and RetinaNet; (2) sugar beet and weed segmentation with Mask R-CNN; (3) plant segmentation with U2-Net; and (4) leaf segmentation with U2-Net. The results support the wide applicability of JustDeepIt in plant science applications. In addition, we believe that JustDeepIt has the potential to be applied to deep learning-based image analysis in various fields beyond plant science.

Aspergillus niger is a major cell factory for citric acid production, and the process of citrate export from mitochondria to cytoplasm is predicted to be one of rate-limiting steps in citric acid accumulation. Currently, the mitochondrial citrate transporters (Ctps) in A. niger are not fully characterized. Here, six putative Ctp encoding genes (ctpA to ctpF) were identified based on their homology with a mitochondrial citrate transporter ScCtp1 from Saccharomyces cerevisiae. Disruption of individual ctpA to ctpF caused varying degrees of decline in citric acid accumulation at different fermentation stages, whereas a mutant strain S1696 with disruption of all six ctps showed complete loss of citiric acid production. S1696 also exhibited delayed growth, reduced conidia formation, and decreased pigmentogenesis. Exogenous addition of citrate partially restored the conidia formation and pigmentogenesis in S1696 mutant. Reintroduction of individual ctps (ctpA to ctpF) into S1696 at the amyA locus showed that ctpA, ctpB, and ctpD restored the citric acid titers to 88.5, 93.8, and 94.6% of the parent strain, respectively. Additionally, the formation of conidia and pigment production was partially restored after reintroduction of ctpA, ctpB, or ctpD. Overexpression of respective ctpA, ctpB, and ctpD in the parent strain resulted in increases in citric acid accumulation by 32.8, 19.3, and 24.2%, respectively. These results demonstrate that CtpA, CtpB, and CtpD play important roles in citric acid transport across the mitochondrial membrane and function in a redundant manner. Enhancement of citric acid transport process can serve as a target for boosting citric acid accumulation in A. niger.

ObjectiveVocal fold nodules (VFNs) are benign lesions, occurring at the junction of the anterior and middle thirds of bilateral vocal cords, for which pediatric prognosis and treatment remains controversial. There is a requirement for a correlation indicator to assess the prognosis by pediatric otolaryngologists.Materials and methodsPatients with VFNs, who were admitted to the department of otolaryngology, were enrolled. The patient’s gender, age, duration of dysphonia, laryngoscopy results and related diseases [allergic rhinitis, sinusitis, laryngopharyngeal reflux (LPR)] were collected and recovery from dysphonia followed up. Correlations between clinical factors and type of laryngoscopic morphology of VFNs were analyzed.ResultsA total of 432 patients with dysphonia were identified, 208 agreed to undergo laryngoscopy and 194 were diagnosed with VFNs as a result. The modal age of patients with dysphonia was between 3 and 7 years with a male: female ratio of 2.1:1 (294:138) and 116 (26.85%; 116/432) had symptoms of allergic rhinitis. The boy to girl ratio among the 194 children with VFNs was about 2.6:1 (140:54) and modal age was consistent with dysphonia. Vocal nodules were the cause of most phonation disorders (93.27%; 194/208) and those with long duration of dysphonia presented more mature (p = 0.026) and discrete types (p = 0.022). Boys were more likely to have mature (p = 0.050) and discrete nodules (p = 0.008). Dysphonia recovery time was closely related to age (p = 0.000), duration of dysphonia (p = 0.000) and morphology of vocal nodules under laryngoscopy (p = 0.000).ConclusionVocal nodules are the most frequent cause of phonation disorders in children. The morphological classification by endoscopy may help with clinical diagnosis and therapy choice. In the case of the older child with longer duration of dysphonia and the appearance of mature, large, discrete nodules by laryngoscopy, active treatment is recommended, such as drug therapy, voice therapy or surgical treatment.

BackgroundAlthough traditional cardiovascular risk factors are closely related to the poor prognosis of acute myocardial infarction (AMI) patients, there are few studies on the relationship of serum phosphorus and calcium with prognosis in AMI patients. The relationship of serum phosphorus and calcium with prognostic biomarkers in AMI remains unclear.Methods and resultsA total of 3,891 AMI patients were enrolled from a prospective cohort study. We investigated the association of serum phosphorus and calcium with prognostic biomarkers. The risk of in-hospital heart failure (HF), post-discharge HF, all-cause mortality and cardiac mortality was estimated across quartiles of serum phosphorus and calcium levels. Serum phosphorus and calcium levels were associated with biomarkers of prognosis. Overall, 969 patients developed in-hospital HF during hospitalization, 549 patients developed post-discharge HF during a median follow-up of 12 months, and 252 patients died, with 170 cardiac deaths since admission. In the fully adjusted model, compared with patients in quartile 2 (Q2), patients with serum phosphorus levels in Q4 were at greater risk of post-discharge HF [sub-distributional hazard ratios (SHR) 1.55; 95% confidence interval (CI), 1.21–1.99], in-hospital HF [odds ratio (OR) 1.84; 95% CI, 1.47–2.31], all-cause mortality (HR 1.59; 95% CI, 1.08–2.32), and cardiac mortality (SHR 1.68; 95% CI, 1.03–2.75). Compared with patients in Q2, patients with corrected calcium levels in Q4 had a higher risk of in-hospital HF (OR 1.62; 95% CI, 1.29–2.04), all-cause mortality (HR 1.99; 95% CI, 1.37–2.88), and cardiac mortality (SHR 1.87; 95% CI, 1.19–2.96; all p-trend < 0.05).ConclusionSerum phosphorus and calcium levels were associated with AMI prognostic biomarkers in AMI. Higher serum phosphorus was independently related to the increased risk of in-hospital HF, postdischarge HF, all-cause mortality and cardiac mortality, and higher serum calcium was independently related to the increased risk of in-hospital HF, all-cause mortality and cardiac mortality after AMI.

Alzheimer's disease and epilepsy are common nervous system diseases in older adults, and their incidence rates tend to increase with age. Patients with mild cognitive impairment and Alzheimer's disease are more prone to have seizures. In patients older than 65 years, neurodegenerative conditions accounted for ~10% of all late-onset epilepsy cases, most of which are Alzheimer's disease. Epilepsy and seizure can occur in the early and late stages of Alzheimer's disease, leading to functional deterioration and behavioral alterations. Seizures promote amyloid-β and tau deposits, leading to neurodegenerative processes. Thus, there is a bi-directional association between Alzheimer's disease and epilepsy. Epilepsy is a risk factor for Alzheimer's disease and, in turn, Alzheimer's disease is an independent risk factor for developing epilepsy in old age. Many studies have evaluated the shared pathogenesis and clinical relevance of Alzheimer's disease and epilepsy. In this review, we discuss the clinical associations between Alzheimer's disease and epilepsy, including their incidence, clinical features, and electroencephalogram abnormalities. Clinical studies of the two disorders in recent years are summarized, and new antiepileptic drugs used for treating Alzheimer's disease are reviewed.

Abyssal flow pathways in the Yap Trench and adjacent regions were investigated by computing geostrophic flows and analyzing water properties. Using boundary values of potential temperature, salinity, oxygen, and silicate, the upper and lower Circumpolar Deep Waters (UCPW, LCPW) were identified as the main abyssal water masses in the trench. At the western East Mariana Basin, some of the LCPW enters the southern Mariana Trench, and the remainder reaches the northern basin and then partly turns to the northern Mariana Trench, eventually joining the southern trench. At the Yap-Mariana Junction, some LCPW enters the West Mariana Basin, and the remainder passes the region east of the Yap Trench and then flows or subsides to the northern and southern trenches, respectively. In the northern trench, the LCPW flows north into the West Mariana Basin. The UCPW enters the northern Yap Trench via the East Mariana Basin and the Mariana Trench, reaches the sill of the Yap Trench via the East Caroline Basin and a narrow channel, and enters the southern trench via the East/West Caroline and Philippine Basins. The UCPW and LCPW circulate anticlockwise in the southern trench and in the northern region of it, respectively. The LCPW may be driven by the downwelling in the trench.

BackgroundAnogenital distance (AGD) is a biomarker used for the evaluation of fetal androgen action. The disruption of fetal androgen action can affect the development of the reproductive system and adversely affect future reproductive functions. However, AGD may differ by race. Currently, there is a lack of data regarding the evaluation of AGD in large Han Chinese samples.ObjectiveAGD for neonates in Shanghai, China, was measured, and relevant factors that influenced AGD were analyzed.MethodsThe AGD of full-term singleton neonates was measured within 3 days of birth, and the results were grouped according to gestational age and body weight at birth. In addition, relevant factors that influenced AGD were investigated.ResultsA total of 1,867 full-term singleton neonates were enrolled in this study. All the neonates were Han Chinese; among them, 986 were male, and 881 were female. Male AGD was 23.18 ± 3.17 mm, and female AGD was 11.65 ± 1.53 mm. Male AGD was 1.99 times longer than female AGD. With the increase in gestational age and body weight, AGD gradually increased. AGD was correlated with gestational age, body weight, and head circumference. The correlation between body weight at birth and AGD was highly significant.ConclusionThis study, for the first time, reported AGD measurement data for Chinese Han neonates. The results indicated that AGD was correlated with gestational age, body weight, and head circumference. The correlation between body weight at birth and AGD was highly significant.

Bee pollen is known as a natural nutrient storehouse and plays a key role in many biological processes. Based on the preliminary separation, identification, and characterization of the main active components of Fagopyrum esculentum Moench. bee pollen (FBP), the protective effects of F. esculentum bee pollen extract (FBPE) on high-fat-diet (HFD) and streptozocin (STZ) induced type II diabetes mellitus (T2DM) was evaluated in this study. The results revealed that FBPE contains 10 active compounds mainly including luteolin (9.46 g/kg), resveratrol (5.25 g/kg), kaemferol (3.67 g/kg), etc. The animal experiment results showed that FBPE could improve HFD-STZ induced T2DM mice. Moreover, the underlying mechanism of the above results could be: (i) FBPE could reduce the inflammation related to phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, and (ii) the gut microbiota remodeling. The results of correlation analysis showed Candidatus Arthromitus and SMB53 indicated positive correlations to tumor necrosis factor-α (TNF-α); Coprococcus, Ruminocossus, and Odoribacteraceae reported negative correlations to transforming growth factor-β (TGF-β). That FBPE has an outstanding ability to improve T2DM and could be used as a kind of potential functional food for the prevention of T2DM.

Chronic inflammation affects many diseases and conditions, including aging. Interferons are a part of the immune defense against viral infections. Paradoxically, various aging tissues and organs from mammalian hosts perpetually accumulate changes brought by interferon pathway activation. Herein, we connote the mechanisms behind this phenomenon and discuss its implications in age-related pathology.

Tumor evolution is influenced by events involving tumor cells and the environment in which they live, known as the tumor microenvironment (TME). TME is a functional and structural niche composed of tumor cells, endothelial cells (ECs), cancer-associated fibroblasts (CAFs), mesenchymal stromal cells (MSCs), and a subset of immune cells (macrophages, dendritic cells, natural killer cells, T cells, B cells). Otto Warburg revealed the Warburg effect in 1923, a characteristic metabolic mechanism of tumor cells that performs high glucose uptake and excessive lactate formation even in abundant oxygen. Tumor tissues excrete a large amount of lactate into the extracellular microenvironment in response to TME’s hypoxic or semi-hypoxic state. High lactate concentrations in tumor biopsies have been linked to metastasis and poor clinical outcome. This indicates that the metabolite may play a role in carcinogenesis and lead to immune escape in TME. Lactate is now recognized as an essential carbon source for cellular metabolism and as a signaling molecule in TME, forming an active niche that influences tumor progression. This review summarized the advanced literature demonstrating the functional role of lactate in TME remodeling, elucidating how lactate shapes the behavior and the phenotype of both tumor cells and tumor-associated cells. We also concluded the intriguing interactions of multiple immune cells in TME. Additionally, we demonstrated how lactate functioned as a novel function factor by being used in a new histone modification, histone lysine lactylation, and to regulate gene expression in TME. Ultimately, because lactate created a favorable niche for tumor progression, we summarized potential anti-tumor strategies targeting lactate metabolism and signaling to investigate better cancer treatment.

The Ocean Drilling Program Site 1177 recovered the oldest (∼23 Ma) sedimentary records in the Shikoku Basin, northeastern part of the Philippine Sea Plate. Changes in sediment provenances bear important implications for the tectonic evolution of the Philippine Sea Plate, but existing data are still controversial for the early Miocene. By integrating Sr-Nd isotopes, rock-magnetic parameters, diffuse reflectance spectroscopy, and the previous data on the detrital zircons and clay minerals from Site 1177, we found that a significant provenance shift occurred at ∼16.5 Ma. The sediments of Site 1177 before ∼16.5 Ma were mainly sourced from the Pearl River and Izu-Bonin Arc, but changed to the Yangtze River and Izu-Bonin Arc sources after that. This provenance shift was strongly linked with the northward motion and clockwise rotation of the Shikoku Basin in the Miocene, which marked the final time of separation between the Shikoku Basin and the South China Sea.

Spiro-OMeTAD is the well-known hole transporting material (HTM) in perovskite solar cells. In this work, its derivatives, namely four D-A shaped triphenylamine or biphenylamine endcapped indenone spirofluorene (SFD-TPA, SFD-OMeTPA, SFD-TAD, and SFD-OMeTAD), were designed and synthesized. With the introduction of electron-donating moieties and the extension of conjugation length, a series of changes in photophysical and electrochemical properties could be detected. Notably, in comparison with the optical gap (2.96 eV) of the reported spiro-OMeTAD, SFD-OMeTAD presents an optical gap as low as 1.87 eV. Moreover, density functional theory simulations were employed to further investigate their geometric and electronic structures. Finally, steady-state photoluminescence measurements proved the efficient charge separation and collection processes at the perovskite/HTM interface. It can be predicted that all four compounds with enhanced sunlight absorption capability and suitable frontier energy levels can be used as hole-transporting materials for perovskite solar cells.

The Belt and Road Initiative (BRI) has had a significant impact on China in political, economic, and cultural terms. This study focuses on the cultural domain, especially on scholarship students from the countries that signed bilateral cooperation agreements with China under the BRI. Using an integrated approach combining the difference-in-differences method and the gravity model, we explore the correlation between the BRI and the increasing number of international scholarship students funded by the Chinese government, as well as the determinants of students' decision to study in China. The panel data from 2010 to 2018 show that the launch of BRI has had a positive impact on the number of scholarship students from BRI countries. The number of scholarship recipients from non-BRI countries also increased, but at a much slower rate than those from BRI countries. The sole exception is the United States, which has trended downward for both state-funded and self-funded students.

Biofilms formed on metal surfaces strongly affect metallic instruments serving in marine environments. However, due to sampling difficulty, less has been known about the bacterial communities of the biofilm on metallic surfaces in hadal environments, so the failure process of these deep-sea metallic instruments influenced by microbial communities could be hardly predicted. In this research, seven alloys, including titanium, aluminum, and copper alloys, were exposed in Yap Trench hadal environment for 1 year. Thus, the communities of the biofilms formed on metallic surfaces at 5,772 m undersea in Yap Trench were initially reported in previous studies. Then, 16S rRNA gene sequencing was performed to visualize the in situ bacterial communities of the biofilms formed on titanium, aluminum, and copper alloys at 5,772 m undersea in Yap Trench. It was found that Proteobacteria was the dominant phylum in all samples, but distinct genera were discovered on various alloys. The titanium alloy provided a suitable substrate for a mutualistic symbiotic biofilm with abundant bacterial richness. Aluminum alloys without copper components showed the least bacterial richness and formed a cold-adapted and oligotrophic-adapted biofilm containing the genera Sulfurimonas and PS1 Clade, while copper-present alloys showed relatively high bacterial richness with copper-resistant or even copper-utilizing biofilms constituting the genera Stenotrophomonas, Burkholderia-Caballeronia-Paraburkholderia, and Achromobacter on the surfaces. Furthermore, among all the element components contained in alloys investigated in this research, copper element showed the strongest influences on the composition and function of microbial communities in the biofilms formed on various metallic surfaces.

Introduction: Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive bone erosion on diarthrodial joints. RA patients usually experienced three stages before final diagnosis: the health period, the pre-clinical period (immune response exists without clinical symptoms), and the pre-RA period (immune response exists with mild inflammatory manifestation). Presently, there is seldom guidance referring to early intervention which is a benefit for stable disease conditions and low morbidity. Prophylactic treatment is a major feature of traditional Chinese medicine (TCM). In this present study, a multi-center, double-blind, placebo-controlled clinical trial is carried out to evaluate both efficacy and safety in preventing RA progression on Yunpi Qufeng Chushi formula (YQCF).Method: The multi-center, double-blind, placebo-controlled clinical trial is conducted in 13 hospitals nationwide. A total of 390 patients ages between 18 and 70 will be recruited in the trial. They will be randomly assigned to the intervention group (YQCF) and placebo group. The follow-up visit will be taken every 3 months from baseline to 1 year. Diagnosis, disease activity scores, clinical disease activity index (CDAI), simplified disease activity index (SDAI), TCM syndrome scores, and safety assessments will be recorded at every visit. Joint color doppler ultrasound, health assessment questionnaire-disability index (HAQ-DI), and functional assessment of chronic illness therapy-fatigue (FACIT-F) will be recorded at baseline and the last visit.Discussion: This work will provide evidence of YQCF in preventing RA progression. However, whether early intervention would benefit the controlling RA disease still needs a long-term follow-up.Ethics and dissemination: Protocol version 2 (201910-1). This research was approved by the medical ethics committee of Zhejiang Chinese Medical University (2019-045). Results will be published in a peer-reviewed academic journal.Trial registration numbers:http://www.chictr.org.cn/index.aspx, ChiCTR1900024166.

Salinity can affect the physiological and productive characteristics of bivalves. The razor clam Sinonovacula constricta naturally distributing in intertidal zones and estuarine waters is extensively cultured in China. High-salinity is a serious threat to its culture, especially in pond culture model. Here, we investigated the effects of high-salinity on the survival, gill tissue, enzyme activity and free amino acid content of S. constricta. Individuals were randomly divided into six groups treated with different salinities of 20, 25, 30, 35, 40, and 45 ppt. The median lethal salinity calculated by linear regression and probit analysis methods were similar, with 46.61, 43.17, 36.99, 35.99, and 34.99 ppt by linear regression, while 44.63, 42.87, 38.45, 37.32, and 36.17 ppt by probit analysis at 72, 96, 120, 144, and 168 h, respectively. Furthermore, paraffin section revealed that the gill of razor clam shrunk quickly under high-salinity and dissolved at 48 h under salinity of 40 ppt, but not under 30 ppt. In addition, the activities of three enzymes including Na+-K+-ATPase, acid phosphatase and alkaline phosphatase changed significantly under high-salinity. Besides, the contents of total free amino acids (TFAAs) in the gill tissues were 61.25 ± 1.58, 89.36 ± 4.18, and 111.98 ± 1.46 mg⋅g–1 at salinity of 20, 30, and 40 ppt, respectively, indicating increasing TFAA contents with salinity. Notably, several amino acid species including taurine, alanine, proline, glycine and glutamic showed significantly changed contents in response to salinity variation, suggesting these amino acids might play an important role in razor clam’s adaptation to salinity stress. Combining all these results, it was referred that razor clams may adapt to moderately high-salinity of 30 ppt in a short time through osmotic adjustment. Although a small proportion of individuals could survive under the salinity of 35 ppt, the death of most individuals still suggested it can hardly be accepted in aquacultural production. Notably, living under a salinity of 40 ppt for more than 48 h could cause great damage to razor clams. Therefore, the seawater salinity is recommended to be lower than 30 ppt for S. constricta aquaculture. Overall, this study provides guidance for the culture and breeding of high-salinity tolerant razor clams.