The impact of vedolizumab therapy on extraintestinal manifestations in patients with inflammatory bowel disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: Extraintestinal manifestations (EIMs) pose a significant threat in inflammatory bowel disease (IBD) patients. Vedolizumab (VDZ) primarily affects the gastrointestinal tract. However, its impact on EIMs remains uncertain. Therefore, we conducted this meta-analysis to examine the effects of VDZ on EIMs during treatment. METHODS: Relevant studies were identified by conducting thorough searches across electronic databases, including PubMed, Ovid Embase, Medline, and Cochrane CENTRAL. Primary outcomes focused on the proportion of patients with resolution for pre-existing EIMs in IBD patients receiving VDZ. Secondary outcomes included the proportion of patients with EIM exacerbations and new onset EIMs during VDZ treatment. RESULTS: Our meta-analysis encompassed 21 studies. The proportion of patients with resolution of pre-existing EIMs in VDZ-treated IBD patients was 39% (150/386; 95% confidence interval [CI] 0.31-0.48). The proportion of patients with EIM exacerbations occurred at a rate of 28% (113/376; 95% CI 0.05-0.50), while new onset EIMs had a rate of 15% (397/2541; 95% CI 0.10-0.20). Subgroup analysis revealed a 40% (136/337) proportion of patients with resolution for articular-related EIMs and a 50% (9/18) rate for erythema nodosum. Exacerbation rates for arthritis/arthralgia, erythema nodosum/pyoderma gangrenosum, and aphthous stomatitis during VDZ use were 28% (102/328), 18% (7/38), and 11% (3/28), respectively. The incidence rate of newly developed EIMs during treatment was 11% (564/4839) for articular-related EIMs, with other EIMs below 2%. CONCLUSION: VDZ demonstrates efficacy in skin-related EIMs like erythema nodosum and joint-related EIMs including arthritis, arthralgia, spondyloarthritis, and peripheral joint diseases. Some joint and skin-related EIMs may experience exacerbation during VDZ therapy.

Metabolic Control During Macrophage Polarization by a Citrate-Functionalized Scaffold for Maintaining Bone Homeostasis.

Metabolites, as markers of phenotype at the molecular level, can regulate the function of DNA, RNA, and proteins through chemical modifications or interactions with large molecules. Citrate is an important metabolite that affects macrophage polarization and osteoporotic bone function. Therefore, a better understanding of the precise effect of citrate on macrophage polarization may provide an effective alternative strategy to reverse osteoporotic bone metabolism. In this study, a citrate functional scaffold to control the metabolic pathway during macrophage polarization based on the metabolic differences between pro-inflammatory and anti-inflammatory phenotypes for maintaining bone homeostasis, is fabricated. Mechanistically, only outside M1 macrophages are accumulated high concentrations of citrate, in contrast, M2 macrophages consume massive citrate. Therefore, citrate-functionalized scaffolds exert more sensitive inhibitory effects on metabolic enzyme activity during M1 macrophage polarization than M2 macrophage polarization. Citrate can block glycolysis-related enzymes by occupying the binding-site and ensure sufficient metabolic flux in the TCA cycle, so as to turn the metabolism of macrophages to oxidative phosphorylation of M2 macrophage, largely maintaining bone homeostasis. These studies indicate that exogenous citrate can realize metabolic control of macrophage polarization for maintaining bone homeostasis in osteoporosis.

Effectiveness and safety of upadacitinib for inflammatory bowel disease: A systematic review and meta-analysis of RCT and real-world observational studies.

BACKGROUND: Upadacitinib, a novel and selective inhibitor of Janus kinase 1, has demonstrated promising efficacy in managing inflammatory bowel disease (IBD). In this systematic review and meta-analysis, our primary aim was to comprehensively assess the therapeutic effectiveness and safety profile of upadacitinib in the treatment of patients with IBD. METHODS: We conducted an extensive literature search across prominent databases, including Medline, Embase, Web of Science, and Cochrane Central, to identify pertinent studies providing insights into the efficacy and safety of upadacitinib in IBD. The primary endpoint was the achievement of clinical remission, while secondary endpoints encompassed clinical response, endoscopic response, endoscopic remission, and the evaluation of adverse events (AEs). RESULTS: In this meta-analysis of nine studies, we categorized results by study type. Clinical remission rates were: RCTs 36 % (95 % CI = 30-42 %), real-world studies 25 % (95 % CI = 1-49 %), retrospective studies 40 % (95 % CI = 24-56 %), cohort studies 55 % (95 % CI = 25-85 %). Clinical response rates were: RCTs 61 % (95 % CI = 55-67 %), real-world studies 42 % (95 % CI = 14-70 %), cohort studies 65 % (95 % CI = 57-73 %). Endoscopic remission rates were: RCTs 19 % (95 % CI = 15-24 %), cohort studies 29 % (95 % CI = 5-52 %). Endoscopic response rates were: RCTs 41 % (95 % CI = 36-47 %), cohort studies 57 % (95 % CI = 31-83 %). Incidence rate for any AEs: IBD 69 % (95 % CI = 63-76 %), UC 65 % (95 % CI = 57-74 %), CD 75 % (95 % CI = 67-82 %). CONCLUSION: Cumulative data from real-world studies and trials confirm the efficacy of upadacitinib in IBD induction and maintenance, with consistent safety. However, further long-term studies are needed to understand its sustained effectiveness and safety.

Regulatory effects of Hemin on prevention and rescue of salt stress in rapeseed (Brassica napus L.) seedlings.

BACKGROUND: Salt stress severely restricts rapeseed growth and productivity. Hemin can effectively alleviate salt stress in plants. However, the regulatory effect of Hemin on rapeseed in salt stress is unclear. Here, we analyzed the response and remediation mechanism of Hemin application to rapeseed before and after 0.6% (m salt: m soil) NaCl stress. Experiment using two Brassica napus (AACC, 2n = 38) rapeseed varieties Huayouza 158R (moderately salt-tolerant) and Huayouza 62 (strongly salt-tolerant). To explore the best optional ways to improve salt stress resistance in rapeseed. RESULTS: Our findings revealed that exogenous application of Hemin enhanced morph-physiological traits of rapeseed and significantly attenuate the inhibition of NaCl stress. Compared to Hemin (SH) treatment, Hemin (HS) significantly improved seedlings root length, seedlings height, stem diameter and accumulated more dry matter biomass under NaCl stress. Moreover, Hemin (HS) significantly improved photosynthetic efficiency, activities of antioxidant enzymes such as superoxide dismutase (SOD), peroxidase (POD), ascorbate peroxidase (APX), and decreased electrolyte leakage (EL) and malondialdehyde (MDA) content, thus resulting in the alleviation of oxidative membrane damage. Hemin (HS) showed better performance than Hemin (SH) under NaCl stress. CONCLUSION: Hemin could effectively mitigate the adverse impacts of salt stress by regulating the morph-physiological, photosynthetic and antioxidants traits of rapeseed. This study may provide a basis for Hemin to regulate cultivated rapeseed salt tolerance and explore a better way to alleviate salt stress.

Combined transcriptomic and metabolomic analysis of alginate oligosaccharides alleviating salt stress in rice seedlings.

BACKGROUND: Salt stress is one of the key factors limiting rice production. Alginate oligosaccharides (AOS) enhance plant stress resistance. However, the molecular mechanism underlying salt tolerance in rice induced by AOS remains unclear. FL478, which is a salt-tolerant indica recombinant inbred line and IR29, a salt-sensitive rice cultivar, were used to comprehensively analyze the effects of AOS sprayed on leaves in terms of transcriptomic and metabolite profiles of rice seedlings under salt stress. RESULTS: In this experiment, exogenous application of AOS increased SOD, CAT and APX activities, as well as GSH and ASA levels to reduce the damage to leaf membrane, increased rice stem diameter, the number of root tips, aboveground and subterranean biomass, and improved rice salt tolerance. Comparative transcriptomic analyses showed that the regulation of AOS combined with salt treatment induced the differential expression of 305 and 1030 genes in FL478 and IR29. The expressed genes enriched in KEGG pathway analysis were associated with antioxidant levels, photosynthesis, cell wall synthesis, and signal transduction. The genes associated with light-trapping proteins and RLCK receptor cytoplasmic kinases, including CBA, LHCB, and Lhcp genes, were fregulated in response to salt stress. Treatment with AOS combined with salt induced the differential expression of 22 and 50 metabolites in FL478 and IR29. These metabolites were mainly related to the metabolism of amino and nucleotide sugars, tryptophan, histidine, and ß -alanine. The abundance of metabolites associated with antioxidant activity, such as 6-hydroxymelatonin, wedelolactone and L-histidine increased significantly. Combined transcriptomic and metabolomic analyses revealed that dehydroascorbic acid in the glutathione and ascorbic acid cycles plays a vital role in salt tolerance mediated by AOS. CONCLUSION: AOS activate signal transduction, regulate photosynthesis, cell wall formation, and multiple antioxidant pathways in response to salt stress. This study provides a molecular basis for the alleviation of salt stress-induced damage by AOS in rice.

Physiological mechanism of exogenous brassinolide alleviating salt stress injury in rice seedlings.

Brassinolide (BR) is a sterol compound, which can regulate plant seed germination, flowering, senescence, tropism, photosynthesis, stress resistance, and is closely related to other signaling molecules. This study aimed to evaluate the ability of soaking with BR to regulate growth quality at rice seedling stage under salt stress. Results demonstrated that salt stress increases the contents of ROS, MDA, Na+ and ABA, reduces the the SPAD value, net photosynthetic rate (Pn), stomatal conductance (Gs), transpiration rate (Tr), maximum fluorescence (Fm), variable fluorescence (Fv), the effective photochemical efficiency of PSII (Fv/Fo) and the maximum photochemical efficiency of PSII (Fv/Fm), reduces the biomass production and inhabits plant growth. All of these responses were effectively alleviated by BR soaking treatment. Soaking with BR could increase the activities of superoxide dismutase, peroxidase, catalase, ascorbate peroxidase, and the contents of ascorbic acid, glutathione as well as soluble protein and proline, while BR soaking treatment inhibited the accumulation of ROS and reduced the content of MDA. BR soaking significantly reduced the contents of Na+ and increased the contents of K+ and Ca2+, indicating that soaking with BR is beneficial to the excretion of Na+, the absorption of K+ and Ca2+ and the maintenance of ion balance in rice seedlings under salt stress. BR also maintained endogenous hormone balance by increasing the contents of indoleacetic acid (IAA), zeatin (ZT), salicylic acid (SA), and decreasing the ABA content. Soaking with BR significantly increased the SPAD value, Pn and Tr and enhanced the Fm, Fv/Fm and Fv/Fo of rice seedlings under NaCl stress, protected the photosythetic system of plants, and improved their biomass. It is suggested that BR was beneficial to protect membrane lipid peroxidation, the modulation of antioxidant defense systems, ion balance and endogenous hormonal balance with imposition to salt stress.

Enhanced prediction performance of a time-delay reservoir computing system based on a VCSEL by dual-training method.

In this paper, a new dual-training method for a time-delay reservoir computing (RC) system based on a single vertical-cavity surface-emitting laser (VCSEL) is proposed and demonstrated experimentally for the first time. The prediction performance of the RC system by using the dual-training method has been experimentally and numerically investigated. Here, the dual-training method is defined as performing a further RC based on the difference between the target value and the predicted value of the traditional single training. It is found that enhanced prediction performance of the RC system can be obtained by employing the dual-training method, compared to the traditional single training method. More specifically, the NMSE values of the RC system with the dual-training method applied can be improved to 760% compared with the single training method in experiments. Besides, the effects of injection power, bias currents, feedback strength, and frequency detuning are also considered. The proposed dual-training method is of great significance to the performance enhancement of the RC and has an important promotion effect on the application of the RC in the future.

VmMon1-Ccz1 Complex Is Required for Conidiation, Autophagy, and Virulence in Valsa mali.

Apple Valsa canker caused by Valsa mali is a serious disease in eastern Asia, especially in China. In our previous proteomics study, monensin sensitivity 1 protein in Valsa mali (VmMon1) was identified to be significantly upregulated during V. mali infection. It was reported Mon1 protein formed a heterodimer called MC (Mon1-Ccz1) complex with caffeine, calcium, and zinc sensitivity 1 protein (Ccz1) in yeast. However, Ccz1 had not been identified in plant-pathogenic fungi such as Fusarium graminearum and Magnaporthe oryzae. Here, we identified a Ccz1 ortholog VmCcz1 in V. mali, by using DELTA-BLAST. The interaction of VmMon1 and VmCcz1 were verified using yeast two-hybrid assay, bimolecular fluorescence complementation, and co-immunoprecipitation assays. Further yeast three-hybrid screenings determined that VmRab7 (Ras-related protein in V. mali) interacted with the MC complex. Targeted gene deletion showed that the ∆VmMon1 and ∆VmCcz1 mutants were defective in vegetative growth, conidiation, and pathogenicity. In addition, both mutants were more sensitive to osmotic and oxidative stresses and intracellular protein transport inhibitors. Cytological examination revealed that the ∆VmMon1 and ∆VmCcz1 mutants were impaired in vacuole fusion and autophagy. More importantly, expression of pectinase genes decreased in both mutants compared with those of the wild type during infection. Overall, our study identified Mon1 and Ccz1 genes in V. mali and provided evidence that VmMon1 and VmCcz1 are critical components that modulate vacuole fusion and autophagy, thereby affecting the development, conidiation, and pathogenicity of V. mali. [Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Folic acid-functionalized L-cys/ZnS:O nanoparticles for homologous targeting and photodynamic therapy of tumor cells.

The combination of photodynamic therapy (PDT) and fluorescence imaging provides a promising approach to theranostics. However, traditional photosensitizers (PSs) have low water solubility and lack active targeting ability. Our ingenious design used L-cys/ZnS:O (LZS) nanoparticles (NPs) modified with folic acid (FA), allowing them to easily enter tumor cells and accurately gather around the nucleus of cancer cells. L-Cysteine were used as intermediates, ZnS:O quantum dots and FA could be connected by a solid-state method and a coupling reaction. In doing so, the cytotoxicity of LZS NPs was further reduced, while the hydrophilicity and dispersibility were improved. Moreover, the as-synthesized FA@LZS NPs had a higher generation of reactive oxygen species (ROS) than commercial Ce6, and they killed HepG2 cells specifically in vitro. These findings give a clear way for the development of advanced PSs with homologous labeling functions. A template for NPs or other fluorophores modified by targeting groups is also provided.

[Differences in light and heat utilization efficiency and yield of soybean in two ecological zones and their response to chemical control regulators]. / ä¸¤ä¸ªç”Ÿæ€åŒºå¤§è±†å ‰çƒ­èµ„æºåˆ©ç”¨çŽ‡å’Œäº§é‡çš„å·®å¼‚åŠå¯¹åŒ–æŽ§å‰‚çš„å“åº”.

The field experiment was conducted at two farms at Jiusan in Heihe (the fourth accumulated temperature zone) and at Lindian County of Daqing (the second accumulated temperature zone), both sites located in Heilongjiang Province, China. With soybean Kenfeng 41 as the test material, uniconazole (S3307, 50 mg·L-1) and 2-N, N- diethylamino ethyl caproate (DTA-6, 50 mg·L-1) were sprayed on leaves in the early flowering period of soybean. Through grey correlation analysis, the main factors affecting soybean yield were examined, and the differences of the light and heat utilization efficiency and soybean yield in two ecological conditions were compared. The regulation effects of chemical control technology on the light and heat utilization efficiency of soybean were explored. The results showed that the total surface radiation and ≥10 ℃ effective accumulated temperature were the main factors affecting soybean yield in both areas compared with rainfall and sunshine hours. The light and heat utilization efficiency from sowing to flowering period was significantly positively correlated with dry matter accumulation, and that from flowering to podding period was significantly positively correlated with dry matter accumulation per plant. There was a significant positive correlation between yield and dry matter accumulation, grain number per plant, grain mass per plant and 100-grain mass at seedling stage to podding stage. S3307 and DTA-6 could significantly improve light and heat utilization efficiency and soybean yield in both areas. S3307 showed the better regulation function to impact the light and heat utilization efficiency and yield than DTA-6 in both sites. In the two ecological areas of Jiusan and Lindian, spraying S3307 increased light utilization efficiency by 13.6% and 17.1%, and increased heat utilization efficiency by 14.1% and 17.2%, respectively. The yield by spraying S3307 was increased by 14.1% and 17.3% separately in Jiusan and Lindian. Therefore, it is the effective way to enhance resources utilization and achieve high-yield by using the reasonable chemical control technology.

[Comparison of growth and field microclimate characteristics of broomcorn millet under different fertilization conditions].

A field experiment with two broomcorn millet varieties Longmi 8 (strong drought-resistant variety) and Jinmi 4 (drought-sensitive variety) was conducted to compare their differences in growth, field microclimate and photosynthetic capacity from anthesis to maturity under different fertility conditions. The results showed that, fertilization decreased canopy temperature, air temperature, soil temperature, illumination, but improved the relative humidity among broomcorn millet plants compared with the non-fertilization treatment. With an increase of the fertilizer level, the plant height, SPAD, LAI, net photosynthetic rate, transpiration rate, stomatal conductance, intercellular CO2 concentration in broomcorn millet showed an increasing trend, which of the high fertilization treatment were 9.2%, 15.1%, 56.6%, 17.8%, 24.6%, 14.2%, 29.7% higher than those of non-fertilization treatment, respectively. Compared with Jinmi 4, Longmi 8 showed a cold wet characteristic, with lower canopy temperature, air temperature, soil temperature; illumination, and higher plant height, LAI, SPAD and relative humidity during grain filling. Moreover, each photosynthetic index of Longmi 8 slowly decreased and extended the period of leaf photosynthetic function so as to accumulate more photosynthetic products.

Analysis of promoters of microRNAs from a Glycine max degradome library.

OBJECTIVE: MicroRNAs (miRNAs) are genome-encoded, small non-coding RNAs that play important functions in development, biotic and abiotic stress responses, and other processes. Our aim was to explore the regulation of miRNA expression. METHODS: We used bioinformatics methods to predict the core promoters of 440 miRNAs identified from a soybean (Glycine max) degradome library and to analyze cis-acting elements for 369 miRNAs. RESULTS: The prediction results showed that 83.86% of the 440 miRNAs contained promoters in their upstream sequences, and 8.64% (38 loci) in their downstream sequences. The distributions of two core promoter elements, TATA-boxes and transcription start sites (TSSs), were similar. The cis-acting elements were examined to provide clues to the function and regulation of spatiotemporal expression of the miRNAs. Analyses of miRNA cis-elements and targets indicated a potential auxin response factor (ARF)- and gibberellin response factor (GARF)-mediated negative feedback loop for miRNA expression. CONCLUSIONS: The features of miRNAs from a Glycine max degradome library obtained here provide insights into the transcription regulation and functions of miRNAs in soybean.

Treatment with vector-expressed small hairpin RNAs against Ki67 RNA-induced cell growth inhibition and apoptosis in human renal carcinoma cells.

Short hairpin RNAs (shRNAs) transcribed by RNA polymerase III promoters can trigger sequence-selective gene silencing in mammalian cells. By virtue of their excellent function in knocking down expression of cancer-associated genes, shRNAs could be used as new therapeutic agents for cancer. As overexpression of Ki67 in renal cancer has been correlated to a more aggressive tumor phenotype, inhibition of Ki67 protein expression by means of shRNAs seems to be a promising approach for the therapy of renal cancer. In this study, we constructed an expression plasmid encoding shRNAs against the Ki67 gene, named pSilencerKi67, and transfected it into human renal carcinoma cells. The pSilencerKi67 was shown to significantly knock down the expression of the Ki67 gene in human renal carcinoma cells, resulting in inhibiting proliferation and inducing apoptotic cell death that can be maintained for at least 6 d. These findings offer the promise of using vector-based shRNAs against Ki67 in renal cancer gene therapy.

Utilization of public mental health services by adults with serious mental illness.

Public mental health (MH) services were examined for non-elderly adults with serious mental illness (SMI) using a database combining information from Medicaid, MH, and substance abuse agencies in three states. These data show that between 23% and 39% of those with SMI received MH services only through Medicaid. Relative use of community versus state hospitals for delivery of psychiatric inpatient care varied across the three states. However, state hospitals accounted for a large proportion of total inpatient days, due to high mean annual days of care. In two states, Medicaid paid for fewer psychiatric inpatient days than expected.

Utilization of public mental health services by children with serious emotional disturbances.

The Integrated Database (IDB) was created to provide a broad picture of the use of state-funded mental health (MH) and substance abuse (SA) services. Assembled separately for three states (Delaware, Oklahoma, and Washington), the IDB links client-level and service-level data maintained by the state MH, SA, and Medicaid agencies. This study used the IDB to examine public MH services for children with serious emotional disturbances (SED) in 1996. Children with SED represented 9% to 22% of all children with MH service use. Between one half and two thirds of children with SED received psychotropic medication; 20% to 40% had a MH inpatient or residential stay. Medicaid was the primary funder of MH services for children with SED; only 2% to 12% of children with SED received services solely through the state MH agency.