TAF5L and TAF6L Maintain Self-Renewal of Embryonic Stem Cells via the MYC Regulatory Network.

Self-renewal and pluripotency of the embryonic stem cell (ESC) state are established and maintained by multiple regulatory networks that comprise transcription factors and epigenetic regulators. While much has been learned regarding transcription factors, the function of epigenetic regulators in these networks is less well defined. We conducted a CRISPR-Cas9-mediated loss-of-function genetic screen that identified two epigenetic regulators, TAF5L and TAF6L, components or co-activators of the GNAT-HAT complexes for the mouse ESC (mESC) state. Detailed molecular studies demonstrate that TAF5L/TAF6L transcriptionally activate c-Myc and Oct4 and their corresponding MYC and CORE regulatory networks. Besides, TAF5L/TAF6L predominantly regulate their target genes through H3K9ac deposition and c-MYC recruitment that eventually activate the MYC regulatory network for self-renewal of mESCs. Thus, our findings uncover a role of TAF5L/TAF6L in directing the MYC regulatory network that orchestrates gene expression programs to control self-renewal for the maintenance of mESC state.

Leveraging intracellular ALDH1A1 activity for selective cancer stem-like cell labeling and targeted treatment via in vivo click reaction.

Inhibition of overexpressed enzymes is among the most promising approaches for targeted cancer treatment. However, many cancer-expressed enzymes are "nonlethal," in that the inhibition of the enzymes' activity is insufficient to kill cancer cells. Conventional antibody-based therapeutics can mediate efficient treatment by targeting extracellular nonlethal targets but can hardly target intracellular enzymes. Herein, we report a cancer targeting and treatment strategy to utilize intracellular nonlethal enzymes through a combination of selective cancer stem-like cell (CSC) labeling and Click chemistry-mediated drug delivery. A de novo designed compound, AAMCHO [N-(3,4,6-triacetyl- N-azidoacetylmannosamine)-cis-2-ethyl-3-formylacrylamideglycoside], selectively labeled cancer CSCs in vitro and in vivo through enzymatic oxidation by intracellular aldehyde dehydrogenase 1A1. Notably, azide labeling is more efficient in identifying tumorigenic cell populations than endogenous markers such as CD44. A dibenzocyclooctyne (DBCO)-toxin conjugate, DBCO-MMAE (Monomethylauristatin E), could next target the labeled CSCs in vivo via bioorthogonal Click reaction to achieve excellent anticancer efficacy against a series of tumor models, including orthotopic xenograft, drug-resistant tumor, and lung metastasis with low toxicity. A 5/7 complete remission was observed after single-cycle treatment of an advanced triple-negative breast cancer xenograft (~500 mm3).

Single hormone or synthetic agonist induces Gs/Gi coupling selectivity of EP receptors via distinct binding modes and propagating paths.

To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, Sci STKE 2001, re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, Nature 402, 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, Nature 390, 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that Gs-biased signaling, but not Gi activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-Gi, EP4-Gs, and EP4-Gi in complex with endogenous prostaglandin E2 (PGE2)or two synthetic agonists and comparing with PGE2-EP2-Gs structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the Gs/Gi transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE2 ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their Gs/Gi coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for Gs/Gi coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.

Discovery of Natural Products Alleviating Renal Fibrosis with a Viscosity-Responsive Molecular Probe.

Renal fibrosis poses a significant threat to individuals suffering from chronic progressive kidney disease. Given the absence of effective medications for treating renal fibrosis, it becomes crucial to assess the extent of fibrosis in real time and explore the development of novel drugs with substantial therapeutic benefits. Due to the accumulation of renal tissue damage and the uncontrolled deposition of fibrotic matrix during the course of the disease, there is an increase in viscosity both intracellularly and extracellularly. Therefore, a viscosity-sensitive near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging probe, BDP-KY, was developed to detect aberrant changes in viscosity during fibrosis. Furthermore, BDP-KY has been applied to screen the effective components of herbal medicine, rhubarb, resulting in the identification of potential antirenal fibrotic compounds such as emodin-8-glucoside and chrysophanol 8-O-glucoside. Ultrasound, PA, and NIRF imaging of a unilateral uretera obstruction mice model show that different concentrations of emodin-8-glucoside and chrysophanol 8-O-glucoside effectively reduce viscosity levels during the renal fibrosis process. The histological results showed a significant decrease in fibrosis factors α-smooth muscle actin and collagen deposition. Combining these findings with their pharmacokinetic characteristics, these compounds have the potential to fill the current market gap for effective antirenal fibrosis drugs. This study demonstrates the potential of BDP-KY in the evaluation of renal fibrosis, and the two identified active components from rhubarb hold great promise for the treatment of renal fibrosis.

A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2.

The ideal vaccine against viruses such as influenza and SARS-CoV-2 must provide a robust, durable and broad immune protection against multiple viral variants. However, antibody responses to current vaccines often lack robust cross-reactivity. Here we describe a polymeric Toll-like receptor 7 agonist nanoparticle (TLR7-NP) adjuvant, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses. When mixed with alum-adsorbed antigens, this TLR7-NP adjuvant elicits cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8+ T-cell responses in mice. This TLR7-NP-adjuvanted influenza subunit vaccine successfully protects mice against viral challenge of a different strain. This strategy also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple viral variants that have emerged. Moreover, this TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve immune responses to viral antigens, with promising implications for developing broadly protective vaccines.

Nitrogen-mediated volatilisation of defensive metabolites in tomato confers resistance to herbivores.

Plants synthesise a vast array of volatile organic compounds (VOCs), which serve as chemical defence and communication agents in their interactions with insect herbivores. Although nitrogen (N) is a critical resource in the production of plant metabolites, its regulatory effects on defensive VOCs remain largely unknown. Here, we investigated the effect of N content in tomato (Solanum lycopersicum) on the tobacco cutworm (Spodoptera litura), a notorious agricultural pest, using biochemical and molecular experiments in combination with insect behavioural and performance analyses. We observed that on tomato leaves with different N contents, S. litura showed distinct feeding preference and growth and developmental performance. Particularly, metabolomics profiling revealed that limited N availability conferred resistance upon tomato plants to S. litura is likely associated with the biosynthesis and emission of the volatile metabolite α-humulene as a repellent. Moreover, exogenous application of α-humulene on tomato leaves elicited a significant repellent response against herbivores. Thus, our findings unravel the key factors involved in N-mediated plant defence against insect herbivores and pave the way for innovation of N management to improve the plant defence responses to facilitate pest control strategies within agroecosystems.

Diversification of freshwater crabs on the sky islands in the Hengduan Mountains Region, China.

The numerous naturally-fragmented sky islands (SIs) in the Hengduan Mountains Region (HMR) of southwestern China constitute discontinuous landscapes where montane habitats are isolated by dry-hot valleys which have fostered exceptional species diversification and endemicity. However, studies documenting the crucial role of SI on the speciation dynamics of native freshwater organisms are scarce. Here we used a novel set of comprehensive genetic markers (24 nuclear DNA sequences and complete mitogenomes), morphological characters, and biogeographical information to reveal the evolutionary history and speciation mechanisms of a group of small-bodied montane potamids in the genus Tenuipotamon. Our results provide a robustly supported phylogeny, and suggest that the vicariance events of these montane crabs correlate well with the emergence of SIs due to the uplift of the HMR during the Late Oligocene. Furthermore, ancestrally, mountain ridges provided corridors for the dispersal of these montane crabs that led to the colonization of moist montane-specific habitats, aided by past climatic conditions that were the crucial determinants of their evolutionary history. The present results illustrated that the mechanisms isolating SIs are reinforced by the harsh-dry isolating climatic features of dry-hot valleys separating SIs and continue to affect local diversification. This offers insights into the causes of the high biodiversity and endemism shown by the freshwater crabs of the HMR-SIs in southwestern China.

Micronutrients and Allergic Diseases: A Mendelian Randomization Study.

INTRODUCTION: Previous studies have indicated a controversy regarding the association between dietary micronutrient concentrations and the risk of allergic diseases. In this study, we employed Mendelian randomization (MR) analysis using data from two samples to investigate the causal relationship between circulating micronutrient concentrations and three allergic diseases. METHODS: In this study, we considered 16 circulating micronutrients as exposure variables (beta carotene, calcium, copper, folate, iron, lycopene, magnesium, phosphorus, selenium, vitamin A1, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, and zinc); and three common allergic diseases (allergic asthma [AA], atopic dermatitis [AD], and allergic rhinitis [AR]) as outcomes. The inverse variance weighted (IVW) method was primarily applied for MR analysis, supplemented by MR-Egger and weighted-median methods to corroborate the IVW results; and sensitivity analysis was conducted to ensure the robustness of the MR assumptions. RESULTS: Our results revealed that an increase in serum phosphorus and zinc concentrations may diminish the risk of AA, while for AD an increase in serum zinc concentration may reduce the risk, but an increase in serum vitamin C concentration may elevate the risk. As for AR, an increase in serum phosphorus and selenium concentrations appeared to be associated with a reduced risk. We did not find evidence for an association between other micronutrients and the risk of allergic diseases. CONCLUSION: Our study indicates that an increase in serum phosphorus and zinc concentrations may reduce the risk of AA, while an increase in serum zinc concentration may reduce the risk of AD, but an increase in serum vitamin C concentration may elevate the risk of AD. An increase in serum phosphorus and selenium concentrations is associated with a reduced risk of AR. This provides additional support for research on the effects of micronutrients on allergic diseases.

The Impact of Hydrogen Sulfide in the Paraventricular Nucleus on the MAPK Pathway in High Salt-Induced Hypertension.

The hypothalamic paraventricular nucleus (PVN) plays a central role in regulating cardiovascular activity and blood pressure (BP). We administered hydroxylamine hydrochloride (HA), a cystathionine-ß-synthase (CBS) inhibitor, into the PVN to suppress endogenous hydrogen sulfide (H2S) and investigate its effects on the mitogen-activated protein kinase (MAPK) pathway in high salt-induced hypertension. We randomly divided 40 male Dahl salt-sensitive rats into 4 groups: the NS+PVN vehicle group, the NS+PVN HA group, the HS+PVN vehicle group, and the HS+PVN HA group, with 10 rats in each group. The rats in the NS (normal salt) groups were fed a normal-salt diet containing 0.3% NaCl, while the HS (high salt) groups were fed a high-salt diet containing 8% NaCl. The mean arterial pressure (MAP) was calculated after noninvasive measurement using an automatic sphygmomanometer to occlude the tail cuff once a week. HA or vehicle was infused into the bilateral PVN using Alzet osmotic mini-pumps for 6 weeks after the hypertension model was successfully established. We measured the levels of H2S in the PVN and plasma norepinephrine (NE) using ELISA. Additionally, we assessed the parameters of the MAPK pathway, inflammation, and oxidative stress through western blotting, immunohistochemical analysis, or real-time PCR. In the current study, we discovered that decreased levels of endogenous hydrogen sulfide in the PVN contributed to the onset of high salt-induced hypertension. This was linked to the activation of the MAPK signaling pathway, proinflammatory cytokines, and oxidative stress in the PVN, as well as the activation of the sympathetic nervous system.

A novel method for evaluating pseudoallergy based on ß-hexosaminidase and its application for traditional Chinese medicine injections.

Pseudoallergy is a typical and common adverse drug reaction to injections, especially in traditional Chinese medicine injections (TCMIs). At present, the evaluation methods for pseudoallergy include cell methods in vitro and animal methods in vivo. The mast cell evaluation method based on the ß-hexosaminidase (ß-Hex)-catalyzed substrate, 4-nitrophenyl-ß-N-acetyl-D-glucosaminide (4-NPG), is an important method for the evaluation of drug-induced pseudoallergy, but it is prone to false positive results and has insufficient sensitivity. In this study, a novel ß-Hex evaluation system with rat basophilic leukemia-2H3 cells based on high-performance liquid chromatography-fluorescence detection (HPLC-FLD) was established, which effectively increased the sensitivity and avoided false positive results. Cell viabilities were measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide assay. In addition, a method for the determination of histamine, which is another indicator in the development of pseudoallergy, was established to validate the above method. The results of this novel method indicated that two TCMIs (Shuxuening injection and Shenqi Fuzheng injection), which were considered to be pseudoallergenic using 4-NPG, were not pseudoallergenic. Overall, the novel ß-Hex/HPLC-FLD evaluation system using Rat basophilic leukemia-2H3 cells established was effective and precise. It could be used for the evaluation of pseudoallergic reactions caused by TCMIs and other injections.

[Value of SOX1 and PAX1 Gene Methylation Detection in Secondary Triage of High-Grade Cervical Lesions].

Objective To evaluate the value of SOX1 and PAX1 gene methylation detection in the secondary triage of high-grade cervical lesions.Methods Exfoliated cervical cells were collected from 122 patients tested positive for human papilloma virus (HPV) and subjected to thin-prep cytologic test (TCT) and SOX1/PAX1 gene methylation tests.Results The HPV test combined with TCT showed the sensitivity of 95.24% and the specificity of 23.75% for detecting cervical intraepithelial neoplasia (CIN) grade 2 and above (CIN2+).After the addition of the SOX1/PAX1 gene methylation detection in secondary triage,the sensitivity for detecting CIN2+ was 83.33%,which had no statistically significant difference from the sensitivity of TCT combined with HPV test (P=0.078).However,the specificity reached 77.50%,which was significantly higher than that of HPV test combined with TCT (P<0.001).The SOX1/PAX1 gene methylation level in the CIN2+ group was higher than those in the normal cervical tissue and the CIN1 group(P<0.001).The cut-off values of SOX1 and PAX1 gene methylation for CIN2+ detection were -11.81 and -11.98,respectively.Conclusion Adding the detection of SOX1/PAX1 gene methylation in secondary triage significantly improves the efficiency and accuracy of CIN2+ detection.

Electrooxidative Rhodium(III)/Chiral Carboxylic Acid-Catalyzed Enantioselective C-H Annulation of Sulfoximines with Alkynes.

The combination of achiral Cp*Rh(III) with chiral carboxylic acids (CCAs) represents an efficient catalytic system in transition metal-catalyzed enantioselective C-H activation. However, this hybrid catalysis is limited to redox-neutral C-H activation reactions and the adopt to oxidative enantioselective C-H activation remains elusive and pose a significant challenge. Herein, we describe the development of an electrochemical Cp*Rh(III)-catalyzed enantioselective C-H annulation of sulfoximines with alkynes enabled by chiral carboxylic acid (CCA) in an operationally friendly undivided cell at room temperature. A broad range of enantioenriched 1,2-benzothiazines are obtained in high yields with excellent enantioselectivities (up to 99 % yield and 98 : 2 er). The practicality of this method is demonstrated by scale-up reaction in a batch reactor with external circulation. A crucial chiral Cp*Rh(III) intermediate is isolated, characterized, and transformed, providing rational support for a Rh(III)/Rh(I) electrocatalytic cycle.

Pre-existing humoral immunity and CD4+ T cell response correlate with cross-reactivity against SARS-CoV-2 Omicron subvariants after heterologous prime-boost vaccination.

BACKGROUND: Information regarding the heterologous prime-boost COVID vaccination has been fully elucidated. The study aimed to evaluate both humoral, cellular immunity and cross-reactivity against variants after heterologous vaccination. METHODS: We recruited healthcare workers previously primed with Oxford/AstraZeneca ChAdOx1-S vaccines and boosted with Moderna mRNA-1273 vaccine boost to evaluate the immunological response. Assay used: anti-spike RBD antibody, surrogate virus neutralizing antibody and interferon-γ release assay. RESULTS: All participants exhibited higher humoral and cellular immune response after the booster regardless of prior antibody level, but those with higher antibody level demonstrated stronger booster response, especially against omicron BA.1 and BA.2 variants. The pre-booster IFN-γ release by CD4+ T cells correlates with post-booster neutralizing antibody against BA.1 and BA.2 variant after adjustment with age and gender. CONCLUSIONS: A heterologous mRNA boost is highly immunogenic. The pre-existing neutralizing antibody level and CD4+ T cells response correlates with post-booster neutralization reactivity against the Omicron variant.

A pervasive phosphorylation cascade modulation of plant transcription factors in response to abiotic stress.

MAIN CONCLUSION: Transcriptional regulation of stress-responsive genes is a crucial step in establishing the mechanisms behind plant abiotic stress tolerance. A sensitive method of regulating transcription factors activity, stability, protein interaction, and subcellular localization is through phosphorylation. This review highlights a widespread regulation mechanism that involves phosphorylation of plant TFs in response to abiotic stress. Abiotic stress is one of the main components limiting crop yield and sustainability on a global scale. It greatly reduces the land area that is planted and lowers crop production globally. In all living organisms, transcription factors (TFs) play a crucial role in regulating gene expression. They participate in cell signaling, cell cycle, development, and plant stress response. Plant resilience to diverse abiotic stressors is largely influenced by TFs. Transcription factors modulate gene expression by binding to their target gene's cis-elements, which are impacted by genomic characteristics, DNA structure, and TF interconnections. In this review, we focus on the six major TFs implicated in abiotic stress tolerance, namely, DREB, bZIP, WRKY, ABF, MYB, and NAC, and the cruciality of phosphorylation of these transcription factors in abiotic stress signaling, as protein phosphorylation has emerged as one of the key post-translational modifications, playing a critical role in cell signaling, DNA amplification, gene expression and differentiation, and modification of other biological configurations. These TFs have been discovered after extensive study as stress-responsive transcription factors which may be major targets for crop development and important contributors to stress tolerance and crop production.

Risk stratification of gallbladder masses by machine learning-based ultrasound radiomics models: a prospective and multi-institutional study.

OBJECTIVE: This study aimed to evaluate the diagnostic performance of machine learning (ML)-based ultrasound (US) radiomics models for risk stratification of gallbladder (GB) masses. METHODS: We prospectively examined 640 pathologically confirmed GB masses obtained from 640 patients between August 2019 and October 2022 at four institutions. Radiomics features were extracted from grayscale US images and germane features were selected. Subsequently, 11 ML algorithms were separately used with the selected features to construct optimum US radiomics models for risk stratification of the GB masses. Furthermore, we compared the diagnostic performance of these models with the conventional US and contrast-enhanced US (CEUS) models. RESULTS: The optimal XGBoost-based US radiomics model for discriminating neoplastic from non-neoplastic GB lesions showed higher diagnostic performance in terms of areas under the curves (AUCs) than the conventional US model (0.822-0.853 vs. 0.642-0.706, p < 0.05) and potentially decreased unnecessary cholecystectomy rate in a speculative comparison with performing cholecystectomy for lesions sized over 10 mm (2.7-13.8% vs. 53.6-64.9%, p < 0.05) in the validation and test sets. The AUCs of the XGBoost-based US radiomics model for discriminating carcinomas from benign GB lesions were higher than the conventional US model (0.904-0.979 vs. 0.706-0.766, p < 0.05). The XGBoost-US radiomics model performed better than the CEUS model in discriminating GB carcinomas (AUC: 0.995 vs. 0.902, p = 0.011). CONCLUSIONS: The proposed ML-based US radiomics models possess the potential capacity for risk stratification of GB masses and may reduce the unnecessary cholecystectomy rate and use of CEUS. CLINICAL RELEVANCE STATEMENT: The machine learning-based ultrasound radiomics models have potential for risk stratification of gallbladder masses and may potentially reduce unnecessary cholecystectomies. KEY POINTS: • The XGBoost-based US radiomics models are useful for the risk stratification of GB masses. • The XGBoost-based US radiomics model is superior to the conventional US model for discriminating neoplastic from non-neoplastic GB lesions and may potentially decrease unnecessary cholecystectomy rate for lesions sized over 10 mm in comparison with the current consensus guideline. • The XGBoost-based US radiomics model could overmatch CEUS model in discriminating GB carcinomas from benign GB lesions.

Characteristics of phenotypic antibiotic resistance of Helicobacter pylori and its correlation with genotypic antibiotic resistance: A retrospective study in Ningxia.

BACKGROUND: Geographic differences exist in the antibiotic resistance patterns of Helicobacter pylori. Personalized treatment regimens based on local or individual resistance data are essential. We evaluated the current status of H. pylori resistance in Ningxia, analyzed resistance-related factors, and assessed the concordance of phenotypic and genotypic resistance. METHODS: Strains were isolated from the gastric mucosa of patients infected with H. pylori in Ningxia and relevant clinical information was collected. Phenotypic antibiotic susceptibility assays (Kirby-Bauer disk diffusion) and antibiotic resistance gene detection (Sanger sequencing) were performed. RESULTS: We isolated 1955 H. pylori strains. The resistance rates of H. pylori to amoxicillin, levofloxacin, clarithromycin, and metronidazole were 0.9%, 42.4%, 40.4%, and 94.2%, respectively. Only five tetracycline-resistant and one furazolidone-resistant strain were identified. Overall, 3.3% of the strains were sensitive to all six antibiotics. Multidrug-resistant strains accounted for 22.9%, of which less than 20% were from Wuzhong. Strains isolated from women and patients with nonulcerative disease had higher rates of resistance to levofloxacin and clarithromycin. Higher rates of resistance to metronidazole, levofloxacin, and clarithromycin were observed in the older age group than in the younger age group. The kappa coefficients of phenotypic resistance and genotypic resistance for levofloxacin and clarithromycin were 0.830 and 0.809, respectively, whereas the remaining antibiotics showed poor agreement. CONCLUSION: H. pylori antibiotic resistance is severe in Ningxia. Therefore, furazolidone, amoxicillin, and tetracycline are better choices for the empirical therapy of H. pylori infection in this region. Host sex, age, and the presence of ulcerative diseases may affect antibiotic resistance of the bacteria. Personalized therapy based on genetic testing for levofloxacin and clarithromycin resistance may be a future direction for the eradication therapy of H. pylori infection in Ningxia.

Description of a New Species of Hua (Gastropoda: Semisulcospiridae) from Guizhou, China, Based on Morphology and Molecular Evidence.

A new species of Hua, Hua qiannanensis sp. nov., is described from Guizhou Province, China, based on morphological and molecular evidence. The new species can be distinguished from its congeners by the following combination of characters: the smooth shell, only three smaller cusps of lateral teeth on the inner side, outer marginal teeth with eight flattened and rounded denticles, an ovipositor pore in females, and BW/H ≥ 80%, B/H = 76.8-82.3%. Molecular analysis based on partial mitochondrial COI and 16S rDNA also supports the systematic position of the new taxon.

Predictive value of red blood cell distribution width and platelet-to-lymphocyte ratio for acute kidney injury in critically ill patients.

OBJECTIVES: The purpose of this study was to explore the value of red blood cell distribution width (RDW) and platelet-to-lymphocyte ratio (PLR) in predicting the occurrence of acute kidney injury (AKI) in critically ill patients. MATERIALS AND METHODS: Among 1,500 adult patients in the intensive care unit (ICU) between January 2016 and December 2019, we examined the associations of baseline RDW and PLR with the risk of AKI development using logistical analysis. In addition, we explored the value of RDW and PLR in predicting in-hospital mortality. RESULTS: Overall, 615 (41%) patients were diagnosed with AKI. We divided the groups into two subgroups each; the high-RDW (≥ 14.045%) group had a high risk of developing AKI (OR = 5.189, 95% CI: 4.088 - 6.588), and the high-PLR (≥ 172.067) group had a risk of developing AKI too (OR = 9.11, 95% CI: 7.09 - 11.71). The areas under the receiver operating characteristic curves (AUCs) for the prediction of AKI incidence based on RDW and PLR were 0.780 (95% CI: 0.755 - 0.804) and 0.728 (95% CI: 0.702 - 0.754) (all p < 0.001), with cut-off values of 14.045 and 172.067, respectively. Moreover, a higher RDW was associated with a higher rate of hospital mortality (OR: 2.907, 2.190 - 3.858), and the risk of in-hospital mortality related to PLR was 1.534 (95% CI: 1.179 - 1.995). CONCLUSION: A higher RDW was related to a higher risk of AKI occurrence and in-hospital mortality in the ICU.

The relationship between vitamin D receptor gene polymorphisms and ankylosing spondylitis: a systematic review, meta-analysis and trial sequential analysis.

The relation between vitamin D receptor (VDR) gene polymorphisms and ankylosing spondylitis (AS) remains unclear. A systematic review and meta-analysis were conducted using six databases, including PubMed, Web of Science, EMBASE, CNKI, Wanfang and Cochrane Library. The selection of each study was based on inclusion and exclusion criteria. The Newcastle-Ottawa Scale was applied to assess the quality of the included studies, while the strength was evaluated by odds ratios and 95% confidence intervals. The following contrasts were used: allele contrast (H vs h), homozygous contrast (HH vs hh), heterozygous contrast (Hh vs hh), dominant contrast (HH + Hh vs hh) and recessive contrast (HH vs Hh + hh). For the BsmI-rs1544410 polymorphism, three studies were included of 782 cases and 863 controls. The data showed a significant relationship under allele contrast H vs h (OR = 1.66, 95% CI 1.20-2.30 (P = 0.002)). For the TaqI-rs731236 polymorphism, 675 cases and 697 controls were included in two studies. The data showed a significant relationship under allele contrast H vs h (OR = 1.57, 95% CI 1.11-2.21 (P < 0.05)), homozygous contrast Hh vs hh (OR = 1.65, 95% CI 1.12-2.43 (P < 0.05)), and recessive contrast HH + Hh vs hh (OR = 1.66, 95% CI 1.13-2.43 (P < 0.05)). There were significant relationships between VDR gene BsmI-rs1544410 and TaqI-rs731236 polymorphisms and AS, while no associations were found between FokI-rs2228570 and ApaI-rs7975232 polymorphisms and AS. In the future, additional studies with larger case numbers are need.

Effect and Mechanism of Curdione Combined with Gemcitabine on Migration and Invasion of Bladder Cancer.

Bladder cancer (BCa), which usually occurs in bladder epithelial cells and is the fifth most common type of cancer in the world. he recurrence rate within 5 years after surgery is 0.8-45% of patients with early bladder cancer. Therefore, finding appropriate drug therapy for patients with bladder cancer can provide a reference for clinical treatment and play an important role in improving the prognosis of patients. In this study, CCK8 assay result showed that the inhibition of bladder cancer cell activity by Curdione and GEM increased with time and dose. Subsequently, CCK8, clone formation assay and Transwell result showed Curdione enhances GEM inhibition of bladder cancer cell activity, clonal formation and migration, these combine therapeutic schedule also could inhibited growth of in vivo xenograft tumors. The comprehensive database showed that CA2 is a potential target genes of Curdione, and Knockdown CA2 enhances GEM induced inhibition of cell proliferation and migration. Based on these advantages, Curdione may be a new type of action drug or adjunct for the treatment of bladder cancer.