Regulation of endogenous hormone and miRNA in leaves of alfalfa (Medicago sativa L.) seedlings under drought stress by endogenous nitric oxide.

BACKGROUND: Alfalfa (Medicago sativa. L) is one of the best leguminous herbage in China and even in the world, with high nutritional and ecological value. However, one of the drawbacks of alfalfa is its sensitivity to dry conditions, which is a global agricultural problem. The objective of this study was to investigate the regulatory effects of endogenous nitric oxide (NO) on endogenous hormones and related miRNAs in alfalfa seedling leaves under drought stress. The effects of endogenous NO on endogenous hormones such as ABA, GA3, SA, and IAA in alfalfa leaves under drought stress were studied. In addition, high-throughput sequencing technology was used to identify drought-related miRNAs and endogenous NO-responsive miRNAs in alfalfa seedling leaves under drought stress. RESULT: By measuring the contents of four endogenous hormones in alfalfa leaves, it was found that endogenous NO could regulate plant growth and stress resistance by inducing the metabolism levels of IAA, ABA, GA3, and SA in alfalfa, especially ABA and SA in alfalfa. In addition, small RNA sequencing technology and bioinformatics methods were used to analyze endogenous NO-responsive miRNAs under drought stress. It was found that most miRNAs were enriched in biological pathways and molecular functions related to hormones (ABA, ETH, and JA), phenylpropane metabolism, and plant stress tolerance. CONCLUSION: In this study, the analysis of endogenous hormone signals and miRNAs in alfalfa leaves under PEG and PEG + cPTIO conditions provided an important basis for endogenous NO to improve the drought resistance of alfalfa at the physiological and molecular levels. It has important scientific value and practical significance for endogenous NO to improve plant drought resistance.

Mechanism of action of microRNA166 on nitric oxide in alfalfa (Medicago sativa L.) under drought stress.

BACKGROUND: Alfalfa is a perennial forage crop of high importance, but its cultivation is often affected by drought stress. Currently, the investigation of drought-related small RNAs is a popular research topic to uncover plant drought resistance mechanisms. Among these small RNAs, microRNA166 (miR166) is associated with drought in numerous plant species. Initial small RNA sequencing studies have shown that miR166 is highly responsive to exogenous nitric oxide (NO) and drought. Therefore, analyzing the expression of Msa-miR166 under nitric oxide and drought treatment is significant. RESULT: Bioinformatics analysis revealed that the miR166 family is widely distributed among plants, ranging from mosses to eudicots, with significant distribution differences between species. The evolutionary degree of Msa-miR166s is highly similar to that of Barrel medic (Medicago truncatula) and Soybean (Glycine max), but significantly different from the model plant Arabidopsis (Arabidopsis thaliana). It is suggested that there are no significant differences in miR166s within the species, and members of Msa-miR166s can form a typical stem-loop. The lowest level of exogenous nitric oxide was observed in Msa-miR166s under drought stress, followed by individual drought, and the highest level was observed after removing endogenous nitric oxide. CONCLUSION: In response to short-term drought, Msa-miR166s down-regulate expression in alfalfa (Medicago sativa L.). Exogenous nitric oxide can reduce the expression of Msa-miR166s in response to short-term drought. These findings suggest that Msa-miR166e-5p is responsive to environmental changes. The expression levels of target genes showed an opposite trend to Msa-miR166s, verifying the accuracy of Degradome sequencing in the early stage. This suggests that alfalfa experiences drought stress when regulated by exogenous nitric oxide, targeting HD ZIP-III, FRI, and CoA ligase genes. Additionally, the expression of Msa-miR166s in response to drought stress varies between leaves and roots, indicating spatiotemporal specificity.

HER2 overexpression in urothelial carcinoma with GATA3 and PPARG copy number gains.

HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.

Controllable Regulation of CO2 Adsorption Behavior via Precise Charge Donation Modulation for Highly Selective CO2 Electroreduction to Formic Acid.

The synthesis of value-added products via CO2 electroreduction (CO2ER) is of great significance, but the development of efficient and versatile strategies for the controllable selectivity tuning is extremely challenging. Herein, the tuning of CO2ER selectivity through the modulation of CO2 adsorption behavior is proposed. Using the constructed zeolitic MOF (SNNU-339), CO2 adsorption behavior is controllably changed from *CO2 to CO2* via the precise ligand-to-metal charge donation (LTMCD) regulation. It is confirmed that the high electronegativity of the coordinate ligand directly restricts the LTMCD, reduces the charge density on the metal sites, lowers the Gibbs free energy for CO2* adsorption, and leads to the transformation of CO2 adsorption mode from *CO2 to CO2*. Owing to the modulated CO2 adsorption behavior and regulated kinetics, SNNU-339 exhibits superior HCOOH selectivity (≈330% promotion, 85.6% Faradaic efficiency) and high CO2ER activity. The wide applicability of the proposed approach sheds light on the efficient CO2ER. This study provides a competitive strategy for rational catalyst design and underscores the significance of adsorption behavior tuning in electrocatalysis.

In situ and General Multidentate Ligand Passivation Achieves Efficient and Ultra-Stable CsPbX3 Perovskite Quantum Dots for White Light-Emitting Diodes.

Inorganic CsPbX3 perovskite quantum dots (PeQDs) show great potential in white light-emitting diodes (WLEDs) due to excellent optoelectronic properties, but their practical application is hampered by low photoluminescence quantum yield (PLQY) and especially poor stability. Herein,  we developed an in-situ and general multidentate ligand passivation strategy that allows for CsPbX3 PeQDs not only near-unit PLQY, but significantly improved stability against storage, heat, and polar solvent. The enhanced optical property arises from high effectiveness of the multidentate ligand, diethylenetriaminepentaacetic acid (DTPA) with five carboxyl groups, in passivating uncoordinated Pb2+ defects and suppressing nonradiative recombination. First-principles calculations reveal that the excellent stability is attributed to tridentate binding mode of DTPA that remarkably boosts the adsorption capacity to PeQD core. Finally, combining the green and red PeQDs with blue chip,  we demonstrated highly luminous WLEDs with distinctly enhanced operation stability, a wide color gamut of 121.3% of national television system committee, standard white light of (0.33,0.33) in CIE 1931, and tunable color temperatures from warm to cold white light readily by emitters' ratio. This study provides an operando yet general approach to achieve efficient and stable PeQDs for WLEDs and accelerates their progress to commercialization.

Isolation and evaluation of bacteriophage cocktail for the control of colistin-resistant Escherichia coli.

The frequent emergence of colistin-resistant E. coli worldwide drives the exploration of alternative therapies, and bacteriophages (phages) have emerged as promising candidates to tackle this challenge. In this study, three E. coli phages were isolated, screened, and evaluated against 96 colistin-resistant strains obtained from diverse sources. The combined recognition rate for these strains was 43.6%, while individually it ranged from 17.0% to 24.5%. Notably, among the tested phages (FJ3-79, SD1-92L, and FJ4-63), FJ4-63 demonstrated exceptional characteristics in regulating host population dynamics upon infection by exhibiting a shorter latent period (20 min) and a larger burst size (95.99 ± 3.61 PFU/cell). Furthermore, it exhibited relative stability at pH 3-11 and below 60°C. Transmission electron microscopy and genomic analysis classified phage FJ4-63 belongs to the Dhakavirus genus within the Straboviridae family. Its genome comprised a linear double-stranded DNA measuring 169,669 bp (containing 272 coding sequences) with a GC content of 39.76%, of which 93 (34.2%) had known functions, and the remaining 177 were annotated as hypothetical proteins. Additionally, two tRNAs were recognized, possess the "holin-endolysin" lytic system, and no resistance or virulence genes were detected. The phylogenetic tree and average nucleotide identity (ANI) analysis revealed that phage FJ4-63 exhibited the highest similarity to Escherichia phage C6 (679410.1), indicating a consistent close relationship within the same branch. The cocktail comprising three phages exhibits enhanced in vitro bactericidal efficacy compared to a single phage. At high doses with MOI = 100, it rapidly and completely eradicates bacteria within 1 h while significantly reducing bacterial biofilms. All this evidence suggests that lytic phages offer an effective solution for clinical treatment, with a phage cocktail demonstrating greater potential in the alternative management of colistin-resistant E. coli infections.

A remote sensing method for mapping alpine grasslines based on graph-cut.

Climate change has induced substantial shifts in vegetation boundaries such as alpine treelines and shrublines, with widespread ecological and climatic influences. However, spatial and temporal changes in the upper elevational limit of alpine grasslands ("alpine grasslines") are still poorly understood due to lack of field observations and remote sensing estimates. In this study, taking the Tibetan Plateau as an example, we propose a novel method for automatically identifying alpine grasslines from multi-source remote sensing data and determining their positions at 30-m spatial resolution. We first identified 2895 mountains potentially having alpine grasslines. On each mountain, we identified a narrow area around the upper elevational limit of alpine grasslands where the alpine grassline was potentially located. Then, we used linear discriminant analysis to adaptively generate from Landsat reflectance features a synthetic feature that maximized the difference between vegetated and unvegetated pixels in each of these areas. After that, we designed a graph-cut algorithm to integrate the advantages of the Otsu and Canny approaches, which was used to determine the precise position of the alpine grassline from the synthetic feature image. Validation against alpine grasslines visually interpreted from a large number of high-spatial-resolution images showed a high level of accuracy (R2 , .99 and .98; mean absolute error, 22.6 and 36.2 m, vs. drone and PlanetScope images, respectively). Across the Tibetan Plateau, the alpine grassline elevation ranged from 4038 to 5380 m (5th-95th percentile), lower in the northeast and southeast and higher in the southwest. This study provides a method for remotely sensing alpine grasslines for the first-time at large scale and lays a foundation for investigating their responses to climate change.

Meta-analysis of SnRK2 gene overexpression in response to drought and salt stress.

SNF1-RELATED KINASE 2 (SnRK2) plays a crucial role in plants' stress response. Although studies have reported that the overexpression of several SnRK2 family members in different plants leads to improved stress tolerance, it is difficult to elucidate the mechanisms by which SnRK2s regulate stress tolerance due to the variability of experimental variables in these studies. Therefore, we used meta-analysis to comprehensively analyze 22 parameters that can reflect drought tolerance and salinity tolerance in SnRK2s-transformed plants and to explore the effects that different experimental variables between studies have on the relevant plant parameters. The results showed that the overexpression of SnRK2s mainly improved plants' drought and salinity tolerance by reducing their osmotic stress and oxidative damage, improving photosynthesis and other biochemical and physiological processes. Out of the 22 physiological parameters, 17 and 19 were significantly affected by drought and salt stress, respectively, and 10 indicators were also significantly changed under non-stress conditions. Under salt stress, the cell membrane permeability among these parameters shows the most significant changes, increasing by 506.57% in SnRK2-overexpressing plants compared to wild type (WT). Therefore, although plants overexpressing SnRK2s respond positively to both drought and salt stress, they demonstrated greater tolerance to salt stress. In addition, among the detected regulatory variables, donor-acceptor type, promoter type, stress type, experimental medium, and duration all affected the extent of SnRK2s overexpression and affected the physiological characteristics of the transgenic plants. Also, different stress conditions (salt, drought stress) led to different degrees of transformation. These studies provide new research directions for studying crop stress tolerance and help to better explore the functions played by SnRK2s in external plant stresses.

Highly sensitive detection of multiple antiviral drugs using graphitized hydroxylated multi-walled carbon nanotubes/ionic liquids-based electrochemical sensors.

Global outbreaks and the spread of viral diseases in the recent years have led to a rapid increase in the usage of antiviral drugs (ATVs), the residues and metabolites of which are discharged into the natural environment, posing a serious threat to human health. There is an urgent need to develop sensitive and rapid detection tools for multiple ATVs. In this study, we developed a highly sensitive electrochemical sensor comprising a glassy carbon electrode (GCE) modified with graphitized hydroxylated multi-walled carbon nanotubes (G-MWCNT-OH) and 1-butyl-3-methylimidazolium hexafluorophosphate (BMIMPF6, IL) for the detection of six ATVs including famciclovir (FCV), remdesivir (REM), favipiravir (FAV), hydroxychloroquine sulfate (HCQ), cepharanthine (CEP) and molnupiravir (MOL). The morphology and structure of the G-MWCNT-OH/IL nanocomposites were characterized comprehensively, and the electroactive surface area and electron conductivity of G-MWCNT-OH/IL/GCE were determined using cyclic voltammetry and electrochemical impedance spectroscopy. The thermodynamic stability and non-covalent interactions between the G-MWCNT-OH and IL were evaluated through quantum chemical simulation calculations, and the mechanism of ATV detection using the G-MWCNT-OH/IL/GCE was thoroughly examined. The detection conditions were optimized to improve the sensitivity and stability of electrochemical sensors. Under the optimal experimental conditions, the G-MWCNT-OH/IL/GCE exhibited excellent electrocatalytic performance and detected the ATVs over a wide concentration range (0.01-120 µM). The limit of detections (LODs) were 42.3 nM, 55.4 nM, 21.9 nM, 15.6 nM, 10.6 nM, and 3.2 nM for FCV, REM, FAV, HCQ, CEP, and MOL, respectively. G-MWCNT-OH/IL/GCE was also highly stable and selective to the ATVs in the presence of multiple interfering analytes. This sensor exhibited great potential for enabling the quantitative detection of multiple ATVs in actual water environment.

Isobavachalcone induces hepatotoxicity in zebrafish embryos and HepG2 cells via the System Xc--GSH-GPX4 signaling pathway in ferroptosis response.

Isobavachalcone (IBC) is a flavonoid component of the traditional Chinese medicine Psoraleae Fructus, with a range of pharmacological properties. However, IBC causes some hepatotoxicity, and the mechanism of toxicity is unclear. The purpose of this paper was to investigate the possible mechanism of toxicity of IBC on HepG2 cells and zebrafish embryos. The results showed that exposure to IBC increased zebrafish embryo mortality and decreased hatchability. Meanwhile, IBC induced liver injury and increased expression of ALT and AST activity. Further studies showed that IBC caused the increase of ROS and MDA the decrease of CAT, GSH, and GSH-Px; the increase of Fe2+ content; and the changes of ferroptosis related genes (acsl4, gpx4, and xct) and iron storage related genes (tf, fth, and fpn) in zebrafish embryos. Through in vitro verification, it was found that IBC also caused oxidative stress and increased Fe2+ content in HepG2 cells. IBC caused depolarization of mitochondrial membrane potential (MMP) and reduction of mitochondrial ATP, as well as altered expression of ACSl4, SLC7A11, GPX4, and FTH1 proteins. Treatment of HepG2 cells with ferrostatin-1 could reverse the effect of IBC. Targeting the System Xc--GSH-GPX4 pathway of ferroptosis and preventing oxidative stress damage might offer a theoretical foundation for practical therapy and prevention of IBC-induced hepatotoxicity.

Enhancing Built-in Electric Fields via Molecular Symmetry Modulation in Supramolecular Photocatalysts for Highly Efficient Photocatalytic Hydrogen Evolution.

Nature-inspired supramolecular self-assemblies are attractive photocatalysts, but their quantum yields are limited by poor charge separation and transportation. A promising strategy for efficient charge transfer is to enhance the built-in electric field by symmetry breaking. Herein, an unsymmetric protonation, N-heterocyclic π-conjugated anthrazoline-based supramolecular photocatalyst SA-DADK-H+ was developed. The unsymmetric protonation breaks the initial structural symmetry of DADK, resulting in ca. 50-fold increase in the molecular dipole, and facilitates efficient charge separation and transfer within SA-DADK-H+. The protonation process also creates numerous active sites for H2O adsorption, and serves as crucial proton relays, significantly improving the photocatalytic efficiency. Remarkably, SA-DADK-H+ exhibits an outstanding hydrogen evolution rate of 278.2 mmol g-1 h-1 and a remarkable apparent quantum efficiency of 25.1 % at 450 nm, placing it among the state-of-the-art performances in organic semiconductor photocatalysts. Furthermore, the versatility of the unsymmetric protonation approach has been successfully applied to four other photocatalysts, enhancing their photocatalytic performance by 39 to 533 times. These findings highlight the considerable potential of unsymmetric protonation induced symmetry breaking strategy in tailoring supramolecular photocatalysts for efficient solar-to-fuel production.

Non-targeted metabolomics analysis of metabolite changes in two quinoa genotypes under drought stress.

BACKGROUND: Quinoa is an important economic crop, drought is one of the key factors affecting quinoa yield. Clarifying the adaptation strategy of quinoa to drought is conducive to cultivating drought-tolerant varieties. At present, the study of quinoa on drought stress-related metabolism and the identification of related metabolites are still unknown. As a direct feature of biochemical functions, metabolites can reveal the biochemical pathways involved in drought response. RESULT: Here, we studied the physiological and metabolic responses of drought-tolerant genotype L1 and sensitive genotype HZ1. Under drought conditions, L1 had higher osmotic adjustment ability and stronger root activity than HZ1, and the relative water content of L1 was also higher than that of HZ1. In addition, the barrier-to- sea ratio of L1 is significantly higher than that of HZ1. Using untargeted metabolic analysis, a total of 523, 406, 301 and 272 differential metabolites were identified in L1 and HZ1 on day 3 and day 9 of drought stress. The key metabolites (amino acids, nucleotides, peptides, organic acids, lipids and carbohydrates) accumulated differently in quinoa leaves. and HZ1 had the most DEMs in Glycerophospholipid metabolism (ko00564) and ABC transporters (ko02010) pathways. CONCLUSION: These results provide a reference for characterizing the response mechanism of quinoa to drought and improving the drought tolerance of quinoa.

Helicobacter pylori infection and risk of cardiovascular disease.

BACKGROUND: Whether Helicobacter pylori (H. pylori) infection is associated with an increased risk of cardiovascular disease (CVD) remains controversial. This study aimed to investigate the association between H. pylori infection and the risk of CVD. METHODS: Potentially related studies were searched in the electronic databases, including PubMed, EMBASE and Cochrane Library, from inception to 31 August 2022. Observational cohort studies that reported the multivariable-adjusted relative risks (RRs) for composite CVD, CHD, stroke, or all-cause mortality associated with H. pylori infection were included in the meta-analysis, using random-effects models. RESULTS: Forty-one cohort studies with 230,288 participants were included. After a median follow-up duration of 6.3 years, H. pylori infection was associated with a mildly increased risk of composite CVD (RR 1.10, 95% CI 1.03, 1.18) and coronary heart disease (RR 1.10, 95% CI 1.02, 1.18) compared with those without H. pylori infection. No significant association was observed between H. pylori infection and risk of stroke (RR 1.08, 95% CI 0.94, 1.23) or all-cause mortality (RR 1.02, 95% CI 0.90, 1.16). Compared with cytotoxin-associated gene-A (CagA) negative H. pylori infection, the risk of CVD was significantly increased in patients with CagA positive H. pylori infection (RR 1.58, 95% CI 1.03, 2.41). CONCLUSIONS: Helicobacter pylori infection is associated with a mildly increased risk of CVD. It may be of great public health and clinical significance to screen H. pylori infection in patients with a high risk of CVD.

Capping Ligand Engineering Enables Stable CsPbBr3 Perovskite Quantum Dots toward White-Light-Emitting Diodes.

All-inorganic perovskite quantum dots (PeQDs) have sparked extensive research focus on white-light-emitting diodes (WLEDs), but stability and photoluminescence efficiency issues are still remain obstacles impeding their practical application. Here, we reported a facile one-step method to synthesize CsPbBr3 PeQDs at room temperature using branched didodecyldimethylammonium fluoride (DDAF) and short-chain-length octanoic acid as capping ligands. The obtained CsPbBr3 PeQDs have a near-unity photoluminescence quantum yield of 97% due to the effective passivation of DDAF. More importantly, they exhibit much improved stability against air, heat, and polar solvents, maintaining >70% of initial PL intensity. Making use of these excellent optoelectronic properties, WLEDs based on CsPbBr3 PeQDs, CsPbBr1.2I1.8 PeQDs, and blue LEDs were fabricated, which show a color gamut of 122.7% of the National Television System Committee standard, a luminous efficacy of 17.1 lm/W, with a color temperature of 5890 K, and CIE coordinates of (0.32, 0.35). These results indicate that the CsPbBr3 PeQDs have great practical potential in wide-color-gamut displays.

Clinical characteristics of tuberculous meningitis in older patients compared with younger and middle-aged patients: a retrospective analysis.

BACKGROUND: Few studies have analyzed the clinical characteristics and adverse factors affecting prognosis in older patients with tuberculous meningitis (TBM). This study aimed to compare the clinical characteristics of TBM in older patients with those in younger and middle-aged patients. METHODS: This single-center retrospective study extracted data on the clinical features, cerebrospinal fluid changes, laboratory results, imaging features, and outcomes of patients with TBM from patient medical records and compared the findings in older patients (aged 60 years and older) with those of younger and middle-aged patients (aged 18-59 years). RESULTS: The study included 197 patients with TBM, comprising 21 older patients aged 60-76 years at onset, and 176 younger and middle-aged patients aged 18-59 years at onset. Fever was common in both older (81%) and younger and middle-aged patients (79%). Compared with younger and middle-aged patients, older patients were more likely to have changes in awareness levels (67% vs. 40%), peripheral nerve dysfunction (57% vs. 29%), changes in cognitive function (48% vs. 20%), and focal seizures (33% vs. 6%), and less likely to have headache (71% vs. 93%), neck stiffness on meningeal stimulation (38% vs. 62%), and vomiting (47% vs. 68%). The Medical Research Council staging on admission of older patients was stage II (52%) and stage III (38%), whereas most younger and middle-aged patients had stage I (33%) and stage II (55%) disease. Neurological function evaluated on the 28th day of hospitalization was more likely to show poor prognosis in older patients than in younger and middle-aged patients (76% vs. 25%). Older patients had significantly higher red blood cell counts and blood glucose levels, and significantly lower serum albumin and sodium levels than those in younger and middle-aged patients. The cerebrospinal fluid protein levels, nucleated cell counts, glucose levels, and chloride levels did not differ significantly by age. CONCLUSION: In patients with TBM, older patients have more severe clinical manifestations, a higher incidence of hydrocephalus and cerebral infarction, and longer hospital stays than younger and middle-aged patients. Older patients thus require special clinical attention.

Sintilimab, bevacizumab biosimilar, and HAIC for unresectable hepatocellular carcinoma conversion therapy: a prospective, single-arm phase II trial.

We assessed the efficacy and safety of sintilimab [an anti-programmed death (PD-1)] plus bevacizumab biosimilar (IBI305), and hepatic arterial infusion chemotherapy (HAIC) in patients with unresectable hepatocellular carcinoma (HCC). The patients received sintilimab (200 mg) plus IBI305 (7.5 mg/kg) and HAIC (FOLFOX for 23 h) and were treated every 3 weeks. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee (IRC) per mRECIST v1.1. Twenty-nine patients were enrolled in our clinical trial (1 patient voluntarily withdrew due to adverse events after the initial treatment). Objective response was reached in 17/29 (58.6%) patients per mRECIST. A total of 19/29 (65.5%) patients became eligible for further treatment; 14 of them completed surgical resection; 1 (5.3%) achieved pathological complete response (pCR); and 5 (26.3%) reached major partial response (mPR). The 1-year OS rate was better in the PR or pCR+mPR+PR group than in the PD+SD group by either mRECIST or pathological assessment (p=0.039 and 0.006). The 1-year EFS rate was better in the PR group than in the PD+SD group by pathological assessment (p=0.007). The most common treatment-related adverse events (TEAEs) in 30 HCC patients included thrombocytopenia (40.0%), hypertension (23.3%), and leukopenia (23.3%). The grade 3-5 TEAEs that were observed were hypertension (10%), diarrhea (6.7%), asthenia (3.3%), and ascites (3.3%). Sintilimab plus IBI305 and HAIC showed promising efficacy and manageable safety in patients with unresectable HCC. It might represent a novel treatment option for these patients.

IMPA2 blocks cervical cancer cell apoptosis and induces paclitaxel resistance through p53-mediated AIFM2 regulation.

Cervical cancer continues to be a concern, and the prognosis of locally advanced cervical cancer remains poor. IMPA2 was previously identified as a potential oncogene and regulator of tumor apoptosis. In this study, we aim to further elucidate the underlying mechanisms of IMPA2 gene in the regulation of cervical cancer apoptosis. First, we identify AIFM2 as an upregulated gene in IMPA2-silenced cervical cancer cells, and inhibition of AIFM2 reverses IMPA2 knockdown-induced apoptosis. Further study reveals that AIFM2 regulates cell apoptosis in a mitochondrial-dependent manner with a redistribution of mitochondrial membrane potential and intracellular Ca 2+ levels. However, the analysis of the STRING database and our experimental results show that AIFM2 has little effect on cervical cancer progression and survival. Further mechanistic study demonstrates that IMPA2 and AIFM2 silencing inhibits apoptosis by activating p53. Meanwhile, the knockdown of IMPA2 enhances the chemosensitivity of cervical cancer cells by strengthening paclitaxel-induced apoptosis. Based on the above results, the IMPA2/AIFM2/p53 pathway may be a new molecular mechanism for paclitaxel treatment of cervical cancer and an effective strategy to enhance the sensitivity of cervical cancer cells to paclitaxel. Our findings display a novel function of IMPA2 in regulating cell apoptosis and paclitaxel resistance mediated by a disturbance of AIFM2 and p53 expression, potentially making it a novel therapeutic target for cervical cancer treatment.

Promotion of Ca2+ Accumulation in Roots by Exogenous Brassinosteroids as a Key Mechanism for Their Enhancement of Plant Salt Tolerance: A Meta-Analysis and Systematic Review.

Brassinosteroids (BRs), the sixth major phytohormone, can regulate plant salt tolerance. Many studies have been conducted to investigate the effects of BRs on plant salt tolerance, generating a large amount of research data. However, a meta-analysis on regulating plant salt tolerance by BRs has not been reported. Therefore, this study conducted a meta-analysis of 132 studies to elucidate the most critical physiological mechanisms by which BRs regulate salt tolerance in plants from a higher dimension and analyze the best ways to apply BRs. The results showed that exogenous BRs significantly increased germination, plant height, root length, and biomass (total dry weight was the largest) of plants under salt stress. There was no significant difference between seed soaking and foliar spraying. However, the medium method (germination stage) and stem application (seedling stage) may be more effective in improving plant salt tolerance. BRs only inhibit germination in Solanaceae. BRs (2 µM), seed soaking for 12 h, and simultaneous treatment with salt stress had the highest germination rate. At the seedling stage, the activity of Brassinolide (C28H48O6) was higher than that of Homobrassinolide (C29H50O6), and post-treatment, BRs (0.02 µM) was the best solution. BRs are unsuitable for use in the germination stage when Sodium chloride is below 100 mM, and the effect is also weakest in the seedling stage. Exogenous BRs promoted photosynthesis, and antioxidant enzyme activity increased the accumulation of osmoregulatory and antioxidant substances and reduced the content of harmful substances and Na+, thus reducing cell damage and improving plant salt tolerance. BRs induced the most soluble protein, chlorophyll a, stomatal conductance, net photosynthetic rate, Glutathione peroxidase, and root-Ca2+, with BRs causing Ca2+ signals in roots probably constituting the most important reason for improving salt tolerance. BRs first promoted the accumulation of Ca2+ in roots, which increased the content of the above vital substances and enzyme activities through the Ca2+ signaling pathway, improving plant salt tolerance.

Adverse events of vonoprazan in the treatments of acid-related diseases: a systematic review and meta-analysis.

BACKGROUND AND AIMS: vonoprazan, a novel potassium-competitive acid blocking agent, has better clinical outcomes in the treatment of acid-related diseases. However, some adverse events have been associated with vonoprazan for the treatment of acid-associated diseases. Therefore, this systematic review and meta-analysis aimed to explore the safety and tolerability of vonoprazan for acid-associated diseases. METHODS: electronic databases were retrieved to determine randomized controlled trials (RCTs) of vonoprazan for acid-associated diseases with any adverse effects and discontinuation. RESULTS: this systematic review and meta-analysis conforming to the selection criteria included 18 RCTs with a total of 7,932 participants. Compared with proton pump inhibitors, oral vonoprazan treatment showed no significant increase in the incidence of adverse effects (95 % CI = 0.987-1.095, p = 0.141). Diarrhea or loose stools analysis showed that there was a statistically significant difference between vonoprazan and proton pump inhibitors (PPIs) treatment (95 % CI = 0.661-0.966, p = 0.021). However, there was no significant difference in constipation, rash or eruption, nausea or vomiting, bloating or abdominal pain, dysgeusia, nasopharyngitis, neurological disorders, upper respiratory tract infection and abnormal investigations between vonoprazan and PPIs treatment. CONCLUSION: vonoprazan, which has better tolerability and safety, may significantly decrease diarrhea and loose stools in acid-related patients compared with PPIs. Our meta-analysis led to safer strategies for treating acid-related diseases. More high-quality studies with larger sample sizes are needed to further elucidate its efficacy and safety.

Interface-Anchored Covalent Organic Frameworks@Amino-Modified Ti3 C2 Tx MXene on Nylon 6 Film for High-Performance Deformable Supercapacitors.

Designing deformable supercapacitors (D-SCs) that have robust skeleton and smoothly active channels for charges kinetic migration and faradic storage are highly crucial for wearable systems. Here, we develop the high-performance D-SCs made of the covalent organic frameworks(COF)@amino-modified Ti3 C2 Tx deposited on decorated nylon 6 (DPA) film (COF@N-Ti3 C2 Tx /DPA) via layer-by-layer fabrication. The hierarchical COF@N-Ti3 C2 Tx /DPA exhibits admirable specific capacitance, rate performance and cycling stability in three-electrode system due to the superior H+ storage property and large interfacial charge transfer clarified by density functional theory calculations. Additionally, the solid-state D-SCs deliver favourable energy density and practical energy-supply applications. Particularly, the solid-state D-SCs present high deformable stabilities, with regard to 80.7, 80.6 and 83.4 % capacitance retention after 5000 bending cycles, 2000 stretching cycles and 5000 folding cycles, separately.