Remote ischemic conditioning may improve graft function following kidney transplantation: a systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: Remote ischemic conditioning (RIC) has the potential to benefit graft function following kidney transplantation by reducing ischemia-reperfusion injury; however, the current clinical evidence is inconclusive. This meta-analysis with trial sequential analysis (TSA) aimed to determine whether RIC improves graft function after kidney transplantation. METHODS: A comprehensive search was conducted on PubMed, Cochrane Library, and EMBASE databases until June 20, 2023, to identify all randomized controlled trials that examined the impact of RIC on graft function after kidney transplantation. The primary outcome was the incidence of delayed graft function (DGF) post-kidney transplantation. The secondary outcomes included the incidence of acute rejection, graft loss, 3- and 12-month estimated glomerular filtration rates (eGFR), and the length of hospital stay. Subgroup analyses were conducted based on RIC procedures (preconditioning, perconditioning, or postconditioning), implementation sites (upper or lower extremity), and graft source (living or deceased donor). RESULTS: Our meta-analysis included eight trials involving 1038 patients. Compared with the control, RIC did not significantly reduce the incidence of DGF (8.8% vs. 15.3%; risk ratio = 0.76, 95% confidence interval [CI], 0.48-1.21, P = 0.25, I2 = 16%), and TSA results showed that the required information size was not reached. However, the RIC group had a significantly increased eGFR at 3 months after transplantation (mean difference = 2.74 ml/min/1.73 m2, 95% CI: 1.44-4.05 ml/min/1.73 m2, P < 0.0001, I2 = 0%), with a sufficient evidence suggested by TSA. The secondary outcomes were comparable between the other secondary outcomes. The treatment effect of RIC did not differ between the subgroup analyses. CONCLUSION: In this meta-analysis with trial sequential analysis, RIC did not lead to a significant reduction in the incidence of DGF after kidney transplantation. Nonetheless, RIC demonstrated a positive correlation with 3-month eGFR. Given the limited number of patients included in this study, well-designed clinical trials with large sample sizes are required to validate the renoprotective benefits of RIC. TRIAL REGISTRATION: This systematic review and meta-analysis was registered at the International Prospective Register of Systematic Reviews (Number CRD42023464447).

Uncovering novel drug targets for bipolar disorder: a Mendelian randomization analysis of brain, cerebrospinal fluid, and plasma proteomes.

BACKGROUND: There is a clear demand for innovative therapeutics for bipolar disorder (BD). METHODS: We integrated the largest BD genome-wide association study (GWAS) dataset (NCase = 41 917, NControl = 371 549) with protein quantitative trait loci from brain, cerebrospinal fluid, and plasma. Using a range of integrative analyses, including Mendelian randomization (MR), Steiger filter analysis, Bayesian colocalization, and phenome-wide MR analysis, we prioritized novel drug targets for BD. Additionally, we incorporated data from the UK Biobank (NCase = 1064, NControl = 365 476) and the FinnGen study (NCase = 7006, NControl = 329 192) for robust biological validation. RESULTS: Through MR analysis, we found that in the brain, downregulation of DNM3, MCTP1, ABCB8 and elevation of DFNA5 and PDF were risk factors for BD. In cerebrospinal fluid, increased BD risk was associated with increased levels of FRZB, AGRP, and IL36A and decreased CTSF and LRP8. Plasma analysis revealed that decreased LMAN2L, CX3CL1, PI3, NCAM1, and TIMP4 correlated with increased BD risk, but ITIH1 did not. All these proteins passed Steiger filtering, and Bayesian colocalization confirmed that 12 proteins were colocalized with BD. Phenome-wide MR analysis revealed no significant side effects for potential drug targets, except for LRP8. External validation further underscored the concordance between the primary and validation cohorts, confirming MCTP1, DNM3, PDF, CTSF, AGRP, FRZB, LMAN2L, NCAM1, and TIMP4 are intriguing targets for BD. CONCLUSIONS: Our study identified druggable proteins for BD, including MCTP1, DNM3, and PDF in the brain; CTSF, AGRP, and FRZB in cerebrospinal fluid; and LMAN2L, NCAM1, and TIMP4 in plasma, delineating promising avenues to development of novel therapies.

Effect of fumigation height and time on cryopreservation of ram semen.

The cooling rate is a crucial factor in the process of freezing semen, influencing the overall freezing effectiveness. The height and time of fumigation can significantly impact the rate of cooling. Appropriate cooling rates can help minimize the formation of ice crystals in spermatozoa and reduce potential damage to them. Therefore, the aim of this study was to evaluate the effect of different fumigation heights and time for the cryopreservation of Hu ram semen. Experiments I-IV assessed the effect of semen cryopreservation by testing the post-thawed spermatozoa total motility (TM), progressive motility (PM) and kinetic parameters fumigated at distances of 2, 4, 6 and 8 cm for durations of 5, 10, 15 and 20 min, respectively. Based on the results of experiments I to IV, experiment V evaluated the effect of semen cryopreservation by testing the post-thawed spermatozoa TM, PM, kinetic parameters, plasma membrane integrity, acrosome integrity and reactive oxygen species (ROS) level fumigated at distances of 2, 4, 6 and 8 cm for duration of 20 min. The results indicated that fumigation at 2 cm for 20 min significantly (P < 0.05) improved spermatozoa TM, PM, mean angular displacement (MAD), plasma membrane integrity and acrosome integrity compared to other groups. Additionally, it significantly (P < 0.05) reduced spermatozoa ROS level compared to the 6 and 8 cm groups. In conclusion, fumigation for 20 min at a distance of 2 cm from the liquid nitrogen surface is the most suitable cooling method for the cryopreservation of Hu ram semen.

Biased virus transmission following sequential coinfection of Aedes aegypti with dengue and Zika viruses.

BACKGROUND: Mosquito-borne arboviruses are expanding their territory and elevating their infection prevalence due to the rapid climate change, urbanization, and increased international travel and global trade. Various significant arboviruses, including the dengue virus, Zika virus, Chikungunya virus, and yellow fever virus, are all reliant on the same primary vector, Aedes aegypti. Consequently, the occurrence of arbovirus coinfection in mosquitoes is anticipated. Arbovirus coinfection in mosquitoes has two patterns: simultaneous and sequential. Numerous studies have demonstrated that simultaneous coinfection of arboviruses in mosquitoes is unlikely to exert mutual developmental influence on these viruses. However, the viruses' interplay within a mosquito after the sequential coinfection seems intricated and not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We conducted experiments aimed at examining the phenomenon of arbovirus sequential coinfection in both mosquito cell line (C6/36) and A. aegypti, specifically focusing on dengue virus (DENV, serotype 2) and Zika virus (ZIKV). We firstly observed that DENV and ZIKV can sequentially infect mosquito C6/36 cell line, but the replication level of the subsequently infected ZIKV was significantly suppressed. Similarly, A. aegypti mosquitoes can be sequentially coinfected by these two arboviruses, regardless of the order of virus exposure. However, the replication, dissemination, and the transmission potential of the secondary virus were significantly inhibited. We preliminarily explored the underlying mechanisms, revealing that arbovirus-infected mosquitoes exhibited activated innate immunity, disrupted lipid metabolism, and enhanced RNAi pathway, leading to reduced susceptibility to the secondary arbovirus infections. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that, in contrast to simultaneous arbovirus coinfection in mosquitoes that can promote the transmission and co-circulation of these viruses, sequential coinfection appears to have limited influence on arbovirus transmission dynamics. However, it is important to note that more experimental investigations are needed to refine and expand upon this conclusion.

Pivotal Evaluation of Novel Dedicated Venous Stent for Iliofemoral Venous Obstruction: A Prospective Cohort Study.

PURPOSE: The purpose was to evaluate the clinical outcomes of a dedicated venous stent with the tripartite composite segments for the treatment of iliofemoral venous obstruction (IVO) in a mixed cohort of nonthrombotic iliac vein lesion (NIVL) and post-thrombotic syndrome (PTS) over a period of 12 months. METHODS: The Grency Trial is a prospective, multicenter, single-arm, open-label, pivotal study, which was conducted at 18 large tertiary hospitals in China from August 2019 to October 2020. A total of 133 hospitalized patients were screened and 110 patients with clinical, etiology, anatomical, and pathophysiology clinical class (CEAP) clinical grade C>3 and iliac vein stenosis >50% or occlusion, including 72 patients with NIVL and 38 patients with PTS, were implanted with Grency venous stents. Primary endpoint was stent patency at 12 months follow-up, and secondary outcomes were technical success; improvement in venous clinical severity score (VCSS) at 3, 6, and 12 month follow-up; and rates of clinical adverse events. RESULTS: Among 110 patients who were implanted with Grency venous stents, 107 patients completed the 12 month follow-up. All 129 stents were successfully implanted in 110 limbs. Twelve-month primary patency rate was 94.39% [95% confidence interval [CI]=88.19%-97.91%] overall, and 100% [94.94%-100%] and 83.33% [67.19%-93.63%] in the NIVL and PTS subgroups, respectively. Venous clinical severity score after iliac vein stenting improved significantly up to 12 months follow-up. There were 3 early major adverse events (1 intracerebral hemorrhage and 2 stent thrombosis events related to anticoagulation therapy), and 7 late major adverse events (1 cardiovascular death, 1 intracranial hemorrhage with uncontrolled hypertension, and 5 in-stent restenosis cases without stent fractures or migration). CONCLUSIONS: The Grency venous stent system appeared excellent preliminary safe and effective for IVO treatment. Further large-scale studies with longer-term follow-up are needed to evaluate long-term patency and durability of stent. CLINICAL IMPACT: The design of venous stents for iliofemoral venous obstruction (IVO) must address engineering challenges distinct from those encountered in arterial stenting. The Grency venous stent, a nitinol self-expanding stent specifically tailored for IVO, features a composite structure designed to meet the stent requirements of various iliac vein segments. The Grency Trial is a prospective, multicenter, single-arm, open-label pivotal study aimed at evaluating the efficacy and safety of the Grency stent system. Following a 12-month follow-up period, the Grency venous stent system has demonstrated both safety and efficacy in treating iliofemoral venous outflow obstruction.

Two-Step Perovskite Solar Cells with > 25% Efficiency: Unveiling the Hidden Bottom Surface of Perovskite Layer.

While significant efforts in surface engineering have been devoted to the conversion process of lead iodide (PbI2) into perovskite and top surface engineering of perovskite layer with remarkable progress, the exploration of residual PbI2 clusters and the hidden bottom surface on perovskite layer have been limited. In this work, a new strategy involving 1-butyl-3-methylimidazolium acetate (BMIMAc) ionic liquid (IL) additives is developed and it is found that both the cations and the anions in ILs can interact with the perovskite components, thereby regulating the crystallization process and diminishing the residue PbI2 clusters as well as filling vacancies. The introduction of BMIMAc ILs induces the formation of a uniform porous PbI2 film, facilitating better penetration of the second-step organic salt and fostering a more extensive interaction between PbI2 and the organic salt. Surprisingly, the oversized residual PbI2 clusters at the bottom surface of the perovskite layer completely diminish. In addition, advanced depth analysis techniques including depth-resolved grazing-incidence wide-angle X-ray scattering (GIWAXS) and bottom thinning technology are employed for a comprehensive understanding of the reduction in residual PbI2. Leveraging effective PbI2 management and regulation of the perovskite crystallization process, the champion devices achieve a power conversion efficiency (PCE) of 25.06% with long-term stability.

Association between per- and poly-fluoroalkyl substances and nonalcoholic fatty liver disease: A nested case-control study in northwest China.

Per- and poly-fluoroalkyl substances (PFAS) have been reported to have hepatotoxic effects. However, it is unclear whether they are linked to non-alcoholic fatty liver disease (NAFLD). This nested case-control study focused on the epidemiological links between PFAS and the prevalence of NAFLD. We selected 476 new cases of NAFLD and 952 age- and sex-matched controls from the Jinchang cohort population between 2014 and 2019. Serum concentrations of PFAS were measured using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Only PFAS with a detection rate of ≥90 % were included for analysis, which included PFPeA, PFOA, PFNA, PFHxS, PFOS, and 9Cl-PF3ONS. The relationship between single and co-exposure to PFAS and the occurrence of NAFLD was evaluated using conditional logistic regression, Quantile g-computation (QgC), and Bayesian kernel machine regression (BKMR) model. Logistic regression indicated that PFPeA, PFOA, and 9Cl-PF3ONS were positive correlation with the incidence of NAFLD after adjusting for confounders, with odds ratios (OR) and 95 % confidence interval (CI) of 3.13 (95 % CI: 2.53, 3.86), 1.39 (95 % CI: 1.12, 1.73), and 1.41 (95 % CI: 1.20, 1.66), respectively. PFNA, PFHxS, and PFOS were nonlinearly and negatively associated with the incidence of NAFLD, with OR (95 % CI) of 0.53 (0.46, 0.62), 0.83 (0.73, 0.95), and 0.52 (0.44, 0.61), respectively. QgC showed a significant joint effect of PFAS mixture on NAFLD onset (OR: 1.52, 95 % CI: 1.24, 1.88). BKMR showed a weak positive trend between PFAS mixtures and NAFLD incidence. Positive correlations were primarily driven by PFPeA and 9Cl-PF3ONS, while negative correlations were mainly influenced by PFNA and PFOS. The BKMR model also suggested that there was an interaction between PFOS and PFNA and other four PFAS compounds. In conclusion, our findings suggest that individual and co-exposure to PFAS is associated with a risk of NAFLD onset.

Patient-Controlled Subcutaneous Analgesia with Hydromorphone versus Oral Oxycontin for Opioid Titration of Cancer Pain: A Prospective Multicenter Randomized Trial.

Background: Studies have shown that oral oxycontin tablets can be used for opioid titration. The European Society for Medical Oncology (ESMO) guidelines for adult cancer pain recommend opioid titration through the parenteral route, usually the intravenous or subcutaneous route. Patient-controlled subcutaneous analgesia (PCSA) with hydromorphone needs further evaluation for opioid titration. This prospective multicenter study was designed to compare the efficacy and safety of hydromorphone PCSA with oral oxycontin tablets for opioid titration of cancer pain. Patients and Methods: Eligible patients with cancer pain were randomly assigned in a 1:1 ratio to the PCSA group or the oxycontin group for dose titration. Different titration methods were given in both groups depending on whether the patient had an opioid tolerance. The primary endpoint of this study was time to successful titration (TST). Results: A total of 256 patients completed this study. The PCSA group had a significantly lower TST compared with the oxycontin group (median [95% confidence interval (CI)], 5.5[95% CI:2.5-11.5] hours vs.16.0 [95% CI:11.5-22.5] hours; p<0.001). The frequency (median; interquartile) of breakthrough pain (Btp) over 24 hours was significantly lower in the PCSA group (2.5;2.0-3.5) than in the oxycontin group.(3.0; 2.5-4.5) (p=0.04). The pain was evaluated by numeric rating scale (NRS) score at 12 hours after the start of titration. The pain score (median; interquartile) was significantly lower in the PCSA versus the oxycontin group (2.5;1.5-3.0) vs 4.5;3.0-6.0) (p=0.02). The equivalent dose of oral morphine (EDOM) for a successful titration was similar in both groups (p=0.29), but there was a significant improvement in quality of life (QoL) in both groups (p=0.03). No between-group difference in the incidence of opioid-related adverse effects was observed (p=0.32). Conclusion: Compared with oral oxycontin tablet, the use of PCSA with hydromorphone achieved a shorter titration duration for patients with cancer pain (p<0.001), without significantly increasing adverse events (p=0.32).

The efficacy and safety of stereotactic body radiotherapy combined with systematic therapy for metastatic renal cell carcinoma: a systematic review and meta-analysis.

There is considerable interest in the potential of stereotactic body radiation therapy (SBRT) combined with systemic therapy such as tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs). However, its efficacy and safety remain unclear. The purpose of this study was to evaluate the efficacy and safety of conducting SBRT during ICI or TKI treatment in different disease settings for patients with metastatic renal cell carcinoma (mRCC). A total of 16 studies were ultimately included. Under the random effects model, the pooled 1-year local control rate (1-yr LCR) and objective response rate (ORR) were 90% (95% confidence interval [CI]: 80%-95%, I 2 = 67%) and 52% (95% CI: 37%-67%, I 2 = 90%), respectively. SBRT concomitant with different systemic therapy yield significant different 1-yr LCR (p < 0.01) and ORR (p = 0.02). Regarding survival benefits, the pooled 1-year progression-free survival (1-yr PFS) and 1-year overall survival (1-yr OS) rates were 45% (95% CI: 29%-62%, I 2 = 91%) and 85% (95% CI: 76%-91%, I 2 = 66%), respectively. 1-yr PFS and 1-yr OS in different disease settings demonstrated significant difference (p < 0.01). As for toxicity, the pooled incidence of grade 3-4 adverse events was 14% (95% CI: 5%-26%, I 2 = 90%). This study highlights the feasibility of utilizing these strategies in mRCC patients, especially those with a low metastatic tumor burden.

[Chemical constituents from Alangium chinense subsp. pauciflorum].

Chemical constituents of 70% ethanol extract of Alangium chinense subsp. pauciflorum were investigated. The 70% ethanol extract of A. chinense subsp. pauciflorum was isolated and purified by D-101 macroporous resins, silica gel, Sephadex LH-20 and other methods. As a result, nineteen compounds were isolated and identified as 4-cyclohexene-1α,2α,3α-triol-1-O-ß-D-glucoside(1), 1ß,4α,6α,13-tetrahydroxy-eudesm-11(12)-ene(2), sucrose(3), 1'-O-benzyl-α-L-rhamnopyranosyl-(1″→6')-ß-D-glucopyranoside(4), bis(2-ethylhexyl)benzene-1,2-dicarboxylate(5),(Z)-10-heneicosenoic acid(6), di-O-methylcrenati(7), methyl-α-D-fructofuranoside(8), ß-daucosterol(9), syringic acid(10), vanillicacid(11), octacosanol(12), isoarborinol(13), 2,7-dihydroxy-6-methyl-4-(1-methylethyl)-1-naphthalenecarboxylate(14),vanillin(15), coniferyl aldehyde(16), 9(11)-dehydroergosterolperoxide(17), 5α,8α-epidioxy-(22E,24R)-ergosta-6,22-dien-3ß-ol(18), ß-sitosterol(19), respectively. Compounds 1 and 2 were new compounds, compounds 5-11, 13, 15-18 were isolated from Alangium for the first time.The anti-inflammatory activity of compourd 1 was determinded by the LPS-induced RAW264.7 macrophage inflammation model. The results showed that the new compound 1 has a certain inhibitory effect on LPS-induced NO production of RAW264.7 cells, and the inhibitory rate was 54.57%.

Hexylammonium Acetate-Regulated Buried Interface for Efficient and Stable Perovskite Solar Cells.

Due to current issues of energy-level mismatch and low transport efficiency in commonly used electron transport layers (ETLs), such as TiO2 and SnO2, finding a more effective method to passivate the ETL and perovskite interface has become an urgent matter. In this work, we integrated a new material, the ionic liquid (IL) hexylammonium acetate (HAAc), into the SnO2/perovskite interface to improve performance via the improvement of perovskite quality formed by the two-step method. The IL anions fill oxygen vacancy defects in SnO2, while the IL cations interact chemically with Pb2+ within the perovskite structure, reducing defects and optimizing the morphology of the perovskite film such that the energy levels of the ETL and perovskite become better matched. Consequently, the decrease in non-radiative recombination promotes enhanced electron transport efficiency. Utilizing HAAc, we successfully regulated the morphology and defect states of the perovskite layer, resulting in devices surpassing 24% efficiency. This research breakthrough not only introduces a novel material but also propels the utilization of ILs in enhancing the performance of perovskite photovoltaic systems using two-step synthesis.

Bioinformatics analysis and identification of potential key genes and pathways in the pathogenesis of nonischemic cardiomyopathy.

Nonischemic cardiomyopathy (NICM) is a major cause of advanced heart failure, and the morbidity and mortality associated with NICM are serious medical problems. However, the etiology of NICM is complex and the related mechanisms involved in its pathogenesis remain unclear. The microarray datasets GSE1869 and GSE9128 retrieved from the Gene Expression Omnibus database were used to identify differentially expressed genes (DEGs) between NICM and normal samples. The co-expressed genes were identified using Venn diagrams. Kyoto Encyclopedia of Genes and Genomes pathway analyses and gene ontology enrichment were used to clarify biological functions and signaling pathways. Analysis of protein-protein interaction networks using Search Tool for the Retrieval of Interacting Genes/Proteins online to define the hub genes associated with NICM pathogenesis. A total of 297 DEGs were identified from GSE1869, 261 of which were upregulated genes and 36 were downregulated genes. A total of 360 DEGs were identified from GSE9128, 243 of which were upregulated genes and 117 were downregulated genes. In the 2 datasets, the screening identified 36 co-expressed DEGs. Kyoto Encyclopedia of Genes and Genomes pathway and gene ontology analysis showed that DEGs were mainly enriched in pantothenate and CoA biosynthesis, beta-alanine metabolism, kinetochore, G-protein beta/gamma-subunit complex, and other related pathways. The PPI network analysis revealed that DUSP6, EGR1, ZEB2, and XPO1 are the 4 hub genes of interest in the 2 datasets. Bioinformatics analysis of hub genes and key signaling pathways is an effective way to elucidate the mechanisms involved in the development of NICM. The results will facilitate further studies on the pathogenesis and therapeutic targets of NICM.

Mating harassment may boost the effectiveness of the sterile insect technique for Aedes mosquitoes.

The sterile insect technique is based on the overflooding of a target population with released sterile males inducing sterility in the wild female population. It has proven to be effective against several insect pest species of agricultural and veterinary importance and is under development for Aedes mosquitoes. Here, we show that the release of sterile males at high sterile male to wild female ratios may also impact the target female population through mating harassment. Under laboratory conditions, male to female ratios above 50 to 1 reduce the longevity of female Aedes mosquitoes by reducing their feeding success. Under controlled conditions, blood uptake of females from an artificial host or from a mouse and biting rates on humans are also reduced. Finally, in a field trial conducted in a 1.17 ha area in China, the female biting rate is reduced by 80%, concurrent to a reduction of female mosquito density of 40% due to the swarming of males around humans attempting to mate with the female mosquitoes. This suggests that the sterile insect technique does not only suppress mosquito vector populations through the induction of sterility, but may also reduce disease transmission due to increased female mortality and lower host contact.

Data-driven assisted real-time optimal control strategy of submerged arc furnace via intelligent energy terminals considering large-scale renewable energy utilization.

This study presents a data-driven assisted real-time optimization model which is an innovative approach to address the challenges posed by integrating Submerged Arc Furnace (SAF) systems with renewable energy sources, specifically photovoltaic (PV) and wind power, with modern intelligent energy terminals. Specifically, the proposed method is divided into two stages. The first stage is related to data-driven prediction for addressing local time-varying renewable energy and electricity market prices with predicted information, and the second stage uses an optimization model for real-time SAF dispatch. Connections between intelligent energy terminals, demand-side devices, and load management systems are established to enhance local renewable resource utilization. Additionally, mathematical formulations of the operating resistance in SAF are explored, and deep neuron networks are employed and modified for dynamic uncertainty prediction. The proposed approach is validated through a case study involving an intelligent energy terminal with a 12.5 MVA SAF system and 12 MW capacity renewable generators in an electricity market with fluctuating prices. The findings of this research underscore the efficacy of the proposed optimization model in reducing operational costs and enhancing the utilization of localized renewable energy generation. By integrating four distinct dissatisfaction coefficients into the optimization framework, we demonstrate the model's adaptability and efficiency. The application of the optimization strategy delineated herein results in the SAF system's profitability oscillating between $111 and $416 across various time intervals, contingent upon the coefficient settings. Remarkably, an aggregate daily loss recovery amounting to $1,906.84 can be realized during the optimization period. Such outcomes not only signify considerable economic advantages but also contribute to grid stability and the diminution of renewable energy curtailment, thereby underscoring the dual benefits of economic efficiency and sustainability in energy management practices.

Effect of Different Dilution Methods and Ratios of Ram Semen on Sperm Parameters after Cryopreservation.

The dilution method and ratio were tested to assess their effects on the Hu ram semen after cryopreservation. Experiment I aimed to explore the effect of various dilution ratios (1:1, 1:2, 1:3, 1:4) of diluent I (Tris-based and egg yolk) under the condition of 1:1 dilution of diluent II (diluent I and glycerol) on the Hu ram semen preserved in liquid nitrogen regarding spermatozoa motility and kinetic parameters. Experiment II aimed to investigate the effect of various dilution ratios (1:1, 1:2, 1:3, 1:4) of diluent I under the condition of 1:2 dilution of diluent II to the Hu ram semen for cryopreservation on spermatozoa motility and kinetic parameters. The purpose of experiment III is to assess the effect of various dilution methods and ratios on the cryopreservation of Hu ram semen by detecting spermatozoa motility, kinetic parameters, plasma membrane integrity, acrosome integrity and reactive oxygen species (ROS) level. Experiment III includes four groups: one-step dilution method and two-step dilution method. The two-step dilution method includes two groups: 1:2, 1:1 and 1:3, 1:2, and the one-step dilution method includes two groups: 1:5 and 1:11. The results indicated that the post-thawed spermatozoa total motility (TM), progressive motility (PM) and average motion degree (MAD) were highest in the 1:2 group and significantly higher (p < 0.05) than those in the 1:1 and 1:4 groups under the condition of 1:1 dilution of diluent II. The post-thawed spermatozoa TM and PM of the 1:3 group were significantly higher (p < 0.05) than those of the other groups under the condition of 1:2 dilution of diluent II. The post-thawed spermatozoa TM, PM, plasma membrane integrity and acrosome integrity of the two-step group (1:3, 1:2) were the highest and significantly higher (p < 0.05) than those in the other groups. Additionally, the post-thawed spermatozoa ROS level of the two-step group (1:3, 1:2) was significantly lower (p < 0.05) than that in the one-step groups (1:5 and 1:11). Therefore, a two-step dilution (1:3, 1:2) was found to be the most suitable method and ratio for diluting the Hu ram semen after cryopreservation.

Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as novel HIV-1 integrase strand transfer inhibitors.

Integrase plays an important role in the life cycle of HIV-1, and integrase strand transfer inhibitors (INSTIs) can effectively impair the viral replication. However, drug resistance mutations have been confirmed to decrease the efficacy of INSTI during the antiviral therapy. Herein, indole-2-carboxylic acid (1) was found to inhibit the strand transfer of integrase, and the indole nucleus of compound 1 was observed to chelate with two Mg2+ ions within the active site of integrase. Through optimization of compound 1, a series of indole-2-carboxylic acid derivatives were designed and synthesized, and compound 17a was proved to markedly inhibit the effect of integrase, with IC50 value of 3.11 µM. Binding mode analysis of 17a demonstrated that the introduced C6 halogenated benzene ring could effectively bind with the viral DNA (dC20) through π-π stacking interaction. These results indicated that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.

Assessment of TUFT1 and Rac1-GTP levels in triple-negative breast cancer patients: clinical and pathological correlations.

OBJECTIVE: The primary goal of this study was to investigate the expressions of TUFT1 (Tuftelin) and Rac1-GTP in the cancerous tissues of individuals with triple-negative breast cancer (TNBC). Additionally, we aimed to explore the correlation between TUFT1 and Rac1-GTP expressions and examine the associations of TUFT1 and Rac1-GTP expressions with the clinical and pathological indicators of the patients. METHODS: Ninety-six patients diagnosed with TNBC, scheduled for surgery between May 2022 and November 2022, were enrolled in this study. Cancerous tissue specimens were collected from these patients, and immunohistochemistry was employed to evaluate the levels of TUFT1 and Rac1-GTP expressions in the cancerous tissues. Subsequent to data collection, a comprehensive analysis was conducted to examine the correlation between TUFT1 and Rac1-GTP expressions. Furthermore, we sought to assess the associations of TUFT1 and Rac1-GTP expressions with the clinical and pathological indicators of the patients. RESULTS: The TUFT1 protein was expressed in both the membrane and cytoplasm of TNBC cancer cells, with notably higher expression observed in the cytoplasm. Rac1-GTP was primarily expressed in the cytoplasm. There was a positive correlation between the levels of TUFT1 and Rac1-GTP expressions (χ2 = 9.816, P < 0.05). The levels of TUFT1 and Rac1-GTP protein expressions showed no correlation with patient age (χ2 = 2.590, 2.565, P > 0.05); however, they demonstrated a positive correlation with tumor size (χ2 = 5.592,5.118), histological grading (χ2 = 6.730, 5.443), and lymph node metastasis (χ2 = 8.221, 5.180) (all with a significance level of P < 0.05). CONCLUSION: A significant correlation was identified between the levels of TUFT1 and Rac1-GTP expressions in the cancerous tissues of patients with TNBC, suggesting a close association with the progression of TNBC. The two molecules play significant roles in facilitating an early diagnosis and treatment of TNBC.

Engineered PDGFA-ligand-modified exosomes delivery T3 for demyelinating disease targeted therapy.

Demyelination is a proper syndrome in plenty of central nervous system (CNS) diseases, which is the main obstacle to recovery and still lacks an effective treatment. To overcome the limitations of the brain-blood barrier on drug permeability, we modified an exosome secreted by neural stem cells (NSCs), which had transfected with lentivirus armed with platelet-derived growth factors A (PDGFA)-ligand. Through the in vivo and in vitro exosomes targeting test, the migration ability to the lesion areas and OPCs significantly improved after ligand modification. Furthermore, the targeted exosomes loaded with 3,5, 30-L-triiodothyronine (T3) have a critical myelination ability in CNS development, administrated to the cuprizone animal model treatment. The data shows that the novel drug vector loaded with T3 significantly promotes remyelination compared with T3 alone. At the same time, it improved the CNS microenvironment by reducing astrogliosis, inhibiting pro-inflammatory microglia, and alleviating axon damage. This investigation provides a straightforward strategy to produce a targeting exosome and indicates a possible therapeutic manner for demyelinating disease.

Self-Assembly of Wheel-Shaped Nanographdiynes and Self-Template Growth of Graphdiyne.

Graphdiyne (GDY) multilayers show stacking-style-dependent physical properties; thus, controlling the stacking style of nanostructures is crucial for utilizing their electrical, optical, and transport properties in electro-optical devices. Herein, we report the assemblies of nanographdiynes decorated with substituents with different steric hindrances to adjust the stacking style. We show that the π-stacked aggregates were influenced by peripheral substituents and the substrate. Steric hexaterphenyl-substituted nanoGDY scaffolds led to dimer structures stacked in the AB-3 configuration with a twist angle of 26.01° or the AB-1 configuration with an in-plane shift along one diyne link. With the interval replacement of steric substituents with long C12 alkyl chains, nanoGDYs were stacked in the AB-2 configuration to decrease the steric congestion, eventually leading to one-dimensional (1D) nanofibrous aggregates. Self-assembly in the presence of substrates can result in ABC-stacked nanoGDYs, which endowed us with the possibility of using nanoGDY as the template for GDY growth in a homogeneous reaction. High-resolution transmission electron microscopy (HRTEM), powder X-ray diffraction (PXRD), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and near-infrared-ultraviolet-visible (NIR-UV-vis) absorption spectroscopy indicate that the crystalline GDY prepared in this way is a 1.18 eV bandgap semiconductor.

Misdiagnosis of eosinophilic cystitis: A case report and literature review.

RATIONALE: Eosinophilic cystitis (EC) is a rare and specific transmural inflammatory disease in clinic. At present, its etiology is unknown, its clinical manifestations are diverse, and its auxiliary examination lacks specificity, so it is easy to be missed or misdiagnosed in clinical practice. PATIENT CONCERNS: A 72-year-old male patient with symptoms of lower urinary tract obstruction accompanied by hematuria was diagnosed with benign prostatic hyperplasia with bleeding by B-ultrasound and urinary CT examination. After being treated with catheterization, anti-infection and hemostasis, he was selectively treated with transurethral resection of prostate, but he saw a pattern mass on the right back wall of the bladder during the operation. Considering bladder tumor, he removed the lesion and gave pirarubicin for bladder perfusion. However, the postoperative pathological result was EC. DIAGNOSIS: The diagnosis of EC can only rely on pathological examination, and the accurate and positive rate of biopsy can be improved by obtaining muscle tissue as much as possible at the same time of multi-point biopsy. INTERVENTION: Prednisone and cetirizine were given orally after transurethral resection of lesions, and tamsulosin and finasteride were given regularly to treat benign prostatic hyperplasia. OUTCOMES: No recurrence and abnormal urination were found during the follow-up for half a year, and the upper urinary tract function was normal. LESSONS: The clinical manifestations of EC are atypical, the laboratory examination and imaging examination are not specific, and it is difficult to make a definite diagnosis before operation. The diagnosis depends on pathological examination. Transurethral resection of the lesion can obviously improve the positive rate of biopsy while completely removing the lesion, and the combined drug treatment can achieve satisfactory results in a short period of time. Active follow-up after operation is very important to identify the recurrence of the disease and prevent the upper urinary tract function from being damaged.