Diterpenoids with Potent Anti-Psoriasis Activity from Euphorbia helioscopia L.

Psoriasis, an immune-mediated inflammatory skin disorder, seriously affects the quality of life of nearly four percent of the world population. Euphorbia helioscopia L. is the monarch constituent of Chinese ZeQi powder preparation for psoriasis, so it is necessary to illustrate its active ingredients. Thus, twenty-three diterpenoids, including seven new ones, were isolated from the whole herb of E. helioscopia L. Compounds 1 and 2, each featuring a 2,3-dicarboxylic functionality, are the first examples in the ent-2,3-sceo-atisane or the ent-2,3-sceo-abietane family. Extensive spectroscopic analysis (1D, 2D NMR, and HRMS data) and computational methods were used to confirm their structures and absolute configurations. According to the previous study and NMR data from the jatropha diterpenes obtained in this study, some efficient 1H NMR spectroscopic rules for assigning the relative configurations of 3α-benzyloxy-jatroph-11E-ene and 7,8-seco-3α-benzyloxy-jatropha-11E-ene were summarized. Moreover, the hyperproliferation of T cells and keratinocytes is considered a key pathophysiology of psoriasis. Anti-proliferative activities against induced T/B lymphocytes and HaCaT cells were tested, and IC50 values of some compounds ranged from 6.7 to 31.5 µM. Compounds 7 and 11 reduced the secretions of IFN-γ and IL-2 significantly. Further immunofluorescence experiments and a docking study with NF-κB P65 showed that compound 13 interfered with the proliferation of HaCaT cells by inhibiting the NF-κB P65 phosphorylation at the protein level.

gp78-regulated KAP1 phosphorylation induces radioresistance in breast cancer by facilitating PPP1CC/PPP2CA ubiquitination.

Adjuvant radiation therapy is a common treatment for breast cancer, yet its effectiveness is often limited by radioresistance in patients. Identifying novel targets to combat this radioresistance is imperative. Recent investigations show that gp78 is upregulated in drug-resistant breast cancer cells. Our study reveals that gp78 markedly increased the phosphorylation of KAP1 and promoted DNA damage repair caused by ionizing radiation. Mechanistically, gp78 degrades phosphatases (PPP1CC/PPP2CA) in a ubiquitination-dependent manner. PPP1CC and PPP2CA are crucial regulators of KAP1 phosphorylation in response to DNA damage. Therefore, gp78 leads to a notable elevation in the phosphorylation of KAP1 by degrading phosphatases, thereby promoting the DNA damage repair process and increasing the radioresistance of tumor cells. The identification of gp78 as a pivotal regulator in radioresistance suggests a promising avenue for intervention. Combining blockade strategies targeting gp78 holds a signification potential for reversing radioresistance and improving the efficacy of breast cancer radiotherapy.

[Application of modified grafted tubularized incised plate urethroplasty in hypospadias].

Objective: To investigate the clinical feasibility and effectiveness of the modified grafted tubularized incised plate urethroplasty (G-TIP), namely "glans G-TIP (GG-TIP) ", in treatment of hypospadias. Methods: A clinical data of 137 children with hypospadias qualified by the selection criteria between January 2021 and June 2023 was retrospectively analyzed. Among them, 75 children were treated with GG-TIP (GG-TIP group) and 62 with G-TIP (G-TIP group). There was no significant difference ( P>0.05) between the two groups in terms of age, hypospadias type, penile length, penile head width, penile head height, penile curvature, meatus-apex distance, urethral plate width, and distance from the distal endpoint of navicular groove to the dorsal or ventral midline point of the glans corona, and the difference between the two. The operation time, reconstructed urethral length, distance from meatus to ventral glans corona, postoperative complications, maximum urinary flow rate at 2 weeks after operation, and the hypospadias objective scoring evaluation (HOSE) score at 6 months after operation in the two groups were recorded and analyzed. Results: The operation time was significantly shorter in GG-TIP group than in G-TIP group ( P<0.05); but there was no significant difference ( P>0.05) between the two groups in terms of reconstructed urethral length and distance from meatus to ventral glans corona. All urinary meatus located at the tip of glans with vertical fissure shape. All children in the two groups were followed up 6-35 months (median, 26 months). During follow-up, there were 3 cases of urethral fistula, 2 cases of urethral stricture, and 1 case of glans separation in GG-TIP group, and 3, 3, and 1 cases in the G-TIP group, respectively. There was no significant difference in the incidence of complications between the two groups ( P>0.05). The maximum urinary flow rate at 2 weeks and the HOSE score at 6 months after operation were significantly higher in GG-TIP group than in G-TIP group ( P<0.05). Conclusion: GG-TIP is safe and effective for repairing hypospadias in children. Compared with G-TIP, it has the advantages of relatively simple operation, shortened operation time, significant improvement in urinary flow rate, and better cosmetic results.

Investigating thermal properties of 2D non-layered material using a NEMS-based 2-DOF approach towards ultrahigh-performance bolometer.

Two-dimensional (2D) non-layered materials in many aspects differ from their layered counterparts, and the exploration of their physical properties has produced many intriguing findings. However, due to challenges in applying existing experimental techniques to such nanoscale samples, their thermal properties have remained largely uncharacterized, hindering further exploration and device application using this promising material system. Here, we demonstrate an experimental study of thermal conduction in ß-In2S3, a typical non-layered 2D material, using a resonant nanoelectromechanical systems (NEMS) platform. We devise a new two-degrees-of-freedom technique, more responsive and sensitive than Raman spectroscopy, to simultaneously determine both the thermal conductivity to be 3.7 W m-1 K-1 and its interfacial thermal conductance with SiO2 as 6.4 MW m-2 K-1. Leveraging such unique thermal properties, we further demonstrate a record-high power-to-frequency responsivity of -447 ppm/µW in ß-In2S3 NEMS sensors, the best among drumhead NEMS-based bolometers. Our findings offer an effective approach for studying thermal properties and exploring potential thermal applications of 2D non-layered materials.

Optical force sensor based on plasmon modulated upconversion luminescence.

We report a novel force sensor exploiting the interaction between plasmonic nanostructures and upconversion nanoparticles (UCNPs). The nanosensor is composed of a gold nanodisk and UCNPs separated by a flexible polymer layer. The gold nanodisk is designed to exhibit a plasmon resonance that selectively enhances one of the emission bands of the UCNPs while leaving the other ones largely unaffected. As the nanosensor is compressed or stretched by an external force, the polymer layer thickness changes, modulating the plasmon-UCNP coupling. The resulting changes in the luminescence intensity provides the basis for sensing. Furthermore, the nanosensor employs ratiometric sensing which makes it highly robust against any environmental variations. Our nanosensors exhibit two orders of magnitude higher responsivity than previously reported UCNP-based force sensors. They can be prepared as an on-chip sensor array or in a colloidal solution, making them suitable for a variety of applications in biology and robotics.

Preparation of hapten and monoclonal antibody of hesperetin and establishment of enzyme-linked immunosorbent assay.

Hesperetin is the aglycone of hesperidin and is widely found in the Rutaceae plants and herbal medicines. It exhibits antioxidant, detoxifying, anti-inflammatory, and antimicrobial properties, similar to hesperidin. It has also shown potential in the regulation of certain diseases. In order to detect hesperetin in complex matrix samples such as citrus and herbal, we developed an anti-hesperetin monoclonal antibody and established an indirect competitive enzyme-linked immunosorbent assay (icELISA). The half maximal inhibitory concentration (IC50) was determined to be 2.03 ng/mL, the detection range was 0.39-12.73 ng/mL. In practical sample testing, the concentration of hesperidin measured by icELISA is consistent with the result of UPLC-MS/MS, and the correlation coefficient (R2) is 0.97. These results showed that the established method has good accuracy, reproducibility and broad application prospects, and can be used for the detection of hesperetin in complex matrix samples (such as citrus and herbal samples).

Diastolic Stress Echocardiography in Patients with Hypertrophy Cardiomyopathy: Association with Exercise Capacity.

Diastolic dysfunction plays a major role in precipitating congestive heart failure (CHF) in hypertrophic cardiomyopathy (HCM) patients. In many such patients, symptoms are unmasked only during exercise, as left ventricular (LV) filling pressure is normal at rest but increase with exercise. We sought to establish if abnormal post-exercise diastolic parameters are associated with reduced exercise capacity in patients with HCM. We examined 590 asymptomatic/minimally symptomatic HCM patients (54±14 years, 57% men, body mass index 30±6 kg/m2, 84% on betablockers) with HCM by two-dimensional and Doppler echocardiography at rest and following maximal treadmill exercise echocardiography (TSE). A complete echocardiogram (including LV ejection fraction, LV thickness, LV outflow tract [LVOT] gradient, degree of mitral regurgitation [MR]) was recorded. Diastolic parameters (septal and lateral [e'] velocities of the mitral annulus, peak early [E] and late [A] mitral inflow velocity, E/A ratio, E/e', right ventricular systolic pressure [RVSP] and left atrial volume index [LAVI]) were recorded at rest and post-TSE. Exercise functional capacity was recorded and divided into <85% or >85% of age-gender predicted metabolic equivalents (AGP-METs). Following maximal exercise, 32% patients had at least moderate MR, mean LVOT gradient was 61±59 mmHg, E/A ratio was 1.2± 1.0, average E/e' ratio 12.9±1.0 and peak RVSP was 36±15 mm Hg. Only 42% patients achieved >85% of AGP-METs; mean Mets were 7±3. On multivariable logistic regression analysis, higher body mass index (odds ratio [OR] 1.05), betablocker use (OR 2.58), higher LAVI (OR 1.02), higher peak-stress LVOTG (OR 1.06), peak-stress E/e' (OR 1.04) and higher RVSP (OR 1.03) were independently associated with <85% AGP-METs achieved (all p<0.05). In conclusion, in asymptomatic/minimally symptomatic patients with HCM undergoing TSE, there is a significant and independent association between abnormal diastolic response to exercise and reduced exercise capacity in HCM. Incorporating diastolic parameters during stress echocardiography could provide incremental diagnostic utility in deciphering the exact etiology of dyspnea in such patients.

Long-term grazing changed the spatial distributions of dominant species in typical steppe of Inner Mongolia.

Dominant species occupy a pivotal role in plant community, influencing the structure and function of the ecosystem. The spatial distributions of dominant species can react to the effect of different grazing intensities, thereby reflecting their tolerance and adaptive strategies toward grazing. In this study, geostatistical methods were mainly used to study the spatial distribution characteristics of Stipa krylovii Roshev. and Leymus chinensis (Trin.) Tzvel. species at two interval scales (quadrat size 5 m × 5 m, 10 m × 10 m) and two treatments (free grazing, FG, 1.66 sheep·ha- 1·a- 1; control, CK, 0 sheep·ha- 1·a- 1) in typical steppe of Inner Mongolia. A systematic sampling method was used in each 100 m × 100 m representative sample plots to obtain the height, coverage, and density of all species in the community. The results showed that grazing altered the concentrated distribution of S. krylovii and the spatial mosaic distribution pattern of S. krylovii and L. chinensis while having no effect on the spatial clumped distribution of L. chinensis. It also found that the spatial distributions of dominant species are primarily affected by structural factors, and random factors such as long-term grazing led to a transition of S. krylovii from a concentrated distribution to a small patchy random pattern should not be overlooked. Our findings suggest that long-term grazing alters the spatial distribution pattern of dominant species and that adaptive strategies may be the key for maintaining the dominant role of structural factors.

CCDC181 is required for sperm flagellum biogenesis and male fertility in mice.

The structural integrity of the sperm flagellum is essential for proper sperm function. Flagellar defects can result in male infertility, yet the precise mechanisms underlying this relationship are not fully understood. CCDC181, a coiled-coil domain-containing protein, is known to localize on sperm flagella and at the basal regions of motile cilia. Despite this knowledge, the specific functions of CCDC181 in flagellum biogenesis remain unclear. In this study, Ccdc181 knockout mice were generated. The absence of CCDC181 led to defective sperm head shaping and flagellum formation. Furthermore, the Ccdc181 knockout mice exhibited extremely low sperm counts, grossly aberrant sperm morphologies, markedly diminished sperm motility, and typical multiple morphological abnormalities of the flagella (MMAF). Additionally, an interaction between CCDC181 and the MMAF-related protein LRRC46 was identified, with CCDC181 regulating the localization of LRRC46 within sperm flagella. These findings suggest that CCDC181 plays a crucial role in both manchette formation and sperm flagellum biogenesis.

Homozygous CCDC146 mutation causes oligoasthenoteratozoospermia in humans and mice.

Infertility represents a significant health concern, with sperm quantity and quality being crucial determinants of male fertility. Oligoasthenoteratozoospermia (OAT) is characterized by reduced sperm motility, lower sperm concentration, and morphological abnormalities in sperm heads and flagella. Although variants in several genes have been implicated in OAT, its genetic etiologies and pathogenetic mechanisms remain inadequately understood. In this study, we identified a homozygous nonsense mutation (c.916C>T, p.Arg306*) in the coiled-coil domain containing 146 ( CCDC146) gene in an infertile male patient with OAT. This mutation resulted in the production of a truncated CCDC146 protein (amino acids 1-305), retaining only two out of five coiled-coil domains. To validate the pathogenicity of the CCDC146 mutation, we generated a mouse model ( Ccdc146 mut/mut ) with a similar mutation to that of the patient. Consistently, the Ccdc146 mut/mut mice exhibited infertility, characterized by significantly reduced sperm counts, diminished motility, and multiple defects in sperm heads and flagella. Furthermore, the levels of axonemal proteins, including DNAH17, DNAH1, and SPAG6, were significantly reduced in the sperm of Ccdc146 mut/mut mice. Additionally, both human and mouse CCDC146 interacted with intraflagellar transport protein 20 (IFT20), but this interaction was lost in the mutated versions, leading to the degradation of IFT20. This study identified a novel deleterious homozygous nonsense mutation in CCDC146 that causes male infertility, potentially by disrupting axonemal protein transportation. These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying CCDC146 mutant-associated infertility in human males.

Radiofrequency vs Steroid Injections for Spinal Facet and Sacroiliac Joint Pain: A Systematic Review and Meta-Analysis.

Purpose: Pain management for spinal facet joint (SFJ) and sacroiliac joint (SIJ) pain is challenging, often requiring interventions like radiofrequency ablation (RFA) or corticosteroid injections (CI). This study aims to assess and compare the effectiveness of CI and RFA in treating SFJ and SIJ pain. We combine these treatments due to their shared pathophysiology, similar therapeutic interventions, and the necessity for an integrated approach to spinal pain management. Patients and methods: Literature search from PubMed, Scopus, CENTRAL and Google Scholar for published studies upto 31st December 2023, and reporting data of patients who were treated using CI of RFA for SFJ and SIJ pain. Pooled standardized mean difference (SMD) with a 95% Confidence Interval (CI) was calculated. Results: Our meta-analysis incorporated thirteen studies. Overall, patients, treated with CI had a higher pain intensity score compared to patients treated with RFA (SMD=0.92; 95% CI: 0.19 to 1.65) at 3 months, and at 6 months (SMD=1.53; 95% CI: 0.66 to 2.40) after the treatment. No significant association was reported at 12 months (SMD=1.47; 95% CI: -0.03 to 2.97). Subgroup analysis based on joint types revealed increased pain intensity scores in patients who were treated with CI for SIJ (SMD=1.25; 95% CI: 0.39 to 2.11) and SFJ (SMD=1.33; 95% CI: 0.09 to 2.57) pain. A negative but not significant effect was detected in patients, treated with CI for cervical joint pain (SMD=-0.40; 95% CI: -0.90 to 0.10). Patients treated with CI exhibited higher functional disability score compared to patients treated with RFA at 3 months (SMD=1.28; 95% CI: 0.20 to 2.35) post-treatment. Conclusion: This study suggests that RFA may offer superior pain relief with longer duration compared to steroid injections for spinal facet and sacroiliac joint pain. Decision regarding specific interventions should be individualized and consider patient preferences, clinical context, and potential risks.

Causal relationship between systemic circulatory inflammatory regulators and intervertebral disc degeneration: A bidirectional 2-sample Mendelian randomization study.

In the context of the development of intervertebral disc degeneration (IDD), inflammatory mediators play a pivotal role. Nevertheless, due to the influence of the inflammatory microenvironment, the causal relationship between specific inflammatory mediators and the development of IDD remains uncertain. The understanding of the causal relationship between inflammatory mediators and IDD is of great importance in preventing and delaying disc degeneration in the future. We utilized genetic data concerning systemic circulating inflammatory regulators obtained from a Genome-Wide Association Study (GWAS) analyzing 41 serum cytokines in a cohort of 8293 individuals from Finland. The genetic data for IDD were derived from the most recent GWAS summary statistics conducted within the FinnGen consortium, encompassing 37,636 IDD cases and 270,964 controls. Our analysis employed bidirectional 2-sample Mendelian randomization (MR) techniques, which included several MR methods such as MR Egger, weighted median, inverse variance weighted, weighted mode, and simple mode. Additionally, the MR-PRESSO method was employed to identify horizontal pleiotropy, heterogeneity was quantified using the Cochran Q statistic, and MR-Egger intercept analysis was performed to assess pleiotropy. We established causal relationships between 3 specific inflammatory factors and IDD. Elevated levels of MIP-1ß (OR = 0.956, 95% CI: -0.08 to -0.006; P = .02) and IFN-G (OR = 0.915, 95% CI: -0.16 to -0.02; P = .01) expression were associated with a reduced risk of IDD. Conversely, genetic susceptibility to IDD was linked to a decrease in IL-13 levels (OR = 0.967, 95% CI: -0.063 to -0.004; P = .03). In this study, we have identified inflammatory factors that exhibit a causal relationship with the onset and progression of IDD, as supported by genetic predictions.

A new infrageneric classification of Gastrochilus (Orchidaceae: Epidendroideae) based on molecular and morphological data.

Gastrochilus is an orchid genus containing 73 species of mainly epiphytic on trees or rocks in mountain forests of tropical and subtropical Asia. Previous phylogenetic analyses and morphological assessments have failed to produce a well-resolved phylogeny at the infrageneric level. In the present study, a new infrageneric classification of Gastrochilus is proposed based on thoroughly morphological and phylogenetic analyses based on 52 species. Our phylogenetic analysis divided the genus into six sections including three new sections, G. sect. Pseudodistichi, G. sect. Brachycaules and G. sect. Acinacifolii. We also reinstate G. suavis to the specific rank. Furthermore, two new species, G. armeniacus Jun Y. Zhang, B. Xu & Yue H. Cheng and G. minjiangensis Jun Y. Zhang, B. Xu & Yue H. Cheng, are described and illustrated. A key to six sections of the genus is presented.

Oral complement factor D inhibitor danicopan for paroxysmal nocturnal hemoglobinuria.

INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder characterized by episodic hemolysis, with additional clinical manifestations including thrombosis and bone marrow failure. The US FDA approved a complement factor D inhibitor, danicopan (Voydeya™), previously known as ACH-4471, for the treatment of extravascular hemolysis in adults with PNH on 29 March 2024. The primary purpose of this review is to examine the clinical efficacy and safety of danicopan. AREAS COVERED: We systematically searched for articles on PubMed, Web of Science, and three publishers Springer, Elsevier, Wiley up to 6 May 2024. EXPERT OPINION: Danicopan acts on the alternative pathway of the complement cascade, preferentially controlling C3 fragment-mediated extravascular hemolysis. Recommended dosage is 150 mg orally three times a day, which can be increased to 200 mg three times a day when necessary. Vaccination is required before administration to prevent infections by encapsulated bacteria. In a pivotal phase 3 trial ALPHA, danicopan significantly increased hemoglobin levels compared to placebo (p < 0.0001), 60% of patients experienced an increase in hemoglobin levels of at least 2 g/dL, compared to none in the placebo group (adjusted difference of 47%; p < 0.0001). Common adverse events during danicopan treatment include headache and upper respiratory tract infection.

Attitudes and perceptions of Chinese oncologists towards artificial intelligence in healthcare: a cross-sectional survey.

Background: Artificial intelligence (AI) is transforming healthcare, yet little is known about Chinese oncologists' attitudes towards AI. This study investigated oncologists' knowledge, perceptions, and acceptance of AI in China. Methods: A cross-sectional online survey was conducted among 228 oncologists across China. The survey examined demographics, AI exposure, knowledge and attitudes using 5-point Likert scales, and factors influencing AI adoption. Data were analyzed using descriptive statistics and chi-square tests. Results: Respondents showed moderate understanding of AI concepts (mean 3.39/5), with higher knowledge among younger oncologists. Only 12.8% used ChatGPT. Most (74.13%) agreed AI is beneficial and could innovate healthcare, 52.19% respondents expressed trust in AI technology. Acceptance was cautiously optimistic (mean 3.57/5). Younger respondents (∼30) show significantly higher trust (p = 0.004) and acceptance (p = 0.009) of AI compared to older respondents, while trust is significantly higher among those with master's or doctorate vs. bachelor's degrees (p = 0.032), and acceptance is higher for those with prior IT experience (p = 0.035).Key drivers for AI adoption were improving efficiency (85.09%), quality (85.53%), reducing errors (84.65%), and enabling new approaches (73.25%). Conclusions: Chinese oncologists are open to healthcare AI but remain prudently optimistic given limitations. Targeted education, especially for older oncologists, can facilitate AI implementation. AI is largely welcomed for its potential to augment human roles in enhancing efficiency, quality, safety, and innovations in oncology practice.

Enhanced photocatalytic CO2 conversion over 0D/2D CsPbBr3/BiOCl S-scheme heterojunction via boosting charge separation.

The stable contact of heterogeneous interfaces and the substantial exposure of active sites are crucial for enhancing the photocatalytic performance of semiconductor catalysts. However, most reported two-dimensional (2D)/2D CsPbBr3 and BiOCl heterostructures are fabricated using electrostatic self-assembly methods, which exhibit significant deficiencies in precise interface quality control and effective active site exposure. In this study, we fabricate a zero-dimensional (0D)/2D CsPbBr3/BiOCl heterojunction via a two-step calcination method, achieving an efficient direct S-scheme configuration. Optimizing interfacial contact and band alignment between CsPbBr3 quantum dots and BiOCl nanosheets enhances cross-plane charge transfer, promoting superior charge separation. This 0D/2D CsPbBr3/BiOCl heterojunction exhibits enhanced carrier mobility and high conversion rates without cocatalysts or sacrificial agents. The mechanism underlying the accelerated S-scheme charge transfer is comprehensively elucidated through a combination of analytical techniques and density functional theory (DFT) calculations. This study offers a novel approach for managing charge carrier segregation and mobility in CO2 reduction photocatalysts.

Preparation of monoclonal antibody against rhoifolin and its application in enzyme-linked immunosorbent assay of rhoifolin and diosmin.

Both rhoifolin and diosmin belong to flavonoids, which are widely present in citrus. Diosmin is not only used in the medical field in the world, but also used as a dietary supplement in the United States. Rhoifolin has a similar structure to diosmin and also exhibits antioxidant and anti-inflammatory properties. In this study, an anti-rhoifolin monoclonal antibody was prepared and an indirect competitive enzyme-linked immunosorbent assay (icELISA) method was established. The half-maximal inhibitory concentration (IC50) of icELISA was determined to be 4.83 ng/mL, and the detection range was 0.97-33.87 ng/mL. The results of UPLC-MS/MS and icELISA generally demonstrate consistency. Moreover, by exploiting the cross-reactivity of the antibody, diosmin in tablets can be detected by icELISA. The results demonstrate that the developed method has good accuracy, reproducibility, and broad application prospects.

Sodium-glucose cotransporter 2 inhibitors and renal cancer in the US FDA adverse event reporting system.

BACKGROUND: Recent evidence suggests an association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and a higher risk of renal cancer. OBJECTIVE: We conducted a pharmacovigilance analysis using the US FDA Adverse Event Reporting System (FAERS) to investigate the disproportionate association between SGLT2 inhibitors and renal cancer. METHODS: We used AERSMine to mine data from FAERS, covering the period from 2014 Q1 to 2023 Q3. The control group was treated with other glucose-lowering medications (ATC-A10B). Disproportionality analysis results were performed using a proportional reporting ratio (PRR) with a 95% confidence interval (CI) and an information component (IC) with 95% credible interval. RESULTS: Compared to the control group, the SGLT2 inhibitor group had a higher disproportionate renal cancer reporting frequency (0.92 vs 0.27/1000 reports; PRR 3.38; 95% CI 2.68-4.25; p < 0.001) with an IC of 1.36 (0.60-2.06), comprising dapagliflozin (PRR 4.14; 2.95-5.80; p < 0.001), empagliflozin (PRR 2.74; 1.94-3.89; p < 0.001), and canagliflozin (PRR 3.56; 2.48-5.12; p < 0.001). Consistent results were obtained in the diabetes indication with the primary outcomes only for the SGLT2 inhibitors group (not individual molecule). The results of the sensitivity analysis (excluding hypertension indication or antihypertensive drugs, obesity, smoking, alpha-1 blockers, or anti-renal cancer drugs) were highly consistent with the main outcomes, indicating good robustness of the results. The results from 2004 Q1 to 2023 Q3 were similar to those from 2014 Q1 to 2023 Q3, with the exception of empagliflozin. CONCLUSION: There was a disproportionate association between SGLT2 inhibitors and renal cancer, which supports the current meta-analysis results indicating an increased risk of renal cancer associated with SGLT2 inhibitors.

Screening antimicrobial peptides and probiotics using multiple deep learning and directed evolution strategies.

Owing to their limited accuracy and narrow applicability, current antimicrobial peptide (AMP) prediction models face obstacles in industrial application. To address these limitations, we developed and improved an AMP prediction model using Comparing and Optimizing Multiple DEep Learning (COMDEL) algorithms, coupled with high-throughput AMP screening method, finally reaching an accuracy of 94.8% in test and 88% in experiment verification, surpassing other state-of-the-art models. In conjunction with COMDEL, we employed the phage-assisted evolution method to screen Sortase in vivo and developed a cell-free AMP synthesis system in vitro, ultimately increasing AMPs yields to a range of 0.5-2.1 g/L within hours. Moreover, by multi-omics analysis using COMDEL, we identified Lactobacillus plantarum as the most promising candidate for AMP generation among 35 edible probiotics. Following this, we developed a microdroplet sorting approach and successfully screened three L. plantarum mutants, each showing a twofold increase in antimicrobial ability, underscoring their substantial industrial application values.