Renal function after ureteral reconstruction surgery in patients with solitary kidney.

Background: Ureteral strictures (US) could lead to impaired kidney function, which was alleviated by ureteral reconstruction surgery. However, solitary kidney (SK) patients with US were more complicated to treat. This study aimed to evaluate the impact of reconstruction surgery on renal function based on estimated glomerular filtration rate (eGFR) in patients with SK. Methods: We retrospectively enrolled patients who underwent reconstruction surgery between April 2014 to March 2022. eGFR was measured pre- and postoperatively. The 'static renal function' was defined as a change in eGFR of 20% or less at the last follow-up, and the 'worsening renal function group' was defined as a decrease of greater than 20%. Results: A total of 61 SK patients were involved. The success rate of ureteral reconstruction surgery was 90.16% (55/61). The median follow-up time was 20.8 months (range, 3.7-109.2 months). The median eGFR was 65.5 (range, 15.1-99.9) and 65.3 (range, 3.8-123.4) mL/min/1.73 m2 at the baseline and the last follow-up. No statistically significant difference in eGFR was observed between the preoperative baseline and last follow-up visits (P=0.58). However, in patients with baseline renal dysfunction [chronic kidney disease (CKD) stage 3-5], the eGFR significantly improved at the last follow-up compared to the baseline (P=0.02). Three patients developed a 'worsening renal function' (4.92%). Besides, the systolic blood pressures (SBP) at follow-up significantly reduced compared to the preoperative baseline (P=0.002). Conclusions: Ureteral reconstruction surgery is an effective treatment to preserve renal function, which also achieves a high success rate and is associated with the reduction of SBP for SK patients with US.

Flow pattern maps of double emulsions transporting through bifurcation microchannels.

The transportation behaviors of compound droplets in confined channels are widespread phenomena while the physical mechanisms are far from being completely unraveled. In this work, behaviors of double emulsions flowing through bifurcation microchannels are experimentally studied with the aim of building universal flow pattern maps. Three flow patterns are categorized according to different features of daughter droplets in terms of size, uniformity, and shell thickness. A detailed analysis of the dynamics of interfacial evolutions in different patterns is carried out and the coupling interaction between interfaces is found to affect the minimum tail distance during transportation. It is feasible to obtain the threshold of the occurrence of the coupling interaction, due to the different variation tendencies in the two states, which relies on three dimensionless parameters, i.e. droplet length, length ratio, and capillary number. Furthermore, a novel physical model is proposed to build the flow pattern map, with the two transition boundaries being expressed as different relationships in terms of the three identified parameters. The physical mechanisms are summarized with the aid of force analysis. An excellent agreement is shown between the model and experimental results in different liquid systems and bifurcation structures, indicating the generality of the proposed model.

High-performance Piezoelectric Two-dimensional Covalent Organic Frameworks.

Organic piezoelectric nanogenerators (PENGs) are attractive in harvesting mechanical energy for various self-powering systems. However, their practical applications are severely restricted by their low output open circuit voltage. To address this issue, herein, we prepared two two-dimensional (2D) covalent organic frameworks (COFs, CityU-13 and CityU-14), functionalized with fluorinated alkyl chains for PENGs. The piezoelectricity of both COFs was evidenced by switchable polarization, characteristic butterfly amplitude loops, phase hysteresis loops, conspicuous surface potentials and high piezoelectric coefficient value (d33). The PENGs fabricated with COFs displayed highest output open circuit voltages (60 V for CityU-13 and 50 V for CityU-14) and delivered satisfactory short circuit current with an excellent stability of over 600 seconds. The superior open circuit voltages of CityU-13 and CityU-14 rank in top 1 and 2 among all reported organic materials-based PENGs.

Identifying behaviour-related and physiological risk factors for suicide attempts in the UK Biobank.

Suicide is a global public health challenge, yet considerable uncertainty remains regarding the associations of both behaviour-related and physiological factors with suicide attempts (SA). Here we first estimated polygenic risk scores (PRS) for SA in 334,706 UK Biobank participants and conducted phenome-wide association analyses considering 2,291 factors. We identified 246 (63.07%) behaviour-related and 200 (10.41%, encompassing neuroimaging, blood and metabolic biomarkers, and proteins) physiological factors significantly associated with SA-PRS, with robust associations observed in lifestyle factors and mental health. Further case-control analyses involving 3,558 SA cases and 149,976 controls mirrored behaviour-related associations observed with SA-PRS. Moreover, Mendelian randomization analyses supported a potential causal effect of liability to 58 factors on SA, such as age at first intercourse, neuroticism, smoking, overall health rating and depression. Notably, machine-learning classification models based on behaviour-related factors exhibited high discriminative accuracy in distinguishing those with and without SA (area under the receiver operating characteristic curve 0.909 ± 0.006). This study provides comprehensive insights into diverse risk factors for SA, shedding light on potential avenues for targeted prevention and intervention strategies.

HSF5 Deficiency Causes Male Infertility Involving Spermatogenic Arrest at Meiotic Prophase I in Humans and Mice.

Meiosis is a specialized cell division process that generates gametes for sexual reproduction. However, the factors and underlying mechanisms involving meiotic progression remain largely unknown, especially in humans. Here, it is first showed that HSF5 is associated with human spermatogenesis. Patients with a pathogenic variant of HSF5 are completely infertile. Testicular histologic findings in the patients reveal rare postmeiotic germ cells resulting from meiotic prophase I arrest. Hsf5 knockout (KO) mice confirms that the loss of HSF5 causes defects in meiotic recombination, crossover formation, sex chromosome synapsis, and sex chromosome inactivation (MSCI), which may contribute to spermatocyte arrest at the late pachytene stage. Importantly, spermatogenic arrest can be rescued by compensatory HSF5 adeno-associated virus injection into KO mouse testes. Mechanistically, integrated analysis of RNA sequencing and chromatin immunoprecipitation sequencing data revealed that HSF5 predominantly binds to promoters of key genes involved in crossover formation (e.g., HFM1, MSH5 and MLH3), synapsis (e.g., SYCP1, SYCP2 and SYCE3), recombination (TEX15), and MSCI (MDC1) and further regulates their transcription during meiotic progression. Taken together, the study demonstrates that HSF5 modulates the transcriptome to ensure meiotic progression in humans and mice. These findings will aid in genetic diagnosis of and potential treatments for male infertility.

The cuproptosis-related signature predicts the prognosis and immune microenvironments of primary diffuse gliomas: a comprehensive analysis.

BACKGROUND: Evidence has revealed a connection between cuproptosis and the inhibition of tumor angiogenesis. While the efficacy of a model based on cuproptosis-related genes (CRGs) in predicting the prognosis of peripheral organ tumors has been demonstrated, the impact of CRGs on the prognosis and the immunological landscape of gliomas remains unexplored. METHODS: We screened CRGs to construct a novel scoring tool and developed a prognostic model for gliomas within the various cohorts. Afterward, a comprehensive exploration of the relationship between the CRG risk signature and the immunological landscape of gliomas was undertaken from multiple perspectives. RESULTS: Five genes (NLRP3, ATP7B, SLC31A1, FDX1, and GCSH) were identified to build a CRG scoring system. The nomogram, based on CRG risk and other signatures, demonstrated a superior predictive performance (AUC of 0.89, 0.92, and 0.93 at 1, 2, and 3 years, respectively) in the training cohort. Furthermore, the CRG score was closely associated with various aspects of the immune landscape in gliomas, including immune cell infiltration, tumor mutations, tumor immune dysfunction and exclusion, immune checkpoints, cytotoxic T lymphocyte and immune exhaustion-related markers, as well as cancer signaling pathway biomarkers and cytokines. CONCLUSION: The CRG risk signature may serve as a robust biomarker for predicting the prognosis and the potential viability of immunotherapy responses. Moreover, the key candidate CRGs might be promising targets to explore the underlying biological background and novel therapeutic interventions in gliomas.

Exposure to a mixture of metal(loid)s and sleep quality in pregnant women during early pregnancy: A cross-sectional study.

Biological characteristics of pregnant women during early pregnancy make them susceptible to both poor sleep quality and metal/metalloid exposure. However, the effects of metal(loid) exposure on sleep quality in pregnant women remain unknown and unexplored. We aimed to examine the relationship between exposure to a mixture of metal(loid)s and pregnant women's sleep quality during early pregnancy. We recruited 493 pregnant women in the first trimester from prenatal clinics in Jinan, Shandong Province, China, and collected their spot urine samples. All urine specimens were assessed for eight metal(loid)s: arsenic (As), cadmium (Cd), iron (Fe), zinc (Zn), molybdenum (Mo), lead (Pb), selenium (Se), and mercury (Hg). We used the Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality. Linear regression, logistic regression, generalized additive models (GAMs), quantile g-computation, and Bayesian kernel machine regression (BKMR) were applied to investigate the relationships between metal(loid) exposure and sleep quality. The results from single metal(loid) models, quantile g-computation models, and BKMR models consistently suggested that Fe was positively related to women's sleep quality. Moreover, in the quantile g-computation models, As was the most critical contributor to the negative effects of the metal(loid) mixture on sleep quality. In addition, we found significant As by Fe interaction for scores of PSQI and habitual sleep efficiency, Pb by Fe interaction for PSQI and sleep latency, and Hg by Fe interaction for PSQI, suggesting the interactive effects of As and Fe, Pb and Fe, Hg and Fe on sleep quality and specific sleep components. Our study provided the first-hand evidence of the effects of metal(loid) exposure on pregnant women's sleep quality. The underlying mechanisms need to be explored in the future.

SNX5-Rab11a protects against cardiac hypertrophy through regulating LRP6 membrane translocation.

BACKGROUNDS: Pathological cardiac hypertrophy is considered one of the independent risk factors for heart failure, with a rather complex pathogenic machinery. Sorting nexins (SNXs), denoting a diverse family of cytoplasmic- and membrane-associated phosphoinositide-binding proteins, act as a pharmacological target against specific cardiovascular diseases including heart failure. Family member SNX5 was reported to play a pivotal role in a variety of biological processes. However, contribution of SNX5 to the development of cardiac hypertrophy, remains unclear. METHODS: Mice underwent transverse aortic constriction (TAC) to induce cardiac hypertrophy and simulate pathological conditions. TAC model was validated using echocardiography and histological staining. Expression of SNX5 was assessed by western blotting. Then, SNX5 was delivered through intravenous administration of an adeno-associated virus serotype 9 carrying cTnT promoter (AAV9-cTnT-SNX5) to achieve SNX5 cardiac-specific overexpression. To assess the impact of SNX5, morphological analysis, echocardiography, histological staining, hypertrophic biomarkers, and cardiomyocyte contraction were evaluated. To unravel potential molecular events associated with SNX5, interactome analysis, fluorescence co-localization, and membrane protein profile were evaluated. RESULTS: Our results revealed significant downregulated protein level of SNX5 in TAC-induced hypertrophic hearts in mice. Interestingly, cardiac-specific overexpression of SNX5 improved cardiac function, with enhanced left ventricular ejection fraction, fraction shortening, as well as reduced cardiac fibrosis. Mechanistically, SNX5 directly bound to Rab11a, increasing membrane accumulation of Rab11a (a Rab GTPase). Afterwards, this intricate molecular interaction upregulated the membrane content of low-density lipoprotein receptor-related protein 6 (LRP6), a key regulator against cardiac hypertrophy. Our comprehensive assessment of siRab11a expression in HL-1 cells revealed its role in antagonism of LRP6 membrane accumulation under SNX5 overexpression. CONCLUSIONS: This study revealed that binding of SNX5 with LRP6 triggers their membrane translocation through Rab11a assisting, defending against cardiac remodeling and cardiac dysfunction under pressure overload. These findings provide new insights into the previously unrecognized role of SNX5 in the progression of cardiac hypertrophy.

Tumor treating fields for newly diagnosed high-grade glioma based on the criteria of 2021 WHO CNS5: A retrospective analysis of Chinese patients in a single center.

BACKGROUND AND OBJECTIVE: High-grade glioma (HGG) is known to be characterized by a high degree of malignancy and a worse prognosis. The classical treatment is safe resection supplemented by radiotherapy and chemotherapy. Tumor treating fields (TTFields), an emerging physiotherapeutic modality that targets malignant solid tumors using medium-frequency, low-intensity, alternating electric fields to interfere with cell division, have been used for the treatment of new diagnosis of glioblastoma, however, their administration in HGG requires further clinical evidence. The efficacy and safety of TTFields in Chinese patients with HGG were retrospectively evaluated by us in a single center. METHODS: We enrolled and analyzed 52 patients with newly diagnosed HGG undergoing surgery and standard chemoradiotherapy regimens from December 2019 to June 2022, and followed them until June 2023. Based on whether they used TTFields, they were divided into a TTFields group and a non-TTFields group. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups. RESULTS: There were 26 cases in the TTFields group and 26 cases in the non-TTFields group. In the TTFields group, the median PFS was 14.2 months (95% CI: 9.50-18.90), the median OS was 19.7 months (95% CI: 14.95-24.25) , the median interval from surgery to the start of treatment with TTFields was 2.47 months (95% CI: 1.47-4.13), and the median duration of treatment with TTFields was 10.6 months (95% CI: 9.57-11.63). 15 (57.69%) patients experienced an adverse event and no serious adverse event was reported. In the non-TTFields group, the median PFS was 9.57 months (95% CI: 6.23-12.91) and the median OS was 16.07 months (95% CI: 12.90-19.24). There was a statistically significant difference in PFS (p = 0.005) and OS (p = 0.007) between the two groups. CONCLUSIONS: In this retrospective analysis, TTFields were observed to improve newly diagnosed HGG patients' median PFS and OS. Compliance was much higher than reported in clinical trials and safety remained good.

Insulin-related traits and prostate cancer: A Mendelian randomization study.

Investigating the causal relationship between insulin secretion and prostate cancer (PCa) development is challenging due to the multifactorial nature of PCa, which complicates the isolation of the specific impact of insulin-related factors. We conducted a Mendelian randomization (MR) study to investigate the associations between insulin secretion-related traits and PCa. We used 36, 60, 56, 23, 48, and 49 single nucleotide polymorphisms (SNPs) as instrumental variables for fasting insulin, insulin sensitivity, proinsulin, and proinsulin in nondiabetic individuals, individuals with diabetes, and individuals receiving exogenous insulin, respectively. These SNPs were selected from various genome-wide association studies. To clarify the causal relationship between insulin-related traits and PCa, we utilized a multivariable MR analysis to adjust for obesity and body fat percentage. Additionally, two-step Mendelian randomization was conducted to assess the role of insulin-like growth factor 1 (IGF-1) in the relationship between proinsulin and PCa. Two-sample MR analysis revealed strong associations between genetically predicted fasting insulin, insulin sensitivity, proinsulin, and proinsulin in nondiabetic individuals and the development of PCa. After adjustment for obesity and body fat percentage using multivariable MR analysis, proinsulin remained significantly associated with PCa, whereas other factors were not. Furthermore, two-step MR analysis demonstrated that proinsulin acts as a negative factor in prostate carcinogenesis, largely independent of IGF-1. This study provides evidence suggesting that proinsulin may act as a negative factor contributing to the development of PCa. Novel therapies targeting proinsulin may have potential benefits for PCa patients, potentially reducing the need for unnecessary surgical treatments.

Garsorasib in patients with KRASG12C-mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 2 trial.

BACKGROUND: Garsorasib (D-1553; InventisBio, Shangai, China), a potent KRASG12C inhibitor, has shown promising antitumour activity in patients with KRASG12C-mutated (ie, Gly12Cys) non-small-cell lung cancer (NSCLC) in a phase 1 study. We report results from a phase 2 study conducted to evaluate the efficacy and safety of garsorasib in patients with locally advanced or metastatic KRASG12C-mutated NSCLC. METHODS: This open-label, multicentre, single-arm, phase 2 trial enrolled adult patients with KRASG12C-mutated NSCLC who had previously been treated with platinum-based chemotherapy and immune checkpoint inhibitors from 43 hospitals in China. Participants received 600 mg garsorasib orally twice per day. Tumour assessments were performed at baseline, at the end of every two cycles (of 21 days) for the first eight cycles, and at the end of every three cycles thereafter. The primary endpoint was objective response rate (ORR) as assessed by an independent review committee (IRC) following the guidelines in Response Evaluation Criteria in Solid Tumours, version 1.1. Efficacy and safety were assessed in all patients who received at least one dose of garsorasib. This trial is registered at ClinicalTrials.gov, NCT05383898, and is active but no longer recruiting. FINDINGS: From June 17, 2022, to May 17, 2023, of 225 patients screened for eligibility, 123 patients were enrolled and treated with garsorasib. Of these 123 participants, the median age was 64 years (IQR 59-68), 108 (88%) were male and 15 (12%) were female. At data cutoff (Nov 17, 2023), the median follow-up duration was 7·9 months (IQR 6·3-10·4), and 82 (67%) of 123 patients had discontinued treatment. The IRC-confirmed ORR was 50% (61 of 123 patients; 95% CI 41-59). 117 (95%) of 123 patients reported treatment-related adverse events, with 61 (50%) experiencing grade 3 or higher events. The most common types of adverse events of grade 3 or higher associated with garsorasib were hepatic and gastrointestinal events, including increased liver enzymes, such as aspartate aminotransferase (21 [17%] of 123 participants), alanine aminotransferase (19 [15%] of 123 participants), and gamma-glutamyltransferase (28 [23%] of 123 participants); nausea (2 [2%] of 123 participants); and vomiting (2 [2%] of 123 participants). No new safety signals were identified, and most of the adverse events were well managed. INTERPRETATION: The results show that garsorasib has a high response rate, long duration of response, and an acceptable and manageable safety profile in patients with previously treated KRASG12C-mutated NSCLC. Garsorasib potentially provides a promising treatment option for this patient population. FUNDING: InventisBio.

Physiological and genetic responses of the benthic dinoflagellate Prorocentrum lima to polystyrene microplastics.

Microplastics are well known as contaminants in marine environments. With the development of biofilms, most microplastics will eventually sink and deposit in benthic environment. However, little research has been done on benthic toxic dinoflagellates, and the effects of microplastics on benthic dinoflagellates are unknown. Prorocentrum lima is a cosmopolitan toxic benthic dinoflagellate, which can produce a range of polyether metabolites, such as diarrhetic shellfish poisoning (DSP) toxins. In order to explore the impact of microplastics on marine benthic dinoflagellates, in this paper, we studied the effects of polystyrene (PS) on the growth and toxin production of P. lima. The molecular response of P. lima to microplastic stress was analyzed by transcriptomics. We selected 100 nm, 10 µm and 100 µm PS, and set three concentrations of 1 mg L-1, 10 mg L-1 and 100 mg L-1. The results showed that PS exposure had limited effects on cell growth, but increased the OA and extracellular polysaccharide content at high concentrations. After exposure to PS MPs, genes associated with DSP toxins synthesis, carbohydrate synthesis and energy metabolism, such as glycolysis, TCA cycle and pyruvate metabolism, were significantly up-regulated. We speculated that after exposure to microplastics, P. lima may increase the synthesis of DSP toxins and extracellular polysaccharides, improve the level of energy metabolism and gene expression of ABC transporter, thereby protecting algal cells from damage. Our findings provide new insights into the effects of microplastics on toxic benthic dinoflagellates.

Chiral MoS2@BC fibrous membranes selectively promote peripheral nerve regeneration.

BACKGROUND: Molybdenum disulfide (MoS2) has excellent physical and chemical properties. Further, chiral MoS2 (CMS) exhibits excellent chiroptical and enantioselective effects, and the enantioselective properties of CMS have been studied for the treatment of neurodegenerative diseases. Intriguingly, left- and right-handed materials have different effects on promoting the differentiation of neural stem cells into neurons. However, the effect of the enantioselectivity of chiral materials on peripheral nerve regeneration remains unclear. METHODS: In this study, CMS@bacterial cellulose (BC) scaffolds were fabricated using a hydrothermal approach. The CMS@BC films synthesized with L-2-amino-3-phenyl-1-propanol was defined as L-CMS. The CMS@BC films synthesized with D-2-amino-3-phenyl-1-propanol was defined as D-CMS. The biocompatibility of CMS@BC scaffolds and their effect on Schwann cells (SCs) were validated by cellular experiments. In addition, these scaffolds were implanted in rat sciatic nerve defect sites for three months. RESULTS: These chiral scaffolds displayed high hydrophilicity, good mechanical properties, and low cytotoxicity. Further, we found that the L-CMS scaffolds were superior to the D-CMS scaffolds in promoting SCs proliferation. After three months, the scaffolds showed good biocompatibility in vivo, and the nerve conducting velocities of the L-CMS and D-CMS scaffolds were 51.2 m/s and 26.8 m/s, respectively. The L-CMS scaffolds showed a better regenerative effect than the D-CMS scaffolds. Similarly, the sciatic nerve function index and effects on the motor and electrophysiological functions were higher for the L-CMS scaffolds than the D-CMS scaffolds. Finally, the axon diameter and myelin sheath thickness of the regenerated nerves were improved in the L-CMS group. CONCLUSION: We found that the CMS@BC can promote peripheral nerve regeneration, and in general, the L-CMS group exhibited superior repair performance. Overall, the findings of this study reveal that CMS@BC can be used as a chiral nanomaterial nerve scaffold for peripheral nerve repair.

[Characterization of carbon and oxygen isotopes of plant on climate and plant physiology at the southeastern margin of Qinghai-Tibet Plateau, China]. / é’è—é«˜åŽŸä¸œå—ç¼˜æ¤ç‰©ç¢³æ°§åŒä½ç´ å¯¹æ°”å€™åŠæ¤ç‰©ç”Ÿç†çš„è¡¨å¾.

To investigate the correlation between carbon and oxygen isotope compositions of plant cellulose and climatic factors as well as plant physiological indices on the southeastern margin of the Qinghai-Tibet Plateau, we examined plant species in eight sampling sites with similar latitudes and different longitudes in this region. Through the characteristics of δ13C and δ18O values, fractionation values (Δ13C and Δ18O) in leaf cellulose, we discussed water use efficiency (WUE) and the environmental factors, the variation of carbon and oxygen isotopes in the southeastern margin of the Qinghai-Tibet Plateau with elevation and longitude, and revealed the indication degrees of isotopic signals to different environments and vegetation physiology. By using the semi-quantitative model of carbon and oxygen dual isotopes, we investigated the physiological adaptation mechanisms of plants to varying environmental conditions. The results demonstrated that both Δ13C and Δ18O of cellulose decreased with increasing elevation and longitude, and Δ13C was more influenced by longitude, while Δ18O was more susceptible to elevation variation. Additionally, Δ13C and Δ18O were significantly and positively correlated with temperature (TEM), precipitation (PRE), potential evapotranspiration (PET), and relative humidity (RH). PRE was the dominant meteorological factor driving the variation of Δ13C, while RH was the dominant meteorological factor influencing Δ18O variation. In contrast to Δ13C, WUE showed a stronger correlation with elevation than with longitude, which increased as elevation and longitude increased. According to the carbon-oxygen model, plant stomatal conductance (gs) and photosynthetic capacity (Amax) decreased with increasing precipitation and relative humidity, while the values increased with increasing elevation and longitude. The combined analysis of carbon and oxygen isotopes of organic matters would yield additional environmental and gas exchange information for studies on climate tracing and vegetation physiology studies on the southeastern margin of the Qinghai-Tibet Plateau.

Synergistic and stepwise treatment of resveratrol and catechol in Haematococcus pluvialis for the overproduction of biomass and astaxanthin.

To increase the production of biomass and astaxanthin from Haematococcus pluvialis to meet the high market demand for astaxanthin, this study recruited two typical and negligible phytohormones (namely resveratrol and catechol) for the stepwise treatments of H. pluvialis. It was found that the hybrid and sequential treatments of resveratrol (200 µmol) and catechol (100 µmol) had achieved the maximum astaxanthin content at 33.96 mg/L and 42.99 mg/L, respectively. Compared with the hybrid treatment, the physiological data of H. pluvialis using the sequential strategy revealed that the enhanced photosynthetic performance via the Calvin cycle by RuBisCO improved the biomass accumulation during the macrozooid stage; meanwhile, the excessive ROS production had occurred to enhance astaxanthin production with the help of NADPH overproduction during the hematocyst stage. Overall, this study provides improved knowledge of the impacts of phytohormones in improving biomass and astaxanthin of H. pluvialis, which shed valuable insights for advancing microalgae-based biorefinery.

Deep learning-based pathological prediction of lymph node metastasis for patient with renal cell carcinoma from primary whole slide images.

BACKGROUND: Metastasis renal cell carcinoma (RCC) patients have extremely high mortality rate. A predictive model for RCC micrometastasis based on pathomics could be beneficial for clinicians to make treatment decisions. METHODS: A total of 895 formalin-fixed and paraffin-embedded whole slide images (WSIs) derived from three cohorts, including Shanghai General Hospital (SGH), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and Cancer Genome Atlas (TCGA) cohorts, and another 588 frozen section WSIs from TCGA dataset were involved in the study. The deep learning-based strategy for predicting lymphatic metastasis was developed based on WSIs through clustering-constrained-attention multiple-instance learning method and verified among the three cohorts. The performance of the model was further verified in frozen-pathological sections. In addition, the model was also tested the prognosis prediction of patients with RCC in multi-source patient cohorts. RESULTS: The AUC of the lymphatic metastasis prediction performance was 0.836, 0.865 and 0.812 in TCGA, SGH and CPTAC cohorts, respectively. The performance on frozen section WSIs was with the AUC of 0.801. Patients with high deep learning-based prediction of lymph node metastasis values showed worse prognosis. CONCLUSIONS: In this study, we developed and verified a deep learning-based strategy for predicting lymphatic metastasis from primary RCC WSIs, which could be applied in frozen-pathological sections and act as a prognostic factor for RCC to distinguished patients with worse survival outcomes.

Occurrence and mechanism of sulfamethoxazole in alginate-like extracellular polymers from excess sludge.

The recovery of biopolymers, particularly alginate-like extracellular polymers, from municipal sludge represents a promising step toward sustainable sludge treatment practices. Originating from wastewater plants in complexly polluted environments, alginate-like extracellular polymers carry potential environmental risks concerning their reuse. This study employs ultrahigh-performance liquid chromatography-tandem mass spectrometry to investigate the distribution coefficients and occurrence of alginate-like extracellular polymers and sulfamethoxazole. Results demonstrate a negative distribution coefficient, suggesting an inhibitory effect on sulfamethoxazole dissolution. The ethanol-extracted alginate-like extracellular polymers exhibits higher sulfamethoxazole levels (approximately 52%) than those obtained via dialysis extraction. Three-dimensional excitation-emission matrix analysis and adsorption studies indicate the absence of tyrosine-like substances in the alginate-like extracellular polymers, unlike in other extracellular polymeric substances. This absence diminishes hydrophobic interactions, highlighting that electrostatic interactions play a more important role. These insights are crucial for understanding the adsorption behavior of alginate-like extracellular polymers and optimizing their large-scale extraction processes.

Genome-editing of a circadian clock gene TaPRR95 facilitates wheat peduncle growth and heading date.

Plant height and heading date are important agronomic traits in wheat (Triticum aestivum L.) that affect final grain yield. In wheat, knowledge of pseudo-response regulator (PRR) genes on agronomic traits is limited. Here, we identify a wheat TaPRR95 gene by genome-wide association study to be associated with plant height. Triple allele mutant plants produced by CRISPR/Cas9 show increased plant height, particularly the peduncle, with an earlier heading date. The longer peduncle is mainly caused by the increased cell elongation at its upper section, whilst the early heading date is accompanied by elevated expression of flowering genes, such as TaFT and TaCO1. A peduncle-specific transcriptome analysis reveals up-regulated photosynthesis genes and down-regulated IAA/Aux genes for auxin signaling in prr95aabbdd plants that may act as a regulatory mechanism to promote robust plant growth. A haplotype analysis identifies a TaPRR95-B haplotype (Hap2) to be closely associated with reduced plant height and increased thousand-grain weight. Moreover, the Hap2 frequency is higher in cultivars than that in landraces, suggesting the artificial selection on the allele during wheat breeding. These findings suggest that TaPRR95 is a regulator for plant height and heading date, thereby providing an important target for wheat yield improvement.

Transcriptome analysis suggests broad jejunal alterations in Linghu's obesity-diarrhea syndrome: A pilot study.

BACKGROUND: Obesity is associated with a significantly increased risk for chronic diarrhea, which has been proposed as Linghu's obesity-diarrhea syndrome (ODS); however, its molecular mechanisms are largely unknown. AIM: To reveal the transcriptomic changes in the jejunum involved in ODS. METHODS: In a cohort of 6 ODS patients (JOD group), 6 obese people without diarrhea (JO group), and 6 healthy controls (JC group), high-throughput sequencing and bioinformatics analyses were performed to identify jejunal mucosal mRNA expression alterations and dysfunctional biological processes. In another cohort of 16 ODS patients (SOD group), 16 obese people without diarrhea (SO group), and 16 healthy controls (SC group), serum diamine oxidase (DAO) and D-lactate (D-LA) concentrations were detected to assess changes in intestinal barrier function. RESULTS: The gene expression profiles of jejunal mucosa in the JO and JC groups were similar, with only 1 differentially expressed gene (DEG). The gene expression profile of the JOD group was significantly changed, with 411 DEGs compared with the JO group and 211 DEGs compared with the JC group, 129 of which overlapped. The enrichment analysis of these DEGs showed that the biological processes such as digestion, absorption, and transport of nutrients (especially lipids) tended to be up-regulated in the JOD group, while the biological processes such as rRNA processing, mitochondrial translation, antimicrobial humoral response, DNA replication, and DNA repair tended to be down-regulated in the JOD group. Eight DEGs (CDT1, NHP2, EXOSC5, EPN3, NME1, REG3A, PLA2G2A, and PRSS2) may play a key regulatory role in the pathological process of ODS, and their expression levels were significantly decreased in ODS patients (P < 0.001). In the second cohort, compared with healthy controls, the levels of serum intestinal barrier function markers (DAO and D-LA) were significantly increased in all obese individuals (P < 0.01), but were higher in the SOD group than in the SO group (P < 0.001). CONCLUSION: Compared with healthy controls and obese individuals without diarrhea, patients with Linghu's ODS had extensive transcriptomic changes in the jejunal mucosa, likely affecting intestinal barrier function and thus contributing to the obesity and chronic diarrhea phenotypes.

Characterization of a small molecule inhibitor of the NLRP3 inflammasome and its potential use for acute lung injury.

Accumulating data support the key roles of the NLRP3 inflammasome, an essential component of the innate immune system, in human pathophysiology. As an emerging drug target and a potential biomarker for human diseases, small molecule inhibitors of the NLRP3 inflammasome have been actively pursued. Our recent studies identified a small molecule, MS-II-124, as a potent NLRP3 inhibitor and potential imaging probe. In this report, MS-II-124 was further characterized by an unbiased and comprehensive analysis through Eurofins BioMAP Diversity PLUS panel that contains 12 human primary cell-based systems. The analysis revealed promising activities of MS-II-124 on inflammation and immune functions, further supporting the roles of the NLRP3 inflammasome in these model systems. Further studies of MS-II-124 in mouse model of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and NLRP3 knockout mice demonstrated its target engagement, efficacy to suppress inflammatory cytokines and infiltration of immune cells in the lung tissues. In summary, the results support the therapeutic potential of MS-II-124 as a NLRP3 inhibitor and warrant future studies of this compound and its analogs to develop therapeutics for ALI/ARDS.