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Yuhao Zeng,1,&ast; Sha Zhu,1,&ast; Zilin Wang,1 Junru Chen,1 Jindong Dai,1 Zhenhua Liu,1 Guangxi Sun,1 Jiayu Liang,1 Xingming Zhang,1 Zhipeng Wang,1 Jinge Zhao,1 Yuchao Ni,1 Jiyu Yang,1 Minghao Wang,1 Qiang Wei,1 Xiang Li,1 Ni Chen,2 Zhiping Li,3 Xin Wang,3 Yali Shen,3 Jin Yao,4 Rui Huang,5 Jiyan Liu,6 Diming Cai,7 Hao Zeng,1 Pengfei Shen1 1Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 5Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 6Department of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 7Department of Medical Ultrasound, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pengfei Shen; Hao Zeng, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China, Email cdhx510@163.com; kucaizeng@163.comPurpose: Multidisciplinary team (MDT) discussion is a widely used model to manage patients diagnosed with cancer. However, there has been no direct evidence to prove its effect on the prognosis of metastatic renal cell carcinoma (mRCC) patients, so this study explored the impact of MDT discussion on mRCC patient survival.Methods: The clinical data of 269 mRCC patients were retrospectively collected from 2012 to 2021. The cases were grouped into the MDT and non-MDT groups, then subgroup analysis was performed according to different histology types, as well as exploring the role of MDT in patients who have undergone multiple-line therapy. Overall survival (OS) and progression free survival (PFS) were set as the study endpoint.Results: Approximately half (48.0%, 129/269) of the patients were in the MDT group, with univariable survival analyses showing these patients had remarkably longer median OS (MDT group: 73.7 months; non-MDT group: 33.2 months, hazard ratio (HR): 0.423 (0.288, 0.622), p< 0.001) and longer median PFS (MDT group: 16.9 months, non-MDT group: 12.7 months, HR: 0.722 (0.542, 0.962), p=0.026). Furthermore, MDT management resulted in longer survival for both ccRCC and non-ccRCC subgroups. Patients in the MDT group were more likely to receive multi-line therapy (MDT group: 79/129, 61.2% vs non-MDT group: 56/140, 40.0%, p< 0.001), and within this patient group, MDT management still resulted in longer OS (MDT group: 94.0 months; non-MDT group: 43.5 months, p=0.009).Conclusion: MDT is associated with prolonged overall survival in mRCC independent of histology, ensuring that patients receive better management and precise treatment.Keywords: mRCC, MDT, overall survival, prognosis, ccRCC, non-ccRCC, multi-line treatment

The exploration of efficient single-atom catalysts provides a prospective pattern for the sustainable development of electrocatalytic nitrogen fixation.

To investigate the association of computed tomography-assessed body composition with survival outcomes of metastatic renal cell carcinoma (mRCC) received immunotherapy.In this multicenter, retrospective study, we reviewed 251 mRCC patients who received anti-PD1 from five centers. We analyzed the relationship between BMI, skeletal muscle area (SM), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and subcutaneous adipose percentage (SAT%) with progression-free survival (PFS) and overall survival (OS). The spatial localization T cells was investigated by multiplex immunofluorescence.Among 224 evaluable patients, 23 (10.3%) patients were underweight, 118 (52.7%) had normal weight, 65 (29%) were overweight, and 18 patients (8%) were obese. The median age was 55 years and most patients were male (71%). No significant improvement in PFS (HR, 0.61; 95% CI, 0.27-1.42) or OS (HR, 1.09; 95% CI, 0.38-3.13) was observed for the obese patients. Besides, SM, VAT, and SAT were not associated with survival outcomes (all p0.05). Interestingly, SAT% independently predicted PFS (as continuous variable, HR: 0.02; 95% CI, 0.01-0.11) and OS (HR:0.05; 95% CI, 0.01-0.39), which remained significant in multivariate modeling (as continuous variable, adjusted HR for PFS, 0.01; 95% CI, 0.00-0.04; adjusted HR for OS, 0.08; 95% CI, 0.01-0.72). These associations were consistent in subgroup analysis of different gender, BMI, PD-L1 positive, and sarcopenia group. Tumor of high SAT% patients had a higher intratumoral PD1High SAT% predicts better outcomes in mRCC patients treated with anti-PD1 and T cell location may account for the better response.• CT-based subcutaneous adipose percentage independently predicted progression-free survival and overall survival. • Patients with a higher subcutaneous adipose percentage had a higher intratumoral PD1

NOTCH2NLC GGC repeat expansions have been identified to be associated with essential tremor (ET). Our aim was to characterize ET patients with NOTCH2NLC repeat expansions versus non-expansions and describe distinctive clinical features of repeat expanded patients with long-term follow-up according to the new tremor classification.Participants included 597 ET pedigrees, 412 sporadic cases and 1085 healthy controls. Repeat expansions of GGC in NOTCH2NLC were screened, and comprehensive clinical features were investigated. A longitudinal clinical assessment and reclassification were performed in NOTCH2NLC expanded patients.In total, 27 ET pedigrees (27/597) and three sporadic patients (3/412) were identified with pathogenic NOTCH2NLC GGC repeat expansions (≥60 repeats). Intermediate-length GGC repeats (41-59 repeats) were found in four sporadic ET cases and one control subject, and the frequency was higher than that in control participants (4/412 vs. 1/1085, p = 0.022). About 46 ET patients (43 familial cases from 27 pedigrees and three sporadic cases) with NOTCH2NLC GGC repeat expansions had higher Essential Tremor Rating Assessment Scale I, Essential Tremor Rating Assessment Scale II and Non-Motor Symptoms Scale scores and lower Mini-Mental State Examination scores than the patients without expansions. Patients with pathogenic GGC repeats were reclassified as pure ET (25/46), ET-plus (11/46) and ET-neuronal intranuclear inclusion disease (10/46) subgroups at 2-8 years of follow-up.Our results further supported that NOTCH2NLC GGC repeat expansions were associated with ET. Patients with pathogenic GGC repeats presented with more severe motor and non-motor symptoms. Further long-term follow-up and subtype studies will help to define the role of NOTCH2NLC in ET.

Soil exchange cations are a basic indicator of soil quality and environmental clean-up potential. The accurate and efficient acquisition of information on soil cation content is of great importance for the monitoring of soil quality and pollution prevention. At present, few scholars focus on soil exchangeable cations using remote sensing technology. This study proposes a new method for estimating soil cation content using hyperspectral data. In particular, we introduce Boruta and successive projection (SPA) algorithms to screen feature variables, and we use Guangdong Province, China, as the study area. The backpropagation neural network (BPNN), genetic algorithm–based back propagation neural network (GABP) and random forest (RF) algorithms with 10-fold cross-validation are implemented to determine the most accurate model for soil cation (Ca2+, K+, Mg2+, and Na+) content estimations. The model and hyperspectral images are combined to perform the spatial mapping of soil Mg2+ and to obtain the spatial distribution information of images. The results show that Boruta was the optimal algorithm for determining the characteristic bands of soil Ca2+ and Na+, and SPA was the optimal algorithm for determining the characteristic bands of soil K+ and Mg2+. The most accurate estimation models for soil Ca2+, K+, Mg2+, and Na+ contents were Boruta-RF, SPA-GABP, SPA-RF and Boruta-RF, respectively. The estimation effect of soil Mg2+ (R2 = 0.90, ratio of performance to interquartile range (RPIQ) = 3.84) was significantly better than the other three elements (Ca2+: R2 = 0.83, RPIQ = 2.47; K+: R2 = 0.83, RPIQ = 2.58; Na+: R2 = 0.85, RPIQ = 2.63). Moreover, the SPA-RF method combined with HJ-1A HSI images was selected for the spatial mapping of soil Mg2+ content with an R2 of 0.71 and RPIQ of 2.05. This indicates the ability of the SPA-RF method to retrieve soil Mg2+ content at the regional scale.

In this paper, make use of PVSOL software studied the generation performance and Economic benefits of PV system at various inclinations. And then analyzed residential load, industrial load and commercial load system performance and self-sufficiency under different battery capacity. The results show that for Shanghai area, when the inclination angle of PV panel is about 23o, the annual total power generation of PV system reaches the maximum. The self-sufficiency rate of PV systems with industrial load is higher than commercial load, and the self-sufficiency rate of PV systems with residential load is the lowest. The self-sufficiency rate of PV systems with batteries are higher than PV systems without batteries, and the increment of installation power can increase self-sufficiency rate of the PV system.

Effects of dietary supplementation of comfrey polysaccharides (CPs) on production performance, egg quality, and microbial composition of cecum in laying hens were evaluated. A total of 240 laying hens were allocated into 4 groups with 6 replicates per group. The laying hens were fed diets containing CPs at levels of 0, 0.5, 1.0, and 1.5 %, respectively. The results showed that the egg production rate increased by 5.97 %, the egg mass improved by 6.71 %, and the feed conversion rate reduced by 5.43 % in the 1.0 % supplementation group of CPs compared with those in the control group. The digestibility of ash, crude fat, and phosphorus was notably improved by the addition of CPs at 1.0 % (P 0.05). The relative abundances of Bacteroidetes at the phylum level, Bacteroidaceae, Rikenellaceae, and Prevotellaceae at the family level were increased by CPs (P 0.05). The relative abundances of Bacteroides, Megamonas, Rikenellaceae_RC9_gut_group, [Ruminococcus]_torques_group, Methanobrevibacter, Desulfovibrio, Romboutsia, Alistipes, and Intestinimonas at the genus level were increased by CPs (P 0.05). Dietary supplementation of CPs could enhance the production performance of laying hens, which might be related to the improvement of nutrient digestibility and microbial community modulations in the cecum. Therefore, CPs have potential application value as prebiotics in laying hens.

Numerous predictive models for Parkinson’s disease (PD) incidence have been published recently. However, the model performance and methodological quality of those available models are yet needed to be summarized and assessed systematically. In this systematic review, we systematically reviewed the published predictive models for PD incidence and assessed their risk of bias and applicability. Three international databases were searched. Cohort or nested case-control studies that aimed to develop or validate a predictive model for PD incidence were considered eligible. The Prediction model Risk Of Bias ASsessment Tool (PROBAST) was used for risk of bias and applicability assessment. Ten studies covering 10 predictive models were included. Among them, four studies focused on model development, covering eight models, while the remaining six studies focused on model external validation, covering two models. The discrimination of the eight new development models was generally poor, with only one model reported C index > 0.70. Four out of the six external validation studies showed excellent or outstanding discrimination. All included studies had high risk of bias. Three predictive models (the International Parkinson and Movement Disorder Society [MDS] prodromal PD criteria, the model developed by Karabayir et al. and models validated by Faust et al.) are recommended for clinical application by considering model performance and resource-demanding. In conclusion, the performance and methodological quality of most of the identified predictive models for PD incidence were unsatisfactory. The MDS prodromal PD criteria, model developed by Karabayir et al. and model validated by Faust et al. may be considered for clinical use.

ObjectiveParkinson's disease (PD) and dystonia are two closely related movement disorders with overlaps in clinical phenotype. Variants in several dystonia-related genes were demonstrated to be associated with PD; however, genetic evidence for the involvement of dystonia-related genes in PD has not been fully studied. Here, we comprehensively investigated the association between rare variants in dystonia-related genes and PD in a large Chinese cohort.MethodsWe comprehensively analyzed the rare variants of 47 known dystonia-related genes by mining the whole-exome sequencing (WES) and whole-genome sequencing (WGS) data from 3,959 PD patients and 2,931 healthy controls. We initially identified potentially pathogenic variants of dystonia-related genes in patients with PD based on different inheritance models. Sequence kernel association tests were conducted in the next step to detect the association between the burden of rare variants and the risk for PD.ResultsWe found that five patients with PD carried potentially pathogenic biallelic variants in recessive dystonia-related genes including COL6A3 and TH. Additionally, we identified 180 deleterious variants in dominant dystonia-related genes based on computational pathogenicity predictions and four of which were considered as potentially pathogenic variants (p.W591X and p.G820S in ANO3, p.R678H in ADCY5, and p.R458Q in SLC2A1). A gene-based burden analysis revealed the increased burden of variant subgroups of TH, SQSTM1, THAP1, and ADCY5 in sporadic early-onset PD, whereas COL6A3 was associated with sporadic late-onset PD. However, none of them reached statistical significance after the Bonferroni correction.ConclusionOur findings indicated that rare variants in several dystonia-related genes are suggestively associated with PD, and taken together, the role of COL6A3 and TH genes in PD is highlighted.

A milestone was set in modern machine learning history when AlphaGo Zero, based on reinforcement learning and with no training data from human players, became the undefeated Go champion against all machines and humans. Currently, Deepmind is building its next generation of protein folding prediction AI expected to surpass the famed AlphaFold that has already surpassed all human scientists, using the same mechanism of Zero, namely, reinforcement learning. In this work, we focus on using reinforcement learning and game theory to solve for the optimal strategies for the dice game Pig, in a novel simultaneous playing setting. First, we derived analytically the optimal strategy for the 2-player simultaneous game using dynamic programming, mixed-strategy Nash equilibrium. At the same time, we proposed a new Stackelberg value iteration framework to approximate the near-optimal pure strategy. Next, we developed the corresponding optimal strategy for the multiplayer independent strategy game numerically. Finally, we presented the Nash equilibrium for simultaneous Pig game with infinite number of players. To help promote the learning of and interest in reinforcement learning, game theory and statistics, we have further implemented a website where users can play both the sequential and simultaneous Pig game against the optimal strategies derived in this work.

Background Fumarate hydratase–deficient renal cell carcinoma (FH-RCC) is a rare highly aggressive subtype of kidney cancer for which the distinct genomic, transcriptomic, and evolutionary relationships between metastatic and primary lesions are still unclear. Methods In this study, whole-exome, RNA-seq, and DNA methylation sequencing were performed on primary-metastatic paired specimens from 19 FH-RCC cases, including 23 primary and 35 matched metastatic lesions. Phylogenetic and clonal evolutionary analyses were used to investigate the evolutionary characteristics of FH-RCC. Transcriptomic analyses, immunohistochemistry, and multiple immunofluorescence experiments were performed to identify the tumor microenvironmental features of metastatic lesions. Results Paired primary and metastatic lesions generally showed similar characteristics of tumor mutation burden, tumor neoantigen burden, microsatellite instability score, CNV burden, and genome instability index. Notably, we identified an FH-mutated founding MRCA (the most recent common ancestor) clone that dominated the early evolutionary trajectories in FH-RCC. Although both primary and metastatic lesions manifested high immunogenicity, metastatic lesions exhibited higher enrichment of T effector cells and immune-related chemokines, together with upregulation of PD-L1, TIGIT, and BTLA. In addition, we found that concurrent NF2 mutation may be associated with bone metastasis and upregulation of cell cycle signature in metastatic lesions. Furthermore, although in FH-RCC metastatic lesions in general shared similar CpG island methylator phenotype with primary lesions, we found metastatic lesions displaying hypomethylated chemokine and immune checkpoints related genomic loci. Conclusions Overall, our study demonstrated the genomic, epigenomic, and transcriptomic features of metastatic lesions in FH-RCC and revealed their early evolutionary trajectory. These results provided multi-omics evidence portraying the progression of FH-RCC.

Purpose To report our early experience of a novel surgical approach for penile urethral strictures after hypospadias repair, using a lateral incision to keep the ventral tissue and vasculature of the penis intact and to avoid the need for tissue interposition. Patients and methods A total of 21 patients underwent lateral incision 1-stage urethroplasty with oral mucosal graft. The median age of the patients was 21 years old (range, 13–47). The median number of prior procedures for hypospadias repair was 3 (range, 1–9) with 18 of 21 patients (85.7%) undergoing greater than 1 prior reconstructive procedure. The mean length of the penile urethral strictures was 4.5 ± 1.7 cm, with a range of 1.0 to 8.0 cm. Selection criteria for lateral incision 1-stage urethroplasty include: non-obliterative stricture, no or mild penile curvature and no urethrocutaneous fistula. Results Median follow-up was 30 months (range, 6–73). Success was achieved in 17 of 21 patients (80.9%). The 4 (19.0%) patients with treatment failure developed recurrent urethral strictures. Of the 4 men with recurrent strictures, 3 were ultimately treated successfully by DVIU (2) or two-stage urethroplasty (1), and one patient chose repeated dilation. Conclusions For patients with penile urethral stricture after hypospadias repair with non-obliterative stricture, no significant penile curvature and no urethrocutaneous fistula, a lateral approach with oral mucosal graft is a simple technique that avoids the need for tissue interposition and keeps the penile ventral tissue and vasculature intact, resulting in a low risk of complications.

Emerging evidence highlights the important impact of early-life exposures on cancer development later in life. The present study aimed to investigate the impacts of a high-fat diet in early life on the mammary microenvironment in relation to breast tumorigenesis. Forty-four female C57BL/6 mice were fed a low-fat diet (LF, 10 kcal% fat) or a high-fat diet (HF, 60 kcal% fat) for 8 weeks starting at ~4 weeks of age. Twenty-two mice were sacrificed immediately after an 8 week feeding, and the rest of mice were switched to a normal diet for maintenance (Lab Diet, #5P76) for additional 12 weeks. A panel of metabolic parameters, inflammatory cytokines, as well as tumorigenic Wnt-signaling target genes were analyzed. The HF diet increased body weight and exacerbated mammary metabolic and inflammatory status. The disrupted microenvironment remains significant to the later life equivalent to young adulthood (p < 0.05). Mammary Wnt-signaling was elevated right after the HF diet as indicated by the upregulated expression of its downstream genes, whereas it was surprisingly suppressed after switching diets (p < 0.05). In summary, HF-induced overweight/obesity in early life altered the mammary metabolic and inflammatory microenvironments in favor of breast tumorigenesis, although its overall impact to breast cancer later in life warrants further investigation.

BACKGROUND Background: Machine learning (ML) algorithms have provided more choices for diabetic patients to manage blood glucose (BG) more properly. However, because of abundant types of algorithms, choosing appropriate models is vital important. OBJECTIVE Objective: Therefore, this study aimed to comprehensively assess the performance of ML algorithms to predict BG values with a systematic review and network Meta-analysis, and those to detect and predict adverse BG events were assessed by calculating pooled estimates of sensitivity and specificity. METHODS Methods: PubMed, EMbase, Web of Science, and IEEE explore were systematically searched for studies on predicting BG values and predicting or detecting adverse BG events using ML algorithm from their inception to November 2022. Primary outcomes were relative ranks of ML algorithms for predicting BG values in different predict horizons (PH), and pooled estimates of sensitivity and specificity of algorithms for detecting or predicting adverse BG events. This study is registered with PROSPERO, registration ID: CRD42022375250. RESULTS Results: In total, 46 eligible studies were included for Meta-analysis. For ML algorithms predicting BG values, the means of root mean absolute error (RMSE(SD)) in PH of 15 min, 30min, 45min, and 60min were 18.88 (19.71), 21.40 (12.56), 21.27 (5.17), and 30.01 (7.23) mg/dl, respectively. Neural network related model (NNM) showed relatively highest performance in different PH. Furthermore, the pooled estimates (95%CI) of positive likelihood ratio (PLR), and negative likelihood ratio (NLR) of ML algorithms were 8.3 (5.7-12.0), and 0.31 (0.22-0.44) for predicting hypoglycemia, and 2.4 (1.6-3.7) and 0.37 (0.29-0.46) for detecting hypoglycemia. CONCLUSIONS Conclusions: In summary, for predicting precise BG values, the RMSE increases with the rise of PH, and NNM showed relatively highest performance among all the algorithms. Meanwhile, current machine learning algorithms have sufficient ability to predict hypoglycemia events, while their ability for detecting hypoglycemia events needs to be enhanced. CLINICALTRIAL Trial Registration: The study protocol has been registered in the international prospective register of systematic reviews (PROSPERO; Registration ID: CRD42022375250).

The catalytic conversion of greenhouse gases, such as N2O, is a promising way to mitigate global warming. In this work, density functional theory (DFT) studies were performed to study N2O reduction by CO over single-atom catalysts (SACs) and compare the performance of noble (Au/C2N) and non-noble (Cu/C2N) SACs. The computational results indicated that catalytic N2O reduction on both catalysts occurs via two mechanisms: (I) the N2O adsorption mechanism—starting from the adsorption on the catalysts, N2O decomposes to a N2 molecule and O-M/C2N intermediate, and then CO reacts with O atom on the O-M/C2N intermediate to form CO2; and (II) the CO adsorption mechanism—CO and N2O are adsorbed on the catalyst successively, and then a synergistic reaction occurs to produce N2 and CO2 directly. The computational results show that mechanism I exhibits an obvious superiority over mechanism II for both catalysts due to the lower activation enthalpy. The activation enthalpies of the rate-determining step in mechanism I are 1.10 and 1.26 eV on Au/C2N and Cu/C2N, respectively. These results imply that Cu/C2N, an abundant-earth SAC, can be as active as expensive Au/C2N. Herein, our research provides a theoretical foundation for the catalytic reduction of N2O and broadens the application of non-noble-metal SACs.

Origanum majorana belongs to the Lamiaceae family as a famous spice plant in Egypt, which is used to treat arthritis, allergies, fever, flu, hypertension, respiratory infections, migraine, and asthma. In our studies, it was found that the ethanol extract of O. marjoram could significantly reduce NO release at 200 ( P < 0.001 ), 100 ( P < 0.001 ) and 50 ( P < 0.01 ) μg/mL compared with the model group. Therefore, the chemical constituents were further studied to obtain the bioactive compounds. As a result, ten compounds were isolated and identified from the 70% ethanol extract of O. marjoram, including six flavonoids (3–8), two terpene derivatives (9-10), one lignan (2), and one phenolic glycoside (1). Among them, compounds 1–3, 5, and 9-10 were isolated from this genus for the first time. Compounds 1, 9, and 10 could significantly decrease the content of NO at the concentration of 100 μm ( P < 0.001 ) in RAW264.7 cells induced by LPS. Furthermore, compounds 9 and 10 were more effective than compound 1 to lower the content at 50 μm ( P < 0.001 ).

The efficiency of plant regeneration from explants is influenced by phytohormones and environmental conditions. Light has a particularly marked effect on in vitro shoot regeneration, and some light signaling factors are involved in shoot regeneration, while the underlying molecular mechanism remains elusive. Here, ELONGATED HYPOCOTYL5 (HY5), as the key transcription factor of light signaling, was found to inhibit shoot regeneration under a range of light conditions. The heightened shoot regeneration capacity of the hy5-215 mutant was less marked in the dark than in the light, showing that HY5-mediated inhibition of shoot regeneration is partly light dependent. The co-localization of WUSCHEL (WUS) and CLAVATA3 (CLV3) expressions was found to coincide with the initiation of stem cell niches in root explants during shoot regeneration. HY5 could directly repress CLV3 and WUS expression by binding to their respective promoters. In parallel, HY5 indirectly repressed CLV3 and WUS by binding to the ARABIDOPSIS RESPONSE REGULATOR12 (ARR12) promoter. The resulting dual regulation exerted by HY5 on WUS and CLV3 impeded the initiation of shoot stem cell niches. A HY5-mediated inhibitory pathway was identified that links cytokinin signaling and the pluripotency pathway during shoot regeneration.