High-contrast en bloc staining of mouse whole-brain and human brain samples for EM-based connectomics.

Connectomes of human cortical gray matter require high-contrast homogeneously stained samples sized at least 2 mm on a side, and a mouse whole-brain connectome requires samples sized at least 5-10 mm on a side. Here we report en bloc staining and embedding protocols for these and other applications, removing a key obstacle for connectomic analyses at the mammalian whole-brain level.

ASD2023: towards the integrating landscapes of allosteric knowledgebase.

Allosteric regulation, induced by perturbations at an allosteric site topographically distinct from the orthosteric site, is one of the most direct and efficient ways to fine-tune macromolecular function. The Allosteric Database (ASD; accessible online at http://mdl.shsmu.edu.cn/ASD) has been systematically developed since 2009 to provide comprehensive information on allosteric regulation. In recent years, allostery has seen sustained growth and wide-ranging applications in life sciences, from basic research to new therapeutics development, while also elucidating emerging obstacles across allosteric research stages. To overcome these challenges and maintain high-quality data center services, novel features were curated in the ASD2023 update: (i) 66 589 potential allosteric sites, covering > 80% of the human proteome and constituting the human allosteric pocketome; (ii) 748 allosteric protein-protein interaction (PPI) modulators with clear mechanisms, aiding protein machine studies and PPI-targeted drug discovery; (iii) 'Allosteric Hit-to-Lead,' a pioneering dataset providing panoramic views from 87 well-defined allosteric hits to 6565 leads and (iv) 456 dualsteric modulators for exploring the simultaneous regulation of allosteric and orthosteric sites. Meanwhile, ASD2023 maintains a significant growth of foundational allosteric data. Based on these efforts, the allosteric knowledgebase is progressively evolving towards an integrated landscape, facilitating advancements in allosteric target identification, mechanistic exploration and drug discovery.

Surf4 collaborates with derlin-2 and derlin-1 to mediate cyclooxygenase-2 translocation to the cytosol for degradation.

Derlin family members participate in the retrotranslocation of endoplasmic reticulum (ER) lumen proteins to the cytosol for ER-associated degradation (ERAD); however, the proteins facilitating this retrotranslocation remain to be explored. Using CRISPR library screening, we have found that derlin-2 and surfeit locus protein 4 (Surf4) are candidates to facilitate degradation of cyclooxygenase-2 (COX-2, also known as PTGS2). Our results show that derlin-2 acts upstream of derlin-1 and that Surf4 acts downstream of derlin-2 and derlin-1 to facilitate COX-2 degradation. Knockdown of derlin-2 or Surf4 impedes the ubiquitylation of COX-2 and the interaction of COX-2 with caveolin-1 (Cav-1) and p97 (also known as VCP) in the cytosol. Additionally, COX-2 degradation is N-glycosylation dependent. Although derlin-2 facilitates degradation of N-glycosylated COX-2, the interaction between derlin-2 and COX-2 is independent of COX-2 N-glycosylation. Derlin-1, Surf4 and p97 preferentially interact with non-glycosylated COX-2, whereas Cav-1 preferentially interacts with N-glycosylated COX-2, regardless of the N-glycosylation pattern. Collectively, our results reveal that Surf4 collaborates with derlin-2 and derlin-1 to mediate COX-2 translocation from the ER lumen to the cytosol. The derlin-2-derlin-1-Surf4-Cav-1 machinery might represent a unique pathway to accelerate COX-2 degradation in ERAD.

ISSAAC-seq enables sensitive and flexible multimodal profiling of chromatin accessibility and gene expression in single cells.

Joint profiling of chromatin accessibility and gene expression from the same single cell provides critical information about cell types in a tissue and cell states during a dynamic process. Here, we develop in situ sequencing hetero RNA-DNA-hybrid after assay for transposase-accessible chromatin-sequencing (ISSAAC-seq), a highly sensitive and flexible single-cell multi-omics method to interrogate chromatin accessibility and gene expression from the same single nucleus. We demonstrated that ISSAAC-seq is sensitive and provides high quality data with orders of magnitude more features than existing methods. Using the joint profiles from over 10,000 nuclei from the mouse cerebral cortex, we uncovered major and rare cell types and cell-type specific regulatory elements and identified heterogeneity at the chromatin level within established cell types defined by gene expression. Finally, we revealed distinct dynamics and relationships of gene expression and chromatin accessibility during an oligodendrocyte maturation trajectory.

DeepAlloDriver: a deep learning-based strategy to predict cancer driver mutations.

Driver mutations can contribute to the initial processes of cancer, and their identification is crucial for understanding tumorigenesis as well as for molecular drug discovery and development. Allostery regulates protein function away from the functional regions at an allosteric site. In addition to the known effects of mutations around functional sites, mutations at allosteric sites have been associated with protein structure, dynamics, and energy communication. As a result, identifying driver mutations at allosteric sites will be beneficial for deciphering the mechanisms of cancer and developing allosteric drugs. In this study, we provided a platform called DeepAlloDriver to predict driver mutations using a deep learning method that exhibited >93% accuracy and precision. Using this server, we found that a missense mutation in RRAS2 (Gln72 to Leu) might serve as an allosteric driver of tumorigenesis, revealing the mechanism of the mutation in knock-in mice and cancer patients. Overall, DeepAlloDriver would facilitate the elucidation of the mechanisms underlying cancer progression and help prioritize cancer therapeutic targets. The web server is freely available at: https://mdl.shsmu.edu.cn/DeepAlloDriver.

AlloReverse: multiscale understanding among hierarchical allosteric regulations.

Increasing data in allostery are requiring analysis of coupling relationships among different allosteric sites on a single protein. Here, based on our previous efforts on reversed allosteric communication theory, we have developed AlloReverse, a web server for multiscale analysis of multiple allosteric regulations. AlloReverse integrates protein dynamics and machine learning to discover allosteric residues, allosteric sites and regulation pathways. Especially, AlloReverse could reveal hierarchical relationships between different pathways and couplings among allosteric sites, offering a whole map of allostery. The web server shows a good performance in re-emerging known allostery. Moreover, we applied AlloReverse to explore global allostery on CDC42 and SIRT3. AlloReverse predicted novel allosteric sites and allosteric residues in both systems, and the functionality of sites was validated experimentally. It also suggests a possible scheme for combined therapy or bivalent drugs on SIRT3. Taken together, AlloReverse is a novel workflow providing a complete regulation map and is believed to aid target identification, drug design and understanding of biological mechanisms. AlloReverse is freely available to all users at https://mdl.shsmu.edu.cn/AlloReverse/ or http://www.allostery.net/AlloReverse/.

Allergic rhinitis phenotypes with distinct transcriptome profiles in children: A birth cohort.

BACKGROUND: Allergic rhinitis (AR) phenotypes in childhood are unclear. OBJECTIVES: This study sought to determine AR phenotypes and investigate their natural course and clinical and transcriptomic characteristics. METHODS: Latent class trajectory analysis was used for phenotyping AR in 1050 children from birth through 12 years using a birth cohort study. Blood transcriptome analyses were performed to define the underlying mechanisms of each phenotype. RESULTS: Five AR phenotypes were identified: early onset (n = 88, 8.4%), intermediate transient (n = 110, 10.5%), late onset (n = 209, 19.9%), very late onset (n=187, 17.8%), and never/infrequent (n = 456, 43.4%). Children with early-onset AR were associated with higher AR severity and sensitizations to foods at age 1 year and inhalants at age 3 years and asthma symptoms, but not with bronchial hyperresponsiveness (BHR). Children with late-onset AR phenotype associated with sensitizations to various foods at age 1 year but not from age 3 years, and to inhalants from age 7 years and with asthma with BHR. Children with very late-onset AR phenotype associated with sensitizations to foods throughout preschool age and to inhalants at ages 7 and 9 years and with asthma with BHR. Transcriptome analysis showed that early-onset AR was associated with viral/bacterial infection-related defense response, whereas late-onset AR was associated with T cell-related immune response. CONCLUSIONS: Early-onset AR phenotype was associated with sensitization to foods and inhalants at an early age and asthma symptoms, but not with BHR, whereas very late- and late-onset AR phenotypes were positively associated with sensitization to inhalants and asthma with BHR. Transcriptomic analyses indicated that early- and late-onset AR phenotypes had distinct underlying mechanisms related to AR as well.

Neoadjuvant chemotherapy plus camrelizumab for locally advanced cervical cancer (NACI study): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Locally advanced cervical cancer constitutes around 37% of cervical cancer cases globally and has a poor prognosis due to limited therapeutic options. Immune checkpoint inhibitors in the neoadjuvant setting could address these challenges. We aimed to investigate the efficacy and safety of neoadjuvant chemo-immunotherapy for locally advanced cervical cancer. METHODS: In this single-arm, phase 2 trial, which was done across eight tertiary hospitals in China, we enrolled patients aged 18-70 years with untreated cervical cancer (IB3, IIA2, or IIB/IIIC1r with a tumour diameter ≥4 cm [International Federation of Gynecology and Obstetrics, 2018]) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients underwent one cycle of priming doublet chemotherapy (75-80 mg/m2 cisplatin, intravenously, plus 260 mg/m2 nab-paclitaxel, intravenously), followed by two cycles of a combination of chemotherapy (cisplatin plus nab-paclitaxel) on day 1 with camrelizumab (200 mg, intravenously) on day 2, with a 3-week interval between treatment cycles. Patients with stable disease or progressive disease received concurrent chemoradiotherapy, and patients with a complete response or partial response proceeded to radical surgery. The primary endpoint was the objective response rate, by independent central reviewer according to Response Evaluation Criteria in Solid Tumours, version 1.1. Activity and safety were analysed in patients who received at least one dose of camrelizumab. This study is registered with ClinicalTrials.gov, NCT04516616, and is ongoing. FINDINGS: Between Dec 1, 2020, and Feb 10, 2023, 85 patients were enrolled and all received at least one dose of camrelizumab. Median age was 51 years (IQR 46-57) and no data on race or ethnicity were collected. At data cutoff (April 30, 2023), median follow-up was 11·0 months (IQR 6·0-14·5). An objective response was noted in 83 (98% [95% CI 92-100]) patients, including 16 (19%) patients who had a complete response and 67 (79%) who had a partial response. The most common grade 3-4 treatment-related adverse events during neoadjuvant chemo-immunotherapy were lymphopenia (21 [25%] of 85), neutropenia (ten [12%]), and leukopenia (seven [8%]). No serious adverse events or treatment-related deaths occurred. INTERPRETATION: Neoadjuvant chemo-immunotherapy showed promising antitumour activity and a manageable adverse event profile in patients with locally advanced cervical cancer. The combination of neoadjuvant chemo-immunotherapy with radical surgery holds potential as a novel therapeutic approach for locally advanced cervical cancer. FUNDING: National Key Technology Research and Development Program of China and the National Clinical Research Center of Obstetrics and Gynecology.

Temperature-sensitive hydrogel releasing pectolinarin facilitate scarless wound healing.

The dressing that promotes scarless healing is essential for both normal function and aesthetics after a wound. With a deeper understanding of the mechanisms involved in scar formation during the wound healing process, the ideal dressing becomes clearer and more promising. For instance, the yes-associated transcriptional regulator (YAP) has been extensively studied as a key gene involved in regulating scar formation. However, there has been limited attention given to pectolinarin, a natural flavonoid that may exhibit strong binding affinity to YAP, in the context of scarless healing. In this study, we successfully developed a temperature-sensitive Pluronic@F-127 hydrogel as a platform for delivering pectolinarin to promote scarless wound healing. The bioactive pectolinarin was released from the hydrogel, effectively enhancing endothelial cell migration, proliferation and the expression of angiogenesis-related genes. Additionally, a concentration of 20 µg/mL of pectolinarin demonstrated remarkable antioxidant ability, capable of counteracting the detrimental effects of reactive oxygen species (ROS). Our results from rat wound healing models demonstrated that the hydrogel accelerated wound healing, promoting re-epithelialization and facilitating skin appendage regeneration. Furthermore, we discovered that a concentration of 50 µg/mL of pectolinarin incorporated to the hydrogel exhibited the most favourable outcomes in terms of promoting wound healing and minimizing scar formation. Overall, our study highlights that the significant potential of locally released pectolinarin might substantially inhibit YAP and promoting scarless wound healing.

Serum immunoglobulin concentrations and risk of type 2 diabetes mellitus in adults: a prospective cohort study from the TCLSIH study.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia resulting from defects in insulin secretion and/or insulin action. Increasing evidence suggests that inflammation played an important role in the pathogenesis of T2DM. Prospective studies on the link between immunoglobulins concentrations and the risk of T2DM in adults are limited. We developed a cohort study including 7,093 adults without T2DM history. The incidence of T2DM was 16.45 per 1,000 person-years. Compared with the lowest quartiles, the hazard ratios (95% confidence intervals) of T2DM for the highest quartiles of IgG, IgE, IgM and IgA were 0.64 (0.48-0.85), 0.94 (0.72-1.23), 0.68 (0.50-0.92) and 1.62 (1.24-2.11) (P for trend was < 0.01, 0.84, 0.02 and < 0.0001), respectively, suggesting that serum IgG and IgM concentrations were inversely associated with the incidence of T2DM, and IgA levels were positively associated with the risk of T2DM in a general adult population.

Metabolic reprogramming and heterogeneity during the decidualization process of endometrial stromal cells.

The human endometrial decidualization is a transformative event in the pregnant uterus that involves the differentiation of stromal cells into decidual cells. While crucial to the establishment of a successful pregnancy, the metabolic characteristics of decidual cells in vivo remain largely unexplored. Here, we integrated the single-cell RNA sequencing (scRNA-seq) datasets on the endometrium of the menstrual cycle and the maternal-fetal interface in the first trimester to comprehensively decrypt the metabolic characteristics of stromal fibroblast cells. Our results revealed that the differentiation of stromal cells into decidual cells is accompanied by increased amino acid and sphingolipid metabolism. Furthermore, metabolic heterogeneity exists in decidual cells with differentiation maturity disparities. Decidual cells with high metabolism exhibit higher cellular activity and show a strong propensity for signaling. In addition, significant metabolic reprogramming in amino acids and lipids also occurs during the transition from non-pregnancy to pregnancy in the uteri of pigs, cattle, and mice. Our analysis provides comprehensive insights into the dynamic landscape of stromal fibroblast cell metabolism, contributing to our understanding of the metabolism at the molecular dynamics underlying the decidualization process in the human endometrium.

Fibroblasts Drive Metabolic Reprogramming in Pacemaker Cardiomyocytes.

BACKGROUND: The sino atrial node (SAN) is characterized by the microenvironment of pacemaker cardiomyocytes (PCs) encased with fibroblasts. An altered microenvironment leads to rhythm failure. Operable cell or tissue models are either generally lacking or difficult to handle. The biological process behind the milieu of SANs to evoke pacemaker rhythm is unknown. We explored how fibroblasts interact with PCs and regulate metabolic reprogramming and rhythmic activity in the SAN. METHODS: Tbx18 (T-box transcription factor 18)-induced PCs and fibroblasts were used for cocultures and engineered tissues, which were used as the in vitro models to explore how fibroblasts regulate the functional integrity of SANs. RNA-sequencing, metabolomics, and cellular and molecular techniques were applied to characterize the molecular signals underlying metabolic reprogramming and identify its critical regulators. These pathways were further validated in vivo in rodents and induced human pluripotent stem cell-derived cardiomyocytes. RESULTS: We observed that rhythmicity in Tbx18-induced PCs was regulated by aerobic glycolysis. Fibroblasts critically activated metabolic reprogramming and aerobic glycolysis within PCs, and, therefore, regulated pacemaker activity in PCs. The metabolic reprogramming was attributed to the exclusive induction of Aldoc (aldolase c) within PCs after fibroblast-PC integration. Fibroblasts activated the integrin-dependent mitogen-activated protein kinase-E2F1 signal through cell-cell contact and turned on Aldoc expression in PCs. Interruption of fibroblast-PC interaction or Aldoc knockdown nullified electrical activity. Engineered Tbx18-PC tissue sheets were generated to recapitulate the microenvironment within SANs. Aldoc-driven rhythmic machinery could be replicated within tissue sheets. Similar machinery was faithfully validated in de novo PCs of adult mice and rats, and in human PCs derived from induced pluripotent stem cells. CONCLUSIONS: Fibroblasts drive Aldoc-mediated metabolic reprogramming and rhythmic regulation in SANs. This work details the cellular machinery behind the complex milieu of vertebrate SANs and opens a new direction for future therapy.

Adherence to a healthy lifestyle including sleep and sedentary behaviors and risk of metabolic dysfunction-associated steatotic liver disease in Chinese adults.

OBJECTIVE: Various lifestyle factors including smoking, alcohol, physical activity, sedentary behavior, diet quality, sleep behavior, and overweight have been related to metabolic dysfunction-associated steatotic liver disease (MASLD); however, their joint impact on risk of MASLD is not well known. We prospectively investigated the association between a combination of lifestyle factors and risk of MASLD. METHODS: This prospective cohort study included 13,303 participants (mean age: 39.1 ± 11.3 years, female: 60.1%) in China. A novel healthy lifestyle score was created combining seven healthy factors: not smoking, no alcohol intake, regular physical activity, short sedentary time, healthy diet, healthy sleep, and healthy weight. Incident MASLD cases were ascertained annually by liver ultrasound and cardiometabolic risk factors. Multivariable Cox proportional hazards regression models were used to estimate the association of healthy lifestyle score with risk of MASLD. RESULTS: Within 48,036 person-years of follow-up, 2823 participants developed MASLD. After adjusting for age, sex, education, occupation, household income, personal and family history of disease, and total energy intake, compared with participants with 0-2 healthy lifestyle factors, the multivariable hazard ratios (95% confidence interval) of MASLD were 0.81 (0.73, 0.89), 0.67 (0.61, 0.75), and 0.55 (0.49, 0.62) for healthy lifestyle score of 3, 4, and 5-7, respectively (P for trend <0.0001). Such associations were consistent across subgroup and sensitivity analyses. CONCLUSION: Our results indicate that a higher healthy lifestyle score is associated with a lower risk of MASLD.

Longitudinal association between soft drink consumption and handgrip strength in adults: a prospective analysis from the Tianjin Chronic Low-Grade Systemic Inflammation and Health (TCLSIH) cohort study.

Soft drink consumption has become a highly controversial public health issue. Given the pattern of consumption in China, sugar-sweetened beverage is the main type of soft drink consumed. Due to containing high levels of fructose, a soft drink may have a deleterious effect on handgrip strength (HGS) due to oxidative stress, inflammation and insulin resistance. However, few studies show an association between soft drink consumption and HGS in adults. We aimed to investigate the association between soft drink consumption and longitudinal changes in HGS among a Chinese adult population. A longitudinal population-based cohort study (5-year follow-up, median: 3·66 years) was conducted in Tianjin, China. A total of 11 125 participants (56·7 % men) were enrolled. HGS was measured using a handheld digital dynamometer. Soft drink consumption (mainly sugar-containing carbonated beverages) was measured at baseline using a validated FFQ. ANCOVA was used to evaluate the association between soft drink consumption and annual change in HGS or weight-adjusted HGS. After adjusting for multiple confounding factors, the least square means (95 % CI) of annual change in HGS across soft drink consumption frequencies were -0·70 (-2·49, 1·09) for rarely drinks, -0·82 (-2·62, 0·97) for < 1 cup/week and -0·86 (-2·66, 0·93) for ≥ 1 cup/week (Pfor trend < 0·05). Likewise, a similar association was observed between soft drink consumption and annual change in weight-adjusted HGS. The results indicate that higher soft drink consumption was associated with faster HGS decline in Chinese adults.

ALKBH5 modulates bone cancer pain in a rat model by suppressing NR2B expression.

Currently, the clinical treatment of bone cancer pain (BCP) is mainly related to its pathogenesis. The aim of the present study was to elucidate the potential role of N6-methyladenosine (m6A) in BCP in the spinal cord dorsal root ganglia (DRG) of BCP rats and its specific regulatory mechanism in N-methyl-d-aspartate receptor subunit 2B (NR2B). A rat model of BCP was constructed by tibial injection of Walker256 cells, and ALKBH5 and NR2B expression in the spinal cord DRG was detected. ALKBH5 was silenced or overexpressed in PC12 cells to verify the regulatory effect of ALKBH5 on NR2B. The specific mechanism underlying the interaction between ALKBH5 and NR2B was investigated using methylated RNA immunoprecipitation and dual-luciferase reporter gene assays. The results showed increased expression of m6A, decreased expression of ALKBH5, and increased expression of NR2B in the DRG of the BCP rat model. Overexpression of ALKBH5 inhibited NR2B expression, whereas interference with ALKBH5 caused an increase in NR2B expression. In NR2B, interference with ALKBH5 caused an increase in m6A modification, which caused an increase in NR2B. Taken together, ALKBH5 affected the expression of NR2B by influencing the stability of the m6A modification site of central NR2B, revealing that ALKBH5 is a therapeutic target for BCP.

Prevalence of human papillomavirus DNA and p16INK4a positivity in vulvar cancer and vulvar intraepithelial neoplasia: a systematic review and meta-analysis.

BACKGROUND: Human papillomavirus (HPV) DNA and p16INK4a positivity have crucial roles in the pathogenesis of vulvar cancer and vulvar intraepithelial neoplasia. We aimed to examine the pooled prevalence of HPV DNA and p16INK4a positivity in vulvar cancer and vulvar intraepithelial neoplasia worldwide. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, and the Cochrane Library databases for studies published between Jan 1, 1986, and May 6, 2022, that reported the prevalence of HPV DNA, or p16INK4a positivity, or both, in histologically verified vulvar cancer or vulvar intraepithelial neoplasia. Studies on a minimum of five cases were included. Study-level data were extracted from the published studies. Random effect models were used to examine the pooled prevalence of HPV DNA and p16INK4a positivity in both vulvar cancer and vulvar intraepithelial neoplasia, which were further investigated using stratified analyses by histological subtype, geographical region, HPV DNA or p16INK4a detection method, tissue sample type, HPV genotype, publication year, and age at diagnosis. Additionally, meta-regression was applied to explore sources of heterogeneity. FINDINGS: We retrieved 6393 search results, of which 6233 were excluded for being duplicates or after application of our inclusion and exclusion criteria. We also identified two studies from manual searches of references lists. 162 studies were eligible for inclusion in the systematic review and meta-analysis. The prevalence of HPV in vulvar cancer (91 studies; n=8200) was 39·1% (95% CI 35·3-42·9) and in vulvar intraepithelial neoplasia (60 studies; n=3140) was 76·1% (70·7-81·1). The most predominant HPV genotype in vulvar cancer was HPV16 (78·1% [95% CI 73·5-82·3]), followed by HPV33 (7·5% [4·9-10·7]). Similarly, HPV16 (80·8% [95% CI 75·9-85·2]) and HPV33 (6·3% [3·9-9·2]) were also the most two predominant HPV genotypes in vulvar intraepithelial neoplasia. The distribution of type-specific HPV genotypes in vulvar cancer among geographical regions was different, with HPV16 varying between regions, showing a high prevalence in Oceania (89·0% [95% CI 67·6-99·5]) and a low prevalence in South America (54·3% [30·2-77·4]). The prevalence of p16INK4a positivity in patients with vulvar cancer was 34·1% (95% CI 30·9-37·4; 52 studies; n=6352), and it was 65·7% (52·5-77·7; 23 studies; n=896) in patients with vulvar intraepithelial neoplasia. Furthermore, among patients with HPV-positive vulvar cancer, p16INK4a positivity prevalence was 73·3% (95% CI 64·7-81·2), compared with 13·8% (10·0-18·1) in HPV-negative vulvar cancer. The prevalence of double positivity for HPV and p16INK4a was 19·6% (95% CI 16·3-23·0) in vulvar cancer and 44·2% (26·3-62·8) in vulvar intraepithelial neoplasia. Most analyses had large heterogeneity (I2>75%). INTERPRETATION: The high prevalence of HPV16 and HPV33 in vulvar cancer and vulvar intraepithelial neoplasia emphasised the importance of nine-valent HPV vaccination in preventing vulvar neoplasm. Additionally, this study highlighted the potential clinical significance of double positivity for HPV DNA and p16INK4a in vulvar neoplasm. FUNDING: Taishan Scholar Youth Project of Shandong Province, China.

The dorsomedial prefrontal cortex represents subjective value across effort-based and risky decision-making.

Decisions that require taking effort costs into account are ubiquitous in real life. The neural common currency theory hypothesizes that a particular neural network integrates different costs (e.g., risk) and rewards into a common scale to facilitate value comparison. Although there has been a surge of interest in the computational and neural basis of effort-related value integration, it is still under debate if effort-based decision-making relies on a domain-general valuation network as implicated in the neural common currency theory. Therefore, we comprehensively compared effort-based and risky decision-making using a combination of computational modeling, univariate and multivariate fMRI analyses, and data from two independent studies. We found that effort-based decision-making can be best described by a power discounting model that accounts for both the discounting rate and effort sensitivity. At the neural level, multivariate decoding analyses indicated that the neural patterns of the dorsomedial prefrontal cortex (dmPFC) represented subjective value across different decision-making tasks including either effort or risk costs, although univariate signals were more diverse. These findings suggest that multivariate dmPFC patterns play a critical role in computing subjective value in a task-independent manner and thus extend the scope of the neural common currency theory.

Novel trial designs in neuro-oncology.

PURPOSE OF REVIEW: An important factor contributing to the low rate of success in identifying effective therapies for brain tumor patients is the slow, inefficient, and expensive process of drug development, as well as small patient numbers, low patient participation in clinical trials, and reluctance of patients to enroll in ineffective control arms. In recent years, a number of novel trial designs have been developed to try to address some of these issues. RECENT FINDINGS: Surgical 'window-of-opportunity' trials that evaluate tumor drug concentrations and pharmacodynamic effects provide invaluable early data early guiding the development of novel therapies. Basket and bucket trials facilitate the development of therapies that target specific biomarkers subsets. Platform trials utilizing Bayesian adaptive randomization and shared control arms such as the INSIGhT and GBM-AGILE trials increase the efficiency and cost-effectiveness of developing novel therapies. There is also growing interest in leveraging external control arms with patient level data to evaluate efficacy in single arm trials, and facilitate interim analysis and potentially reduce the number of control patients in randomized trials. SUMMARY: These novel designs will hopefully reduce the inefficiencies of developing novel therapies in neuro-oncology and facilitate the identification of more effective therapies for brain tumor patients.

Pancreatic Cancer and its Attributable Risk Factors in East Asia, Now and Future.

BACKGROUND: The disease burden of pancreatic cancer in East Asia is at a high level, but the epidemiological characteristics of pancreatic cancer in the region have not been systematically studied. METHOD: Joinpoint analysis was used to identify average annual percentage change (AAPC) and annual percentage change (APC) in mortality. Age-period-cohort models were used to analyze age-period cohort effects across countries. Bayesian age-period-cohort (BAPC) analysis was used to project the burden of disease for 2020-2030. RESULTS: Pancreatic cancer mortality in males in Japan (2012-2019, APC = -0.97) and Korea (2012-2019, APC = -0.91) has shown a decreasing trend since 2012 (P < .05). However, China (2016-2019, APC = 3.21), Mongolia (2015-2.019, APC = 2.37), and North Korea (2012-2019, APC = 0.47) showed a significant increase in pancreatic cancer in both genders (P < .05). Risk factors for pancreatic cancer in East Asia remained largely stable between 2010 and 2019. Mortality of pancreatic cancer due to smoking began to decline in areas with high socio-demographic index (SDI), and mortality of pancreatic cancer due to high body mass index and high fasting plasma glucose increased with SDI. The age-standardized mortality for pancreatic cancer in Chinese males is expected to exceed that of Japan and South Korea by 2030, but the disease burden of pancreatic cancer in Japan and South Korea remains at extremely high levels. CONCLUSION: Economically developed countries are beginning to show a decreasing trend in the burden of pancreatic cancer disease, and developing countries are experiencing a rapid increase in the age-standardized death rate (ASDR) of pancreatic cancer.

Protein foods from animal sources and risk of nonalcoholic fatty liver disease in representative cohorts from North and South China.

BACKGROUND: Emerging evidence suggests that animal protein foods may increase the risk of nonalcoholic fatty liver disease (NAFLD). We therefore examined the NAFLD risk reduction related to substituting plant protein foods for animal protein foods. METHODS: The cohort in North China included 14,541 participants from the Tianjin Chronic Low-Grade Systemic Inflammation and Health (TCLSIH) study, and the cohort in South China included 1297 participants from the Guangzhou Nutrition and Health Study (GNHS). Dietary intake was assessed using validated food frequency questionnaires. NAFLD was ascertained by abdominal ultrasound. The Cox model was used to fit the substitution analysis. RESULTS: In the TCLSIH cohort, when replacing one type of animal protein food (eggs, processed meat, unprocessed red meat, poultry, and fish) with an equivalent serving of plant protein foods (nuts, legumes, and whole grains), the replacement of animal protein foods with whole grains showed the strongest benefit; substituting one serving per day of whole grains for an equal amount of eggs (hazard ratio [HR] = 0.89; 95% confidence interval [CI]: 0.79, 1.00), processed meat (HR = 0.76; 95% CI: 0.64, 0.91), unprocessed red meat (HR = 0.90; 95% CI: 0.81, 1.00), poultry (HR = 0.81; 95% CI: 0.72, 0.92), or fish (HR = 0.87; 95% CI: 0.78, 0.97) was associated with a lower risk of NAFLD. In both the TCLSIH and GNHS cohorts, replacing poultry with fish, nuts, legumes, or whole grains was associated with a lower risk of NAFLD. When different numbers of protein foods were simultaneously replaced, the risk reduction of NAFLD was stronger. CONCLUSIONS: Our findings suggest that replacing animal protein foods with plant protein foods is related to a significant reduction in NAFLD risk.