Efficacy and safety of PARPis combined with an ICIs for advanced or metastatic triple-negative breast cancer: a single-arm meta-analysis.

Although the intervention for triple-negative breast cancer (TNBC) patients has improved and survival time has increased, the combination of immune checkpoint inhibitors(ICIs) and PARP inhibitors (Poly ADP-Ribose Polymerase inhibitors, PARPis) is still controversial. Previous studies revealed that the combined use of ICIs and PARPis led to increased antitumor activity. However, most of these combined regimens are nonrandomized controlled trials with small sample sizes. The purpose of this meta-analysis was to evaluate the efficacy and safety of ICIs combined with PARPis in patients with advanced or metastatic TNBC. The PubMed, Embase, Cochrane Library and Web of Science databases were systematically searched. The results including the objective remission rate (ORR), disease control rate (DCR), progression-free survival (PFS) and adverse events (AEs), were subjected to further analysis. Four studies involving 110 subjects were included in this meta-analysis. The combined ORR and DCR were 23.6% and 53.6%, respectively; while the ORR and DCR of BRCAmut patients were 38.1% and 71.4%, respectively. The median PFS of the patients was 4.29 months. As for safety, the most common AEs were nausea (49.0%), anemia (44.3%) and fatigue (40.6%). Most of them were grade 1 or 2, and the incidence of adverse events ≥ III was obviously low. Except for anemia, the incidence of AEs ≥ III was < 10%. This meta-analysis revealed that the combination of ICIs and PARPis has good efficacy and safety for advanced or metastatic TNBC patients.

Delaying Renal Aging: Metformin Holds Promise as a Potential Treatment.

Given the rapid aging of the population, age-related diseases have become an excessive burden on global health care. The kidney, a crucial metabolic organ, ages relatively quickly. While the aging process itself does not directly cause kidney damage, the physiological changes that accompany it can impair the kidney's capacity for self-repair. This makes aging kidneys more susceptible to diseases, including increased risks of chronic kidney disease and end-stage renal disease. Therefore, delaying the progression of renal aging and preserving the youthful vitality of the kidney are crucial for preventing kidney diseases. However, effective strategies against renal aging are still lacking due to the underlying mechanisms of renal aging, which have not been fully elucidated. Accumulating evidence suggests that metformin has beneficial effects in mitigating renal aging. Metformin has shown promising anti-aging results in animal models but has not been tested for this purpose yet in clinical trials. These findings indicate the potential of metformin as an anti-renal aging drug. In this review, we primarily discuss the characteristics and mechanisms of kidney aging and the potential effects of metformin against renal aging.

Exploring the Mechanism of Shen Qi Gui Oral Liquid against Chemotherapy-Induced Myelosuppression in Cancer Patients Based on Network Pharmacology and Molecular Docking.

BACKGROUND: Shen Qi Gui oral liquid (SQG) may be beneficial for chemotherapyinduced myelosuppression (CIM). However, the underlying mechanism of CIM treated with SQG is still lacking. METHODS: A total of 27 blood samples from cancer patients were selected to perform RNA-seq to obtain the Differentially Expressed Genes (DEGs). Then, the active components and target genes of SQG were acquired. Next, the drug targets and DEGs were intersected to obtain the intersection genes, followed by functional enrichment analysis and construction of a drug-compoundgene- disease network. Subsequently, core genes were selected. Then, immune cell infiltration, molecular docking, pharmacokinetic and toxicity prediction, and RT-qPCR were performed. RESULTS: A total of 1,341 DEGs, 51 active compounds, and 264 target genes were identified. Then, 30 intersection genes were acquired. Next, a drug-compound-gene-disease network was constructed, and 7 core genes were acquired. Immune infiltration analysis exhibited that only T follicular helper cells were significantly increased in the CIM group, which was significantly negatively correlated with MAPK1, MAPK14, MCL1, PTEN, and PTGS2. The luteolin, quercetin, and beta-sitosterol showed better affinity with core genes. Luteolin and quercetin, which satisfied Lipinski's rule of five, were likely absorbed by the gastrointestinal system. Toxicity predictions showed that neither luteolin nor quercetin exhibited carcinogenicity or hepatotoxicity. CONCLUSION: PTEN, PTGS2, CCL2, FOS, MCL1, MAPK1, and MAPK14 were identified as the core genes in CIM patients, which were involved in the MAPK and PI3K-Akt signaling pathways. Luteolin and quercetin may be the promising drugs against CIM.

Causal effects of genetic birth weight and gestational age on adult esophageal diseases: Mendelian randomization study.

BACKGROUND: Few studies have investigated the association between gestational age, birth weight, and esophageal cancer risk; however, causality remains debated. We aimed to establish causal links between genetic gestational age and birth weight traits and gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), and esophageal adenocarcinoma (EA). Additionally, we explored if known risk factors mediate these links. AIM: To analyze of the relationship between gestational age, birth weight and GERD, BE, and EA. METHODS: Genetic data on gestational age and birth weight (n = 84689 and 143677) from the Early Growth Genetics Consortium and outcomes for GERD (n = 467253), BE (n = 56429), and EA (n = 21271) from genome-wide association study served as instrumental variables. Mendelian randomization (MR) and mediation analyses were conducted using MR-Egger, weighted median, and inverse variance weighted methods. Robustness was ensured through heterogeneity, pleiotropy tests, and sensitivity analyses. RESULTS: Birth weight was negatively correlated with GERD and BE risk [odds ratio (OR) = 0.78; 95% confidence interval (CI): 0.69-0.8] and (OR = 0.75; 95%CI: 0.60-0.9), respectively, with no significant association with EA. No causal link was found between gestational age and outcomes. Birth weight was positively correlated with five risk factors: Educational attainment (OR = 1.15; 95%CI: 1.01-1.31), body mass index (OR = 1.06; 95%CI: 1.02-1.1), height (OR = 1.12; 95%CI: 1.06-1.19), weight (OR = 1.13; 95%CI: 1.10-1.1), and alcoholic drinks per week (OR = 1.03; 95%CI: 1.00-1.06). Mediation analysis showed educational attainment and height mediated the birth weight-BE link by 13.99% and 5.46%. CONCLUSION: Our study supports the protective role of genetically predicted birth weight against GERD, BE, and EA, independent of gestational age and partially mediated by educational attainment and height.

Twin fetuses associated with double amniotic sacs diagnosed using transvaginal ultrasonography: A case report.

BACKGROUND: Conjoined twins are a rare twin malformation commonly presenting as single amniotic sac twinning, with double amniotic sac twinning being extremely rare and poorly reported. Most conjoined twins are females. CASE SUMMARY: A woman of childbearing age conceived naturally, and at 8 wk of gestation, transvaginal ultrasonography showed an embryo and cardiac tube pulsation in both amniotic sacs. On dynamic observation, the two embryos were connected in the lower abdomen, with restricted movement. A repeat transvaginal ultrasound at 11 wk showed that the intestinal tubes of both fetuses were connected in the lower abdomen. The pregnancy was terminated and labor was induced. CONCLUSION: Transvaginal ultrasound may detect conjoined twin malformations in an early stage. Our case provides diagnostic insights for ultrasonographers and can help develop early therapeutic interventions.

Norepinephrine may promote the progression of Fusobacterium nucleatum related colorectal cancer via quorum sensing signalling.

Fusobacterium nucleatum (F. nucleatum) is closely correlated with tumorigenesis in colorectal cancer (CRC). We aimed to investigate the effects of host norepinephrine on the carcinogenicity of F. nucleatum in CRC and reveal the underlying mechanism. The results revealed that both norepinephrine and bacterial quorum sensing (QS) molecule auto-inducer-2 (AI-2) were positively associated with the progression of F. nucleatum related CRC (p < 0.01). In vitro studies, norepinephrine induced upregulation of QS-associated genes and promoted the virulence and proliferation of F. nucleatum. Moreover, chronic stress significantly increased the colon tumour burden of ApcMin/+ mice infected with F. nucleatum (p < 0.01), which was decreased by a catecholamine inhibitor (p < 0.001). Our findings suggest that stress-induced norepinephrine may promote the progression of F. nucleatum related CRC via bacterial QS signalling. These preliminary data provide a novel strategy for the management of pathogenic bacteria by targeting host hormones-bacterial QS inter-kingdom signalling.

Intestinal metabolite xylulose inhibits colorectal cancer by inducing apoptosis through the MAPK signalling pathway.

BACKGROUND: The intestinal metabolites are involved in the initiation, progression and metastasis of colorectal cancer (CRC). They are a potential source of agents for cancer therapy. Our previous study identified altered faecal metabolites between CRC patients and healthy volunteers. However, no specific metabolite was clearly illustrated for CRC therapy. RESULTS: We found that the level of xylulose was lower in the stools of CRC patients than in those of healthy volunteers. Xylulose inhibited cell growth without affecting the cell cycle by inducing apoptosis in CRC cells, which was evidenced by increased expression of the proapoptotic proteins C-PARP and C-Caspase3 and decreased expression of the antiapoptotic protein BCL-2 in CRC cells. Mechanistically, xylulose reduced the activity of the MAPK signalling pathway, represented by reduced phosphorylation of JNK, ERK, and P38. Furthermore, an ALI model was used to show the tumour killing ability of xylulose on human CRC spheres, as well as human colorectal adenoma (AD) spheres. CONCLUSION: Xylulose inhibits CRC growth by inducing apoptosis through attenuation of the MAPK signalling pathway. These results suggest that xylulose may serve as an effective agent for CRC therapy.

MRI radiomics nomogram integrating postoperative adjuvant treatments in recurrence risk prediction for patients with early-stage cervical cancer.

BACKGROUND AND PURPOSE: Adjuvant treatments are valuable to decrease the recurrence rate and improve survival for early-stage cervical cancer patients (ESCC), Therefore, recurrence risk evaluation is critical for the choice of postoperative treatment. A magnetic resonance imaging (MRI) based radiomics nomogram integrating postoperative adjuvant treatments was constructed and validated externally to improve the recurrence risk prediction for ESCC. MATERIAL AND METHODS: 212 ESCC patients underwent surgery and adjuvant treatments from three centers were enrolled and divided into the training, internal validation, and external validation cohorts. Their clinical data, pretreatment T2-weighted images (T2WI) were retrieved and analyzed. Radiomics models were constructed using machine learning methods with features extracted and screen from sagittal and axial T2WI. A nomogram for recurrence prediction was build and evaluated using multivariable logistic regression analysis integrating radiomic signature and adjuvant treatments. RESULTS: A total of 8 radiomic features were screened out of 1020 extracted features. The extreme gradient boosting (XGboost) model based on MRI radiomic features performed best in recurrence prediction with an area under curve (AUC) of 0.833, 0.822 in the internal and external validation cohorts, respectively. The nomogram integrating radiomic signature and clinical factors achieved an AUC of 0.806, 0.718 in the internal and external validation cohorts, respectively, for recurrence risk prediction for ESCC. CONCLUSION: In this study, the nomogram integrating T2WI radiomic signature and clinical factors is valuable to predict the recurrence risk, thereby allowing timely planning for effective treatments for ESCC with high risk of recurrence.

Comprehensive multi-omics analysis of pyroptosis for optimizing neoadjuvant immunotherapy in patients with gastric cancer.

Background: Pyroptosis plays a crucial role in immune responses. However, the effects of pyroptosis on tumor microenvironment remodeling and immunotherapy in gastric cancer (GC) remain unclear. Patients and Methods: Large-sample GEO data (GSE15459, GSE54129, and GSE62254) were used to explore the immunoregulatory roles of pyroptosis. TCGA cohort was used to elucidate multiple molecular events associated with pyroptosis, and a pyroptosis risk score (PRS) was constructed. The prognostic performance of the PRS was validated using postoperative GC samples from three public databases (n=925) and four independent Chinese medical cohorts (n=978). Single-cell sequencing and multiplex immunofluorescence were used to elucidate the immune cell infiltration landscape associated with PRS. Patients with GC who received neoadjuvant immunotherapy (n=48) and those with GC who received neoadjuvant chemotherapy (n=49) were enrolled to explore the value of PRS in neoadjuvant immunotherapy. Results: GC pyroptosis participates in immune activation in the tumor microenvironment and plays a powerful role in immune regulation. PRS, composed of four pyroptosis-related differentially expressed genes (BATF2, PTPRJ, RGS1, and VCAN), is a reliable and independent biomarker for GC. PRSlow is associated with an activated pyroptosis pathway and greater infiltration of anti-tumor immune cells, including more effector and CD4+ T cells, and with the polarization of tumor-associated macrophages in the tumor center. Importantly, PRSlow marks the effectiveness of neoadjuvant immunotherapy and enables screening of GC patients with combined positive score ≥1 who benefit from neoadjuvant immunotherapy. Conclusion: Our study demonstrated that pyroptosis activates immune processes in the tumor microenvironment. A low PRS correlates with enhanced infiltration of anti-tumor immune cells at the tumor site, increased pyroptotic activity, and improved patient outcomes. The constructed PRS can be used as an effective quantitative tool for pyroptosis analysis to guide more effective immunotherapeutic strategies for patients with GC.

Optimization of ultrasonic conditions for improving the characteristics of corn starch-glycyrrhiza polysaccharide composite to prepare enhanced quality lycopene inclusion complex.

In this study, based on response surface optimization of ultrasound pre-treatment conditions for encapsulating lycopene, the corn starch-glycyrrhiza polysaccharide composite (US-CS-GP) was used to prepare a novel lycopene inclusion complex (US-CS-GP-Lyc). Ultrasound treatment (575 W, 25 kHz) at 35 °C for 25 min significantly enhanced the rheological and starch properties of US-CS-GP, facilitating the preparation of US-CS-GP-Lyc with an encapsulation efficiency of 76.12 ±â€¯1.76 %. In addition, the crystalline structure, thermal properties, and microstructure of the obtained lycopene inclusion complex were significantly improved and showed excellent antioxidant activity and storage stability. The US-CS-GP-Lyc exhibited a V-type crystal structure, enhanced lycopene loading capacity, and reduced crystalline regions due to increased amorphous regions, as well as superior thermal properties, including a lower maximum thermal decomposition rate and a higher maximum decomposition temperature. Furthermore, its smooth surface with dense pores provides enhanced space and protection for lycopene loading. Moreover, the US-CS-GP-Lyc displayed the highest DPPH scavenging rate (92.20 %) and enhanced stability under light and prolonged storage. These findings indicate that ultrasonic pretreatment can boost electrostatic forces and hydrogen bonding between corn starch and glycyrrhiza polysaccharide, enhance composite properties, and improve lycopene encapsulation, which may provide a scientific basis for the application of ultrasound technology in the refined processing of starch-polysaccharides composite products.

Evodiamine Inhibits Colorectal Cancer Growth via RTKs Mediated PI3K/AKT/p53 Signaling Pathway.

Objective: To investigate the inhibitory effect of EVO on colorectal cancer (CRC) growth and further explore the potential mechanism involving the RTKs-mediated PI3K/AKT/p53 signaling pathway. Methods: Firstly, the inhibitory effect of EVO on CRC cells was detected in vitro by cell viability assay and colony formation assay. The effects of EVO on spatial migration and invasion capacity of cells were detected by Transwell assay. The effects of EVO on apoptosis and cycle of cells were detected by flow cytometry. Then, the molecular mechanism of EVO against CRC was revealed by qRT-PCR and Western blot. Finally, the excellent anti-tumour activity of EVO was verified by in vivo experiments. Results: The results demonstrated that EVO exerts inhibitory effects on CRC cell proliferation, invasion, and colony formation. The cell cycle assay revealed that EVO induces G1/S phase arrest. Through RNA seq, we explored the influence of EVO on the transcriptional profile of colon cancer and observed significant activation of RTKs and the PI3K/AKT pathway, along with its downstream signaling pathways. Furthermore, we observed upregulation of p53 proteins by EVO, which led to the inhibition of Bcl-2 expression and an increase in Bax expression. Consistently, EVO exhibited remarkable suppression of tumor xenograft growth in nude mice. Conclusion: This study confirmed that EVO inhibits the proliferation of CRC cells and promotes cell apoptosis. The possible mechanism of action is inhibiting the expression of the RTK protein family, activating the PI3K/AKT/p53 apoptotic signaling pathway, thereby inhibiting Bcl-2 expression and increasing Bax expression, promoting apoptosis of CRC cells. As a natural product, EVO has very high potential application value.

The Norepinephrine-QseC Axis Aggravates F. nucleatum-associated Colitis Through Interkingdom Signaling.

AIMS: Inflammatory bowel disease (IBD) is associated with F. nucleatum, and chronic stress can increase the risk of aggravation. However, whether norepinephrine (NE) can enhance the pathogenicity of F. nucleatum to aggravate dextran sulfate sodium salt (DSS)-induced colitis is unclear. METHODS: Transcriptome sequencing was used to identify differentially expressed genes in bacteria treated with NE. Affinity testing and molecular docking were applied to calculate and predict the binding of NE and Quorum sensing  regulators C (QseC). The pathogenicity of Fusobacterium nucleatum treated with NE and QseC inhibitors was examined in vitro and further verified using the IBD mouse model induced by DSS. RESULTS: Norepinephrine could bind to QseC directly to upregulate the quorum sensing pathway of F. nucleatum and enhance its virulence gene expression (FadA, FomA, Fap2) and invasiveness in vitro. Meanwhile, it promoted the invasion of F. nucleatum into the intestine and increased the expression of host inflammatory cytokines (IL-6, IL-1ß) to aggravate colonic inflammation in IBD mice. The QseC inhibitor LED209 inhibited the effect of NE on F. nucleatum and partially restored short-chain fatty acid (SCFA)-producing bacteria (Prevotellaceae, Lactobacillaceae) to attenuate colonic inflammation in IBD mice. CONCLUSIONS: Generally, the NE-QseC axis enhanced the pathogenicity of F. nucleatum through interkingdom signaling to aggravate colonic inflammation in IBD mice. We see that QseC may be a potential target for microbiota management of IBD under chronic pressure.

Norepinephrine could bind to QseC directly to enhance the pathogenicity of F. nucleatum to aggravate colonic inflammation. The QseC inhibitor inhibited the effect of NE on F. nucleatum and partially restored short-chain fatty acid­producing bacteria to attenuate colonic inflammation.

Association of serum uric acid with all-cause and cardiovascular mortality in chronic kidney disease stages 3-5.

BACKGROUND AND AIMS: The role of serum uric acid (SUA) in the prognosis of chronic kidney disease (CKD) is inconclusive. To explore the association of SUA level with all-cause and cardiovascular disease (CVD) mortality in patients with CKD. METHODS AND RESULTS: Leveraging data from the National Health and Nutritional Examination Survey (NHANES) and linked national death records up to December 31 2019, we explored the association of SUA with all-cause and CVD mortality using weighted cox proportional hazards regression models and restricted cubic spline (RCS) models in patients with CKD stages 3-5. The study finally included 2644 patients with CKD stages 3-5, with a median SUA level of 6.5 mg/dL. After a median follow-up of 55 months, a total of 763 deaths were recorded, with 279 of them attributed to CVD. In the fully adjusted model, per 1 mg/dL increment in SUA concentration was found to be associated with increased HRs (95% CIs) of 1.07 (1.00, 1.14) for all-cause mortality and 1.11 (1.00, 1.24) for CVD mortality. Compared to Q2 (reference), those in Q4 had adjusted HRs of 1.72 (1.36, 2.17) for all-cause mortality and 2.17 (1.38, 3.41) for CVD mortality, while those in Q1 had adjusted HRs of 1.49 (1.19, 1.85) for all-cause mortality and 1.93 (1.26, 2.98) for CVD mortality. CONCLUSIONS: Both higher and lower SUA levels were associated with increased risks of all-cause and CVD mortality in patients with CKD stages 3-5.

Effect of subcritical water temperature on the chain conformation and immune activity of ginger polysaccharides.

In this study, the ginger polysaccharides extracted from hot water (HW-G) were modified with subcritical water (SW-G) to effectively regulate their immune activity, and the relationship between polysaccharide chain conformation and immune activity at different subcritical water temperatures was investigated. The results indicated that, compared with HW-G, the xylose and mannose were degraded at high temperatures. The molecular weight of ginger polysaccharide decreased from 1.083 × 106 g/mol to 3.113 × 105 g/mol after subcritical water modification (100-160 °C). The chain conformation transitioned from rigid rod chain to semi-rigid chain and eventually to random coil. The degree of relaxation of the polysaccharide chains showed a continuous increase trend. Additionally, ginger polysaccharide modified by subcritical water at 130 °C was found to promote the proliferation and phagocytosis of 264.7 cells more obviously and signally increase the secretion levels of NO, IL-6, TNF-α and IL-1ß. When the subcritical water temperature exceeds 130 °C, the activity of ginger polysaccharide begins to decline rapidly. These findings demonstrate a close correlation between polysaccharide chain conformation and immunomodulatory activity, confirming the feasibility of the subcritical water temperature effect as a means of immune activity regulation, which opens up a new approach to obtaining highly active polysaccharides.

(-)-Asarinin alleviates gastric precancerous lesions by promoting mitochondrial ROS accumulation and inhibiting the STAT3 signaling pathway.

BACKGROUND: (-)-Asarinin (Asarinin) is the primary component in the extract of the herb Asarum sieboldii Miq. It possesses various functions, including pain relief, anti-viral and anti-tuberculous bacilli effects, and inhibition of tumor growth. Gastric precancerous lesion (GPL) is a common but potentially carcinogenic chronic gastrointestinal disease, and its progression can lead to gastric dysfunction and cancer development. However, the protective effects of asarinin against GPL and the underlying mechanisms remain unexplored. METHODS: A premalignant cell model (methylnitronitrosoguanidine-induced malignant transformation of human gastric epithelial cell strain, MC cells) and a GPL animal model were established and then were treated with asarinin. The cytotoxic effect of asarinin was assessed using a CCK8 assay. Detection of intracellular reactive oxygen species (ROS) using DCFH-DA. Apoptosis in MC cells was evaluated using an annexin V-FITC/PI assay. We performed western blot analysis and immunohistochemistry (IHC) to analyze relevant markers, investigating the in vitro and in vivo therapeutic effects of asarinin on GPL and its intrinsic mechanisms. RESULTS: Our findings showed that asarinin inhibited MC cell proliferation, enhanced intracellular ROS levels, and induced cell apoptosis. Further investigations revealed that the pharmacological effects of asarinin on MC cells were blocked by the ROS scavenger N-acetylcysteine. IHC revealed a significant upregulation of phospho-signal transducer and activator of transcription 3 (p-STAT3) protein expression in human GPL tissues. In vitro, asarinin exerted its pro-apoptotic effects in MC cells by modulating the STAT3 signaling pathway. Agonists of STAT3 were able to abolish the effects of asarinin on MC cells. In vivo, asarinin induced ROS accumulation and inhibited the STAT3 pathway in gastric mucosa of mice, thereby halting and even reversing the development of GPL. CONCLUSION: Asarinin induces apoptosis and delays the progression of GPL by promoting mitochondrial ROS production, decreasing mitochondrial membrane potential (MMP), and inhibiting the STAT3 pathway.

Left ventricular global longitudinal strain using a novel fully automated method: A head-to-head comparison with a manual layer-specific strain and establishment of normal reference ranges.

BACKGROUND: A novel automated method for measuring left ventricular (LV) global longitudinal strain (GLS) along the endocardium has advantages in terms of its rapid application and excellent reproducibility. However, it remains unclear whether the available normal range for conventional GLS using the manual method is applicable to the automated GLS method. This study aimed to compare automated GLS head-to-head with manual layer-specific GLS, and to identify whether a specialized normal reference range for automated GLS is needed and explore the main determinants. METHODS: In total, 1683 healthy volunteers (men, 43%; age, 18-80 years) were prospectively enrolled from 55 collaborating laboratories. LV GLS was measured using both manual layer-specific and automated methods. RESULTS: Automated GLS was higher than endocardial, mid-myocardial, and epicardial GLS. Women had a higher automated GLS than men. GLS had no significant age dependency in men, but first increased and then decreased with age in women. Accordingly, sex- and age-specific normal ranges for automated GLS were proposed. Moreover, GLS appeared to have different burdens in relation to dominant determinants between the sexes. GLS in men showed no dominant determinants; however, GLS in women correlated with age, body mass index, and heart rate. CONCLUSIONS: Using the novel automated method, was LV GLS higher than when using the manual GLS method. The normal ranges of automated GLS stratified according to sex and age were provided, with dominant determinants showing sex disparities that require full consideration in clinical practice.

An opponent striatal circuit for distributional reinforcement learning.

Machine learning research has achieved large performance gains on a wide range of tasks by expanding the learning target from mean rewards to entire probability distributions of rewards - an approach known as distributional reinforcement learning (RL)1. The mesolimbic dopamine system is thought to underlie RL in the mammalian brain by updating a representation of mean value in the striatum2,3, but little is known about whether, where, and how neurons in this circuit encode information about higher-order moments of reward distributions4. To fill this gap, we used high-density probes (Neuropixels) to acutely record striatal activity from well-trained, water-restricted mice performing a classical conditioning task in which reward mean, reward variance, and stimulus identity were independently manipulated. In contrast to traditional RL accounts, we found robust evidence for abstract encoding of variance in the striatum. Remarkably, chronic ablation of dopamine inputs disorganized these distributional representations in the striatum without interfering with mean value coding. Two-photon calcium imaging and optogenetics revealed that the two major classes of striatal medium spiny neurons - D1 and D2 MSNs - contributed to this code by preferentially encoding the right and left tails of the reward distribution, respectively. We synthesize these findings into a new model of the striatum and mesolimbic dopamine that harnesses the opponency between D1 and D2 MSNs5-15 to reap the computational benefits of distributional RL.

Comparison of diffusion tensor imaging (DTI) tissue characterization parameters in white matter tracts of patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD).

OBJECTIVE: To investigate the microstructural properties of T2 lesion and normal-appearing white matter (NAWM) in 20 white matter tracts between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) and correlations between the tissue damage and clinical variables. METHODS: The white matter (WM) compartment of the brain was segmented for 56 healthy controls (HC), 48 patients with MS, and 38 patients with NMOSD, and for the patients further subdivided into T2 lesion and NAWM. Subsequently, the diffusion tensor imaging (DTI) tissue characterization parameters of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were compared for 20 principal white matter tracts. The correlation between tissue damage and clinical variables was also investigated. RESULTS: The higher T2 lesion volumes of 14 fibers were shown in MS compared to NMOSD. MS showed more microstructure damage in 13 fibers of T2 lesion, but similar microstructure in seven fibers compared to NMOSD. MS and NMOSD had microstructure damage of NAWM in 20 fibers compared to WM in HC, with more damage in 20 fibers in MS compared to NMOSD. MS patients showed higher correlation between the microstructure of T2 lesion areas and NAWM. The T2 lesion microstructure damage was correlated with duration and impaired cognition in MS. CONCLUSIONS: Patients with MS and NMOSD show different patterns of microstructural damage in T2 lesion and NAWM areas. The prolonged disease course of MS may aggravate the microstructural damage, and the degree of microstructural damage is further related to cognitive impairment. CLINICAL RELEVANCE STATEMENT: Microstructure differences between T2 lesion areas and normal-appearing white matter help distinguish multiple sclerosis and neuromyelitis optica spectrum disorder. In multiple sclerosis, lesions rather than normal-appearing white matter should be a concern, because the degree of lesion severity correlated both with normal-appearing white matter damage and cognitive impairment. KEY POINTS: • Multiple sclerosis and neuromyelitis optica spectrum disorder have different damage patterns in T2 lesion and normal-appearing white matter areas. • The microstructure damage of normal-appearing white matter is correlated with the microstructure of T2 lesion in multiple sclerosis and neuromyelitis optica spectrum disorder. • The microstructure damage of T2 lesion in multiple sclerosis is correlated with duration and cognitive impairment.

Effect of subcritical water temperature on the structure, antioxidant activity and immune activity of polysaccharides from Glycyrrhiza inflata Batalin.

In this study, the polysaccharide from Glycyrrhiza inflata Batalin extracted by hot water (HW-GP) was further physically modified with subcritical water to obtain novel polysaccharides (SW-GP). Comparative analysis was conducted to examine the disparities in conformation and bioactivity between HW-GP and SW-GP, aiming to precisely regulate the structure of the polysaccharides and enhance their bioactivity by controlling subcritical water temperature. The results showed that, compared with HW-GP, subcritical water modification (100-160 °C) not only significantly reduced the molecular weight of polysaccharides (from 5.586 × 105 g/mol to 1.484 × 105 g/mol), but also modulated the intermolecular interaction forces, which maintain the conformation of the polysaccharides, including electrostatic and hydrophobic interactions, thereby dynamically transforming the polysaccharide chain conformation from triple helix to random coil, and the strength of the chain conformation shifted from rigid to flexible. In addition, the modification of the SW-GP structure by subcritical water also enhanced its biological activity. SW-GP (140 °C) with low molecular weight and semi-rigid triple helix conformation showed the best scavenging effect on the DPPH, ABTS, and hydroxyl radicals, and exhibited excellent antioxidant activity. SW-GP (130 °C) with medium molecular weight and semi-rigid triple helix conformation significantly promoted the proliferation and phagocytosis of RAW264.7 cells, as well as increased the release levels of NO, TNF-α, IL-6, and IL-1ß, and the immunomodulatory activity was much higher than that of other polysaccharides. These findings confirmed the feasibility of using subcritical water temperature as a regulatory feature for the structure and bioactivity of glycyrrhiza polysaccharides, which may have reference significance for the modification of polysaccharides with heightened bioactivity.

Development and validation of an artificial intelligence assisted prenatal ultrasonography screening system for trainees.

OBJECTIVE: Fetal anomaly screening via ultrasonography, which involves capturing and interpreting standard views, is highly challenging for inexperienced operators. We aimed to develop and validate a prenatal-screening artificial intelligence system (PSAIS) for real-time evaluation of the quality of anatomical images, indicating existing and missing structures. METHODS: Still ultrasonographic images obtained from fetuses of 18-32 weeks of gestation between 2017 and 2018 were used to develop PSAIS based on YOLOv3 with global (anatomic site) and local (structures) feature extraction that could evaluate the image quality and indicate existing and missing structures in the fetal anatomical images. The performance of the PSAIS in recognizing 19 standard views was evaluated using retrospective real-world fetal scan video validation datasets from four hospitals. We stratified sampled frames (standard, similar-to-standard, and background views at approximately 1:1:1) for experts to blindly verify the results. RESULTS: The PSAIS was trained using 134 696 images and validated using 836 videos with 12 697 images. For internal and external validations, the multiclass macro-average areas under the receiver operating characteristic curve were 0.943 (95% confidence interval [CI], 0.815-1.000) and 0.958 (0.864-1.000); the micro-average areas were 0.974 (0.970-0.979) and 0.973 (0.965-0.981), respectively. For similar-to-standard views, the PSAIS accurately labeled 90.9% (90.0%-91.4%) with key structures and indicated missing structures. CONCLUSIONS: An artificial intelligence system developed to assist trainees in fetal anomaly screening demonstrated high agreement with experts in standard view identification.