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Abstract Behavioral flexibility relies on the brain’s ability to switch rapidly between multiple tasks, even when the task rule is not explicitly cued but must be inferred through trial and error. The underlying neural circuit mechanism remains poorly understood. We investigated recurrent neural networks (RNNs) trained to perform an analog of the classic Wisconsin Card Sorting Test. The networks consist of two modules responsible for rule representation and sensorimotor mapping, respectively, where each module is comprised of a circuit with excitatory neurons and three major types of inhibitory neurons. We found that rule representation by self-sustained persistent activity across trials, error monitoring and gated sensorimotor mapping emerged from training. Systematic dissection of trained RNNs revealed a detailed circuit mechanism that is consistent across networks trained with different hyperparameters. The networks’ dynamical trajectories for different rules resided in separate subspaces of population activity; the subspaces collapsed and performance was reduced to chance level when dendrite-targeting somatostatin-expressing interneurons were silenced, illustrating how a phenomenological description of representational subspaces is explained by a specific circuit mechanism.

Abstract Saliva, an oral secretion primarily originating from salivary glands (SGs), exert critical roles in the ongoing evolutionary interaction between insects and plants. However, identifying insect salivary components poses challenges due to the tiny size of insects, low secretion amounts, and the propensity for degradation after secretion. In this study, we developed a transcriptome-based approach to comprehensively analyze the salivary proteins of the short-headed planthopper, Epeurysa nawaii, a species with unique feeding habits on bamboo. A total of 165 salivary proteins were identified, with 114 secretory genes highly and specifically expressed in SGs. Consistent with most phloem-feeding insects, digestive enzymes, calcium-binding proteins, oxidoreductases, and a few previously reported salivary effectors were ubiquitously distributed in E. nawaii saliva. However, we also identified a substantial portion of salivary proteins exhibiting taxonomy specificity, including 60 E. nawaii-specific and 62 Delphacidae-specific proteins. These taxonomy-restricted proteins potentially play a role in insect adaptation to specific host plants. Our study provides an efficient pipeline for salivary protein identification and serves as a valuable resource for the functional characterization of effectors.

Ileostomy diverts the flow of feces, which can result in malnutrition in the distal part of the intestine. The diversity of the gut microbiota consequently decreases, ultimately leading to intestinal dysbiosis and dysfunction. This condition can readily result in diversion colitis (DC). Potential treatment strategies include interventions targeting the gut microbiota. In this case study, we effectively treated a patient with severe DC by ileostomy and allogeneic fecal microbiota transplantation (FMT). A 69-year-old man presented with a perforated malignant tumor in the descending colon and an iliac abscess. He underwent laparoscopic radical sigmoid colon tumor resection and prophylactic ileostomy. Follow-up colonoscopy 3 months postoperatively revealed diffuse intestinal mucosal congestion and edema along with granular inflammatory follicular hyperplasia, leading to a diagnosis of severe DC. After two rounds of allogeneic FMT, both the intestinal mucosal bleeding and edema significantly improved, as did the diversity of the gut microbiota. The positive outcome of allogeneic FMT in this case highlights the potential advantages that this procedure can offer patients with DC. However, few studies have focused on allogeneic FMT, and more in-depth research is needed to gain a better understanding.

Recent advances in connectomics and neurophysiology make it possible to probe whole-brain mechanisms of cognition and behavior. We developed a large-scale model of the multiregional mouse brain for a cardinal cognitive function called working memory, the brain’s ability to internally hold and process information without sensory input. The model is built on mesoscopic connectome data for interareal cortical connections and endowed with a macroscopic gradient of measured parvalbumin-expressing interneuron density. We found that working memory coding is distributed yet exhibits modularity; the spatial pattern of mnemonic representation is determined by long-range cell type-specific targeting and density of cell classes. Cell type-specific graph measures predict the activity patterns and a core subnetwork for memory maintenance. The model shows numerous attractor states, which are self-sustained internal states (each engaging a distinct subset of areas). This work provides a framework to interpret large-scale recordings of brain activity during cognition, while highlighting the need for cell type-specific connectomics.

Precise regulation of photogenic electron transfer path plays an important role in improving photocatalytic carbon dioxide reduction efficiency and product selectivity. Herein, under the guidance of density functional theory calculation, the interface chemical bond (CoN2 bond) at the atomic level is designed, and g‐C3N4/CoCo‐layered double hydroxide (LDH) heterostructure is manufactured. CoCo‐LDH with water oxidation ability and g‐C3N4 were combined to construct S‐scheme heterojunction with redox ability. The valence band and conduction band of g‐C3N4 and CoCo‐LDH are precisely connected by the interfacial CoN2 bond, which realizes the high‐speed transfer of electron transport. Despite the absence of cocatalyst, the heterojunction exhibits high water oxidation and carbon reduction capacity due to the precise regulation of CoN2 bonds. Theoretical calculations and experimental results show that the addition of CoCo‐LDH: reduces the oxidation overpotential of water to provide more H protons; regulates the delocalization charge of g‐C3N4; and reduces the energy barrier of the CO2 intermediate (*COOH) in the reduction half‐reaction. The results show that the selectivity of carbon‐based substances in the products was 100%, and the optimal CO yield was 71.39 μmol g−1 h−1, which is among the highest values of g‐C3N4‐based photocatalysts.

Background Oral squamous cell carcinoma (OSCC) is a devastating disease most often associated with tobacco consumption that induces a field of mutations from which a tumor arises. Identification of ways to prevent the emergence of cancer in high-risk patients is an ultimate goal for combatting all types of cancer, including OSCC.Methods Our study employs a mouse model of tongue carcinogenesis induced by tobacco carcinogen mimetic, 4-nitroquinoline 1-oxide (4NQO), to establish tongue dysplasia and OSCC. We use conventional histology, immunohistochemistry, multispectral imaging, mass cytometry, novel cell lines, pharmaceutical inhibition of PI3Kγ, T-cell suppression assays and mouse transplant models in our functional experimentation.Results In our study, we identify Ly6G+ granulocytes as the most abundant immune cell type in a model of tongue carcinogenesis induced by tobacco carcinogen mimetic 4NQO. Targeting Ly6G+ granulocytes with a pharmacologic inhibitor of PI3Kγ, an isoform of PI3K exclusively expressed by myeloid cells, resulted in reduced tongue dysplasia severity, and reduced rates of OSCC. Importantly, we performed functional assays with the Ly6G+ granulocytes induced in cell line models of 4NQO carcinogenesis to demonstrate that these granulocytes have increased polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) activity against T-cell proliferation and these PMN-MDSCs play a functional role in promoting tumor formation by inhibiting tumor regression in a PI3Kγ-dependent manner.Conclusions Overall, our data suggest that recruitment of PMN-MDSCs to sites of dysplasia is critical to immune suppression of CD8 T cells, thereby permitting malignancy, and PI3Kγ inhibitors are one mechanism to reduce PMN-MDSC recruitment, immunosuppression and tumorigenesis in OSCC.

Sclera is an important tissue to maintain the structure and function of eyes.Its unique biomechanical properties influence the occurrence and development of ocular diseases. The biomechanical properties of sclera are mainly determined by extracellular matrix(ECM), which contains different types of collagen fibers, proteoglycan and other substances. In many ocular diseases, the change of the content and arrangement of these scleral ingredients as well as scleral biomechanics can be called scleral remodeling. In recent years, studies have shown that the scleral remodeling is a complex and dynamic process in many ocular diseases,with many key molecules and signaling pathways participating and regulating. Those key molecules and signaling pathways influencing the scleral remodeling of ocular diseases are reviewed, and the availability of scleral intervention in the treatment of ocular diseases is explored.

Abstract In the setting of conventional radiation therapy, even when combined with immunotherapy, head and neck cancer often recurs locally and regionally. Elective nodal irradiation (ENI) is commonly employed to decrease regional recurrence. Given our developing understanding that immune cells are radio-sensitive, and that T cell priming occurs in the draining lymph nodes (DLNs), we hypothesize that radiation therapy directed at the primary tumor only will increase the effectiveness of immunotherapies. We find that ENI increases local, distant, and metastatic tumor growth. Multi-compartmental analysis of the primary/distant tumor, the DLNs, and the blood shows that ENI decreases the immune response systemically. Additionally, we find that ENI decreases antigen-specific T cells and epitope spreading. Treating the primary tumor with radiation and immunotherapy, however, fails to reduce regional recurrence, but this is reversed by either concurrent sentinel lymph node resection or irradiation. Our data support using lymphatic sparing radiation therapy for head and neck cancer.

Based on quantitative cyto- and receptor architectonic analyses, we identified 35 prefrontal areas, including novel subdivisions of Walker’s areas 10, 9, 8B, and 46. Statistical analysis of receptor densities revealed regional differences in lateral and ventrolateral prefrontal cortex. Indeed, structural and functional organization of subdivisions encompassing areas 46 and 12 demonstrated significant differences in the interareal levels of α2 receptors. Furthermore, multivariate analysis included receptor fingerprints of previously identified 16 motor areas in the same macaque brains and revealed 5 clusters encompassing frontal lobe areas. We used the MRI datasets from the non-human primate data sharing consortium PRIME-DE to perform functional connectivity analyses using the resulting frontal maps as seed regions. In general, rostrally located frontal areas were characterized by bigger fingerprints, that is, higher receptor densities, and stronger regional interconnections. Whereas more caudal areas had smaller fingerprints, but showed a widespread connectivity pattern with distant cortical regions. Taken together, this study provides a comprehensive insight into the molecular structure underlying the functional organization of the cortex and, thus, reconcile the discrepancies between the structural and functional hierarchical organization of the primate frontal lobe. Finally, our data are publicly available via the EBRAINS and BALSA repositories for the entire scientific community.

Deoxynivalenol (DON) is a common mycotoxin that is widely found in various foods and feeds, posing a potential threat to human and animal health. This study aimed to investigate the protective effect of the natural polyphenol piceatannol (PIC) against DON-induced damage in porcine intestinal epithelial cells (IPEC-J2 cells) and the underlying mechanism. The results showed that PIC promotes IPEC-J2 cell proliferation in a dose-dependent manner. Moreover, it not only significantly relieved DON-induced decreases in cell viability and proliferation but also reduced intracellular reactive oxygen species (ROS) production. Further studies demonstrated that PIC alleviated DON-induced oxidative stress damage by increasing the protein expression levels of the antioxidant factors NAD(P)H quinone oxidoreductase-1 (NQO1) and glutamate–cysteine ligase modifier subunit (GCLM), and the mRNA expression of catalase (CAT), Superoxide Dismutase 1 (SOD1), peroxiredoxin 3 (PRX3), and glutathione S-transferase alpha 4 (GSTα4). In addition, PIC inhibited the activation of the nuclear factor-B (NF-κB) pathway, downregulated the mRNA expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) to attenuate DON-induced inflammatory responses, and further mitigated DON-induced cellular intestinal barrier injury by regulating the protein expression of Occludin. These findings indicated that PIC had a significant protective effect against DON-induced damage. This study provides more understanding to support PIC as a feed additive for pig production.

Transforming growth factor‐β (TGF‐β) and programmed death ligand 1 (PD‐L1) initiate signaling pathways with complementary, nonredundant immunosuppressive functions in the tumor microenvironment (TME). In the TME, dysregulated TGF‐β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial‐to‐mesenchymal transition, and angiogenesis. Meanwhile, PD‐L1 expression inactivates cytotoxic T cells and restricts immunosurveillance in the TME. Anti‐PD‐L1 therapies have been approved for the treatment of various cancers, but TGF‐β signaling in the TME is associated with resistance to these therapies. In this review, we discuss the importance of the TGF‐β and PD‐L1 pathways in cancer, as well as clinical strategies using combination therapies that block these pathways separately or approaches with dual‐targeting agents (bispecific and bifunctional immunotherapies) that may block them simultaneously. Currently, the furthest developed dual‐targeting agent is bintrafusp alfa. This drug is a first‐in‐class bifunctional fusion protein that consists of the extracellular domain of the TGF‐βRII receptor (a TGF‐β ‘trap’) fused to a human immunoglobulin G1 (IgG1) monoclonal antibody blocking PD‐L1. Given the immunosuppressive effects of the TGF‐β and PD‐L1 pathways within the TME, colocalized and simultaneous inhibition of these pathways may potentially improve clinical activity and reduce toxicity.

Zingiber zerumbet and Zingiber corallinum are economically valuable species in the genus Zingiber. While Z. corallinum is sexually active, Z. zerumbet adopts clonal propagation, although it has the potential for sexual reproduction. It is unclear so far at which step during the sexual reproduction of Z. zerumbet inhibition occurs, and what are the regulatory mechanisms underlying this inhibition. Here, by comparing with the fertile species Z. corallinum using microscopy-based methods, we show that rare differences were observed in Z. zerumbet up to the point when the pollen tubes invaded the ovules. However, a significantly higher percentage of ovules still contained intact pollen tubes 24 h after pollination, suggesting pollen tube rupture was impaired in this species. Further RNA-seq analysis generated accordant results, showing that the transcription of ANX and FER, as well as genes for the partners in the same complexes (e.g., BUPS and LRE, respectively), and those putative peptide signals (e.g., RALF34), were timely activated in Z. corallinum, which ensured the pollen tubes being able to grow, reorient to ovules, and receipt by embryo sacs. In Z. zerumbet, genes for these complexes were cooperatively suppressed, which would result in the maintenance of PT integrity due to the disruption of RALF34-ANX/BUPS signaling in PT and the failure of PT reception by an active synergid due to the insufficiency of the synergid-harbored FER/LRE complex. Taking the results from the cytological and RNA-seq studies together, a model is proposed to illustrate the possible regulation mechanisms in Z. zerumbet and Z. corallinum, in which the regulations for pollen tube rupture and reception are proposed as the barrier for sexual reproduction in Z. zerumbet.

Abstract Background While immune checkpoint inhibitors (ICI) were approved for head and neck squamous cell carcinomas (HNSCCs), the response rate remains relatively low. Mechanisms underlying ICI unresponsiveness versus sensitivity are not fully understood. Method To better delineate differential responses to ICI treatment, we employed mouse SCC models, termed KPPA tumors that were caused by deleting p53 and hyperactivating PIK3CA, two most frequently mutated genes in human HNSCCs. We transplanted two KPPA tumor lines (TAb2 versus TCh3) into C57BL/6 recipients and examined the immune tumor microenvironment using flow cytometry. Furthermore, we employed single-cell RNA sequencing to identify the difference in tumor infiltrating lymphocytes (TILs). Results We found that different KPPA tumors exhibited heterogeneous immune profiles pre-existing treatment that dictated their sensitivity or unresponsiveness to anti-PD-L1. Unresponsive TAb2 tumors were highly enriched with functional tumor-associated macrophages (TAMs), especially M2-TAMs. In contrast, sensitive TCh3 tumors contained more CD8 TILs with better effector functions. TAb2 tumor cells drastically expanded F4/80+ TAMs from bone marrow precursors, requiring CSF1 and VEGF. Consistently, a higher combined expression of VEGF-C and CSF1 predicts worse survival in PIK3CAAmp/TP53Mutated HNSCC patients. Unresponsive TAb2 tumors upregulated distinct signaling pathways that correlate with aggressive tumor phenotypes. While anti-PD-L1 did not affect the TME of TAb2 tumors, it significantly increased the number of CD8 TILs in TCh3 tumors. Conclusions We uncovered tumor-intrinsic differences that may underlie the differential responses to ICI by establishing and employing two SCC tumor lines, TAb2 vs. TCh3, both of which harbor TP53 deletion and PIK3CA hyperactivation. Our study indicates the limitation of stratifying cancers according to their genetic alterations and suggests that evaluating HNSCC tumor-intrinsic cues along with immune profiles in the TME may help better predict ICI responses. Our experimental models may provide a platform for pinpointing tumor-intrinsic differences underlying an immunosuppressive TME in HNSCCs and for testing combined immunotherapies targeting either tumor-specific or TAM-specific players to improve ICI efficacy.

Abstract Basic helix-loop-helix (bHLH) proteins are transcription factors (TFs) that have been shown to regulate anthocyanin biosynthesis in many plant species. However, the bHLH gene family in Populus deltoids has not yet been reported. In this study, 185 PdbHLH genes were identified in the Populus deltoids genome and were classified into 15 groups based on their sequence similarity and phylogenetic relationships. Analysis of the gene structure, chromosome location and conserved motif of the PdbHLH genes were performed by bioinformatic methods. Gene duplication analyses revealed that 114 PdbHLH were expanded and retained after WGD/segmental and proximal duplication. Investigation of cis-regulatory elements of PdbHLH genes indicated that many PdbHLH genes are involved in the regulation of anthocyanin biosynthesis. The expression patterns of PdbHLHs were obtained from previous data in two colored-leaf poplar (QHP and JHP) and green leaf poplar (L2025). Further analysis revealed that 12 candidate genes, including 3 genes (PdbHLH57, PdbHLH143, and PdbHLH173) from the subgroup III(f) and 9 gene from other groups, were positively associated with anthocyanin biosynthesis. In addition, 4 genes (PdbHLH4, PdbHLH1, PdbHLH18, and PdbHLH164) may be involved in negatively regulating the anthocyanin biosynthesis. These results provide a basis for the functional characterization of bHLH genes and investigations on the molecular mechanisms of anthocyanin biosynthesis in colored-leaf poplar.

ObjectiveThis study aims to digitally obtain the morphological data of children's primary teeth in northwest China and evaluate the reliability of digitally obtaining the anatomical morphological data of primary teeth.MethodsA total of 308 extracted primary teeth and cone-beam computed tomography (CBCT) images of 407 primary teeth were collected in northwest China. Electronic digital Vernier callipers (accuracy: 0.01 mm) were used to measure the mesiodistal and buccolingual diameters and crown length of the extracted primary teeth and calculate the crown area and crown index. Each sample was scanned with an intraoral scanner (Trios2 3shape, Denmark), and the resulting stl format files were imported into Geomagic Wrap 2015 to measure the axial and buccolingual diameters and crown length. The crown area and crown index were then calculated. After verifying the accuracy of the CBCT image measurement, the CBCT image data of 407 samples were measured in SmartV software using the “measure length” function by referring to the coronal, sagittal, and horizontal planes to adjust the position of the reference line.ResultsNorthern Chinese have larger primary teeth than other populations (Japanese, white American, African, Icelander, Spanish, and Dominican Mestizo) but smaller primary teeth than native Australians. Compared to Indian primary teeth, northwest Chinese's primary teeth have larger diameters on the central axis and smaller diameters on the buccolingual surface. Male teeth are usually larger than female teeth. Compared with the results of Wang Huiyun's study, the axial and buccolingual diameters and crown length of all native tooth types in this total sample were significantly smaller at the 0.1% level, and only the axial diameters of the upper first molar and lower second molar and the crown length of the lower lateral incisor were significantly smaller at the 1% level. The results of the intraclass correlation coefficient of 308 extracted primary teeth expressed an excellent degree of agreement between the callipers and intraoral scanner for the following: mesiodistal diameter (0.956–0.991), buccolingual diameter (0.963–0.989), crown length [0.864–0.992, except for the upper canine (0.690)], crown index (0.850–0.975), and crown area (0.946–0.993).ConclusionThe digital measurements of the intraoral scanner and CBCT image are in good agreement with the manual measurement of the Vernier calliper. The difference between the anatomical morphology size of the primary teeth measured in this study and the results of different populations could be due to different genetic backgrounds and environmental factors.

The bean bug, Riptortus pedestris (Hemiptera: Heteroptera), poses a significant threat to soybean production, resulting in substantial crop losses. Throughout the soybean cultivation period, these insects probe and suck on various parts of plants, including leaves, pods, and beans. However, the specific mechanisms by which they adapt to different food resources remain unknown. In this study, we conducted gut transcriptomic analyses of R. pedestris fed with soybean leaves, pods, and beans. A total of 798, 690, and 548 differently expressed genes (DEGs) were monitored in G—pod vs. G—leaf (comparison of insect feeding on pods and leaves), G—bean vs. G—leaf (comparison of insect feeding on beans and leaves), and G—pod vs. G—bean (comparison of insect feeding on pods and beans), respectively. When fed on pods and beans, there was a significant increase in the expression of digestive enzymes, particularly cathepsins, serine proteases, and lipases. Conversely, when soybean leaves were consumed, detoxification enzymes, such as ABC transporters and 4-coumarate-CoA ligase, exhibited higher expression. Our findings indicate that R. pedestris dynamically regulates different metabolic pathways to cope with varying food resources, which may contribute to the development of effective strategies for managing this pest.

Strait et al describe distinct immune microenvironment profiles of responders versus non-responders to combined TGF-β/PD-L1 blockade in mouse models of squamous cell carcinoma (SCC). The results emphasize the potential of combined TGF-β/PD-L1 targeting and provide important clues to guide personalized SCC immunotherapy.

Abstract. Background:. Coronavirus disease 2019 (COVID-19) is a serious and even lethal respiratory illness. The mortality of critically ill patients with COVID-19, especially short term mortality, is considerable. It is crucial and urgent to develop risk models that can predict the mortality risks of patients with COVID-19 at an early stage, which is helpful to guide clinicians in making appropriate decisions and optimizing the allocation of hospital resoureces. Methods:. In this retrospective observational study, we enrolled 949 adult patients with laboratory-confirmed COVID-19 admitted to Tongji Hospital in Wuhan between January 28 and February 12, 2020. Demographic, clinical and laboratory data were collected and analyzed. A multivariable Cox proportional hazard regression analysis was performed to calculate hazard ratios and 95% confidence interval for assessing the risk factors for 30-day mortality. Results:. The 30-day mortality was 11.8% (112 of 949 patients). Forty-nine point nine percent (474) patients had one or more comorbidities, with hypertension being the most common (359 [37.8%] patients), followed by diabetes (169 [17.8%] patients) and coronary heart disease (89 [9.4%] patients). Age above 50 years, respiratory rate above 30 beats per minute, white blood cell count of more than10 × 109/L, neutrophil count of more than 7 × 109/L, lymphocyte count of less than 0.8 × 109/L, platelet count of less than 100 × 109/L, lactate dehydrogenase of more than 400 U/L and high-sensitivity C-reactive protein of more than 50 mg/L were independent risk factors associated with 30-day mortality in patients with COVID-19. A predictive CAPRL score was proposed integrating independent risk factors. The 30-day mortality were 0% (0 of 156), 1.8% (8 of 434), 12.9% (26 of 201), 43.0% (55 of 128), and 76.7% (23 of 30) for patients with 0, 1, 2, 3, ≥4 points, respectively. Conclusions:. We designed an easy-to-use clinically predictive tool for assessing 30-day mortality risk of COVID-19. It can accurately stratify hospitalized patients with COVID-19 into relevant risk categories and could provide guidance to make further clinical decisions.

With the climate constantly changing, plants suffer more frequently from various abiotic and biotic stresses. However, they have evolved biosynthetic machinery to survive in stressful environmental conditions. Flavonoids are involved in a variety of biological activities in plants, which can protect plants from different biotic (plant-parasitic nematodes, fungi and bacteria) and abiotic stresses (salt stress, drought stress, UV, higher and lower temperatures). Flavonoids contain several subgroups, including anthocyanidins, flavonols, flavones, flavanols, flavanones, chalcones, dihydrochalcones and dihydroflavonols, which are widely distributed in various plants. As the pathway of flavonoid biosynthesis has been well studied, many researchers have applied transgenic technologies in order to explore the molecular mechanism of genes associated with flavonoid biosynthesis; as such, many transgenic plants have shown a higher stress tolerance through the regulation of flavonoid content. In the present review, the classification, molecular structure and biological biosynthesis of flavonoids were summarized, and the roles of flavonoids under various forms of biotic and abiotic stress in plants were also included. In addition, the effect of applying genes associated with flavonoid biosynthesis on the enhancement of plant tolerance under various biotic and abiotic stresses was also discussed.

Gliomas are the most frequent primary malignant brain tumors of the central nervous system, causing significant impairment and death. There is mounting evidence that N7 methylguanosine (m7G) RNA dysmethylation plays a significant role in the development and progression of cancer. However, the expression patterns and function of the m7G RNA methylation regulator in gliomas are yet unknown. The goal of this study was to examine the expression patterns of 31 critical regulators linked with m7G RNA methylation and their prognostic significance in gliomas. To begin, we systematically analyzed patient clinical and prognostic data and mRNA gene expression data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. We found that 17 key regulators of m7G RNA methylation showed significantly higher expression levels in gliomas. We then divided the sample into two subgroups by consensus clustering. Cluster 2 had a poorer prognosis than cluster 1 and was associated with a higher histological grade. In addition, cluster 2 was significantly enriched for cancer-related pathways. Based on this discovery, we developed a risk model involving three m7G methylation regulators. Patients were divided into high-risk and low-risk groups based on risk scores. Overall survival (OS) was significantly lower in the high-risk group than in the low-risk group. Further analysis showed that the risk score was an independent prognostic factor for gliomas.

Multiple sclerosis (MS) is an incurable and progressive neurodegenerative disease that affects more than 2.5 million people worldwide and brings tremendous economic pressures to society. However, the pathophysiology of MS is still not fully elucidated, and there is no effective treatment. Demyelination is thought to be the primary pathophysiological alteration in MS, and our previous study found abnormal lipid metabolism in the demyelinated corpus callosum. Growing evidence indicates that central nervous system (CNS) demyelinating diseases never result from one independent factor, and the simultaneous participation of abnormal lipid metabolism, oxidative stress, and neuroinflammation could potentiate each other in the pathogenesis of MS. Therefore, a single omics analysis cannot provide a full description of any neurodegenerative disease. It has been demonstrated that oxidative stress and neuroinflammation are two reciprocal causative reasons for the progression of MS disease. However, the potential crosstalk between oxidative stress and neuroinflammation remains elusive so far. With an integrated analysis of targeted lipidomics and transcriptomics, our research presents the potential interaction between abnormalities of lipid metabolism, mitochondrial dysfunction, oxidative stress, and neuroinflammation in CNS demyelinating diseases. The findings of this paper may be used to identify possible targets for the therapy of CNS demyelinating diseases.

Abstract Background N-acetylneuraminic acid (Neu5Ac) is a functional metabolite involved in coronary artery disease (CAD). We aimed to evaluate the relationship between serum Neu5Ac and the risk and prognosis of acute coronary syndrome (ACS) in a real-world prospective study. Methods Patients with suspected ACS who underwent coronary angiography were included. Serum Neu5Ac was measured at admission. Coronary lesion severity was evaluated by Gensini Score. GRACE risk stratification was performed at admission. Major adverse cardiac events (MACEs) were recorded during follow-up. Results A total of 766 patients, including 537 with unstable angina (UAP), 100 with myocardial infarction (MI), and 129 without CAD were included. The circulating Neu5Ac level was significantly higher in patients with MI (median [1QR]: 297[220, 374] ng/ml) than in those with UAP (227 [114, 312] ng/ml) or without CAD (207 [114, 276] ng/ml; both p

Abstract Background Immunocompetent animal models are required to study tumor-host interactions, immunotherapy, and immunotherapeutic combinations, however the currently available immunocompetent lung cancer models have substantial limitations. While orthotopic models potentially help fill this gap, the utility of these models has been limited by the very small number of murine lung cancer cell lines capable of forming orthotopic tumors in immunocompetent C57BL/6 hosts. Methods Primary lung tumors with specific genetic alterations were created in C57BL/6 background mice. These tumors were then passaged through other animals to increase tumorigenicity and select for the ability to grow in a non-self animal. Once tumors demonstrated growth in a non-self host, cell lines were established. Successful cell lines were evaluated for the ability to produce orthotopic lung tumors in immunocompetent hosts. Results We produced six murine lung cancer lines capable of orthotopic lung tumor formation in immunocompetent C57BL/6 animals. These lines demonstrate the expected genetic alterations based on their primary tumor genetics. Conclusions These novel cell lines will be useful for evaluating tumor-host interactions, the impact of specific oncogenic alterations on the tumor microenvironment, and immunotherapeutic approaches. This method of generating murine lines capable of orthotopic growth can likely be applied to other tumors and will broaden the applicability of pre-clinical testing of immunotherapeutic treatment regimens.

Understanding principles of neuronal connectivity requires tools for quantification and visualization of large datasets. Here, the authors introduce an online resource encompassing the coordinates of two million neurons labelled by tracer injections in the marmoset cortex, and analysis tools.

Palladium is a precious metal, which has been widely used for various organic transformations in the past decades. Currently, the palladium-catalyzed direct activation of the aromatic ring C–H bonds is one of the frontier areas in organic chemistry, and the progress of research in this field is very rapid. Compared with other transition metals, palladium has the advantages of high catalytic activity and strong selectivity. Combining the domestic and foreign scholars' research on this aspect, this paper summarizes the research progress of the palladium-catalyzed activation of aromatic ring C–H bonds in the past ten years. Keywords: Aromatic ring C–H bonds, Palladium catalyst, Direct conversion

Neural activity underlying working memory is not a local phenomenon but distributed across multiple brain regions. To elucidate the circuit mechanism of such distributed activity, we developed an anatomically constrained computational model of large-scale macaque cortex. We found that mnemonic internal states may emerge from inter-areal reverberation, even in a regime where none of the isolated areas is capable of generating self-sustained activity. The mnemonic activity pattern along the cortical hierarchy indicates a transition in space, separating areas engaged in working memory and those which do not. A host of spatially distinct attractor states is found, potentially subserving various internal processes. The model yields testable predictions, including the idea of counterstream inhibitory bias, the role of prefrontal areas in controlling distributed attractors, and the resilience of distributed activity to lesions or inactivation. This work provides a theoretical framework for identifying large-scale brain mechanisms and computational principles of distributed cognitive processes.

Chayote (Sechium edule), a member of the Cucurbitaceae family, is cultivated throughout tropical and subtropical regions of the world and utilized in pharmaceutical, cosmetic and food industries because it is an excellent source of minerals, dietary fibers, protein, vitamins, carotenoids, polysaccharides, phenolic and flavonoid compounds, and other nutrients. Chayote extracts process various medicinal properties, such as anti-cardiovascular, antidiabetic, antiobesity, antiulcer, and anticancer properties. With the rapid advancements of molecular biology and sequencing technology, studies on chayote have been carried out. Research advances, including molecular makers, breeding, genomic research, chemical composition, and pests and diseases, regarding chayote are reviewed in this paper. Future exploration and application trends are briefly described. This review provides a reference for basic and applied research on chayote, an important Cucurbitaceae vegetable crop.

Cancer-associated fibroblasts (CAFs) have been shown to enhance squamous cell carcinoma (SCC) growth, but it is unclear whether they promote SCC lung metastasis. We generated CAFs from K15.KrasG12D.Smad4–/– mouse SCCs. RNA expression analyses demonstrated that CAFs had enriched transforming growth factor-beta (TGFβ) signaling compared to normal tissue-associated fibroblasts (NAFs), therefore we assessed how TGFβ-enriched CAFs impact SCC metastasis. We co-injected SCC cells with CAFs to the skin, tail vein, or the lung to mimic sequential steps of lung metastasis. CAFs increased SCC volume only in lung co-transplantations, characterized with increased proliferation and angiogenesis and decreased apoptosis compared to NAF co-transplanted SCCs. These CAF effects were attenuated by a clinically relevant TGFβ receptor inhibitor, suggesting that CAFs facilitated TGFβ-dependent SCC cell seeding and survival in the lung. CAFs also increased tumor volume when co-transplanted to the lung with limiting numbers of SCC cancer stem cells (CSCs). In vitro, CSC sphere formation and invasion were increased either with co-cultured CAFs or with CAF conditioned media (which contains the highest TGFβ1 concentration) and these CAF effects were blocked by TGFβ inhibition. Further, TGFβ activation was higher in primary human oral SCCs with lung metastasis than SCCs without lung metastasis. Similarly, TGFβ activation was detected in the lungs of mice with micrometastasis. Our data suggest that TGFβ-enriched CAFs play a causal role in CSC seeding and expansion in the lung during SCC metastasis, providing a prognostic marker and therapeutic target for SCC lung metastasis.

The nature of the signals that propagate through feedforward networks is not well understood. Here, the authors combine microfabrication, multilayer cortical cultures, and optogenetic stimulation to show that NMDA-mediated synaptic current generates a sustained phase of activity that propagates firing rate signals.

The work is focused on the design of drugs that prevent and treat Alzheimer’s disease (AD) and its complications. A series of 3–(4-aminophenyl)-coumarin derivatives designed, synthesised, fully characterised and evaluated in vitro/vivo. The biological assay experiments showed that some compounds displayed a clearly selective inhibition for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among all compounds, compound 4m exhibited the highest AChE inhibition with an IC50 value of 0.091 ± 0.011 µM and compound 4k exhibited the highest BuChE inhibition with an IC50 value of 0.559 ± 0.017 µM. A zebrafish behaviour analyser (Zebrobox) was used to determine the behavioural effects of the active compound on the movement distance of the aluminium chloride-induced zebrafish. Compound 4m offered a potential drug design concept for the development of therapeutic or preventive agents for AD and its complications.

We are constantly faced with decisions between alternatives defined by multiple attributes, necessitating an evaluation and integration of different information sources. Time-varying signals in multiple brain areas are implicated in decision-making; but we lack a rigorous biophysical description of how basic circuit properties, such as excitatory-inhibitory (E/I) tone and cascading nonlinearities, shape attribute processing and choice behavior. Furthermore, how such properties govern choice performance under varying levels of environmental uncertainty is unknown. We investigated two-attribute, two-alternative decision-making in a dynamical, cascading nonlinear neural network with three layers: an input layer encoding choice alternative attribute values; an intermediate layer of modules processing separate attributes; and a final layer producing the decision. Depending on intermediate layer E/I tone, the network displays distinct regimes characterized by linear (I), convex (II) or concave (III) choice indifference curves. In regimes I and II, each option's attribute information is additively integrated. In regime III, time-varying nonlinear operations amplify the separation between offer distributions by selectively attending to the attribute with the larger differences in input values. At low environmental uncertainty, a linear combination most consistently selects higher valued alternatives. However, at high environmental uncertainty, regime III is more likely than a linear operation to select alternatives with higher value. Furthermore, there are conditions where readout from the intermediate layer could be experimentally indistinguishable from the final layer. Finally, these principles are used to examine multi-attribute decisions in systems with reduced inhibitory tone, leading to predictions of different choice patterns and overall performance between those with restrictions on inhibitory tone and neurotypicals.

Hierarchy is a major organizational principle of the cortex and underscores modern computational theories of cortical function. The local microcircuit amplifies long-distance inter-areal input, which show distance-dependent changes in their laminar profiles. Statistical modeling of these changes in laminar profiles demonstrates that inputs from multiple hierarchical levels to their target areas show remarkable consistency, allowing the construction of a cortical hierarchy based on a principle of hierarchical distance. The statistical modeling that is applied to structure can also be applied to laminar differences in the oscillatory coherence between areas thereby determining a functional hierarchy of the cortex. Close examination of the anatomy of inter-areal connectivity reveals a dual counterstream architecture with well-defined distance-dependent feedback and feedforward pathways in both the supra- and infragranular layers, suggesting a multiplicity of feedback pathways with well-defined functional properties. These findings are consistent with feedback connections providing a generative network involved in a wide range of cognitive functions. A dynamical model constrained by connectivity data sheds insight into the experimentally observed signatures of frequency-dependent Granger causality for feedforward versus feedback signaling. Concerted experiments capitalizing on recent technical advances and combining tract-tracing, high-resolution fMRI, optogenetics and mathematical modeling hold the promise of a much improved understanding of lamina-constrained mechanisms of neural computation and cognition. However, because inter-areal interactions involve cortical layers that have been the target of important evolutionary changes in the primate lineage, these investigations will need to include human and non-human primate comparisons.

Background Antitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences.Methods We developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes.Results We discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRβ sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status.Conclusions We reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.

Core-shell heterostructured BiVO4@Fe2O3 photocatalysts are fabricated through a facile solution combustion and in-situ precipitation methods. Transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) images verify their core-shell structure. X-ray photoelectron spectroscopy (XPS) results indicate there are interaction between BiVO4 and Fe2O3, confirming the formation of heterojunction. Mott–Schottky measurements exhibit that hybridizing with Fe2O3 makes the conduction band of BiVO4 to be shifted up by 1.05 V from 0.21 to −0.84 V, which endows BiVO4 to be effective for photocatalytic H2 generation. Meanwhile, photoluminescence spectra show that the heterosturcture decreases the recombination efficiency of photo-induced electrons and holes. Hydrogen experiments indicate that BiVO4@Fe2O3 composite containing 10 wt% Fe2O3 has the highest catalytic activity. Keywords: BiVO4/Fe2O3 heterojunction, Solution combustion synthesis, Hydrogen production, Core-shell structure, Visible-light photocatalysis

Salivary gland tumor (SGT) is a rare tumor type, which exhibits broad-spectrum phenotypic, biological, and clinical heterogeneity. Currently, the molecular mechanisms that cause SGT pathogenesis remain poorly understood. A lack of animal models that faithfully recapitulate the naturally occurring process of human SGTs has hampered research progress on this field. In this report, we developed an inducible keratin 5-driven conditional knockout mouse model to delete gene(s) of interest in murine salivary gland upon local RU486 delivery. We have deleted two major tumor suppressors, Pten, a negative regulator of the PI3K pathway, and Smad4, the central signaling mediator of TGFβ pathway, in the murine salivary gland. Our results have shown that deletion of either Pten or Smad4 in murine salivary gland resulted in pleomorphic adenomas, the most common tumor in human SGT patients. Deletion of both Pten and Smad4 in murine salivary gland developed several malignancies, with salivary adenoid cystic carcinoma (SACC) being the most frequently seen. Molecular characterization showed that SACC exhibited mTOR activation and TGFβ1 overexpression. Examination of human SGT clinical samples revealed that loss of Pten and Smad4 is common in human SACC samples, particularly in the most aggressive solid form, and is correlated with survival of SACC patients, highlighting the human relevance of the murine models. In summary, our results offer significant insight into synergistic role of Pten and Smad4 in SGT, providing a rationale for targeting mTOR and/or TGFβ signaling to control SGT formation and progression.

Spathiphyllum is a very important tropical plant used as a small, potted, ornamental plant in South China, with an annual output value of hundreds of millions of yuan. In this study, we sequenced and analyzed the complete nucleotide sequence of the Spathiphyllum 'Parrish' chloroplast genome. The whole chloroplast genome is 168,493 bp in length, and includes a pair of inverted repeat (IR) regions (IRa and IRb, each 31,600 bp), separated by a small single-copy (SSC, 15,799 bp) region and a large single-copy (LSC, 89,494 bp) region. Our annotation revealed that the S. 'Parrish' chloroplast genome contained 132 genes, including 87 protein coding genes, 37 transfer RNA genes, and 8 ribosomal RNA genes. In the repeat structure analysis, we detected 281 simple sequence repeats (SSRs) which included mononucleotides (223), dinucleotides (28), trinucleotides (12), tetranucleotides (11), pentanucleotides (6), and hexanucleotides (1), in the S. 'Parrish' chloroplast genome. In addition, we identified 50 long repeats, comprising 18 forward repeats, 13 reverse repeats, 17 palindromic repeats, and 2 complementary repeats. Single nucleotide polymorphism (SNP) and insertion/deletion (indel) analyses of the chloroplast genome of the S. 'Parrish' relative S. cannifolium revealed 962 SNPs in S. 'Parrish'. There were 158 indels (90 insertions and 68 deletions) in the S. 'Parrish' chloroplast genome relative to the S. cannifolium chloroplast genome. Phylogenetic analysis of five species found S. 'Parrish' to be more closely related to S. kochii than to S. cannifolium. This study identified the characteristics of the S. 'Parrish' chloroplast genome, which will facilitate species identification and phylogenetic analysis within the genus Spathiphyllum.

Transforming growth factor-β (TGF-β) signaling is essential in embryo development and maintaining normal homeostasis. Extensive evidence shows that TGF-β activation acts on several cell types, including epithelial cells, fibroblasts, and immune cells, to form a pro-fibrotic environment, ultimately leading to fibrotic diseases. TGF-β is stored in the matrix in a latent form; once activated, it promotes a fibroblast to myofibroblast transition and regulates extracellular matrix (ECM) formation and remodeling in fibrosis. TGF-β signaling can also promote cancer progression through its effects on the tumor microenvironment. In cancer, TGF-β contributes to the generation of cancer-associated fibroblasts (CAFs) that have different molecular and cellular properties from activated or fibrotic fibroblasts. CAFs promote tumor progression and chronic tumor fibrosis via TGF-β signaling. Fibrosis and CAF-mediated cancer progression share several common traits and are closely related. In this review, we consider how TGF-β promotes fibrosis and CAF-mediated cancer progression. We also discuss recent evidence suggesting TGF-β inhibition as a defense against fibrotic disorders or CAF-mediated cancer progression to highlight the potential implications of TGF-β-targeted therapies for fibrosis and cancer.

Cortical circuits receive simultaneous inputs from multiple pathways and are able to flexibly select the appropriate inputs for processing. Here the authors propose a network model in which dendritic branch-specific disinhibition established through synaptic plasticity achieves pathway-specific gating.

Abstract Background Protein tyrosine kinase 6 (PTK6) is overexpressed in many epithelial tumors and predicts poor prognosis. However, PTK6 expression status and its role in cervical squamous cell cancer are unknown. This study aimed to investigate the expression level and clinical significance of PTK6 in early-stage cervical squamous cell cancer. Methods Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting analysis were performed to detect PTK6 mRNA and protein expression levels in 10 freshly frozen, early-stage cervical squamous cell cancer specimens and adjacent non-tumorous cervical tissues. The expression of PTK6 was detected using immunohistochemical staining in 150 formalin-fixed, paraffin-embedded, early-stage cervical squamous cell cancer sections and 10 normal cervical tissue sections. Results The mRNA and protein levels of PTK6 in cancer tissues were higher than those in adjacent non-tumorous cervical tissues. Immunohistochemical analysis showed that PTK6 was not expressed in normal cervical tissues but was overexpressed in the cytoplasm of cervical squamous cell cancer cells. The level of PTK6 expression was significantly associated with tumor grade (P = 0.020). The 5-year overall survival rate of patients with high PTK6 expression was lower than that of patients with low PTK6 expression (81.3% vs. 96.2%, P = 0.008). Multivariate Cox regression analysis showed that the expression level of PTK6 in cervical squamous cell cancer was an independent prognostic factor for patient survival (hazard ratio = 5.999, 95% confidence interval 1.622–22.191, P

Squamous cell carcinoma (SCC) is the second commonest type of skin cancer, and SCCs make up about 90% of head and neck cancers (HNSCCs). HNSCCs harbor two frequent molecular alterations, namely, gain-of-function alterations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and loss-of-function mutations of tumor protein p53 (TP53). However, it remains poorly understood whether HNSCCs harboring different genetic alterations exhibit differential immune tumor microenvironments (TME). It also remains unknown whether PIK3CA hyperactivation and TP53 deletion can lead to SCC development spontaneously. Here, we analyzed the Cancer Genome Atlas (TCGA) datasets of HNSCCs and found that patients with both PIK3CA and TP53 alterations exhibited worse survival, significantly lower CD8 tumor infiltrating lymphocytes (TILs) and higher M0 macrophages than other controls. To better model human tumorigenesis, we deleted TP53 and constitutively activated PIK3CA in mouse keratin-15-expressing stem cells, which leads to the spontaneous development of multilineage tumors including SCCs, termed Keratin-15-p53-PIK3CA (KPPA) tumors. KPPA tumors were heavily infiltrated with myeloid-derived suppressor cells (MDSCs), with a drastically increased ratio of polymorphonuclear-MDSC (PMN-MDSC) versus monocytic-MDSC (M-MDSC). CD8 TILs expressed more PD-1 and reduced their polyfunctionality. Overall, we established a genetic model to mimic human HNSCC pathogenesis, manifested with an immunosuppressive TME, which may help further elucidate immune evasion mechanisms and develop more effective immunotherapies for HNSCCs.

Cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptor 1 (CELSR1) is a member of a special subgroup of adhesion G protein-coupled receptors. Although Celsr1 has been reported to be a sensitive gene for stroke, the effect of CELSR1 in ischemic stroke is still not known. Here, we investigated the effect of CELSR1 on neuroprotection, neurogenesis and angiogenesis in middle cerebral artery occlusion (MCAO) rats. The mRNA expression of Celsr1 was upregulated in the subventricular zone (SVZ), hippocampus and ischemic penumbra after cerebral ischemic injury. Knocking down the expression of Celsr1 in the SVZ with a lentivirus significantly reduced the proliferation of neuroblasts, the number of CD31-positive cells, motor function and rat survival and increased cell apoptosis and the infarct volume in MCAO rats. In addition, the expression of p-PKC in the SVZ and peri-infarct tissue was downregulated after ischemia/ reperfusion. Meanwhile, in the dentate gyrus of the hippocampus, knocking down the expression of Celsr1 significantly reduced the proliferation of neuroblasts; however, it had no influence on motor function, cell apoptosis or angiogenesis. These data indicate that CELSR1 has a neuroprotective effect on cerebral ischemia injury by reducing cell apoptosis in the peri-infarct cerebral cortex and promoting neurogenesis and angiogenesis, mainly through the Wnt/PKC pathway.

We reported and characterized the complete nucleotide sequence of the Spathiphyllum cannifolium chloroplast (cp) genome in this study. The circular molecule of the cp genome is 171,420 bp containing a pair of 31,460 bp IR regions, separated by a small single-copy region (SSC) of 16,331 bp and a large single-copy region (LSC) of 92,169 bp, respectively. A total of 132 genes were successfully annotated in the cp genome, including 87 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. The G + C content of the whole cp genome is 35.62%, while the LSC, SSC, and IR region are 33.94, 28.02, and 40.05%, respectively.

Pyramidal cells and interneurons expressing parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) show cell-type-specific connectivity patterns leading to a canonical microcircuit across cortex. Experiments recording from this circuit often report counterintuitive and seemingly contradictory findings. For example, the response of SST cells in mouse V1 to top-down behavioral modulation can change its sign when the visual input changes, a phenomenon that we call response reversal. We developed a theoretical framework to explain these seemingly contradictory effects as emerging phenomena in circuits with two key features: interactions between multiple neural populations and a nonlinear neuronal input-output relationship. Furthermore, we built a cortical circuit model which reproduces counterintuitive dynamics observed in mouse V1. Our analytical calculations pinpoint connection properties critical to response reversal, and predict additional novel types of complex dynamics that could be tested in future experiments.

Trained neural network models, which exhibit features of neural activity recorded from behaving animals, may provide insights into the circuit mechanisms of cognitive functions through systematic analysis of network activity and connectivity. However, in contrast to the graded error signals commonly used to train networks through supervised learning, animals learn from reward feedback on definite actions through reinforcement learning. Reward maximization is particularly relevant when optimal behavior depends on an animal’s internal judgment of confidence or subjective preferences. Here, we implement reward-based training of recurrent neural networks in which a value network guides learning by using the activity of the decision network to predict future reward. We show that such models capture behavioral and electrophysiological findings from well-known experimental paradigms. Our work provides a unified framework for investigating diverse cognitive and value-based computations, and predicts a role for value representation that is essential for learning, but not executing, a task.

Fetal alcohol spectrum disorder (FASD) can cause severe mental retardation in children who are prenatally exposed to ethanol. The effects of prenatal and early postnatal ethanol exposure on adult hippocampal neurogenesis have been investigated; however, the effects of prenatal ethanol exposure on the subventricular zone (SVZ) have not. Gypenosides (GPs) have been reported to have neuroprotective effects in addition to other bioactivities. The effects of GPs on neural stem cells (NSCs) in the FASD model are unknown. Here, we test the effect of prenatal ethanol exposure on the neonatal SVZ, and the protection potential of GPs on NSCs in FASD rats. Our results show that prenatal ethanol exposure can suppress the cell proliferation and differentiation of neural stem cells in the neonatal SVZ and that GPs (400 mg/kg/day) can significantly increase the cell proliferation and differentiation of neural stem cells inhibited by ethanol. Our data indicate that GPs have neuroprotective effects on the NSCs and can enhance the neurogenesis inhibited by ethanol within the SVZ of neonatal rats. These findings provide new evidence for a potential therapy involving GPs for the treatment of FASD.