Miracle-dz/UniFAR-FTUs huggingface dataset:
A prognostic signature based on adenosine metabolism related genes for ovarian cancer

Background Ovarian cancer is one of the most common cause of cancer death in women due to its late diagnosis and susceptibility to drug resistance. Adenosine (ADO) signaling plays a key role in immune activity and tumor progression. In this study, we constructed a signature of ADO metabolism related genes expression in patients with ovarian cancer. Methods A total of 372 ovarian cancer patients from TCGA was used as training set and 1,137 patients from six GEO datasets were as validation set. The gene expression and drug response inhibitory concentration values for ovarian cancer cell line from GDSC were used for drug sensitivity analysis. The non-negative matrix factorization algorithm and ssGSVA were used to construct the ADO score. Results Patients with high ADO score had shorter overall survival (OS) than those with low ADO score in both training set (HR = 1.42, 95% CI, 1.06-1.88) and validation sets (pooled HR = 1.24, 95% CI = 1.02-1.51). In GSEA analysis, genes in ATP synthesis related pathways were enriched in the low ADO score group (adjusted P value = 0.02). Further, we observed that the high ADO score group had significantly higher levels of most cancer hallmark signatures (all adjusted P values < 0.01) and T cell dysfunction and exclusion signatures than the low ADO score group (all adjusted P values < 0.001). Patients with lower ADO score tended to be sensitive to common drugs including Olaparib and Paclitaxel (adjusted P values = 0.05 and 0.04, respectively). Conclusions In conclusion, the established ADO signature could be used as a prognostic biomarker to stratify ovarian cancer patients and had the potential to guide the drug exploitation and personalized therapy selection.
Succinate aggravates intestinal injury in mice with necrotizing enterocolitis

Background Necrotizing enterocolitis (NEC) is the most prevalent gastrointestinal disorder that predominantly threatens preterm newborns. Succinate is an emerging metabolic signaling molecule that was recently studied in relation to the regulation of intestinal immunity and homeostasis. We aimed to investigate the relationship between NEC and gut luminal succinate and preliminarily explored the effect of succinate on NEC pathogenesis. Methods Fecal samples from human neonates and mouse pups were analyzed by HPLC – MS/MS and 16S rRNA gene sequencing. C57BL/6 mice were randomly divided into four groups: control, NEC, Lsuc, and Hsuc. The mortality, weight gain, and intestinal pathological changes in four mouse groups were observed. Inflammatory cytokines and markers of macrophages were identified by quantitative real-time PCR. Succinate receptor 1 (SUCNR1) localization was visualized by immunohistochemistry. The protein levels of SUCNR1 and hypoxia-inducible factor 1a (HIF-1a) were quantified by western blotting. Results The levels of succinate in feces from NEC patients were higher than those in feces from non-NEC patients (P <0.05). In the murine models, succinate levels in intestinal content samples were also higher in the NEC group than in the control group (P <0.05). The change in succinate level was closely related to intestinal flora composition. In samples from human neonates, relative to the control group, the NEC group showed a higher abundance of Enterobacteriaceae and a lower abundance of Lactobacillaceae and Lactobacillus (P <0.05). In the murine models, relative to the control group, increased abundance was observed for Clostridiaceae, Enterococcaceae, Clostridium_sensu_stricto_1, and Enterococcus, whereas decreased abundance was observed for Lactobacillaceae and Lactobacillus (P <0.05). Increased succinate levels prevented mice from gaining weight, damaged their intestines, and increased their mortality; upregulated the gene expression of interleukin-1β (IL-1β), IL-6, IL-18 and tumor necrosis factor (TNF); and downregulated the gene expression of IL-10 and transforming growth factor (TGF)-β. Exogenous succinic acid increased inducible nitric oxide synthase (iNOS) gene expression but decreased Arginase-1 (Arg1) gene expression; and increased the protein expression of SUCNR1 and HIF-1a. Conclusion Succinate plays an important role in the development of necrotizing enterocolitis severity, and the activation of the HIF-1a signaling pathway may lead to disease progression.
A cerebellum inspired spiking neural network as a multi-model for pattern classification and robotic trajectory prediction

Spiking neural networks were introduced to understand spatiotemporal information processing in neurons and have found their application in pattern encoding, data discrimination, and classification. Bioinspired network architectures are considered for event-driven tasks, and scientists have looked at different theories based on the architecture and functioning. Motor tasks, for example, have networks inspired by cerebellar architecture where the granular layer recodes sparse representations of the mossy fiber (MF) inputs and has more roles in motor learning. Using abstractions from cerebellar connections and learning rules of deep learning network (DLN), patterns were discriminated within datasets, and the same algorithm was used for trajectory optimization. In the current work, a cerebellum-inspired spiking neural network with dynamics of cerebellar neurons and learning mechanisms attributed to the granular layer, Purkinje cell (PC) layer, and cerebellar nuclei interconnected by excitatory and inhibitory synapses was implemented. The model’s pattern discrimination capability was tested for two tasks on standard machine learning (ML) datasets and on following a trajectory of a low-cost sensor-free robotic articulator. Tuned for supervised learning, the pattern classification capability of the cerebellum-inspired network algorithm has produced more generalized models than data-specific precision models on smaller training datasets. The model showed an accuracy of 72%, which was comparable to standard ML algorithms, such as MLP (78%), Dl4jMlpClassifier (64%), RBFNetwork (71.4%), and libSVM-linear (85.7%). The cerebellar model increased the network’s capability and decreased storage, augmenting faster computations. Additionally, the network model could also implicitly reconstruct the trajectory of a 6-degree of freedom (DOF) robotic arm with a low error rate by reconstructing the kinematic parameters. The variability between the actual and predicted trajectory points was noted to be ± 3 cm (while moving to a position in a cuboid space of 25 × 30 × 40 cm). Although a few known learning rules were implemented among known types of plasticity in the cerebellum, the network model showed a generalized processing capability for a range of signals, modulating the data through the interconnected neural populations. In addition to potential use on sensor-free or feed-forward based controllers for robotic arms and as a generalized pattern classification algorithm, this model adds implications to motor learning theory.
Developmental endothelial locus-1 in cardiovascular and metabolic diseases: A promising biomarker and therapeutic target

Cardiovascular and metabolic diseases (CVMDs) are a leading cause of death worldwide and impose a major socioeconomic burden on individuals and healthcare systems, underscoring the urgent need to develop new drug therapies. Developmental endothelial locus-1 (DEL-1) is a secreted multifunctional domain protein that can bind to integrins and play an important role in the occurrence and development of various diseases. Recently, DEL-1 has attracted increased interest for its pharmacological role in the treatment and/or management of CVMDs. In this review, we present the current knowledge on the predictive and therapeutic role of DEL-1 in a variety of CVMDs, such as atherosclerosis, hypertension, cardiac remodeling, ischemic heart disease, obesity, and insulin resistance. Collectively, DEL-1 is a promising biomarker and therapeutic target for CVMDs.
Vanadyl sulfate-enhanced oncolytic virus immunotherapy mediates the antitumor immune response by upregulating the secretion of pro-inflammatory cytokines and chemokines

Oncolytic viruses (OVs) are promising anticancer treatments that specifically replicate in and kill cancer cells and have profound immunostimulatory effects. We previously reported the potential of vanadium-based compounds such as vanadyl sulfate (VS) as immunostimulatory enhancers of OV immunotherapy. These compounds, in conjunction with RNA-based OVs such as oncolytic vesicular stomatitis virus (VSVΔ51), improve viral spread and oncolysis, leading to long-term antitumor immunity and prolonged survival in resistant tumor models. This effect is associated with a virus-induced antiviral type I IFN response shifting towards a type II IFN response in the presence of vanadium. Here, we investigated the systemic impact of VS+VSVΔ51 combination therapy to understand the immunological mechanism of action leading to improved antitumor responses. VS+VSVΔ51 combination therapy significantly increased the levels of IFN-γ and IL-6, and improved tumor antigen-specific T-cell responses. Supported by immunological profiling and as a proof of concept for the design of more effective therapeutic regimens, we found that local delivery of IL-12 using VSVΔ51 in combination with VS further improved therapeutic outcomes in a syngeneic CT26WT colon cancer model.
Response of the wheat mycobiota to flooding revealed substantial shifts towards plant pathogens

Rainfall extremes are intensifying as a result of climate change, leading to increased flood risk. Flooding affects above- and belowground ecosystem processes, representing a substantial threat to crop productivity under climate change. Plant-associated fungi play important roles in plant performance, but their response to abnormal rain events is unresolved. Here, we established a glasshouse experiment to determine the effects of flooding stress on the spring wheat-mycobiota complex. Since plant phenology could be an important factor in the response to hydrological stress, flooding was induced only once and at different plant growth stages, such as tillering, booting and flowering. We assessed the wheat mycobiota response to flooding in three soil-plant compartments (phyllosphere, roots and rhizosphere) using metabarcoding. Key soil and plant traits were measured to correlate physiological plant and edaphic changes with shifts in mycobiota structure and functional guilds. Flooding reduced plant fitness, and caused dramatic shifts in mycobiota assembly across the entire plant. Notably, we observed a functional transition consisting of a decline in mutualist abundance and richness with a concomitant increase in plant pathogens. Indeed, fungal pathogens associated with important cereal diseases, such as Gibberella intricans, Mycosphaerella graminicola, Typhula incarnata and Olpidium brassicae significantly increased their abundance under flooding. Overall, our study demonstrate the detrimental effect of flooding on the wheat mycobiota complex, highlighting the urgent need to understand how climate change-associated abiotic stressors alter plant-microbe interactions in cereal crops.
Forest succession improves the complexity of soil microbial interaction and ecological stochasticity of community assembly: Evidence from Phoebe bournei-dominated forests in subtropical regions

Forest succession is a central ecological topic, due to the importance of the associated dynamic processes for terrestrial ecosystems. However, very little is currently known about the community assembly and interaction of soil microbial communities along forest successional trajectories, particularly regarding the microbial community dynamics in contrasting seasons. To bridge these knowledge gaps, we studied soil bacterial and fungal community compositions, assemblages, and co-occurrence networks in a well-established successional gradient of Phoebe bournei-dominated forest, spanning about 65 years of forest development in a subtropical region. Illumina MiSeq sequencing of 16S and ITS genes was employed for the assessment of soil bacterial and fungal community composition and diversity, respectively. The relative abundance and α–diversity of soil bacteria and fungi showed a differential trend over forest succession. The dominant fungal phyla (Basidiomycota and Ascomycota) changed more frequently than the dominant bacterial phyla (Proteobacteria, Acidobacteriota, and Actinobacteriota), indicating that soil fungi have a more sensitive relationship with forest succession compared with bacteria. The soil microbial community variation induced by forest succession was significantly affected by soil total phosphorus, dissolved organic carbon content and pH. Compared to deterministic processes, stochastic processes mainly dominated the community assembly of soil microbial communities. Meanwhile, the relative importance of stochasticity in soil fungal communities increased in the later stages. In Particular, dispersal limitation and drift accounted for a large proportion of bacterial and fungal community assembly, respectively. In addition, the co-occurrence networks of soil microbial communities became more complex as succession proceeds. Soil bacteria and fungi exhibited more competition and cooperation along the forest successional gradient. Collectively, our findings suggest that forest succession improves the complexity of soil microbial interactions and the ecological stochasticity of community assembly in Phoebe bournei-dominated forests, providing key insights into the relationship between microbial communities and forest succession.
Childhood Socioeconomic Position and Cardiovascular Disease Among Older Women and Men: The Moderating Role of Parenthood Onset

Objectives: Based on a life-course approach, the purpose of this study is to analyze how the age at the birth of a first child moderates the relationship between childhood socioeconomic position (SEP) and cardiovascular diseases (CVD) incidence in old age, separately for women and men. Methods: We used a rich and representative life history survey of people aged from 65 to 75 living in Santiago, Chile (n = 802), and weighted multivariate statistical models. Data collection process involved the use of face-to-face life history calendars, administered by well-trained interviewers. Results: Early motherhood increases the risk of suffering CVD among older women with a disadvantaged childhood SEP, while late motherhood decreases it. By contrast, early fatherhood decreases CVD risk among older men with an adverse childhood SEP, while late fatherhood increases it. Conclusion: Our findings about the moderating role of parenthood onset on CVD risk among older women and men with a disadvantaged childhood SEP contributes to public health reflections on unexplored cardiovascular risk factors, which lead to substantial changes in women’s and men’s life courses, and might optimize cardiovascular prevention strategies.
Exploration and validation of a combined immune and metabolism gene signature for prognosis prediction of colorectal cancer

Background Colorectal cancer (CRC) is still one of the most frequently diagnosed malignancy around the world. The complex etiology and high heterogeneity of CRC necessitates the identification of new reliable signature to identify different tumor prognosis, which may help more precise understanding of the molecular properties of CRC and identify the appropriate treatment for CRC patients. In this study, we aimed to identify a combined immune and metabolism gene signature for prognosis prediction of CRC from large volume of CRC transcriptional data. Methods Gene expression profiling and clinical data of HCC samples was retrieved from the from public datasets. IRGs and MRGs were identified from differential expression analysis. Univariate and multivariate Cox regression analysis were applied to establish the prognostic metabolism-immune status-related signature. Kaplan-Meier survival and receiver operating characteristic (ROC) curves were generated for diagnostic efficacy estimation. Real-time polymerase chain reaction (RT-PCR), Western blot and immunohistochemistry (IHC) was conducted to verified the expression of key genes in CRC cells and tissues. Results A gene signature comprising four genes (including two IRGs and two MRGs) were identified and verified, with superior predictive performance in discriminating the overall survival (OS) of high-risk and low-risk compared to existing signatures. A prognostic nomogram based on the four-gene signature exhibited a best predictive performance, which enabled the prognosis prediction of CRC patients. The hub gene ESM1 related to CRC were selected via the machine learning and prognostic analysis. RT-PCR, Western blot and IHC indicated that ESM1 was high expressed in tumor than normal with superior predictive performance of CRC survival. Conclusions A novel combined MRGs and IRGs-related prognostic signature that could stratify CRC patients into low-and high- risk groups of unfavorable outcomes for survival, was identified and verified. This might help, to some extent, to individualized treatment and prognosis assessment of CRC patients. Similarly, the mining of key genes provides a new perspective to explore the molecular mechanisms and targeted therapies of CRC.
I can see my virtual body in a mirror: The role of visual perspective in changing implicit racial attitudes using virtual reality

Introduction Recent studies showed that VR is a valid tool to change implicit attitudes toward outgroup members. Here, we extended this work by investigating conditions under which virtual reality (VR) is effective in changing implicit racial attitudes. Methods To this end, participants were embodied in a Black or White avatar and we manipulated the perspective through which they could see their virtual body. Participants in one condition, could see their virtual body both from a first-person perspective (i.e., by looking down toward themselves) and reflected in a mirror placed in front of them in the VR environment. Participants in another condition could instead see their virtual body only from a first-person perspective (i.e., by looking down toward themselves) as no mirror was placed in the VR environment. Implicit racial attitudes were assessed using the Implicit Association Test (IAT) before and immediately after the VR intervention. Results Results showed that when White participants were embodied in a Black avatar compared to a White avatar, they showed a decrease in their implicit pro-White attitudes but only when they could see their virtual body both from a first-person perspective and in a mirror. Discussion These results suggest that, in immersive virtual reality interventions, the possibility for participants to see their body also reflected in a mirror, might be a critical factor in changing their implicit racial attitudes.
Evaluation of therapeutic strategies targeting BCAA catabolism using a systems pharmacology model

Background: Abnormal branched-chained amino acids (BCAA) accumulation in cardiomyocytes is associated with cardiac remodeling in heart failure. Administration of branched-chain α-keto acid dehydrogenase (BCKD) kinase inhibitor BT2 has been shown to reduce cardiac BCAA levels and demonstrated positive effects on cardiac function in a preclinical setting. The current study is focused on evaluating the impact of BT2 on the systemic and cardiac levels of BCAA and their metabolites as well as activities of BCAA catabolic enzymes using a quantitative systems pharmacology model. Methods: The model is composed of an ordinary differential equation system characterizing BCAA consumption with food, disposal in the proteins, reversible branched-chain-amino-acid aminotransferase (BCAT)-mediated transamination to branched-chain keto-acids (BCKA), followed by BCKD-mediated oxidation. Activity of BCKD is regulated by the balance of BCKDK and protein phosphatase 2Cm (PP2Cm) activities, affected by BT2 treatment. Cardiac BCAA levels are assumed to directly affect left ventricular ejection fraction (LVEF). Biochemical characteristics of the enzymes are taken from the public domains, while plasma and cardiac BCAA and BCKA levels in BT2 treated mice are used to inform the model parameters. Results: The model provides adequate reproduction of the experimental data and predicts synchronous BCAA responses in the systemic and cardiac space, dictated by rapid BCAA equilibration between the tissues. The model-based simulations indicate maximum possible effect of BT2 treatment on BCAA reduction to be 40% corresponding to 12% increase in LVEF. Model sensitivity analysis demonstrates strong impact of BCKDK and PP2Cm activities as well as total BCKD and co-substrate levels (glutamate, ketoglutarate and ATP) on BCAA and BCKA levels. Conclusion: Model based simulations confirms using of plasma measurements as a marker of cardiac BCAA changes under BCKDK inhibition. The proposed model can be used for optimization of preclinical study design for novel compounds targeting BCAA catabolism.
Variable seismic responsiveness to stress perturbations along the shallow section of subduction zones: The role of different slip modes and implications for the stability of fault segments

Assessing the stability state of fault interfaces is a task of primary interest not only for seismic hazards, but also for understanding how the earthquake machine works. Nowadays it is well known that a relationship exists between slow and fast earthquakes; moreover, it is more and more evident that such a connection is quite diffuse all over the Earth. In this paper, we perform a spatial and temporal analysis of both geodetic and seismic—non-volcanic tremors, low-frequency events (LFEs), and regular earthquakes—time series. We focus on the relationship between the clustering of properties of the different kinds of seismicity and their response to stress perturbations. Earth tides and large earthquakes are used as a source of additional stress. Seismic activity hosted in the Cascadia subduction zone, Manawatu region in New Zealand, and Japan during the last two decades is considered. Our analysis suggests that tremors become more and more sensitive to Earth-tide perturbations as the fault interface is seismically locked. Therefore, tremors and regular events show a similar response to tidal stress perturbations. This feature is also accompanied by relatively lower spatial and temporal coefficients of variation. A series of recordings by several GNSS stations along the Hikurangi Trench, North Island, New Zealand, and along the Nankai coasts in Japan is taken into account for studying how large thrust-faulting earthquakes affect silent events and geodetic signals and vice versa. In the last section, a simple model for grasping a glimpse of the local stability condition of the Earth’s crust and for explaining previous observations is provided.