In silico Genetic Network Models for Pre-clinical Drug Prioritization

The high rates of failure in oncology drug clinical trials highlight the problems of using pre-clinical data to predict the clinical effects of drugs. Patient population heterogeneity and unpredictable physiology complicate pre-clinical cancer modeling efforts. We hypothesize that gene networks associated with cancer outcome in heterogeneous patient populations could serve as a reference for identifying drug effects. Here we propose a novel in vivo genetic interaction which we call ‘synergistic outcome determination’ (SOD), a concept similar to ‘Synthetic Lethality’. SOD is defined as the synergy of a gene pair with respect to cancer patients' outcome, whose correlation with outcome is due to cooperative, rather than independent, contributions of genes. The method combines microarray gene expression data with cancer prognostic information to identify synergistic gene-gene interactions that are then used to construct interaction networks based on gene modules (a group of genes which share similar function). In this way, we identified a cluster of important epigenetically regulated gene modules. By projecting drug sensitivity-associated genes on to the cancer-specific inter-module network, we defined a perturbation index for each drug based upon its characteristic perturbation pattern on the inter-module network. Finally, by calculating this index for compounds in the NCI Standard Agent Database, we significantly discriminated successful drugs from a broad set of test compounds, and further revealed the mechanisms of drug combinations. Thus, prognosis-guided synergistic gene-gene interaction networks could serve as an efficient in silico tool for pre-clinical drug prioritization and rational design of combinatorial therapies.
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Rethink Baseline of Integrated Gradients from the Perspective of Shapley Value

Numerous approaches have attempted to interpret deep neural networks (DNNs) by attributing the prediction of DNN to its input features. One of the well-studied attribution methods is Integrated Gradients (IG). Specifically, the choice of baselines for IG is a critical consideration for generating meaningful and unbiased explanations for model predictions in different scenarios. However, current practice of exploiting a single baseline fails to fulfill this ambition, thus demanding multiple baselines. Fortunately, the inherent connection between IG and Aumann-Shapley Value forms a unique perspective to rethink the design of baselines. Under certain hypothesis, we theoretically analyse that a set of baseline aligns with the coalitions in Shapley Value. Thus, we propose a novel baseline construction method called Shapley Integrated Gradients (SIG) that searches for a set of baselines by proportional sampling to partly simulate the computation path of Shapley Value. Simulations on GridWorld show that SIG approximates the proportion of Shapley Values. Furthermore, experiments conducted on various image tasks demonstrate that compared to IG using other baseline methods, SIG exhibits an improved estimation of feature's contribution, offers more consistent explanations across diverse applications, and is generic to distinct data types or instances with insignificant computational overhead.Comment: 12 page

Observations of TCRV β

Environmental dampness is one factor which can cause human diseases. The effects of exposure to humidity on human immune function are diverse and numerous. In the theory of traditional Chinese medicine (TCM), dampness is defined as one of the major pathogenic factors in the human body. It is divided into “external dampness” and “internal dampness.” However the molecular mechanism leading to humidity-induced immunosuppression is obscure. In the present study, we investigated the expression of the T-cell antigen receptor variable β (TCRVβ) subfamilies in rats which were fed in different humid environment. And the expression levels of the TCRVβ subfamilies were detected using FQ-PCR. We found that the dampness might reduce the immunological recognition function of rats. And the obstruction of the immunological recognition function might be caused by internal dampness rather than external dampness

Development of Catalytic Combustion and CO\u3csub\u3e2\u3c/sub\u3e Capture and Conversion Technology

Changes are needed to improve the efficiency and lower the CO2 emissions of traditional coal-fired power generation, which is the main source of global CO2 emissions. The integrated gasification fuel cell (IGFC) process, which combines coal gasification and high-temperature fuel cells, was proposed in 2017 to improve the efficiency of coal-based power generation and reduce CO2 emissions. Supported by the National Key R&D Program of China, the IGFC for nearzero CO2 emissions program was enacted with the goal of achieving near-zero CO2 emissions based on (1) catalytic combustion of the flue gas from solid oxide fuel cell (SOFC) stacks and (2) CO2 conversion using solid oxide electrolysis cells (SOECs). In this work, we investigated a kW-level catalytic combustion burner and SOEC stack, evaluated the electrochemical performance of the SOEC stack in H2O electrolysis and H2O/CO2 co-electrolysis, and established a multiscale and multi-physical coupling simulation model of SOFCs and SOECs. The process developed in this work paves the way for the demonstration and deployment of IGFC technology in the future

Characterization of a Superconducting Microstrip Single-Photon Detector Shunted with an External Resistor

A superconducting microstrip single-photon detector (SMSPD) generally requires a shunt resistor to avoid latching, caused by its high current-carrying capacity and low kinetic inductance. Here, the effect of the shunt resistor on the behaviors of microbridge SMSPDs was investigated. We analyzed the change in equivalent switching current at different shunt resistances in two ways and determined the operating current range using intrinsic dark count rate (iDCR) curves. We observed that the reduction in shunt resistance can increase the operating current range, which helps to improve the internal detection efficiency (IDE) and reduce the iDCR. However, the reduction in the shunt resistance can reduce the pulse amplitude and increase the pulse decay time, which can degrade the timing jitter and count rate performance of the SMSPD. The trends of the experimental results can be qualitatively reproduced using a circuit model for an SMSPD with a shunt resistor, which provides useful information for the selection of shunt resistors. Furthermore, we report the improved detection performance of a helium-ion-irradiated SMSPD shunted with a small resistance of 5.2 {\Omega}. We observed a weak IDE saturation with a bias current at a wavelength up to 2000 nm and a nonlinear relation between detection current and photon energy.Comment: 13 pages, 8 figures, 1 tabl

Comparison of curative effect between OBS assisted by 3D printing and PFNA in the treatment of AO/OTA type 31-A3 femoral intertrochanteric fractures in elderly patients

ObjectiveTo compare and analyze the Ortho-Bridge System (OBS) clinical efficacy assisted by 3D printing and proximal femoral nail anti-rotation (PFNA) of AO/OTA type 31-A3 femoral intertrochanteric fractures in elderly patients.MethodsA retrospective analysis of 25 elderly patients diagnosed with AO/OTA type 31-A3 femoral intertrochanteric fracture was conducted from January 2020 to August 2022 at Yan’an Hospital, affiliated to Kunming Medical University. The patients were divided into 10 patients in the OBS group and 15 in the PFNA group according to different surgical methods. The OBS group reconstructed the bone models and designed the guide plate by computer before the operation, imported the data of the guide plate and bone models into a stereolithography apparatus (SLA) 3D printer, and printed them using photosensitive resin, thus obtaining the physical object, then simulating the operation and finally applying the guide plate to assist OBS to complete the operation; the PFNA group was treated by proximal femoral nail anti-rotation. The operation time, the intraoperative blood loss, Harris hip score (HHS), Oxford Hip Score (OHS), and complications were compared between the two groups.ResultsThe operation time and the intraoperative blood loss in the PFNA group were less than that in the OBS group, and there was a significant difference between the two groups (P < 0.05). The HHS during the 6th month using OBS was statistically higher than PFNA (P < 0.05), however, there were no significant differences in OHS during the 6th month between the OBS group and PFNA group (P > 0.05). The HHS and OHS during the 12th month in the OBS group were statistically better than in the PFNA group (P < 0.05).ConclusionThe OBS assisted by 3D printing and PFNA are effective measures for treating intertrochanteric fractures. Prior to making any decisions regarding internal fixation, it is crucial to evaluate the distinct circumstances of each patient thoroughly

Immunomodulatory Hydrogels:Advanced Regenerative Tools for Diabetic Foot Ulcer

Diabetic foot ulcer (DFU) is one of the most common complications of diabetes, bringing physical and mental challenges for patients due to the lack of efficient curative therapy. Despite considerable advances in pharmacological and surgical approaches, clinical trials for DFU patients remain disappointing due to the local overactive and excessive inflammation. Immunomodulatory hydrogels has significant advantages to overcome the clinical challenge of DFUs therapy. Here, recent fabrication and regenerative advances in the utilization of functional hydrogels for altering the immune microenvironment of DFUs are comprehensively reviewed. The pathological features and the healing processes of DFUs, followed by summarizing the physicochemical properties essential for the design of regenerative hydrogels for immunomodulation in DFUs, are briefly introduced. Then, the potential immuno-therapeutic modalities of hydrogels and emerging trends used to treat DFUs via multitherapeutic approaches and enhanced efficacy and safety are discussed. Taken together, by linking the structural properties of hydrogels to their functions in DFU therapy with a particular focus on immunomodulatory stimuli, this review can promote further advances in designing advanced hydrogels for DFUs, resulting in improved diabetic wound repair through translation into clinical setting in the near future.</p

Poor-Grade Aneurysmal Subarachnoid Hemorrhage: Risk Factors Affecting Clinical Outcomes in Intracranial Aneurysm Patients in a Multi-Center Study

Objective: Patients with poor-grade aneurysm subarachnoid hemorrhage (SAH) have commonly been considered to have a poor prognosis. The objective of this study was to investigate the independent risk factors affecting clinical outcomes in intracranial aneurysm patients with poor-grade aneurysm subarachnoid hemorrhage (aSAH) underwent different intervention therapies.Methods: A multicenter observational registry of 324 poor-grade aSAH patients treated at tertiary referral centers from October 2010 to March 2012 were enrolled in this study. The clinical data including patient characteristics on admission and during treatment course, treatment modality, aneurysm size and location, radiologic features, signs of cerebral herniation (dilated pupils), and functional neurologic outcome were collected. Clinical outcomes were assessed via a modified Rankin Scale at 12 months. Multivariate logistic regression models were used to develop prognostic models. The area under the receiver operator characteristic curves (AUC) and Hosmer-Lemeshow tests were used to assess discrimination and calibration. WAP score was developed to predict risk of poor outcome.Results: Older age, female gender, ventilated breathing status, non-reactive pupil response, pupil dilation, lower GCS score, a WFNS grade of V, intraventricular hemorrhage, a higher Fisher grade, a higher modified Fisher grade, and conservative treatment were calculated to be associated with a relatively poor outcome. Multivariate analyses revealed that older age, lower Glasgow coma scale score (GCS), the absence of pupillary reactivity, higher modified Fisher grade, and conservative treatment were independent predictors of poor outcome, showed good discrimination and calibration. Patients with WFNS grade V, older age and non-reactive pupillary reactivity were predicted to have a poor outcome by WAP risk score.Conclusions: A simple WAP risk score had good discrimination and calibration in the prediction of outcome. The risk score can be easily measured and may complement treatment decision-making

Graphene Quantum Dots Doped PVDF(TBT)/PVP(TBT) Fiber Film with Enhanced Photocatalytic Performance

We report the fabrication of polyvinylidene fluoride (tetrabutyl titanate)/polyvinyl pyrrolidone ((tetrabutyl titanate))-graphene quantum dots [PVDF(TBT)/PVP(TBT)-GQDs] film photocatalyst with enhanced photocatalytic performance. The polyvinylidene fluoride (tetrabutyl titanate)/polyvinyl pyrrolidone ((tetrabutyl titanate)) [PVDF(TBT)/PVP(TBT)] film was first prepared with a dual-electrospinning method and then followed by attaching graphene quantum dots (GQDs) to the surface of the composite film through a hydrothermal method. Later, part of the PVP in the composite film was dissolved by a hydrothermal method. As a result, a PVDF(TBT)/PVP(TBT)-GQDs film photocatalyst with a larger specific surface area was achieved. The photocatalytic degradation behavior of the PVDF(TBT)/PVP(TBT)-GQDs film photocatalyst was examined by using Rhodamine B as the target contaminant. The PVDF(TBT)/PVP(TBT)-GQDs photocatalyst showed a higher photocatalytic efficiency than PVDF(TBT)-H2O, PVDF(TBT)/PVP(TBT)-H2O, and PVDF(TBT)-GQDs, respectively. The enhanced photocatalytic efficiency can be attributed to the broader optical response range of the PVDF(TBT)/PVP(TBT)-GQDs photocatalyst, which makes it useful as an effective photocatalyst under white light irradiation