Generalizable transcriptome-based tumor malignant level evaluation and molecular subtyping towards precision oncology.

In cancer treatment, therapeutic strategies that integrate tumor-specific characteristics (i.e., precision oncology) are widely implemented to provide clinical benefits for cancer patients. Here, through in-depth integration of tumor transcriptome and patients' prognoses across cancers, we investigated dysregulated and prognosis-associated genes and catalogued such important genes in a cancer type-dependent manner. Utilizing the expression matrices of these genes, we built models to quantitatively evaluate the malignant levels of tumors across cancers, which could add value to the clinical staging system for improved prediction of patients' survival. Furthermore, we performed a transcriptome-based molecular subtyping on hepatocellular carcinoma, which revealed three subtypes with significantly diversified clinical outcomes, mutation landscapes, immune microenvironment, and dysregulated pathways. As tumor transcriptome was commonly profiled in clinical practice with low experimental complexity and cost, this work proposed easy-to-perform approaches for practical clinical promotion towards better healthcare and precision oncology of cancer patients.

Linker Histone H1.4 Inhibits the Growth, Migration and EMT Process of Non-Small Cell Lung Cancer by Regulating ERK1/2 Expression.

H1.4 is one of the 11 variants of linker histone H1, and is associated with tumorigenesis and development of various cancers. However, it is unclear for the role of histone H1.4 in non-small cell lung cancer (NSCLC). In this study, we found that overexpression of H1.4 significantly inhibited the cell viability, migration, invasion and epithelial-mesenchymal transition (EMT) processes, whereas silencing H1.4 by shRNA knockdown promoted these processes in NSCLC cell lines A549 and H1299. We further showed that H1.4 overexpression reduced ERK1/2 expression or its phosphorylation levels, while H1.4 knockdown increased ERK1/2 expression or phosphorylation levels in NSCLC. Furthermore, we demonstrated that H1.4 bound to the promoter of ERK1/2, and acted as a transcriptional suppressor to inhibit ERK1/2 expression in A549 or H1299 cells. Importantly, we found that ERK ecto-expression can largely recovered the inhibitory effects of H1.4 on cell viability, migration, invasion and EMT processes. In summary, our study reveals that the H1.4-ERK pathway is crucial for cell viability, migration, invasion and EMT of NSCLC and could be a therapeutic target for NSCLC.

AI-Driven Diagnostic Assistance in Medical Inquiry: Reinforcement Learning Algorithm Development and Validation.

BACKGROUND: For medical diagnosis, clinicians typically begin with a patient's chief concerns, followed by questions about symptoms and medical history, physical examinations, and requests for necessary auxiliary examinations to gather comprehensive medical information. This complex medical investigation process has yet to be modeled by existing artificial intelligence (AI) methodologies. OBJECTIVE: The aim of this study was to develop an AI-driven medical inquiry assistant for clinical diagnosis that provides inquiry recommendations by simulating clinicians' medical investigating logic via reinforcement learning. METHODS: We compiled multicenter, deidentified outpatient electronic health records from 76 hospitals in Shenzhen, China, spanning the period from July to November 2021. These records consisted of both unstructured textual information and structured laboratory test results. We first performed feature extraction and standardization using natural language processing techniques and then used a reinforcement learning actor-critic framework to explore the rational and effective inquiry logic. To align the inquiry process with actual clinical practice, we segmented the inquiry into 4 stages: inquiring about symptoms and medical history, conducting physical examinations, requesting auxiliary examinations, and terminating the inquiry with a diagnosis. External validation was conducted to validate the inquiry logic of the AI model. RESULTS: This study focused on 2 retrospective inquiry-and-diagnosis tasks in the emergency and pediatrics departments. The emergency departments provided records of 339,020 consultations including mainly children (median age 5.2, IQR 2.6-26.1 years) with various types of upper respiratory tract infections (250,638/339,020, 73.93%). The pediatrics department provided records of 561,659 consultations, mainly of children (median age 3.8, IQR 2.0-5.7 years) with various types of upper respiratory tract infections (498,408/561,659, 88.73%). When conducting its own inquiries in both scenarios, the AI model demonstrated high diagnostic performance, with areas under the receiver operating characteristic curve of 0.955 (95% CI 0.953-0.956) and 0.943 (95% CI 0.941-0.944), respectively. When the AI model was used in a simulated collaboration with physicians, it notably reduced the average number of physicians' inquiries to 46% (6.037/13.26; 95% CI 6.009-6.064) and 43% (6.245/14.364; 95% CI 6.225-6.269) while achieving areas under the receiver operating characteristic curve of 0.972 (95% CI 0.970-0.973) and 0.968 (95% CI 0.967-0.969) in the scenarios. External validation revealed a normalized Kendall τ distance of 0.323 (95% CI 0.301-0.346), indicating the inquiry consistency of the AI model with physicians. CONCLUSIONS: This retrospective analysis of predominantly respiratory pediatric presentations in emergency and pediatrics departments demonstrated that an AI-driven diagnostic assistant had high diagnostic performance both in stand-alone use and in simulated collaboration with clinicians. Its investigation process was found to be consistent with the clinicians' medical investigation logic. These findings highlight the diagnostic assistant's promise in assisting the decision-making processes of health care professionals.

Distribution, risk evaluation, and source allocation of cesium and strontium in surface soil in a mining city.

Radioactive nuclides cesium (Cs) and strontium (Sr) possess long half-lives, with 135Cs at approximately 2.3 million years and 87Sr at about 49 billion years. Their persistent accumulation can result in long-lasting radioactive contamination of soil ecosystems. This study employed geo-accumulation index (Igeo), pollution load index (PLI), potential ecological risk index (PEPI), health risk assessment model (HRA), and Monte Carlo simulation to evaluate the pollution and health risks of Cs and Sr in the surface soil of different functional areas in a typical mining city in China. Positive matrix factorization (PMF) model was used to elucidate the potential sources of Cs and Sr and the respective contribution rates of natural and anthropogenic sources. The findings indicate that soils in the mining area exhibited significantly higher levels of Cs and Sr pollution compared to smelting factory area, agricultural area, and urban residential area. Strontium did not pose a potential ecological risk in any studied functional area. The non-carcinogenic health risk of Sr to the human body in the study area was relatively low. Because of the lack of parameters for Cs, the potential ecological and human health risks of Cs was not calculated. The primary source of Cs in the soil was identified as the parent material from which the soil developed, while Sr mainly originated from associated contamination caused by mining activities. This research provides data for the control of Cs and Sr pollution in the surface soil of mining city.

Research on the improvement effect of Saposhnikovia divaricata (Trucz.) Schischk on rheumatoid arthritis based on the "component-target-pathway" association.

OBJECTIVE: To investigate the therapeutic effect and mechanism of the traditional Chinese medicine Saposhnikovia divaricata (Trucz.) Schischk in rats with complete Freund's adjuvant-induced rheumatoid arthritis (RA). METHODS: The chemical targets and RA targets of Saposhnikovia divaricata (Trucz.) Schischk were acquired by the network pharmacological method. The complete Freund's adjuvant-induced rat RA model was used to further explore the mechanism of Saposhnikovia divaricata (Trucz.) Schischk in improving RA. Pathological changes in the volume of toes, body weight and synovial tissues of joints as well as serum inflammatory factor levels before and after the intervention of Saposhnikovia divaricata (Trucz.) Schischk were investigated. The key metabolic pathways were screened by correlations between metabolites and key targets. Finally, a quantitative analysis of key targets and metabolites was experimentally validated. RESULTS: Saposhnikovia divaricata (Trucz.) Schischk administration increased body weight, mitigated foot swelling and downregulated inflammatory cytokine levels in model rats. The histopathology showed that treatment with Saposhnikovia divaricata (Trucz.) Schischk can induce inflammatory cell infiltration and synovial hyperplasia and obviously reduce cartilage injuries, thus improving arthritis symptoms in rats. According to the network pharmacology-metabonomics association analysis results, the purine metabolic signaling pathway might be the key pathway for RA intervention with Saposhnikovia divaricata (Trucz.) Schischk. Targeted metabonomics, Western blotting (WB) and reverse transcription-polymerase chain reaction (RT‒PCR) assays showed that the recombinant adenosine deaminase (ADA) mRNA expression level and metabolic level of inosine in Saposhnikovia divaricata (Trucz.) Schischk administration group were lower than those of the model group. This reflected that Saposhnikovia divaricata (Trucz.) Schischk could improve RA by downregulating ADA mRNA expression levels and the metabolic level of inosine in the purine signaling pathway. CONCLUSION: Based on the "component-disease-target" association analysis, this study concludes that Saposhnikovia divaricata (Trucz.) Schischk improves complete Freund's adjuvant-induced RA symptoms in rats mainly by downregulating ADA mRNA expression levels in the purine metabolic signaling pathway, mitigating foot swelling, improving the levels of serum inflammatory factors (IL-1ß, IL-6 and TNF-α), and decreasing the ADA protein expression level to intervene in purine metabolism.

Total Cerebral Small Vessel Disease Burden Predicts the Outcome of Acute Stroke Patients after Intra-Arterial Thrombectomy.

INTRODUCTION: Various types of cerebral small vessel diseases (cSVD) markers commonly coexist. The neurological function outcome is affected by their combined effect. To investigate the effect of cSVD on intra-arterial thrombectomy (IAT), our study aimed at developing and testing a model with fusing a combination of multiple cSVD markers as total cSVD burden to predict the outcome of acute ischemic stroke (AIS) patients after IAT treatment. METHODS: From October 2018 to March 2021, continuous AIS patients with IAT treatment were enrolled. We calculated the cSVD markers identified by magnetic resonance imaging. The outcomes of all patients were assessed according to the modified Rankin Scale (mRS) score at 90 days after stroke. The relationship between total cSVD burden and outcomes was analyzed by logistics regression analysis. RESULTS: A total of 271 AIS patients were included in this study. The proportions of score 0∼4 in the total cSVD burden group (i.e., score 0, 1, 2, 3, and 4 groups) were 9.6%, 19.9%, 23.6%, 32.8%, and 14.0%, respectively. The higher the cSVD score, the more patients with a poor outcome. Heavier total cSVD burden (1.6 [1.01∼2.27]), diabetes mellitus (1.27 [0.28∼2.23]), and higher national institute of health stroke scale (NIHSS) on admission (0.15 [0.07∼0.23]) were associated with poor outcome. In the two Least Absolute Shrinkage and Selection Operator regression models, model 1 using age, duration from onset to reperfusion, Alberta stroke program early CT score (ASPECTS), NIHSS on admission, modified thrombolysis in cerebral infarction (mTICI) and total cSVD burden as variables perform well on predicting short-term outcome in area under curve (AUC) of 0.90. Model 2, including all of the variables above except cSVD, showed less predictive capability than model 1 (AUC 0.90 vs. 0.82, p = 0.045). CONCLUSIONS: The total cSVD burden score was independently associated with the clinical outcomes of AIS patients after IAT treatment and it may be a reliable predictor for poor outcomes of AIS patients after IAT treatment.

Integrated Amino Acids and Transcriptome Analysis Reveals Arginine Transporter SLC7A2 Is a Novel Regulator of Myogenic Differentiation.

Skeletal muscle differentiation is a precisely coordinated process. While many of the molecular details of myogenesis have been investigated extensively, the dynamic changes and functions of amino acids and related transporters remain unknown. In this study, we conducted a comprehensive analysis of amino acid levels during different time points of C2C12 myoblast differentiation using high-performance liquid chromatography (HPLC). Our findings revealed that the levels of most amino acids exhibited an initial increase at the onset of differentiation, reaching their peak typically on the fourth or sixth day, followed by a decline on the eighth day. Particularly, arginine and branched-chain amino acids showed a prominent increase during this period. Furthermore, we used RNA-seq analysis to show that the gene encoding the arginine transporter, Slc7a2, is significantly upregulated during differentiation. Knockdown of Slc7a2 gene expression resulted in a significant decrease in myoblast proliferation and led to a reduction in the expression levels of crucial myogenic regulatory factors, hindering the process of myoblast differentiation, fusion, and subsequent myotube formation. Lastly, we assessed the expression level of Slc7a2 during aging in humans and mice and found an upregulation of Slc7a2 expression during the aging process. These findings collectively suggest that the arginine transporter SLC7A2 plays a critical role in facilitating skeletal muscle differentiation and may hold potential as a therapeutic target for sarcopenia.

Choosing the right policy: Factors influencing the preferences of consumption-side personal carbon reduction policies.

With the development of the social economy and the improvement of personal income, the government must consider formulating personal carbon reduction policies to reduce carbon emissions from the consumption side. Therefore, it is valuable to understand the public's preferences for different policies and the factors influencing the willingness of policy support, which can help policy selection and promotion. Using data collected from 2801 college students and a multinomial logit model, this study explores the influence of personal and social factors on preferences for three different personal carbon reduction policies (personal carbon trading, carbon tax, and carbon generalized system of preferences). The results show that individuals with higher levels of affluence, social trust, and social norms prefer personal carbon trading; individuals with higher levels of affluence, self-motivation, and social norms prefer carbon tax; individuals with higher levels of low-carbon behavioral attitudes and social trust prefer carbon generalized system of preferences; and low-carbon responsibility, access to low-carbon information, and social equity are beneficial to all three policies. In addition, this study examined the heterogeneity of individuals with different levels of affluence and low-carbon behavioral attitudes. This study compares the differences in influencing factors of policy preferences, clarifies the effects of various personal and social factors, which can help the government to design consumption-side personal carbon reduction policies in the future, and provide a reference for the promotion of corresponding policies.

Prevalence and associated factors of mortality after percutaneous coronary intervention for adult patients with ST-elevation myocardial infarction: A systematic review and meta-analysis.

Background: There is a paucity of systematic reviews on the associated factors of mortality among ST-elevation myocardial infarction (STEMI) patients after percutaneous coronary intervention (PCI). This meta-analysis was designed to synthesize available evidence on the prevalence and associated factors of mortality after PCI for adult patients with STEMI. Materials and Methods: Databases including the Cochrane Library, PubMed, Web of Science, Embase, Ovid, Scopus, ProQuest, MEDLINE, and CINAHL Complete were searched systematically to identify relevant articles published from January 2008 to March 2020 on factors affecting mortality after PCI in STEMI patients. Meta-analysis was conducted using Stata 12.0 software package. Results: Our search yielded 91 cohort studies involving a total of 199, 339 participants. The pooled mortality rate for STEMI patients after PCI was 10%. After controlling for grouping criteria or follow-up time, the following 17 risk factors were significantly associated with mortality for STEMI patients after PCI: advanced age (odds ratio [OR] = 3.89), female (OR = 2.01), out-of-hospital cardiac arrest (OR = 5.55), cardiogenic shock (OR = 4.83), renal dysfunction (OR = 3.50), admission anemia (OR = 3.28), hyperuricemia (OR = 2.71), elevated blood glucose level (OR = 2.00), diabetes mellitus (OR = 1.8), chronic total occlusion (OR = 2.56), Q wave (OR = 2.18), without prodromal angina (OR = 2.12), delay in door-to-balloon time (OR = 1.72), delay in symptom onset-to-balloon time (OR = 1.43), anterior infarction (OR = 1.66), ST-segment resolution (OR = 1.40), and delay in symptom onset-to-door time (OR = 1.29). Conclusion: The pooled prevalence of mortality after PCI for STEMI patients was 10%, and 17 risk factors were significantly associated with mortality for STEMI patients after PCI.

Ghrelin ameliorates diabetes-associated behavioral deficits and NLRP3 inflammasome activation via autophagic flux enhancement.

Ghrelin has recently been associated with the development of diabetes comorbid with depression, but its underlying molecular mechanisms remains poorly understood. Here, molecular and histological methods were applied both in vivo and in vitro studies to investigate the mechanisms of ghrelin in diabetes comorbid with depression. Our results demonstrated the anti-depressive, anxiolytic, and neuroprotective effects of ghrelin, as evidenced by the amelioration of anxiety- and depression-like behaviors, reduction in apoptosis, and preservation of neuron integrity in streptozotocin (STZ)-treated rats. STZ treatment induced M1-phenotypic microglial polarization, accompanied by neuroinflammation, which was reversed by ghrelin treatment. Further exploration showed that autophagy was inhibited, the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and nuclear factor (NF)-κB signaling pathway were activated in STZ rats. In line with the in vivo results, ghrelin could suppress the NLRP3 inflammasome and NF-κB signaling pathway activation via the amelioration of impaired autophagic flux in microglial BV2 cells. Importantly, clinical evidence further verified the anti-inflammatory and antidepressant effects of ghrelin. Collectively, these results suggested that ghrelin ameliorates diabetes-associated behavioral deficits and NLRP3 inflammasome activation via autophagic flux enhancement, highlighting the importance of ghrelin as a potential target of immune regulation in diabetes comorbid with depression.

A Retrospective Study to Determine the Association Between Serum Albumin Levels and Atrial Fibrillation by Sex in 950 Patients from a Single Center in China.

BACKGROUND It remains unclear whether there is a sex difference in the association between serum albumin (ALB) and atrial fibrillation (AF). This retrospective case-control study from a single center in China aimed to determine the association between serum ALB levels and AF by sex in 950 patients. MATERIAL AND METHODS Data of 950 AF patients and 963 age- and sex-matched non-AF patients with sinus rhythm were collected and analyzed retrospectively. Clinical baseline data were analyzed using the t test or Mann-Whitney U test, analysis of variance (ANOVA), and chi-square test. The interrelationships were determined by Pearson correlation analysis, and multivariate logistic regression analysis was performed to adjust for covariables. RESULTS ALB levels of AF patients were significantly lower in both sexes (P<0.05), especially paroxysmal AF. ALB was positively correlated with total cholesterol (TC) (r=0.359, P<0.05), low-density lipoprotein cholesterol (LDL-C) (r=0.283, P<0.05), and serum apolipoprotein A1 (APOA1) (r=0.429, P<0.05) and was negatively correlated with serum creatinine (SCr) (r=0.129, P<0.05) in patients with AF. We found an independent negative association between ALB levels and AF in men after adjusting for confounding factors (OR=0.889, 95% CI: 0.845-0.934, P<0.05). CONCLUSIONS In patients at a single center in China, low serum ALB levels in male patients were significantly associated with AF. These findings support those from previous studies in other populations and highlight the importance of monitoring and treating the cause of hypoalbuminemia in cardiac patients.

Case-Control Study to Investigate the Association Between Serum Apolipoprotein B/A1 Ratio and Atrial Fibrillation by Sex in 920 Patients from China.

BACKGROUND The serum apolipoprotein B/A1 ratio (APOB/APOA1) has been shown to predict cardiovascular events, whereas the effect of the APOB/APOA1 ratio on atrial fibrillation (AF) is less known. We investigated the association between the APOB/APOA1 ratio and AF by sex in 920 patients from China. MATERIAL AND METHODS We reviewed clinical data on 1840 hospitalized patients, including 920 patients with AF (male/female: 460/460, age: 68.62±10.36 years) and 920 age- and sex-matched patients without AF with sinus rhythm in China between January 2019 and September 2021. Pearson correlation analysis was performed to investigate the correlation between APOB/APOA1 ratio and AF-related metabolic factors. Logistic regression analysis was used to determine the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS Low serum APOB/APOA1 ratios in male and female patients were significantly associated with AF after adjusting for confounding factors (OR 0.159, 95% CI 0.058-0.432, P<0.05). Serum APOB/APOA1 ratio was positively correlated with triglyceride (TG) (r=0.146, P<0.05) and total cholesterol (TC) (r=0.227, P<0.05) and was negatively correlated with albumin (ALB) (r=-0.128, P<0.05) and prealbumin (PAB) (r=-0.107, P<0.05). There was no significant difference of APOB/APOA1 ratio in different subtypes, complications, and statin use in patients with AF (P>0.05). CONCLUSIONS A low serum APOB/APOA1 ratio in male and female patients from China was significantly related to AF. This finding implies that a low serum APOB/APOA1 ratio may be associated with the causes of AF. Further studies are needed to determine causalities.

Calcitriol confers neuroprotective effects in traumatic brain injury by activating Nrf2 signaling through an autophagy-mediated mechanism.

BACKGROUND: The present study aimed to further explore the potential interaction between oxidative stress and autophagy in the progression of traumatic brain injury (TBI) and therapeutic mechanism of calcitriol, the active form of vitamin D (VitD). METHODS: Neuroprotective effects of calcitriol were examined following TBI. We further evaluated the impacts of TBI and calcitriol treatment on autophagic process and nuclear factor E2-related factor 2 (Nrf2) signaling. RESULTS: We found that treatment of calcitriol markedly ameliorated the neurological deficits and histopathological changes following TBI. The brain damage impaired autophagic flux and impeded Nrf2 signaling, the major regulator in antioxidant response, consequently leading to uncontrolled and excessive oxidative stress. Meanwhile, calcitriol promoted autophagic process and activated Nrf2 signaling as evidenced by the reduced Keap1 expression and enhanced Nrf2 translocation, thereby mitigating TBI-induced oxidative damage. In support, we further found that chloroquine (CQ) treatment abrogated calcitriol-induced autophagy and compromised Nrf2 activation with increased Keap1 accumulation and reduced expression of Nrf2-targeted genes. Additionally, both CQ treatment and Nrf2 genetic knockout abolished the protective effects of calcitriol against both TBI-induced neurological deficits and neuronal apoptosis. CONCLUSIONS: Therefore, our work demonstrated a neuroprotective role of calcitriol in TBI by triggering Nrf2 activation, which might be mediated by autophagy.

Mapping static core-holes and ring-currents with X-ray scattering.

Measuring the attosecond movement of electrons in molecules is challenging due to the high temporal and spatial resolutions required. X-ray scattering-based methods are promising, but many questions remain concerning the sensitivity of the scattering signals to changes in density, as well as the means of reconstructing the dynamics from these signals. In this paper, we present simulations of stationary core-holes and electron dynamics following inner-shell ionization of the oxazole molecule. Using a combination of time-dependent density functional theory simulations along with X-ray scattering theory, we demonstrate that the sudden core-hole ionization produces a significant change in the X-ray scattering response and how the electron currents across the molecule should manifest as measurable modulations to the time dependent X-ray scattering signal. This suggests that X-ray scattering is a viable probe for measuring electronic processes at time scales faster than nuclear motion.

Strong-field induced fragmentation and isomerization of toluene probed by ultrafast femtosecond electron diffraction and mass spectrometry.

We investigate the fragmentation and isomerization of toluene molecules induced by strong-field ionization with a femtosecond near-infrared laser pulse. Momentum-resolved coincidence time-of-flight ion mass spectrometry is used to determine the relative yield of different ionic products and fragmentation channels as a function of laser intensity. Ultrafast electron diffraction is used to capture the structure of the ions formed on a picosecond time scale by comparing the diffraction signal with theoretical predictions. Through the combination of the two measurements and theory, we are able to determine the main fragmentation channels and to distinguish between ions with identical mass but different structures. In addition, our diffraction measurements show that the independent atom model, which is widely used to analyze electron diffraction patterns, is not a good approximation for diffraction from ions. We show that the diffraction data is in very good agreement with ab initio scattering calculations.

Regioselective Synthesis of 2,4-Diaryl-6-trifluoromethylated Pyridines through Copper-Catalyzed Cyclization of CF3-Ynones and Vinyl Azides.

A novel copper-catalyzed cyclization of readily available vinyl azides with CF3-ynones is steadily achieved under mild conditions to furnish the versatile 2,4-diaryl-6-trifluoromethylated pyridine products, which are of great interest in medicinal chemistry. The generation of the vinyl iminophosphorane intermediates from vinyl azides through the Staudinger-Meyer reaction ensures the subsequent 1,4-addition process with CF3-ynones in this transformation.

Circulating sortilin levels are associated with inflammation in patients with moyamoya disease.

BACKGROUND: Systemic inflammation has been implicated in the pathogenesis of moyamoya disease (MMD). Sortilin is a critical regulator of proinflammatory cytokine secretion in several cell types. The present study investigated the association between circulating sortilin and proinflammatory cytokine levels and the occurrence of MMD. METHODS: Forty-two MMD cases and 76 age- and sex-matched controls were enrolled in this study between January 2018 and June 2019 at the Affiliated Hospital of Jining Medical University. The demographic and clinical characteristics were evaluated, and the circulating serum and cerebrospinal fluid (CSF) levels of sortilin, sortilin-related receptor with A-type repeats (SorLA), and proinflammatory cytokines including C-reactive protein (CRP), interleukin (IL)-6, interferon (IFN)-γ were measured by enzyme-linked immunosorbent assay. Linear regression and correlation analyses were used to estimate the associations between sortilin, SorLA, and proinflammatory cytokine levels. RESULTS: MMD patients had higher serum levels of sortilin (P = 0.012), CRP (P = 0.013), IL-6 (P = 0.004), and IFN-γ (P = 0.033) than healthy controls. In MMD patients, serum sortilin was positively correlated with serum proinflammatory cytokines (CRP: r = 0.459, P = 0.0022; IL-6: r = 0.445, P = 0.0032; and IFN-γ: r = 0.448, P = 0.0029) and CSF sortilin (r = 0.440, P = 0.0035); the latter was positively correlated with CSF levels of CRP (r = 0.542, P = 0.0002), IL-6 (r = 0.440, P = 0.0036), and IFN-γ (r = 0.443, P = 0.0033). CONCLUSIONS: Elevated sortilin level is associated MMD onset and may be a clinically useful biomarker along with proinflammatory cytokine levels.

Ru(II)-Catalyzed Tunable Cascade Reaction via C-H/C-C Bond Cleavage.

A facile synthesis of various 3-(alkoxyalkyl)-1H-indoles from pyrazolidinones, 2-acetylenic ketones, and alkyl alcohols via C-H/C-C bond activation has been developed. The reaction proceeds smoothly under the proper reaction conditions, and preliminary mechanistic studies suggest that NaOAc is crucial for C-C bond activation. The advantages of the present method represent a redox-neutral process and exhibit excellent chemo and regioselectivity.

The impact of Dl-3-n-butylphthalide on the lipidomics of the hippocampus in a rat model of lipopolysaccharide-induced depression.

Elevated inflammation is commonly observed in depression, but whether this association is causal is not determined. Our previous basic research indicated that Dl-3-n-butylphthalide (NBP) possessed an anti-inflammatory effect. Additional recent evidence consistently suggests that depression is associated with lipid metabolism. Therefore, our study performed an untargeted lipidomics approach of ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) to reveal the potential discriminating lipid profile of the hippocampus for NBP involvement in lipopolysaccharide (LPS)-induced depression. Male Sprague-Dawley(SD) rats were randomly allocated to one of three groups (n = 6): control, LPS-induced model of depression (LPS), or NBP involvement in the LPS-induced model of depression (LPS + NBP). Statistical analysis was used to identify differential hippocampus lipids in the LPS, NBP + LPS, and control groups. Our study demonstrated that most of the differentially expressed lipid metabolites were involved in glycerophospholipid metabolism, sphingolipid metabolism, glycerolipid metabolism, and glycosylphosphatidylinositol(GPI)-anchor biosynthesis, which may partially account for the pathophysiological process of depression. However, more pre-clinical and clinical evidence is warranted to determine the extent and consistency of the role of NBP and further elucidate the pathophysiological mechanisms underlying inflammation-induced depression.

Pharmacophore features for machine learning in pharmaceutical virtual screening.

Methods of three-dimensional molecular alignment generally treat all pharmacophore features equally when superimposing. However, some pharmacophore features can be more important in a specific system. In this work, we derived the overlap volume of pharmacophore features from a molecular alignment approach as new features of molecules to build machine learning models. Features can be assigned weights to indicate their importance. With validation on DUD-E collection, models based on pharmacophore features represented by the overlap volume yielded significant performances with median AUC of approximately 0.98 and recall rate of almost 0.8.