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Perhexiline is a prophylactic antianginal agent developed in the 1970s. Although, therapeutically, it remained a success, the concerns of its severe adverse effects including hepatotoxicity caused the restricted use of the drug, and eventually its withdrawal from the market in multiple countries. In the clinical setting, cytochrome P450 (CYP) 2D6 is considered as a possible risk factor for the adverse effects of perhexiline. However, the role of CYP-mediated metabolism in the toxicity of perhexiline, particularly in the intact cells, remains unclear. Using our previously established HepG2 cell lines that individually express 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7) and human liver microsomes, we identified that CYP2D6 plays a major role in the hydroxylation of perhexiline. We also determined that CYP1A2, 2C19, and 3A4 contribute to the metabolism of perhexiline. The toxic effect of perhexiline was reduced significantly in CYP2D6-overexpressing HepG2 cells, in comparison to the control cells. In contrast, overexpression of CYP1A2, 2C19, and 3A4 did not show a significant protective effect against the toxicity of perhexiline. Pre-incubation with quinidine, a well-recognized CYP2D6 inhibitor, significantly attenuated the protective effect in CYP2D6-overexpressing HepG2 cells. Furthermore, perhexiline-induced mitochondrial damage, apoptosis, and ER stress were also attenuated in CYP2D6-overexpressing HepG2 cells. These findings suggest that CYP2D6-mediated metabolism protects the cells from perhexiline-induced cytotoxicity and support the clinical observation that CYP2D6 poor metabolizers may have higher risk for perhexiline-induced hepatotoxicity.

Adverse psychological states are stimulated by multiple types of environmental factors in human being. However, only few animal models of adverse psychological states were established by applying multiple types of stressors to mimic real conditions. A multisensory stress simulation device was designed to apply a combination of stressors to animals. Selected types and intensity of stressors were stimulated by this multisensory stress simulation device to induce chronic multiple mild stress (CMMS) in rats, modeling sustained adverse psychological states caused by long-term exposure in relative extreme environments with limited social interaction in human being. Fourteen-day treatment of CMMS-induced anhedonia, anxiety, and the loss of body weight in rats, which were similar to those in human being with adverse psychological states. Moreover, CMMS treatment leads to decreased production of serotonin and increased expression of corticotropin-releasing factor receptor 1, adrenocorticotropic hormone, and glucocorticoid in the brain, which were prevented by paroxetine and sertraline, two clinical-used antidepressants. Furthermore, these antidepressants prevented the CMMS-induced inhibition of brain-derived neurotrophic factor/cAMP-response element binding protein pathway, reduction of synaptic protein expression, and the activation of microglia and astrocytes in the hippocampus and the prefrontal cortex of rats. In addition, 14-day CMMS-induced long-term depressive-like behaviors, even after 14 days of CMMS treatment. And sertraline reversed CMMS-induced behavioral and biochemical changes in rats. All these results suggested that CMMS protocol induced sustained adverse psychological states in rats. By adjusting the intensity and the type of stressors in the multisensory stress simulation device, it might be practicable to establish animal models with complicated and changeable environmental factors.

Drug resistance, either intrinsic or acquired, represents a major hurdle to achieving optimal therapeutic outcomes during cancer treatment. In addition to acquisition of resistance-conferring genetic mutations, accumulating evidence suggests an intimate involvement of the epigenetic machinery in this process as well. Recent studies have revealed that epigenetic reprogramming, such as altered expression or relocation of DNA/histone modulators accompanied with chromatin structure remodeling, can lead to transcriptional plasticity in tumor cells, thereby driving their transformation towards a persistent state. These "persisters" represent a pool of slow-growing cells that can either re-expand when treatment is discontinued or acquire permanent resistance. Targeting epigenetic reprogramming or plasticity represents a new strategy to prevent the emergence of drug-refractory populations and to enable more consistent clinical responses. With the growing numbers of drugs or drug candidates developed to target epigenetic regulators, more and more epigenetic therapies are under preclinical evaluation, early clinical trials or approved by FDA as single agent or in combination with existing antitumor drugs. In this review, we highlight latest discoveries in the mechanistic understanding of epigenetically-induced drug resistance. In parallel, we discuss the potential of combining epigenetic drugs with existing anticancer regimens as a promising strategy for overcoming cancer drug resistance.

The gut microbiota (GM) has been proven to play a role in the regulation of host lipid metabolism, which provides a new theory about the pathogenesis of dyslipidemia. However, the associations of GM with dyslipidemia based on sex differences remain unclear and warrant elucidation.To investigate the associations of GM features with serum lipid profiles based on sex differences in a Chinese population.This study ultimately recruited 142 participants (73 females and 69 males) at Honghui Hospital, Xi'an Jiaotong University. The anthropometric and blood metabolic parameters of all participants were measured. According to their serum lipid levels, female and male participants were classified into a high triglyceride (H_TG) group, a high total cholesterol (H_CHO) group, a low high-density lipoprotein cholesterol (L_HDL-C) group, and a control (CON) group with normal serum lipid levels. Fresh fecal samples were collected for 16S rRNA gene sequencing. UPARSE software, QIIME software, the RDP classifier and the FAPROTAX database were used for sequencing analyses.The GM composition at the phylum level included Firmicutes and Bacteroidetes as the core GM. Different GM features were identified between females and males, and the associations between GM and serum lipid profiles were different in females and males. The GM features in different dyslipidemia subgroups changed in both female patients and male patients. Proteobacteria, Lactobacillaceae,This study indicates associations of GM with serum lipid profiles, supporting the notion that GM dysbiosis may participate in the pathogenesis of dyslipidemia, and sex differences should be considered.

Although the treatment of hepatocellular carcinoma (HCC) has been revolutionized by the advent of effective systemic therapies, the prognosis of patients with HCC remains dismal. Herein, we examined the pathophysiological role of PARG and assessed the utility of targeting dePARylation for HCC therapy.The oncogenic function of PARG was evaluated in 2 orthotopic xenograft models and a PargHigh PARG expression was strongly associated with poor HCC prognosis. Hepatocyte-specific PARG deletion significantly impaired liver tumorigenesis. PARG promoted HCC growth and metastasis through DDB1-dependent modulation of c-Myc. Specifically, PARG dePARylated DDB1 and consequently promoted DDB1 autoubiquitination, thus stabilizing the c-Myc protein in HCC cells. PARG downregulation attenuated c-Myc-induced MMR expression and PARG deficiency was correlated with a favorable prognosis in patients with HCC treated with anti-PD-1-based immunotherapy. In addition, PARG inhibitors could act in synergy with anti-PD-1 antibodies in orthotopic mouse models.PARG can act as an oncogene in HCC by modulating PARG/DDB1/c-Myc signaling and could be used as a biomarker to identify patients with HCC who may benefit from anti-PD-1 treatment. Our findings suggest that co-inhibition of PARG and PD-1 is an effective novel combination strategy for patients with HCC.The increase in deaths due to hepatocellular carcinoma (HCC) is a growing concern, with the mechanisms responsible for HCC development still incompletely understood. Herein, we identify a novel mechanism by which the protein PARG contributes to HCC development. Inhibition of PARG increased the efficacy of anti-PD-1 therapy (a type of immunotherapy) in HCC. These findings support the future clinical development of PARG inhibitors, potentially in combination with anti-PD-1 inhibitors.

Cerebral cortex development undergoes a variety of processes, which provide valuable information for the study of the developmental mechanism of cortical folding as well as its relationship to brain structural architectures and brain functions. Despite the variability in the anatomy-function relationship on the higher-order cortex, recent studies have succeeded in identifying typical cortical landmarks, such as sulcal pits, that bestow specific functional and cognitive patterns and remain invariant across subjects and ages with their invariance being related to a gene-mediated proto-map. Inspired by the success of these studies, we aim in this study at defining and identifying novel cortical landmarks, termed gyral peaks, which are the local highest foci on gyri. By analyzing data from 156 MRI scans of 32 macaque monkeys with the age spanned from 0 to 36 months, we identified 39 and 37 gyral peaks on the left and right hemispheres, respectively. Our investigation suggests that these gyral peaks are spatially consistent across individuals and relatively stable within the age range of this dataset. Moreover, compared with other gyri, gyral peaks have a thicker cortex, higher mean curvature, more pronounced hub-like features in structural connective networks, and are closer to the borders of structural connectivity-based cortical parcellations. The spatial distribution of gyral peaks was shown to correlate with that of other cortical landmarks, including sulcal pits. These results provide insights into the spatial arrangement and temporal development of gyral peaks as well as their relation to brain structure and function.

To assess the efficacy of transcatheter arterial embolization (TAE) plus propranolol treatment for infantile hepatic hemangioma (IHH).A retrospective study of symptomatic IHH and hemodynamic changes in IHH was conducted between 2016 and 2019.There were five boys and seven girls with diffuse lesions (n = 7) and multifocal lesions (n = 5). Hepatomegaly and abdominal distension (n = 6) were the predominant clinical presentations. Seven patients (58.3%) had multiple cutaneous hemangiomas. Pulmonary arterial hypertension, heart failure (n = 4), and hypothyroidism (n = 4) were observed. A total of 17 TAE procedures were performed in 12 IHH cases, with a technical success rate of 100%. All patients received standard propranolol orally, and one patient was orally administered metacortandracin. Two patients died of heart failure and multiple organ dysfunction caused by an enlarged liver. In addition, one patient was not reexamined after discharge. Of the remaining nine children, the average follow-up time was 10.78 months (range 2-28 months), and they all responded well to TAE combined with oral propranolol.TAE combined with propranolol is safe and effective for the treatment of IHH, demonstrating low complication rates.

Autophagy in tumor was also found to influence immune microenvironment. The relation between autophagy and cancer intrinsic PD1 and PD-L1 expression was not clear.With data from TCGA and GTEx databases, mRNA expression levels of autophagy-related genes were compared between tumor samples and normal tissues, which were also correlated with survival status. Expression of autophagy-related genes were also associated with clinical traits in datasets of GSE14520 and ICGC LIRI. Single sample gene set enrichment analysis (ssGSEA) was used to calculate autophagy scores in tumor samples, using signatures from MSigDB database. Lentivirus (PD1 and PD-L1), siRNA (ATG13) and plasmids (LC3A/B) were used to target specific genes in tumor cells; Western blot was used to examine protein expression accordingly. Co-immunoprecipitation was performed to find PD1 or PD-L1 interacting proteins; colony formation and EdU analysis were used to evaluate tumor cell growth abilities.mRNA levels of autophagy markers were increased in tumor and correlated with worse survival of cancer patients. In hepatocellular carcinoma (HCC), high mRNA expression of autophagy markers was related to poor clinical status; increasing LC3 expression in HCC cell lines could promote tumor growth. Tumor intrinsic PD1 or PD-L1 were related to higher autophagy levels in specific tumor types; over-expression of PD1 or PD-L1 could increase autophagy in tumor cells through ATG13 interaction.Autophagy could promote tumor growth in specific cancer types. Tumor intrinsic PD1 or PD-L1 could both increase autophagy through ATG13 interaction.

The clinical use of microwave tomography (MT) requires addressing the significant mismatch between simulated environment, which is used in the forward solver, and real-life system. To alleviate this mismatch, a calibrated tomography, which uses two homogeneous calibration phantoms and a modified distorted Born iterative method (DBIM), is presented. The two phantoms are used to derive a linear model that matches the forward solver to real-life measurements. Moreover, experimental observations indicate that signal quality at different frequencies varies between different antennas due to inevitably inconsistent manufacturing tolerance and variances in radio-frequency chains. An optimum frequency, at which the simulated and measured signals of the antenna present maximum similarity when irradiating the calibrated phantoms, is thus calculated for each antenna. A frequency-division DBIM (FD-DBIM), in which different antennas in the array transmit their corresponding optimum frequencies, is subsequently developed. A clinical brain scanner is then used to assess performance of the algorithm in lab and healthy volunteers' tests. The linear calibration model is first used to calibrate the measured data. After that FD-DBIM is used to solve the problem and map the dielectric properties of the imaged domain. The simulated and experimental results confirm validity of the presented approach and its superiority to other tomographic method.

Mitochondrial replacement therapy (MRT) has been used to prevent maternal transmission of disease-causing mutations in mitochondrial DNA (mtDNA). However, because MRT requires nuclear transfer, it carries the risk of mtDNA carryover and hence of the reversion of mtDNA to pathogenic levels owing to selective replication and genetic drift. Here we show in HeLa cells, mouse embryos and human embryos that mtDNA heteroplasmy can be reduced by pre-labelling the mitochondrial outer membrane of a donor zygote via microinjection with an mRNA coding for a transmembrane peptide fused to an autophagy receptor, to induce the degradation of the labelled mitochondria via forced mitophagy. Forced mitophagy reduced mtDNA carryover in newly reconstructed embryos after MRT, and had negligible effects on the growth curve, reproduction, exercise capacity and other behavioural characteristics of the offspring mice. The induction of forced mitophagy to degrade undesired donor mtDNA may increase the clinical feasibility of MRT and could be extended to other nuclear transfer techniques.

Shaoke Meng,1,* Lei Guo,1,* Zhishuai Ye,2 Junjie Wang,1 Huaiyu Ding,1 Shanshan Wu,3 Rongchong Huang2 1Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian City, People’s Republic of China; 2Cardiac Center/Division of Cardiovascular Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing City, People’s Republic of China; 3Department of Clinical Epidemiology and EBM, Beijing Friendship Hospital, Capital Medical University, Beijing City, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rongchong Huang, Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, 95 Yong’an Road, Beijing City, 100053, People’s Republic of China, Email rchuang@ccmu.edu.cnBackground: Age is a strong predictor of adverse outcomes due both to a higher risk of bleeding and ischemia. The purpose of this study was to evaluate the safety and efficacy of ticagrelor in elderly patients.Methods: Patients ≥ 75 years of age admitted to our center from January, 2015 to December, 2019 who had undergone percutaneous coronary intervention (PCI) and received dual antiplatelet therapy (DAPT) were included in our study. Eligible patients were divided into clopidogrel and ticagrelor groups according to the P2Y12 receptor inhibitor and were followed up for 1 year. The primary safety endpoint was types 2, 3, and 5 bleeding, as defined by Bleeding Academic Research Consortium (BARC), and the primary efficacy endpoint was combined major adverse cardiovascular and cerebrovascular events (MACCEs). A Cox proportional hazard model and propensity score matching were used to correct confounding factors.Results: Of 1505 patients enrolled in this study, 442 were assigned to ticagrelor group and 1063 were assigned to clopidogrel group. The incidence of BARC 2, 3, and 5 bleeding (HR, 2.304; 95% CI, 1.540– 3.447), and any bleeding (HR, 2.476; 95% CI, 1.802– 3.403) in ticagrelor group was significantly higher than clopidogrel group. There were no significant difference between the two groups with respect to BARC 3 and 5 bleeding (HR, 1.566; 95% CI, 0.767– 3.198) and MACCEs (HR, 0.957; 95% CI, 0.702– 1.305).Conclusion: Compared with clopidogrel, DAPT with ticagrelor significantly increased the risk of BARC 2, 3, and 5 bleeding without reducing MACCEs in elderly patients who underwent PCI.Trial Registration: The study was retrospectively registered in clinicaltrials.gov (NCT 04999293).Keywords: ticagrelor, elderly, percutaneous coronary intervention, dual antiplatelet therapy

A modified distorted Born iterative method (DBIM), which includes clustering of reconstructed electrical properties (EPs) after certain iterations, is presented for brain imaging aiming at stroke detection and classification. For this approach to work, a rough estimation of number of different materials (or bio-tissues) in the imaged domain and their corresponding rough dielectric properties (permittivity and conductivity) are needed as a prior information. The proposed adaptive clustering DBIM (AC-DBIM) is compared with three conventional methods (DBIM, multiplicative regularized contrast source inversion (MR-CSI), and CSI for shape and location reconstruction (SL-CSI)) in two-dimensional scenario on a head phantom and numerical head model with different strokes. Three-dimensional simulations are also conducted to indicate the suitability of AC-DBIM in real-life brain imaging. Lastly, the proposed algorithm is assessed using a clinical electromagnetic head scanner developed on phantoms. The simulation and experimental results show superiority of AC-DBIM compared to conventional methods. AC-DBIM achieves significant improvement in the size and shape reconstruction and reduction in errors and standard deviation of the reconstructed _r and at clinical scenarios compared with conventional DBIM.

There are varying definitions of women at high risk of breast cancer across different institutions, and there are reports suggesting that the breast cancer risk assessment tools have not been well integrated into clinical practice. In this study, we tried to investigate the perceived importance of different breast cancer risk factors by physicians in China. A cross-sectional survey involving 386 anonymous physicians was conducted using a 20-item, 5-point Likert scale questionnaire. The Kruskal-Wallis test and post-hoc pairwise comparisons were used to compare the differences in response. Most of the respondents were either breast surgeons/specialists (n=161; 41.7%) or medical oncologists (n=151; 39.1%), and the results showed that the breast cancer risk factors were not perceived as equally important. The weighting of each risk factor also varied depending on the physician's medical specialty, location of practice, and the number of years of clinical experience. This study provides a more updated insight into the perceptions of physicians in China toward the breast cancer risk factors, as well as underlines the potential improvements in breast cancer risk assessment strategies that can be done.

β-Hydroxybutyl acid (βOHB), the most prevalent type of ketone in the human body, is involved in the pathogenesis of cognitive disorders, especially Alzheimer's dementia (AD), through a variety of mechanisms, such as enhancing mitochondrial metabolism, regulating signaling molecule, increasing histone acetylation, affecting the metabolism of Aβ and Tau proteins, inhibiting inflammation and lipid metabolism, and regulating intestinal microbes. Based on the above findings, clinical drug development in AD has begun to focus on βOHB.

Paraquat is a quaternary ammonium herbicide with an excellent herbicidal effect but is highly toxic to human and animals. Although prohibited by many countries, paraquat intoxication occurred occasionally and caused severe consequences. Rapid and accurate determination of paraquat concentration in intoxication samples is urgently needed in the clinic to promptly evaluate the prognosis of poisoning patients. Here we report an internal standard surface-enhanced Raman spectroscopy (IS-SERS) quantification method on paraquat in mouse plasma and lung tissues for the first time. One measurement per sample was fulfilled within 10 s via this IS-SERS method. Paraquat had good linearity in the range of 1 ~ 500 μg/L (plasma sample) and 1 ~ 100 μg/g (lung sample), with the LOD and LOQ of 0.5 μg/L and 0.1 μg/g (plasma sample), and 5 μg/L and 1 μg/g (lung sample), respectively. This IS-SERS method was validated according to the international guidelines and applied to a quantitative determination and the toxicokinetics on paraquat in mouse plasma and lung tissues. The results indicated that paraquat had a fast absorption rate and a slow elimination rate in mouse plasma and lung tissues. Paraquat was prone to accumulate in target organs after entering the blood. It also proved its good practical applicability in one clinical intoxication sample. Meanwhile, we unveiled an underestimation of free paraquat amount towards common biological sample pretreatment, a certain amount of paraquat bound to components with molecular weight less than 30 kDa in the plasma; we hope it could provide some interesting information for possible clinic treatment.

In vitro genotoxicity testing plays an important role in chemical risk assessment. The human B-lymphoblastoid cell line TK6 is widely used as a standard cell line for regulatory safety evaluations. Like many other mammalian cell lines, TK6 cells have limited metabolic capacity; therefore, usually require a source of exogenous metabolic activation for use in genotoxicity testing. Previously, we developed a set of TK6-derived cell lines that individually express one of fourteen cytochrome P450s (CYPs). In the present study, we surveyed a panel of major Phase II drug-metabolizing enzymes to characterize their baseline expression in TK6 cells. These results may serve as a reference enzymatic profile of this commonly used cell line.

Environmental pollution is a global problem that endangers human health and ecological balance. As a new type of functional material, two-dimensional material (2DM)-based aerogel is one of the most promising candidates for pollutant detection and environmental remediation. The porous, network-like, interconnected three-dimensional (3D) structure of 2DM-based aerogels can not only preserve the characteristics of the original 2DMs, but also bring many distinct physical and chemical properties to offer abundant active sites for adsorbing and combining pollutants, thereby facilitating highly efficient monitoring and treatment of hazardous pollutants. In this review, the synthesis methods of 2DM aerogels and their broad environmental applications, including various sensors, adsorbents, and photocatalysts for the detection and treatment of pollutants, are summarized and discussed. In addition, the sustainability of 2DM aerogels compared to other water purification materials, such as activated carbon, 2DMs, and other aerogels are analyzed by the Sustainability Footprint method. According to the characteristics of different 2DMs, special focuses and perspectives are given on the adsorption properties of graphene, MXene, and boron nitride aerogels, as well as the sensing and photocatalytic properties of transition metal dichalcogenide/oxide and carbon nitride aerogels. This comprehensive work introduces the synthesis, modification, and functional tailoring strategies of different 2DM aerogels, as well as their unique characteristics of adsorption, photocatalysis, and recovery, which will be useful for the readers in various fields of materials science, nanotechnology, environmental science, bioanalysis, and others.

Alzheimer's disease (AD) has complex etiologies, and the impact of sex on AD varies over the course of disease development. The literature provides some evidence of sex-specific contributions to AD. However, molecular mechanisms of sex-biased differences in AD remain elusive. Multiomics data in tandem with systems biology approaches offer a new avenue to dissect sex-stratified molecular mechanisms of AD and to develop sex-specific diagnostic and therapeutic strategies for AD. Single-cell transcriptomic datasets and cell deconvolution of bulk tissue transcriptomic data provide additional insights into brain cell type-specific impact on sex-biased differences in AD. In this review, we summarize the impact of sex chromosomes and sex hormones on AD, the impact of sex-biased differences during AD development, and the interplay between sex and a major AD genetic risk factor, the APOE ε4 genotype, through the multiomics landscape. Several sex-biased molecular pathways such as neuroinflammation and bioenergetic metabolism have been identified. The importance of sex chromosome and sex hormones, as well as the associated pathways in AD pathogenesis, is further strengthened by findings from omics studies. Future research efforts should integrate the multiomics data from different brain regions and different cell types using systems biology approaches, and leverage the knowledge into a holistic examination of sex differences in AD. Advances in systems biology technologies and increasingly available large-scale multiomics datasets will facilitate future studies dissecting such complex signaling mechanisms to better understand AD pathogenesis in both sexes, with the ultimate goals of developing efficacious sex- and APOE-stratified preventive and therapeutic interventions for AD.

To assess and compare the therapeutic effects of Anterior Cervical Discectomy and Fusion (ACDF) and Cervical Laminectomy and Fusion (CLF) in the treatment of 4-level cervical.We performed a retrospective review on 39 patients with 4-level CSM who underwent ACDF or CLF in the Third Hospital of Hebei Medical University from January 2010 to December 2018. The patients were divided into ACDF group and CLF group according to the treatment. The operative index was evaluated based on intraoperative blood loss and operation time. The functional outcomes including Japanese Orthopedic Association (JOA) score and visual analogue scale (VAS) of axial pain were compared. The Cobb angle, Cobb angle improvement rate, range of motion (ROM) and ROM loss ratio were measured for radiographic evaluation.No major complications or deaths occurred. The average age at baseline was 55 years. There was no significant difference between the ACDF and CLF group in follow-up time (26.29 months, 25.39 months, P 0.05). The intraoperative blood loss was higher in the CLF group than in the ACDF group (692.67 ± 38.68 vs 392.14 ± 128.06, P 0.05). The operation time was longer in the CLF group than in the ACDF group (206.60 ± 49.37 vs 172.64 ± 31.96, P 0.05). Significant improvements in the VAS and JOA scores were observed in both groups (P 0.05). No significant difference in VAS was found between the ACDF and CLF groups (P 0.05). There was a significantly larger improvement rate of JOA score in the ACDF group than in the CLF group (60.9% ± 9.57% vs 31.5% ± 15.70%, P 0.05). There were two (9.6%) cases with complications In the ACDF group, including one (4.8%) case of dysphagia and one (4.8%) case of pharyngodynia. In the CLF group, two patients (11.1%) developed CBoth ACDF and CLF were effective in the treatment of multi-level cervical spondylosis and ACDF is more suitable for patients with 4-level CSM.

Dynamic functional connectivity (dFC) has been increasingly used to characterize the brain transient temporal functional patterns and their alterations in diseased brains. Meanwhile, naturalistic neuroimaging paradigms have been an emerging approach for cognitive neuroscience with high ecological validity. However, the test-retest reliability of dFC in naturalistic paradigm neuroimaging is largely unknown. To address this issue, we examined the test-retest reliability of dFC in functional magnetic resonance imaging (fMRI) under natural viewing condition. The intraclass correlation coefficients (ICC) of four dFC statistics including standard deviation (Std), coefficient of variation (COV), amplitude of low frequency fluctuation (ALFF), and excursion (Excursion) were used to measure the test-retest reliability. The test-retest reliability of dFC in naturalistic viewing condition was then compared with that under resting state. Our experimental results showed that: (a) Global test-retest reliability of dFC was much lower than that of static functional connectivity (sFC) in both resting-state and naturalistic viewing conditions; (b) Both global and local (including visual, limbic and default mode networks) test-retest reliability of dFC could be significantly improved in naturalistic viewing condition compared to that in resting state; (c) There existed strong negative correlation between sFC and dFC, weak negative correlation between dFC and dFC-ICC (i.e., ICC of dFC), as well as weak positive correlation between dFC-ICC and sFC-ICC (i.e., ICC of sFC). The present study provides novel evidence for the promotion of naturalistic paradigm fMRI in functional brain network studies.

Osteoporosis is a common systemic skeletal metabolism disorder resulting in bone fragility and increased fracture risk. Silent information regulator factor 2 homolog 1 (SIRT1) is crucial in the regulation of several biological processes, including bone metabolism, autophagy, apoptosis, and aging. This study aimed to assess whether the up-regulation of SIRT1 induced by 17beta-estradiol (17β-E2) could promote autophagy and inhibit apoptosis in osteoblasts via the AMPK-mTOR and FOXO3a pathways, respectively. The study found that 17β-E2 (10-6 M) administration induced the up-regulation of SIRT1 in osteoblasts. Up-regulation of SIRT1 induced by 17β-E2 increased the expression level of LC3, Beclin-1, Bcl-2, p-AMPK, FOXO3a but decreased caspase-3 and p-mTOR expression, and then promoted autophagy and inhibited apoptosis. More autophagosomes were observed under a transmission electron microscope (TEM) in 17β-E2 and SRT1720 (a selective SIRT1 activator) co-treated group. When Ex527 (a SIRT1-specific inhibitor) was pretreated, the reversed changes were observed. Taken together, our findings demonstrated that the up-regulation of SIRT1 induced by 17β-E2 could promote autophagy via the AMPK-mTOR pathway and inhibit apoptosis via the FOXO3a activation in osteoblasts, and SIRT1 might become a more significant target in osteoporosis treatment.

Objective Limited data are available on the predictors of major adverse cardiac events (MACE) after a successful coronary chronic total occlusion (CTO) percutaneous coronary intervention (PCI) and medical therapy. This study aimed to identify predictors of MACE in CTO patients undergoing successful recanalization and medical therapy. Methods A total of 2015 patients with CTOs were enrolled. About 718 patients underwent successful CTO recanalization, and 1297 patients received medical therapy. The primary outcome was the frequency of MACE, defined as a composite of cardiac death, myocardial infarction, and target-vessel revascularization. Multivariate models were used to determine predictors of MACE. Results In successful CTO recanalization group, MACE occurred in 123 (17.1%) patients. In multivariate analysis, heart failure (hazard ratio [HR] 1.77, 95% confidence interval [CI]: 1.04–3.04, p = 0.036) was identified as independent predictors for MACE in successful CTO recanalization. Additionally, in medical therapy group, the significant predictors of MACE were male gender (HR 1.53, 95% CI: 1.13–2.05, p = 0.005), diabetes mellitus (HR 1.39, 95% CI: 1.11–1.74, p = 0.003), heart failure (HR 1.44, 95% CI: 1.10–1.87, p = 0.007), J-CTO score (HR 1.17, 95% CI: 1.07–1.28, p = 0.001) and multivessel disease (HR 2.20, 95% CI: 1.42–3.39, p < 0.001). Conclusion Heart failure was predictor for composite cardiovascular events in patients with CTO after successful recanalization. Male gender, diabetes mellitus, heart failure, J-CTO score and multivessel disease were predictors of MACE in CTO patients with medical therapy.

This study aimed to expand our understanding of metformin (Met) in inhibiting hepatocellular carcinoma (HCC) progression and to investigate its underlying mechanism. Met was administrated to HCC cells at 5, 10, and 20 μM, after which the cell phenotype was evaluated. RNA-seq cluster analysis was used to screen for target genes modulated by Met. Luciferase activity and ChIP assays were performed to detect the effect of FOXO3 on the transcriptional activation of NLRP3. We evaluated the effect of Met and FOXO3 and on the growth of HCC cells in vivo. Met inhibited HCC cell proliferation and promoted apoptosis. Met also induced pyroptosis of HCC cells. FOXO3 was significantly upregulated by Met treatment, and FOXO3 activated transcription of NLRP3. Cells after Met treatment together with FOXO3 knockdown have a stronger colony formation and migration ability but a lower apoptosis rate compared to the Met treatment alone group. In vivo, Met inhibited HCC tumor growth. The tumors in Met treatment and FOXO3 knockdown group grew faster than in Met treatment group. Thus, Met attenuates HCC cell development by inducing apoptosis and pyroptosis. This effect of metformin is partially dependent on FOXO3 which can activate the transcription of NLRP3.

Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) drives spontaneous development of mammary carcinosarcoma tumors, lacking ER, PR and HER2. Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Comparison of Trim24COE metaplastic carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24COE gene signature reveals strong correlation with human MpBC tumors and MpBC patient-derived xenograft (PDX) models. Global and single-cell tumor profiling reveal Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. Here, we find that pharmacological inhibition of these pathways in primary Trim24COE tumor cells and TRIM24-PROTAC treatment of MpBC TNBC PDX tumorspheres decreased cellular viability, suggesting potential in therapeutically targeting TRIM24 and its regulated pathways in TRIM24-expressing TNBC.

BackgroundChinese Tibetans have long hours of sitting without much physical activity given their religious behavior, raising potential harmful health hazards. However, the relationship between sedentary time and metabolic syndrome (MetS) has not been investigated in Chinese Tibetans.MethodsFrom Jan 2021 to Jun 2022, residents in Garze Tibetan Autonomous Prefecture in Southwest China's Sichuan province were recruited using a multi-stage, stratified, random-cluster sampling strategy. MetS were ascertained using definition proposed by the International Diabetes Federation. Associations between sedentary time and the prevalence of MetS in the total sample and by age and sex were estimated using logistic regression models.ResultsAmong 971 Chinese Tibetan participants (mean age 41.1 years and 73.8% female), 319 (32.9%) were diagnosed as having MetS. We found positive associations of sedentary time over 11 h per day with the prevalence of MetS in crude (OR: 1.23; 95% CI: 1.12–1.36, p < 0.001), age and sex adjusted (OR: 1.18; 95% CI: 1.08–1.29, p < 0.001), and fully adjusted (OR: 1.17; 95% CI: 1.08–1.29, p < 0.001) models, compared to those who had ConclusionsSedentary time longer than 11 h per day is significantly associated with increased risk of MetS, suggesting that polices to advocate health education may alleviate the health burden of MetS among Tibetans in China.

Nearly half of all cancer deaths in the US are attributed to 4 common cancers: lung, colorectal, breast, and prostate. Illinois residents experience higher rates of cancer death from all 4 cancers compared with the US overall. We developed the Illinois Cancer Risk Index (ICRI), which incorporates many predictors of these cancers into a single summary measure, to identify Illinois counties that would benefit most from public health intervention.We identified 90 county-level predictors of 4 common cancers, used multicollinearity testing to reduce this number to 61, and applied factor analysis to extract and analyze 4 factors representing 25 variables. Next, we created the ICRI by regressing the 4 factors on our outcome of interest - an age-adjusted common cancers mortality rate (CCMR), incorporating the direction of the β-coefficients from regression models to sum factor scores. Finally, we mapped and assessed the geographic distributions of both ICRI and CCMR by county across the state.The ICRI was positively associated with the CCMR (r = 0.59, P.001) and explained 32.2% of the variance in the CCMR across Illinois. The ICRI showed distinct geospatial patterns across the state, with the highest risk counties located in the east-central, far northern, and southern regions. The CCMR showed similar geospatial patterns.Our study identifies counties in Illinois that may benefit most from interventions that target multiple cancer risk factors simultaneously. The ICRI may be adapted for use in other geographic locations where data are available.

As an emerging non-invasive brain stimulation technique, transcranial direct current stimulation (tDCS) has received increasing attention in the field of stroke disease rehabilitation. However, its efficacy needs to be further studied. The tDCS has three stimulation modes: bipolar-stimulation mode, anode-stimulation mode and cathode-stimulation mode. Nineteen stroke patients were included in this research (10 with left-hemisphere lesion and 9 with right). Resting electroencephalogram (EEG) signals were collected from subjects before and after bipolar-stimulation, anodal-stimulation, cathodal-stimulation, and pseudo-stimulation, with pseudo-stimulation serving as the control group. The changes of multi-scale intrinsic fuzzy entropy (MIFE) of EEG signals before and after stimulation were compared. The results revealed that MIFE was significantly greater in the frontal and central regions after bipolar-stimulation (P < 0.05), in the left central region after anodal-stimulation (P < 0.05), and in the frontal and right central regions after cathodal-stimulation (P < 0.05) in patients with left-hemisphere lesions. MIFE was significantly greater in the frontal, central and parieto-occipital joint regions after bipolar-stimulation (P < 0.05), in the left frontal and right central regions after anodal- stimulation (P < 0.05), and in the central and right occipital regions after cathodal-stimulation (P < 0.05) in patients with right-hemisphere lesions. However, the difference before and after pseudo-stimulation was not statistically significant (P > 0.05). The results of this paper showed that the bipolar stimulation pattern affected the largest range of brain areas, and it might provide a reference for the clinical study of rehabilitation after stroke.

To analyze dynamic electromyography characteristics and related factors of lumbar back muscle activity in patients with lumbar disc herniation, and to clarify the clinical significance of dynamic electromyography in the diagnosis and treatment of patients with lumbar disc herniation(LDH).From September 2014 to March 2021, 40 patients with lumbar disc herniation(LDH group) were detected by surface electromyography telemeter. There were 14 males and 26 females, aged from 20 to 61 years old, with an average of(40.68±10.56) years old, the course of illness was from 1 to 120 months, with an average of (17.75±27.56) months. In addition, 12 normal people were recruited as the control group. There were 2 males and 10 females. The age ranged from 24 to 53 years old, with an average of(36.50±10.30) years old. All subjects were subjected to dynamic electromyographic tests of the subthoracic erector spinae, lumbar erector spinae, and multifidus muscles during static standing and trunk flexion and extension. Compare the EMG activity data (average EMG amplitude, median frequency, original EMG graph) of the tested muscles between patients with lumbar disc herniation and normal people, and analyze the correlation between the general data of patients with lumbar disc herniation and the tested muscle EMG data.When standing still, the average electromyographic amplitude of the erector spinal muscle of the right and left thoracic segments of the subjects in the LDH group increased compared with the control group, and the difference was significant(Patients with lumbar disc herniation have characteristic surface EMG changes in the back muscles that are different from those of normal people. These features can more objectively reflect the patient's muscle condition and can be an effective indicator for the diagnosis and treatment effect evaluation of patients with lumbar disc herniation. It can be seen that surface electromyography is not only a detection method, it can be considered in the routine diagnosis and treatment plan of LDH to guide clinical work.

Spatial segmentation is a critical procedure in mass spectrometry imaging (MSI)-based biochemical analysis. However, the commonly used unsupervised MSI segmentation methods may lead to inappropriate segmentation results as the MSI data is characterized by high dimensionality and low signal-to-noise ratio. This process can be improved by the incorporation of precise prior knowledge, which is hard to obtain in most cases. In this study, we show that the incorporation of partial or coarse prior knowledge from different sources such as reference images or biological knowledge may also help to improve MSI segmentation results. Here, we propose a novel interactive segmentation strategy for MSI data called iSegMSI, which incorporates prior information in the form of scribble-regularization of the unsupervised model to fine-tune the segmentation results. By using two typical MSI data sets (including a whole-body mouse fetus and human thyroid cancer), the present results demonstrate the effectiveness of the iSegMSI strategy in improving the MSI segmentations. Specifically, the method can be used to subdivide a region into several subregions specified by the user-defined scribbles or to merge several subregions into a single region. Additionally, these fine-tuned results are highly tolerant to the imprecision of the scribbles. Our results suggest that the proposed iSegMSI method may be an effective preprocessing strategy to facilitate the analysis of MSI data.

Objective To assess and compare the pathological and radiological outcomes of multifidus degeneration in scoliosis and lumbar disc herniation patients. Methods We performed a retrospective review on 24 patients with scoliosis and 26 patients with lumbar disc herniation (LDH) in the Third Hospital of Hebei Medical University from January 2017 to March2021. The patients were divided into scoliosis group and LDH group according to the treatment. The MRI fatty infiltration rate (FIR) of multifidus and strength of back muscle were calculated to evaluate muscle condition. Multifidus biopsy samples were obtained during surgery in the affected side at L4 or L5 segment in LDH group and on the concavity side of apical vertebrae in scoliosis group. The biopsy fatty infiltration degree (FID) and FIR in two groups, the FIR of affected and unaffected side in LDH group, and the FIR of concavity and convexity side in scoliosis group were compared. The correlation between concavity-convexity FIR difference and cobb angle in scoliosis group, back muscle strength and FIR in LDH group, FID and FIR in both groups was calculated respectively. Results The FIR was higher in scoliosis group than in LDH group, higher in concavity side than convexity side in scoliosis group (both P P P > 0.05). There was a positive correlation between concavity-convexity FIR difference and cobb angle, FIR and FID (both P P Conclusion The scoliosis patients showed more serious fatty infiltration than LDH patients and rare pathological findings were found in both diseases.

Nowadays, with the increasing proportion of osteoporosis in patients with lumbar degenerative diseases, doctors are facing the choice of intraoperative internal fixation methods. The purpose of this study was to compare and assess the clinical results of posterior bilateral pedicle screw fixation and lateral fixation in the extreme lateral interbody fusion (XLIF) in patients with osteopenia or osteoporosis.The retrospective review was performed on 67 degenerative lumbar diseases patients with osteopenia or osteoporosis who underwent XLIF in our hospital from January 2018 to July 2021. Patients in this study were classified into lateral screw (LS) group, lateral self-locking plate (LP) group, and bilateral pedicle screw (BPS) group. The functional evaluation factors containing Japanese Orthopaedic Association (JOA) score, visual analogue scale (VAS) of leg pain, and VAS of low back pain, radiological factors such as disc height (DH), lumbar lordotic (LL) angle, segmental lordotic (SL) angle, cage subsidence degree and interbody fusion degree were compared.Primary outcomes: no differences were observed with regards to the incidence of complications among LS, LP and BS group (P 0.05). The JOA and leg pain VAS were significantly improved after operation (P 0.05) and all groups demonstrated similar improvements in the leg pain VAS and JOA score (P 0.05). When comparing VAS of leg pain and JOA scores, no differences were identified among LS, LP and BPS groups (P 0.05). There are four thigh sensory complaint, one hip flexor weakness and one thigh pain occurred and no death was observed. There were significantly better DH, LL angle, SL angle, cage subsidence degree and interbody fusion degree in the BPS group than in LS and LP groups 1 year after surgery (P 0.05). The DH loss ratio, LL angle loss ratio, SL angle loss ratio in the BPS group was significantly lower than in the LP and LS groups (P 0.05). The 12-month SL angle improvement rate in the BPS group was significantly higher than in the LP and LS groups (20.20 ± 14.69, 0.73 ± 4.68, 6.20 ± 12.31, P 0.05).the BPS patients had significantly worse intraoperative blood loss and operation time than LS and LP patients (P 0.05).In lumbar diseases patients with osteopenia or osteoporosis, the bilateral pedicle screw fixation has better orthopedic effect than lateral internal fixation, and can better maintain the stability of the spine in the long-term follow-up, which is a better choice in XLIF surgery.

Using detection markers in serum has the advantages of simplicity, repeatability and the capability. This study combined the use of serum glial fibrillary acidic protein (GFAP) and S100B protein (S100B) with imaging tools to confirm the role of serum biomarkers in evaluating the cerebral vessel reactivity after carotid artery stenting (CAS). After CAS, the serum concentrations of GFAP and S100B increased to the peak at 24 hours after operation, and then gradually decreased. The mean flow velocity (MFV) (pre-operation, post-operation, 30 days follow-up: 47.65 ± 17.24 cm/s, 62.37 ± 18.25 cm/s, 70.29 ± 16.89 cm/s; P

Background In our previous study, we indicated that scutellarin (SCU) induced an anticancer effect in A549 cells. However, whether SCU regulates the radiosensitivity of non‐small cell lung cancer (NSCLC) and its related mechanism is still unclear. Methods In this study, we explored the anticancer effect induced by iodine‐125 (125I) and SCU at a sensitizing concentration in A549 and H1975 cells. Cellular apoptosis and proliferation were detected by flow cytometry, Bcl‐2/Bax expression level, cell cycle, CCK‐8, and EdU staining. A tumor model using nude mice was also carried out to investigate the combined effect of 125I and SCU in vivo. In addition, the expression level of AKT/mTOR pathway was detected to investigate whether it is linked to the anticancer effect of 125I and SCU. Results SCU at a sensitizing concentration promoted the 125I‐induced apoptosis and antiproliferative effect in A549 and H1975 cells. Moreover, the same results were obtained in vivo. Based on our findings, the AKT/mTOR pathway was significantly downregulated after combined treatment with 125I and SCU. Conclusions The results of our study suggested that SCU promotes the anticancer effects induced by 125I in NSCLC cells by downregulating the AKT/mTOR pathway and lays a foundation for future application of this combined treatment., Scutellarin (SCU) enhanced inhibition of 125I‐induced proliferation, promoted 125I‐induced apoptosis, and boosted 125I‐induced tumor inhibition in vivo in non‐small cell lung cancer (NSCLC) cells, as well as enhanced downregulation of the 125I‐induced AKT/mTOR pathway.

Purpose: Patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have poor prognoses. Pyrotinib has shown promising antitumor activity in MBC to improve progression-free survival (PFS). However, findings based on real-world data to analyze whether pyrotinib affects overall survival (OS) remain scarce. Experimental Design: This real-world study is an exploratory analysis of brain metastasis (BM) and the final update of our preceding study of 168 patients with HER2+ MBC. PFS, OS, tumor mutation burden (TMB), clinical benefit rate (CBR), and overall response rate (ORR) were analyzed. Results: Pyrotinib treatment led to a median PFS time of 8.00 months and a median OS of 19.07 months in the 168 participants. High TMB was associated with poor OS (P = 0.0072) and PFS (P = 0.0028). In the 39 patients with BM, the median PFS and OS were 8.67 and 13.93 months, respectively. The surgery/radiation (S/R) group of patients with BM had prolonged survival (PFS: 9.97 vs. 7.73 months P = 0.19; OS: 20.67 vs. 12.43 months P = 0.021) compared with the no surgery/no radiation group (NS/NR). The CBR was 58.6% (S/R) vs. 41.4% (NS/NR), while the ORR was 24.1% (S/R) vs. 31.0% (NS/NR). Conclusions: Pyrotinib shows promise as a novel pan-HER2 tyrosine kinase inhibitor (TKI) for the treatment of BM and should be evaluated further. Surgical or radiotherapy in combination with pyrotinib was found to statistically improve OS in our cohort. TMB could be an exploratory biomarker for predicting PFS and OS, but its clinical application still needs further verification.

Background Botulinum toxin is a neurotoxin generated during the growth of Clostridium botulinum and can lead to a rare but life-threatening disease with neurologic symptoms. Relatively little is known about the many types of botulinum toxins in China. The clinical symptoms of the different types of botulism toxin–induced illnesses appear after an incubation period and vary greatly by the serotype and degree of exposure to the toxin. Case Report We describe 4 patients who consumed vacuum-packaged salted fish and ham and then presented with severe gastrointestinal symptoms, resulting in vomiting and one death. Blood serum and urine samples tested by the botulinum neurotoxin Endopep-MS assay were positive for botulinum toxin types A, B, and E. The patient who consumed the largest amount of fish and ham died after 36 h, and the other patients were treated with botulism antitoxin after being diagnosed with a botulinum toxin–induced illness and recovered after 1 month. These cases illustrate the importance of early diagnosis and early treatment of botulism type E, in particular, because of the risk of respiratory failure and treatment delays, which can result in increased mortality and poorer overall outcomes. Why Should an Emergency Physician Be Aware of This? Our cases illustrate the importance of early diagnosis and especially the treatment of illnesses related to botulism type E because of the risk of respiratory failure and because treatment delays can result in increased mortality and worsened overall outcomes.

Luteolin (5,7,3′,4′-tetrahydroxyflavone) belongs to the flavone subclass of flavonoids. Luteolin and its glycosides are present in many botanical families, including edible plants, fruits, and vegetables. While the beneficial properties of luteolin have been widely studied, fewer studies have investigated its toxicity. In the present study, using human lymphoblastoid TK6 cells and our newly developed TK6-derived cell lines that each stably express a single human cytochrome P450 (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C18, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7), we systematically evaluated luteolin-induced cytotoxicity and genotoxicity, and the role of specific CYPs in the bioactivation of luteolin. Treatments with luteolin for 4–24 h induced cytotoxicity, apoptosis, DNA damage, and chromosome damage in a concentration-dependent manner. Subsequently, we observed that luteolin-induced cytotoxicity and genotoxicity, measured by the high-throughput micronucleus assay, were significantly increased in TK6 cells transduced with CYP1A1 and 1A2. In addition, key apoptosis and DNA damage biomarkers, including cleaved PARP-1, cleaved caspase-3, and phosphorylated histone 2AX (γH2A.X), were all significantly increased in the CYP1A1- and 1A2-expressing cells compared with the empty vector controls. Analysis by LC-MS/MS revealed that TK6 cells biotransformed the majority of luteolin into diosmetin, a less toxic O-methylated flavone, after 24 h; the presence of CYP1A1 and 1A2 partially reversed this process. Altogether, these results indicate that metabolism by CYP1A1 and 1A2 enhanced the toxicity of luteolin in vitro. Our results further support the utility of our TK6 cell system for identification of the specific CYPs responsible for chemical bioactivation and toxicity potential.

Posterior-stabilized total knee prostheses have been widely used in orthopedic clinical treatment of knee osteoarthritis, but the patients and surgeons are still troubled by the complications, for example severe wear and fracture of the post, as well as prosthetic loosening. Understanding the后稳定型全膝关节假体已经被广泛应用于骨科临床治疗膝骨关节炎，但是胫骨衬垫立柱的磨损、断裂以及假体松动等失效问题依然困扰着患者和医生。了解患者体内膝关节假体的生物力学特性有利于降低术后的假体翻修率和患者不满意度。本文针对6种不同后稳定型全膝关节假体分别建立了全膝关节置换的骨肌多体动力学模型，在模拟走路、右转和下蹲3种生理活动下，对比研究了6种后稳定型全膝关节假体的生物力学差异。结果表明，在走路、右转和下蹲活动中PFC Sigma和 Scorpio NGR两种假体的立柱所受接触力较大，增加了立柱断裂和磨损破坏以及假体早期松动的风险。Gemini SL的螺旋型立柱设计更有利于膝关节的内外旋转运动，同时避免了立柱边沿接触磨损。后稳定型全膝关节假体矢状面较低的关节面匹配度设计和较晚的立柱-凸轮相遇接触设计将导致较大的前后平移运动。本文为临床指导医生选择、改进假体设计和降低假体失效提供了理论支撑。.

Surface area of the human cerebral cortex expands extremely dynamically and regionally heterogeneously from the third trimester of pregnancy to 2 y of age, reflecting the spatial heterogeneity of the underlying microstructural and functional development of the cerebral cortex. However, little is known about the developmental patterns and regionalization of cortical surface area during this critical stage, due to the lack of high-quality imaging data and accurate computational tools for pediatric brain MRI data. To fill this critical knowledge gap, by leveraging 1,037 high-quality MRI scans with the age between 29 post-menstrual weeks and 24 mo from 735 pediatric subjects in two complementary datasets, i.e., the Baby Connectome Project (BCP) and the developing Human Connectome Project (dHCP), and state-of-the-art dedicated image-processing tools, we unprecedentedly parcellate the cerebral cortex into a set of distinct subdivisions purely according to the developmental patterns of the cortical surface. Our discovered developmentally distinct subdivisions correspond well to structurally and functionally meaningful regions and reveal spatially contiguous, hierarchical, and bilaterally symmetric patterns of early cortical surface expansion. We also show that high-order association subdivisions, where cortical folds emerge later during prenatal stages, undergo more dramatic cortical surface expansion during infancy, compared with the central regions, especially the sensorimotor and insula cortices, thus forming a distinct central-pole division in early cortical surface expansion. These results provide an important reference for exploring and understanding dynamic early brain development in health and disease.

Adult white adipose tissue (WAT) harbors distinct mesenchymal stromal cell subpopulations that differentially impact WAT function and plasticity. Here, we unveil the cellular landscape of the perinatal epididymal WAT (eWAT) primordium using single-cell transcriptomics in male mice. We reveal that adipocyte precursor cells (APCs) and fibro-inflammatory progenitors (FIPs) emerge as functionally distinct PDGFRβ+ subpopulations within the eWAT anlagen prior to adipocyte accrual. We further identify important molecular and functional differences between perinatal and adult FIPs, including differences in their pro-inflammatory response, adipogenic capacity, and anti-adipogenic behavior. Notably, we find that transient overexpression of Pparg in PDGFRβ+ cells only during postnatal day 0.5 to 7.5 in male mice leads to hyperplastic WAT development, durable progenitor cell reprogramming, and protection against pathologic WAT remodeling and glucose intolerance in adult-onset obesity. Thus, factors that alter the adipogenic capacity of perinatal adipose progenitors can have long-lasting effects on progenitor plasticity, tissue expandability, and metabolic health into adulthood.

To compare survival outcomes of radiotherapy (RT) prior to transcatheter arterial chemoembolization (TACE) (RT + TACE) with TACE followed with RT (TACE + RT) in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT).A randomized controlled study was conducted from August 2016 to December 2019 on patients with unresectable HCC and PVTT. The patients were randomly assigned to RT + TACE group or TACE + RT group in a 1:1 ratio. Evaluation of therapeutic effects on the primary tumor was based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST), while that on PVTT was based on the changing of Cheng's PVTT classification. The primary end-point was overall survival (OS).The 120 patients who entered this study were evenly assigned to two groups. In the intention-to-treat (ITT) population, the OS rates for RT + TACE group at 1, 2 and 3 years were 61.7%, 27.4% and 15.6%, compared with 45.0%, 16.1% and 4.7% in TACE + RT group. The median OS was increased in patients with RT + TACE compared with those who had TACE + RT with a marginally significance (15.4 versus 11.5 months, HR = 0.68, 95% CI 0.46-1.01, p = 0.054). The median progression-free survival (PFS) in RT + TACE group was 6.6 months versus 4.2 months in TACE + RT group (HR = 0.66, 95% CI 0.46-0.96, p = 0.030). The corresponding disease control rate (DCR) at 3 months was 86.7% versus 66.7% (p = 0.017) and 61.7% versus 46.7% (p = 0.099) at 6 months. In subgroup analyses, RT + TACE was associated with better OS (HR, 0.48; 95% CI 0.33-0.99, p = 0.048) and PFS (HR, 0.55; 95% CI 0.33-0.93, p = 0.026) versus TACE + RT among patients with type III/IV PVTT. There were 3 patients in RT + TACE group and 2 in TACE + RT group had adverse events ≥ grade 3.Applying RT prior to TACE provided better survival outcomes than TACE followed by RT for patients with HCC and PVTT, which may act as an optimized regional modality to further improve local control rates (Trial registration: ChiCTR ChiCTR2000033573.).

Transcranial direct current stimulation (tDCS) has become a new method of post-stroke rehabilitation treatment and is gradually accepted by people. However, the neurophysiological mechanism of tDCS in the treatment of stroke still needs further study. In this study, we recruited 30 stroke patients with damage to the left side of the brain and randomly divided them into a real tDCS group (15 cases) and a sham tDCS group (15 cases). The resting EEG signals of the two groups of subjects before and after stimulation were collected, then the difference of power spectral density was analyzed and compared in the band of delta, theta, alpha and beta, and the delta/alpha power ratio (DAR) was calculated. The results showed that after real tDCS, delta band energy decreased significantly in the left temporal lobes, and the difference was statistically significant (经颅直流电刺激（tDCS）已成为卒中后康复治疗的新手段，并且逐渐被人们所接受。然而，tDCS治疗脑卒中的神经生理机制仍需进一步探讨。本文纳入了30例大脑左侧受损的脑卒中患者，随机分为tDCS真刺激组（15例）和tDCS伪刺激组（15例）。采集两组受试者刺激前、后的静息态脑电（EEG）信号，分析对比刺激前、后EEG信号δ、θ、α和β频带的功率谱密度差异，并计算了δ/α功率比值（DAR）。结果发现，真刺激后δ频带能量在左颞叶区明显降低，差异具有统计学意义（

MRI-derived brain networks have been widely used to understand functional and structural interactions among brain regions, and factors that affect them, such as brain development and diseases. Graph mining on brain networks can facilitate the discovery of novel biomarkers for clinical phenotypes and neurodegenerative diseases. Since brain functional and structural networks describe the brain topology from different perspectives, exploring a representation that combines these cross-modality brain networks has significant clinical implications. Most current studies aim to extract a fused representation by projecting the structural network to the functional counterpart. Since the functional network is dynamic and the structural network is static, mapping a static object to a dynamic object may not be optimal. However, mapping in the opposite direction (i.e., from functional to structural networks) are suffered from the challenges introduced by negative links within signed graphs. Here, we propose a novel graph learning framework, named as Deep Signed Brain Graph Mining or DSBGM, with a signed graph encoder that, from an opposite perspective, learns the cross-modality representations by projecting the functional network to the structural counterpart. We validate our framework on clinical phenotype and neurodegenerative disease prediction tasks using two independent, publicly available datasets (HCP and OASIS). Our experimental results clearly demonstrate the advantages of our model compared to several state-of-the-art methods.

Prolonged activation of nuclear factor (NF)-кB signaling significantly contributes to the development of colorectal cancer (CRC). New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction. Here, we discovered the critical role of RING finger 138 (RNF138) in CRC tumorigenesis through regulating the NF-кB signaling, which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response. RNF138−/− mice were hyper-susceptible to the switch from colitis to aggressive malignancy, which coincided with sustained aberrant NF-кB signaling in the colonic cells. Furthermore, RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein (NIBP) to the cytoplasm, which requires the ubiquitin interaction motif (UIM) domain. More importantly, we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings, raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling. Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients, we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth. Overall, our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression, and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.

Graphical abstract It is important to know whether SARS-CoV-2 is spread through the air conditioning systems. Taking the central air conditioning system as an example, we analyze the mechanism and potential health risk of respiratory virus transmission in air-conditioned rooms and propose a method to study the risk of virus transmission in central air conditioning systems by investigating the data from medical experiments. The virus carrying capacity and the decay characteristics of indoor pathogen droplets are studied in this research. Additionally, the effects of air temperature and relative humidity on the virus survival in the air or on surfaces are investigated. The removal efficiency of infectious droplet nuclei by using an air conditioning filter was then determined. Thus, the transmission risk during the operation of the centralized air conditioning system is evaluated. The results show that the indoor temperature and humidity are controlled in the range of 20–25 °C and 40–70% by central air conditioning during the epidemic period, which not only benefits the health and comfort of residents, but also weakens the vitality of the virus. The larger the droplet size, the longer the viruses survive. Since the filter efficiency of the air conditioning filter increases with the increase in particle size, increasing the number of air changes of the circulating air volume can accelerate the removal of potential pathogen particles. Therefore, scientific operation of centralized air conditioning systems during the epidemic period has more advantages than disadvantages.

Plant-based photosensors, such as the light-oxygen-voltage sensing domain 2 (LOV2) from oat phototropin 1, can be modularly wired into cell signaling networks to remotely control protein activity and physiological processes. However, the applicability of LOV2 is hampered by the limited choice of available caging surfaces and its preference to accommodate the effector domains downstream of the C-terminal Jα helix. Here, we engineered a set of LOV2 circular permutants (cpLOV2) with additional caging capabilities, thereby expanding the repertoire of genetically encoded photoswitches to accelerate the design of optogenetic devices. We demonstrate the use of cpLOV2-based optogenetic tools to reversibly gate ion channels, antagonize CRISPR-Cas9-mediated genome engineering, control protein subcellular localization, reprogram transcriptional outputs, elicit cell suicide and generate photoactivatable chimeric antigen receptor T cells for inducible tumor cell killing. Our approach is widely applicable for engineering other photoreceptors to meet the growing need of optogenetic tools tailored for biomedical and biotechnological applications.

The typical aim of user matching is to detect the same individuals cross different social networks. The existing efforts in this field usually focus on the users' attributes and network embedding, but these methods often ignore the closeness between the users and their friends. To this end, we present a friend closeness based user matching algorithm (FCUM). It is a semi-supervised and end-to-end cross networks user matching algorithm. Attention mechanism is used to quantify the closeness between users and their friends. We considers both individual similarity and their close friends similarity by jointly optimize them in a single objective function. Quantification of close friends improves the generalization ability of the FCUM. Due to the expensive costs of labeling new match users for training FCUM, we also design a bi-directional matching strategy. Experiments on real datasets illustrate that FCUM outperforms other state-of-the-art methods that only consider the individual similarity.

Astrocytes-mediated neuroinflammation has been involved in the process of several neurodegenerative diseases. Ramelteon is a novel agonist of melatonin receptors and licensed for the management of insomnia. In this study, our results demonstrate that Ramelteon ameliorated lipopolysaccharide (LPS)-induced inflammatory responses in astrocytes. First, we found that the optimized incubation concentrations of Ramelteon applied in the present study were 50 and 100 nM. Second, treatment with Ramelteon reduced expressions of IL-6, TNF-α, and IL-1β. Additionally, Ramelteon prevented an LPS-induced increase in the expressions of iNOS, COX-2, NO, and PGE2. Importantly, we found that Ramelteon reduced the expression of GFAP. Mechanistically, we found that Ramelteon inhibited the TLR4/IκBα/NF-κB p65 axis. Notably, the protective effects of Ramelteon were verified in an in vivo rodent model. Based on these findings, we concluded that Ramelteon might prevent LPS-induced damage in astrocytes.

To develop a prediction model that combined magnetic resonance images (MRI)-based radiomics features with clinical factors to predict recurrence-free survival (RFS) of hepatocellular carcinoma (HCC) patients treated with surgical resection. HCC patients treated with surgical resection (n = 153) were randomly divided into training (n = 107) and validation (n = 46) datasets. The volumes of interest were manually outlined around the lesion and additional 2 mm and 5 mm peritumoral areas were created with automated dilatation in MRI to extract tumoral (T) and peritumoral (PT) radiomics features. The radiomics models were constructed using least absolute shrinkage and selection operator Cox regression. The combined model incorporated clinical factors and radiomics features using multivariable Cox regression based on the Akaike information criterion principle. Predictive performance of different models were evaluated by receiver operating characteristic (ROC) curves, decision curves, and calibration curves. Among the radiomics models, similar performance was observed in the 2 mm and 5 mm PT models (C-index both 0.657), which were better than the T model or T + PT model (C-index 0.607 and 0.641, respectively) in the validation dataset, whereas the model combined with the three identified clinical risk factors showed the best performance (C-index 0.725). Results of the ROC curves, decision curves, and the calibration curves indicated that the combined model and the derived nomogram had better prediction performance, greater clinical benefits, and fair calibration efficiency. The prediction model that combined MRI radiomics signatures with clinical factors can effectively predict the prognosis of patients with HCC treated with surgical resection.

Objective To describe the effectiveness and security of DSA-guided percutaneous sclerotherapy for venous malformations of penile region in children. Methods A total of 9 cases children with penile venous malformations treated by DSA-guided percutaneous sclerotherapy from January 2017 to June 2018 were enrolled in this study. Local angiography was performed under DSA fluoroscopy, and the shape, extent and venous drainage of the tumor nest were judged. Then sclerosing agents (Pingyangmycin and Polidocanol) were selected according to the flow rate of angiography and treated by percutaneous injection under DSA monitoring. Imaging examination (MRI) was performed to evaluate clinical improvement. Results A total of 26 interventional sclerotherapy sessions were performed in 9 children, with an average of (2.3 ± 0.5) sessions per case. After a mean follow-up of 7.3 months, 6 cases were cured, and 3 cases were in basic remission. There were 9 cases of temporary edema secondary to the treatment site and 3 cases of mild pain. No serious complications such as ulceration, hemorrhage, infection and dysfunction occurred in any patients. Conclusion DSA-guided percutaneous sclerotherapy for venous malformations of penile region in children is safe and effective, does not affect the appearance and function of penis, and is worthy of clinical promotion. Type of study Treatment Study. Level of evidence Level IV, Case series with no comparison group.