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Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe disease with a poor prognosis, whose clinical treatment is still limited to therapeutic hypothermia with limited efficacy. Perillyl alcohol (POH), a natural monoterpene found in various plant essential oils, has shown neuroprotective properties, though its effects on HIE are not well understood. This study investigates the neuroprotective effects of POH on HIE both in vitro and in vivo. We established an in vitro model using glucose deprivation and hypoxia/reperfusion (OGD/R) in PC12 cells, alongside an in vivo model via the modified Rice-Vannucci method. Results indicated that POH acted as an indirect antioxidant, reducing inducible nitric oxide synthase and malondialdehyde production, maintaining content of antioxidant molecules and enzymes in OGD/R-induced PC12 cells. In vivo, POH remarkably lessened infarct volume, reduced cerebral edema, accelerated tissue regeneration, and blocked reactive astrogliosis after hypoxic-ischemic brain injury. POH exerted antiapoptotic activities through both the intrinsic and extrinsic apoptotic pathways. Mechanistically, POH activated Nrf2 and inactivated its negative regulator Keap1. The use of ML385, a Nrf2 inhibitor, reversed these effects. Overall, POH mitigates neuronal damage in HIE by combating oxidative stress, reducing inflammation, and inhibiting apoptosis via the Nrf2/Keap1 pathway, suggesting its potential for HIE treatment. [ABSTRACT FROM AUTHOR]

Purpose: Neonatal bacterial meningitis (NBM) is a serious disease with high morbidity and mortality. This study aimed to establish a foundation for the selection of empirical antibiotics for NBM through an analysis of pathogen distribution and shift in antimicrobial resistant pattern. Patients and Methods: A retrospective cohort study on culture confirmed NBM from 2005 to 2022. Results: A total of 191 cases were enrolled, 48 for premature infants and 70 for early-onset meningitis. The incidence of NBM in first half and last half period was 0.2‰ and 0.24‰, while the mortality was 12.0% and 5.6% respectively. The top two pathogens were Escherichia coli (E. coli) (40.3%) and Group B Streptococcus (GBS) (29.8%). E. coli was the most common pathogen in both periods, Enterococcus (13.3% vs 0.9%, P < 0.05) and Staphylococcus aureus (8.4% vs 1.9%, P < 0.05) decreased, while GBS increased significantly in the periods [16.9% vs 39.8%, P < 0.001]. Gram-positive bacteria were more common in full term infants (53.8% vs 27.1%, P = 0.001), while gram-negative bacteria were more common in preterm infants (72.9% vs 46.2%, P = 0.001). All isolated GBS strains were susceptible to penicillin. On the other hand, less than 60% of E. coli were susceptible to third generation of cephalosporins, and were only susceptible to carbapenem or amikacin. This was mainly due to production of extended-spectrum beta-lactamase (ESBLs) which was higher in late-onset group than that in early-onset group (45.1% vs 19.2%, P = 0.026). Conclusion: Incidence of NBM has not changed significantly over the last 2 decades. E. coli remains as the most common pathogen of NBM despite that GBS has increased in recent 9 years, especially in full-term infants. While all isolated GBS are susceptible to penicillin, over a third of E. coli strains are multidrug resistant due to production of ESBLs. [ABSTRACT FROM AUTHOR]

Introduction China has approximately 1 million new cases of tuberculosis per year, (1-3) resulting in a substantial burden of premature mortality. (2) Several factors are known to increase the risk [...], Objective To determine excess mortality in a cohort of people with tuberculosis in Shanghai. Methods Participants were local residents in 4 (of 19) districts in Shanghai, registered In one of four tuberculosis clinics between January 1, 2004 and December 31, 2008. Baseline data were collected at the most recent diagnosis of tuberculosis and mortality was assessed between March and May of 2014. We calculated standardized mortality ratios (SMR) and case-fatality rates for all participants and for subgroups. Univariate and multivariate Cox regression models were used to quantify associations between co-morbidities and mortality from all causes and from tuberculosis. Findings We registered 4569 subjects in the cohort. Overall, the cohort had an SMR for deaths from all causes of 5.2 (95% confidence interval, CI: 4.8-5.6). Males had a higher SMR than females (6.1 versus 3.0). After adjustment for age and sex, hazard ratios (HR) for deaths from all causes were significantly greater in previously treated people (HR: 1.26; 95% CI: 1.08-1.49) and sputum smear-test positive people (HR: 1.55; 95% CI: 1.35-1.78). The risk of death from tuberculosis was. also significantly greater for previously treated people (HR: 1.88; 95% CI: 1.24-2.86) and smear positive people (HR: 3.16; 95% CI: 2.06-4.87). Conclusion People with tuberculosis in Shanghai have an increased risk of mortality. Earlier diagnosis and more vigilant follow-up may help to reduce mortality In this group. Objectif Determiner la surmortalite dans une cohorte de personnes atteintes de tuberculose a Shanghai. Methodes Les participants etaient des habitants de 4 districts (sur 19) de Shanghai, enregistres dans une des quatre cliniques de la tuberculose entre le 1er janvier 2004 et le 31 decembre 2008. Des donnees de reference ont ete recueillies lors du diagnostic le plus recent de tuberculose et la mortalite a ete evaluee entre mars et mai 2014. Nous avons calcule les rapports standardises de mortalite (RSM) et les taux de letalite pour tous les participants ainsi que pourdes sous-groupes. Des modeles de regression univariee et multivariee de Cox ont ete utilises pour quantifier les associations entre les comorbidites et la mortalite, toutes causes confondues et due a la tuberculose. Resultats Nous avons enregistre 4569 sujets dans la cohorte. Globalement, la cohorte avait un RSM pour les deces toutes causes confondues de 5,2 (intervalle de confiance (IC) de 95%: 4,8-5,6). Les hommes affichaient un RSM plus eleve que les femmes (6,1 contre 3,0). Apres ajustement en fonction de l'age et du sexe, les ratios de risque (RR) de deces toutes causes confondues etaient nettement plus eleves chez les personnes ayant precedemment recu un traitement (RR: 1,26; IC 95%: 1,08-1,49) et les personnes a frottis d'expectoration positif (RR: 1,55; IC 95%: 1,35-1,78). Le risque de deces du a la tuberculose etait egalement beaucoup plus important pour les personnes ayant precedemment recu un traitement (RR: 1,88; IC 95%: 1,24-2,86) et les personnes a frottis positif (RR: 3,16; IC 95%: 2,06-4,87). Conclusion Les personnes atteintes de tuberculose a Shanghai presentent un risque accru de mortalite. Un diagnostic plus precoce et un suivi plus attentif pourraient permettre de reduire la mortalite dans ce groupe. Objetivo Determinar el exceso de mortalidad en una cohorte de personas con tuberculosis en Shanghai. Metodos Los participantes eran residentes locales de 4 (de 19) distritos de Shanghai, registrados en uno de los cuatro consultorios antituberculosos entre el 1 de enero de 2004 y el 31 de diciembre de 2008. Se recogieron datos de referencia de los diagnosticos de tuberculosis mas recientes y se evaluo la mortalidad entre marzo y mayo de 2014. Se calcularon las tasas de mortalidad estandarizadas (SMR) y la tasa de letalidad de todos los participantes y por subgrupos. Se utilizaron modelos de regresion de Cox univariables y multivariables para cuantificar las asociaciones entre la comorbilidad y la mortalidad de todas las causas de tuberculosis. Resultados Se registraron 4.569 sujetos en la cohorte. En general, la cohorte tenia una SMR para muertes de todas las causas de 5,2 (intervalo de confianza del 95%, IC: 4,8-5,6). Los hombres tenian una SMR mayor que las mujeres (6,1 frente a 3,0). Tras ajustarlos de acuerdo a edad y sexo, los cocientes de riesgo (HR) para las muertes de todas las causas eran significantemente mayores en personas tratadas con anterioridad (HR: 1,26 (IC del 95%: 1,08-1,49) y personas con pruebas de esputo positivas (H R: 1,55 (IC del 95%: 1,35-1,78). El riesgo de muerte por tuberculosis tambien era significativamente mayor en personas tratadas con anterioridad (HR: 1,88 (IC del 95%: 1,24-2,86) y personas con pruebas de esputo positivas (HR: 3,16 (IC del 95%: 2,06-4,87). Conclusion Las personas con tuberculosis en Shanghai tienen un mayor riesgo de mortalidad. Unos diagnosticos mas tempranos y un seguimiento mas atento podrian ayudar a reducir la mortalidad de este grupo.

Objective: An increasing number of cases of neonatal sepsis due to extended-spectrum beta-lactamase (ESBL)-producing multi-drug resistant (MDR) Escherichia coli (E. coli) have been reported worldwide. The aim of this study was to explore the risk factors associated with ESBL-producing MDR E. coli among neonates with culture-confirmed E. coli sepsis and thereby to help selection of appropriate empirical antibiotics. Patients and Methods: All newborn infants with a confirmed pathogen isolated from blood or cerebrospinal fluid (CSF) from 2016 to 2021 were identified and those with E. coli infection were included in this analysis. We compared a group of neonatal patients with ESBL-producing MDR E. coli sepsis (n=69) to a group with ESBL-negative E. coli (n=70) based on antimicrobial susceptibility reports. We used multivariable regression analysis to determine the risk factors associated with ESBL-producing MDR E. coli strains among the neonates with culture-confirmed E. coli sepsis. Results: ESBL-producing MDR E. coli sepsis was more common in premature infants and newborns with hospital-acquired late-onset sepsis (HALOS). The mortality rate of neonatal sepsis caused by ESBL-producing E. coli was about twice as that of sepsis caused by ESBL-negative E. coli. Antepartum exposure to cephalosporins (OR=25.191, 95% CI: 3.184– 199.326, P< 0.01) and parenteral nutrition for more than 1 week (OR=4.495, 95% CI: 2.009– 10.055, P< 0.01) were independent risk factors for neonatal infection with ESBL-producing stains among infants with E. coli sepsis. Conclusion: E. coli remains the most common Gram-negative bacterial pathogen causing neonatal sepsis. A higher proportion of ESBL-producing MDR E. coli is seen in premature infants and those newborns with HALOS and is associated with higher mortality. Antepartum use of cephalosporins and prolonged use of parenteral nutrition may be important factors to consider in the selection of empirical antibiotics for use in neonatal sepsis caused by gram-negative rods prior to the availability of the results of antimicrobial susceptibility. [ABSTRACT FROM AUTHOR]

Fragility modeling and real-time risk assessment can be widely applied to evaluate and enhances the resilience of the power system to High-Impact and Low Probability events. In previous studies, fragility modeling generally targets extreme weather conditions other than thunderstorm. This paper proposes a fragility model to describe the relationship between the duration of a thunderstorm and the probability of lightning related trip-out. The duration of thunderstorms, which can usually be forecasted from the meteorological department, together with the fragility function expression can help a power company to predict the possibility of lightning related trip-out. Furthermore, this paper proposes a real-time risk assessment model that can dynamically adjust the risk value based on the update of the location, peak current, and subsequent stroke of real-time thunderstorm. A case study conducted on the lightning related trip-out data in Southwest China demonstrates that the average risk of transmission line trip-out in high risk group is about ten times that in low risk group. It clearly demonstrates that real-time risk assessment can efficiently distinguish the trip-out risks of different real-time thunderstorms. [ABSTRACT FROM AUTHOR]

Lightning performance evaluation is aimed at classifying transmission lines into different risk levels of thunderstorm-induced trip-out. Its applications range from better lightning protection guidance, arrester installation design, transmission line retrofits, and line corridor design. Previous studies fail to consider the real-time lightning intensity, which is an essential factor of lightning trip-out that must not be ignored. This article proposes a novel lightning performance evaluation model based on the idea that the tower, which has a record of lightning trip-out with weaker real-time lightning intensity, is more susceptible to trip out, which means low lightning performance. In order to quantify the lightning intensity, this article puts forward a new definition of lightning intensity which includes three kinds of real-time characteristics, that is the location, the current of lightning strike, and the number of times the lightning movement track crosses the transmission line. More specifically, with the rapid development of lightning location system, a novel Lightning Identification, Tracking, and Analysis algorithm is proposed to search lightning movement track based on a database of 17 million lightning records. When lightning trip-out happens, the lightning performance level is graded according to the real-time lightning intensity. By comparing the similarity of static characteristics, the lightning performance level is extended to the tower, which has no record of lightning trip-out. By comparison with the traditional model, the proposed model is closer to the actual situation and can significantly improve the accuracy of lightning performance evaluation, which is improved by 66.7%. [ABSTRACT FROM AUTHOR]

The characteristic impedance value of the overhead line is different from that of the underground cable. Existing traveling wave‐based fault location methods for mixed power transmission systems have setbacks including location error caused by wave velocity and difficulty in detecting wave arrival time. In order to solve these problems, the increase of available information from different locations by installing wire‐based sensors along the power line is a feasible solution. In this paper, a traveling wave‐based fault location system, which is based on the current data measured at the midpoint of the overhead line and the joint point, is introduced. The data at these two locations are measured by the wire‐based current sensor we designed. The whole transmission line system is divided by these two sensors into three segments. The first step of this proposed method is to record the postfault current data at the two measuring devices. Second, by comparing the amplitudes and polarities of the current at these two measurement points, the faulty segment can be identified. Finally, postfault wave propagation paths are ascertained; the accurate velocity values of the waves in the overhead line and underground cable are obtained; and then, the fault point is located without the need of time synchronization. © 2019 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc. [ABSTRACT FROM AUTHOR]

Summary: With the increasing interdependency of electricity and gas, it is necessary to simultaneously investigate electric power system and natural gas system from the perspective of an electricity‐gas integrated energy system (EGIES). As an extension and integration of both optimal power flow (OPF) and optimal gas flow (OGF), optimal energy flow (OEF) is regarded as the cornerstone of the EGIES and lays an essential foundation for further research on the EGIES's operation and analysis considering stochastic conditions and contingency states. The objective of this paper is to develop a generalized mathematical model and a universally applicable simulation tool for the OEF problem. First, natural gas system is modeled in a way similar to electric power system according to electricity‐gas analogy analysis, where gas admittance, gas nodal admittance matrix, and the nodal equation of gas flow conservation are derived. Then, a generalized accurate OEF model is formulated by simultaneously integrating the OPF model and the OGF model as well as their coupling constraints in a unified modeling framework. Furthermore, an available hybrid optimization approach consisting of whale optimization algorithm, MATPOWER, hydraulic calculation iterative program, and nonstationary penalty function method is put forward to solve the OEF problem. The accuracy, feasibility, and applicability of the proposed modeling and solution method is finally demonstrated by analyzing Belgian 20‐node gas system combined with IEEE 30‐bus test system. Gas nodal admittance matrix is formulated to describe natural gas system with electricity‐gas analogy analysis. A nodal admittance matrix‐based mathematical model for optimal energy flow of electricity‐gas integrated energy system is presented by combining optimal power flow and optimal gas flow as well as their coupling constraints in a unified modeling framework. An effective hybrid optimization approach is developed to solve optimal energy flow by integrating whale optimization algorithm, MATPOWER, hydraulic calculation iterative program, and nonstationary penalty function. [ABSTRACT FROM AUTHOR]

A novel traveling-wave-based fault-location algorithm for multiterminal transmission lines is introduced in this paper. Existing traveling-wave fault-location methods that based on the data measured at line terminals lack reliability and accuracy because time synchronization is needed, which brings error. To solve this problem, the complex structure of multiterminal power system is divided into several fault identification branches, current at the midpoint of each branched is measured, a novel fault-location algorithm is proposed, and the time synchronization error is eliminated. A line-based device is designed to measure the current at the midpoint of each branch. An accurate value of the traveling wave speed can be obtained by merely applying the data record in one measuring device. Thus, the fault-location accuracy is improved. The system model applied in this paper comprises one transmission line and two tapped lines, and the proposed method applies to networks with more terminals. Performance of this method is tested by different cases by PSCAD. The hardware platform has been tested in Sichuan Province, China. [ABSTRACT FROM AUTHOR]

Summary: This paper presents a distributed energy system (DES) for a local district and formulates a constrained nonlinear multiobjective optimization model for the daily operation of the system. The main objective of the study is to increase the efficiency by minimizing energy cost, energy consumption, and energy losses. It is implemented through the integration and complementation of renewable energies and fossil fuels as well as the recycling utilization of waste heat in the DES. The consideration of network topology and energy losses of water heating network could also contribute to the improvement of energy efficiency. To solve the optimization problem, a novel Whale Optimization Algorithm is employed. Furthermore, the economic and energy performance of the DES are evaluated and compared with that of conventional centralized energy systems, ie, the EG and MG energy‐supply modes. After simulation studies, the hourly optimal energy (both natural gas and electricity) purchasing schedule as well as the hourly optimal set points of mass water flow rates and supply/return water temperatures could be determined. The results show that the DES saves more than 50% of energy costs/energy consumption than the MG mode and over 22% than the EG mode for a whole day, verifying the competitive advantage and great potential of both energy saving and cost reduction of the DES. [ABSTRACT FROM AUTHOR]

Existing single‐ and double‐terminal travelling‐wave fault‐location approaches have some disadvantages including difficulty in distinguishing the sources of reflect and refract waves, system error in time synchronisation and wave propagation velocity. In this study, a distributed travelling‐wave‐based fault‐location system, which eliminates the time synchronisation and wave propagation velocity error, is introduced. This novel system is consisted of three measurement points, which are located at both ends and the mid‐point of the line. At first, the measurement points, installed at both line ends, record the post‐fault current data for a time interval. The measurement point, located at the mid‐point, records the time tags of the three sequential wavefronts as t1, t2 and t3 separately including the initial wave and following waves reflected at both the ends. Second, by comparing fault current recorded by the three measurement points, the fault interval can be determined based on current deviation theorem. Finally, travelling‐wave propagation velocity is calculated according to mathematic equation in terms of t1,2,3. Then, the fault point is located without the need of time synchronisation. The simulation and hardware tests match the theoretical analysis well, showing that the proposed location method provides not only high accuracy, but also good reliability. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic-ischemic encephalopathy (HIE) is a brain injury caused by perinatal asphyxia and is the main cause of neonatal death and chronic neurological diseases. Protection of neuron after hypoxic-ischemic (HI) brain injury is considered as a potential therapeutic target of HI brain injury. To date, there are no effective medicines for neonatal HI brain injury. Lycopene (Lyc), a member of the carotenoids family, has been reported to have anti-oxidative and anti-inflammatory effects. However, its effects and potential mechanisms in HI brain injury have not yet to be systematically evaluated. In this study, we investigated whether Lyc could ameliorate HI brain injury and explored the associated mechanism both in vivo and in vitro experiments. In vivo study, Lyc significantly reduced infarct volume and ameliorated cerebral edema, decreased inflammatory response, promoted the recovery of tissue structure, and improved prognosis following HI brain injury. In vitro study, results showed that Lyc reduced expression of apoptosis mediators in oxygen-glucose deprivation (OGD)-induced primary cortical neurons. Mechanistically, we found that Lyc-induced Nrf2/NF-κB pathway could partially reversed by Brusatol (an Nrf2 inhibitor), indicated that the Nrf2/NF-κB pathway was involved in the therapy of Lyc. In summary, our findings indicate that Lyc can attenuated HI brain injury in vivo and OGD-induced apoptosis of primary cortical neurons in vitro through the Nrf2/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Microgrid (MG) is an effective way to integrate renewable energy into power system at the consumer side. In the MG, the energy management system (EMS) is necessary to be deployed to realize efficient utilization and stable operation. To help the EMS make optimal schedule decisions, we proposed a real-time dynamic optimal energy management (OEM) based on deep reinforcement learning (DRL) algorithm. Traditionally, the OEM problem is solved by mathematical programming (MP) or heuristic algorithms, which may lead to low computation accuracy or efficiency. While for the proposed DRL algorithm, the MG-OEM is formulated as a Markov decision process (MDP) considering environment uncertainties, and then solved by the PPO algorithm. The PPO is a novel policy-based DRL algorithm with continuous state and action spaces, which includes two phases: offline training and online operation. In the training process, the PPO can learn from historical data to capture the uncertainty characteristic of renewable energy generation and load consumption. Finally, the case study demonstrates the effectiveness and the computation efficiency of the proposed method. • A real-time MG OEM model with uncertainty is built and mapped into the MDP. • The proximal policy optimization (PPO) is proposed to find the OEM strategy. • The offline training and online dispatch are combined to deal with uncertainty. • The computational efficiency and accuracy are verified in the test case. [ABSTRACT FROM AUTHOR]

The cellular characteristics of intestinal cells involved in the therapeutic effects of astragaloside IV (AS-IV) for treating slow transit constipation (STC) remain unclear. This study aimed to determine the dynamics of colon tissue cells in the STC model and investigate the effects of AS-IV treatment by single-cell RNA sequencing (scRNA-seq). STC mouse models were developed using loperamide, with subsequent treatment using AS-IV. Colon tissues and feces were collected for scRNA-seq and targeted short-chain fatty acid quantification. We integrated scRNA-seq data with network pharmacology to analyze the effect of AS-IV on constipation. AS-IV showed improvement in defecation for STC mice induced by loperamide. Notably, in STC mice, epithelial cells, T cells, B cells, and fibroblasts demonstrated alterations in cell proportions and aberrant functions, which AS-IV partially rectified. AS-IV has the potential to modulate the metabolic pathway of epithelial cells through its interaction with peroxisome proliferator-activated receptor gamma (PPARγ). AS-IV reinstated fecal butyrate levels and improved energy metabolism in epithelial cells. The proportion of naïve CD4+T cells is elevated in STC, and the differentiation of these cells into regulatory T cells (Treg) is regulated by B cells and fibroblasts through the interaction of ligand-receptor pairs. AS-IV treatment can partially alleviate this trend. The status of fibroblasts in STC undergoes alterations, and the FB&#95;C4&#95;Adamdec1 subset, associated with angiogenesis and the Wingless-related integration (Wnt) pathway, emerges. Our comprehensive analysis identifies perturbations of epithelial cells and tissue microenvironment cells in STC and elucidates mechanisms underlying the therapeutic efficacy of AS-IV.

Purpose: Slow transit constipation (STC) is a common gastrointestinal disorder characterized by altered gut microbiota and reduced number of enterochromaffin cells (ECs). Astragaloside IV (AS-IV), a low drug permeability saponin, has showed beneficial effects on patients with STC. However, the specific mechanism by which AS-IV regulates STC remains unclear. In this study, we aimed to investigate the effect of AS-IV on STC and its associated mechanisms involving gut microbiota. Methods: The effect of AS-IV on STC was evaluated on STC mice induced with loperamide. We measured defecation frequency, intestinal mobility, ECs loss, and colonic lesions in STC mice treated with AS-IV. We also analyzed the changes in gut microbiota and metabolites after AS-IV treatment. Moreover, we investigated the relationship between specific gut microbes and altered fecal metabolites, such as 3-bromotyrosine (3-BrY). We also conducted in vitro experiments to investigate the effect of 3-BrY on caspase-dependent apoptosis of ECs and the activation of the p38 MAPK and ERK signaling pathways induced by loperamide. Results: AS-IV treatment promoted defecation, improved intestinal mobility, suppressed ECs loss, and alleviated colonic lesions in STC mice. AS-IV treatment also affected gut microbiota and metabolites, with a significant correlation between specific gut microbes and altered fecal metabolites such as 3-BrY. Furthermore, 3-BrY may potentially reduce caspase-dependent apoptosis of ECs and protect cell survival by inhibiting the activation of the p38 MAPK and ERK signaling pathways induced by loperamide. Conclusion: Our findings suggest that changes in gut microbiota and ECs mediated the therapeutic effect of STC by AS-IV. These results provide a basis for the use of AS-IV as a prebiotic agent for treating STC. The specific mechanism by which AS-IV regulates gut microbiota and ECs warrants further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wan, Zhou, Chen, Li, Mo, Liu, Zhang, He, Xiao, Zheng, Lin and Ren.)

Neoadjuvant chemotherapy (NAC) for rectal cancer (RC) shows promising clinical response. The modulation of the tumor microenvironment (TME) by NAC and its association with therapeutic response remain unclear. Here, we use single-cell RNA sequencing and spatial transcriptome sequencing to examine the cell dynamics in 29 patients with RC, who are sampled pairwise before and after treatment. We construct a high-resolution cellular dynamic landscape remodeled by NAC and their associations with therapeutic response. NAC markedly reshapes the populations of cancer-associated fibroblasts (CAFs), which is strongly associated with therapeutic response. The remodeled CAF subsets regulate the TME through spatial recruitment and crosstalk to activate immunity and suppress tumor progression through multiple cytokines, including CXCL12, SLIT2, and DCN. In contrast, the epithelial-mesenchymal transition of malignant cells is upregulated by CAF&#95;FAP through MIR4435-2HG induction, resulting in worse outcomes. Our study demonstrates that NAC inhibits tumor progression and modulates the TME by remodeling CAFs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cholangiocarcinoma (CCA) is a complex and refractor type of cancer with global prevalence. Several barriers remain in CCA diagnosis, treatment, and prognosis. Therefore, exploring more biomarkers and therapeutic drugs for CCA management is necessary. CCA gene expression data was downloaded from the TCGA and GEO databases. KEGG enrichment, GO analysis, and protein-protein interaction network were used for hub gene identification. miRNA were predicted using Targetscan and validated according to several GEO databases. The relative RNA and miRNA expression levels and prognostic information were obtained from the GEPIA. The candidate drug was screened using pharmacophore-based virtual screening and validated by molecular modeling and through several in vitro studies. 301 differentially expressed genes (DEGs) were screened out. Complement and coagulation cascades-related genes (including AHSG, F2, TTR, and KNG1), and cell cycle-related genes (including CDK1, CCNB1, and KIAA0101) were considered as the hub genes in CCA progression. AHSG, F2, TTR, and KNG1 were found to be significantly decreased and the eight predicted miRNA targeting AHSG, F2, and TTR were increased in CCA patients. CDK1, CCNB1, and KIAA0101 were found to be significantly abundant in CCA patients. In addition, Molport-003-703-800, which is a compound that is derived from pharmacophores-based virtual screening, could directly bind to CDK1 and exhibited anti-tumor activity in cholangiocarcinoma cells. AHSG, F2, TTR, and KNG1 could be novel biomarkers for CCA. Molport-003-703-800 targets CDK1 and work as potential cell cycle inhibitors, thereby having potential for consideration for new chemotherapeutics for CCA.

Esophageal squamous cell carcinoma (ESCC) is the most common primary esophageal malignancy with poor prognosis. Here, due to the necessity for exploring potential therapies against ESCC, we obtained the gene expression data on ESCC from the TCGA and GEO databases. Venn diagram analysis was applied to identify common targets. The protein-protein interaction network was constructed by Cytoscape software, and the hub targets were extracted from the network via cytoHubba. The potential hub nodes as drug targets were found by pharmacophore-based virtual screening and molecular modeling, and the antitumor activity was evaluated through in vitro studies. A total of 364 differentially expressed genes (DEGs) in ESCC were identified. Pathway enrichment analyses suggested that most DEGs were mainly involved in the cell cycle. Three hub targets were retrieved, including CENPF, CCNA2 (cyclin A), and CCNB1 (cyclin B1), which were highly expressed in esophageal cancer and associated with prognosis. Moreover, amentoflavone, a promising drug candidate found by pharmacophore-based virtual screening, showed antiproliferative and proapoptotic effects and induced G1 in esophageal squamous carcinoma cells. Taken together, our findings suggested that amentoflavone could be a potential cell cycle inhibitor targeting cyclin B1, and is therefore expected to serve as a great therapeutic agent for treating esophageal squamous cell carcinoma.

Mutations in the doublecortin ( DCX ) gene, which encodes a microtubule (MT)-binding protein, cause human cortical malformations, including lissencephaly and subcortical band heterotopia. A deficiency in DCX and DCX-like kinase 1 (DCLK1), a functionally redundant and structurally similar cognate of DCX, decreases neurite length and increases the number of primary neurites directly arising from the soma. The underlying mechanism is not completely understood. In this study, the elongation of the somatic Golgi apparatus into proximal dendrites, which have been implicated in dendrite patterning, was significantly decreased in the absence of DCX/DCLK1. Phosphorylation of DCX at S47 or S327 was involved in this process. DCX deficiency shifted the distribution of CLASP2 proteins to the soma from the dendrites. In addition to CLASP2, dynein and its cofactor JIP3 were abnormally distributed in DCX-deficient neurons. The association between JIP3 and dynein was significantly increased in the absence of DCX. Down-regulation of CLASP2 or JIP3 expression with specific shRNAs rescued the Golgi phenotype observed in DCX-deficient neurons. We conclude that DCX regulates the elongation of the Golgi apparatus into proximal dendrites through MT-associated proteins and motors.