Oncoproteins E6 and E7 upregulate topoisomerase I to activate the cGAS-PD-L1 pathway in cervical cancer development.

Background: Cervical cancer (CC) stands as a significant health threat to women globally, with high-risk human papillomaviruses as major etiologic agents. The DNA damage repair (DDR) protein topoisomerase I (TOP1) has been linked to various cancers, yet its distinct roles and mechanisms in CC are not fully elucidated. Methods: We investigated TOP1 expression in cervical intraepithelial neoplasia (CIN) and CC tissues utilizing qRT-PCR and IHC, correlating findings with patient prognosis. Subsequent knockdown studies were performed in vitro and in vivo to evaluate the influence of TOP1 on tumor growth, DNA repair, and inflammatory responses. Results: TOP1 was highly expressed in CIN and CC, negatively correlating with patient prognosis. Inhibition of TOP1 impeded CC cell growth and disrupted DNA repair. TOP1 was shown to regulate tumor-promoting inflammation and programmed death-ligand 1 (PD-L1) production in a cGAS-dependent manner. HPV oncoproteins E6 and E7 upregulated TOP1 and activated the cGAS-PD-L1 pathway. Conclusions: TOP1 acts as a DNA repair mediator, promoting CC development and immune evasion. Targeting the TOP1-cGAS-PD-L1 axis could be a potential therapeutic strategy for CC.

Preeclampsia and its prediction: traditional versus contemporary predictive methods.

OBJECTIVE: Preeclampsia (PE) poses a significant threat to maternal and perinatal health, so its early prediction, prevention, and management are of paramount importance to mitigate adverse pregnancy outcomes. This article provides a brief review spanning epidemiology, etiology, pathophysiology, and risk factors associated with PE, mainly discussing the emerging role of Artificial Intelligence (AI) deep learning (DL) technology in predicting PE, to advance the understanding of PE and foster the clinical application of early prediction methods. METHODS: Our narrative review comprehensively examines the PE epidemiology, etiology, pathophysiology, risk factors and predictive approaches, including traditional models and AI deep learning technology. RESULTS: Preeclampsia involves a wide range of biological and biochemical risk factors, among which poor uterine artery remodeling, excessive immune response, endothelial dysfunction, and imbalanced angiogenesis play important roles. Traditional PE prediction models exhibit significant limitations in sensitivity and specificity, particularly in predicting late-onset PE, with detection rates ranging from only 30% to 50%. AI models have exhibited a notable level of predictive accuracy and value across various populations and datasets, achieving detection rates of approximately 70%. Particularly, they have shown superior predictive capabilities for late-onset PE, thereby presenting novel opportunities for early screening and management of the condition. CONCLUSION: AI DL technology holds promise in revolutionizing the prediction and management of PE. AI-based approaches offer a pathway toward more effective risk assessment methods by addressing the shortcomings of traditional prediction models. Ongoing research efforts should focus on expanding databases and validating the performance of AI in diverse populations, leading to the development of more sophisticated prediction models with improved accuracy.

Nrf1 Reduces COX-2 Expression and Maintains Cellular Homeostasis After Cerebral Ischemia/Reperfusion By Targeting IL-6/TNF-α Protein Production.

Neuroinflammation has been considered involved in the process of cerebral ischemia-reperfusion injury (CIRI). Transcription factors play a crucial role in regulating gene transcription and the expressions of specific proteins during the progression of various neurological diseases. Evidence showed that transcription factor nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as Nrf1) possessed strong biological activities including antioxidant, anti-inflammatory and neuroprotective properties. However, its role and potential molecular mechanisms in CIRI remain unclear. In our study, we observed a significant elevation of Nrf1 in the cerebral cortex following cerebral ischemia-reperfusion in rats. The Nrf1 downregulation markedly raised COX-2, TNF-α, IL-1ß, and IL-6 protein levels during middle cerebral artery occlusion/reperfusion in rats, which led to worsened neurological deficits, higher cerebral infarct volume, and intensified cortical histopathological damage. In subsequent in vitro studies, the expression of Nrf1 protein increased following oxygen-glucose deprivation/reperfusion treatment on neurons. Subsequently, Nrf1 knockdown resulted in a significant upregulation of inflammatory factors, leading to a substantial increase in the cell death rate. Through analyzing the alterations in the expression of inflammatory factors under diverse interventions, it is indicated that Nrf1 possesses the capacity to discern variations in inflammatory factors via specific structural domains. Our findings demonstrate the translocation of the Nrf1 protein from the cytoplasm to the nucleus, thereby modulating the protein expression of IL-6/TNF-α and subsequently reducing the expression of multiple inflammatory factors. This study signifies, for the first time, that during cerebral ischemia-reperfusion, Nrf1 translocases to the nucleus to regulate the protein expression of IL-6/TNF-α, consequently suppressing COX-2 expression and governing cellular inflammation, ultimately upholding cellular homeostasis.

The role and therapeutic strategies for tissue-resident memory T cells, central memory T cells, and effector memory T cells in psoriasis.

Psoriasis is a skin disease that is inflammatory and persistent, causing a high rate of recurrence, poor quality of life, and significant socioeconomic burden. Its main pathological manifestations are abnormal activation and infiltration of T cells and excessive proliferation of keratinocytes (KCs). The great majority of patients with psoriasis will relapse after remission. It usually lasts a lifetime and necessitates long-term treatment strategies. During periods of activity and remission, one of the main cell types in psoriasis is memory T cells, which include tissue-resident memory T (TRM) cells, central memory T (TCM) cells, and effector memory T (TEM) cells. They work by releasing inflammatory factors, cytotoxic particles, or altering cell subpopulations, leading to increased inflammation or recurrence. This review summarizes the role of memory T cells in the pathology and treatment of psoriasis, with a view to potential novel therapies and therapeutic targets.

Systematic development of a highly efficient cell factory for 5-aminolevulinic acid production.

The versatile applications of 5-aminolevulinic acid (5-ALA) across the fields of agriculture, livestock, and medicine necessitate a cost-efficient biomanufacturing process. In this study, we achieved the economic viability of biomanufacturing this compound through a systematic engineering framework. First, we obtained a 5-ALA synthase (ALAS) with superior performance by exploring its natural diversity with divergent evolution. Subsequently, using a genome-scale model, we identified and modified four key targets from distinct pathways in Escherichia coli, resulting in a final enhancement of 5-ALA titers up to 21.82 g/l in a 5-l bioreactor. Furthermore, recognizing that an imbalance of redox equivalents hindered further titer improvement, we developed a dynamic control system that effectively balances redox status and carbon flux. Ultimately, we collaboratively optimized the artificial redox homeostasis system at the transcription level with other cofactors at the feeding level, demonstrating the highest recorded performance to date with a titer of 63.39 g/l for the biomanufacturing of 5-ALA.

Association between frailty and adverse outcomes in patients undergoing maintenance hemodialysis: a systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to determine the strength of the association between frailty and adverse outcomes in patients undergoing maintenance hemodialysis. DESIGN: A systematic review and meta-analysis. SETTING AND PARTICIPANTS: Patients aged ≥18 years who were undergoing maintenance hemodialysis. METHODS: PubMed, Web of Science, Embase, the Cochrane Library, Scopus, the China Knowledge Resource Integrated Database, the Wanfang Database and the Weipu Database were searched from inception until 11 April 2024. The reviewers independently selected the studies, extracted the data and evaluated the quality of the studies. Stata 15.1 software was used to perform the meta-analysis. RESULTS: A total of 36 articles were included in this study, including 56,867 patients. The primary outcome events in this study were mortality, hospitalization, and vascular access events. The secondary outcomes were depression, cognitive impairment, falls, fracture, sleep disturbances, and quality of life. This study suggested that frailty was associated with mortality in patients undergoing maintenance hemodialysis [hazard ratio (HR), 1.97; 95% CI, 1.62-2.40]. Frailty increased the risk of mortality in patients [odds ratio (OR), 2.33; 95% CI, 1.47-3.68]. In addition, we found that frailty was significantly associated with hospitalization in patients undergoing maintenance hemodialysis (OR, 2.47; 95% CI, 1.52-4.03). Patients who were undergoing maintenance hemodialysis and who were frail had a greater risk of hospitalization [RR, 1.47; 95% CI, 1.05-2.08] and emergency visits (RR, 2.28; 95% CI, 1.78-2.92). The results of this study also suggested that frailty was associated with a greater risk of vascular access events (HR, 1.72; 95% CI, 1.50-1.97). Finally, frailty increased the risk of depression (OR, 4.31; 95% CI, 1.83-10.18), falls and fractures, and reduced quality of life. CONCLUSIONS: The findings of this study suggested that frailty was an important predictor of adverse outcomes in patients undergoing maintenance hemodialysis. In the future, medical staff should regularly evaluate signs of weakness, formulate individual diagnosis and treatment plans, adjust dialysis plans according to the patient's condition, and reduce the occurrence of adverse events. REGISTRATION: The study protocol was registered on PROSPERO (https://www.crd.york.ac.uk/PROSPERO/, number: CRD42023486239).

Mitochondrial GRIM19 Loss Induces Liver Fibrosis through NLRP3/IL33 Activation via Reactive Oxygen Species/NF-кB Signaling.

Background and Aims: Hepatic fibrosis (HF) is a critical step in the progression of hepatocellular carcinoma (HCC). Gene associated with retinoid-IFN-induced mortality 19 (GRIM19), an essential component of mitochondrial respiratory chain complex I, is frequently attenuated in various human cancers, including HCC. Here, we aimed to investigate the potential relationship and underlying mechanism between GRIM19 loss and HF pathogenesis. Methods: GRIM19 expression was evaluated in normal liver tissues, hepatitis, hepatic cirrhosis, and HCC using human liver disease spectrum tissue microarrays. We studied hepatocyte-specific GRIM19 knockout mice and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 (Cas9) lentivirus-mediated GRIM19 gene-editing in murine hepatocyte AML12 cells in vitro and in vivo. We performed flow cytometry, immunofluorescence, immunohistochemistry, western blotting, and pharmacological intervention to uncover the potential mechanisms underlying GRIM19 loss-induced HF. Results: Mitochondrial GRIM19 was progressively downregulated in chronic liver disease tissues, including hepatitis, cirrhosis, and HCC tissues. Hepatocyte-specific GRIM19 heterozygous deletion induced spontaneous hepatitis and subsequent liver fibrogenesis in mice. In addition, GRIM19 loss caused chronic liver injury through reactive oxygen species (ROS)-mediated oxidative stress, resulting in aberrant NF-кB activation via an IKK/IкB partner in hepatocytes. Furthermore, GRIM19 loss activated NLRP3-mediated IL33 signaling via the ROS/NF-кB pathway in hepatocytes. Intraperitoneal administration of the NLRP3 inhibitor MCC950 dramatically alleviated GRIM19 loss-driven HF in vivo. Conclusions: The mitochondrial GRIM19 loss facilitates liver fibrosis through NLRP3/IL33 activation via ROS/NF-кB signaling, providing potential therapeutic approaches for earlier HF prevention.

A novel indicator for lead poisoning beyond blood lead level: Facile diagnosis of lead poisoning using random urine with point-of-care testing.

Lead (Pb) poisoning is estimated to account for 1 % of the global disease burden. The gold standard for diagnosing lead poisoning in human body relies on blood lead level (BLL), which is always performed in hospitals using expensive instruments. However, there are still many countries and regions with a lack of medical resources (without enough professional medical staff and analytical instruments). To achieve a facile diagnosis of lead poisoning by ordinary residents (without any expertise), this study conducted a research study on 810 participants to discover and validate a new lead poisoning indicator (creatinine-corrected urinary lead level, cULL) beyond BLL in non-invasive samples. A point-of-care testing (POCT) device to measure cULL was developed, equipped with liquid-phase microextraction and electromembrane extraction on a paper-based analytical device for on-site separation of lead and creatinine in the urine, using a smartphone for the quantification of analytes. The cULL as a novel indicator and the POCT device developed could be effective in reducing the risk of damage from lead contamination.

Meniscal Allograft versus Synthetic Graft in Treatment Outcomes of Meniscus Repair: A Mini-review and Meta-analysis.

Meniscal injuries are highly correlated with osteoarthritis (OA) onset and progression. Although meniscal allograft transplantation (MAT) is a therapeutic option to restore meniscal anatomy, a shortage of donor material and the donor-derived infectious risk may be concerns in clinics. This review summarizes the literature reporting meniscus repair status in preclinical models and clinical practice using allografts or synthetic grafts. The advantages and limitations of biodegradable polymer-based meniscal scaffolds, applied in preclinical studies, are discussed. Then, the long-term treatment outcomes of patients with allografts or commercial synthetic scaffolds are compared. A total of 47 studies are included in our network meta-analysis. Compared with the meniscal allografts, the commercial synthetic products significantly improved clinical treatment outcomes in terms of the Knee Injury and Osteoarthritis Outcome Score (KOOS), Visual Analog Scale (VAS) scores, and Lysholm scores. In addition, development strategies for the next generation of novel synthetic scaffolds are proposed through optimization of structural design and fabrication, and selection of cell sources, external stimuli, and active ingredients. This review may inspire researchers and surgeons to design and fabricate clinic-orientated grafts with improved treatment outcomes.

Effect of Micellar Morphology on the Temperature-Induced Structural Evolution of ABC Polypeptoid Triblock Terpolymers into Two-Compartment Hydrogel Network.

We investigated the temperature-dependent structural evolution of thermoreversible triblock terpolypeptoid hydrogels, namely poly(N-allyl glycine)-b-poly(N-methyl glycine)-b-poly(N-decyl glycine) (AMD), using small-angle neutron scattering (SANS) with contrast matching in conjunction with X-ray scattering and cryogenic transmission electron microscopy (cryo-TEM) techniques. At room temperature, A100M101D10 triblock terpolypeptoids self-assemble into core-corona-type spherical micelles in aqueous solution. Upon heating above the critical gelation temperature (T gel), SANS analysis revealed the formation of a two-compartment hydrogel network comprising distinct micellar cores composed of dehydrated A blocks and hydrophobic D blocks. At T ≳ T gel, the temperature-dependent dehydration of A block further leads to the gradual rearrangement of both A and D domains, forming well-ordered micellar network at higher temperatures. For AMD polymers with either longer D block or shorter A block, such as A101M111D21 and A43M92D9, elongated nonspherical micelles with a crystalline D core were observed at T < T gel. Although these enlarged crystalline micelles still undergo a sharp sol-to-gel transition upon heating, the higher aggregation number of chains results in the immediate association of the micelles into ordered aggregates at the initial stage, followed by a disruption of the spatial ordering as the temperature further increases. On the other hand, fiber-like structures were also observed for AMD with longer A block, such as A153M127D10, due to the crystallization of A domains. This also influences the assembly pathway of the two-compartment network. Our findings emphasize the critical impact of initial micellar morphology on the structural evolution of AMD hydrogels during the sol-to-gel transition, providing valuable insights for the rational design of thermoresponsive hydrogels with tunable network structures at the nanometer scale.

Effectiveness of Virtual Reality in the Management of Anxiety and Pain Peri-Treatment for Breast Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Breast cancer is the second most common cancer in humans. Its therapy procedures such as breast biopsy can cause anxiety and persistent pain in patients. Virtual reality (VR) has been applied to promote comfort in various populations. However, the effectiveness of VR in relieving pain and anxiety in patients undergoing breast cancer treatment is unclear. PURPOSE: This study was designed to examine the effect of VR on anxiety and pain in people undergoing treatment for breast cancer. METHODS: PubMed, Cochrane, Embase, Scopus, Web of Science, and MEDLINE databases were searched for studies involving VR, pain, and anxiety in patients with breast cancer published up to March 2022. The Cochrane Handbook for Systems quality evaluation standard 6.3.0 was followed to assess risk of bias in the identified studies, with the results reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Subsequently, a meta-analysis of the included data was conducted using RevMan 5.3 software. RESULTS: Six randomized controlled trials and one quasi-experimental study were included. The strength of the evidence ranged from moderate to high. Although VR was found to ameliorate anxiety in patients with breast cancer, only three studies showed statistically significant changes. All of the included studies reported statistically significant improvement in pain levels. In addition, two of the studies reported cybersickness symptoms as a common side effect of VR. CONCLUSIONS: VR has an important role to play in alleviating pain in patients with breast cancer. However, evidence demonstrating VR's importance in alleviating anxiety symptoms in this population is insufficient. Studies conducted with larger sample sizes and high-quality research methodologies will be necessary to clarify this issue. Clinical nurses should address the potential side effects of VR.

DNA damage response and inflammatory response: Two traffic lights for HPVs on the road to transformation.

Human papillomaviruses (HPVs) are non-enveloped double-stranded DNA viruses. When HPV infection persists, infected tissues can develop many HPV-related diseases such as cervical cancer and head and neck squamous cell carcinoma. To establish their persistent infection, HPVs have evolved mechanisms to manipulate the host cellular processes such as DNA damage response (DDR), which includes homologous recombination, nonhomologous end joining, and microhomology-mediated end joining. Additionally, HPVs utilize host inflammatory processes to facilitate their life cycles. Here, we bridge the concepts of DDR and inflammatory response, and discuss how HPV proteins orchestrate a sophisticated manipulation of DDR and inflammation to promote their viral replication, ultimately fostering the progression of infected cells towards oncogenic transformation to malignancy.

Synthesis, characterization, antioxidant and bacteriostasis in preservation of isoorientin loaded Zein/GA nanoparticles.

Isoorientin (Iso) is a natural flavone with multiple activities. In the present study, the partial chemical properties and activities of Iso were improved by the nanoparticle loading technique. Zein/GA nanoparticles were successfully synthesized with the antisolvent precipitation method, and the structure and stability of the Zein/GA nanoparticles loaded with Iso (Zein/GA-Iso nanoparticles) were characterized by FTIR, UV-vis spectroscopy and zeta-sizer analysis. Results showed that Zein/GA-Iso nanoparticles possessed greater stability, light stability, hydrophilicity and antioxidant activity. Furthermore, Zein/GA-Iso nanoparticles exerted notable antibacterial activity against E. coli, S. aureus, and P. aeruginosa by destroying the permeability and integrity of cell membrane. On this basis, Zein/GA-Iso nanoparticles do have a bacteriostatic effect on pork. In conclusion, Zein/GA-Iso nanoparticles had better stability and pork preservation for applications in the food processing field as a new type of antiseptic and freshening agent.

Evolution and Genetic Differentiation of Pleurotus tuoliensis in Xinjiang, China, Based on Population Genomics.

Pleurotus tuoliensis is a unique species discovered in Xinjiang, China, which is recognized for its significant edible, medicinal, and economic value. It has been successfully incorporated into industrial production. Controversy has emerged concerning the evolution and environmental adaptability of this species due to inadequate interspecific ecology and molecular data. This study examines the germplasm resources of P. tuoliensis in the Xinjiang region. A total of 225 wild and cultivated strains of P. tuoliensis were gathered from seven representative regions. Phylogenetic analysis revealed that seven populations were notably segregated into three distinct groups, primarily attributed to environmental factors as the underlying cause for this differentiation. Population historical size data indicate that P. tuoliensis underwent two expansion events, one between 2 and 0.9 Mya (Miocene) and the other between 15 and 4 Mya (Early Pleistocene). The ancient climate fluctuations in the Xinjiang region might have contributed to the comparatively modest population size during the Pliocene epoch. Moreover, through the integration of biogeography and ancestral state reconstruction, it was determined that group C of P. tuoliensis emerged initially and subsequently dispersed to groups D and B, in that order. Subsequently, group D underwent independent evolution, whereas group B continued to diversify into groups A and EFG. The primary factor influencing this mode of transmission route is related to the geographical conditions and prevailing wind direction of each group. Subsequent research endeavors focused on assessing the domestication adaptability of P. tuoliensis to different substrates. It was found that the metabolic processes adapted during the domestication process were mainly related to energy metabolism, DNA repair, and environmental adaptability. Processes adapted to the host adaptability include responses to the host (meiosis, cell cycle, etc.) and stress in the growth environment (cysteine and methionine metabolism, sulfur metabolism, etc.). This study analyzed the systematic evolution and genetic differentiation of P. tuoliensis in Xinjiang. The identified loci and genes provide a theoretical basis for the subsequent improvement of germplasm resources and conducting molecular breeding.

Combination therapy using Cel-CSO/Taxol NPs for reversing drug resistance in breast cancer through inhibiting PI3K/AKT/NF-κB/HIF-1α pathway.

The resistance of malignant tumors to multiple drugs is a significant obstacle in cancer treatment and prognosis. Accordingly, we synthesized a celastrol (Cel) prodrug (Cel-CSO) by conjugating chitosan oligosaccharides (CSO) to Cel for reversing Taxol resistance in chemotherapy, followed by self-assembly with Taxol into a novel nanoplatform of Cel-CSO/Taxol nanoparticles (termed NPs). NPs showed a suitable size (about 153 nm), excellent stability and prolonged release of Cel and Taxol in a manner that depended on both pH and time. NPs effectively inhibited the overexpression of multidrug resistance-related protein P-gp, hypoxia inducible factor-1α (HIF-1α), and triggered the MCF-7/Taxol cell apoptosis through inhibiting the PI3K/AKT/NF-κB/HIF-1α pathway. In tumor-bearing mice, NPs exhibited significant curative effects in inducing apoptosis of MCF-7/Taxol tumors which showed a low expression level of P-gp, microtubule-related proteins TUBB3 and Tau. The results indicated that NPs may be a promising strategy to overcome drug resistance caused by P-gp, which improve the antitumor effects in drug-resistant breast cancer.

Identification of Angiogenesis-Related Genes and Molecular Subtypes for Psoriasis Based on Random Forest Algorithm.

Psoriasis is a chronic immune-mediated recurrent skin disease causing systemic damage. Increased angiogenesis has been reported to participate in the progression of psoriasis. However, angiogenesis-related genes (ARGs) in psoriasis have not been systematically elucidated. Therefore, we aim to identify potential biomarkers and subtypes using two algorithms. Transcriptome sequencing data of patients with psoriasis were obtained, in which differentially expressed genes were assessed by principal component analysis (PCA). A diagnostic model was developed using random forest algorithm (ntree=400) and validated by ROC curves. Subsequently, we performed consensus clustering to calculate angiogenesis-associated molecular subtypes of psoriasis. Additionally, a correlation analysis was conducted between ARGs and immune cell infiltration. Finally, validation of potential ARG genes was performed by qRT-PCR. We identified 29 differentially expressed ARGs, including 13 increased and 16 decreased. Ten ARGs, CXCL8, ANG, EGF, HTATIP2, ANGPTL4, TNFSF12, RHOB, PML, FOXO4, and EMCN were subsequently sifted by the diagnostic model based on a random forest algorithm. Analysis of the ROC curve (area under the curve [AUC] = 1.0) indicated high diagnostic performance in internal validation. The correlation analysis suggested that CXCL8 has a high positive correlation with neutrophil (R =0.8, P<0.0001) and interleukins pathway (R=0.79, P<0.0001). Furtherer, two ARG-mediated subtypes were obtained, indicating potential heterogeneity. Finally, the qRT-PCR demonstrated that the mRNA expression levels of CXCL8 and ANGPTL4 were elevated in psoriasis patients, with a reduced expression of EMCN observed. The current paper indicated potential ARG-related biomarkers of psoriasis, including CXCL8, ANGPTL4, and EMCN, with two molecular subtypes.

Structural and electronic properties of clathrate-like hydride: MH6 and MH9 (M = Sc, Y, La).

CONTEXT: The addition of central metal atoms to hydrogen clathrate structures is thought to provide a certain amount of "internal chemical pressure" to offset some of the external physical pressure required for compound stability. The size and valence of the central atoms significantly affect the minimum pressure required for the stabilization of hydrogen-rich compounds and their superconducting transition temperature. In recent years, many studies have calculated the minimum stable pressure and superconducting transition temperature of compounds with H24, H29, and H32 hydrogen clathrates, with centrally occupied metal atoms. In order to investigate the stability and physical properties of compounds with H cages in which the central atoms change in the same third group B, herein, based on first-principles calculations, we systematically investigated the lattice parameters, crystal volume, band structures, density of states, Mulliken analysis, charge density, charge density difference, and electronic localization function in I m 3 ¯ m -MH6 and P63/mmc-MH9 systems with different centered rare earth atoms M (M = Sc, Y, La) under a series of pressures. We find that for MH9, the pressure mainly changes the crystal lattice parameters along the c-axis, and the contributions of the different H atoms in MH9 to the Fermi level are H3 > H1 > H2. The density of states at the Fermi level of MH6 is mainly provided by H 1 s. Moreover, the size of the central atom M is particularly important for the stability of the crystal. By observing a series of properties of the structures with H24 and H29 cages wrapping the same family of central atoms under a series of pressures, our theoretical study is helpful for further understanding the formation mechanism of high-temperature superconductors and provides a reference for future research and design of high-temperature superconductors. METHODS: The first principles based on the density functional theory and density functional perturbation theory were employed to execute all calculations by using the CASTEP code in this work.

Retracing from Outcomes to Causes: NRF2-Driven GSTA4 Transcriptional Regulation Controls Chronic Inflammation and Oxidative Stress in Atopic Dermatitis Recurrence.

Atopic dermatitis (AD), a chronic and recurrent inflammatory skin disorder, presents a high incidence and imposes a substantial economic burden. Preventing its recurrence remains a significant challenge in dermatological therapy owing to poorly understood underlying mechanisms. In our study, we adopted a strategy of tracing the mechanisms of recurrence from clinical outcomes. We developed a mouse model of recurrent AD and applied clinically validated treatment regimens. Transcriptomic analyses revealed a pronounced enrichment in the glutathione metabolic pathway in the treated group. Through integrated bioinformatics and in vivo validation, we identified glutathione S-transferase alpha 4 (GSTA4) as a pivotal mediator in AD recurrence. Immunohistochemical analysis demonstrated decreased GSTA4 expression in lesions from patients with AD. Functionally, in vitro overexpression of GSTA4 significantly curtailed AD-like inflammatory responses and ROS production. Moreover, we discovered that NRF2 transcriptional activity regulates GSTA4 expression and function. Our treatment notably augmented NRF2-mediated GSTA4 transcription, yielding pronounced anti-inflammatory and ROS-neutralizing effects. Conclusively, our findings implicate GSTA4 as a critical factor in the recurrence of AD, particularly in the context of oxidative stress and chronic inflammation. Targeting the NRF2-GSTA4 axis emerges as a promising anti-inflammatory and antioxidative strategy for preventing AD recurrence.

Efficacy of Baclofen as Add-on Therapy for Refractory Gastroesophageal Reflux Disease: A Meta-analysis.

OBJECTIVES: As a GABAB receptor agonist, baclofen has demonstrated efficacy in alleviating symptoms of refractory gastroesophageal reflux disease (r-GERD). This meta-analysis aims to evaluate the safety and effectiveness of baclofen as an add-on therapy for this condition. METHOD: We conducted a comprehensive search of the PubMed, Embase, and Web of Science databases for studies published up until October 2023. Subsequently, we performed a meta-analysis encompassing all eligible trials. RESULTS: From 719 records, 10 studies were included, most of these studies were moderate risk. The findings demonstrated that the addition of baclofen as a supplementary treatment effectively improves symptoms (GERD Q score) in r-GERD (standardized mean difference=-0.78, 95% CI: -1.06 to -0.51, I2=0%). The addition of this treatment also resulted in a decrease in the frequency of nonacidic reflux episodes (standardized mean difference=-0.93, 95% CI: -1.49 to -0.37, I2=63%) and an improvement in DeMeester scores (standardized mean difference=-0.82, 95% CI: -1.61 to -0.04, I2=81%) among patients with r-GERD when compared with the use of proton pump inhibitor (PPI) drugs alone. However, no significant disparity was observed in terms of reducing acid reflux episodes (standardized mean difference=-0.12, 95% CI: -0.49 to 0.19, I2=0%) and proximal reflux (standardized mean difference=-0.47, 95% CI: -1.08 to 0.14, I2=60%). CONCLUSION: Baclofen as an add-on treatment can effectively improve the symptoms of patients with r-GERD and reduce the incidence of nonacidic reflux and improve DeMeester score. However, long-term use of baclofen leads to an increased incidence of side effects and is not effective in reducing the occurrence of acid reflux.

Insights Into Preaggregation Control of Y-Series Nonfullerene Acceptors in Liquid State for Highly Efficient Binary Organic Solar Cells.

Leveraging breakthroughs in Y-series nonfullerene acceptors (NFAs), organic solar cells (OSCs) have achieved impressive power conversion efficiencies (PCEs) exceeding 19%. However, progress in advancing OSCs has decelerated due to constraints in realizing the full potential of the Y-series NFAs. Herein, a simple yet effective solid additive-induced preaggregation control method employing 2-chloro-5-iodopyridine (PDCI) is reported to unlock the full potential of the Y-series NFAs. Specifically, PDCI interacts predominantly with Y-series NFAs enabling enhanced and ordered phase-aggregation in solution. This method leads to a notable improvement and a redshifted absorption of the acceptor phase during film formation, along with improved crystallinity. Moreover, the PDCI-induced preaggregation of NFAs in the solution enables ordered molecule packing during the film-formation process through delicate intermediate states transition. Consequently, the PDCI-induced preaggregated significantly improves the PCE of PM6:Y6 OSCs from 16.12% to 18.12%, among the best values reported for PM6:Y6 OSCs. Importantly, this approach is universally applicable to other Y-series NFA-based OSCs, achieving a champion PCE of 19.02% for the PM6:BTP-eC9 system. Thus, the preaggregation control strategy further unlocks the potential of Y-series NFAs, offering a promising avenue for enhancing the photovoltaic performance of Y-series NFA-based OSCs.