Ancient nitrogenases are ATP dependent.

Life depends on a conserved set of chemical energy currencies that are relics of early biochemistry. One of these is ATP, a molecule that, when paired with a divalent metal ion such as Mg2+, can be hydrolyzed to support numerous cellular and molecular processes. Despite its centrality to extant biochemistry, it is unclear whether ATP supported the function of ancient enzymes. We investigate the evolutionary necessity of ATP by experimentally reconstructing an ancestral variant of the N2-reducing enzyme nitrogenase. The Proterozoic ancestor is predicted to be ~540-2,300 million years old, post-dating the Great Oxidation Event. Growth rates under nitrogen-fixing conditions are ~80% of those of wild type in Azotobacter vinelandii. In the extant enzyme, the hydrolysis of two MgATP is coupled to electron transfer to support substrate reduction. The ancestor has a strict requirement for ATP with no other nucleotide triphosphate analogs (GTP, ITP, and UTP) supporting activity. Alternative divalent metal ions (Fe2+, Co2+, and Mn2+) support activity with ATP but with diminished activities compared to Mg2+, similar to the extant enzyme. Additionally, it is shown that the ancestor has an identical efficiency in ATP hydrolyzed per electron transferred to the extant of two. Our results provide direct laboratory evidence of ATP usage by an ancient enzyme.IMPORTANCELife depends on energy-carrying molecules to power many sustaining processes. There is evidence that these molecules may predate the rise of life on Earth, but how and when these dependencies formed is unknown. The resurrection of ancient enzymes provides a unique tool to probe the enzyme's function and usage of energy-carrying molecules, shedding light on their biochemical origins. Through experimental reconstruction, this research investigates the ancestral dependence of a nitrogen-fixing enzyme on the energy carrier ATP, a requirement for function in the modern enzyme. We show that the resurrected ancestor does not have generalist nucleotide specificity. Rather, the ancestor has a strict requirement for ATP, like the modern enzyme, with similar function and efficiency. The findings elucidate the early-evolved necessity of energy-yielding molecules, delineating their role in ancient biochemical processes. Ultimately, these insights contribute to unraveling the intricate tapestry of evolutionary biology and the origins of life-sustaining dependencies.

Dynamic changes in key factors of the blood-brain barrier in early diabetic mice.

Chronic hyperglycemia can result in damage to the hippocampus and dysfunction of the blood-brain barrier (BBB), potentially leading to neurological disorders. This study examined the histological structure of the hippocampus and the expression of critical genes associated with the BBB at 2 early stage time points in a streptozotocin-induced diabetes mellitus (DM) mouse model. Routine histology revealed vascular congestion and dilation of Virchow-Robin spaces in the hippocampal CA1 region of the DM group. Neuronal alterations included rounding and swelling and reduction in Nissl bodies and increased apoptosis. Compared to the control group, TJP1 mRNA expression in the DM group was significantly lower (P < .05 or P < .01), while mRNA levels of JAM3, TJP3, CLDN5, CLDN3, and OCLN initially increased and then decreased. At 7, 14, and 21 days, mRNA levels of the receptor for advanced glycation end products (AGER) were greater in the DM group than in the control group (P < .05 or P < .01). These findings indicate that early-stage diabetes may cause structural and functional impairments in hippocampal CA1 in mice. These abnormalities may parallel alterations in the expression of key BBB tight junction molecules and elevated AGER expression in early DM patients.

[Research progress on structure and hydrological processes in the karst critical zone of southwest China]. / è¥¿å—å–€æ–¯ç‰¹å ³é”®å¸¦ç»“æž„åŠå ¶æ°´æ–‡è¿‡ç¨‹ç ”ç©¶è¿›å±•.

The southwestern region of China is the largest exposed karst area in the world and serves as an important ecological security barrier for the upstream of Yangtze River and Pearl River. Different from the critical zone of non-karst areas, the epikarst, formed by an interwoven network of denudation pores, is the core area of karst critical zone. Water is the most active component that participates in internal material cycle and energy flow within the critical zone. We reviewed relevant research conducted in the southwestern region from three aspects: the characte-rization of critical zone structure, the hydrological processes of soil-epikarst system, and their model simulations. We further proposed potential research hotpots. The main approach involved multi-scale and multi-method integrated observations, as well as interdisciplinary collaboration. Precisely characterizing the eco-hydrological processes of the vegetation-soil-epikarst coupling system was a new trend in the future research. This review would provide scientific reference for further studies on hydrological processes in critical zones and regional hydrological water resource management in karst areas.

Icariin Ameliorates D-galactose-induced Cell Injury in Neuron-like PC12 Cells by Inhibiting MPTP Opening.

OBJECTIVE: Icariin (ICA) has a good neuroprotective effect and can upregulate neuronal basal autophagy in naturally aging rats. Mitochondrial dysfunction is associated with brain aging-related neurodegenerative diseases. Abnormal opening of the mitochondrial permeability transition pore (mPTP) is a crucial factor in mitochondrial dysfunction and is associated with excessive autophagy. This study aimed to explore that ICA protects against neuronal injury by blocking the mPTP opening and down-regulating autophagy levels in a D-galactose (D-gal)-induced cell injury model. METHODS: A cell model of neuronal injury was established in rat pheochromocytoma cells (PC12 cells) treated with 200 mmol/L D-gal for 48 h. In this cell model, PC12 cells were pre-treated with different concentrations of ICA for 24 h. MTT was used to detect cell viability. Senescence associated ß-galactosidase (SA-ß-Gal) staining was used to observe cell senescence. Western blot analysis was performed to detect the expression levels of a senescence-related protein (p21), autophagy markers (LC3B, p62, Atg7, Atg5 and Beclin 1), mitochondrial fission and fusion-related proteins (Drp1, Mfn2 and Opa1), and mitophagy markers (Pink1 and Parkin). The changes of autophagic flow were detected by using mRFP-GFP-LC3 adenovirus. The intracellular ultrastructure was observed by transmission electron microscopy. Immunofluorescence was used to detect mPTP, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mtROS) and ROS levels. ROS and apoptosis levels were detected by flow cytometry. RESULTS: D-gal treatment significantly decreased the viability of PC12 cells, and markedly increased the SA-ß-Gal positive cells as compared to the control group. With the D-gal stimulation, the expression of p21 was significantly up-regulated. Furthermore, D-gal stimulation resulted in an elevated LC3B II/I ratio and decreased p62 expression. Meanwhile, autophagosomes and autolysosomes were significantly increased, indicating abnormal activation of autophagy levels. In addition, in this D-gal-induced model of cell injury, the mPTP was abnormally open, the ROS generation was continuously increased, the MMP was gradually decreased, and the apoptosis was increased. ICA effectively improved mitochondrial dysfunction to protect against D-gal-induced cell injury and apoptosis. It strongly inhibited excessive autophagy by blocking the opening of the mPTP. Cotreatment with ICA and an mPTP inhibitor (cyclosporin A) did not ameliorate mitochondrial dysfunction. However, the protective effects were attenuated by cotreatment with ICA and an mPTP activator (lonidamine). CONCLUSION: ICA inhibits the activation of excessive autophagy and thus improves mitochondrial dysfunction by blocking the mPTP opening.

Activity-induced stiffness, entanglement network and dynamic slowdown in unentangled semidilute polymer solutions.

Active polymers possess numerous unique properties that are quite different from those observed in the system of small active molecules due to the intricate interplay between their activity and topological constraints. This study focuses on the conformational changes induced by activity, impacting effective stiffness and crucially influencing entanglement and dynamics. When the two terminals of a linear chain undergo active modification through coupling to a high-temperature thermal bath, there is a substantial increase in chain size, indicating a notable enhancement in effective stiffness. Unlike in passive semiflexible chains where stiffness predominantly affects local bond angles, activity-induced stiffness manifests at the scale of tens of monomers. While activity raises the ambient temperature, it significantly decreases diffusion by over an order of magnitude. The slowdown of the dynamics observed can be attributed to increased entanglement due to chain elongation.

Antitumor Effect of Apcin on Endometrial Carcinoma via p21-Mediated Cell Cycle Arrest and Apoptosis.

OBJECTIVE: Endometrial carcinoma (EC) is a prevalent gynecological malignancy characterized by increasing incidence and mortality rates. This underscores the critical need for novel therapeutic targets. One such potential target is cell division cycle 20 (CDC20), which has been implicated in oncogenesis. This study investigated the effect of the CDC20 inhibitor Apcin on EC and elucidated the underlying mechanism involved. METHODS: The effects of Apcin on EC cell proliferation, apoptosis, and the cell cycle were evaluated using CCK8 assays and flow cytometry. RNA sequencing (RNA-seq) was subsequently conducted to explore the underlying molecular mechanism, and Western blotting and coimmunoprecipitation were subsequently performed to validate the results. Animal studies were performed to evaluate the antitumor effects in vivo. Bioinformatics analysis was also conducted to identify CDC20 as a potential therapeutic target in EC. RESULTS: Treatment with Apcin inhibited proliferation and induced apoptosis in EC cells, resulting in cell cycle arrest. Pathways associated with apoptosis and the cell cycle were activated following treatment with Apcin. Notably, Apcin treatment led to the upregulation of the cell cycle regulator p21, which was verified to interact with CDC20 and consequently decrease the expression of downstream cyclins in EC cells. In vivo experiments confirmed that Apcin treatment significantly impeded tumor growth. Higher CDC20 expression was observed in EC tissue than in nonmalignant tissue, and increased CDC20 expression in EC patients was associated with shorter overall survival and progress free interval. CONCLUSION: CDC20 is a novel molecular target in EC, and Apcin could be developed as a candidate antitumor drug for EC treatment.

Intensive chemotherapy with dual induction and ALL-like consolidation for childhood acute myeloid leukemia: a respective report from multiple centers in China.

Background: Pediatric acute myeloid leukemia (AML) has poor prognosis and high rate of relapse and mortality, and exploration of new treatment options is still critically needed. Objectives: To summarize the outcome of our new treatment strategies for pediatric AML, which is characterized by dual induction and acute lymphoblastic leukemia (ALL) elements consolidation. Design: Retrospective, single-arm study. Methods: From July 2012 to December 2019, an intensive chemotherapy protocol was used for newly diagnosed children with AML, which contains dual induction, three courses of consolidations based on high-dose cytarabine, and two courses of consolidations composed of high-dose methotrexate, vincristine, asparaginase, and mercaptopurine (ALL-like elements). Blasts were monitored by bone marrow smears at intervals, and two lumbar punctures were performed during chemotherapy. We retrospectively analyzed the efficacy and safety of this study. The last follow-up was on 26 May 2023. Results: A total of 70 pediatric AMLs were included. The median age at diagnosis was 6.7 (0.5-16.0) years. The median initial WBC count was 23.74 × 109/L, 11 of whom ⩾100 × 109/L. After dual induction, there were 62 cases of complete remission (CR), 5 cases of partial remission, and 3 cases of nonremission. The CR rate was 88.57%. The median follow-up time was 5.8 (0.2-9.4) years, the 5-year overall survival was 78.2% ± 5%, the event-free survival (EFS) was 71.2% ± 5.6%, and the cumulative recurrence rate was 27.75%. The 5-year EFS of patients with initial WBC < 100 × 109/L (n = 59) and ⩾100 × 109/L (n = 11) were 76.4% ± 5.7% and 45.5% ± 15% (p = 0.013), respectively. A total of 650 hospital infections occurred. The main causes of infection were respiratory tract infection (26.92%), septicemia (18.46%), stomatitis (11.85%), and skin and soft-tissue infection (10.46%). Conclusion: This intensive treatment protocol with dual induction and ALL-like elements is effective and safe for childhood AML. Initial WBC ⩾ 100 × 109/L was the only independent risk factor in this cohort. Trial registration: It is a retrospective study, and no registration on ClinicalTrials.gov.

Efficacy and Safety of Insulin Degludec/Insulin Aspart versus Biphasic Insulin Aspart 30 in Patients with Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials.

Background: We systematically reviewed and analyzed the efficacy and safety of insulin degludec/insulin as-part (IDegAsp) versus biphasic insulin aspart 30 (BIAsp 30) in patients with type 2 diabetes (T2D). Methods: We used computers to search the Embase, PubMed, Clinical Trials, and the Cochrane Library database, and collected randomized controlled trials (RCTs) on the treatment of IDegAsp versus BIAsp 30 in T2D patients. The research period was from the establishment of the database to May 19, 2023. We used Review Manager 5.20 statistical software for systematic meta-analysis. Results: We included 8 RCTs with 2281 participants. IDegAsp was better to BIAsp30 in improving fasting plasma glucose (FPG) levels (P<0.001) and reducing the endpoint daily average insulin dose (P<0.01). Furthermore, compared with BIAsp30, IDegAsp significantly reduced the risk of nocturnal hypoglycemic events (P<0.001). However, there was no significant difference in the improvement of body weight change (P=0.99), glycosylated hemoglobin (P=0.50), the overall risk of hypoglycemic events (P=0.57) and adverse events (P=0.89) between the two groups. Conclusion: Compared with BIAsp30, IDegAsp could significantly reduce FPG levels, insulin dosage, and the risk of nocturnal hypoglycemic events in T2D patients, without increasing the overall risk of adverse events.

Neoadjuvant sintilimab plus chemotherapy in EGFR-mutant NSCLC: Phase 2 trial interim results (NEOTIDE/CTONG2104).

The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon's two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) in vitro. Infiltration and T cell receptor (TCR) clonal expansion of CCR8+ regulatory T (Treg)hi/CXCL13+ exhausted T (Tex)lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC.

Endovascular treatment of ruptured lobulated anterior communicating artery aneurysms: A retrospective study of 24 patients.

BACKGROUND: Lobulated intracranial aneurysm is a special type of aneurysm with at least one additional cyst in the neck or body of the aneurysm. Lobulated intracranial aneurysm is a complex aneurysm with complex morphology and structure and weak tumor wall, which is an independent risk factor for rupture and hemorrhage. Lobular aneurysms located in the anterior communicating artery complex account for 36.9% of all intracranial lobular aneurysms. Due to its special anatomical structure, both craniotomy and endovascular treatment are more difficult. Compared with single-capsule aneurysms, craniotomy for lobular intracranial aneurysms has a higher risk and complication rate. AIM: To investigate the efficacy and safety of endovascular treatment for ruptured lobulated anterior communicating artery aneurysm (ACoAA). METHODS: Patients with ruptured lobulated ACoAA received endovascular treatment in Sanming First Hospital Affiliated to Fujian Medical University from June 2020 to June 2022 were retrospectively included. Their demographic, clinical and imaging characteristics, endovascular treatment methods and follow-up results were collected. RESULTS: A total of 24 patients with ruptured lobulated ACoAA were included, including 9 males (37.5%) and 15 females (62.5%). Their age was 56.2 ± 8.9 years old (range 39-74). The time from rupture to endovascular treatment was 10.9 ± 12.5 h. The maximum diameter of the aneurysms was 5.1 ± 1.0 mm and neck width were 3.0 ± 0.7 mm. Nineteen patients (79.2%) were double-lobed and 5 (20.8%) were multilobed. Fisher's grade: Grade 2 in 16 cases (66.7%), grade 3 in 6 cases (25%), and grade 4 in 2 cases (8.3%). Hunt-Hess grade: Grade 0-2 in 5 cases (20.8%), grade 3-5 in 19 cases (79.2%). Glasgow Coma Scale score: 9-12 in 14 cases (58.3%), 13-15 in 10 cases (41.7%). Immediately postprocedural Raymond-Roy grade: grade 1 in 23 cases (95. 8%), grade 2 in 1 case (4.2%). Raymond-Roy grade in imaging follow-up for 2 wk to 3 months: grade 1 in 23 cases (95.8%), grade 2 in 1 case (4.2%). Follow-up for 2 to 12 months showed that 21 patients (87.5%) had good functional outcomes (modified Rankin Scale score ≤ 2), and there were no deaths. CONCLUSION: Endovascular treatment is a safe and effective treatment for ruptured lobulated AcoAA.

MCT1-mediated transport of valeric acid promotes porcine preimplantation embryo development by improving mitochondrial function and inhibiting the autophagic AMPK-ULK1 pathway.

Oocytes and embryos are highly sensitive to environmental stress in vivo and in vitro. During in vitro culture, many stressful conditions can affect embryo quality and viability, leading to adverse clinical outcomes such as abortion and congenital abnormalities. In this study, we found that valeric acid (VA) increased the mitochondrial membrane potential and ATP content, decreased the level of reactive oxygen species that the mitochondria generate, and thus improved mitochondrial function during early embryonic development in pigs. VA decreased expression of the autophagy-related factors LC3B and BECLIN1. Interestingly, VA inhibited expression of autophagy-associated phosphorylation-adenosine monophosphate-activated protein kinase (p-AMPK), phosphorylation-UNC-51-like autophagy-activated kinase 1 (p-ULK1, Ser555), and ATG13, which reduced apoptosis. Short-chain fatty acids (SCFAs) can signal through G-protein-coupled receptors on the cell membrane or enter the cell directly through transporters. We further show that the monocarboxylate transporter 1 (MCT1) was necessary for the effects of VA on embryo quality, which provides a new molecular perspective of the pathway by which SCFAs affect embryos. Importantly, VA significantly inhibited the AMPK-ULK1 autophagic signaling pathway through MCT1, decreased apoptosis, increased expression of embryonic pluripotency genes, and improved embryo quality.

Bifonazole caffeate: The first molecular salt of bifonazole with enhanced biopharmaceutical property based on experiments and quantum chemistry research.

In order to make novel breakthroughs in molecular salt studies of BCS class-IV antifungal medication bifonazole (BIF), a salification-driven strategy towards ameliorating attributes and aiding augment efficiency is raised. This strategy fully harnesses structural characters together attributes and benefits of caffeic acid (CAF) to concurrently enhance dissolvability and permeability of BIF by introducing the two ingredients into the identical molecular salt lattice through the salification reaction, which, coupled with the aroused potential activity of CAF significantly amplifies the antifungal efficacy of BIF. Guided by this route, the first BIF-organic molecular salt, BIF-CAF, is directionally designed and synthesized with satisfactorily structural characterizations and integrated theoretical and experimental explorations on the pharmaceutical properties. Single-crystal X-ray diffraction resolving confirms that there is a lipid-water amphiphilic sandwich structure constructed by robust charge-assistant hydrogen bonds in the salt crystal, endowing the molecular salt with the potential to enhance both dissolvability and permeability relative to the parent drug, which is validated by experimental evaluations. Remarkably, the comprehensive DFT-based theoretical investigations covering frontier molecular orbital, molecular electrostatic potential, Hirshfeld surface analysis, reduced density gradient, topology, sphericity and planarity analysis strongly support these observations, thereby allowing some positive relationships between macroscopic properties and microstructures of the molecular salt can be made. Intriguingly, the optimal properties, together with the stimulated activity of CAF markedly augment in vitro antifungal ability of the molecular salt, with magnifying inhibition zones and reducing minimum inhibitory concentrations. These findings fill in the gaps on researches of BIF-organic molecular salt, and adequately exemplify the feasibility and validity by integrating theoretical and experimental approaches to resolve BIF's problems via the salification-driven tactic.

Primary Ewing's sarcoma of the uterine cervix: a case report and review of the literature.

BACKGROUND: Ewing's sarcoma (ES) is an aggressive cancer of bone and soft tissue, most of which tend to occur in the bone. Extraosseous Ewing's sarcoma (EES) of the cervix is extremely rare. CASE PRESENTATION: In the present work, we reported a 39-year-old cervical EES patient with a 2.5*2.1*1.8 cm tumor mass. According to previous literatures, our case is the smallest tumor found in primary cervical ES ever. The patient initially came to our hospital due to vaginal bleeding, and then the gynecological examination found a neoplasm between the cervical canal and partially in the external cervical orifice. The diagnosis of EES was confirmed below: Hematoxylin & Eosin staining (H&E) revealed small round blue malignant cells in biopsy specimens. Immunohistochemistry (IHC) showed the positive staining for CD99, NKX2.2, and FLI1. Disruption of EWSR1 gene was found by fluorescence in situ hybridization (FISH), and the EWSR1-FLI1 gene fusion was determined by next-generation sequencing (NGS). The patient received laparoscopic wide hysterectomy, bilateral adnexectomy, pelvic lymphadenectomy, and postoperative adjuvant chemotherapy and remained disease free with regular follow-up for 1 year. CONCLUSIONS: Through a systematic review of previously reported cervical ES and this case, we highlighted the importance of FISH and NGS for the accuracy of ESS diagnosis, which could assist on the optimal treatment strategy. However, due to the rarity of the disease, there is no standard treatment schemes. Investigation on molecular pathological diagnosis and standardization of treatment regimens for cervical ES are critical to patients' prognosis.

[Research progress on mechanism of traditional Chinese medicine intervention in angiogenesis in prevention and treatment of nontraumatic avascular necrosis of femoral head].

Nontraumatic avascular necrosis of the femoral head(NANFH) is a common and refractory femoral head disease that causes bone death due to interruption of blood supply. Early clinical symptoms are atypical, such as hip pain and limited joint function. In the late stage, severe pain, shortening of the affected limb, claudication, and other serious symptoms are common, which se-riously affects the quality of life of patients. Therefore, it is of great significance to actively improve the clinical symptoms of NANFH to enhance the quality of life of patients. The pathogenesis of NANFH is complex, such as traumatic vascular circulatory disorders, the use of hormones or other drugs, alcoholism, and diabetes mellitus. These factors directly or indirectly lead to femoral head vascular damage, thrombosis, and coagulation system disorders, which reduce the blood supply to the acetabulum and femoral head, thus causing ischaemic death of the femoral head or even femoral head collapse. NANFH is mainly categorized as "bone impotence" and "bone paralysis" in traditional Chinese medicine(TCM). The treatment of NANFH with TCM has the characteristics and advantages of a long history, stable and reliable therapeutic effect, fewer adverse reactions, good patient tolerance, and high acceptance. Previous studies have shown that the promotion of angiogenesis is a key initiative in the prevention and treatment of NANFH, and TCM can promote fe-moral head angiogenesis by interfering with the expression of angiogenesis-related factors, which in turn can help to restore the blood supply of the femoral head and thus improve clinical symptoms of NANFH and prevent and treat NANFH. This article described the roles of blood supply interruption and angiogenesis in NANFH and the accumulated knowledge and experience of TCM in NANFH and summarized the role of angiogenesis-related factors in NANFH and the research progress on TCM intervention, so as to provide an idea for the subsequent research and a new basis for the clinical application of TCM in the treatment of NANFH.

Advancing Integration of Direct C-H Arylation-Derived Star-Shaped Oligomers as Second Acceptors for Ternary Organic Solar Cells.

Organic solar cells (OSCs) could benefit from the ternary bulk heterojunction (BHJ), a method that allows for fine-tuning of light capture, cascade energy levels, and film shape, in order to increase their power conversion efficiency (PCE). In this work, the third components of PM6:Y6 and PM6:BTP-eC9 BHJs are a set of four star-shaped unfused ring electron acceptors (SSUFREAs), i.e., BD-IC, BFD-IC, BD-2FIC, and BFD-2FIC, that are facilely synthesized by direct C-H arylation. The four SSUFREAs all show complete complementary absorption with PM6, Y6, and BTP-eC9, which facilitates light harvesting and exciton collection. When BFD-2FIC is added as a third component, the PCEs of PM6:Y6 and PM6:BTP-eC9 binary BHJs are able to be improved from 15.31% to 16.85%, and from 16.23% to 17.23%, respectively, showing that BFD-2FIC is useful for most effective ternary OSCs in general, and increasing short circuit current (JSC) and better film morphology are two additional benefits. The ternary PM6:Y6:BFD-2FIC exhibits a 9.7% percentage of increase in PCE compared to the PM6:Y6 binary BHJ, which is one of the highest percentage increases among the reported ternary BHJs, showing the huge potential of BFD-2FIC for ternary BHJ OSCs.

ECG-surv: A deep learning-based model to predict time to 1-year mortality from 12-lead electrocardiogram.

BACKGROUND: Electrocardiogram (ECG) abnormalities have demonstrated potential as prognostic indicators of patient survival. However, the traditional statistical approach is constrained by structured data input, limiting its ability to fully leverage the predictive value of ECG data in prognostic modeling. METHODS: This study aims to introduce and evaluate a deep-learning model to simultaneously handle censored data and unstructured ECG data for survival analysis. We herein introduce a novel deep neural network called ECG-surv, which includes a feature extraction neural network and a time-to-event analysis neural network. The proposed model is specifically designed to predict the time to 1-year mortality by extracting and analyzing unique features from 12-lead ECG data. ECG-surv was evaluated using both an independent test set and an external set, which were collected using different ECG devices. RESULTS: The performance of ECG-surv surpassed that of the Cox proportional model, which included demographics and ECG waveform parameters, in predicting 1-year all-cause mortality, with a significantly higher concordance index (C-index) in ECG-surv than in the Cox model using both the independent test set (0.860 [95% CI: 0.859- 0.861] vs. 0.796 [95% CI: 0.791- 0.800]) and the external test set (0.813 [95% CI: 0.807- 0.814] vs. 0.764 [95% CI: 0.755- 0.770]). ECG-surv also demonstrated exceptional predictive ability for cardiovascular death (C-index of 0.891 [95% CI: 0.890- 0.893]), outperforming the Framingham risk Cox model (C-index of 0.734 [95% CI: 0.715-0.752]). CONCLUSION: ECG-surv effectively utilized unstructured ECG data in a survival analysis. It outperformed traditional statistical approaches in predicting 1-year all-cause mortality and cardiovascular death, which makes it a valuable tool for predicting patient survival.

Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells.

BACKGROUND: Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC. METHODS: The clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA+ B cells. RESULTS: HCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8+ T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA+ B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha, resulting in the induction of IgA+ B cells. CONCLUSIONS: IL-21R plays a cancer-promoting role by inducing IgA+ B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.

General anesthetic agents induce neurotoxicity through oligodendrocytes in the developing brain.

General anesthetic agents can impact brain function through interactions with neurons and their effects on glial cells. Oligodendrocytes perform essential roles in the central nervous system, including myelin sheath formation, axonal metabolism, and neuroplasticity regulation. They are particularly vulnerable to the effects of general anesthetic agents resulting in impaired proliferation, differentiation, and apoptosis. Neurologists are increasingly interested in the effects of general anesthetic agents on oligodendrocytes. These agents not only act on the surface receptors of oligodendrocytes to elicit neuroinflammation through modulation of signaling pathways, but also disrupt metabolic processes and alter the expression of genes involved in oligodendrocyte development and function. In this review, we summarize the effects of general anesthetic agents on oligodendrocytes. We anticipate that future research will continue to explore these effects and develop strategies to decrease the incidence of adverse reactions associated with the use of general anesthetic agents.

Association between Serum Ferritin Levels and Metabolic-associated Fatty Liver Disease in Adults: a Cross-sectional Study Based on the NHANES.

OBJECTIVE: Ferritin, initially acting as an iron-storage protein, was found to be associated with metabolic diseases. Our study was designed to investigate the association between serum ferritin and metabolic-associated fatty liver disease (MAFLD) using data from the National Health and Nutrition Examination Survey (NHANES) of the United State of America. METHODS: A cross-sectional study was conducted, enrolling a total of 2145 participants from the NHANES in the 2017-2018 cycles. Hepatic steatosis and liver fibrosis were assessed by ultrasound images and several non-invasive indexes. Multiple regression analysis was conducted to determine the associations between serum ferritin concentration and MAFLD and liver fibrosis. RESULTS: The analysis revealed that participants with higher serum ferritin levels (Q3 and Q4 groups) had a higher prevalence of MAFLD than those with the lowest serum ferritin levels [Q3 vs. Q1: OR=2.17 (1.33, 3.53), P<0.05 in fatty liver index (FLI); Q4 vs. Q1: OR=3.13 (1.91, 5.13), P<0.05 in FLI]. Additionally, participants with the highest serum ferritin levels (Q4 group) displayed a higher prevalence of liver fibrosis [Q4 vs. Q1: OR=2.59 (1.19, 5.62), P<0.05 in liver stiffness measurement; OR=5.06 (1.12, 22.94), P<0.05 in fibrosis-4 index], with significantly increased risk observed in participants with concomitant diabetes [OR=7.45 (1.55, 35.72), P=0.012]. CONCLUSION: Our study revealed that elevated serum ferritin levels are associated with a higher prevalence of MAFLD and advanced liver fibrosis in patients. Elevated serum ferritin levels combined with diabetes are important risk factors for liver fibrosis.

A portable transistor immunosensor for fast identification of porcine epidemic diarrhea virus.

Widespread distribution of porcine epidemic diarrhea virus (PEDV) has led to catastrophic losses to the global pig farming industry. As a result, there is an urgent need for rapid, sensitive and accurate tests for PEDV to enable timely and effective interventions. In the present study, we develop and validate a floating gate carbon nanotubes field-effect transistor (FG CNT-FET)-based portable immunosensor for rapid identification of PEDV in a sensitive and accurate manner. To improve the affinity, a unique PEDV spike protein-specific monoclonal antibody is prepared by purification, and subsequently modified on FG CNT-FET sensor to recognize PEDV. The developed FET biosensor enables highly sensitive detection (LoD: 8.1 fg/mL and 100.14 TCID50/mL for recombinant spike proteins and PEDV, respectively), as well as satisfactory specificity. Notably, an integrated portable platform consisting of a pluggable FG CNT-FET chip and a portable device can discriminate PEDV positive from negative samples and even identify PEDV and porcine deltacoronavirus within 1 min with 100% accuracy. The portable sensing platform offers the capability to quickly, sensitively and accurately identify PEDV, which further points to a possibility of point of care (POC) applications of large-scale surveillance in pig breeding facilities.