The E3 ligase ASB3 downregulates antiviral innate immunity by targeting MAVS for ubiquitin-proteasomal degradation.

E3 ubiquitin ligases are very important for regulating antiviral immunity during viral infection. Here, we discovered that Ankyrin repeat and SOCS box-containing protein 3 (ASB3), an E3 ligase, are upregulated in the presence of RNA viruses, particularly influenza A virus (IAV). Notably, overexpression of ASB3 inhibits type I IFN (IFN-I) responses induced by Sendai virus (SeV) and IAV, and ablation of ASB3 restores SeV and H9N2 infection-mediated transcription of IFN-ß and its downstream interferon-stimulated genes (ISGs). Interestingly, animals lacking ASB3 presented decreased susceptibility to H9N2 and H1N1 infections. Mechanistically, ASB3 interacts with MAVS and directly mediates K48-linked polyubiquitination and degradation of MAVS at K297, thereby inhibiting the phosphorylation of TBK1 and IRF3 and downregulating downstream antiviral signaling. These findings establish ASB3 as a critical negative regulator that controls the activation of antiviral signaling and describe a novel function of ASB3 that has not been previously reported.

Global, regional, and national trends in the burden of breast cancer among individuals aged 70 years and older from 1990 to 2021: an analysis based on the global burden of disease study 2021.

BACKGROUND: Breast cancer poses a substantial health challenge for the world's over-70 population. However, data on the impact and epidemiology of breast cancer in this age group are limited. We aimed to evaluate global, regional, and national breast cancer trends among those aged 70 and older between 1990 and 2021. METHODS: In this trend analysis based on the 2021 Global Burden of Diseases (GBD), we report on the incidence rates and Global Burden of Diseases (GBD) disability-adjusted life years (DALYs) counts, as well as the incidence rates per 100,000 individuals and average annual percentage changes (AAPCs) for breast cancer among individuals aged 70 and above at the global, regional, and national levels. We analyzed these global trends by age, sex, and socio-developmental index (SDI). Joinpoint regression elucidates pivotal trend shifts. RESULTS: From 1990 to 2021, the global incidence of breast cancer in the over-70 population modestly increased from 104 to 107 per 100,000, with significant trend changes in 1995, 2005, and 2018. Regionally, High-income North America had the highest incidence in 2021, while North Africa and the Middle East saw the steepest rise in incidence and DALYs. The only decrease was in the High SDI quintile. The 70-74 age group experienced the largest increase globally, with rates rising from 86.3 to 90 per 100,000 (AAPC 0.27). CONCLUSION: From 1990 to 2021, global breast cancer incidence in the over-70 population saw a slight uptick, contrasted by a significant reduction in DALYs, likely due to progress in endocrine and targeted therapies. This underscores the critical need for enhanced screening and personalized treatments for older patients.

Burkitt lymphoma manifested by initial oral and maxillofacial lesions: a case report in a child patient and review of related articles.

Burkitt lymphoma is a highly aggressive B-cell lymphoma and the fastest proliferating human malignant tumor. If the disease is found in the early stage, the patient could have a high possibility to be cured successfully, whereas the prognosis is poor in the late stage. Burkitt lymphoma can occur in children and adults, and it is categorized as local (Africa), sporadic, and immunodeficiency associated type. Sporadic Burkitt lymphoma mainly affects children and adolescents, and the most common initial sites are abdominal organs and lymph nodes. Sporadic Burkitt lymphoma manifested by initial oral and maxillofacial lesions is relatively rare. Here, a case of pediatric sporadic Burkitt lymphoma, with oral and maxillofacial lesions as the first symptoms, was reported. The patient was treated in the Department of Periodontology, Shandong University School and Hospital of Stomatology. After timely checkup was provided, the patient was transferred to another hospital and had good results. In this article, an incidence of Burkitt lymphoma, with oral and maxillofacial lesions as the first symptom, was reviewed to provide reference for oral clinicians to achieve early diagnosis and treatment of patients with Burkitt lymphoma with oral diseases and improve the success rate of treatment.

CircATXN7 regulates the proliferation and invasion of esophageal cancer cells through miR-4319/NLRC5.

BACKGROUND: This study aimed to explore the molecular mechanism through which circular RNA of ataxin 7 (circATXN7) regulates the proliferation and invasion of esophageal cancer (EC) cells via microRNA (miR)-4319/NLR family CARD domain containing 5 (NLRC5). METHODS: The localization of circATXN7 in EC cells was determined by RNA fluorescent in situ hybridization (RNA-FISH). The mRNA levels of circATXN7, miR-4319, and NLRC5 were quantified by reverse transcription-polymerase chain reactions. The binding activity of circATXN7 to miR-4319 was assessed using RNA-binding protein immunoprecipitation. Whether circATXN7 regulates the proliferation of EC cells via miR-4319 was explored using dual-luciferase reporter gene colony formation assays. Protein levels were quantified by western blot. The effect of NLRC5 on the proliferation and invasion of EC cells was examined using colony formation and Transwell assays. A subcutaneous transplanted tumor nude mouse model was established to observe the effect of circATXN7 on the proliferation of EC cells in vivo. RESULTS: circATXN7 localized mainly to the cytoplasm. Overexpression or inhibition of miR-4319 significantly regulated the proliferation of EC cells, while circATXN7 competitively inhibited miR-4319 expression. Overexpression of miR-4319 significantly inhibited NLRC5 expression, indicating NLRC5 is a downstream regulatory target of miR-4319. circATXN7 influenced NLRC5 expression via miR-4319. In vivo tumor formation experiments in nude mice revealed that knocking down circATXN7 regulated NLRC5 expression via miR-4319 and significantly inhibited the proliferation of EC cells. CONCLUSIONS: In vitro cell and in vivo animal experiments showed that circATXN7 regulates the proliferation, invasion, and migration of EC cells through the miR-4319/NLRC5 signaling pathway.

ASB3 expression aggravates inflammatory bowel disease by targeting TRAF6 protein stability and affecting the intestinal microbiota.

E3 ubiquitin ligase (E3) plays a vital role in regulating inflammatory responses by mediating ubiquitination. Previous studies have shown that ankyrin repeat and SOCS box-containing protein 3 (ASB3) is involved in immunomodulatory functions associated with cancer. However, the impact of ASB3 on the dynamic interplay of microbiota and inflammatory responses in inflammatory bowel disease (IBD) is unclear. Here, we systematically identify the E3 ligase ASB3 as a facilitative regulator in the development and progression of IBD. We observed that ASB3 exhibited significant upregulation in the lesions of patients with IBD. ASB3-/- mice are resistant to dextran sodium sulfate-induced colitis. IκBα phosphorylation levels and production of proinflammatory factors IL-1ß, IL-6, and TNF-α were reduced in the colonic tissues of ASB3-/- mice compared to WT mice. This colitis-resistant phenotype was suppressed after coprophagic microbial transfer and reversed after combined antibiotics removed the gut commensal microbiome. Mechanistically, ASB3 specifically catalyzes K48-linked polyubiquitination of TRAF6 in intestinal epithelial cells. In contrast, in ASB3-deficient organoids, the integrity of the TRAF6 protein is shielded, consequently decelerating the onset of intestinal inflammation. ASB3 is associated with dysregulation of the colitis microbiota and promotes proinflammatory factors' production by disrupting TRAF6 stability. Strategies to limit the protein level of ASB3 in intestinal epithelial cells may help in the treatment of colitis. IMPORTANCE: Ubiquitination is a key process that controls protein stability. We determined the ubiquitination of TRAF6 by ASB3 in intestinal epithelial cells during colonic inflammation. Inflammatory bowel disease patients exhibit upregulated ASB3 expression at focal sites, supporting the involvement of degradation of TRAF6, which promotes TLR-Myd88/TRIF-independent NF-κB aberrant activation and intestinal microbiota imbalance. Sustained inflammatory signaling in intestinal epithelial cells and dysregulated protective probiotic immune responses mediated by ASB3 collectively contribute to the exacerbation of inflammatory bowel disease. These findings provide insights into the pathogenesis of inflammatory bowel disease and suggest a novel mechanism by which ASB3 increases the risk of colitis. Our results suggest that future inhibition of ASB3 in intestinal epithelial cells may be a novel clinical strategy.

Primary hyperaldosteronism associated with type 3 autoimmune polyendocrine syndrome: A rare case report.

Key Clinical Message: Primary hyperaldosteronism with type 3 autoimmune polyendocrine syndrome was a rare combination of both hyper- and hypoendocrine gland function. Comprehensive treatment including surgery and replacement therapy might be an effective strategy. Abstract: Primary aldosteronism (PA) is a common cause of secondary hypertension originating from hormones. Type 3 autoimmune polyendocrine syndrome (APS-3) is characterized by the simultaneous or subsequent occurrence of autoimmune-mediated endocrine gland damage, except for Addison disease. Here we reported an extremely rare case of a 63-year-old woman with PA and APS-3 who initially presented with hypertension (HT). The APS-3 of this patient mainly exhibited type 1 diabetes mellitus (T1DM) and Hashimoto's thyroiditis. She underwent the adrenal adenoma resection with a histopathologic diagnosis of adrenal cortical adenoma. After surgery, the HT of this patient was immediately reversed, and the concentration of serum potassium went back to normal. Then, this patient was administered with replacement therapy of insulin and levothyroxine sodium tablets (L-T4).

TSPAN4 influences glioblastoma progression through regulating EGFR stability.

Glioblastoma (GBM) is characterized by high morbidity, mortality, and low cure rates. Recent studies suggest that TSPAN4 is recognized as a marker protein for migrasomes, a vesicular organelle associated with cell migration. However, the intrinsic role of TSPAN4 in cancers has not been clarified, especially in GBM. Here, we report that TSPAN4 promotes GBM progression by interacting with epidermal growth factor receptor (EGFR) and regulating its stability. Clinically, TSPAN4 is highly expressed in GBM and is significantly correlated with poor prognosis. Functionally, TSPAN4 knockdown dramatically inhibits GBM cell proliferation and invasion in vitro, as well as tumorigenicity in vivo. Conversely, overexpression of TSPAN4 facilitates GBM progression. Mechanistically, TSPAN4 knockdown disrupts interaction with EGFR, destabilizing its expression and inactivating EGFR and downstream signaling pathways, such as MEK/ERK, STAT3, and AKT. Our study reveals that TSPAN4 drives GBM progression through regulating EGFR stability and could be a potential target for cancer therapy.

Effect of PR status on the prognosis of advanced ER-high HER2-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy.

BACKGROUND: This study was designed to evaluate the effect of progesterone receptor (PR) status on the prognosis of advanced estrogen receptor (ER)-high human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy. METHODS: Advanced ER-high HER2-negative breast cancer patients who were admitted to Harbin Medical University Cancer Hospital and received cyclin-dependent kinase (CDK)4/6 inhibitor combined with endocrine as first-line therapy were included for analysis. Patients were divided into PR-high group (11-100%), PR-low group (1-10%), and PR-negative group (< 1%) according to the expression of PR. Chi-square test was used to analyze the correlation of variables between groups. COX regression analysis were used to analyze the risk factors of survival. Kaplan-Meier survival curve was used to analyze the differences of progression-free survival (PFS) and overall survival (OS) between groups. RESULTS: Among the 152 patients, 72 were PR-high, 32 were PR-low, and 48 were PR-negative. Compared with PR-negative group, the proportions of disease-free survival (DFS) ≥ 5 years and Ki-67 index ≤ 30% in PR-low group and PR-high group were significant higher. PR-negative patients were more likely to occur first-line progression of disease within 24 months (POD24) than PR-high(P = 0.026). Univariate and multivariate analysis showed that PR-negative and first-line POD24 occurrence were risk factors for survival. Survival curve analysis showed that compared with PR-high group, the PFS and OS were significantly lower in PR-negative group (P = 0.001, P = 0.036, respectively). Patients with first-line POD24 had shorter OS in the overall population as well as in subgroups stratified by PR status. CONCLUSIONS: PR-negative and first-line POD24 occurrence were risk factors of advanced ER-high HER2-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy. PR-negative patients had shortest PFS and OS. Regardless of PR status, first-line POD24 occurrence predicted shorter OS.

Effects of Silicone Rubber on Rheological Properties and Aging Characteristics of Asphalt Binder.

Silicone rubber (SR) is a kind of polymer insulation material with excellent performance. With the service life of silicone rubber products reaching the limit, how to dispose of waste silicone rubber is an urgent problem to be solved. In this paper, silicone rubber-modified asphalt binder (SRMA) was prepared by SR and 90# base asphalt binder. The simulated short-term aging and long-term aging tests of SRMA were carried out using the thin film oven aging test (TFOT) and pressure aging vessel test (PAV). The rotary viscosity test and dynamic shear rheological test (DSR) were applied to the rheological properties of SRMA before and after aging. The degradation degree and chemical composition changes of SR were explored by the toluene insoluble matter test, Fourier transform infrared spectroscopy (FTIR), and a Fluorescence microscope (FM). The results demonstrate that SR can significantly affect the aging resistance, fatigue life, and high-temperature stability of SRMA. As the content of SR rose, the elastic component in SRMA increased, leading to a nice performance in stability at high temperatures and fatigue resistance. However, excessive content (14%wt and 16%wt) had a negative influence on the performance of SRMA. So, the optimal content was speculated to be between 12% and 14%. Furthermore, SR and asphalt binder would be aged and degraded together in the aging process, and this phenomenon was more obvious during long-term aging.

Monovalent, bivalent and biparatopic nanobodies targeting S1 protein of porcine epidemic diarrhea virus efficiently neutralized the virus infectivity.

BACKGROUND: Porcine epidemic diarrhea virus (PEDV) is a highly contagious coronavirus that causes severe diarrhea and death in neonatal piglets, which has brought huge economic losses to the pork industry worldwide since its first discovery in the early 1970s in Europe. Passive immunization with neutralizing antibodies against PEDV is an effective prevention measure. To date, there are no effective therapeutic drugs to treat the PEDV infection. RESULTS: We conducted a screening of specific nanobodies against the S1 protein from a phage display library obtained from immunized alpacas. Through competitive binding to antigenic epitopes, we selected instead of chose nanobodies with high affinity and constructed a multivalent tandem. These nanobodies were shown to inhibit PEDV infectivity by the neutralization assay. The antiviral capacity of nanobody was found to display a dose-dependent pattern, as demonstrated by IFA, TCID50, and qRT-PCR analyses. Notably, biparatopic nanobody SF-B exhibited superior antiviral activity. Nanobodies exhibited low cytotoxicity and high stability even under harsh temperature and pH conditions, demonstrating their potential practical applicability to animals. CONCLUSIONS: Nanobodies exhibit remarkable biological properties and antiviral effects, rendering them a promising candidate for the development of anti-PEDV drugs.

RNF8-mediated multi-ubiquitination of MCM7: Linking disassembly of the CMG helicase with DNA damage response in human cells.

DNA damage causes genomic instability. To maintain genome integrity, cells have evolved DNA damage response, which is involved in replication fork disassembly and DNA replication termination. However, the mechanism underlying the regulation of replication fork disassembly and its connection with DNA damage repair remain elusive. The CMG-MCM7 subunit ubiquitination functions on the eukaryotic replication fork disassembly at replication termination. Until now, only ubiquitin ligases CUL2LRR1 have been reported catalyzing MCM7 ubiquitination in human cells. This study discovered that in human cells, the ubiquitin ligase RNF8 catalyzes K63-linked multi-ubiquitination of MCM7 at K145 both in vivo and in vitro. The multi-ubiquitination of MCM7 is dynamically regulated during the cell cycle, primarily presenting on chromatin during the late S phase. Additionally, MCM7 polyubiquitylation is promoted by RNF168 and BRCA1 during DNA replication termination. Upon DNA damage, the RNF8-mediated polyubiquitination of MCM7 decreased significantly during the late S phase. This study highlights the novel role of RNF8-catalyzed polyubiquitination of MCM7 in the regulation of replication fork disassembly in human cells and linking it to DNA damage response.

Trans-complementation of the viral movement protein mediates efficient expression of large target genes via a tobacco mosaic virus vector.

The development of plant virus-based expression systems has expanded rapidly owing to their potential applications in gene functional and disease resistance research, and industrial production of pharmaceutical proteins. However, the low yield of certain proteins, especially high-molecular-mass proteins, restricts the production scale. In this study, we observed that the tobacco mosaic virus (TMV)-mediated expression of a foreign protein was correlated with the amount of the movement protein (MP) and developed a TMV-derived pAT-transMP vector system incorporating trans-complementation expression of MP. The system is capable of efficient expression of exogenous proteins, in particular those with a high molecular mass, and enables simultaneous expression of two target molecules. Furthermore, viral expression of competent CRISPR-Cas9 protein and construction of CRISPR-Cas9-mediated gene-editing system in a single pAT-transMP construct was achieved. The results demonstrated a novel role for TMV-MP in enhancing the accumulation of a foreign protein produced from the viral vector or a binary expression system. Further investigation of the mechanism underlying this role will be beneficial for optimization of plant viral vectors with broad applications.

Fc-Fc interactions and immune inhibitory effects of IgG4: implications for anti-PD-1 immunotherapies.

BACKGROUND: The majority of anti-programmed cell-death 1 (PD-1) monoclonal antibodies (mAbs) use S228P mutation IgG4 as the structural basis to avoid the activation of immune cells or complement. However, little attention has been paid to the Fc-Fc interactions between IgG4 and other IgG Fc fragments that could result in adverse effects. Fc-null IgG1 framework is a potential safer alternative to avoid the undesirable Fc-Fc interactions and Fc receptor binding derived effects observed with IgG4. This study provides a comprehensive evaluation of anti-PD-1 mAbs of these two frameworks. METHODS: Trastuzumab and rituximab (both IgG1), wildtype IgG1 and IgG4 were immobilized on nitrocellulose membranes, coated to microplates and biosensor chips, and bound to tumor cells as targets for Fc-Fc interactions. Wildtype IgG1 and IgG4, anti-PD-1 mAb nivolumab (IgG4 S228P), penpulimab (Fc-null IgG1), and tislelizumab (Fc-null IgG4 S228P-R409K) were assessed for their binding reactions to the immobilized IgG proteins and quantitative kinetic data were obtained. To evaluate the effects of the two anti-PD-1 mAbs on immune responses mediated by trastuzumab and rituximab in the context of combination therapy, we employed classic immune models for antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement dependent cytotoxicity. Tumor-bearing mouse models, both wildtype and humanized, were used for in vivo investigation. Furthermore, we also examined the effects of IgG1 and IgG4 on diverse immune cell populations RESULTS: Experiments demonstrated that wildtype IgG4 and nivolumab bound to immobilized IgG through Fc-Fc interactions, diminishing antibody-dependent cell-mediated cytotoxicity and phagocytosis reactions. Quantitative analysis of kinetic parameters suggests that nivolumab and wildtype IgG4 exhibit comparable binding affinities to immobilized IgG1 in both non-denatured and denatured states. IgG4 exerted inhibitory effects on various immune cell types. Wildtype IgG4 and nivolumab both promoted tumor growth in wildtype mouse models. Conversely, wildtype IgG1, penpulimab, and tislelizumab did not show similar adverse effects. CONCLUSIONS: Fc-null IgG1 represents a safer choice for anti-PD-1 immunotherapies by avoiding both the adverse Fc-Fc interactions and Fc-related immune inhibitory effects of IgG4. Fc-null IgG4 S228P-R409K and Fc-null IgG1 displayed similar structural properties and benefits. This study contributes to the understanding of immunotherapy resistance and the advancement of safer immune therapies for cancer.

Fullerenols Ameliorate Social Deficiency and Rescue Cognitive Dysfunction of BTBR T+Itpr3tf/J Autistic-Like Mice.

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a type of carbon nanomaterial known for its neuroprotective properties, have not yet been studied for their potential in treating ASD. We aimed to investigate its role in improving autistic behaviors in BTBR T+Itpr3tf/J (BTBR) mice and its underlying mechanism, which could provide reliable clues for future ASD treatments. Methods: Our research involved treating C57BL/6J (C57) and BTBR mice with either 0.9% NaCl or fullerenols (10 mg/kg) daily for one week at seven weeks of age. We then conducted ASD-related behavioral tests in the eighth week and used RNA-seq to screen for vital pathways in the mouse hippocampus. Additionally, we used real-time quantitative PCR (RT-qPCR) to verify related pathway genes and evaluated the number of stem cells in the hippocampal dentate gyrus (DG) by Immunofluorescence staining. Results: Our findings revealed that fullerenols treatment significantly improved the related ASD-like behaviors of BTBR mice, manifested by enhanced social ability and improved cognitive deficits. Immunofluorescence results showed that fullerenols treatment increased the number of DCX+ and SOX2+/GFAP+ cells in the DG region of BTBR mice, indicating an expanded neural progenitor cell (NPC) pool of BTBR mice. RNA-seq analysis of the mouse hippocampus showed that VEGFA was involved in the rescued hippocampal neurogenesis by fullerenols treatment. Conclusion: In conclusion, our findings suggest that fullerenols treatment improves ASD-like behavior in BTBR mice by upregulating VEGFA, making nanoparticle- fullerenols a promising drug for ASD treatment.

Research on the pharmacognostic characteristics, physicochemical properties and in vitro antioxidant potency of Rosa laxa Retz. flos.

Rosa laxa Retz. is an unexplored Rosaceae plant in Xinjiang, China, and its flower is traditionally used in Kazak to treat the common cold, fever, and epileptic seizures and lessen the effects of aging. In the present study, the pharmacognostic profiles, physicochemical properties, phytochemical characteristics, and in vitro antioxidant potency of Rosa laxa Retz. flos (RLF) were presented. In the pharmacognostic evaluation of RLF, organoleptic characteristics, internal structures, and powder information were observed, and physicochemical parameters, including moisture content, ash, pH value, swelling degree, and extractives were examined. The quantitative analysis of the chemical composition of four different polar extracts of RLF showed that the aqueous part had the highest total triterpene acid, flavonoid, and polyphenol content (4.50 ± 0.04 mg/g, 50.56 ± 0.03 mg/g, and 60.20 ± 0.09 mg/g, respectively). A high-performance liquid chromatography (HPLC)-diode array detector (DAD) method was established and the contents of gallic acid, ellagic acid, astragalin, and tiliroside in RLF were determined simultaneously. In the set concentration range, the linear relationship among the four components was good (r > 0.999), the average recoveries were 97.36%-100.54%. The contents of gallic acid, ellagic acid, astragalin, and tiliroside in RLF samples were (9.46 ± 2.31) mg/g, (10.60 ±0.75) mg/g, (1.13 ± 2.50) mg/g, and (1.11 ± 2.65) mg/g, respectively. The types of its secondary metabolites were determined by fluorescence, color reaction by chemical solvent method, and ultraviolet-visible (UV-Vis) spectroscopy. The functional groups of its secondary metabolites were determined by Fourier transform infrared (FTIR) spectroscopy. Results showed that RLF contains a variety of secondary metabolic products, including flavonoids, phenolic acid, glycoside, and organic acid. TLC identification showed it contains ursolic acid, ß-sitosterol, tiliroside, astragalin, isoquercitrin, kaempferol-3-O-rutinoside, gallic acid, and ellagic acid. The in vitro antioxidant activity of different polar parts of RLF was investigated by DPPH, ABTS, and reduction performance experiments. The aqueous extract had the strongest antioxidant capacity, consistent with the high content of triterpene acids, flavonoids, and polyphenolic compounds. These findings will provide critical information for the study of quality standards and medicinal value of RLF and its extracts, justify its usage in traditional medicinal systems, and encourage the use of this plant in disease prevention and treatment. Its phytochemical composition and pharmacological studies need to be explored in future. RESEARCH HIGHLIGHTS: Optical microscope and scanning electron microscope (SEM) were used to observe the morphology, and microstructure of Rosa laxa Retz. flos (RLF). The physicochemical properties, fluorescence and phytochemical composition of four different polar extracts of RLF were analyzed by UV-Vis and FTIR. Determination of total triterpenic acid, total flavonoids, and total polyphenols in four different polar extracts of RLF by UV spectrophotometry. A high-performance liquid chromatography (HPLC)-diode array detector (DAD) method was established and the contents of gallic acid, ellagic acid, astragalin, and tiliroside in RLF were determined simultaneously. TLC confirmed that RLF contains ursolic acid, ß-sitosterol, tiliroside, astragalin, isoquercitrin, kaempferol 3-rutinoside, gallic acid, and ellagic acid. The in vitro antioxidant activity of RLF was studied by DPPH, ABTS, and reducing ability experiments.

Computational Investigation of Coaggregation and Cross-Seeding between Aß and hIAPP Underpinning the Cross-Talk in Alzheimer's Disease and Type 2 Diabetes.

The coexistence of amyloid-ß (Aß) and human islet amyloid polypeptide (hIAPP) in the brain and pancreas is associated with an increased risk of Alzheimer's disease (AD) and type 2 diabetes (T2D) due to their coaggregation and cross-seeding. Despite this, the molecular mechanisms underlying their interaction remain elusive. Here, we systematically investigated the cross-talk between Aß and hIAPP using atomistic discrete molecular dynamics (DMD) simulations. Our results revealed that the amyloidogenic core regions of both Aß (Aß10-21 and Aß30-41) and hIAPP (hIAPP8-20 and hIAPP22-29), driving their self-aggregation, also exhibited a strong tendency for cross-interaction. This propensity led to the formation of ß-sheet-rich heterocomplexes, including potentially toxic ß-barrel oligomers. The formation of Aß and hIAPP heteroaggregates did not impede the recruitment of additional peptides to grow into larger aggregates. Our cross-seeding simulations demonstrated that both Aß and hIAPP fibrils could mutually act as seeds, assisting each other's monomers in converting into ß-sheets at the exposed fibril elongation ends. The amyloidogenic core regions of Aß and hIAPP, in both oligomeric and fibrillar states, exhibited the ability to recruit isolated peptides, thereby extending the ß-sheet edges, with limited sensitivity to the amino acid sequence. These findings suggest that targeting these regions by capping them with amyloid-resistant peptide drugs may hold potential as a therapeutic approach for addressing AD, T2D, and their copathologies.

Successful management of a multiple endocrine neoplasia type 1-associated thymic neuroendocrine neoplasms with acute chest pain as initial symptom: A rare case report.

Key Clinical Message: Acute chest pain can be the first manifestation of multiple endocrine neoplasia type 1(MEN1)-associated thymic neuroendocrine neoplasms (NEN). Comprehensive treatment may be an effective strategy for MEN1-associated NEN. Abstract: Multiple endocrine neoplasia type 1(MEN1)-associated thymic neuroendocrine neoplasms (NEN) is caused by the mutation of tumor suppressor MEN1 gene. Patients with MEN1-associated NEN initially presenting with acute chest pain are very rare. In the manuscript, we reported a case of a 45-year-old man who developed MEN1-associated NEN with acute chest pain as initial symptom. Thoracoscopic thymotomy was performed and thymic NEN was successfully removed. Genetic test showed a germline mutation of MEN1 gene in this patient. Immunohistochemical staining exhibited Syn(+), CgA(+), INSM1(+), CD56(+) and Ki67-positive cells (2%) in MEN1-associated NEN. Further evaluation unveiled MEN1-associated benign tumors including digestive NEN and pituitary gland adenoma. The 99mTc-HYNIC-TOC scintigraphy showed that focally increased radioactivity in the mid-upper abdomen. This patient was administered with 50Gy/25F of radiation dose to treat the postoperative lesions. Subsequently, sandostatin LAR (30 mg per week) was used as systemic therapy. He had no recurrence or metastasis for 6-month follow-up. Thus, acute chest pain can be the first manifestation of MEN1-associated NEN, and comprehensive treatment including surgery, radiation and systemic treatment may be an effective strategy for MEN1-associated NEN.

Formation of compounds with diverse polyelectrolyte morphologies and nonlinear ion conductance in a two-dimensional nanofluidic channel.

Aqueous electrolytes subjected to angstrom-scale confinement have recently attracted increasing interest because of their distinctive structural and transport properties, as well as their promising applicability in bioinspired nanofluidic iontronics and ion batteries. Here, we performed microsecond-scale molecular dynamics simulations, which provided evidence of nonlinear ionic conductance under an external lateral electric field due to the self-assembly of cations and anions with diverse polyelectrolyte morphologies (e.g., extremely large ion clusters) in aqueous solutions within angstrom-scale slits. Specifically, we found that the cations and anions of Li2SO4 and CaSO4 formed chain-like polyelectrolyte structures, whereas those of Na2SO4 and MgSO4 predominantly formed a monolayer of hydrated salt. Additionally, the cations and anions of K2SO4 assembled into a hexagonal anhydrous ionic crystal. These ion-dependent diverse polyelectrolyte morphologies stemmed from the enhanced Coulomb interactions, weakened hydration and steric constraints within the angstrom-scale slits. More importantly, once the monolayer hydrated salt or ionic crystal structure was formed, the field-induced ion current exhibited an intriguing gating effect at a low field strength. This abnormal ion transport was attributed to the concerted movement of cations and anions within the solid polyelectrolytes, leading to the suppression of ion currents. When the electric field exceeded a critical strength, however, the ion current surged rapidly due to the dissolution of many cations and anions within a few nanoseconds in the aqueous solution.

Study on load transfer mechanisms and impact on adjacent railway subgrade within loess regions.

Clarifying load transfer mechanism and the influence of the widening of a newly-built railway is the premise for the construction of adjacent project in loess region. This paper uses monitoring datas obtained from three sections in different stages to analyze the distribution laws of load exert on piles and soil between piles, investigates the variation laws of filling height on the earth pressure at different excavation steps and elucidates the influence of the filling height of newly built subgrade on the existing subgrade. In addition, a fitting formula y = a(1-e-bx) + cx is proposed to describe the relationship between the ratio of the additional displacement to the filling height, which is applicable for similar projects.

Comparison of the pregnancy outcomes of progestin-primed vs. antagonist ovarian stimulation in patients with poor ovarian response: a retrospective study.

OBJECTIVES: Progestin-primed ovarian stimulation (PPOS) is an efficient controlled ovarian stimulation (COS) method. The study explored the pregnancy outcomes between PPOS and antagonist ovarian stimulation protocol (GnRH-ant) in infertile patients with poor ovarian response (POR). METHODS: This retrospective study included patients with POR who underwent COS at the Reproductive Medical Center of Shanxi Maternal and Child Health Hospital from January 2021 to April 2022. The cycles were grouped as the GnRH-ant group and the PPOS group. The primary outcome was the clinical pregnancy rate; the secondary outcomes included the biochemical pregnancy abortion rate and live birth rate. RESULTS: Frozen embryo transfer was used in all cycles in this study. The cycles were divided into the GnRH-ant (n = 236 cycles) and PPOS (n = 273 cycles) groups. Age, BMI, type of infertility, infertility duration, FSH, LH, PRL, E2, T, P, and the number of cycles in the hospital were similar between the two groups (all p > 0.05). No statistically significant differences were observed in the clinical pregnancy rate (primary outcome, 32.71% vs. 43.90%, p = 0.082), total Gn dose, total Gn days, ART mode (IVF or ICSI), AFC, MII follicles, 2PN embryos, fertility, cycle cancelation rate, biochemical pregnancy rate, abortion rate, or live birth rate between the two groups (all p > 0.05). The PPOS group exhibited a higher rate of high-quality embryos than the GnRH-ant group (50.12% vs. 42.90%, p = 0.045). CONCLUSIONS: The PPOS protocol was comparable to the GnRH-ant protocol regarding induction parameters and cycle cancelation, biochemical pregnancy, clinical pregnancy, and abortion rates but might be associated with a higher proportion of high-quality embryos.