Fasudil in Combination With Bone Marrow Stromal Cells (BMSCs) Attenuates Alzheimer\u27s Disease-Related Changes Through the Regulation of the Peripheral Immune System.

Alzheimer\u27s disease (AD) is a chronic progressive neurodegenerative disease. Its mechanism is still not clear. Majority of research focused on the central nervous system (CNS) changes, while few studies emphasize on peripheral immune system modulation. Our study aimed to investigate the regulation of the peripheral immune system and its relationship to the severity of the disease after treatment in an AD model of APPswe/PSEN1dE9 transgenic (APP/PS1 Tg) mice. APP/PS1 Tg mice (8 months old) were treated with the ROCK-II inhibitor 1-(5-isoquinolinesulfonyl)-homo-piperazine (Fasudil) (intraperitoneal (i.p.) injections, 25 mg/kg/day), bone marrow stromal cells (BMSCs; caudal vein injections, 1 × 1

RNA-Puzzles Round IV:3D structure predictions of four ribozymes and two aptamers

International audienceRNA-Puzzles is a collective endeavor dedicated to the advancement and improvement of RNA 3D structure prediction. With agreement from crystallographers, the RNA structures are predicted by various groups before the publication of the crystal structures. We now report the prediction of 3D structures for six RNA sequences: four nucleolytic ribozymes and two riboswitches. Systematic protocols for comparing models and crystal structures are described and analyzed. In these six puzzles, we discuss (i) the comparison between the automated web servers and human experts; (ii) the prediction of coaxial stacking; (iii) the prediction of structural details and ligand binding; (iv) the development of novel prediction methods; and (v) the potential improvements to be made. We show that correct prediction of coaxial stacking and tertiary contacts is essential for the prediction of RNA architecture, while ligand binding modes can only be predicted with low resolution and simultaneous prediction of RNA structure with accurate ligand binding still remains out of reach. All the predicted models are available for the future development of force field parameters and the improvement of comparison and assessment tools

Risk factors for extraurothelial recurrence in upper tract urothelial carcinoma after radical nephroureterectomy: a retrospective study based on a Chinese population

ObjectivesThe risk factors for extraurothelial recurrence (EUR) after radical nephroureterectomy (RNU) in patients with upper urinary tract urothelial carcinoma (UTUC) are currently inconsistent and unclear. In this study, we aimed to identify these risk factors and develop a grading system for EUR.MethodsWe retrospectively analyzed 220 patients who underwent RNU for UTUC in our center from January 2009 to December 2020. Overall survival (OS) and extraurothelial recurrence-free survival (EURFS) were compared using the Kaplan–Meier curve with a log-rank test. Univariate and multivariate Cox regression models were applied to identify the independent risk factors related to EUR.ResultsThe median follow-up period was 42 (range: 2–143) months. Of the 220 patients, 61 patients developed EUR in our cohort, which had worse survival outcome. Multivariate Cox regression analysis showed pathologic stage, lymph node (LN) status, lymphovascular invasion (LVI), Ki-67, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were independent risk factors for EUR. The Kaplan–Meier curves revealed a significant difference in EUR among the three risk groups.ConclusionOur study suggests that pathologic stage, LN status, LVI, Ki-67, NLR, and PLR are independent risk factors for EUR in UTUC patients after RNU. The development of a grading system for EUR risk stratification may assist urologists in making clinical decisions regarding the management of UTUC

AMPK activation by hepatitis E virus infection inhibits viral replication through attenuation of autophagosomes and promotion of innate immunity

Hepatitis E virus (HEV) infection is generally asymptomatic or leads to acute and self-limiting hepatitis. The mechanisms orchestrating such an infection course remain to be elucidated. AMP-activated protein kinase (AMPK) is a pivotal cellular sensor for maintaining metabolic homeostasis. Here, we show that AMPK is activated in response to HEV infection and is associated with mitochondrial damage and ATP deficiency. AMPK activation, in turn, inhibits HEV replication. Mechanistic studies reveal that AMPK activation triggers the expression of interferon (IFN)-stimulated genes that possess antiviral properties. In parallel, AMPK inhibits autophagosome accumulation to exert antiviral effects. Interestingly, AMPK activation also suppresses the inflammatory response triggered by HEV infection. Consistently, AMPK activation simultaneously exerts anti-inflammatory and antiviral effects in a coculture system of HEV-infected liver cells with macrophages. These findings pave the way for the development of AMPK-targeted therapeutics to treat hepatitis E.</p

Global trends of 131I-therapy for differentiated thyroid cancer in children and adolescents: a bibliometric analysis (1993-2003)

This study aimed to delineate the characteristics and trends of scholarly publications within the domain of 131I-therapy for differentiated thyroid cancer in children and adolescents (caDTC) through a bibliometric approach. A retrieval of publications concerning 131I-therapy for caDTC from the Web of Science Core Collection (WoSCC) database was conducted, spanning from January 1993 to December 2023. Visualization analysis was performed utilizing VOSviewer 1.6.20 and CiteSpace 6.2.R6 software. A total of 150 English publications, including articles and reviews, were analyzed in this study, with the earliest work traced back to 1994. A fluctuating yet overall ascending trend in annual publication volume was observed over the three decades, with a slight recent downturn post 2020. The United States, Italy and China emerged as the most prolific contributors. International network mapping revealed robust collaboration predominantly between European and American entities. Journals featuring predominantly in this field were primarily categorized under endocrinology, metabolism or pediatrics, with Thyroid and Journal of Clinical Endocrinology &#x00026; Metabolism recognized as highly influential. The "Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer", published in 2015, was the most frequently cited document. A total of 869 scholars published literature in this field, with high-producing scholars mainly coming from Europe and the United States. Huang Rui from China was ranked among the top ten. References and keywords clustering illuminated focal points of research such as “metastasis”, “fusion oncogene”, and “late effects”. The timelines viewer of keywords underscored enduring interest in “131I”, complimented by significant terms like “management guidelines”, “2nd primary malignancy”, and “term follow up”, encompassing standardization, efficacy, and surveillance of adverse events in 131I-therapy for caDTC. The 131I-therapy research for caDTC is largely steered by European and American efforts. China’s substantial patient demographic is positioned to enhance both domestic and international collaborative research. The current paucity of clinical standardization in 131I-therapy for caDTC needs to be addressed. Future endeavors should be scrutinizing the short and long-term efficacy of 131I-therapy of caDTC, probing into the relationship between molecular profiles such as RET fusion and the therapeutic effectiveness of 131I-therapy, and pinpointiing efficacious biomarkers for 131I-resistance, which are pivotal for informed decision-making in the therapeutic application of 131I-therapy for caDTC

Macrophage Membrane-Coated, Nanostructured Adsorbent Surfaces in a microfluidic Device for Extracorporeal Blood Cleansing in Bacterially Induced Sepsis

Sepsis is a dysregulated host response to infection that can lead to life-threatening organ failure. Circulating bacterial toxins, termed pathogen-associated molecular patterns (PAMPs), and excess cytokines produced by the immune system play a key role in the response that can progress into organ failure. Yet, no therapy is available to effectively remove these PAMPs and cytokines from the circulation or effectively block their action. Macrophage membrane coatings possess a natural blood compatibility, ideal for coating of adsorbent surfaces in extracorporeal blood-cleansing. Here, the ability of Escherichia coli-activated macrophage membrane coatings on silicon nanowired (SiNW) surfaces in a microfluidic device to remove PAMPs and cytokines from blood is determined. In vitro, such membrane-coated SiNW adsorbent surfaces remove significantly more PAMPS or cytokines from spiked human blood than achieved by hemofiltration. Cleansing of plasma from patients with bacterial sepsis using membrane-coated SiNW adsorbent surfaces reduces cytokine concentrations to healthy levels. In vivo, this coincides with two-fold better restoration of healthy cytokine levels after 4 h of extracorporeal blood-cleansing in rats with lipopolysaccharides (LPS)-induced sepsis and four-fold higher survival rates. Collectively, blood-cleansing microfluidic devices using bacterially activate macrophage membrane-coated SiNW surfaces are more effective than hemofiltration for therapeutic intervention in septic patients

Fasudil in Combination With Bone Marrow Stromal Cells (BMSCs) Attenuates Alzheimer’s Disease-Related Changes Through the Regulation of the Peripheral Immune System

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease. Its mechanism is still not clear. Majority of research focused on the central nervous system (CNS) changes, while few studies emphasize on peripheral immune system modulation. Our study aimed to investigate the regulation of the peripheral immune system and its relationship to the severity of the disease after treatment in an AD model of APPswe/PSEN1dE9 transgenic (APP/PS1 Tg) mice. APP/PS1 Tg mice (8 months old) were treated with the ROCK-II inhibitor 1-(5-isoquinolinesulfonyl)- homo-piperazine (Fasudil) (intraperitoneal (i.p.) injections, 25 mg/kg/day), bone marrow stromal cells (BMSCs; caudal vein injections, 1 × 106 BMSCs /time/mouse), Fasudil combined with BMSCs, or saline (i.p., control) for 2 months. Morris water maze (MWM) test was used to evaluate learning and memory. The mononuclear cells (MNCs) of spleens of APP/PS1 Tg mice were analyzed using flow cytometry for CD4+ T-cells, macrophages, and the pro-inflammatory and anti-inflammatory molecules of the macrophages. Immunohistochemical staining was used to examine the expression of ROCK-II in the spleens of APP/PS1 Tg mice. The MWM test showed improved spatial learning ability in APP/PS1 Tg mice treated with Fasudil or BMSCs alone or in combination, compared to untreated APP/PS1 Tg mice. Fasudil combined with BMSCs intervention significantly promoted the proliferation of CD4+/CD25+ and CD4+/ IL-10 lymphocytes, induced the release of cytokine factors, and regulated the balance of the immune system to work functionally. It also shifted M1 (MHC-II, CD86) to M2 (IL-10, CD206) phenotype of macrophages of CD11b and significantly enhanced the anti-inflammatory and phagocytic abilities (CD16/32) of macrophages of CD11b. Immunohistochemical staining showed significantly decreased expression of ROCK-II in mice treated with combination of Fasudil with BMSCs as compared to saline control. Fasudil in combination of BMSCs improved cognition of APP/PS1 Tg mice through the regulation of the peripheral immune system, including reduction of ROCK-II expression and increased proportion of anti-inflammatory M2 mononuclear phenotype and phagocytic macrophages in the spleen of the peripheral immune system. The latter was achieved through the communication between brain and spleen to improve the immunoregulation of CNS and AD disease conditions

Improving the early diagnosis of suspected patients with COVID-19: a retrospective study of 106 patients

Introduction: An outbreak of coronavirus disease 2019 (COVID-19) occurred in Wuhan, Hubei Province, China. This study aimed to analyze the clinical and epidemiologic characteristics of patients with COVID-19 to better differentiate the suspected patients in Beijing, China. Methodology: This was a retrospective, single-center study. Clinical and epidemiologic data were collected from suspected patients with COVID-19 admitted to Beijing Ditan Hospital from January 29 to February 21, 2020. Results: One hundred and six patients (60 males and 46 females, median age 36 years) were enrolled. Thirty-six patients were ultimately laboratory confirmed. Fifty-three were excluded from the diagnosis of COVID-19. The remaining 17 patients were highly suspected, although their nucleic acid tests were repeatedly negative. The confirmed patients and highly suspected patients had a significantly higher proportion of epidemiologic history than the excluded patients (P < 0.001). There was no significant difference in clinical symptoms or the underlying diseases among the three groups. The confirmed patients had a higher frequency of lymphopenia and eosinopenia than the highly suspected and excluded patients. Chest computed tomography scans showed bilateral lung involvement, and ground-glass opacity was more likely observed in the confirmed patients. Conclusion: The clinical features of the confirmed patients with COVID-19 were insufficient for early diagnosis of COVID-19. The epidemiologic history was of great significance in the early diagnosis of COVID-19. More sensitive diagnostic methods are needed to aid the differential diagnosis of suspected patients with COVID-19

Fasudil in Combination With Bone Marrow Stromal Cells (BMSCs) Attenuates Alzheimer’s Disease-Related Changes Through the Regulation of the Peripheral Immune System

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease. Its mechanism is still not clear. Majority of research focused on the central nervous system (CNS) changes, while few studies emphasize on peripheral immune system modulation. Our study aimed to investigate the regulation of the peripheral immune system and its relationship to the severity of the disease after treatment in an AD model of APPswe/PSEN1dE9 transgenic (APP/PS1 Tg) mice. APP/PS1 Tg mice (8 months old) were treated with the ROCK-II inhibitor 1-(5-isoquinolinesulfonyl)-homo-piperazine (Fasudil) (intraperitoneal (i.p.) injections, 25 mg/kg/day), bone marrow stromal cells (BMSCs; caudal vein injections, 1 × 106 BMSCs /time/mouse), Fasudil combined with BMSCs, or saline (i.p., control) for 2 months. Morris water maze (MWM) test was used to evaluate learning and memory. The mononuclear cells (MNCs) of spleens of APP/PS1 Tg mice were analyzed using flow cytometry for CD4+ T-cells, macrophages, and the pro-inflammatory and anti-inflammatory molecules of the macrophages. Immunohistochemical staining was used to examine the expression of ROCK-II in the spleens of APP/PS1 Tg mice. The MWM test showed improved spatial learning ability in APP/PS1 Tg mice treated with Fasudil or BMSCs alone or in combination, compared to untreated APP/PS1 Tg mice. Fasudil combined with BMSCs intervention significantly promoted the proliferation of CD4+/CD25+ and CD4+/ IL-10 lymphocytes, induced the release of cytokine factors, and regulated the balance of the immune system to work functionally. It also shifted M1 (MHC-II, CD86) to M2 (IL-10, CD206) phenotype of macrophages of CD11b and significantly enhanced the anti-inflammatory and phagocytic abilities (CD16/32) of macrophages of CD11b. Immunohistochemical staining showed significantly decreased expression of ROCK-II in mice treated with combination of Fasudil with BMSCs as compared to saline control. Fasudil in combination of BMSCs improved cognition of APP/PS1 Tg mice through the regulation of the peripheral immune system, including reduction of ROCK-II expression and increased proportion of anti-inflammatory M2 mononuclear phenotype and phagocytic macrophages in the spleen of the peripheral immune system. The latter was achieved through the communication between brain and spleen to improve the immunoregulation of CNS and AD disease conditions