Clinical outcomes of endoscopic resection for the treatment of intermediate- or high-risk gastric small gastrointestinal stromal tumors: a multicenter retrospective study.

BACKGROUND AND AIMS: Many studies of gastric gastrointestinal stromal tumors (g-GISTs) following endoscopic resection (ER) have typically focused on tumor size, with most tumors at low risk of aggressiveness after risk stratification. There have been few systematic studies on the oncologic outcomes of intermediate- or high-risk g-GISTs after ER. METHODS: From January 2014 to January 2020, we retrospectively collected patients considered at intermediate- or high-risk of g-GISTs according to the modified NIH consensus classification system. The primary outcome was overall survival (OS). RESULTS: Six hundred and seventy nine (679) consecutive patients were diagnosed with g-GISTs and treated by ER between January 2014 and January 2020 in three hospitals in Shanghai, China. 43 patients (20 males and 23 females) were confirmed at intermediate-or high-risk. The mean size of tumors was 2.23 ± 1.01 cm. The median follow-up period was 62.02 ± 15.34 months, with a range of 28 to 105 months. There were no recurrences or metastases, even among patients having R1 resections. The 5-year OS rate was 97.4% (42/43). CONCLUSION: ER for intermediate- or high-risk gastric small GISTs is a feasible and safe method, which allows for a wait-and-see approach before determining the necessity for imatinib adjuvant or surgical treatment. This approach to g-GISTs does require that patients undergo close follow-up.

Effect of Polymorphism on the Sorption Properties of a Flexible Square-Lattice Topology Coordination Network.

The stimulus-responsive behavior of coordination networks (CNs), which switch between closed (nonporous) and open (porous) phases, is of interest because of its potential utility in gas storage and separation. Herein, we report two polymorphs of a new square-lattice (sql) topology CN, X-sql-1-Cu, of formula [Cu(Imibz)2]n (HImibz = {[4-(1H-imidazol-1-yl)phenylimino]methyl}benzoic acid), isolated from the as-synthesized CN X-sql-1-Cu-(MeOH)2·2MeOH, which subsequently transformed to a narrow pore solvate, X-sql-1-Cu-A·MeOH, upon mild activation (drying in air or heating at 333 K under nitrogen). X-sql-1-Cu-A·MeOH contains MeOH in cavities, which was removed through exposure to vacuum for 2 h, yielding the nonporous (closed) phase X-sql-1-Cu-A. In contrast, a more dense polymorph, X-sql-1-Cu-B, was obtained by exposing X-sql-1-Cu-(MeOH)2·2MeOH directly to vacuum for 2 h. Gas sorption studies conducted on X-sql-1-Cu-A and X-sql-1-Cu-B revealed different switching behaviors to two open phases (X-sql-1-Cu·CO2 and X-sql-1-Cu·C2H2), with different gate-opening threshold pressures for CO2 at 195 K and C2H2 at 278 K. Coincident CO2 sorption and in situ powder X-ray diffraction studies at 195 K revealed that X-sql-1-Cu-A transformed to X-sql-1-Cu-B after the first sorption cycle and that the CO2-induced switching transformation was thereafter reversible. The results presented herein provide insights into the relationship between two polymorphs of a CN and the effect of polymorphism upon gas sorption properties. To the best of our knowledge, whereas sql networks such as X-sql-1-Cu are widely studied in terms of their structural and sorption properties, this study represents only the second example of an in-depth study of the sorption properties of polymorphic sql networks.

Garlic oil supplementation blocks inflammatory pyroptosis-related acute lung injury by suppressing the NF-κB/NLRP3 signaling pathway via H2S generation.

Acute lung injury (ALI) is a major cause of acute respiratory failure with a high morbidity and mortality rate, and effective therapeutic strategies for ALI remain limited. Inflammatory response is considered crucial for the pathogenesis of ALI. Garlic, a globally used cooking spice, reportedly exhibits excellent anti-inflammatory bioactivity. However, protective effects of garlic against ALI have never been reported. This study aimed to investigate the protective effects of garlic oil (GO) supplementation on lipopolysaccharide (LPS)-induced ALI models. Hematoxylin and eosin staining, pathology scores, lung myeloperoxidase (MPO) activity measurement, lung wet/dry (W/D) ratio detection, and bronchoalveolar lavage fluid (BALF) analysis were performed to investigate ALI histopathology. Real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were conducted to evaluate the expression levels of inflammatory factors, nuclear factor-κB (NF-κB), NLRP3, pyroptosis-related proteins, and H2S-producing enzymes. GO attenuated LPS-induced pulmonary pathological changes, lung W/D ratio, MPO activity, and inflammatory cytokines in the lungs and BALF. Additionally, GO suppressed LPS-induced NF-κB activation, NLRP3 inflammasome expression, and inflammatory-related pyroptosis. Mechanistically, GO promoted increased H2S production in lung tissues by enhancing the conversion of GO-rich polysulfide compounds or by increasing the expression of H2S-producing enzymes in vivo. Inhibition of endogenous or exogenous H2S production reversed the protective effects of GO on ALI and eliminated the inhibitory effects of GO on NF-κB, NLRP3, and pyroptotic signaling pathways. Overall, these findings indicate that GO has a critical anti-inflammatory effect and protects against LPS-induced ALI by suppressing the NF-κB/NLRP3 signaling pathway via H2S generation.

Optical Force Effects of Rayleigh Particles by Cylindrical Vector Beams.

High-order cylindrical vector beams possess flexible spatial polarization and exhibit new effects and phenomena that can expand the functionality and enhance the capability of optical systems. However, building a general analytical model for highly focused beams with different polarization orders remains a challenge. Here, we elaborately develop the vector theory of high-order cylindrical vector beams in a high numerical aperture focusing system and achieve the vectorial diffraction integrals for describing the tight focusing field with the space-variant distribution of polarization orders within the framework of Richards-Wolf diffraction theory. The analytical formulae include the exact three Cartesian components of electric and magnetic distributions in the tightly focused region. Additionally, utilizing the analytical formulae, we can achieve the gradient force, scattering force, and curl-spin force exerted on Rayleigh particles trapped by high-order cylindrical vector beams. These results are crucial for improving the design and engineering of the tightly focused field by modulating the polarization orders of high-order cylindrical vector beams, particularly for applications such as optical tweezers and optical manipulation. This theoretical analysis also extends to the calculation of complicated optical vortex vector fields and the design of diffractive optical elements with high diffraction efficiency and resolution.

Daily Low-Level Red Light for Spherical Equivalent Error and Axial Length in Children With Myopia: A Randomized Clinical Trial.

Importance: Treatments are needed to slow progression of or reduce incidence of myopia. Objective: To evaluate the efficacy and safety of daily 650-nm low-level red light (LLRL) for myopia treatment. Design, Setting, and Participants: Single-masked, randomized clinical trial at 1 site in China. Baseline measurements were completed from August to September 2021. Participants were children aged 6 to 12 years with spherical equivalent error (SER) of -6 diopters (D) to 3 D. Data were analyzed from March to July 2023. Interventions: Irradiation daily with 650-nm LLRL for 3 minutes twice daily 4 or more hours apart or no intervention. Main Outcomes and Measures: Primary outcomes were changes in cycloplegia SER and axial length (AL) at 6- and 12-month follow-up visits. Safety was assessed on masked fundus photograph evaluations. Results: A total of 336 children were randomly allocated into the LLRL group or control group in a 1:1 ratio. The control group contained 86 female patients (51.2%), and the treatment group contained 90 female patients (53.6%). The mean (SD) age, SER, and AL were 9.0 (1.9) years, -1.3 (1.5) D, and 23.8 (1.0) mm for all patients. A total of 161 (95.8%) in the LLRL group and 159 (94.6%) in the control group returned for the 6-month follow-up. A total of 157 (93.5%) in the LLRL group and 152 (90.5%) in the control group returned for the 12-month follow-up. Mean (SD) changes in SER were 0.15 (0.16) D and -0.26 (0.21) D for the LLRL group and the control group, respectively (difference, -0.41 D; 95% CI, -0.48 to -0.34 D; P < .001), at 6 months and 0.24 (0.27) D and -0.65 (0.33) D for the LLRL group and the control group, respectively (difference, -0.89 D; 95% CI, -0.95 to -0.83 D; P < .001), at 12 months. Mean (SD) changes in AL were -0.06 (0.08) mm and 0.13 (0.12) mm for the LLRL group and control group, respectively (difference, 0.19 mm; 95% CI, 0.16 to 0.22 mm; P < .001), at 6 months and -0.11 (0.10) mm and 0.26 (0.16) mm for the LLRL group and control group, respectively (difference, 0.37 mm; 95% CI, 0.34 to 0.40 mm; P < .001). Masked fundus photograph review did not identify retinal changes in either group. Conclusions and relevance: These findings suggest daily use of 650-nm LLRL for 1 year can slow progression of SER and AL without safety concerns identified. Confirmation of these findings at independent sites seems warranted, as well as determining whether these effects can be sustained with or without continued treatment and whether LLRL has any effect on pathological myopia. Trial Registration: ChiCTR2200058963.

[Cases Analysis of Hemoglobin H Disease Caused by HBA2:c.2T>C and HBA2:c.2delT Mutations].

OBJECTIVE: To investigate two cases of rare pathogenic genes, initiation codon mutations in HBA2 gene, combined with Southeast Asian deletion and their family members to understand the relationship of HBA2:c.2T>C and HBA2:c.2delT mutations with clinical phenotype. METHODS: The peripheral blood of family members was obtained for blood cell analysis and capillary electrophoresis hemoglobin analysis. Gap-PCR and reverse dot blotting (RDB) were used to detect common types of mutations in ɑ-thalassaemia gene. Sanger sequencing was used to analyze HBA1 and HBA2 gene sequence. RESULTS: Two proband genotypes were identified as --SEA/αα with HBA2:c.2T>C and --SEA/αα with HBA2:c.2delT. HBA2:c.2T>C/WT and HBA2:c.2delT/WT was detected in family members. They all presented with microcytic hypochromic anemia. CONCLUSION: When HBA2:c.2T>C and HBA2:c.2delT are heterozygous that can lead to static α-thalassemia phenotype, and when combined with mild α-thalassemia, they can lead to the clinical manifestations of hemoglobin H disease. This study provides a basis for genetic counseling.

Engineering a functional ACL reconstruction graft containing a triphasic enthesis-like structure in bone tunnel for the enhancement of graft-to-bone integration.

Background: Anterior cruciate ligament (ACL) rupture is a common sports injury, which causes knee instability and abnormal joint kinematics. The current ACL graft was single-phasic, and not convenient for the formation of enthesis-like tissue in the bone tunnel, resulting in poor integration of graft-to-bone. Methods: A band-shaped acellular tendon (BAT) was prepared as the core component of the ACL reconstruction graft at first, while sleeve-shaped acellular cartilage (SAC) or sleeve-shaped acellular bone (SAB) was fabricated using a vacuum aspiration system (VAS)-based decellularization protocol. The biocompatibility of the three acellular matrixes was evaluated. Furthermore, a collagen-binding peptide (CBP) derived from the A3 domain of von Willebrand factor was respectively fused into the N-terminal of GDF7, TGFß3, or BMP2 to synthesize three recombinant growth factors capable of binding collagen (named C-GDF7, C-TGFß3, or C-BMP2), which were respectively tethered to the BAT, SAC or SAB for improving their inducibilities in stem cell differentiation. An in-vitro experiment was performed to evaluate theirs osteogenic, chondrogenic, and tenogenic inducibilities. Then, C-TGFß3-tethering SAC (C-TGFß3@SAC) and C-BMP2-tethering SAB (C-BMP2@SAB) were sequentially surrounded at the bone tunnel part of C-GDF7-tethering BAT (C-GDF7@BAT), thus a sleeve-shaped acellular graft with a triphasic enthesis-like structure in bone tunnel part (named tissue-engineered graft, TE graft) was engineered. Lastly, a canine ACL reconstruction model was used to evaluate the in-vivo performance of this TE graft in enhancing graft-to-bone integration. Results: The BAT, SAC, and SAB well preserved the structure and components of native tendon, cartilage, and bone, showing good biocompatibility. C-GDF7, C-TGFß3, or C-BMP2 showed a stronger binding ability to BAT, SAC, and SAB. The C-GDF7@BAT, C-TGFß3@SAC, or C-BMP2@SAB was a controlled delivery system for the scaffold-specific release of GDF7, TGFß3, and BMP2, thus showing superior tenogenic, chondrogenic, or osteogenic inducibility, respectively. Using a canine ACL reconstruction model, abundant newly-formed bone and connective collagen fibers could be observed at the integration site between TE graft and bone tunnel at postoperative 16 weeks. Meanwhile, the failure load of the reconstructed ACL by TE graft was significantly higher than that of the autograft. Conclusion: The TE graft could be used to reconstruct ruptured ACL and augment graft-to-bone integration, thus demonstrating high potential for clinical translation in ACL reconstruction. Translational potential of this article: The findings of the study indicated that the TE graft could be a novel graft for ACL reconstruction with the ability to augment graft-to-bone integration, which may provide a foundation for future clinical application.

Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

Gelatin/heparin coated bio-inspired polyurethane composite fibers to construct small-caliber artificial blood vessel grafts.

Long-term patency and ability for revascularization remain challenges for small-caliber blood vessel grafts to treat cardiovascular diseases clinically. Here, a gelatin/heparin coated bio-inspired polyurethane composite fibers-based artificial blood vessel with continuous release of NO and biopeptides to regulate vascular tissue repair and maintain long-term patency is fabricated. A biodegradable polyurethane elastomer that can catalyze S-nitrosothiols in the blood to release NO is synthesized (NPU). Then, the NPU core-shell structured nanofiber grafts with requisite mechanical properties and biopeptide release for inflammation manipulation are fabricated by electrospinning and lyophilization. Finally, the surface of tubular NPU nanofiber grafts is coated with heparin/gelatin and crosslinked with glutaraldehyde to obtain small-caliber artificial blood vessels (ABVs) with the ability of vascular revascularization. We demonstrate that artificial blood vessel grafts promote the growth of endothelial cells but inhibit the growth of smooth muscle cells by the continuous release of NO; vascular grafts can regulate inflammatory balance for vascular tissue remodel without excessive collagen deposition through the release of biological peptides. Vascular grafts prevent thrombus and vascular stenosis to obtain long-term patency. Hence, our work paves a new way to develop small-caliber artificial blood vessel grafts that can maintain long-term patency in vivo and remodel vascular tissue successfully.

Exercise preconditioning inhibits doxorubicin-induced cardiotoxicity via YAP/STAT3 signaling.

Doxorubicin (DOX) possesses strong anti-tumor effects but is limited by its irreversible cardiac toxicity. The relationship between exercise, a known enhancer of cardiovascular health, and DOX-induced cardiotoxicity has been a focus of recent research. Exercise has been suggested to mitigate DOX's cardiac harm by modulating the Yes-associated protein (YAP) and Signal transducer and activator of transcription 3 (STAT3) pathways, which are crucial in regulating cardiac cell functions and responses to damage. This study aimed to assess the protective role of exercise preconditioning against DOX-induced cardiac injury. We used Sprague-Dawley rats, divided into five groups (control, DOX, exercise preconditioning (EP), EP-DOX, and verteporfin + EP + DOX), to investigate the potential mechanisms. Our findings, including echocardiography, histological staining, Western blot, and q-PCR analysis, demonstrated that exercise preconditioning could alleviate DOX-induced cardiac dysfunction and structural damage. Notably, exercise preconditioning enhanced the nuclear localization and co-localization of YAP and STAT3. Our study suggests that exercise preconditioning may counteract DOX-induced cardiotoxicity by activating the YAP/STAT3 pathway, highlighting a potential therapeutic approach for reducing DOX's cardiac side effects.

Evaluation of the effectiveness of using prednisolone, tacrolimus, and intravenous immunoglobulin combination therapy on immune-mediated necrotizing myopathy-A non-randomized, observational research.

OBJECTIVE: To recruit immune-mediated necrotizing myopathy (IMNM) patients with extramuscular manifestations who were refractory to initial therapy with either monotherapy with prednisolone or dual therapy with prednisolone and immunosuppressants. These patients subsequently received a combination of prednisolone, tacrolimus, and intravenous immunoglobulin (IVIG), and the efficacy of this treatment regimen was assessed in patients with IMNM. METHOD: ①Clinical data and treatment measures are as follows: This study enrolled IMNM patients who were treated at the Neurology Department of the First Medical Center of PLA General Hospital from April 2020 to May 2023. These patients received a combination therapy of prednisolone, tacrolimus, and IVIG. ②Observational indicators included manual muscle test for 8 groups of muscles (MMT-8), muscle enzyme levels (creatine kinase (CK), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST)), and myositis disease activity assessment tool (MDAAT). RESULTS: This study enrolled eight patients. All observational indicators declined after treatment compared to before treatment, and these changes were statistically significant. Moreover, extramuscular manifestations also ameliorated compared to before treatment. CONCLUSION: The combination therapy of prednisolone, tacrolimus, and IVIG has demonstrated favorable efficacy in IMNM and broadened the treatment options for this disease. However, the results still require further validation by large-scale and randomized controlled studies.

rs2736098, a synonymous polymorphism, is associated with carcinogenesis and cell count in multiple tissue types by regulating TERT expression.

rs2736098 is a synonymous polymorphism in TERT (telomerase reverse transcriptase), an enzyme involved in tumor onset of multiple tissues, and should play no roles in carcinogenesis. However, a search in cancer somatic mutation database indicated that the mutation frequency at rs2736098 is much higher than the average one for TERT. Moreover, there are significant H3K4me1 and H3K27Ac signals, two universal histone modifications for active enhancers, surrounding rs2736098. Therefore, we hypothesized that rs2736098 might be within an enhancer region, regulate TERT expression and influence cancer risk. Through luciferase assay, it was verified that the enhancer activity of rs2736098C allele is significantly higher than that of T in multiple tissues. Transfection of plasmids containing TERT coding region with two different alleles indicated that rs2736098C allele can induce a significantly higher TERT expression than T. By chromatin immunoprecipitation, it was observed that the fragment spanning rs2736098 can interact with USF1 (upstream transcription factor 1). The two alleles of rs2736098 present evidently different binding affinity with nuclear proteins. Database and literature search indicated that rs2736098 is significantly associated with carcinogenesis in multiple tissues and count of multiple cell types. All these facts indicated that rs2736098 is also an oncogenic polymorphism and plays important role in cell proliferation.

Is there a finite mobility for the one vibrational mode Holstein model? Implications from real time simulations.

The question of whether there exists a finite mobility in the standard Holstein model with one vibrational mode on each site remains unclear. In this Communication, we approach this problem by employing the hierarchical equation of motion method to simulate model systems where the vibrational modes are dissipative. It is found that, as the friction becomes smaller, the charge carrier mobility increases significantly and a friction-free limit cannot be obtained. The current autocorrelation functions are also calculated for the friction-free Holstein model, and converged results cannot be obtained with an increase in the number of sites. Based on these observations, we conclude that a finite mobility cannot be defined for the standard Holstein model in the parameter regime explored in this work.

CircHIPK3 regulates fatty acid metabolism through miR-637/FASN axis to promote esophageal squamous cell carcinoma.

The oncogenic role of circRNA in cancers including esophageal cancer (EC) has been well studied. However, whether and how circRNAs are involved in cancer cell metabolic processes remains largely unknown. Here, we reported that circRNA, circHIPK3, is highly expressed in ESCC cell lines and tissues. Knockdown of circHIPK3 significantly restrained cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, circHIPK3 was found to act as a ceRNA by sponging miR-637 to regulate FASN expression and fatty acid metabolism in ESCC cells. Anti-sense oligonucleotide (ASO) targeting circHIPK3 substantially inhibited ESCC both in vitro and in vivo. Therefore, these results uncover a modulatory axis constituting of circHIPK3/miR-637/FASN may be a potential biomarker and therapeutic target for ESCC in the clinic.

LncRNA LUESCC promotes esophageal squamous cell carcinoma by targeting the miR-6785-5p/NRSN2 axis.

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent gastrointestinal malignancies with high mortality worldwide. Emerging evidence indicates that long noncoding RNAs (lncRNAs) are involved in human cancers, including ESCC. However, the detailed mechanisms of lncRNAs in the regulation of ESCC progression remain incompletely understood. LUESCC was upregulated in ESCC tissues compared with adjacent normal tissues, which was associated with gender, deep invasion, lymph node metastasis, and poor prognosis of ESCC patients. LUESCC was mainly localized in the cytoplasm of ESCC cells. Knockdown of LUESCC inhibited cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth in vivo. Mechanistic investigation indicated that LUESCC functions as a ceRNA by sponging miR-6785-5p to enhance NRSN2 expression, which is critical for the malignant behaviors of ESCC. Furthermore, ASO targeting LUESCC substantially suppressed ESCC both in vitro and in vivo. Collectively, these data demonstrate that LUESCC may exerts its oncogenic role by sponging miR-6785-5p to promote NRSN2 expression in ESCC, providing a potential diagnostic marker and therapeutic target for ESCC patients.

Association between albumin-corrected anion gap and in-hospital mortality of intensive care patients with trauma: A retrospective study based on MIMIC-â ¢ and â £ databases.

BACKGROUND: To investigate the correlation between albumin-corrected anion gap(ACAG) within the first 24 hours of admission and in-hospital mortality in trauma patients in intensive care unit(ICU). MATERIALS AND METHODS: We utilized the MIMIC-Ⅲ and MIMIC-Ⅳ databases to examine trauma patients admitted to the ICU. The relationship between ACAG and in-hospital mortality in trauma patients was analyzed using Receiver Operating Characteristic(ROC) curve, Kaplan-Meier (K-M) survival curve, and Cox regression model. Propensity score matching (PSM) and subgroup analysis were conducted to enhance stability and reliability of the findings. Mortality at 30-day and 90-day served as secondary outcomes. RESULTS: The study enrolled a total of 1038 patients. The AUC for ACAG (0.701, 95%CI: 0.652-0.749) was notably higher than that for anion gap and albumin. The Log-rank test revealed that the optimal cut-off point of ACAG for predicting in-hospital mortality was determined to be 20.375mmol/L. The multivariate Cox regression analysis demonstrated an independent association between high ACAG level and a higher risk of in-hospital mortality (HR = 3.128, 95% CI: 1.615-6.059). After PSM analysis, a matched cohort consisting of 291 subjects was obtained. We found no signifcant interaction in most stratas. Finally, The in-hospital, 30-day, and 90-day survival rates in the high ACAG group exhibited a statistically decrease compared to those in the low ACAG group both pre- and post-matching. CONCLUSION: The elevated level of ACAG was found to be independently associated with increased in-hospital mortality among trauma patients in the ICU.

Myricetin Oligomer Triggers Multi-Receptor Mediated Penetration and Autophagic Restoration of Blood-Brain Barrier for Ischemic Stroke Treatment.

Restoration of blood-brain barrier (BBB) dysfunction, which drives worse outcomes of ischemic stroke, is a potential target for therapeutic opportunities, whereas a sealed BBB blocks the therapeutics entrance into the brain, making the BBB protection strategy paradoxical. Post ischemic stroke, hypoxia/hypoglycemia provokes the up-regulation of transmembrane glucose transporters and iron transporters due to multiple metabolic disorders, especially in brain endothelial cells. Herein, we develop a myricetin oligomer-derived nanostructure doped with Ce to bypass the BBB which is cointermediated by glucose transporters and iron transporters such as glucose transporters 1 (GLUT1), sodium/glucose cotransporters 1 (SGLT1), and transferrin(Tf) reporter (TfR). Moreover, it exhibits BBB restoration capacity by regulating the expression of tight junctions (TJs) through the activation of protective autophagy. The myricetin oligomers scaffold not only acts as targeting moiety but is the prominent active entity that inherits all diverse pharmacological activities of myricetin. The suppression of oxidative damage, M1 microglia activation, and inflammatory factors makes it a multitasking nanoagent with a single component as the scaffold, targeting domain and curative components.

Metagenomic analysis of individual mosquito viromes reveals the geographical patterns and drivers of viral diversity.

Mosquito transmitted viruses are responsible for an increasing burden of human disease. Despite this, little is known about the diversity and ecology of viruses within individual mosquito hosts. Here, using a meta-transcriptomic approach, we determined the viromes of 2,438 individual mosquitoes (81 species), spanning ~4,000 km along latitudes and longitudes in China. From these data we identified 393 viral species associated with mosquitoes, including 7 (putative) species of arthropod-borne viruses (that is, arboviruses). We identified potential mosquito species and geographic hotspots of viral diversity and arbovirus occurrence, and demonstrated that the composition of individual mosquito viromes was strongly associated with host phylogeny. Our data revealed a large number of viruses shared among mosquito species or genera, enhancing our understanding of the host specificity of insect-associated viruses. We also detected multiple virus species that were widespread throughout the country, perhaps reflecting long-distance mosquito dispersal. Together, these results greatly expand the known mosquito virome, linked viral diversity at the scale of individual insects to that at a country-wide scale, and offered unique insights into the biogeography and diversity of viruses in insect vectors.

Insight into the Gas-Induced Phase Transformations in a 2D Switching Coordination Network via Coincident Gas Sorption and In Situ PXRD.

Switching coordination networks (CNs) that reversibly transform between narrow or closed pore (cp) and large pore (lp) phases, though fewer than their rigid counterparts, offer opportunities for sorption-related applications. However, their structural transformations and switching mechanisms remain underexplored at the molecular level. In this study, we conducted a systematic investigation into a 2D switching CN, [Ni(bpy)2(NCS)2]n, sql-1-Ni-NCS (1 = bpy = 4,4'-bipyridine), using coincident gas sorption and in situ powder X-ray diffraction (PXRD) under low-temperature conditions. Gas adsorption measurements revealed that C2H4 (169 K) and C2H6 (185 K) exhibited single-step type F-IVs sorption isotherms with sorption uptakes of around 180-185 cm3 g-1, equivalent to four sorbate molecules per formula unit. Furthermore, parallel in situ PXRD experiments provided insight into sorbate-dependent phase switching during the sorption process. Specifically, CO2 sorption induced single-step phase switching (path I) solely between cp and lp phases consistent with the observed single-step type F-IVs sorption isotherm. By contrast, intermediate pore (ip) phases emerged during C2H4 and C2H6 desorption as well as C3H6 adsorption, although they remained undetectable in the sorption isotherms. To our knowledge, such a cp-lp-ip-cp transformation (path II) induced by C2H4/6 and accompanied by single-step type F-IVs sorption isotherms represents a novel type of phase transition mechanism in switching CNs. By virtue of Rietveld refinements and molecular simulations, we elucidated that the phase transformations are governed by cooperative local and global structural changes involving NCS- ligand reorientation, bpy ligand twist and rotation, cavity edge (Ni-bpy-Ni) deformation, and interlayer expansion and sliding.

ADSC-Exos enhance functional recovery after spinal cord injury by inhibiting ferroptosis and promoting the survival and function of endothelial cells through the NRF2/SLC7A11/GPX4 pathway.

BACKGROUND: Spinal cord injury (SCI) is a devastating disease that causes major motor, sensory and autonomic dysfunctions. Currently, there is a lack of effective treatment. In this study, we aimed to investigate the potential mechanisms of Exosomes from adipose-derived stem cells (ADSC-Exos) in reducing ferroptosis and promoting angiogenesis after spinal cord injury. METHODS: We isolated ADSC-Exos, the characteristics of which were confirmed. In vitro, we tested the potential of ADSC-Exos to promote the survival and function of human brain microvascular endothelial cells (HBMECs) and analyzed the ferroptosis of HBMECs. In vivo, we established rat models of SCI and locally injected ADSC-Exos to verify their efficacy. RESULTS: ADSC-Exos can reduce reactive oxygen species (ROS) accumulation and cell damage induced by an excessive inflammatory response in HBMECs. ADSC-Exos inhibit ferroptosis induced by excessive inflammation and upregulate the expression of glutathione peroxidase 4(GPX4) in HBMECs. It can also effectively promote proliferation, migration, and vessel-like structure formation. In vitro, ADSC-Exos improved behavioral function after SCI and increased the number and density of blood vessels around the damaged spinal cord. Moreover, we found that ADSC-Exos could increase nuclear factor erythroid-2-related factor 2(NRF2) expression and nuclear translocation, thereby affecting the expression of solute carrier family 7 member 11(SLC7A11) and GPX4, and the NRF2 inhibitor ML385 could reverse the above changes. CONCLUSION: Our results suggest that ADSC-Exos may inhibit ferroptosis and promote the recovery of vascular and neural functions after SCI through the NRF2/SLC7A11/GPX4 pathway. This may be a potential therapeutic mechanism for spinal cord injury.