Role of TSP-1 and its receptor ITGB3 in the renal tubulointerstitial injury of focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS), a common cause of primary glomerulonephritis, has a poor prognosis and is pathologically featured by tubulointerstitial injury. Thrombospondin-1 (TSP-1) is an extracellular matrix protein that acts in combination with different receptors in the kidney. Here, we analyzed the tubular expression of TSP-1 and its receptor integrin ß3 (ITGB3) in FSGS. Previously the renal interstitial chip analysis of FSGS patients with tubular interstitial injury showed that the expression of TSP-1 and ITGB3 were upregulated. We found that the expression of TSP-1 and ITGB3 increased in the tubular cells of FSGS patients. The plasma level of TSP-1 increased and was correlated to the degree of tubulointerstitial lesions in FSGS patients. TSP-1/ITGB3 signaling induced renal tubular injury in HK-2 cells exposure to bovine serum albumin and the adriamycin (ADR)-induced nephropathy model. THBS1 KO ameliorated tubular injury and renal fibrosis in ADR-treated mice. THBS1 knockdown decreased the expression of KIM-1 and caspase 3 in the HK-2 cells treated with bovine serum albumin, while THBS1 overexpression could induce tubular injury. In vivo, we identified cyclo-RGDfK as an agent to block the binding of TSP-1 to ITGB3. Cyclo-RGDfK treatment could alleviate ADR-induced renal tubular injury and interstitial fibrosis in mice. Moreover, TSP-1 and ITGB3 were colocalized in tubular cells of FSGS patients and ADR-treated mice. Taken together, our data showed that TSP-1/ITGB3 signaling contributed to the development of renal tubulointerstitial injury in FSGS, potentially identifying a new therapeutic target for FSGS.

Farnesoid X Receptor Protects Murine Lung against IL-6-promoted Ferroptosis Induced by Polyriboinosinic-Polyribocytidylic Acid.

Various infections trigger a storm of proinflammatory cytokines in which IL-6 acts as a major contributor and leads to diffuse alveolar damage in patients. However, the metabolic regulatory mechanisms of IL-6 in lung injury remain unclear. Polyriboinosinic-polyribocytidylic acid [poly(I:C)] activates pattern recognition receptors involved in viral sensing and is widely used in alternative animal models of RNA virus-infected lung injury. In this study, intratracheal instillation of poly(I:C) with or without an IL-6-neutralizing antibody model was combined with metabonomics, transcriptomics, and so forth to explore the underlying molecular mechanisms of IL-6-exacerbated lung injury. We found that poly(I:C) increased the IL-6 concentration, and the upregulated IL-6 further induced lung ferroptosis, especially in alveolar epithelial type II cells. Meanwhile, lung regeneration was impaired. Mechanistically, metabolomic analysis showed that poly(I:C) significantly decreased glycolytic metabolites and increased bile acid intermediate metabolites that inhibited the bile acid nuclear receptor farnesoid X receptor (FXR), which could be reversed by IL-6-neutralizing antibody. In the ferroptosis microenvironment, IL-6 receptor monoclonal antibody tocilizumab increased FXR expression and subsequently increased the Yes-associated protein (YAP) concentration by enhancing PKM2 in A549 cells. FXR agonist GW4064 and liquiritin, a potential natural herbal ingredient as an FXR regulator, significantly attenuated lung tissue inflammation and ferroptosis while promoting pulmonary regeneration. Together, the findings of the present study provide the evidence that IL-6 promotes ferroptosis and impairs regeneration of alveolar epithelial type II cells during poly(I:C)-induced murine lung injury by regulating the FXR-PKM2-YAP axis. Targeting FXR represents a promising therapeutic strategy for IL-6-associated inflammatory lung injury.

Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

Phosphomolybdates for Dual-Mode Photoelectrochemical Sensing toward Trace Chromium(VI) and Tetracycline.

Highly sensitive photoelectrochemical (PEC) sensors for trace carcinogens, such as heavy metal chromium(VI) [Cr(VI)] and antibiotic tetracycline (TC) are crucial. Herein, by integration of photoactive and redox phosphomolybdates with conjugated organic components, types of dual-mode PEC sensors were synthesized for sensing trace Cr(VI) and TC pollutants, with formulas of (H2bimb)2[Co2(bimb)1.5][Co(H2O)4][Co(P4Mo6O31H6)2]·6H2O (1), (H2bib)2[Co(H2O)3][Co2(H2O)5][Co(P4Mo6O31H6)2]·9H2O (2), and (H2bib)6[Co(Hbib)2(H2O)5][Co(P4Mo6O31H7)2]2·15H2O (3), where bimb represents 1,4-bis(1-imidazolyl)benzene and bib is 4,4'-bis(imidazolyl)bibphenyl. Hybrid 1 consisted of a three-dimensional framework structure constructed by Co{P4Mo6}2 clusters and one-dimensional (1D) {Co-bimb} chains, hybrid 2 exhibited 1D Co ion-bridged Co{P4Mo6}2 chains hydrogen-bonding with [H2bib]2+ cations, and hybrid 3 showed a discrete hybrid structure built upon a Co{P4Mo6}2 cluster modified by the {Co-bib} unit. Hybrids 1-3 displayed wide spectral absorption and excellent electrochemical redox properties, enabling dual-mode PEC responses to Cr(VI) reduction and TC oxidation. For Cr(VI) detection, hybrids 1-3 exhibited high sensitivities of 364.40, 225.72, and 124.29 µA·µM-1 as well as "nM" level detection limits (LODs) of 4.9, 10.0, and 11.0 nM, respectively. For TC detection, the sensitivities of hybrids 1-3 were 494.72, 308.78, and 174.03 µA·µM-1 and the LODs were 5.2, 6.1, and 12.9 nM, respectively. This research offers significant insights into designing efficient PEC sensors for the detection of environmental pollutants.

Bridging Component Strategy in Phosphomolybdate-Based Sensors for Electrochemical Determination of Trace Cr(VI).

Rapid and sensitive electrochemical determination of trace carcinogenic Cr(VI) pollutants remains an urgent and important task, which requires the development of active sensing materials. Herein, four cases of reduced phosphomolybdates with formulas of the (H2bib)3[Zn(H2PO4)]2{Mn[P4Mo6O31H7]2}·6H2O (1), (H2bib)2[Na(H2O)]2[Mn(H2O)]2{Mn[P4Mo6O31H6]2}·5H2O (2), (H2bib)3[Mo2(µ2-O)2(H2O)4]2{Ni[P4Mo6O31H2]2}·4H2O (3), and (H2bib)2{Ni[P4Mo6O31H9]2}·9H2O (4) (bib = 4,4'-bis(1-imidazolyl)-biphenyl) were hydrothermally synthesized under the guidance of a bridging component strategy, which function as effective electrochemical sensors to detect trace Cr(VI). The difference of hybrids 1-4 is in the inorganic moiety, in which the reduced phosphomolybdates {M[P4MoV6O31]2} (M{P4Mo6}2) exhibited different arrangements bridged by different cationic components ({Zn(H2PO4)} subunit for 1, [Mn2(H2O)2]4+ dimer for 2, and [MoV2(µ2-O)2(H2O)4]6+ for 3). As a result, hybrids 1 and 3 display noticeable Cr(VI) detection activity with low detection limits of 14.3 nM (1.48 ppb) for 1 and 6.61 nM (0.69 ppb) for 3 and high sensitivities of 97.3 and 95.3 µA·mM-1, respectively, which are much beyond the World Health Organization's detection threshold (0.05 ppm) and superior to those of the contrast samples (inorganic Mn{P4Mo6}2 salt and hybrid 4), even the most reported noble-metal catalysts. This work supplies a prospective pathway to build effective electrochemical sensors based on phosphomolybdates for environmental pollutant treatment.

Effect of deep neuromuscular block on the quality of early recovery after sleeve gastrectomy in obese patients: a randomized controlled trial.

BACKGROUND: Deep neuromuscular block (NMB) has been shown to improve surgical conditions and alleviate post-operative pain in bariatric surgery compared with moderate NMB. We hypothesized that deep NMB could also improve the quality of early recovery after laparoscopic sleeve gastrectomy (LSG). METHODS: Eighty patients were randomized to receive either deep (post-tetanic count 1-3) or moderate (train-of-four count 1-3) NMB. The QoR-15 questionnaire was used to evaluate the quality of early recovery at 1 day before surgery (T0), 24 and 48 h after surgery (T2, T3). Additionally, we recorded diaphragm excursion (DE), postoperative pain, surgical condition, cumulative dose of analgesics, time of first flatus and ambulation, post-operative nausea and vomiting, time of tracheal tube removal and hospitalization time. MAIN RESULTS: The quality of recovery was significantly better 24 h after surgery in patients who received a deep versus moderate block (114.4 ± 12.9 versus 102.1 ± 18.1). Diaphragm excursion was significantly greater in the deep NMB group when patients performed maximal inspiration at T2 and T3 (P < 0.05). Patients who underwent deep NMB reported lower visceral pain scores 40 min after surgery; additionally, these patients experienced lower pain during movement at T3 (P < 0.05). Optimal surgical conditions were rated in 87.5% and 64.6% of all measurements during deep and moderate NMB respectively (P < 0.001). The time to tracheal tube removal was significantly longer in the deep NMB group (P = 0.001). There were no differences in other outcomes. CONCLUSION: In obese patients receiving deep NMB during LSG, we observed improved QoR-15 scores, greater diaphragmatic excursions, improved surgical conditions, and visceral pain scores were lower. More evidence is needed to determine the effects of deep NMB on these outcomes. TRIAL REGISTRATION: ChiCTR2200065919. Date of retrospectively registered: 18/11/2022.

Exploring the Role of Traditional Chopstick Culture and Interpersonal Communication in Health Campaign-Targeted Behavior.

Traditional chopstick culture is widely recognized as a vital factor associated with health behavior. After the outbreak of COVID-19 in China, the Gongkuai campaign aims to change long-held traditions of communal eating habits. Little is known about the effect of individuals' perception of traditional chopstick culture and other factors on Gongkuai campaign-targeted goal. This study investigates how social-environmental and cognitive factors motivate individuals to use serving chopsticks (the Chinese Gongkuai campaign-targeted goal) and how such effects are moderated by traditional chopstick culture. Data was collected using a nationwide online survey and analyzed using structural equation modeling. The findings revealed that campaign-generated interpersonal communication positively affects individual cognitive factors. Furthermore, cognitive factors promote behavioral intentions to use serving chopsticks. While traditional chopstick culture does not directly influence an intention to use serving chopsticks, it plays a different role in the relationships between three cognitive factors and serving chopsticks use intention. Based on the results, policy implications about how to motivate individuals to use serving chopsticks are discussed.

Indolo[3,2-b]indole-based multi-resonance emitters for efficient narrowband pure-green organic light-emitting diodes.

Organic light-emitting diodes (OLEDs) utilizing multi-resonance (MR) emitters show great potential in ultrahigh-definition display benefitting from superior merits of MR emitters such as high color purity and photoluminescence quantum yields. However, the scarcity of narrowband pure-green MR emitters with novel backbones and facile synthesis has limited their further development. Herein, two novel pure-green MR emitters (IDIDBN and tBuIDIDBN) are demonstrated via replacing the carbazole subunits in the bluish-green BCzBN skeleton with new polycyclic aromatic hydrocarbon (PAH) units, 5-phenyl-5,10-dihydroindolo[3,2-b]indole (IDID) and 5-(4-(tert-butyl)phenyl)-5,10-dihydroindolo[3,2-b]indole (tBuIDID), to simultaneously enlarge the π-conjugation and enhance the electron-donating strength. Consequently, a successful red shift from aquamarine to pure-green is realized for IDIDBN and tBuIDIDBN with photoluminescence maxima peaking at 529 and 532 nm, along with Commission Internationale de l'Eclairage (CIE) coordinates of (0.25, 0.71) and (0.28, 0.70). Furthermore, both emitters revealed narrowband emission with small full width at half-maximum (FWHM) below 28 nm. Notably, the narrowband pure-green emission was effectively preserved in corresponding devices, which afford elevated maximum external quantum efficiencies of 16.3% and 18.3% for IDIDBN and tBuIDIDBN.

Chanling Gao suppresses colorectal cancer via PI3K/Akt/mTOR pathway modulation and enhances quality of survival.

The Chinese medicine formula Chanling Gao (CLG) exhibits significant tumor inhibitory effects in colorectal cancer (CRC) nude mice. However, the detailed mechanisms remain elusive. CRC in situ nude mouse models were treated with CLG. Small animal magnetic resonance imaging (MRI) tracked tumor progression, and overall health metrics such as food and water intake, body weight, and survival were monitored. Posttreatment, tissues and blood were analyzed for indicators of tumor inhibition and systemic effects. Changes in vital organs were observed via stereoscope and hematoxylin-eosin staining. Immunohistochemistry quantified HIF-1α and P70S6K1 protein expression in xenografts. Double labeling was used to statistically analyze vascular endothelial growth factor (VEGF) and CD31 neovascularization. Enzyme-linked immunosorbent assay was used to determine the levels of VEGF, MMP-2, MMP-9, IL-6, and IL-10 in serum, tumors, and liver. Western blotting was used to assess the expression of the PI3K/Akt/mTOR signaling pathway-related factors TGF-ß1 and smad4 in liver tissues. CLG inhibited tumor growth, improved overall health metrics, and ameliorated abnormal blood cell counts in CRC nude mice. CLG significantly reduced tumor neovascularization and VEGF expression in tumors and blood. It also suppressed HIF-1α, EGFR, p-PI3K, Akt, p-Akt, and p-mTOR expression in tumors while enhancing PTEN oncogene expression. Systemic improvements were noted, with CLG limiting liver metastasis, reducing pro-inflammatory cytokines IL-6 and IL-10 in liver tissues, decreasing MMP-2 in blood and MMP-2 and MMP-9 in tumors, and inhibiting TGF-ß1 expression in liver tissues. CLG can enhance survival quality and inhibit tumor growth in CRC nude mice, likely through the regulation of the PI3K/Akt/mTOR signaling pathway.

Agreement of zero-heat-flux thermometry with the oesophageal and tympanic core temperature measurement in patient receiving major surgery.

To identify and prevent perioperative hypothermia, most surgical patients require a non-invasive, accurate, convenient, and continuous core temperature method, especially for patients undergoing major surgery. This study validated the precision and accuracy of a cutaneous zero-heat-flux thermometer and its performance in detecting intraoperative hypothermia. Adults undergoing major non-cardiac surgeries with general anaesthesia were enrolled in the study. Core temperatures were measured with a zero-heat-flux thermometer, infrared tympanic membrane thermometer, and oesophagal monitoring at 15-minute intervals. Taking the average value of temperature measured in the tympanic membrane and oesophagus as a reference, we assessed the agreement using the Bland-Altman analysis and linear regression methods. Sensitivity, specificity, and predictive values of detecting hypothermia were estimated. 103 patients and one thousand sixty-eight sets of paired temperatures were analyzed. The mean difference between zero-heat-flux and the referenced measurements was -0.03 ± 0.25 °C, with 95% limits of agreement (-0.52 °C, 0.47 °C) was narrow, with 94.5% of the differences within 0.5 °C. Lin's concordance correlation coefficient was 0.90 (95%CI 0.89-0.92). The zero-heat-flux thermometry detected hypothermia with a sensitivity of 82% and a specificity of 90%. The zero-heat-flux thermometer is in good agreement with the reference core temperature based on tympanic and oesophagal temperature monitoring in patients undergoing major surgeries, and appears high performance in detecting hypothermia.

Effects of Ginsenoside Rb1 on the Crosstalk between Intestinal Stem Cells and Microbiota in a Simulated Weightlessness Mouse Model.

Exposure to the space microenvironment has been found to disrupt the homeostasis of intestinal epithelial cells and alter the composition of the microbiota. To investigate this in more detail and to examine the impact of ginsenoside Rb1, we utilized a mouse model of hindlimb unloading (HU) for four weeks to simulate the effects of microgravity. Our findings revealed that HU mice had ileum epithelial injury with a decrease in the number of intestinal stem cells (ISCs) and the level of cell proliferation. The niche functions for ISCs were also impaired in HU mice, including a reduction in Paneth cells and Wnt signaling, along with an increase in oxidative stress. The administration of Rb1 during the entire duration of HU alleviated the observed intestinal defects, suggesting its beneficial influence on epithelial cell homeostasis. Hindlimb unloading also resulted in gut dysbiosis. The supplementation of Rb1 in the HU mice or the addition of Rb1 derivative compound K in bacterial culture in vitro promoted the growth of beneficial probiotic species such as Akkermansia. The co-housing experiment further showed that Rb1 treatment in ground control mice alone could alleviate the defects in HU mice that were co-housed with Rb1-treated ground mice. Together, these results underscore a close relationship between dysbiosis and impaired ISC functions in the HU mouse model. It also highlights the beneficial effects of Rb1 in mitigating HU-induced epithelial injury by promoting the expansion of intestinal probiotics. These animal-based insights provide valuable knowledge for the development of improved approaches to maintaining ISC homeostasis in astronauts.

The effects of dietary loading on the transdifferentiation of condylar chondrocytes.

INTRODUCTION: Transdifferentiation of chondrocytes into bone cells explains most condylar growth during prenatal and early postnatal stages, but the mechanisms regulating chondrocyte transdifferentiation during late postnatal growth remain unknown. This study aimed to quantify the effects of dietary loading on chondrocyte-derived osteogenesis during late postnatal condylar growth. METHODS: Two compound mouse lines were used to trace the fate of chondrocyte lineage in vivo. Twelve 3-week-old male Aggrecan-CreERT2 (AcanLineage); R26RTdTomato; 2.3 Col10a1-GFP and twelve 3-week-old male Col10a1-Cre (Col10a1Lineage); R26RTdTomato; 2.3Col1a1-GFP were randomly divided into experimental (soft-food diet, n = 6) and control (hard-food diet, n = 6) groups and kept for 6 weeks. One time, tamoxifen injections were given to AcanLineage mice at 3 weeks. Radiographic, microcomputed tomographic, and histomorphometric analyses were performed. RESULTS: Radiologic analysis showed that mice with a soft-food diet had smaller mandible lengths as well as decreased bone volume and density for their condylar process. Histologically, mice with soft diets had reduced activity in chondrocyte proliferation and maturation compared with the controls. Cell lineage tracing results showed the number of AcanLineage-derived bone cells (293.8 ± 39.8 vs 207.1 ± 44.6; P = 0.005), as well as total bone cells (445.6 ± 31.7 vs 360.7 ± 46.9; P = 0.004), was significantly higher in the hard-diet group than in the soft-diet group, whereas the number of non-AcanLineage-derived bone cells was not significantly different among groups (P = 0.938). Col10a1Lineage mice showed the same trend. CONCLUSIONS: Dietary loading directly affects condyle chondrogenesis and chondrocyte transdifferentiation, which alters the extent of condylar growth and remodeling.

[Analysis of 41 cases of non-metastatic Ewing's sarcoma in children]. / 儿童非转移性尤文肉瘤41例分析.

OBJECTIVES: To summarize the clinical characteristics, treatment outcomes, and prognostic factors of children with non-metastatic Ewing's sarcoma (ES). METHODS: A retrospective analysis was conducted on the clinical data of 41 children with non-metastatic ES diagnosed and treated at the Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine from January 2010 to December 2018. All patients underwent chemotherapy based on the RMS-2009 protocol of the center, and local treatment such as surgery and/or radiotherapy was performed according to risk grouping. The Kaplan-Meier method was used to calculate the overall survival (OS) and event-free survival (EFS) rates. Univariate prognostic analysis was performed using the log-rank test, and multivariate analysis was conducted with Cox regression. RESULTS: Of the 41 children, 21 were male and 20 were female. The median age at diagnosis was 7.7 years (range: 1.2-14.6 years). The median follow-up time for patients with event-free survival was 68.1 months (range: 8.1-151.7 months). As of the last follow-up, 33 patients were in complete remission, and the overall 5-year EFS and OS rates were (78±6)% and (82±6)%, respectively. Univariate analysis by the log-rank test showed that a tumor diameter ≥8 cm, time from diagnosis to start of local treatment ≥16 weeks, and incomplete surgical resection were associated with poor prognosis (P<0.05). Multivariate Cox regression analysis indicated that incomplete surgical resection (HR=8.381, 95%CI: 1.681-41.801, P=0.010) was an independent risk factor for poor prognosis in children with ES. Secondary tumors occurred in 2 cases. CONCLUSIONS: A comprehensive treatment strategy incorporating chemotherapy, surgery, and radiotherapy can improve the prognosis of children with ES. Poor prognosis is associated with an initial tumor diameter ≥8 cm, while complete surgical resection and early initiation of local treatment can improve outcomes.

Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has severely affected human lives around the world as well as the global economy. Therefore, effective treatments against COVID-19 are urgently needed. Here, we screened a library containing Food and Drug Administration (FDA)-approved compounds to identify drugs that could target the SARS-CoV-2 main protease (Mpro), which is indispensable for viral protein maturation and regard as an important therapeutic target. We identified antimalarial drug tafenoquine (TFQ), which is approved for radical cure of Plasmodium vivax and malaria prophylaxis, as a top candidate to inhibit Mpro protease activity. The crystal structure of SARS-CoV-2 Mpro in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate-binding pocket of Mpro by altering the loop region (residues 139-144) near the catalytic Cys145, which could block the catalysis of its peptide substrates. We also found that TFQ inhibited human transmembrane protease serine 2 (TMPRSS2). Furthermore, one TFQ derivative, compound 7, showed a better therapeutic index than TFQ on TMPRSS2 and may therefore inhibit the infectibility of SARS-CoV-2, including that of several mutant variants. These results suggest new potential strategies to block infection of SARS-CoV-2 and rising variants.

Novel Semiconductive Ternary Hybrid Heterostructures for Artificial Optoelectronic Synapses.

Synaptic devices that mimic biological synapses are considered as promising candidates for brain-inspired devices, offering the functionalities in neuromorphic computing. However, modulation of emerging optoelectronic synaptic devices has rarely been reported. Herein, a semiconductive ternary hybrid heterostructure is prepared with a D-D'-A configuration by introducing polyoxometalate (POM) as an additional electroactive donor (D') into a metalloviologen-based D-A framework. The obtained material features an unprecedented porous 8-connected bcu-net that accommodates nanoscale [α-SiW12 O40 ]4- counterions, displaying uncommon optoelectronic responses. Besides, the fabricated synaptic device based on this material can achieve dual-modulation of synaptic plasticity due to the synergetic effect of electron reservoir POM and photoinduced electron transfer. And it can successfully simulate learning and memory processes similar to those in biological systems. The result provides a facile and effective strategy to customize multi-modality artificial synapses in the field of crystal engineering, which opens a new direction for developing high-performance neuromorphic devices.

Toward Antifragility: Social Defeat Stress Enhances Learning and Memory in Young Mice Via Hippocampal Synaptosome Associated Protein 25.

Social adversity not only causes severe psychological diseases but also may improve people's ability to learn and grow. However, the beneficial effects of social adversity are often ignored. In this study, we investigated whether and how social adversity affects learning and memory in a mouse social defeat stress (SDS) model. A total of 652 mice were placed in experimental groups of six to 23 mice each. SDS enhanced spatial, novelty, and fear memory with increased synaptosome associated protein 25 (SNAP-25) level and dendritic spine density in hippocampal neurons among young but not middle-aged mice. Chemogenetic inhibition of hippocampal CaMK2A+ neurons blocked SDS-induced enhancement of learning or memory. Knockdown of SNAP-25 or blockade of N-methyl-D-aspartate (NMDA) receptor subunit GluN2B in the hippocampus prevented SDS-induced learning memory enhancement in an emotion-independent manner. These findings suggest that social adversity promotes learning and memory ability in youths and provide a neurobiological foundation for biopsychological antifragility.

Sorafenib induces cardiotoxicity through RBM20-mediated alternative splicing of sarcomeric and mitochondrial genes.

Sorafenib, a multi-targeted tyrosine kinase inhibitor, is a first-line treatment for advanced solid tumors, but it induces many adverse cardiovascular events, including myocardial infarction and heart failure. These cardiac defects can be mediated by alternative splicing of genes critical for heart function. Whether alternative splicing plays a role in sorafenib-induced cardiotoxicity remains unclear. Transcriptome of rat hearts or human cardiomyocytes treated with sorafenib was analyzed and validated to define alternatively spliced genes and their impact on cardiotoxicity. In rats, sorafenib caused severe cardiotoxicity with decreased left ventricular systolic pressure, elongated sarcomere, enlarged mitochondria and decreased ATP. This was associated with alternative splicing of hundreds of genes in the hearts, many of which were targets of a cardiac specific splicing factor, RBM20. Sorafenib inhibited RBM20 expression in both rat hearts and human cardiomyocytes. The splicing of RBM20's targets, SLC25A3 and FHOD3, was altered into fetal isoforms with decreased function. Upregulation of RBM20 during sorafenib treatment reversed the pathogenic splicing of SLC25A3 and FHOD3, and enhanced the phosphate transport into mitochondria by SLC25A3, ATP synthesis and cell survival.We envision this regulation may happen in many drug-induced cardiotoxicity, and represent a potential druggable pathway for mitigating sorafenib-induced cardiotoxicity.

Decreased syntaxin17 expression contributes to the pathogenesis of acute pancreatitis in murine models by impairing autophagic degradation.

Acute pancreatitis (AP) is an inflammatory disease of the exocrine pancreas. Disruptions in organelle homeostasis, including macroautophagy/autophagy dysfunction and endoplasmic reticulum (ER) stress, have been implicated in human and rodent pancreatitis. Syntaxin 17 (STX17) belongs to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) subfamily. The Qa-SNARE STX17 is an autophagosomal SNARE protein that interacts with SNAP29 (Qbc-SNARE) and the lysosomal SNARE VAMP8 (R-SNARE) to drive autophagosome-lysosome fusion. In this study, we investigated the role of STX17 in the pathogenesis of AP in male mice or rats induced by repeated intraperitoneal injections of cerulein. We showed that cerulein hyperstimulation induced AP in mouse and rat models, which was characterized by increased serum amylase and lipase activities, pancreatic edema, necrotic cell death and the infiltration of inflammatory cells, as well as markedly decreased pancreatic STX17 expression. A similar reduction in STX17 levels was observed in primary and AR42J pancreatic acinar cells treated with CCK (100 nM) in vitro. By analyzing autophagic flux, we found that the decrease in STX17 blocked autophagosome-lysosome fusion and autophagic degradation, as well as the activation of ER stress. Pancreas-specific STX17 knockdown using adenovirus-shSTX17 further exacerbated pancreatic edema, inflammatory cell infiltration and necrotic cell death after cerulein injection. These data demonstrate a critical role of STX17 in maintaining pancreatic homeostasis and provide new evidence that autophagy serves as a protective mechanism against AP.

Evaluation of retinal microvasculature in exotropia with abnormal binocular vision by optical coherence tomography angiography.

BACKGROUND: To explore the retinal microvasculature in large-angle concomitant exotropia patients with abnormal binocular vision using optical coherence tomography angiography (OCTA) analysis. METHODS: OCTA images of 52 healthy and 100 strabismic eyes were analyzed to quantify the retinal thickness (RT), superficial capillary plexus (SCP), deep capillary plexus (DCP), and foveal avascular zone (FAZ). Paired t-tests were performed to compare differences between the two groups, the dominant eye and the deviated eye in the exotropia group, respectively. A p-value < 0.01 was considered significant. RESULTS: The mean angle of deviation was 79.38 [± 25.64] (prism diopters, PD). There were significant differences in the DCP in deviated eyes between the exotropia group and the control group (fovea: p = 0.007; temporal: p = 0.014; nasal: p = 0.028; inferior: p = 0.013). The temporal SCP in the exotropia group was significantly higher than in the control group in deviated eyes (p = 0.020). No significant difference was found between dominant eyes and strabismic eyes (p > 0.01). CONCLUSIONS: The study showed that OCTA revealed subnormal DCP in patients with large-angle exotropia and abnormal binocularity which may be related to retinal suppression. Changes in the macular microvasculature may provide valuable insights into the development of strabismus. Further studies are needed to determine the clinical relevance of this finding. TRIAL REGISTRATION: This trial is registered as ChiCTR2100052577 at www.Chictr.org.cn .

A retrospective study on the relationship between 5 modified frailty index (5-mFI) and postoperative complications of gynecological elderly patients undergoing abdominal surgery.

INTRODUCTION: Aim to evaluate the application of 5 modified frailty index (5-mFI) in predicting postoperative complications in elderly gynecological patients undergoing abdominal surgery. METHODS: A total of 294 elderly gynecological patients who were hospitalized in the affiliated Hospital of North Sichuan Medical College and underwent abdominal surgery from November 2019 to May 2022 were collected from the Union Digital Medical Record (UniDMR) Browser of the hospital. According to whether postoperative complications (infection, hypokalemia, hypoproteinemia, poor wound healing and intestinal obstruction) occurred, the patients were divided into complication group (n = 98) and non-complication group (n = 196). Univariate and multivariate logistic regression analysis were used to analyze the risk factors of complications in elderly gynecological patients undergoing abdominal surgery. The receiver operating characteristic (ROC) curve was used to determine the predictive value of the frailty index score in elderly gynecological patients with postoperative complications after abdominal surgery. RESULTS: Postoperative complications occurred in 98 of 294 elderly gynecological patients undergoing abdominal surgery, accounting for 33.3%, 5-mFI (OR1.63, 95%CI 1.07-2.46,P = 0.022), age (OR1.08,95%CI 1.02-1.15, P = 0.009), operation time (OR 1.01, 95%CI 1.00-1.01). P < 0.001) were independent risk factors for postoperative complications in elderly patients undergoing abdominal surgery, and the area under the curve of postoperative complications in elderly gynecological patients was 0.60. (95%CI: 0.53-0.67, P = 0.005) CONCLUSION: Five modified frailty index can effectively predict the occurrence of postoperative complications in elderly gynecological patients.