Isolinderalactone suppresses pancreatic ductal adenocarcinoma by activating p38 MAPK to promote DDIT3 expression and trigger endoplasmic reticulum stress.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies worldwide, and its incidence rate is increasing. PDAC patients are prone to acquired chemotherapy resistance, necessitating the development of novel drugs to provide alternative treatment options. In recent years, traditional folk medicine and its active ingredients have garnered increasing attention for their effectiveness in treating tumors. Here, we discovered that isolinderalactone (ILL), a sesquiterpenoid compound extracted from the traditional Chinese medicine Lindera aggregata (Sims) Kosterm., possesses anti-PDAC pharmacological activity. Our results revealed that ILL decreased the proliferative capacity of PDAC cells in a time- and dose-dependent manner. The migration and invasion abilities of tumor cells were significantly suppressed due to the inhibition of epithelial-to-mesenchymal transition (EMT). Additionally, the cell cycle was arrested in the G2/M phase, leading to apoptosis, and inhibiting inflammatory responses. Mechanistically, bioinformatics analysis of molecular expression changes combined with in vivo and in vitro experiments demonstrated that ILL induces persistent ER stress by activating p38 MAPK signaling pathway, thus promoting the expression of DDIT3, and ultimately suppressing progression-related cell behaviors. Animal experiments confirmed that ILL also inhibited PDAC development in vivo with minimal toxicity. In summary, our study identified ILL as a potential therapeutic compound for PDAC treatment.

Unveiling the immunogenicity of allogeneic mesenchymal stromal cells: Challenges and strategies for enhanced therapeutic efficacy.

Mesenchymal stromal cells (MSCs) exhibit significant potential in the context of cell therapy because of their capacity to perform a range of interconnected functions in damaged tissues, including immune modulation, hematopoietic support, and tissue regeneration. MSCs are hypoimmunogenic because of their diminished expression of major histocompatibility molecules, absence of costimulatory molecules, and presence of coinhibitory molecules. While autologous MSCs reduce the risk of rejection and infection, variability in cell numbers and proliferation limits their potential applications. Conversely, allogeneic MSCs (allo-MSCs) possess broad clinical applications unconstrained by donor physiology. Nonetheless, preclinical and clinical investigations highlight that transplanted allo-MSCs are subject to immune attack from recipients. These cells exhibit anti-inflammatory and proinflammatory phenotypes contingent on the microenvironment. Notably, the proinflammatory phenotype features enhanced immunogenicity and diminished immunosuppression, potentially triggering allogeneic immune reactions that impede long-term clinical efficacy. Consequently, preserving the low immunogenicity of allo-MSCs in vivo and mitigating immune rejection in diverse microenvironments represent crucial challenges for the widespread clinical application of MSCs. In this review, we elucidate the immune regulation of allo-MSCs, specifically focusing on two distinct subgroups, MSC1 and MSC2, that exhibit varying polarization states and immunogenicity. We discuss the factors and underlying mechanisms that induce MSC immunogenicity and polarization, highlighting the crucial role of major histocompatibility complex class I/II molecules in rejection post-transplantation. Additionally, we summarize the immunogenic regulatory targets and applications of allo-MSCs and outline strategies to address challenges in this promising field, aiming to enhance allo-MSC therapeutic efficacy for patients.

Spatio-temporal mapping of leaf area index in rice: spectral indices and multi-scale texture comparison derived from different sensors.

Introduction: Monitoring the leaf area index (LAI), which is directly related to the growth status of rice, helps to optimize and meet the crop's fertilizer requirements for achieving high quality, high yield, and environmental sustainability. The remote sensing technology of the unmanned aerial vehicle (UAV) has great potential in precision monitoring applications in agriculture due to its efficient, nondestructive, and rapid characteristics. The spectral information currently widely used is susceptible to the influence of factors such as soil background and canopy structure, leading to low accuracy in estimating the LAI in rice. Methods: In this paper, the RGB and multispectral images of the critical period were acquired through rice field experiments. Based on the remote sensing images above, the spectral indices and texture information of the rice canopy were extracted. Furthermore, the texture information of various images at multiple scales was acquired through resampling, which was utilized to assess the estimation capacity of LAI. Results and discussion: The results showed that the spectral indices (SI) based on RGB and multispectral imagery saturated in the middle and late stages of rice, leading to low accuracy in estimating LAI. Moreover, multiscale texture analysis revealed that the texture of multispectral images derived from the 680 nm band is less affected by resolution, whereas the texture of RGB images is resolution dependent. The fusion of spectral and texture features using random forest and multiple stepwise regression algorithms revealed that the highest accuracy in estimating LAI can be achieved based on SI and texture features (0.48 m) from multispectral imagery. This approach yielded excellent prediction results for both high and low LAI values. With the gradual improvement of satellite image resolution, the results of this study are expected to enable accurate monitoring of rice LAI on a large scale.

Carbapenem-resistant Enterobacterales sepsis following endoscopic retrograde cholangiopancreatography: risk factors for 30-day all-cause mortality and the development of a nomogram based on a retrospective cohort.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) has become a routine endoscopic procedure that is essential for diagnosing and managing various conditions, including gallstone extraction and the treatment of bile duct and pancreatic tumors. Despite its efficacy, post-ERCP infections - particularly those caused by carbapenem-resistant Enterobacterales (CRE) - present significant risks. These risks highlight the need for accurate predictive models to enhance postprocedural care, reduce the mortality risk associated with post-ERCP CRE sepsis, and improve patient outcomes in the context of increasing antibiotic resistance. OBJECTIVE: This study aimed to examine the risk factors for 30-day mortality in patients with CRE sepsis following ERCP and to develop a nomogram for accurately predicting 30-day mortality risk. METHODS: Data from 195 patients who experienced post-ERCP CRE sepsis between January 2010 and December 2022 were analyzed. Variable selection was optimized via the least absolute shrinkage and selection operator (LASSO) regression model. Multivariate logistic regression analysis was then employed to develop a predictive model, which was evaluated in terms of discrimination, calibration, and clinical utility. Internal validation was achieved through bootstrapping. RESULTS: The nomogram included the following predictors: age > 80 years (hazard ratio [HR] 2.61), intensive care unit (ICU) admission within 90 days prior to ERCP (HR 2.64), hypoproteinemia (HR 4.55), quick Pitt bacteremia score ≥ 2 (HR 2.61), post-ERCP pancreatitis (HR 2.52), inappropriate empirical therapy (HR 3.48), delayed definitive therapy (HR 2.64), and short treatment duration (< 10 days) (HR 5.03). The model demonstrated strong discrimination and calibration. CONCLUSIONS: This study identified significant risk factors associated with 30-day mortality in patients with post-ERCP CRE sepsis and developed a nomogram to accurately predict this risk. This tool enables healthcare practitioners to provide personalized risk assessments and promptly administer appropriate therapies against CRE, thereby reducing mortality rates.

Spatial domain dedispersion transform and its application extracting horizontal wavenumber structure.

Dispersion and multipath effects contribute to the complexity of the shallow water acoustic field. However, this complexity contains valuable information regarding both the waveguide and the acoustic source. The horizontal wavenumber and relative amplitude of the modes comprising the acoustic field are crucial pieces of information for addressing acoustic inversion problems in shallow water. However, when employing a horizontal array to extract this information, limitations arise due to array aperture and signal-to-noise ratio constraints. To attempt to solve these challenges, the approach of spatial domain dedispersion transform and frequency domain accumulation is proposed. The objective can be attained by leveraging broadband source with slowly varying phase spectrum or known phase spectrum under the constraints of small aperture arrays and low signal-to-noise ratio. Additionally, the approach is validated on dual-hydrophone horizontal array by relaxing the signal-to-noise ratio requirement. In this paper, theoretical proof of the algorithms' performance is provided, accompanied by analysis of the impact of parameters such as acoustic source bandwidth, the number of elements and array aperture. The effectiveness of the algorithms are validated through simulations and experimental data.

Long-chain fatty acids - The turning point between 'mild' and 'severe' acute pancreatitis.

Acute pancreatitis (AP) is an inflammatory disease characterized by localized pancreatic injury and a systemic inflammatory response. Fatty acids (FAs), produced during the breakdown of triglycerides (TGs) in blood and peripancreatic fat, escalate local pancreatic inflammation to a systemic level by damaging pancreatic acinar cells (PACs) and triggering M1 macrophage polarization. This paper provides a comprehensive analysis of lipases' roles in the onset and progression of AP, as well as the effects of long-chain fatty acids (LCFAs) on the function of pancreatic acinar cells (PACs). Abnormalities in the function of PACs include Ca2+ overload, premature trypsinogen activation, protein kinase C (PKC) expression, endoplasmic reticulum (ER) stress, and mitochondrial and autophagic dysfunction. The study highlights the contribution of long-chain saturated fatty acids (LC-SFAs), especially palmitic acid (PA), to M1 macrophage polarization through the activation of the NLRP3 inflammasome and the NF-κB pathway. Furthermore, we investigated lipid lowering therapy for AP. This review establishes a theoretical foundation for pro-inflammatory mechanisms associated with FAs in AP and facilitating drug development.

Aspirin treatment for unruptured intracranial aneurysms: Focusing on its anti-inflammatory role.

Intracranial aneurysms (IAs), as a common cerebrovascular disease, claims a worldwide morbidity rate of 3.2%. Inflammation, pivotal in the pathogenesis of IAs, influences their formation, growth, and rupture. This review investigates aspirin's modulation of inflammatory pathways within this context. With IAs carrying significant morbidity and mortality upon IAs rupture and current interventions limited to surgical clipping and endovascular coiling, the quest for pharmacological options is imperative. Aspirin's role in cardiovascular prevention, due to its anti-inflammatory effects, presents a potential therapeutic avenue for IAs. In this review, we examine aspirin's efficacy in experimental models and clinical settings, highlighting its impact on the progression and rupture risks of unruptured IAs. The underlying mechanisms of aspirin's impact on IAs are explored, with its ability examined to attenuate endothelial dysfunction and vascular injury. This review may provide a theoretical basis for the use of aspirin, suggesting a promising strategy for IAs management. However, the optimal dosing, safety, and long-term efficacy remain to be established. The implications of aspirin therapy are significant in light of current surgical and endovascular treatments. Further research is encouraged to refine aspirin's clinical application in the management of unruptured IAs, with the ultimate aim of reducing the incidence of aneurysms rupture.

Comparative Effects of Exercise Interventions and Mindfulness-Based Interventions for Cognitive Impairment and Quality of Life in Breast Cancer Survivors During or After Cancer Treatment: A Systematic Review and Bayesian Network Meta-analysis.

OBJECTIVE: The aim of this network meta-analysis was to compare the improvement effects of various exercise interventions and mindfulness-based interventions to determine the best interventions for the improvement of cognitive impairment. DESIGN: Seven databases were searched to screen randomized controlled trials of exercise interventions and mindfulness-based interventions to improve cognitive impairment. The network meta-analysis was performed using Revman 5.3, R 4.2.1 and ADDIS 1.16.8 software. RESULTS: Thirty-four randomized controlled trials involving 14 interventions were included in the study. In terms of cognitive function, except for mindfulness-based stress reduction, all interventions showed significantly greater improvement in cognitive function compared with conventional therapy. Physical activity and Qigong showed better effect in improving executive function. In terms of improving verbal memory, compensatory cognitive training, neurofeedback training, Qigong, and sham Qigong were more effective than other interventions. On performing surface under the cumulative ranking curve analysis, acceptance and commitment therapy, neurofeedback training, Qigong, and mediation had the best effects on cognitive function, quality of life, executive function, and processing speed, respectively. CONCLUSIONS: Mindfulness-based interventions were found to be more effective than exercise interventions for alleviating cognitive impairment. More robust randomized controlled trials focusing on acceptance and commitment therapy for cognitive impairment are required to support the current evidence.

Toll-like receptor 2 deficiency promotes the generation of alloreactive γδT17 cells after cardiac transplantation in mice.

Homograft rejection is the main cause of heart transplantation failure. The role of TLR2, a major member of the toll-like receptor (TLR) family, in transplantation rejection is has yet to be elucidated. In this study, we used a mouse model of acute cardiac transplantation rejection to investigate whether the TLR2 signalling pathway can regulate cardiac transplantation rejection by regulating alloreactive IL-17+γδT (γδT17) cells. We found that the expression of TLR2 on the surface of dendritic cells (DCs) and macrophages increased during acute transplantation rejection. In addition, our investigation revealed that γδT17 cells exert a significant influence on acute cardiac transplantation rejection. TLR2 gene knockout resulted in an increase in alloreactive γδT17 cells in the spleen and heart grafts of recipient mice compared with wild-type recipient mice and an increase in the mRNA expression of IL-17, IL-1ß, CCR6, and CCL20 in the heart grafts. In an in vitro experiment, a mixed lymphocyte reaction was conducted to assess the impact of TLR2 deficiency on the generation of γδT17 cells, which further substantiated a significant increase compared to that in wild-type controls. Furthermore, the mixed lymphocyte reaction showed that TLR2 regulated the production of γδT17 cells by regulating the ability of DCs to secrete IL-1ß. These results suggest that TLR2 signalling is important for regulating the generation of γδT17 cells after cardiac allograft transplantation.

Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice.

Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude sickness. Autophagy plays a critical role in ischemic brain injury, but its role in hypobaric hypoxia (HH) remains unknown. Here we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain, and is partially responsible for HH-induced oxidative stress, neuronal loss, and brain damage. The autophagic agonist rapamycin only promotes the initiation of autophagy. By proteome analysis, a screen showed that protein dynamin2 (DNM2) potentially regulates autophagic flux. Overexpression of DNM2 significantly increased the formation of autolysosomes, thus maintaining autophagic flux in combination with rapamycin. Furthermore, the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH exposure. These results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.

Shank3 ameliorates neuronal injury after cerebral ischemia/reperfusion via inhibiting oxidative stress and inflammation.

Shank3, a key molecule related to the development and deterioration of autism, has recently been found to downregulate in the murine brain after ischemia/reperfusion (I/R). Despite this discovery, however, its effects on neuronal injury and the mechanism underlying the effects remain to be clarified. To address this, in this study, based on genetically modified mice models, we revealed that the expression of Shank3 showed a time-dependent change in murine hippocampal neurons after I/R, and that conditional knockout (cko) of Shank3 in neurons resulted in aggravated neuronal injuries. The protective effects of Shank3 against oxidative stress and inflammation after I/R were achieved through direct binding STIM1 and subsequent proteasome-mediated degradation of STIM1. The STIM1 downregulation induced the phosphorylation of downstream Nrf2 Ser40, which subsequently translocated to the nucleus, and further increased the expression of antioxidant genes such as NQO1 and HO-1 in HT22 cells. In vivo, the study has further confirmed that double knockout of Shank3 and Stim1 alleviated oxidative stress and inflammation after I/R in Shank3cko mice. In conclusion, the present study has demonstrated that Shank3 interacts with STIM1 and inhibits post-I/R neuronal oxidative stress and inflammatory response via the Nrf2 pathway. This interaction can potentially contribute to the development of a promising method for I/R treatment.

Palladium-Catalyzed Cross-Coupling of gem-Difluorocyclopropanes with gem-Diborylalkanes for the Synthesis of Boryl-Substituted Fluorinated Alkenes.

This study presents a novel method for the regioselective coupling of gem-difluorinated cyclopropanes with gem-diborylmethane, utilizing a Pd-catalyst system. This innovative approach enables the synthesis of 2-fluoroalkenyl monoboronate scaffolds with high Z-selectivity. The resulting products undergo further transformations, including oxidation, Suzuki cross-coupling, and trifluoroborylation, all of which are achieved with good yields. This work introduces a valuable synthetic pathway to access important fluorinated compounds for various applications in organic chemistry.

Cucurbitacin C suppresses the progression of pancreatic ductal adenocarcinoma via inhibition of the cGMP-PKG-VASP axis.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating diseases; it has a considerably poor prognosis and may become the second most lethal malignancy in the next 10 years. Chemotherapeutic resistance is common in PDAC; thus, it is necessary to exploit effective alternative drugs. In recent years, traditional folk medicines and their extracts have shown great potential in cancer treatment. The seed of Lagenaria siceraria (Molina) Standl. is a traditional medicine in Asia. Because of its analgesic effects and ability to reduce swelling, it is often used as an adjuvant treatment for abdominal tumors. Cucurbitacin compounds are extracts abundant in Lagenaria siceraria (Molina) Standl. Here, we found that cucurbitacin C (CuC), a member of the cucurbitacin family, has apparent anti-PDAC therapeutic properties. CuC decreased the viability and suppressed the proliferation of PDAC cells in a time- and dose-dependent manner. Further studies revealed that CuC inhibited cell migration and invasion by inhibiting epithelial-mesenchymal transition (EMT). In addition, G2/M arrest was induced, and the apoptotic pathway was activated. Transcriptomic and bioinformatic analyses showed that CuC inhibited the cGMP-PKG-VASP axis, increasing the content of cGMP to restore tumor characteristics. The antitumor activity of CuC in vivo was verified through animal experiments, and no obvious side effects were observed. Overall, our study indicates a candidate therapeutic compound for PDAC that is worthy of further development.

Adhesion of Escherichia coli O157:H7 during sublethal injury and resuscitation: Importance of pili and surface properties.

Escherichia coli O157:H7 can recover from sublethally injured (SI) state, which causes threat of foodborne illness. Adhesion plays a key role in the carriage of pathogens in food. In this study, we investigated the adhesion ability of SI and recovered E. coli O157:H7 wildtype and its three pili-deficient mutants (curli, type 1 fimbriae, and type IV pili) on six food-related surfaces. Plate counting was used to determine adhesion population after washing and oscillating the surfaces. Spinach exhibited the stronger adhesion population of E. coli O157:H7 than the other fresh produces (p < 0.05). In addition, at least one key pili dominated adhesion on these surfaces, and curli was always included. The adhesion population and contribution of different types of pili were jointly affected by surface and physiological state. This can be attributed to high hydrophobicity and positive charge density on surface and different expression levels of csgB, fimA, fimC and ppdD in SI and recovered cells. Among glucose, mannose, maltose, fructose, lactose, and sucrose, addition of 0.5% mannose could reduce adhesion of cells at all physiological states on stainless steel. Overall, this research will provide support for controlling adhesion of SI and recovered E. coli O157:H7.

Toll-like receptor 2 deficiency alleviates acute pancreatitis by inactivating the NF-κB/NLRP3 pathway.

The early aseptic immune response is the key factor leading to the aggravation of acute pancreatitis (AP). Toll-like receptor (TLR) 2 is an important member of the TLR family, but the role of TLR2 in AP remains to be investigated. In the present study, we found that TLR2 expression was significantly increased in AP patients. In a mouse model of cerulein-induced AP, TLR2 deficiency resulted in reduced inflammation, reduced infiltration of pancreatic neutrophils and macrophages, and decreased expression of proinflammatory cytokines such as interleukin (IL)-1ß, IL-6, IL-17 and IL-18. In addition, transcriptomic analysis revealed that nod-like receptor family pyrin domain-containing 3 (NLRP3) expression was increased in AP, and there was a significant correlation between NLRP3 and TLR2. This study found that TLR2 deficiency can lead to a decrease in the activation of the NF-κB/NLRP3 signalling pathway, and the NLRP3 inhibitor MCC950 can alleviate AP in mice. Therefore, this study confirmed that TLR2 participates in the development of AP by activating the NF-κB/NLRP3 pathway. This study suggested that TLR2 might be a novel therapeutic target for AP.

Visible-Light-Induced Selective α-Fluoroarylation of Secondary N-Alkyl Anilines with Polyfluoroarenes via Direct C-H/C-F Coupling.

Direct and selective fluoroarylations of nucleophilic secondary alkylanilines with polyfluoroarenes were first realized through visible-light-induced C-H/C-F couplings with the assistance of bases. Varieties of α-polyfluoroarylanilines were selectively produced with this protocol from polyfluoroarenes and N-alkylanilines, including natural products and pharmaceutical molecule derivatives. Mechanistic studies illustrated base-promoted photochemical C-H cleavage of the α-C-H bonds of alkylanilines to produce the N-α-carbon radical and then radical addition to polyfluoroarenes.

The causal effects of inflammatory bowel disease on primary biliary cholangitis: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Observational studies have indicated that the incidence of primary biliary cholangitis (PBC) is higher in inflammatory bowel disease (IBD) patients than that in healthy people. However, whether the correlation is causal remains unclear. METHODS: The genetic associations with IBD were obtained from publicly available genome-wide association studies (GWAS) of European ancestry with 31 665 cases and 33 977 controls, consisting of 17 897 Crohn's disease (CD) and 13 768 ulcerative colitis (UC) cases. The genetic associations with PBC were obtained from a European GWAS with 2764 cases and 10 475 controls. A bidirectional two-sample Mendelian randomization (MR) design was implemented to determine the causal relationship between IBD and PBC. In the forward MR, the IBD was treated as the exposure while the PBC was the exposure in the reverse MR. The inverse-variance-weighted (IVW) method was utilized as the main statistic method, and a series of sensitivity analyses were performed to detect heterogeneity and horizontal pleiotropy. RESULTS: A total of 99 valid instrumental variables (IVs) were selected for IBD and the number of IVs for PBC was 18. The forward MR analysis indicated that genetically predicted IBD (UC and CD) was significantly associated with an increased risk of PBC (IVW OR = 1.343; 95% CI: 1.220-1.466). Similar casual associations were observed in UC (IVW OR = 1.244; 95% CI: 1.057-1.430) and CD (IVW OR = 1.269; 95% CI: 1.159-1.379). Such results were still consistent in multiple MR methods. The reverse MR analysis implicated that genetic susceptibility to PBC might not alter the risk of IBD (IVW OR = 1.070; 95% CI: 0.984-1.164). CONCLUSION: Our study found that genetically predicted IBD can increase the risk of PBC while not vice versa in the European population, which may enlighten the aetiology of PBC, together with the IBD patient management.

What affects self-regulated learning ability in undergraduate nursing students: A structural equation modelling approach.

AIM: To examine how the effects of hardiness, self-efficacy and positive academic emotion related to the SRL ability of undergraduate nursing students. DESIGN: A cross-sectional survey was designed. METHODS: A total of 395 Chinese undergraduate nursing students from two undergraduate colleges filled out the questionnaires from May to June 2019. The relationships between hardiness, self-efficacy, positive academic emotion and SRL ability were analysed by structural equation modelling. RESULTS: The response rate was 94.05%. SRL ability was significantly positive correlated with hardiness, self-efficacy and positive academic emotion in undergraduate nursing students. Self-efficacy (ß = 0.417, p < 0.001) and positive academic emotion (ß = 0.232, p < 0.001) showed a direct effect on the SRL ability. Although hardiness showed no direct effect on the SRL ability, it affected SRL ability through three indirect ways: self-efficacy (77.778%), positive academic emotion (14.184%) and the chain mediating effect from self-efficacy to positive academic emotion (8.038%). CONCLUSIONS: Nursing students with a higher level of hardiness would have higher self-efficacy, and more positive and stable academic emotions to obtain the better SRL ability. The produced model provides insights into several factors associated with SRL ability of nursing students. Hardiness, self-efficacy and positive academic emotion should be emphasized in the education of nursing students because these factors could improve their SRL ability and promote their life-long learning.

Stromal Interaction Molecule 1-Mediated Store-Operated Calcium Entry Promotes Autophagy Through AKT/Mammalian Target of Rapamycin Pathway in Hippocampal Neurons After Ischemic Stroke.

The pathophysiological process of neuronal injury due to cerebral ischemia is complex among which disturbance of calcium homeostasis and autophagy are two major pathogenesis. However, it remains ambiguous whether the two factors are independent. Stromal interaction molecule 1 (STIM1) is the most important Ca2+ sensor mediating the store-operated Ca2+ entry (SOCE) through interacting with Orai1 and has recently been proven to participate in autophagy in multiple cells. In this study, we aimed to investigate the potential role of STIM1-induced SOCE on autophagy and whether its regulator function contributes to neuronal injury under hypoxic conditions using in vivo transient middle cerebral artery occlusion (tMCAO) model and in vitro oxygen and glucose deprivation (OGD) primary cultured neuron model respectively. The present data indicated that STIM1 induces autophagic flux impairment in neurons through promoting SOCE and inhibiting AKT/mTOR signaling pathway. Pharmacological inhibition of SOCE or downregulation of STIM1 with siRNA suppressed the autophagic activity in neurons. Moreover, stim1 knockdown attenuated neurological deficits and brain damage after tMCAO, which could be reversed by AKT/mTOR pathway inhibitor AZD5363. Together, the modulation of STIM1 on autophagic activation indicated the potential link between Ca2+ homeostasis and autophagy which provided evidence that STIM1 could be a promising therapeutic target for ischemic stroke.

Development and Assessment of a Novel Predictive Nomogram to Predict the Risk of Secondary CR-GNB Bloodstream Infections among CR-GNB Carriers in the Gastroenterology Department: A Retrospective Case-Control Study.

BACKGROUND: With the number of critically ill patients increasing in gastroenterology departments (GEDs), infections associated with Carbapenem-resistant Gram-negative bacteria (CR-GNB) are of great concern in GED. However, no CR-GNB bloodstream infection (BSI) risk prediction model has been established for GED patients. Almost universally, CR-GNB colonization precedes or occurs concurrently with CR-GNB BSI. The objective of this study was to develop a nomogram that could predict the risk of acquiring secondary CR-GNB BSI in GED patients who are carriers of CR-GNB. METHODS: We conducted a single-center retrospective case-control study from January 2020 to March 2022. Univariate and multivariable logistic regression analysis was used to identify independent risk factors of secondary CR-GNB bloodstream infections among CR-GNB carriers in the gastroenterology department. A nomogram was constructed according to a multivariable regression model. Various aspects of the established predicting nomogram were evaluated, including discrimination, calibration, and clinical utility. We assessed internal validation using bootstrapping. RESULTS: The prediction nomogram includes the following predictors: high ECOG PS, severe acute pancreatitis, diabetes mellitus, neutropenia, a long stay in hospital, and parenteral nutrition. The model demonstrated good discrimination and good calibration. CONCLUSIONS: With an estimate of individual risk using the nomogram developed in this study, clinicians and nurses can identify patients with a high risk of secondary CR-GNB BSI early.