RAD51 Expression as a Biomarker to Predict Efficacy of Platinum-Based Chemotherapy and PD-L1 Blockade for Muscle-Invasive Bladder Cancer.

RAD51, a key recombinase that catalyzes homologous recombination (HR), is commonly overexpressed in multiple cancers. It is curial for DNA damage repair (DDR) to maintain genomic integrity which could further determine the therapeutic response. Herein, we attempt to explore the clinical value of RAD51 in therapeutic guidance in muscle-invasive bladder cancer (MIBC). In this retrospective study, a total of 823 patients with MIBC were included. Zhongshan hospital (ZSHS) cohort (n=134) and The Cancer Genome Atlas-Bladder Cancer (TCGA-BLCA) cohort (n=391) were included for the investigation of chemotherapeutic response. The IMvigor210 cohort (n=298) was utilized to interrogate the predictive efficacy of RAD51 status to programmed cell death ligand-1 (PD-L1) blockade. In addition, the association of RAD51 with genomic instability and tumor immune contexture was investigated. Patients with RAD51 overexpression were more likely to benefit from both platinum-based chemotherapy and immunotherapy rather than RAD51-low patients. The TMBhighPD-L1highRAD51high subgroup possessed the best clinical benefits from PD-L1 blockade. RAD51-high tumors featured by genomic instability were correlated to highly inflamed and immunogenic contexture with activated immunotherapeutic pathway in MIBC. RAD51 could serve as a prognosticator for treatment response to platinum-based chemotherapy and PD-L1 inhibitor in MIBC patients. Besides, it could also improve the predictive efficacy of TMB and PD-L1.

Association of air temperature exposure during pregnancy with risk of preeclampsia in Guangzhou, China.

Environmental exposures during pregnancy have been associated with adverse obstetric outcomes. However, limited and inconsistent evidence exists regarding the association between air temperature exposure and the risk of preeclampsia (PE). This study aimed to evaluate the correlation between ambient temperature exposure during pregnancy and PE risk, as well as identify the specific time window of temperature exposure that increases PE risk. A population-based cohort study was conducted from January 2012 to April 2022 in Guangzhou, China. Pregnant women were recruited in early pregnancy and followed until delivery. A total of 3,314 PE patients and 114,201 normal pregnancies were included. Ambient temperature exposures at different gestational weeks were recorded for each participant. Logistic regression models were used to evaluate the correlation between ambient temperature exposure and PE risk. Stratified analyses were conducted based on maternal age and pre-pregnancy BMI. Distributed lag models were employed to identify the time window of temperature exposure related to PE. Exposure to extreme high temperature (aOR = 1.24, 95 % CI 1.12-1.38) and moderate high temperature (aOR = 1.22, 95 % CI 1.10-1.35) during early pregnancy was associated with an increased risk of PE. Furthermore, women with higher pre-pregnancy BMI had a higher risk of developing PE when exposed to high temperature during early pregnancy compared to normal-weight women. The time window of temperature exposure related to PE was identified as pregnancy weeks 1 to 8. This study provides evidence for the association of high temperature exposure during early pregnancy with the risk of PE, as well as identifies the specific time window of temperature exposure related to PE. These findings have implications for developing potential strategies to protect pregnant women, particularly those with higher pre-pregnancy BMI, from the adverse effects of extreme temperatures during early pregnancy.

Therapeutic robots for post-stroke rehabilitation.

Stroke is a prevalent, severe, and disabling health-care issue on a global scale, inevitably leading to motor and cognitive deficits. It has become one of the most significant challenges in China, resulting in substantial social and economic burdens. In addition to the medication and surgical interventions during the acute phase, rehabilitation treatment plays a crucial role in stroke care. Robotic technology takes distinct advantages over traditional physical therapy, occupational therapy, and speech therapy, and is increasingly gaining popularity in post-stroke rehabilitation. The use of rehabilitation robots not only alleviates the workload of healthcare professionals but also enhances the prognosis for specific stroke patients. This review presents a concise overview of the application of therapeutic robots in post-stroke rehabilitation, with particular emphasis on the recovery of motor and cognitive function.

POLQ identifies a better response subset to immunotherapy in muscle-invasive bladder cancer with high PD-L1.

BACKGROUND: Though programmed cell death-ligand 1 (PD-L1) has been used in predicting the efficacy of immune checkpoint blockade (ICB), it is insufficient as a single biomarker. As a key effector of an intrinsically mutagenic microhomology-mediated end joining (MMEJ) pathway, DNA polymerase theta (POLQ) was overexpressed in various malignancies, whose expression might have an influence on genomic stability, therefore altering the sensitivity to chemotherapy and immunotherapy. METHODS: A total of 1304 patients with muscle-invasive bladder cancer (MIBC) from six independent cohorts were included in this study. The Zhongshan Hospital (ZSHS) cohort (n = 134), The Cancer Genome Atlas (TCGA) cohort (n = 391), and the Neo-cohort (n = 148) were included for the investigation of chemotherapeutic response. The IMvigor210 cohort (n = 234) and the UNC-108 cohort (n = 89) were used for the assessment of immunotherapeutic response. In addition, the relationship between POLQ and the immune microenvironment was assessed, and GSE32894 (n = 308) was used only for the evaluation of the immune microenvironment. RESULTS: We identified POLQhigh PD-L1high patients could benefit more from immunotherapy and platinum-based chemotherapy. Further analysis revealed that high POLQ expression was linked to chromosome instability and higher tumor mutational burden (TMB), which might elicit the production of neoantigens. Further, high POLQ expression was associated with an active tumor immune microenvironment with abundant infiltration of immune effector cells and molecules. CONCLUSIONS: The study demonstrated that high POLQ expression was correlated with chromosome instability and antitumor immune microenvironment in MIBC, and the combination of POLQ and PD-L1 could be used as a superior companion biomarker for predicting the efficacy of immunotherapy.

Obesity correlates with the immunosuppressive ILC2s-MDSCs axis in advanced breast cancer.

AIM: We investigated the relationship between the group 2 innate lymphoid cells (ILC2s)-myeloid-derived suppressor cells (MDSCs) axis and obesity-related breast cancer. METHODS: Fifty-eight patients with breast cancer who had first relapse and metastasis between January 2019 and August 2021 were enrolled. The proportions of ILC2s and MDSCs in blood and the levels of cytokines in serum were detected with flow cytometry. Correlation analysis among clinical characteristics (such as body mass index [BMI]), cytokines, ILC2s, and MDSCs was conducted. RESULTS: There was a significant difference in the proportions of ILC2s and MDSCs between the high BMI group and the normal BMI group (p < .05). In the triple-negative breast cancer (TNBC) patients, the proportions of ILC2s and MDSCs in the obese group were significantly higher than those in the nonobese group (p < .05). In all breast cancer patients, there was a positive correlation between BMI and the ILC2s-MDSCs axis (p < .05). However, there was no correlation observed between the number of metastases, progression-free survival, and the ILC2s-MDSCs axis (p > .05). Additionally, ILC2s showed positive correlations with MDSCs, interleukin-5 (IL-5), IL-10, IL-17A, (PD-L1), programmed cell death 2 ligand 2 (PD-L2), and molecular typing (p < .05). Similarly, MDSCs exhibited positive correlations with IL-5, IL-8, IL-9, IL-17A, PD-L1, and PD-L2 (p < .05). In patients with TNBC, there was a positive correlation between BMI and IL-5 (p < .05). CONCLUSION: Conclusively, obesity may enhance the immunosuppressive effect of the ILC2-MDSC axis in advanced breast cancer. IL-5 may play a vital role in the ILC2-MDSC axis and obesity in TNBC.

Integrating molecular subtype and CD8+ T cells infiltration to predict treatment response and survival in muscle-invasive bladder cancer.

BACKGROUND: Luminal and Basal are the primary intrinsic subtypes of muscle-invasive bladder cancer (MIBC). The presence of CD8+ T cells infiltration holds significant immunological relevance, potentially influencing the efficacy of antitumor responses. This study aims to synergize the influence of molecular subtypes and CD8+ T cells infiltration in MIBC. METHODS: This study included 889 patients with MIBC from Zhongshan Hospital, The Cancer Genome Atlas, IMvigor210 and NCT03179943 cohorts. We classified the patients into four distinct groups, based on the interplay of molecular subtypes and CD8+ T cells and probed into the clinical implications of these subgroups in MIBC. RESULTS: Among patients with Luminal-CD8+Thigh tumors, the confluence of elevated tumor mutational burden and PD-L1 expression correlated with a heightened potential for positive responses to immunotherapy. In contrast, patients featured by Luminal-CD8+Tlow displayed a proclivity for deriving clinical advantages from innovative targeted interventions. The Basal-CD8+Tlow subgroup exhibited the least favorable three-year overall survival outcome, whereas their Basal-CD8+Thigh counterparts exhibited a heightened responsiveness to chemotherapy. CONCLUSIONS: We emphasized the significant role of immune-molecular subtypes in shaping therapeutic approaches for MIBC. This insight establishes a foundation to refine the process of selecting subtype-specific treatments, thereby advancing personalized interventions for patients.

Integration of CD4+ T cells and molecular subtype predicts benefit from PD-L1 blockade in muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4+ T cells, there is an emerging need to integrate CD4+ T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune-molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4+ Thigh, which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4+ Tlow, characterized by the highest level of fibroblast growth factor receptor 3 (FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4+ Thigh, which could benefit from a combination of ICB and chemotherapy; and basal CD4+ Tlow, characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor-ß (TGF-ß) inhibition. This immune-molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC.

Logic "AND Gate Circuit"-Based Gasdermin Protein Expressing Nanoplatform Induces Tumor-Specific Pyroptosis to Enhance Cancer Immunotherapy.

Pyroptosis mediated by gasdermin protein has shown great potential in cancer immunotherapies. However, the low expression of gasdermin proteins and the systemic toxicity of nonspecific pyroptosis limit its clinical application. Here, we designed a synthetic biology strategy to construct a tumor-specific pyroptosis-inducing nanoplatform M-CNP/Mn@pPHS, in which a pyroptosis-inducing plasmid (pPHS) was loaded onto a manganese (Mn)-doped calcium carbonate nanoparticle and wrapped in a tumor-derived cell membrane. M-CNP/Mn@pPHS showed an efficient tumor targeting ability. After its internalization by tumor cells, the degradation of M-CNP/Mn@pPHS in the acidic endosomal environment allowed the efficient endosomal escape of plasmid pPHS. To trigger tumor-specific pyroptosis, pPHS was designed according to the logic "AND gate circuit" strategy, with Hif-1α and Sox4 as two input signals and gasdermin D induced pyroptosis as output signal. Only in cells with high expression of Hif-1α and Sox4 simultaneously will the output signal gasdermin D be expressed. Since Hif-1α and Sox4 are both specifically expressed in tumor cells, M-CNP/Mn@pPHS induces the tumor-specific expression of gasdermin D and thus pyroptosis, triggering an efficient immune response with little systemic toxicity. The Mn2+ released from the nanoplatform further enhanced the antitumor immune response by stimulating the cGAS-STING pathway. Thus, M-CNP/Mn@pPHS efficiently inhibited tumor growth with 79.8% tumor regression in vivo. We demonstrate that this logic "AND gate circuit"-based gasdermin nanoplatform is a promising strategy for inducing tumor-specific pyroptosis with little systemic toxicity.

Self-Adjuvanting Polyguanidine Nanovaccines for Cancer Immunotherapy.

Tapping into the innate immune system's power, nanovaccines can induce tumor-specific immune responses, which is a promising strategy in cancer immunotherapy. However, traditional vaccine design, requiring simultaneous loading of antigens and adjuvants, is complex and poses challenges for mass production. Here, we developed a tumor nanovaccine platform that integrates adjuvant functions into the delivery vehicle, using branched polyguanidine (PolyGu) nanovaccines. These nanovaccines were produced by modifying polyethylenimine (PEI) with various guanidine groups, transforming PEI's cytotoxicity into innate immune activation. The PolyGu nanovaccines based on poly(phenyl biguanidine ) (Poly-PBG) effectively stimulated dendritic cells, promoted their maturation via the TLR4 and NLRP3 pathways, and displayed robust in vivo immune activity. They significantly inhibited tumor growth and extended mouse survival. The PolyGu also showed promise for constructing more potent mRNA-based nanovaccines, offering a platform for personalized cancer vaccine. This work advances cancer immunotherapy toward potential clinical application by introducing a paradigm for developing self-adjuvanting nanovaccines.

The effect of intelligent management interventions in intensive care units to reduce false alarms: An integrative review.

Objective: In intensive care units (ICU), frequent false alarms from medical equipment can cause alarm fatigue among nurses, which might lead to delayed or missed responses and increased risk of adverse patient events. This review was conducted to evaluate the effectiveness of intelligent management interventions to reduce false alarms in ICU. Method: Following the framework of Whitmore and Knafl, the reviewers systematically searched six databases: PubMed, EMBASE, CINAHL, OVID, Cochrane Library, and Scopus, and studies included intelligent management of clinical alarms published in the English or Chinese language from the inception of each database to December 2022 were retrieved. The researchers used the PICOS framework to formulate the search strategy, developed keywords, screened literature, and assessed the studies' quality using the Joanna Briggs Institute-Meta-Analysis of Statistics, Assessment, and Review Instrument (JBI-MAStARI). The review was preregistered on PROSPERO (CRD42023411552). Results: Seven studies met the inclusion criteria. The results showed that different interventions for intelligent management of alarms were beneficial in reducing the number of false alarms, the duration of alarms, the response time to important alarms for nurses, and the alarm fatigue levels among nurses. Positive results were found in practice after the application of the novel alarm management approaches. Conclusion: Intelligent management intervention may be an effective way to reduce false alarms. The application of systems or tools for the intelligent management of clinical alarms is urgent in hospitals. To ensure more effective patient monitoring and less distress for nurses, more alarm management approaches combined with artificial intelligence will be needed in the future to enable accurate identification of critical alarms, ensure nurses are responding accurately to alarms, and make a real difference to alarm-ridden healthcare environments.

Nurses' engagement in antimicrobial stewardship and its influencing factors: A cross-sectional study.

Objective: This study aimed to investigate the level and influencing factors of nurses' antimicrobial stewardship (AMS) engagement in China based on the capability, opportunity, motivation, and behavior (COM-B) theory, providing valuable insights for developing effective strategies to improve nursing quality in AMS. Methods: This cross-sectional study was conducted in 17 tertiary hospitals in Hunan, China, from November 2021 to January 2022. A total of 4,514 nurses were selected. The Nurse AMS Engagement Questionnaire (NAEQ), developed using the COM-B theory, was used for evaluation. The questionnaire included capability (14 items), opportunity (7 items), motivation (6 items), and behavior (12 items) four dimensions, 39 items. Results: The total NAEQ score was 155.08 ± 27.12, indicating a moderate level. The score of the capability, opportunity, motivation, and behavior dimensions were 52.33 ± 13.48, 28.64 ± 5.76, 24.57 ± 4.57 and 49.53 ± 8.83, respectively. Significant differences in nurses' AMS engagement were based on professional titles, whether working as a part-time infection control nurse, whether knowing the AMS teams and the defined daily doses of antibiotics, department type, the deployment of clinical pharmacists, and frequency of antimicrobial training and physician-nurse joint rounds (P < 0.05). Nurses with junior titles had higher scores on the NAEQ than nurses with intermediate titles (P < 0.05). Nurses who worked as part-time infection control nurses, knew the AMS team, and the defined daily doses of antibiotics had higher NAEQ scores than those who didn't (P < 0.01). Nurses working in the ICU and infectious disease department had lower NAEQ scores than those in other departments, such as the ear, nose, and throat (ENT) department (P < 0.01). Nurses who had clinical pharmacists deployed in their department had higher NAEQ scores than those without or unclear deployment (P < 0.01). Furthermore, nurses who received more frequent antimicrobial training and participated in physician-nurse joint rounds had higher NAEQ scores (P < 0.01). Conclusion: Multiple strategies, including enhanced education and training and improved multidisciplinary communication and collaboration, are expected to improve nurse AMS engagement. It is important to give more attention to nurses with intermediate professional titles, less experience, and those working in specific departments.

Status and related factors of professional growth among young nursing talents: a cross-sectional study in China.

BACKGROUND: The shortage of nurses has been a global human resources problem. A good professional growth environment is essential to developing potential nursing students and attracting nurses to join, and it has great significance in reducing nurse turnover. However, nurses' comprehensive perceptions of professional growth have not yet been examined. METHODS: A cluster sampling method was used to conduct a professional growth questionnaire survey on young nursing talents from a large Chinese public tertiary A hospital in March 2022. RESULTS: The score of professional growth among 243 young nursing talents was 57.92 ± 9.607, with a scoring rate of 77.23%. The scores for dimensions of professional growth, from lowest to highest, were rehabilitation growth, promotion speed, professional goal progress, and professional ability development. Attitudes towards participating in training, service as the quality manager or clinical teacher, self-efficacy, professional title, work-family support, education, and organizational commitment of young nursing talents were significantly associated with professional growth. CONCLUSION: The professional growth of young nursing talents was at a moderate level and needed to be strengthened. Nursing leaders and managers are expected to develop management practices to enhance young nursing talents' professional growth in combination with the related factors.

TP53 disruptive mutation predicts platinum-based chemotherapy and PD-1/PD-L1 blockade response in urothelial carcinoma.

TP53 mutation is one of the most common genetic alterations in urothelial carcinoma (UrCa), and heterogeneity of TP53 mutants leads to heterogeneous clinical outcomes. This study aimed to investigate the clinical relevance of specific TP53 mutations in UrCa. In this study, a total of eight cohorts were enrolled, along with matched clinical annotation. TP53 mutations were classified as disruptive and nondisruptive according to the degree of disturbance of p53 protein function and structure. We evaluated the clinical significance of TP53 mutations in our local datasets and publicly available datasets. The co-occurring events of TP53 mutations in UrCa, along with their therapeutic indications, functional effects, and the tumor immune microenvironment, were also investigated. TP53 mutations were identified in 49.7% of the UrCa patients. Within this group, 25.1% of patients carried TP53Disruptive mutations, a genetic alteration correlated with a significantly poorer overall survival (OS) when compared to individuals with TP53Nondisruptive mutations and those with wild-type TP53. Significantly, patients with TP53Disruptive mutations exhibit an increased probability of responding favorably to PD-1/PD-L1 blockade and chemoimmunotherapy. Meanwhile, there was no noteworthy distinction in OS among patients with varying TP53 mutation status who underwent chemotherapy. Samples with TP53Disruptive mutations showed an enriched APOBEC- and POLE-related mutational signature, as well as an elevated tumor mutation burden. The sensitivity to immunotherapy in tumors carrying TP53Disruptive mutation may be attributed to the inflamed tumor microenvironment characterized by increased CD8+T cell infiltration and interferon-gamma signaling activation. In conclusion, UrCa patients with TP53Disruptive mutations have shown reduced survival rates, yet they may respond well to PD-1/PD-L1 blockade therapy and chemoimmunotherapy. By distinguishing specific TP53 mutations, we can improve risk stratification and offer personalized genomics-guided therapy to UrCa patients. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Biomimetic-gasdermin-protein-expressing nanoplatform mediates tumor-specific pyroptosis for cancer immunotherapy.

Pyroptosis, mediated by gasdermin proteins, has shown excellent efficacy in facilitating cancer immunotherapy. The strategies commonly used to induce pyroptosis suffer from a lack of tissue specificity, resulting in the nonselective activation of pyroptosis and consequent systemic toxicity. Moreover, pyroptosis activation usually depends on caspase, which can induce inflammation and metabolic disorders. In this study, inspired by the tumor-specific expression of SRY-box transcription factor 4 (Sox4) and matrix metalloproteinase 2 (MMP2), we constructed a doubly regulated plasmid, pGMD, that expresses a biomimetic gasdermin D (GSDMD) protein to induce the caspase-independent pyroptosis of tumor cells. To deliver pGMD to tumor cells, we used a hyaluronic acid (HA)-shelled calcium carbonate nanoplatform, H-CNP@pGMD, which effectively degrades in the acidic endosomal environment, releasing pGMD into the cytoplasm of tumor cells. Upon the initiation of Sox4, biomimetic GSDMD was expressed and cleaved by MMP2 to induce tumor-cell-specific pyroptosis. H-CNP@pGMD effectively inhibited tumor growth and induced strong immune memory effects, preventing tumor recurrence. We demonstrate that H-CNP@pGMD-induced biomimetic GSDMD expression and tumor-specific pyroptosis provide a novel approach to boost cancer immunotherapy.

The action mechanism by which C1q/tumor necrosis factor-related protein-6 alleviates cerebral ischemia/reperfusion injury in diabetic mice.

JOURNAL/nrgr/04.03/01300535-202409000-00034/figure1/v/2024-01-16T170235Z/r/image-tiff Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of CTRP6 in cerebral ischemia/reperfusion injury associated with diabetes mellitus, a diabetes mellitus mouse model of cerebral ischemia/reperfusion injury was established by occlusion of the middle cerebral artery. To overexpress CTRP6 in the brain, an adeno-associated virus carrying CTRP6 was injected into the lateral ventricle. The result was that oxygen injury and inflammation in brain tissue were clearly attenuated, and the number of neurons was greatly reduced. In vitro experiments showed that CTRP6 knockout exacerbated oxidative damage, inflammatory reaction, and apoptosis in cerebral cortical neurons in high glucose hypoxia-simulated diabetic cerebral ischemia/reperfusion injury. CTRP6 overexpression enhanced the sirtuin-1 signaling pathway in diabetic brains after ischemia/reperfusion injury. To investigate the mechanism underlying these effects, we examined mice with depletion of brain tissue-specific sirtuin-1. CTRP6-like protection was achieved by activating the sirtuin-1 signaling pathway. Taken together, these results indicate that CTRP6 likely attenuates cerebral ischemia/reperfusion injury through activation of the sirtuin-1 signaling pathway.

Constipation preceding depression: a population-based cohort study.

Background: Constipation is generally considered a common physical symptom of depression or a side effect of antidepressant treatments. However, according to the gut-brain axis hypothesis, the association between depression and constipation might be bi-directional. This study investigated the association between premorbid constipation and depression. Methods: We conducted a retrospective cohort study using data from UK Biobank. Individuals free of depression between 2006 and 2010 were included. Constipation status was determined using diagnostic codes from electronic health records or a baseline questionnaire. Data on covariates, including socio-demographic characteristics, lifestyle factors, health conditions, and regular medication use, were also collected through a baseline questionnaire. The primary outcome is incident depression, which was extracted from hospital inpatient admissions, primary care, self-report, and death data from baseline to 2022. The secondary outcome is depressive symptoms, which was assessed by Patient Health Questionnaire-9 (PHQ-9) from an online survey in 2016. Cox proportional hazard regression models were employed to assess the prospective association between constipation and incident depression. Logistic regression models were used to assess its association with depressive symptoms. Findings: Among the 449,459 participants included in the study, 18,596 (4.1%) experienced constipation at baseline, and 18,576 (4.1%) developed depression over a median follow-up period of 12.3 years. Premorbid constipation is associated with a 2.28-fold higher risk of depression. After adjusting the covariates, we found those with constipation still had a 48% higher risk of developing depression (adjusted hazard ratio [aHR] 1.48; 95% CI, 1.41-1.56) than those without constipation. Self-reported and diagnosed constipation were both associated with a higher risk of depression, with the aHR being 1.42 (95% CI: 1.34-1.51) and 1.66 (95% CI: 1.51-1.82), respectively. Participants with constipation were more likely to report depressive symptoms than people without (adjusted odds ratio 2.18; 95% CI, 1.97-2.43). These findings remained consistent in sensitivity analyses. Interpretation: Diagnosed and self-reported constipation are both prospectively associated with an elevated risk of depression. These explorative findings suggest that constipation may be an independent risk factor or a prodromal symptom of depression. Gastroenterologists and primary care physicians should pay more attention to the depressive symptoms of their constipation patients. Funding: The Shenzhen Science and Technology Program and the Strategic Priority Research Program of Chinese Academy of Sciences.

Elaborating the Crystal Water of Prussian Blue for Outstanding Performance of Sodium Ion Batteries.

Prussian blue (PB) is one of the main cathode materials with industrial prospects for the sodium ion battery. The structural stability of PB materials is directly associated with the presence of crystal water within the open 3D framework. However, there remains a lack of consensus regarding whether all forms of crystal water have detrimental effects on the structural stability of the PB materials. Currently, it is widely accepted that interstitial water is the stability troublemaker, whereas the role of coordination water remains elusive. In this work, the dynamic evolution of PB structures is investigated during the crystal water (in all forms) removal process through a variety of online monitoring techniques. It can be inferred that the PB-130 °C retains trace coordination water (1.3%) and original structural integrity, whereas PB-180 °C eliminates almost all of crystal water (∼12.1%, including both interstitial and coordinated water), but inevitably suffers from structural collapse. This is mainly because the coordinated water within the PB material plays a crucial role in maintaining structural stability via forming the -N≡C-FeLS-C≡N- conjugate bridge. Consequently, PB-130 °C with trace coordination water delivers superior reversible capacity (113.6 mAh g-1), high rate capability (charge to >80% capacity in 3 min), and long cycling stability (only 0.012% fading per cycle), demonstrating its promising prospect in practical applications.

Anti-aging Factor GRSF1 Attenuates Cerebral Ischemia-Reperfusion Injury in Mice by Inhibiting GPX4-Mediated Ferroptosis.

Abnormal accumulation of senescent cells in tissues has been shown to facilitate the onset and progression of various diseases. As an important protein involving in the regulation of cellular senescence process, researches suggested GRSF1 as a potential senolytic target to improve multiple physiological and pathological processes. However, the underlying mechanism of cellular senescence on cerebral ischemia-reperfusion injury (CIRI) has not been revealed. Here, we investigated the effect of GRSF1 on CIRI and delved into its specific mechanisms. In the present study, we established a mouse model of cerebral ischemia-reperfusion (CIR) and observed low expression of anti-aging factor GRSF1, along with greatly increased levels of senescence-related markers p16 and p21 and senescence-associated secretory phenotype TNF-α. Furthermore, we found that the expression of GPX4 was elevated parallel to GRSF1 in CIR mice with overexpression of GRSF1, oxidative stress, and iron metabolism-related proteins were inhibited. Functionally, overexpressing GRSF1 significantly ameliorated infarct volume and neurological function scores and suppressed apoptosis in CIR mice, while administration of GPX4 inhibitors reversed these beneficial phenotypes. Taken together, our results indicate cellular senescence as an important pathological mechanism to exacerbate cerebral injury during CIRI, while GRSF1 could inhibit oxidative stress-mediated ferroptosis through upregulating GPX4 to attenuate reperfusion injury, which makes senolytic treatment, especially GRSF1, a promising therapeutic target for CIRI.

Postweaning intermittent sleep deprivation enhances defensive attack in adult female mice via the microbiota-gut-brain axis.

Sleep is one of the most important physiological activities in life and promotes the growth and development of an individual. In modern society, sleep deprivation (SD), especially among adolescents, has become a common phenomenon. However, long-term SD severely affected adolescents' neurodevelopment leading to abnormal behavioral phenotypes. Clinical studies indicated that sleep problems caused increased aggressive behavior in adolescents. Aggressive behavior was subordinate to social behaviors, in which defensive attack was often the last line for survival. Meanwhile, increasing studies shown that gut microbiota regulated social behaviors by affecting specific brain regions via the gut-brain axis. However, whether postweaning intermittent SD is related to defensive attack in adulthood, and if so, whether it is mediated by the microbiota-gut-brain axis are still elusive. Combined with microbial sequencing and hippocampal metabolomics, the present study mainly investigated the long-term effects of postweaning intermittent SD on defensive attack in adult mice. Our study demonstrated that postweaning intermittent SD enhanced defensive attack and impaired long-term memory formation in adult female mice. Moreover, microbial sequencing and LC-MS analysis showed that postweaning intermittent SD altered the gut microbial composition and the hippocampal metabolic profile in female mice, respectively. Our attention has been drawn to the neuroactive ligand-receptor interaction pathway and related metabolites. In conclusion, our findings provide a new perspective on the relationship of early-life SD and defensive attack in adulthood, and also highlight the importance of sleep in early-life, especially in females.

Non-steroidal mineralocorticoid receptor antagonist finerenone ameliorates mitochondrial dysfunction via PI3K/Akt/eNOS signaling pathway in diabetic tubulopathy.

Diabetic tubulopathy (DT) is a recently recognized key pathology of diabetic kidney disease (DKD). The mitochondria-centric view of DT is emerging as a vital pathological factor in different types of metabolic diseases, such as DKD. Finerenone (FIN), a novel non-steroidal mineralocorticoid receptor antagonist, attenuates kidney inflammation and fibrosis in DKD, but the precise pathomechanisms remain unclear. The role of mineralocorticoid receptor (MR) in perturbing mitochondrial function via the PI3K/Akt/eNOS signaling pathway, including mitochondrial dynamics and mitophagy, was investigated under a diabetic state and high glucose (HG) ambiance. To elucidate how the activation of MR provokes mitochondrial dysfunction in DT, human kidney proximal tubular epithelial (HK-2) cells were exposed to HG, and then mitochondrial dynamics, mitophagy, mitochondrial ROS (mitoROS), signaling molecules PI3K, Akt, Akt phosphorylation and eNOS were probed. The above molecules or proteins were also explored in the kidneys of diabetic and FIN-treated mice. FIN treatment reduced oxidative stress, mitochondrial fragmentation, and apoptosis while restoring the mitophagy via PI3K/Akt/eNOS signaling pathway in HK-2 cells exposed to HG ambiance and tubular cells of DM mice. These findings linked MR activation to mitochondrial dysfunction via PI3K/Akt/eNOS signaling pathway in DT and highlight a pivotal but previously undiscovered role of FIN in alleviating renal tubule injury for the treatment of DKD.