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Multiple sclerosis (MS) and inflammatory bowel disease (IBD) are both autoimmune disorders caused by dysregulated immune responses. Still, there is a growing awareness of the comorbidity between MS and IBD. However, the shared pathophysiological mechanisms between these two diseases are still lacking. RNA sequencing datasets (GSE126124, GSE9686, GSE36807, GSE21942) were analyzed to identify the shared differential expressed genes (DEGs) for IBD and experimental allergic encephalomyelitis (EAE). Other datasets (GSE17048, GSE75214, and GSE16879) were downloaded for further verification and analysis. Shared pathways and regulatory networks were explored based on these DEGs. The single-cell transcriptome of central nervous system (CNS) immune cells sequenced from EAE brains and the public datasets of IBD (PRJCA003980) were analyzed for the immune characteristics of the shared DEGs. Mass cytometry by time-of-flight (CyTOF) of peripheral blood mononuclear cells (PBMCs) was performed for the systematic immune response in the EAE model. Machine learning algorithms were also used to identify the diagnostic biomarkers of MS. We identified 74 common DEGs from the selected RNA sequencing datasets, and single-cell RNA data of the intestinal tissues of IBD patients showed that 56 of 74 DEGs were highly enriched in IL1B + macrophages. These 56 DEGs, defined as inflammation-related DEGs (IRGs), were also highly expressed in pro-inflammatory macrophages of EAE mice and MS patients. The abundance of systematic CD14 + monocytes was validated by CyTOF data. These IRGs were highly enriched in immune response, NOD-like receptor signaling pathway, IL-18 signaling pathway, and other related pathways. In addition, 'AddModuleScore_UCell' analysis further validated that these IRGs (such as IL1B, S100A8, and other inflammatory factors) are highly expressed mainly in pro-inflammatory macrophages, which play an essential role in pro-inflammatory activation in IBD and multiple sclerosis, such as IL-17 signaling pathway, NF-kappa B signaling pathway, and TNF signaling pathway. Finally, suppressors of cytokine signaling 3(SOCS3) and formyl peptide receptor 2(FPR2) were identified as potential biomarkers by machine learning. Two genes were highly expressed in pro-inflammatory macrophages of IBD and MS disease compared to control, and other datasets and experiments further revealed that SOCS3 and FPR2 were highly expressed in IBD and EAE samples. These shared IRGs, which encode inflammatory cytokines, exhibit high expression levels in inflammatory macrophages in IBD and may play a significant role in the inflammatory cytokine storm in MS patients. Two potential biomarkers, SOCS3 and FPR2, were screened out with great diagnostic value for MS and IBD., Competing Interests: Declarations. Ethics Approval and Consent to Participate: The experimental protocol was reviewed and approved by the Animal Research Ethics Committee of Guizhou Medical University. Consent for Publication: Not applicable. Competing interest: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Potentially inappropriate medication (PIM) use is a common problem among older patients. This study aimed to compare the prevalence of PIMs in older patients with newly diagnosed non-small cell lung cancer (NSCLC), and to identify the correlates of PIMs., Research Design and Methods: A secondary analysis of a prospective cohort study was conducted. Patients were enrolled from January 2014 to December 2020 and information were extracted from patients' electronic medical records (EMRs). We evaluated the PIMs using four different PIM criteria. The concordance among the four PIM criteria was calculated using kappa tests. The possible risk factors associated with PIMs were analyzed by multivariate logistic regression., Results: The prevalence of at least one PIM identified by the four criteria ranged from 25.1% to 48.2% among 514 patients. There was moderate consistency between the GO-PIM scale and the AGS/Beers criteria, while poor consistency with the other criteria (the STOPP criteria and the Chinese criteria). Polypharmacy was found to be significantly associated with the occurrence of PIMs in all criteria ( p  < 0.001)., Conclusions: Our results showed a high prevalence of PIMs in older patients with NSCLC, which was significantly associated with polypharmacy, and the consistency across the four criteria was poor-to-moderate.

Despite advancements in breast cancer treatment, bone metastases remain a significant concern for advanced breast cancer patients. Current theranostics strategies face challenges in integrating tumor theranostics and bone formation. Herein, this work develops an activatable targeted nanomedicine AuMnCO@BSA-N 3 (AMCBN) to enable a novel collaborative integration of second near-infrared (NIR-II) fluorescence imaging guided precise theranostics for breast cancer bone metastases and osteogenic microenvironment remolding. This strategy employs a chemical coordination between noble metal complex and metal carbonyl (MnCO), with surface modification of azide groups to enhance tumor affinity through passive and active targeting. The initiated respondent behavior of AMCBN by tumor microenvironment accelerate the degradation of coordinated MnCO, resulting in a rapid release of multifunctional agents for efficient chemodynamic therapy (CDT)/gas synergistic therapy. Meanwhile, the exceptional bone-binding properties enable the efficient and controlled release of Mn 2+ ions and carbon monoxide (CO) in the bone microenvironment, thereby facilitating the expression of osteogenesis-related proteins and establishing a novel synchronous theranostics process for tumor-bone repair., (© 2024 Wiley‐VCH GmbH.)

ADP-ribosylation is a highly dynamic and fully reversible post-translational modification performed by poly(ADP-ribose) polymerases (PARPs) that modulates protein function, abundance, localization and turnover. Here we show that influenza A virus infection causes a rapid and dramatic upregulation of global ADP-ribosylation that inhibits viral replication. Mass spectrometry defined for the first time the global ADP-ribosylome during infection, creating an infection-specific profile with almost 4,300 modification sites on ~1,080 host proteins, as well as over 100 modification sites on viral proteins. Our data indicate that the global increase likely reflects a change in the form of ADP-ribosylation rather than modification of new targets. Functional assays demonstrated that modification of the viral replication machinery antagonizes its activity and further revealed that the anti-viral activity of PARPs and ADP-ribosylation is counteracted by the influenza A virus protein NS1, assigning a new activity to the primary viral antagonist of innate immunity. We identified PARP1 as the enzyme producing the majority of poly(ADP-ribose) present during infection. Influenza A virus replicated faster in cells lacking PARP1, linking PARP1 and ADP-ribosylation to the anti-viral phenotype. Together, these data establish ADP-ribosylation as an anti-viral innate immune-like response to viral infection antagonized by a previously unknown activity of NS1., Competing Interests: DECLARATION OF INTERESTS CP is an employee of ARase Therapeutics.

Dysfunction of pancreatic δ cells contributes to the etiology of diabetes. Despite their important role, human δ cells are scarce, limiting physiological studies and drug discovery targeting δ cells. To date, no directed δ-cell differentiation method has been established. Here, we demonstrate that fibroblast growth factor (FGF) 7 promotes pancreatic endoderm/progenitor differentiation, whereas FGF2 biases cells towards the pancreatic δ-cell lineage via FGF receptor 1. We develop a differentiation method to generate δ cells from human stem cells by combining FGF2 with FGF7, which synergistically directs pancreatic lineage differentiation and modulates the expression of transcription factors and SST activators during endoderm/endocrine precursor induction. These δ cells display mature RNA profiles and fine secretory granules, secrete somatostatin in response to various stimuli, and suppress insulin secretion from in vitro co-cultured β cells and mouse β cells upon transplantation. The generation of human pancreatic δ cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation studies in diabetes., (© 2024. The Author(s).)

Excessive exposure to manganese (Mn) through drinking water and food during pregnancy significantly heightens the likelihood of neurodevelopmental damage in offspring. Multiple studies have indicated that melatonin (Mel) may help to relieve neurodevelopmental disorders caused by Mn, but potential mechanisms underlying this effect require further exploration. Here, we utilized primary neural stem cells (NSCs) as a model to elucidate the molecular mechanism underlying the protective function of Mel on Mn-induced cell proliferation dysfunction and cycle arrest. Our results showed that Mn disrupted the cell cycle in NSCs by suppressing positive regulatory proteins (CDK2, Cyclin A, Cyclin D 1 , and E2F1) and enhancing negative ones (p27 KIP1 and p57 KIP2 ), leading to cell proliferation dysfunction. Mel inhibited the Mn-dependent changes to these proteins and the cell cycle through nuclear receptor-related protein 1 (Nurr1), thus alleviating the proliferation dysfunction. Knockdown of Nurr1 using lentivirus-expressed shRNA in NSCs resulted in a diminished protective effect of Mel. We concluded that Mel mitigated Mn-induced proliferation dysfunction and cycle arrest in NSCs through Nurr1., (© 2024 Wiley Periodicals LLC.)

Simultaneously improving electrochemical activity and stability is a long-term goal for water splitting. Herein, hierarchical N-doped carbon nanotubes on carbon nanowires derived from PPy are grown on carbon cloth, serving as a support for NiCo oxides/sulfides. The hierarchical electrodes annealed in N 2 or H 2 /N 2 display improved intrinsic activity and stability for hydrogen evolution reaction (HER) and glucose oxidation reaction. Compared with Pt/C||Ir/C in alkaline media, the glucose electrolysis assembled with electrodes exhibits a cell voltage of 1.38 V at 10 mA cm -2 , durability for >12 h at 50 mA cm -2 , and resistance to glucose/gluconic acid poisoning. In addition, electrocatalysts can also be applied in ethanol oxidation reactions. Systematic characterizations reveal the strong interactions between NiCo and N-doped carbon support-induced partial charge transfer at the interface and regulate the local electronic structure of active sites. Density functional theory calculations demonstrate that the synergistic effect between N-doped carbon supports, metallic NiCo, and NiCo oxides/sulfides optimize the adsorption energy of H 2 O and the H* free energy for HER. The energy barrier of the dehydrogenation of glucose effectively decreased. This work will attract attention to the role of metal-support interactions in enhancing the intrinsic activity and stability of electrocatalysts., (© 2024 Wiley‐VCH GmbH.)

Background: Potentially inappropriate medications (PIMs) are common among older adults with cancer, but their association with overall survival (OS) among non-small cell lung cancer (NSCLC) patients remains unclear. This study aimed to investigate the association between the use of PIMs and OS in patients with NSCLC., Methods: In this cohort study, we included patients ≥ 65 years with newly diagnosed NSCLC from January 2014 to December 2020. Potentially inappropriate medication (PIM) is defined by the Beers criteria of 2019 at baseline and within six months following the initiation of systemic therapy. Multivariable Cox regression model was built to assess the association between PIMs and overall survival (OS)., Results: We finally included 338 patients with a median follow-up for OS of 1777 days. The prevalence of patients receiving at least one PIM was 39.9% (135/338) and 61.2% (71/116) at baseline and after systemic therapy, respectively. The most important factor associated with PIM use was the number of prescribed medications (P < 0.001). Baseline PIM use and PIM after systemic therapy were significantly associated with inferior OS (476 days vs. 844 days, P = 0.044; and 633 days vs. 1600 days, P = 0.007; respectively). In multivariable analysis, both baseline PIM use and PIM after systemic therapy were independent predictors of poor prognosis (adjusted HR, 1.33; 95% CI, 1.01-1.75; P = 0.041; and adjusted HR, 1.86; 95% CI, 1.11-3.14; P = 0.020; respectively)., Conclusions: PIMs are prevalent among older patients with NSCLC and are independent predictors of NSCLC prognosis. There is an urgent need for clinicians to conduct medication reconciliation and appropriate deprescribing for this population, especially for patients with multiple PIMs., (© 2024. The Author(s).)

The water quality in the drinking water reservoir directly affects people's quality of life and health. When external pollution input is effectively controlled, endogenous release is considered the main cause of water quality deterioration. As the major nitrogen (N) and phosphorus (P) sources in reservoirs, sediment plays a vital role in affecting the water quality. To understand the spatial and temporal variation of N and P in the sediment, this study analyzed the current characteristics and cumulative effects of a semi-humid reservoir, Yuqiao Reservoir, in North China. The N and P concentrations in the reservoir sediment were decreased along the flow direction, while the minimum values were recorded at the central sediment profile. External input and algal deposition were the main factors leading to higher sediment concentrations in the east (Re-E) and west (Re-W) areas of reservoir sediment profiles. According to the long-term datasets, the peaks of both sediment total nitrogen content and deposition rate were observed in the 2010s, which has increased about three times and six times than in the1990s, respectively. Therefore, the increase in phosphorus concentration may be the main reason for eutrophication in water in recent years. The mineralization of organic matter has a significant promoting effect on releasing N and P from sediments, which will intensify eutrophication in water dominated by P and bring huge challenges to water environment management. This study highlights that the current imbalance in N and P inputs into reservoirs and the endogenous P release from sediment will have a significant impact on water quality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Although lots of nanomaterials modified anodes have been reported to improve the bacterial attachment and extracellular electron transfer (EET) in microbial fuel cells (MFCs), the lack of a three dimensional (3D) conductive and capacitive network severely limited MFCs performance. In this work, 3D conductive networks derived from mucor mycelia were grown on carbon cloth (CC), and capacitive FeMn phosphides/oxides were further anchored on these 3D networks by electrochemical deposition (denoted as FeMn/CMM@CC) to simultaneously address the above challenges. As a result, the multivalent metal active sites were evenly distributed on 3D conductive network, which favored the enrichment of exoelectrogens, mass transport and EET. Consequently, the as-prepared FeMn/CMM@CC anode displayed accumulated charge of 131.4C/m 2 , higher than bare CC. Meanwhile, FeMn/CMM@CC anode substantially promoted flavin excretion and the amounts of nano conduits. The abundance of Geobacter was 63 % on bare CC, and greatly increased to 83 % on FeMn/CMM@CC. MFCs equipped by FeMn/CMM@CC anode presented the power density of 3.06 W/m 2 and coulombic efficiency (29.9 %), evidently higher than bare CC (1.29 W/m 2 , 7.3 %), and the daily chemical oxygen demand (COD) removal amount also increased to 92.6 mg/L/d. This work developed a facile method to optimize the abiotic-biotic interface by introducing 3D conductive and capacitive network, which was proved to be a promising strategy to modify macro-porous electrodes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Complex degenerative cervical spondylotic myelopathy (DCM) is characterized by a variety of complex imaging features. The surgical method for DCM remains controversial. This study aimed to examine the correlation between the imaging characteristics of DCM with varying degrees of complexity and the surgical approach and clinical outcome., Methods: A retrospective cohort study involving retrospective data collection was performed. A total of 139 patients with DCM who underwent surgery between January 2015 and January 2018 in the Orthopedics Department of Shanxi Bethune Hospital were divided into 3 groups according to the complexity of imaging features: 18 patients in the mild group, 66 patients in the moderate group, and 55 patients in the severe group. The Visual Analog Scale (VAS) and Japanese Orthopaedic Association (JOA) scores were used to compare the effects of neck pain and neural function prior to surgery according to the rate of improvement as of the last follow-up. Routine X-ray films were obtained at the follow-up of 3-6 months. The necessity of computed tomography (CT) and magnetic resonance imaging (MRI) examinations was determined based on clinical findings and X-ray images. Analysis of variance (ANOVA) was used to compare groups, the least significant difference (LSD) test was used for multiple comparisons, and the Chi-square test was used to compare classification indicators (imaging manifestations, gender), with P<0.05 being statistically significant. Binary logistic regression analysis was performed to determine the primary influencing factors of the JOA recovery rate., Results: In all three groups, JOA and VAS scores at the final follow-up were significantly higher than those before surgery (P<0.001). There were significant differences in the preoperative VAS and JOA scores between any two groups, as well as in the VAS and JOA scores and improvement rates at the last follow-up between the mild group and the moderate group and between the mild group and the severe group (P<0.001). Age, preoperative JOA scores, MRI intramedullary hyperintensity signal, and the degree of spinal cord compression were primarily related to the nervous system recovery rate (P<0.001)., Conclusions: Age, MRI intramedullary hyperintensity signal, degree of spinal cord compression, and other variables were associated with the improvement of neural function in patients with DCM. Therefore, in addition to the JOA improvement rate or VAS score, additional factors, such as the patient's condition, the improvement in quality of life, and the patient's financial capacity, should be considered in evaluating the improvement of postoperative neck pain and neural function., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-1481/coif). The authors have no conflicts of interest to declare., (2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Medical titanium-based (Ti-based) implants in the human body are prone to infection by pathogenic bacteria, leading to implantation failure. Constructing antibacterial nanocoatings on Ti-based implants is one of the most effective strategies to solve bacterial contamination. However, single antibacterial function was not sufficient to efficiently kill bacteria, and it is necessary to develop multifunctional antibacterial methods. This study modifies medical Ti foils with Cu-doped Co 3 O 4 rich in oxygen vacancies, and improves their biocompatibility by polydopamine (PDA/Cu-O v -Co 3 O 4 ). Under near-infrared (NIR) irradiation, nanocoatings can generate •OH and 1 O 2 due to Cu + Fenton-like activity and a photodynamic effect of Cu-O v -Co 3 O 4 , and the total reactive oxygen species (ROS) content inside bacteria significantly increases, causing oxidative stress of bacteria. Further experiments prove that the photothermal process enhances the bacterial membrane permeability, allowing the invasion of ROS and metal ions, as well as the protein leakage. Moreover, PDA/Cu-O v -Co 3 O 4 can downregulate ATP levels and further reduce bacterial metabolic activity after irradiation. This coating exhibits sterilization ability against both Escherichia coli and Staphylococcus aureus with an antibacterial rate of ca. 100%, significantly higher than that of bare medical Ti foils (ca. 0%). Therefore, multifunctional synergistic antibacterial nanocoating will be a promising strategy for preventing bacterial contamination on medical Ti-based implants.

Background: Aggressive care near patients' end-of-life (EOL) entails limited therapeutic values, high costs, and compromised quality of life (QoL). In this study, we aimed to estimate the global prevalence of aggressive care in patients with cancer and explore potential subgroup differences., Methods: We searched PubMed, Embase, and the Cochrane Library from database inception to Feb 16, 2024. Eligible studies reported the prevalence of aggressive EOL care using at least one quantifiable measure. Random-effects models were used to derive the pooled prevalence and subgroup analyses were performed to investigate differences in the prevalence of aggressive care across regions, the country's level of economic development, tumor types, ages, and sample sizes. This review is registered with PROSPERO, number CRD42023467839., Findings: A total of 129 studies were included in this systematic review, of which 118 (91.5%) were from high-income countries. Studies were mostly conducted in the Americas (60, 46.5%), Europe (34, 26.4%), and Western Pacific (31, 24.0%). Measures of aggressive care were inconsistent across studies, with the most commonly used measure being the use of chemotherapy in the last 14 days of life (DOLs) (n = 87, 67.4%) and intensive care unit (ICU) stay in the last 30 DOLs (n = 87, 67.4%). The prevalence of the five claims-based measures of aggressive care, i.e., chemotherapy in the last 14 DOLs, ICU stay in the last 30 DOLs, repeated hospital admission in the last 30 DOLs, repeated emergency room (ER) visit in the last 30 DOLs, and hospice care <3 days before death were 11.6% (95% CI, 9.8%-13.4%), 14.4% (95% CI, 11.8%-17.0%), 17.9% (95% CI, 14.4%-21.4%), 14.8% (95% CI, 12.0%-17.6%), and 14.4% (95% CI, 11.2%-17.6%), respectively. Regional differences were statistically significant in the prevalence of ICU stay and repeated hospital admission in the last 30 DOLs (p < 0.01; p = 0.03). Patients with hematologic malignancies were more likely to receive aggressive care than those with solid tumors, as seen in their higher rates of chemotherapy in the last 14 DOLs (21.7% versus 11.6%; p = 0.03), ICU stay in the last 30 DOLs (25.5% versus 10.8%; p < 0.01), and hospice care <3 days before death (26.7% versus 14.2%; p < 0.01). In addition, the prevalence of chemotherapy in the last 14 DOLs (26.2%; p < 0.01) and repeated hospital admission in the last 30 DOLs (31.4%; p < 0.01) were highest among pediatric patients with cancer., Interpretation: This meta-analysis found that aggressive EOL care was common in patients with cancer, regardless of the definition used, and varied by regions and populations. It is necessary to be aware of the global burden of aggressive care for patients with cancer near their EOL and take prompt action to address it., Funding: National Natural Science Foundation of China (Grant No. 72274004)., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s).)

Manganese (Mn) overexposure induces hippocampal synaptotoxicity by the accumulation of dysfunctional synaptic vesicles (SVs). Leucine-rich repeat kinase 2 (LRRK2) kinase activity is involved in regulating axonal transport (autophagosomal maturation) and lysosomal function. Nevertheless, it remains unclear whether Mn-induced synaptotoxicity is associated with the LRRK2-mediated disruption of autophagosomal maturation in axonal transport and the impairment of lysosomes in hippocampal neurons. Here, we established models of manganism in C57BL/6 mice and hippocampal neuronal HT22 cells to verify the role of LRRK2-mediated Rab10 phosphorylation in the Mn-induced dysfunction of autophagy- lysosomal fusion. Our results proved that Mn-induced the disorder of axonal transport and that lysosome impairments were associated with the increased recruitment of phospho-Rab10 at the axon and lysosomes. Next, we established Lrrk2-KD and LRRK2 kinase- specific inhibitor (GNE-0877, GNE) pre-treated HT22 cells to inhibit Lrrk2 gene expression and kinase activity, respectively. In Mn-treated Lrrk2-KD or GNE-pretreated normal neurons, our results indicated that lysosomal pH and integrity and autophagic flow were restored, indicating by decreased levels of phospho-Rab10 on lysosomes and JNK-interacting proteins (JIP4). In addition, GNE pretreatment could provide protection against Mn-induced synaptotoxicity in vivo, which was evidenced by the partial recovery in synaptic plasticity and synaptic damage. Thus, the Mn-induced abnormal activation of LRRK2 affected lysosomes and the recruitment of phospho-Rab10 by JIP4, which disrupted autophagosomal maturation in proximal axons and resulted in the hippocampal synaptic toxicity of mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Anticancer drug-induced interstitial lung disease (DIILD) has received increasing clinical attention, and the quality of relevant guidance documents has become critical. Our purpose was to assess the quality of documents for anticancer DIILD and summarize the recommendations. Clinical practice guidelines (CPGs) and consensus statements with recommendations were searched in electronic databases, websites of guideline organizations, and professional societies. The quality of documents was assessed using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) methodology, and the specific recommendations were aggregated and compared. A total of 11 documents were eligible, including 6 CPGs and 5 consensus statements, and the quality of AGREE II assessments differed greatly. The domains of scope and purpose and clarity of presentation received the highest median scores, while the stakeholder involvement domain received the lowest score. Recommendations were inconsistent between documents, particularly regarding the selection of steroid regimens. The methodological quality of the guidance documents needs to be enhanced, especially in the domain of stakeholder involvement. Inconsistencies exist in documents, and further discussions among multidisciplinary experts are needed. Particularly, differences in steroid regimens require attentions, and researches on the risks of adverse events and discovery of precise biomarkers are necessary.

Excessive exposure of children to manganese (Mn) in the environment has a bearing on developmental neurotoxicity. Although melatonin (Mel) can play a neuroprotective role by modulating the differentiation of neural stem cells (NSCs) in the developing brain, its specific mechanism under Mn overexposure remains to be explored. Here, we cultured primary NSCs as an available model to investigate the relevant molecular mechanism of Mel mitigation on Mn-induced disorder of NSCs differentiation through sirtuin 1 (SIRT1)/β-catenin pathway. It was found that Mel could facilitate the differentiation of Mn-treated NSCs into neurons. Further, our results uncovered that the pro-differentiation mechanism of Mel depended upon ascending the activity of SIRT1, thereby weakening β-catenin acetylation and increasing phosphorylation of β-catenin ser675 in the cytoplasm, which facilitates the nuclear translocation of β-catenin. Furthermore, the role of SIRT1 in Mel-mediated signal transduction was investigated through the pretreatment of NSCs using a highly specific SIRT1 inhibitor, EX527. After EX527 pretreatment, Mel could not maintain its protective effect. Overall, our results revealed that Mel could alleviate Mn-induced disorder of NSCs differentiation through the activation of the SIRT1/β-catenin pathway., Competing Interests: Declaration of competing interest The authors announce that they have no known competitive financial benefits or personal relationships that could impinge the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The escalating integration of Artificial Intelligence (AI) in clinical settings carries profound implications for the doctrine of informed consent, presenting challenges that necessitate immediate attention. China, in its advancement in the deployment of medical AI, is proactively engaging in the formulation of legal and ethical regulations. This paper takes China as an example to undertake a theoretical examination rooted in the principles of medical ethics and legal norms, analyzing informed consent and medical AI through relevant literature data. The study reveals that medical AI poses fundamental challenges to the accuracy, adequacy, and objectivity of information disclosed by doctors, alongside impacting patient competency and willingness to give consent. To enhance adherence to informed consent rules in the context of medical AI, this paper advocates for a shift towards a patient-centric information disclosure standard, the restructuring of medical liability rules, the augmentation of professional training, and the advancement of public understanding through educational initiatives., (© 2024 John Wiley & Sons Ltd.)

Background: In the context of sepsis patients, hypertension has a significant impact on the likelihood of developing sepsis-associated acute kidney injury (S-AKI), leading to a considerable burden. Moreover, sepsis is responsible for over 50 % of cases of acute kidney injuries (AKI) and is linked to an increased likelihood of death during hospitalization. The objective of this research is to develop a dependable and strong nomogram framework, utilizing the variables accessible within the first 24 h of admission, for the anticipation of S-AKI in sepsis patients who have hypertension., Methods: In this study that looked back, a total of 462 patients with sepsis and high blood pressure were identified from Nanfang Hospital. These patients were then split into a training set (consisting of 347 patients) and a validation set (consisting of 115 patients). A multivariate logistic regression analysis and a univariate logistic regression analysis were performed to identify the factors that independently predict S-AKI. Based on these independent predictors, the model was constructed. To evaluate the efficacy of the designed nomogram, several analyses were conducted, including calibration curves, receiver operating characteristics curves, and decision curve analysis., Results: The findings of this research indicated that diabetes, prothrombin time activity (PTA), thrombin time (TT), cystatin C, creatinine (Cr), and procalcitonin (PCT) were autonomous prognosticators for S-AKI in sepsis individuals with hypertension. The nomogram model, built using these predictors, demonstrated satisfactory discrimination in both the training (AUC = 0.823) and validation (AUC = 0.929) groups. The S-AKI nomogram demonstrated superior predictive ability in assessing S-AKI within the hypertension grade I (AUC = 0.901) set, surpassing the hypertension grade II (AUC = 0.816) and III (AUC = 0.810) sets. The nomogram exhibited satisfactory calibration and clinical utility based on the calibration curve and decision curve analysis., Conclusion: In patients with sepsis and high blood pressure, the nomogram that was created offers a dependable and strong evaluation for predicting S-AKI. This evaluation provides valuable insights to enhance individualized treatment, ultimately resulting in improved clinical outcomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Microbial fuel cell (MFC) performance is affected by the metabolic activity of bacteria and the extracellular electron transfer (EET) process. The deficiency of nanostructures on macroporous anode obstructs the enrichment of exoelectrogens and the EET. Herein, a N-doped carbon nanowire-modified macroporous carbon foam was prepared and served as an anode in MFCs. The anode has a hierarchical porous structure, which can solve the problem of biofilm blockage, ensure mass transport, favor exoelectrogen enrichment, and enhance the metabolic activity of bacteria. The microscopic morphology, spectroscopy, and electrochemical characterization of the anode confirm that carbon nanowires can penetrate biofilm, decrease charge resistance, and enhance long-distance electron transfer efficiency. In addition, pyrrolic N can effectively reduce the binding energy and electron transfer distance of bacterial outer membrane hemin. With this hierarchical anode, a maximum power density of 5.32 W/m 3 was obtained, about 2.5-fold that of bare carbon cloth. The one-dimensional nanomaterial-modified macroporous anodes in this study are a promising strategy to improve the exoelectrogen enrichment and EET for MFCs.

In response to the trend of drug-resistant and super bacteria, the existing single antibacterial methods are not sufficient to kill bacteria, and the development of multifunctional antibacterial nanomaterials is urgent. Our study aims to construct copper-doped polydopamine-coated Ti 3 C 2 T x (CuPDA@Ti 3 C 2 T x ) with an enhanced photothermal property and Fenton-like activity. The nanocomposite hydrogel consisting of CuPDA@Ti 3 C 2 T x and alginate can improve the antioxidant activity of two-dimensional MXene nanosheets by coating them with a thin layer of PDA nanofilm. Meanwhile, Cu ions are adsorbed through the coordination of PDA-rich oxygen-containing functional groups and amino groups. Calcium ions were further used to crosslink sodium alginate to obtain antibacterial hydrogel materials with combined chemotherapy and photothermal therapy properties. The photothermal conversion efficiency of CuPDA@Ti 3 C 2 T x is as high as 57.7% and the antibacterial rate of Escherichia coli reaches 96.12%. The photothermal effect leads to oxidative stress in bacteria, increases cell membrane permeability, and a high amount of ROS and copper ions enter the interior of the bacteria, causing protein denaturation and DNA damage, synergistically leading to bacterial death. Our study involves a multifunctional synergistic antibacterial nanodrug platform, which is conducive to the development of high-performance antibacterial agents and provides important research ideas for solving the problem of drug-resistant bacteria.

Commonly used dense arrays of nanomaterials on carbon cloth (CC) are not suitable to accommodate microorganisms in microbial fuel cells (MFCs) due to their unmatched size. To simultaneously enrich exoelectrogens and accelerate the extracellular electron transfer (EET) process, SnS 2 nanosheets were selected as sacrificial templates to prepare binder-free N,S-codoped carbon microflowers (N,S-CMF@CC) by polymer coating and pyrolysis. N,S-CMF@CC showed a cumulative total charge of 125.70C/m 2 , approximately 2.11 times higher than that of CC, indicating its better electricity storage capacity. Moreover, the interface transfer resistance and diffusion coefficient in bioanodes were 42.68 Ω and 9.27 × 10 -10 cm 2 /s, respectively, superior to CC (141.3 Ω and 1.06 × 10 -11 cm 2 /s). Remarkably, N,S-codoped carbon microflowers excreted more flavin than CC, as confirmed by continuous fluorescence monitoring. Biofilm and 16S rRNA gene sequence analysis revealed that exoelectrogens were enriched, and nanoconduits were generated on the N,S-CMF@CC anode. In particular, flavin excretion was also promoted on our hierarchical electrode, effectively driving the EET process. MFCs equipped with the N,S-CMF@CC anode could deliver a power density of 2.50 W/m 2 , coulombic efficiency of 22.77 %, and chemical oxygen demand (COD) removal amount of 90.72 mg/L/d, higher than that of bare CC. These findings not only demonstrate that our anode is capable of solving the cell enrichment issue, but it may also increase EET rates by bound flavin with outer membrane c-type cytochromes (OMCs) to simultaneously boost the power generation and wastewater treatment performance of MFCs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Artificial Intelligence (AI) technology has been developed significantly in recent years. The fairness of medical AI is of great concern due to its direct relation to human life and health. This review aims to analyze the existing research literature on fairness in medical AI from the perspectives of computer science, medical science, and social science (including law and ethics). The objective of the review is to examine the similarities and differences in the understanding of fairness, explore influencing factors, and investigate potential measures to implement fairness in medical AI across English and Chinese literature., Methods: This study employed a scoping review methodology and selected the following databases: Web of Science, MEDLINE, Pubmed, OVID, CNKI, WANFANG Data, etc., for the fairness issues in medical AI through February 2023. The search was conducted using various keywords such as "artificial intelligence," "machine learning," "medical," "algorithm," "fairness," "decision-making," and "bias." The collected data were charted, synthesized, and subjected to descriptive and thematic analysis., Results: After reviewing 468 English papers and 356 Chinese papers, 53 and 42 were included in the final analysis. Our results show the three different disciplines all show significant differences in the research on the core issues. Data is the foundation that affects medical AI fairness in addition to algorithmic bias and human bias. Legal, ethical, and technological measures all promote the implementation of medical AI fairness., Conclusions: Our review indicates a consensus regarding the importance of data fairness as the foundation for achieving fairness in medical AI across multidisciplinary perspectives. However, there are substantial discrepancies in core aspects such as the concept, influencing factors, and implementation measures of fairness in medical AI. Consequently, future research should facilitate interdisciplinary discussions to bridge the cognitive gaps between different fields and enhance the practical implementation of fairness in medical AI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Persimmon leaves usually as agricultural and forestry waste were fermented by Lactiplantibacillus plantarum and Saccharomyces cerevisiae. Growth and metabolic performances of L. plantarum and S. cerevisiae, as well as the effect of fermentation on the antioxidant abilities of the extract was investigated, including the content of flavonoids, 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical clearance rates. Growth of L. plantarum was limited, even though the acid production was sustainable, while S. cerevisiae was more suitable to inhabit in the persimmon leaves extract. A symbiotic relationship was observed between the two microbes, reflected in aspects of growth of S. cerevisiae, pH reduction, and ethanol production. The DPPH radical clearance rates of all groups decreased at the early period, and increased later. The co-culture group reached the second highest value of DPPH radical clearance rate only next to the single group of L. plantarum at 9 h. All groups showed an overall downward trend of the hydroxyl radical clearance rates during the 9 h-fermentation. These findings highlight the promising industrial application of fermentation of the plant-based materials with Lactiplantibacillus and Saccharomyces species to improve the biological properties., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Biomimetic switchable adhesion interfaces (BSAIs) with dynamic adhesion states have demonstrated significant advantages in micro-manipulation and bio-detection. Among them, gecko-inspired adhesives have garnered considerable attention due to their exceptional adaptability to extreme environments. However, their high adhesion strength poses challenges in achieving flexible control. Herein, we propose an elegant and efficient approach by fabricating three-dimensional mushroom-shaped polydimethylsiloxane (PDMS) micropillars on a flexible PDMS substrate to mimic the bending and stretching of gecko footpads. The fabrication process that employs two-photon polymerization ensures high spatial resolution, resulting in micropillars with exquisite structures and ultra-smooth surfaces, even for tip/stem ratios exceeding 2 (a critical factor for maintaining adhesion strength). Furthermore, these adhesive structures display outstanding resilience, enduring 175% deformation and severe bending without collapse, ascribing to the excellent compatibility of the micropillar's composition and physical properties with the substrate. Our BSAIs can achieve highly controllable adhesion force and rapid manipulation of liquid droplets through mechanical bending and stretching of the PDMS substrate. By adjusting the spacing between the micropillars, precise control of adhesion strength is achieved. These intriguing properties make them promising candidates for various applications in the fields of microfluidics, micro-assembly, flexible electronics, and beyond.

Understanding pancreas development can provide clues for better treatments of pancreatic diseases. However, the molecular heterogeneity and developmental trajectory of the early human pancreas are poorly explored. Here, we performed large-scale single-cell RNA sequencing and single-cell assay for transposase accessible chromatin sequencing of human embryonic pancreas tissue obtained from first-trimester embryos. We unraveled the molecular heterogeneity, developmental trajectories and regulatory networks of the major cell types. The results reveal that dorsal pancreatic multipotent cells in humans exhibit different gene expression patterns than ventral multipotent cells. Pancreato-biliary progenitors that generate ventral multipotent cells in humans were identified. Notch and MAPK signals from mesenchymal cells regulate the differentiation of multipotent cells into trunk and duct cells. Notably, we identified endocrine progenitor subclusters with different differentiation potentials. Although the developmental trajectories are largely conserved between humans and mice, some distinct gene expression patterns have also been identified. Overall, we provide a comprehensive landscape of early human pancreas development to understand its lineage transitions and molecular complexity., (© 2023. Springer Nature Limited.)

Overexposure to manganese (Mn) is conducive to neurodegenerative diseases and neuronal injury. Persistent activation of the integrated stress response (ISR) has a substantial impact on the etiology of neurodegenerative disorders by interfering with intracellular homeostasis. Nevertheless, the precise mechanism through which ISR engages in Mn-related neurotoxicity remains unclear. Sirtuin 1 (SIRT1), a typical NAD + -dependent protein deacetylase, which is known to participate in Mn-induced neuronal damage. Therefore, the aim of our study was to clarify how SIRT1 regulates persistent ISR activation in mouse hippocampal neuronal cells (HT-22 cells) exposed to various concentrations of Mn. We discovered that persistent ISR activation was engaged in Mn-triggered mitochondrial and exogenous apoptotic signaling pathways, which was attributed to the excessive phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). Growth arrest and DNA damage-inducible protein 34 (GADD34) is known to be responsible for down-regulating the phosphorylation of eIF2α. However, Mn promoted GADD34 protein expression and its acetylation level. We further investigated the effect of SIRT1 on the acetylation of GADD34 by overexpressing and silencing SIRT1. We discovered that SIRT1 activation significantly declined the acetylation level of GADD34, thus alleviating persistent ISR activation-mediated neuronal apoptosis in HT-22 cells-treated with Mn. In summary, these results suggested that Mn induced persistent activation of the ISR by inhibition of SIRT1 on deacetylation of GADD34., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Serious phosphatidylinositol 3 kinase (PI3K) inhibitor-related pneumonitis has raised clinical concerns, and integrated data for this condition are lacking., Methods: Randomized controlled trials (RCTs) comparing PI3K inhibitor therapy with control treatments from electronic databases and registrations were searched from inception to 1 April 20231 April 2023seven1 April 2023. The outcomes of our study were the incidence and risk of all-grade and grade ≥ 3 PI3K inhibitor-associated pneumonitis compared with controls., Results: The meta-analysis included 13 studies comprising 3916 patients. The incidence of all-grade and grade ≥ 3 pneumonitis was 3.7% (82/2210) and 3.0% (35/1162) in patients treated with PI3K inhibitors. PI3K inhibitors significantly increased the risk of all-grade and grade ≥ 3 pneumonitis compared with controls (RR 5.63, 95% CI [2.97, 10.65], P  < 0.00001; RR 6.85, 95% CI [2.45, 19.11], P  = 0.0002, respectively) with no significant heterogeneity across studies. In terms of different PI3K inhibitors, copanlisib and idelalisib significantly increased the risk of pneumonitis compared to controls (RR 4.99, 95% CI [1.19, 21.01], P  = 0.03; RR 5.53, 95% CI [2.35, 13.01], P  < 0.0001, respectively)., Conclusion: PI3K inhibitors significantly increased the risk of pneumonitis compared with controls, and most cases are severe or even life-threatening., Prospero Registration Number: CRD42022318878.

Background: Anaplastic lymphoma kinases (ALK) tyrosine kinase inhibitors (TKIs) are effective and safe targeted therapies used in advanced ALK-positive non-small cell lung cancers (NSCLC). However, ALK-TKIs associated cardiovascular toxicities in patients with ALK-positive NSCLCremain incompletely characterized. We conducted the first meta-analysis to investigate this., Research Design and Methods: To determine the cardiovascular toxicities associated with these agents, we carried out a meta-analysis comparing ALK-TKIs with chemotherapy and a meta-analysis comparing crizotinib with other ALK-TKIs. Statistical analysis was conducted to calculate the RRs and 95% confidence intervals (CIs) by using either random effects or fixed-effect models according to the heterogeneity of the included studies., Results: A total of 11 studies (2855 patients) were included. ALK-TKIs ranked to have more severe cardiovascular toxicities than chemotherapy (RR 5.03, 95% CI 1.97-12.84, P = 0.0007) . Compared with other ALK-TKIs, increased risks of cardiac disorders and VTEs associated with crizotinib were found (cardiac disorders RR 1.75, 95% CI 1.07-2.86, P = 0.03; risk of VTEs RR 3.97, 95% CI 1.69-9.31, P = 0.002; respectively)., Conclusion: ALK-TKIs were associated with higher risks of cardiovascular toxicities. Special attention should be given to the risks of cardiac disorders and VTEs related to crizotinib therapy.

Microactuators can autonomously convert external energy into specific mechanical motions. With the feature sizes varying from the micrometer to millimeter scale, microactuators offer many operation and control possibilities for miniaturized devices. In recent years, advanced microfluidic techniques have revolutionized the fabrication, actuation, and functionalization of microactuators. Microfluidics can not only facilitate fabrication with continuously changing materials but also deliver various signals to stimulate the microactuators as desired, and consequently improve microfluidic chips with multiple functions. Herein, this cross-field that systematically correlates microactuator properties and microfluidic functions is comprehensively reviewed. The fabrication strategies are classified into two types according to the flow state of the microfluids: stop-flow and continuous-flow prototyping. The working mechanism of microactuators in microfluidic chips is discussed in detail. Finally, the applications of microactuator-enriched functional chips, which include tunable imaging devices, micromanipulation tools, micromotors, and microsensors, are summarized. The existing challenges and future perspectives are also discussed. It is believed that with the rapid progress of this cutting-edge field, intelligent microsystems may realize high-throughput manipulation, characterization, and analysis of tiny objects and find broad applications in various fields, such as tissue engineering, micro/nanorobotics, and analytical devices., (© 2023 Wiley-VCH GmbH.)

Central nervous injury and regeneration repair have always been a hot and difficult scientific questions in neuroscience, such as spinal cord injury (SCI) caused by a traffic accident, fall injury, and war. After SCI, astrocytes further migrate to the injured area and form dense glial scar through proliferation, which not only limits the infiltration of inflammatory cells but also affects axon regeneration. We aim to explore the effect and underlying mechanism of miR-155-5p overexpression promoted astrocyte activation and glial scarring in an SCI model. MiR-155-5p mimic (50 or 100 nm) was used to transfect CTX-TNA2 rat brain primary astrocyte cell line. MiR-155-5p antagonist and miR-155-5p agomir were performed to treat SCI rats. MiR-155-5p mimic dose-dependently promoted astrocyte proliferation, and inhibited cell apoptosis. MiR-155-5p overexpression inhibited nuclear PTEN expression by targeting Nedd4 family interacting protein 1 (Ndfip1). Ndfip1 overexpression reversed astrocyte activation which was induced by miR-155-5p mimic. Meanwhile, Ndfip1 overexpression abolished the inhibition effect of miR-155-5p mimic on PTEN nuclear translocation. In vivo, miR-155-5p silencing improved SCI rat locomotor function and promoted astrocyte activation and glial scar formation. And miR-155-5p overexpression showed the opposite results. MiR-155-5p aggravated astrocyte activation and glial scarring in a SCI model by targeting Ndfip1 expression and inhibiting PTEN nuclear translocation. These findings have ramifications for the development of miRNAs as SCI therapeutics., (© 2023. The Author(s).)

Francisella tularensis is a highly virulent Gram-negative bacterium that causes the fatal zoonotic disease tularemia. The mechanisms and signaling pathways leading to the absent in melanoma 2 (Aim2) inflammasome activation have been elegantly elucidated using Francisella novicida as a model. Although not pathogenic for humans, F . novicida can cause tularemia in mice, and the inflammatory response it triggers is the polar opposite to that observed in mice infected with F . tularensis strains. This study aimed to understand the mechanisms of Aim2 inflammasome activation in F . tularensis- infected macrophages. The results reveal that macrophages infected with the F . tularensis live vaccine strain (LVS) induce lower levels of Aim2-dependent IL-1β than those infected with F . novicida . The suppression/weak activation of Aim2 in F . tularensis LVS-infected macrophages is due to the suppression of the cGAS-STING DNA-sensing pathway. Furthermore, the introduction of exogenous F . tularensis LVS DNA into the cytosol of the F . tularensis LVS-infected macrophages, alone or in conjunction with a priming signal, failed to restore IL-1β levels similar to those observed for F . novicida- infected macrophages. These results indicated that, in addition to the bacterial DNA, DNA from some other sources, specifically from the damaged mitochondria, might contribute to the robust Aim2-dependent IL-1β levels observed in F . novicida -infected macrophages. The results indicate that F . tularensis LVS induces mitophagy that may potentially prevent the leakage of mitochondrial DNA and the subsequent activation of the Aim2 inflammasome. Collectively, this study demonstrates that the mechanisms of Aim2 inflammasome activation established for F . novicida are not operative in F . tularensis ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Alqahtani, Ma, Miller, Yu, Malik and Bakshi.)

Background: Recent randomized trials have suggested that endovascular thrombectomy (EVT) alone may provide similar functional outcomes as the current standard of care, EVT combined with intravenous alteplase treatment, for acute ischemic stroke secondary to large vessel occlusion. We conducted an economic evaluation of these 2 therapeutic options., Methods: We constructed a decision analytic model with a hypothetical cohort of 1000 patients to assess the cost-effectiveness of EVT with intravenous alteplase treatment versus EVT alone for acute ischemic stroke secondary to large vessel occlusion from both the societal and public health care payer perspectives. We used studies and data published in 2009-2021 for model inputs, and acquired cost data for Canada and China, representing high- and middle-income countries, respectively. We calculated incremental cost-effectiveness ratios (ICERs) using a lifetime horizon and accounted for uncertainty using 1-way and probabilistic sensitivity analyses. All costs are reported in 2021 Canadian dollars., Results: In Canada, the difference in quality-adjusted life-years (QALYs) gained between EVT with alteplase and EVT alone was 0.10 from both the societal and health care payer perspectives. The difference in cost was $2847 from a societal perspective and $2767 from the payer perspective. In China, the difference in QALYs gained was 0.07 from both perspectives, and the difference in cost was $1550 from the societal perspective and $1607 from the payer perspective. One-way sensitivity analyses showed that the distributions of modified Rankin Scale scores at 90 days after stroke were the most influential factor on ICERs. For Canada, compared to EVT alone, the probability that EVT with alteplase would be cost-effective at a willingness-to-pay threshold of $50 000 per QALY gained was 58.7% from a societal perspective and 58.4% from a payer perspective. The corresponding values for at a willingness-to-pay threshold of $47 185 (3 times the Chinese gross domestic product per capita in 2021) were 65.2% and 67.4%., Interpretation: For patients with acute ischemic stroke due to large vessel occlusion eligible for immediate treatment with both EVT alone and EVT with intravenous alteplase treatment, it is uncertain whether EVT with alteplase is cost-effective compared to EVT alone in Canada and China., Competing Interests: Competing interests: Michael Hill reports grants to the University of Calgary: for the TEMPO-2 trial from Boehringer-Ingelheim; from Biogen, outside the submitted work; for the ESCAPE-NA1 trial and ESCAPE-NEXT trial from NoNO and the Canadian Institutes of Health Research; and for the HERMES collaboration from Medtronic. He also reports an Alberta Innovates grant to the University of Calgary for the QuICR Alberta Stroke Program (some of the funds were used for the ESCAPE-NA1 trial). He has received fees for adjudication of clinical trial outcomes from Sun Pharma and Brainsgate. He holds US Patents 62/086,077 and 10,916,346 (licensed to Circle Neurovascular Imaging). He was chair of the data safety monitoring committee for the RACECAT trial (ended in 2020), and is chair of the data safety monitoring committee for the Oncovir Hiltonol trial, chair of the data safety monitoring committee for the DUMAS trial, a member of the data safety monitoring board for the ARTESiA trial and a member of the data safety monitoring board for the BRAIN-AF trial. He is president of the Canadian Neurological Sciences Federation and a board member of the Canadian Stroke Consortium. He holds stock in Circle and PureWeb. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

Occupational exposure and non-occupational exposure to excessive levels of manganese (Mn) result in neuronal cell damage through mitochondrial dysfunction. The functional integrity of mitochondria is maintained by mitophagy and mitochondrial biogenesis. Although Mn-induced S-nitrosylation of PTEN-induced putative kinase 1 (PINK1) can interfere with mitophagy, its effect on mitochondrial biogenesis remains unclear. In this study, we established a rat model of Mn poisoning or "manganism" to examine the relationship between PINK1 S-nitrosylation and impairment of mitochondrial biogenesis, and found that treatment with 60 mg/kg Mn induced marked neurobehavioral abnormalities in rats and significantly increased the S-nitrosylation level of PINK1. We also found that the nuclear-encoded peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A)-mediated mitochondrial biogenesis was significantly upregulated in rats treated with 15 and 30 mg/kg Mn, and downregulated in rats treated with 60 mg/kg Mn. We further investigated the role of S-nitrosylated PINK1 and its molecular mechanism in the high-dose Mn-mediated impairment of mitochondrial biogenesis in primary cultured neurons treated with the nitric oxide synthase 2 (NOS2) inhibitor 1400 W. Our results revealed that the PPARGC1A-mediated mitochondrial biogenesis was upregulated in neurons treated with 100 μM, but downregulated in neurons treated with 200 μM Mn, which was similar to the in vivo results. However, treatment with 1400W could effectively prevent the 200 μM Mn-mediated impairment of mitochondrial biogenesis by suppressing nitric oxide (NO)-mediated PINK1 S-nitrosylation and rescuing Parkin-interacting substrate (PARIS, ZNF746) degradation, thereby upregulating mitochondrial biogenesis via PPARGC1A. These findings demonstrated that S-nitrosylation of PINK1 and subsequent prevention of ZNF746 degradation were crucial signaling processes involved in the Mn-mediated impairment of mitochondrial biogenesis, which might serve as an underlying mechanism of Mn-induced neurotoxicity. Furthermore, this study provided a reliable target for the prevention and treatment of manganism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Epidermal Growth Factor Receptor/ Anaplastic Lymphoma Kinase Tyrosine kinase inhibitors (EGFR/ALK TKIs) may provoke fatal interstitial pneumonitis (IP). The study was conducted to characterize the main characteristics of EGFR/ALK TKI-induced IP and identify factors associated with death., Research Design and Methods: A disproportionality analysis was conducted using Vigibase, the World Health Organization pharmacovigilance database. Clinical features of patients with EGFR/ALK-TKI-related IP were compared between the fatal and non-fatal groups., Results: A total of 3355 EGFR/ALK-TKI-IP events were identified, over half of them from Asia (57.47%) and mostly the aged (63.21%). Osimertinib appeared the strongest IP association. The median time to onset (TTO) was 40 (interquartile range [IQR] 16-84) days. There were significant differences between the fatal and non-fatal groups in terms of reporting year and TKI regimens (P < 0.05). The fatality rate of erlotinib-induced IP was the highest (35.54%)., Conclusion: Our study showed that EGFR/ALK TKIs were associated with IP that had a high fatality rate and tended to occur earlier in fatal cases. It is necessary to raise awareness of IP surveillance when EGFR/ALK TKIs were administered.

Background: Cutaneous adverse effects (AEs) are common following the phosphoinositide-3-kinase (PI3K) inhibitors treatment. We aim to estimate the incidence and risk of PI3K inhibitor-related cutaneous AEs., Methods: The protocol was submitted to the PROSPERO registry. We searched ClinicalTrials.gov and international databases up to July 29, 2022. Meta-analysis was conducted by using risk ratios (RRs) with 95% confidence intervals (CIs)., Results: Fourteen randomized controlled trials (RCTs) comprising 3877 patients were analyzed in this study. Compared with control arms, PI3K inhibitors showed a significant increase in the risk of all-grade rash, high-grade rash, and serious rash events (RR 2.29, 95% CI 1.58-3.31, p < 0.00001; RR 9.34, 95% CI 4.21-20.69, p < 0.00001; RR 5.11, 95% CI 2.11-12.36, p = 0.0003). The overall incidences of all-grade rash and high-grade rash were 26.2% (592/2257) and 4.4% (66/1487). Subgroup analyses of all-grade rash according to cancer types and PI3K inhibitor assignations identified the significant associations. PI3K inhibitors also significantly increased the risk of pruritus and dry skin (RR 1.63, 95% CI 1.14-2.33, p = 0.007; RR 3.34, 95% CI 2.30-4.85, p < 0.00001), with incidences of 13.4% (284/2115) and 9.8% (141/1436) in the treatment group., Conclusion: There is a significantly increased risk of some cutaneous AEs in patients using PI3K inhibitors. Advance intervention is recommended in case of severe and life-threatening events. Further research is required to investigate the risk factors and pathogenesis., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Manganese (Mn) overexposure induces learning and memory impairments in mice by disrupting the functions of synapses and synaptic vesicles (SVs) in the hippocampus, which is associated with α-synuclein (α-Syn) overexpression. Rab26-dependent autophagy is a key signaling step required for impaired SV clearance; however, it is unclear whether Mn-induced α-Syn overexpression is linked to dysregulated Rab26-dependent autophagy in presynaptic neurons. In this study, we developed manganism models in male C57BL/6 mice and hippocampal primary neurons to observe the associations between Mn-induced α-Syn overexpression and impaired SV accumulation. The results of the in vivo experiments showed that 100 and 200 μmol/kg Mn exposure significantly impaired memory and synaptic plasticity in the mice, which was related to the accumulation of impaired SVs in the hippocampus. Consistent with the in vivo outcomes, the level of in vitro injured SVs in the 50 and 100 μmol/L Mn-exposed neuron group were higher than that in the control group. Moreover, 100 μmol/L Mn suppressed the initiation of Rab26-dependent autophagy at the synapse. Then, we transfected neurons with LV-α-Syn short hairpin RNA (shRNA) and exposed the neurons to Mn for an additional 24 h. Surprisingly, the area of colocalization between Rab26 and Atg16L1 and the expression level of LC3II-positive SVs were both higher in Mn-exposed LV-α-Syn shRNA-transfected neurons than those in Mn-treated normal or Mn-treated LV-scrambled shRNA-transfected neurons. Thus, Mn-induced α-Syn overexpression was responsible for the dysregulation of Rab26-dependent autophagy, thereby promoting the accumulation of injured SVs, and causing synaptotoxicity and cognitive and memory deficits in mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Competing Interests: The authors declare no conflict of interest.

Background: Few studies have compared the clinical efficacy of unilateral and bilateral pedicle screw fixation and fusion in treating atlantoaxial fracture-dislocation., Objective: To compare the efficacy of unilateral and bilateral fixation and fusion for atlantoaxial fracture-dislocation and to explore the feasibility of the unilateral surgical procedure., Methods: Twenty-eight consecutive patients with atlantoaxial fracture-dislocation were included in the study from June 2013 to May 2018. They were divided into a unilateral fixation group and a bilateral fixation group (14 patients in each group with an average age of 43.6 ± 16.3 years and 51.8 ± 15.4 years, respectively). The unilateral group had a unilateral anatomical variation of the pedicle or vertebral artery, or traumatic pedicle destruction. All patients underwent atlantoaxial unilateral or bilateral pedicle screw fixation and fusion. Intraoperative blood loss and operation time were recorded. The visual analog scale (VAS) and Japanese Orthopedic Association (JOA) scoring systems were used to evaluate pre- and postoperative occipital-neck pain and neurological function. X-ray and computerized tomography (CT) were used to assess atlantoaxial stability, the implants' position, and bone graft fusion., Results: All patients were followed up for 39-71 months postoperatively. Intraoperatively, no spinal cord or vertebral artery injury was observed. At the last follow-up, occipital-neck pain and neurological function in the two groups were significantly improved (P< 0.05). The X-ray films and CT showed satisfactory atlantoaxial stability, implant position, and osseous fusion in all the patients at 6 months postoperatively., Conclusion: Unilateral and bilateral pedicle screw fixation and fusion can restore atlantoaxial stability and improve occipital-neck pain and neurological function in patients with atlantoaxial fracture-dislocation. The unilateral surgical procedure can be a supplementary option for patients with unilateral abnormal atlantoaxial lesions.

It is urgent to develop non-noble metal electrocatalysts with both excellent activity and durable stability for H 2 production via water electrolysis. Electric energy is mainly consumed by the sluggish anodic oxygen evolution reaction (OER). The electrocatalytic urea oxidation reaction (UOR) has been regarded as a promising reaction to replace OER because of its small thermodynamic oxidation potential. However, developing a facile and large-scale preparation method for bifunctional hydrogen evolution reaction (HER) and UOR electrocatalysts is still challenging. Herein, phosphate-modified (4.46 atomic%) NiMoO 4-x net-like nanostructures are formed on Ni foam (NF) via H 3 PMo 12 O 40 etching strategy at room temperature (denoted as NF/P-NiMoO 4-x ). The etched NF can directly serve as HER electrode, and delivers overpotential of 116 mV at current density of 10 mA/cm 2 with Tafel slope of 77.5 mV/dec. Furthermore, it displays excellent UOR activity with potential of 1.359 V at current density of 10 mA/cm 2 and Tafel slope of 19.3 mV/dec. The apparent activation energy of NF/P-NiMoO 4-x is 20.6 kJ/mol, lower than that of NF (37.7 kJ/mol), indicating smaller apparent barrier for CN bond cleavage in urea. The cell voltage of urea electrolysis is around 1.48 V for H 2 production to deliver current density of 10 mA/cm 2 , and better long-term stability for 50 h than that of Ir/C||Pt/C. The etching solution can be recycled for five times by addition of H 2 O 2 , turning heteropoly blue into its original state. This work develops a facile and large-scale method to prepare bifunctional HER and UOR electrocatalysts for H 2 production in a less-energy saving way via urea electrolysis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We modified and extended laminoplasty to the upper cervical spine on patients with canal stenosis associated with upper cervical spinal ossified lesions. However, whether the extended decompression range of laminoplasty can cause further effects on cervical stability is rarely studied at present. A retrospective study to analyze the relationship between the surgical levels and cervical sagittal parameters effects was performed in patients with cervical spondylosis myelopathy who had undergone posterior cervical expansive open-door laminoplasty with/without extending to C2. In total, 64 patients were divided into 2 groups according to the surgical levels. Radiologic outcomes of occipito-cervical angle (C0-2 Cobb angle), CL C27 Cobb angle, cervical sagittal vertical alignment, T1-Slope (T1S), T1S minus CL (T1S-CL), spino-cranial angle and center of the sella turcica-C7 SVA (St-SVA) were evaluated on lateral X-rays of the cervical spine at pre-operation, post-operation, and 2-year follow-up. The patient's health-related quality of life was obtained including neck disability index, Japanese orthopaedic association scores, and visual analog scale. Changes in sagittal parameters were observed in both groups after surgery. T1S, cervical sagittal vertical alignment, and T1S-CL significantly increased and CL decreased in 2 groups of patients postoperative. After a 2-year follow-up period, the C0-2 Cobb angle was found to increase compared to preoperative records. In addition, there were no significant differences in spino-cranial angle and st-SVA between preoperative and 2 years follow-up measurements. Health-related quality of life was improved in both groups and was not significantly different. Herein, the parameters indicated a tilting forward of the lower cervical spine and a more lordotic upper cervical spine to maintain a horizontal gaze in patients. However, C2 to 7 laminoplasty was performed to achieve satisfactory clinical results without significantly changing the spinal sagittal parameters., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

As a typical micro/nano processing technique, femtosecond laser fabrication provides the opportunity to achieve delicate microstructures. The outstanding advantages, including nanoscale feature size and 3D architecting, can bridge the gap between the complexity of the central nervous system in virto and in vivo . Up to now, various types of microstructures made by femtosecond laser are widely used in the field of neurobiological research. In this mini review, we present the recent advancement of femtosecond laser fabrication and its emerging applications in neurobiology. Typical structures are sorted out from nano, submicron to micron scale, including nanoparticles, micro/nano-actuators, and 3D scaffolds. Then, several functional units applied in neurobiological fields are summarized, such as central nervous system drug carriers, micro/nano robots and cell/tissue scaffolds. Finally, the current challenges and future perspective of integrated neurobiology research platform are discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer DH declared a past co-authorship with the author BH to the handling editor., (Copyright © 2022 Tian, Ma, Han, Suo, Zhang and Han.)

Background: Interstitial lung disease (ILD) events associated with anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates (ADCs) have aroused wide attention., Research Design and Methods: In meta-analysis, we systematically reviewed literatures, and the outcomes were the proportion and risk of ILD related to anti-HER2 ADCs. A disproportionality analysis based on data from VigiBase was conducted to characterize the main features of anti-HER2 ADC-related ILD/pneumonitis., Results: Two hundred and forty-five all-grade and 47 grade ≥ 3 ILD events with the proportion of 4.4% (95% confidence interval (CI) [2.0%, 6.8%]) and 0.5% (95% CI [0.3%, 0.8%]) were observed for anti-HER2 ADCs, respectively. Trastuzumab emtansine, trastuzumab deruxtecan and trastuzumab duocarmazine significantly increased the risk of all-grade and grade ≥ 3 ILD events with Peto odd ratios of 2.62 (95% CI [1.71, 4.04], P < 0.0001) and 2.82 (95% CI [1.07, 7.42], P = 0.04), respectively. In VigiBase, 271 cases of ILD/pneumonitis related to trastuzumab emtansine and trastuzumab deruxtecan were extracted. The median time to the onset of event was 86 days and 54.95% of events occurred within 3 months., Conclusions: Trastuzumab emtansine, trastuzumab deruxtecan and trastuzumab duocarmazine increased the risk of ILD, which can lead to serious outcomes and tends to occur early.

Manganese (Mn) toxicity is mainly caused by excessive Mn content in drinking water and occupational exposure. Moreover, overexposure to Mn can impair mental, cognitive, memory, and motor capacities. Although melatonin (Mel) can protect against Mn-induced neuronal damage and mitochondrial fragmentation, the underlying mechanism remains elusive. Here, we examined the related molecular mechanisms underlying Mel attenuating Mn-induced mitochondrial fragmentation through the mammalian sterile 20-like kinase-1 (Mst1)/JNK signaling path. To test the role of Mst1 in mitochondrial fragmentation, we treated mouse primary neurons overexpressing Mst1 with Mel and Mn stimulation. In normal neurons, 10 μM Mel reduced the effects of Mn (200 μM) on Mst1 expression at the mRNA and protein levels and on phosphorylation of JNK and Drp1, Drp1 mitochondrial translocation, and mitochondrial fragmentation. Conversely, overexpression of Mst1 hindered the protective effect of Mel (10 μM) against Mn-induced mitochondrial fragmentation. Anisomycin (ANI), an activator of JNK signaling, was similarly found to inhibit the protective effect of Mel on mitochondria, while Mst1 levels were not significantly changed. Thus, our results demonstrated that 10 μM Mel negatively regulated the Mst1-JNK pathway, thereby reducing excessive mitochondrial fission, maintaining the mitochondrial network, and alleviating Mn-induced mitochondrial dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background:  The association between immune checkpoint inhibitors (ICIs) and thromboembolic events (TEEs) remains controversial., Objective:  The goal of this study was to assess the risk of major TEEs associated with ICIs., Methods:  We explored ICI-related TEEs in randomized controlled trials available in ClinicalTrials.gov and electronic databases up to June 30, 2021. Meta-analysis was performed by using Peto odds ratios (ORs) with 95% confidence intervals (CIs)., Results:  A total of 61 studies were included. Patients treated with ICIs had a similar risk of venous thromboembolism (VTE) but a significantly increased risk of arterial thromboembolism (ATE) (Peto OR: 1.58 [95% CI: 1.21-2.06]) compared with non-ICI regimens. Stratified by different regimens, only PD-L1 (programmed cell death ligand 1) inhibitors showed a significant increase in ATE (Peto OR: 2.07 [95% CI: 1.26-3.38]). The incidence of VTE was higher in PD-1/PD-L1 inhibitor and CTLA-4 (cytotoxic T lymphocyte antigen 4) inhibitor combination therapies compared with monotherapies (Peto OR: 2.23 [95% CI: 1.47-3.37]). Stratified by tumor, for pulmonary embolism (PE) and cerebral ATE, the statistically significant results were only seen in lung cancer patients (Peto OR: 1.42 [95% CI: 1.02-1.97]; Peto OR: 2.10 [1.07-4.12]), and for myocardial infarction, the statistically significant result was only seen in other tumor types (Peto OR: 2.66 [95% CI: 1.68-4.20], p  < 0.0001)., Conclusion:  There was no significant increase in the overall risk of VTE in patients treated with ICIs; however, special attention should be given to the risk of VTE in PD-1/PD-L1 inhibitor and CTLA-4 inhibitor combination therapy and PE in lung cancer patients. PD-L1 inhibitors were associated with a significant increase in ATE., Competing Interests: None declared., (Thieme. All rights reserved.)

Femtosecond laser (FSL) technology has created an evolution in ophthalmic surgery in the last few decades. With the advantage of high precision, accuracy, and safety, FSLs have helped surgeons overcome surgical limits in refractive surgery, corneal surgery, and cataract surgery. They also open new avenues in ophthalmic areas that are not yet explored. This review focuses on the fundamentals of FSLs, the advantages in interaction between FSLs and tissues, and typical clinical applications of FSLs in ophthalmology. With the rapid progress that has been made in the state of the art research on FSL technologies, their applications in ophthalmic surgery may soon undergo a booming development.

The influence of the molecular structures of flavor compounds (specifically, variations in chain length and functional groups) on the binding of the flavor compounds (Z)-2-penten-1-ol, hexanal, and (E)-2-octenal to pea protein was investigated. The results showed that the molecular structures of the flavor compounds strongly influenced their binding affinity for pea protein. Specifically, (E)-2-octenal exhibited a higher binding affinity and a higher Stern-Volmer constant with pea protein than both hexanal and (Z)-2-penten-1-ol. Thermodynamic analysis indicated that the flavor compound-pea protein interactions were spontaneous. Hydrophobic interactions were dominant in the non-covalent interactions between (E)-2-octenal/(Z)-2-penten-1-ol and pea protein, whereas hydrogen bonding was dominant in the non-covalent interactions between hexanal and pea protein. Surface hydrophobicity measurements, the use of bond-disrupting agents, and molecular docking further supported the hypothesis that hydrogen bonding, as well as hydrophobic interactions, occurred between the flavor compounds and pea protein., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The B cell receptor (BCR) complex plays a critical role in B cell development and immune responses. The assembly mechanisms underlying the BCR complex remain unknown. We determined the cryo-electron microscopy (cryo-EM) structures of human IgG-BCR and IgM-BCR, which consist of membrane-bound immunoglobulin molecules (mIg) and Igα/β subunits at a 1:1 stoichiometry. Assembly of both BCR complexes involves their extracellular domains, membrane-proximal connection peptides, and transmembrane (TM) helices. The TM helices of mIgG and mIgM share a conserved set of hydrophobic and polar interactions with Igα/β TM helices. By contrast, the IgG-Cγ3 and IgM-Cμ4 domains interact with extracellular Ig-like domains of Igα/β through head-to-tail and side-by-side modes, respectively. This work reveals the structural basis for BCR assembly and provides insights into BCR triggering.

Chronic exposure to excess manganese (Mn) causes neurotoxicity, which is characterized by Parkinson-like symptoms and referred to as manganism. In the last few decades, mitochondrial damage and subsequent energy failure have been reported to be important mechanisms of Mn toxicity, yet how Mn causes mitochondrial damage remains largely unknown. Here, we demonstrated that Mn induced S-nitrosation of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), a master regulator in the mitophagy pathway, results in dysregulation of mitophagy and nerve cell injury in the rat striatum. We cultured primary neurons and used 1400 W, a potent and selective inducible nitric oxide synthase (iNOS) inhibitor, as an intervention to verify the precise mechanism of Mn-induced dysregulation of mitophagy. We demonstrated that Mn-induced S-nitrosylation of PINK1 decreased the phosphorylated level of parkin RBR E3 ubiquitin-protein ligase (Parkin), as well as the translocation of Parkin to damaged mitochondria, which led to the accumulation of damaged mitochondria and mitochondrial-mediated apoptosis. Our findings indicated the unusual connection between nitrative stress and mitochondrial dysfunction in Mn-induced neurotoxicity. These data highlight the role of S-nitrosation of PINK1 in Mn-induced dysregulation of mitophagy and provide a reliable target for the development of specific drugs and the early treatment of manganism, which has important theoretical and practical significance., Competing Interests: Declaration of competing interest The authors have no financial conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Microbial fuel cells (MFCs) are promising ecofriendly techniques for harvesting bioenergy from organic and inorganic matter. Currently, it is challenging to design MFC anodes with favorable microorganism attachment and fast extracellular electron transfer (EET) rate for high MFC performance. Here we prepared N-doped carbon nanotubes (NCNTs) on carbon felt (CF) and used it as a support for growing hierarchical Co 8 FeS 8 -FeCo 2 O 4 /NCNTs core-shell nanostructures (FeCo/NCNTs@CF). We observed improved wettability, specific areal capacitance, and diffusion coefficient, as well as small charge transfer resistance compared with bare CF. MFCs equipped with FeCo/NCNTs@CF displayed a power density of 3.04 W/m 2 and COD removal amount of 221.0 mg/L/d, about 47.6 and 290.1% improvements compared with that of CF. Biofilm morphology and 16s rRNA gene sequence analysis proved that our anode facilitated the enrichment growth of exoelectrogens. Flavin secretion was also promoted on our hierarchical elelctrode, effectively driving the EET process. This work disclosed that hierarchical nanomaterials modified electrode with tailored physicochemical properties is a promising platform to simultaneously enhance exoelectrogen attachment and EET efficiency for MFCs.