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Sepsis, a life-threatening condition, involves complex interactions among metabolic alterations, inflammatory mediators, and host responses. This study utilized a bidirectional Mendelian randomization approach to investigate the causal relationships between 1400 metabolites and sepsis, and the mediating role of inflammatory factors. We identified 36 metabolites significantly associated with sepsis (p < 0.05), with AXIN1, FGF-19, FGF-23, IL-4, and OSM showing an inverse association, suggesting a protective role, while IL-2 exhibited a positive correlation, indicating a potential risk factor. Among these metabolites, Piperine and 9-Hydroxystearate demonstrated particularly interesting protective effects against sepsis. Piperine’s protective effect was mediated through its interaction with AXIN1, contributing to a 16.296% reduction in sepsis risk. This suggests a potential pathway where Piperine influences sepsis outcomes by modulating AXIN1 levels. 9-Hydroxystearate also exhibited a protective role against sepsis, mediated through its positive association with FGF-19 and negative association with IL-2, contributing 9.436% and 12.565%, respectively, to its protective effect. Experimental validation confirmed significantly elevated IL-2 levels and reduced FGF-19, AXIN1, piperine, and 9-hydroxyoctadecanoic acid levels in sepsis patients compared to healthy controls. Piperine levels positively correlated with AXIN1, while 9-hydroxyoctadecanoic acid levels negatively correlated with IL-2 and positively correlated with FGF-19, supporting the Mendelian randomization findings. Our findings provide insights into the molecular mechanisms of sepsis, highlighting the unique roles and contributions of specific metabolites and their interactions with inflammatory mediators. This study enhances our understanding of sepsis pathophysiology and opens avenues for targeted therapeutic interventions and biomarker development for sepsis management. However, further research is essential to validate these pathways across diverse populations and fully explore the roles of these metabolites in sepsis.

BackgroundSepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infection, yet the potential causal relationship between the immunophenotype and sepsis remains unclear.MethodsGenetic variants associated with the immunophenotype served as instrumental variables (IVs) in Mendelian randomization (MR) to elucidate the causal impact of the immunophenotype on three sepsis outcomes. Additionally, a two-step MR analysis was conducted to identify significant potential mediators between the immunophenotype and three sepsis outcomes.ResultsOur MR analysis demonstrated a significant association between the immunophenotype and sepsis outcome, with 36, 36, and 45 the immunophenotype associated with the susceptibility, severity, and mortality of sepsis, respectively. Specifically, our analysis highlighted the CD14+ CD16+ monocyte phenotype as a significant factor across all three sepsis outcomes, with odds ratios (ORs) and corresponding confidence intervals (CIs) indicating its impact on sepsis (OR = 1.047, CI: 1.001-1.096), sepsis in Critical Care Units (OR = 1.139, CI: 1.014-1.279), and sepsis-related 28-day mortality (OR = 1.218, CI: 1.104-1.334). Mediation analyses identified seven cytokines as significant mediators among 91 potential cytokines, including interleukin-5 (IL-5), S100A12, TNF-related apoptosis-inducing ligand (TRAIL), T-cell surface glycoprotein CD6 isoform, cystatin D, interleukin-18 (IL-18), and urokinase-type plasminogen activator (uPA). Furthermore, reverse MR analysis revealed no causal effect of sepsis outcomes on the immunophenotype.ConclusionOur MR study suggests that the immunophenotype is significantly associated with the susceptibility, severity, and mortality of patient with sepsis, providing, for the first time, robust evidence of significant associations between immune traits and their potential risks. This information is invaluable for clinicians and patients in making informed decisions and merits further attention.

BackgroundAcute pancreatitis (AP) is a severe digestive system disorder with a significant risk of progressing to sepsis, a major cause of mortality. Unraveling the immunological pathways in AP is essential for developing effective treatments, particularly understanding the role of specific immune cell traits in this progression.MethodsEmploying a bidirectional two-sample Mendelian Randomization (MR) approach, this study first examined the causal relationship between AP and 731 immune cell traits to identify those significantly associated with AP. Subsequently, we explored the causal associations between 731 immune cell traits and sepsis. The analysis utilized extensive genome-wide association studies (GWAS) summary datasets, with a focus on identifying common immune cell traits with statistically significant causal associations between AP and sepsis.ResultsOur investigation identified 44 immune cell traits unidirectionally associated with AP and 36 traits unidirectionally associated with sepsis. Among these, CD127 on CD28+ CD45RA- CD8+ T cells emerged as a common mediator, accounting for 5.296% of the increased risk of sepsis in AP patients. This finding highlights the significant role of specific memory CD8+ T cells in the pathophysiology of AP and its progression to sepsis.ConclusionThis study elucidates the critical role of specific immune cell traits, particularly CD127hi memory CD8+ T cells, in the progression of AP to sepsis. Our findings provide a foundation for future research into targeted immune-modulatory therapies, potentially improving patient outcomes in AP-related sepsis and offering new insights into the complex immunological dynamics of this condition.

With the increasing penetration of new-type loads such as electric vehicles and hydrogen fuel vehicles in urban power grids, the peak-to-valley load difference increases sharply, and a multi-energy coordination model is desirable. This article proposes a day-ahead operation model of an urban energy system considering traffic flows and peak shaving, which can positively contribute to multi-energy complement and low-carbon emission. The proposed model minimizes the total cost of electricity and gas by optimizing the charging and discharging strategies of energy storage, in which the output of the wind turbine and energy management of the energy hub are adaptively adjusted. The urban energy system is represented by a second-order cone (SOC) energy flow model, and hence, the optimization problem is modeled as a mixed integer SOC programming (MISOCP). Finally, test results on an integrated urban energy network indicate that the energy storage and multi-energy coordination can alleviate the peak load cutting and valley filling. The relationship between urban grid operation cost and peak-valley difference is also discussed. The maximum utilization of renewable energy sources using gasoline vehicles has been presented in this study to illustrate cost and emission reductions for a sustainable integrated electricity and transportation infrastructure.

Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder and characterized by early childhood-onset impairments in social interaction and communication, restricted and repetitive patterns of behavior or interests. So far there is no effective treatment for ASD, and the pathogenesis of ASD remains unclear. Genetic and epigenetic factors have been considered to be the main cause of ASD. It is known that endocannabinoid and its receptors are widely distributed in the central nervous system, and provide a positive and irreversible change toward a more physiological neurodevelopment. Recently, the endocannabinoid system (ECS) has been found to participate in the regulation of social reward behavior, which has attracted considerable attention from neuroscientists and neurologists. Both animal models and clinical studies have shown that the ECS is a potential target for the treatment of autism, but the mechanism is still unknown. In the brain, microglia express a complete ECS signaling system. Studies also have shown that modulating ECS signaling can regulate the functions of microglia. By comprehensively reviewing previous studies and combining with our recent work, this review addresses the effects of targeting ECS on microglia, and how this can contribute to maintain the positivity of the central nervous system, and thus improve the symptoms of autism. This will provide insights for revealing the mechanism and developing new treatment strategies for autism.

Spinal stenosis is a common disease affecting the elderly that is present in a various forms. Its high incidence forces researchers to pay more attention and offer countermeasures. We used the Web of Science Core collection and PubMed database to obtain 5,606 scientific studies concerning spinal stenosis, and the number of publications maintained a roughly increasing trend from 108 in 2000 to 512 in 2018, only declining in 2011. Bibliometric analysis was conducted using the online analysis software CiteSpace and Bibliographic Item Co-Occurrence Matrix Builder (BICOMB). The United States maintains academic leadership in this field. The journal SPINE was the most authoritative, with 695 articles and an average of 12.73 citations. The exported major MeSH terms were further biclustered with gCLUTO according to co-word analysis to reveal research hotspots, including etiology, pathogenesis, clinical manifestation, conservative treatment, operative indication, internal implantation, and postoperative complications. After combination, the main topics focused on pathogenesis and surgical treatment. Narrowing causes flavum ligamentum hypertrophy, and posterior longitudinal ligament ossification is widely accepted. Additionally, minimally invasive surgery and internal implantation fixation are more valid in the clinic. Refining pathological classification and optimizing surgical methods and instrument properties will be important future research directions for spinal stenosis.

Ischemic stroke, which accounts for 87% of all strokes, constitutes the leading cause of morbidity and mortality in China. Although the genetics and epigenetics of stroke have been extensively investigated, few studies have examined their relationships at different stages of stroke. This study assessed the characteristics of transcriptome changes at different stages of ischemic stroke using a mouse model of transient middle cerebral artery occlusion (tMCAO) and bioinformatics analyses. Cerebral cortex tissues from tMCAO mice at days 1, 3, 7, 14, and 28 were removed for RNA-Seq and small RNA-Seq library construction, sequencing, and bioinformatics analysis. We identified differentially expressed (DE) genes and miRNAs and revealed an association of the up-regulated or down-regulated DEmiRNAs with the correspondingly altered DEgene targets at each time point. In addition, different biological pathways were activated at different time points; thus, three groups of miRNAs were verified that may represent potential clinical biomarkers corresponding to days 1, 3, and 7 after ischemic stroke. Notably, this represents the first functional association of some of these miRNAs with stroke, e.g., miR-2137, miR-874-5p, and miR-5099. Together, our findings lay the foundation for the transition from a single-point, single-drug stroke treatment approach to multiple-time-point multi-drug combination therapies.

Sepsis is a life-threatening state of organ dysfunction caused by infection and which can induce severe neurological disorders that lead to neuroinflammation and cognitive impairment. Inflammation has been reported to cause neuronal apoptosis in sepsis, which can finally lead to cognitive impairment. Previous studies have suggested that BML-111 can exhibit anti-inflammatory and proresolution activities. Additionally, silent information regulator 1 (SIRT1) can inhibit the NF-κB signaling pathway in an inflammation state. However, the role of the SIRT1/NF-κB signaling pathway in the protective effects of BML-111 against sepsis-induced neuroinflammation and cognitive impairment remains unclear. This study aimed to determine the effects of BML-111 on neuroinflammation and cognitive impairment induced by sepsis. Male C57BL/6J mice were subjected to cecal ligation and puncture (CLP) or a sham operation. BML-111 was administered via intracerebroventricular injection (0.1 mg/kg) immediately after CLP. Boc-2 (50 μg/kg) was administered intracerebroventricularly 30 min before CLP, and EX527 (10 μg) was administered every 2 days for a total of three times before CLP, also intracerebroventricularly. Some of the surviving mice underwent open-field, novel-object-recognition, and fear-conditioning behavioral tests at 7 days after surgery. Some of the other surviving mice were killed at 24 h after surgery to assess synaptic damage (PSD95 and Synapsin1), markers of inflammation [tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β], cytoplasmic p65, nuclear p65, Ac- NF-κB and SIRT1. At 48 h after CLP, TUNEL and glia-activation by immunofluorescence investigations were performed on a separate cohort of surviving animals. The results suggested that sepsis resulted in cognitive impairment, which was accompanied by the decreased the expression of PSD95 and Synapsin1, increased amount of TUNEL-positive cells and the activation of glias, increased production of TNF-α and IL-1β, increased expression of nuclear p65, Ac- NF-κB, and decreased expression of SIRT1 and cytoplasmic p65. It is especially notable that these abnormalities could be reduced by BML-111 treatment. EX527, an SIRT1 inhibitor, abolished the effects of BML-111. These results demonstrate that BML-111 can reduce the neuroinflammation and cognitive impairment induced by sepsis via SIRT/NF-κB signaling pathway.

Research on fast-growing microbes holds promise for many industrial applications, including shortening test and trial times in research and development stages and reducing the operation costs for production. Such microbes can be obtained either by selecting naturally occurring variants or via metabolic engineering approaches, either eliminating ‘unnecessary’ or adding necessary pathways affecting growth speed in the cell. Here, we review recent research and development of engineered fast-growing strains in industrial biotechology, with a special focus on vaccine production using (synthetic biology) engineered pathogenic strains. We will discuss whether this represents a security concern and whether the industrial biotech sector needs to pay more attention to issues of Gain-of-Function (GoF) while developing and harnessing these fast-growing microbes. We will also shed a light on the use of in-built biosafety circuits as a way to control the propagation of fast-growing strains, including their capacity to survive in the environment. Other possible GoF concerns raised by the publication of research results in this field will be also addressed. In conclusion, judging from the current development from the field, assessing the potential GoF risks on engineered fast-growing microbes does not lead to a clear generalized outcome. We argue that fast growing strains need to be evaluated in combination with their wild type and engineered characteristics, and require always a case-by-case assessment. Monitoring the progress of the field and proactively raising awareness on the GoF issues among the scientists are important for the further development of the field.

Dementia is known to be induced by vascular dementia and certain neurodegenerative diseases. The presenting features of disordered memory, intellect and personality often result in referral to a neurologist initially. Septum pellucidum cyst (SPC) is a rare clinical finding and defined as a cystic structure between the lateral ventricles. SPC induced memory disorder and dementia has been seldom reported in which the clinical features are atypical and can be misdiagnosed. The main difficulty is to establish a correlation between symptoms and the cyst. When indicated, the treatment is essentially surgical and the ideal operative technique is also a matter of debate. Here, we reported a 58-year-male Chinese patient who presented with memory impairment 1 year ago. Both the physical and laboratory examinations were performed to evaluate the general conditions of the patient. Brain magnetic resonance imaging (MRI) was applied to observe SPC and the neighboring brain structures. Mini-Mental State Exam (MMSE) and Montreal Cognitive Assessment (MoCA) were used to assess cognitive function. The results of the patient’s laboratory examinations were normal. However, the patient exhibited severe sleeplessness along with cognitive deteriorations despite short-term (less than 2 weeks) use of benzodiazepines with regular dose. MRI fulfills the consensus criteria for clinical diagnosis of SPC. Furthermore, the results of MMSE and MoCA were showed mild cognitive impairment (MCI) before the treatment of SPC. After neuroendoscopic fenestration of SPC, the patient’s syndromes were disappeared, and his cognitive function was improved. In conclusion, the patient’s symptoms were due to a secondary lesion attributed to the cyst. Comprehensive clinical evaluation and MRI help diagnose SPC induced dementia.

Neuroinflammation has been identified as a causative factor of multiple neurological diseases. The nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome, a subcellular multiprotein complex that is abundantly expressed in the central nervous system (CNS), can sense and be activated by a wide range of exogenous and endogenous stimuli such as microbes, aggregated and misfolded proteins, and adenosine triphosphate, which results in activation of caspase-1. Activated caspase-1 subsequently leads to the processing of interleukin-1β (IL-1β) and interleukin-18 (IL-18) pro-inflammatory cytokines and mediates rapid cell death. IL-1β and IL-18 drive inflammatory responses through diverse downstream signaling pathways, leading to neuronal damage. Thus, the NLRP3 inflammasome is considered a key contributor to the development of neuroinflammation. In this review article, we briefly discuss the structure and activation the NLRP3 inflammasome and address the involvement of the NLRP3 inflammasome in several neurological disorders, such as brain infection, acute brain injury and neurodegenerative diseases. In addition, we review a series of promising therapeutic approaches that target the NLRP3 inflammasome signaling including anti-IL-1 therapy, small molecule NLRP3 inhibitors and other compounds, however, these approaches are still experimental in neurological diseases. At present, it is plausible to generate cell-specific conditional NLRP3 knockout (KO) mice via the Cre system to investigate the role of the NLRP3 inflammasome, which may be instrumental in the development of novel pharmacologic investigations for neuroinflammation-associated diseases.

Various environmental stresses strongly influence plant development. Among these stresses is drought, which is a serious threat that can reduce agricultural productivity and obstruct plant growth. Although the mechanism of plants in response to drought has been studied extensively, the adaptive strategies of Amygdalus mira (Koehne) Yü et Lu grown in drought and rewatered habitats remain undefined. Amygdalus mira from the Tibetan Plateau has outstanding nutritional and medicinal values and can thrive in extreme drought. In this study, the physiological and proteomic responses in leaves of A. mira were investigated during drought and recovery period. The changes in plant growth, photosynthesis, enzymes, and non-enzymatic antioxidant under drought and rewatering were also analyzed in leaves. Compared with controls, A. mira showed stronger adaptive and resistant characteristics to drought. In addition, the proteomic technique was also used to study drought tolerance mechanisms in A. mira leaves. Differentially expressed proteins were identified using mass spectrometry. Accordingly, 103 proteins involved in 10 functional categories: cytoskeleton dynamics, energy metabolism, carbohydrate metabolism, photosynthesis, transcription and translation, transport, stress and defense, molecular chaperones, other materials metabolism, and unknown function were identified. These results showed that an increase of stress-defense-related proteins in leaves after drought treatment contributed to coping with drought. Importantly, A. mira developed an adaptive mechanism to scavenge reactive oxygen species (ROS), including enhancing antioxidant enzyme activities and non-enzymatic antioxidant contents, reducing energy, and adjusting the efficiency of gas exchanges. These results may help to understand the acclimation of A. mira to drought. [ABSTRACT FROM AUTHOR]

xMAP technology is applicable for high-throughput, multiplex and simultaneous detection of different analytes within a single complex sample. xMAP multiplex assays are currently available in various nucleic acid and immunoassay formats, enabling simultaneous detection and typing of pathogenic viruses, bacteria, parasites and fungi and also antigen or antibody interception. As an open architecture platform, the xMAP technology is beneficial to end users and therefore it is used in various pharmaceutical, clinical and research laboratories. The main aim of this review is to summarize the latest findings and applications in the field of pathogen detection using microsphere-based multiplex assays. [ABSTRACT FROM AUTHOR]