The assessment of consciousness status in primary brainstem hemorrhage (PBH) patients can be achieved by monitoring changes in basic vital signs.

The objective of the study was to explore the association between basic vital signs and consciousness status in patients with primary brainstem hemorrhage (PBH). Patients with PBH were categorized into two groups based on Glasgow Coma Scale (GCS) scores: disturbance of consciousness (DOC) group (GCS=3-8) and non-DOC group (GCS=15). Within DOC group, patients were further divided into behavioral (GCS=4-8) and non-behavioral (GCS=3) subgroups. Basic vital signs, such as body temperature, heart rate, and respiratory rate, were monitored every 3 hours during the acute bleeding phase (1st day) and the bleeding stable phase (7th day) of hospitalization. The findings revealed a negative correlation between body temperature and heart rate with GCS scores in DOC group at both time points. Moreover, basic vital signs were notably higher in the DOC group compared to non-DOC group. Specifically, the non-behavioral subgroup within DOC group exhibited significantly elevated heart rates on the 1st day of hospitalization and moderately increased respiratory rates on the 7th day compared to the control group. Scatter plots illustrated a significant relationship between body temperature and heart rate with consciousness status, while no significant correlation was observed with respiratory rate. In conclusion, the study suggests that monitoring basic vital signs, particularly body temperature and heart rate, can serve as valuable indicators for evaluating consciousness status in PBH patients. These basic vital signs demonstrated variations corresponding to lower GCS scores. Furthermore, integrating basic vital sign monitoring with behavioral assessment could enhance the assessment of consciousness status in PBH patients.

Excessive accumulation of epicardial adipose tissue promotes microvascular obstruction formation after myocardial ischemia/reperfusion through modulating macrophages polarization.

BACKGROUND: Owing to its unique location and multifaceted metabolic functions, epicardial adipose tissue (EAT) is gradually emerging as a new metabolic target for coronary artery disease risk stratification. Microvascular obstruction (MVO) has been recognized as an independent risk factor for unfavorable prognosis in acute myocardial infarction patients. However, the concrete role of EAT in the pathogenesis of MVO formation in individuals with ST-segment elevation myocardial infarction (STEMI) remains unclear. The objective of the study is to evaluate the correlation between EAT accumulation and MVO formation measured by cardiac magnetic resonance (CMR) in STEMI patients and clarify the underlying mechanisms involved in this relationship. METHODS: Firstly, we utilized CMR technique to explore the association of EAT distribution and quantity with MVO formation in patients with STEMI. Then we utilized a mouse model with EAT depletion to explore how EAT affected MVO formation under the circumstances of myocardial ischemia/reperfusion (I/R) injury. We further investigated the immunomodulatory effect of EAT on macrophages through co-culture experiments. Finally, we searched for new therapeutic strategies targeting EAT to prevent MVO formation. RESULTS: The increase of left atrioventricular EAT mass index was independently associated with MVO formation. We also found that increased circulating levels of DPP4 and high DPP4 activity seemed to be associated with EAT increase. EAT accumulation acted as a pro-inflammatory mediator boosting the transition of macrophages towards inflammatory phenotype in myocardial I/R injury through secreting inflammatory EVs. Furthermore, our study declared the potential therapeutic effects of GLP-1 receptor agonist and GLP-1/GLP-2 receptor dual agonist for MVO prevention were at least partially ascribed to its impact on EAT modulation. CONCLUSIONS: Our work for the first time demonstrated that excessive accumulation of EAT promoted MVO formation by promoting the polarization state of cardiac macrophages towards an inflammatory phenotype. Furthermore, this study identified a very promising therapeutic strategy, GLP-1/GLP-2 receptor dual agonist, targeting EAT for MVO prevention following myocardial I/R injury.

IL-38 Aggravates Atopic Dermatitis via Facilitating Migration of Langerhans cells.

Atopic dermatitis (AD) is a common inflammation skin disease that involves dysregulated interplay between immune cells and keratinocytes. Interleukin-38 (IL-38), a poorly characterized IL-1 family cytokine, its role and mechanism in the pathogenesis of AD is elusive. Here, we show that IL-38 is mainly secreted by epidermal keratinocytes and highly expressed in the skin and downregulated in AD lesions. We generated IL-38 keratinocyte-specific knockout mice (K14Cre/+-IL-38f/f ) and induced AD models by 2,4-dinitrofluorobenzene (DNFB). Unexpectedly, after treatment with DNFB, K14Cre/+-IL-38f/f mice were less susceptible to cutaneous inflammation of AD. Moreover, keratinocyte-specific deletion of IL-38 suppressed the migration of Langerhans cells (LCs) into lymph nodes which results in disturbed differentiation of CD4+T cells and decreased the infiltration of immune cells into AD lesions. LCs are a type of dendritic cell that reside specifically in the epidermis and regulate immune responses. We developed LC-like cells in vitro from mouse bone marrow (BM) and treated with recombined IL-38. The results show that IL-38 depended on IL-36R, activated the phosphorylated expression of IRAK4 and NF-κB P65 and upregulated the expression of CCR7 to promoting the migration of LCs, nevertheless, the upregulation disappeared with the addition of IL-36 receptor antagonist (IL-36RA), IRAK4 or NF-κB P65 inhibitor. Furthermore, after treatment with IRAK4 inhibitors, the experimental AD phenotypes were alleviated and so IRAK4 is considered a promising target for the treatment of inflammatory diseases. Overall, our findings indicated a potential pathway that IL-38 depends on IL-36R, leading to LCs migration to promote AD by upregulating CCR7 via IRAK4/NF-κB and implied the prevention and treatment of AD, supporting potential clinical utilization of IRAK4 inhibitors in AD treatment.

Mecp2 Deficiency in Peripheral Sensory Neuron Improves Cognitive Function by Enhancing Hippocampal Dendritic Spine Densities in Mice.

Methyl-CpG-binding protein 2 (Mecp2) is an epigenetic modulator and numerous studies have explored its impact on the central nervous system manifestations. However, little attention has been given to its potential contributions to the peripheral nervous system (PNS). To investigate the regulation of Mecp2 in the PNS on specific central regions, we generated Mecp2fl/flAdvillincre mice with the sensory-neuron-specific deletion of the Mecp2 gene and found the mutant mice had a heightened sensitivity to temperature, which, however, did not affect the sense of motion, social behaviors, and anxiety-like behavior. Notably, in comparison to Mecp2fl/fl mice, Mecp2fl/flAdvillincre mice exhibited improved learning and memory abilities. The levels of hippocampal synaptophysin and PSD95 proteins were higher in Mecp2fl/flAdvillincre mice than in Mecp2fl/fl mice. Golgi staining revealed a significant increase in total spine density, and dendritic arborization in the hippocampal pyramidal neurons of Mecp2fl/flAdvillincre mice compared to Mecp2fl/fl mice. In addition, the activation of the BDNF-TrkB-CREB1 pathway was observed in the hippocampus and spinal cord of Mecp2fl/flAdvillincre mice. Intriguingly, the hippocampal BDNF/CREB1 signaling pathway in mutant mice was initiated within 5 days after birth. Our findings suggest a potential therapeutic strategy targeting the BDNF-TrkB-CREB1 signaling pathway and peripheral somasensory neurons to treat learning and cognitive deficits associated with Mecp2 disorders.

BmSPP is a virus resistance gene in Bombyx mori.

Introduction: Signal peptide peptidase (SPP) is an intramembrane protease involved in a variety of biological processes, it participates in the processing of signal peptides after the release of the nascent protein to regulate the endoplasmic reticulum associated degradation (ERAD) pathway, binds misfolded membrane proteins, and aids in their clearance process. Additionally, it regulates normal immune surveillance and assists in the processing of viral proteins. Although SPP is essential for many viral infections, its role in silkworms remains unclear. Studying its role in the silkworm, Bombyx mori , may be helpful in breeding virus-resistant silkworms. Methods: First, we performed RT-qPCR to analyze the expression pattern of BmSPP. Subsequently, we inhibited BmSPP using the SPP inhibitor 1,3-di-(N-carboxybenzoyl-L-leucyl-L-leucylaminopropanone ((Z-LL)2-ketone) and downregulated the expression of BmSPP using CRISPR/Cas9 gene editing. Furthermore, we assessed the impact of these interventions on the proliferation of Bombyx mori nucleopolyhedrovirus (BmNPV). Results: We observed a decreased in the expression of BmSPP during viral proliferation. It was found that higher concentration of the inhibitor resulted in greater inhibition of BmNPV proliferation. The down-regulation of BmSPP in both in vivo and in vitro was found to affect the proliferation of BmNPV. In comparison to wild type silkworm, BmSPPKO silkworms exhibited a 12.4% reduction in mortality rate. Discussion: Collectively, this work demonstrates that BmSPP plays a negative regulatory role in silkworm resistance to BmNPV infection and is involved in virus proliferation and replication processes. This finding suggests that BmSPP servers as a target gene for BmNPV virus resistance in silkworms and can be utilized in resistance breeding programs.

Reporting form and content of research priorities identified in knee osteoarthritis clinical practice guidelines: a methodological literature analysis.

OBJECTIVES: Clinical practice guideline (CPG) developers conduct systematic summaries of research evidence, providing them great capacity and ability to identify research priorities. We systematically analysed the reporting form and content of research priorities in CPGs related to knee osteoarthritis (KOA) to provide a valuable reference for guideline developers and clinicians. DESIGN: A methodological literature analysis was done and the characteristics of the reporting form and the content of the research priorities identified in KOA CPGs were summarised. DATA SOURCES: Six databases (PubMed, Embase, China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals, Wanfang and Chinese Biomedical Literature Database) were searched for CPGs published from 1 January 2017 to 4 December 2022. The official websites of 40 authoritative orthopaedic societies, rheumatology societies and guideline development organisations were additionally searched. ELIGIBILITY CRITERIA: We included all KOA CPGs published in English or Chinese from 1 January 2017 that included at least one recommendation for KOA. We excluded duplicate publications, older versions of CPGs as well as guidance documents for guideline development. DATA EXTRACTION AND SYNTHESIS: Reviewers worked in pairs and independently screened and extracted the data. Descriptive statistics were used, and absolute frequencies and proportions of related items were calculated. RESULTS: 187 research priorities reported in 41 KOA CPGs were identified. 24 CPGs reported research priorities, of which 17 (41.5%) presented overall research priorities for the entire guideline rather than for specific recommendations. 110 (58.8%) research priorities were put forward due to lack of evidence. Meanwhile, more than 70% of the research priorities reflected the P (population) and I (intervention) structural elements, with 135 (72.2%) and 146 (78.1%), respectively. More than half of the research priorities (118, 63.8%) revolved around evaluating the efficacy of interventions. Research priorities primarily focused on physical activity (32, 17.3%), physical therapy (30, 16.2%), surgical therapy (27, 14.6%) and pharmacological treatment (26, 14.1%). CONCLUSIONS: Research priorities reported in KOA CPGs mainly focused on evaluating non-pharmacological interventions. There exists considerable room for improvement for a comprehensive and standardised generation and reporting of research priorities in KOA CPGs.

MSC-Derived Exosomes Mitigate Myocardial Ischemia/Reperfusion Injury by Reducing Neutrophil Infiltration and the Formation of Neutrophil Extracellular Traps.

Introduction: Acute inflammatory storm is a major cause of myocardial ischemia/reperfusion (I/R) injury, with no effective treatment currently available. The excessive aggregation of neutrophils is correlated with an unfavorable prognosis in acute myocardial infarction (AMI) patients. Exosomes derived from mesenchymal stromal cells (MSC-Exo) have certain immunomodulatory potential and might be a therapeutic application. Therefore, we investigated the protective role of MSC-Exo in modulating neutrophil infiltration and formation of neutrophil extracellular traps (NETs) following myocardial I/R injury. Methods: Exosomes were isolated from the supernatant of MSCs using a gradient centrifugation method. We used flow cytometry, histochemistry, and immunofluorescence to detect the changes of neutrophils post-intravenous MSC-Exo injection. Additionally, cardiac magnetic resonance (CMR) and thioflavin S experiments were applied to detect microvascular obstruction (MVO). The NLR family pyrin domain containing 3 (NLRP3) inflammasome was examined for mechanism exploration. Primary neutrophils were extracted for in vitro experiment. Antibody of Ly6G was given to depleting the neutrophils in mice for verification the effect of MSC-Exo. Finally, we analyzed the MiRNA sequence of MSC-Exo and verified it in vitro. Results: MSC-Exo administration reduced neutrophil infiltration and NETs formation after myocardial I/R. MSC-Exo treatment also could attenuate the activation of NLRP3 inflammasome both in vivo and in vitro. At the same time, the infarction size and MVO following I/R injury were reduced by MSC-Exo. Moreover, systemic depletion of neutrophils partly negated the therapeutic effects of MSC-Exo. Up-regulation of miR-199 in neutrophils has been shown to decrease the expression of NETs formation after stimulation. Discussion: Our results demonstrated that MSC-Exo mitigated myocardial I/R injury in mice by modulating neutrophil infiltration and NETs formation. This study provides novel insights into the potential therapeutic application of MSC-Exo for myocardial ischemia/reperfusion injury.

Emphasis should be placed on identifying and reporting research priorities to increase research value: An empirical analysis.

OBJECTIVES: To compared the presentation of research priorities in the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) clinical practice guidelines (CPGs) developed under the guidance of the GRADE working group or its two co-chair, and the Chinese CPGs. METHODS: This was a methodological empirical analysis. We searched PubMed, Embase, and four Chinese databases (Wanfang, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure and Chinese Biomedical Literature Database) and retrieved nine Chinese guideline databases or Society websites as well as GRADE Pro websites. We included all eligible GRADE CPGs and a random sample of double number of Chinese CPGs, published 2018 to 2022. The reviewers independently screened and extracted the data, and we summarized and analyzed the reporting on the research priorities in the CPGs. RESULTS: Of the 135 eligible CPGs (45 GRADE CPGs and 90 Chinese CPGs), 668, 138 research priorities were identified respectively. More than 70% of the research priorities in GRADE CPGs and Chinese CPGs had population and intervention (PI) structure. 99 (14.8%) of GRADE CPG research priorities had PIC structures, compared with only 4(2.9%) in Chinese. And 28.4% (190) GRADE CPG research priorities reflected comparisons between PICO elements, approximately double those in Chinese. The types of research priorities among GRADE CPGs and Chinese CPGs were mostly focused on the efficacy of interventions, and the type of comparative effectiveness in the GRADE research priorities was double those in Chinese. CONCLUSIONS: There was still considerable room for improvement in the developing and reporting of research priorities in Chinese CPGs. Key PICO elements were inadequately presented, with more attention on intervention efficacy and insufficient consideration given to values, preferences, health equity, and feasibility. Identifying and reporting of research priorities deserves greater effort in the future.

Photocatalytic Sulfonyl Peroxidation of Alkenes via Deamination of N-Sulfonyl Ketimines.

A photocatalytic three-component sulfonyl peroxidation of alkenes with N-sulfonyl ketimines and tert-butyl hydroperoxide is reported. The reaction takes place via the photoinduced EnT process, which allows the efficient synthesis of a variety of ß-peroxyl sulfones under mild reaction conditions in the absence of a transition metal catalyst. The downstream derivatizations of the peroxides were also performed. Furthermore, the utility of this protocol was manifested by the synthesis of 11ß-HSD1 inhibitor and the antiprostate cancer drug bicalutamide.

Bacterial polyynes uncovered: a journey through their bioactive properties, biosynthetic mechanisms, and sustainable production strategies.

Covering: up to 2023Conjugated polyynes are natural compounds characterized by alternating single and triple carbon-carbon bonds, endowing them with distinct physicochemical traits and a range of biological activities. While traditionally sourced mainly from plants, recent investigations have revealed many compounds originating from bacterial strains. This review synthesizes current research on bacterial-derived conjugated polyynes, delving into their biosynthetic routes, underscoring the variety in their molecular structures, and examining their potential applications in biotechnology. Additionally, we outline future directions for metabolic and protein engineering to establish more robust and stable platforms for their production.

Optogenetic Activation of Peripheral Somatosensory Neurons in Transgenic Mice as a Neuropathic Pain Model for Assessing the Therapeutic Efficacy of Analgesics.

Optogenetics is a novel biotechnology widely used to precisely manipulate a specific peripheral sensory neuron or neural circuit. However, the use of optogenetics to assess the therapeutic efficacy of analgesics is elusive. In this study, we generated a transgenic mouse stain in which all primary somatosensory neurons can be optogenetically activated to mimic neuronal hyperactivation in the neuropathic pain state for the assessment of analgesic effects of drugs. A transgenic mouse was generated using the advillin-Cre line mated with the Ai32 strain, in which channelrhodopsin-2 fused to enhanced yellow fluorescence protein (ChR2-EYFP) was conditionally expressed in all types of primary somatosensory neurons (advillincre/ChR2+/+). Immunofluorescence and transdermal photostimulation on the hindpaws were used to verify the transgenic mice. Optical stimulation to evoke pain-like paw withdrawal latency was used to assess the analgesic effects of a series of drugs. Injury- and pain-related molecular biomarkers were investigated with immunohistofluorescence. We found that the expression of ChR2-EYFP was observed in many primary afferents of paw skin and sciatic nerves and in primary sensory neurons and laminae I and II of the spinal dorsal horns in advillincre/ChR2+/+ mice. Transdermal blue light stimulation of the transgenic mouse hindpaw evoked nocifensive paw withdrawal behavior. Treatment with gabapentin, some channel blockers, and local anesthetics, but not opioids or COX-1/2 inhibitors, prolonged the paw withdrawal latency in the transgenic mice. The analgesic effect of gabapentin was also verified by the decreased expression of injury- and pain-related molecular biomarkers. These optogenetic mice provide a promising model for assessing the therapeutic efficacy of analgesics in neuropathic pain.

Comprehensive consideration of multiple determinants from evidence to recommendations in guidelines for most traditional Chinese medicine was suboptimal: a systematic review.

BACKGROUND: The overall comprehensive consideration of the factors influencing the recommendations in the traditional Chinese medicine (TCM) guidelines remains poorly studied. This study systematically evaluate the factors influencing recommendations formation in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) clinical practice guidelines (CPGs) and TCM CPGs. METHODS: This was a methodological review in which we searched six databases and multiple related websites. The GRADE CPGs were identified as the guidelines developed by the GRADE Working Group or the two Co-Chairs. For the TCM CPGs, we randomly selected guidelines that were published by the TCM or integrative medicine academic societies from China mainland (published by the TCM or integrative medicine academic societies of China mainland). Two reviewers independently screened and extracted data. We included CPGs published in 2018-2022. We extracted information on the influencing factors of evidence to recommendation and conducted the analyses using descriptive statistics and calculated the proportion of relevant items by IBM SPSS Statistics and Microsoft Excel to compare the differences between the GRADE CPGs and the TCM CPGs. RESULTS: Forty-five GRADE CPGs (including 912 recommendations) and 88 TCM CPGs (including 2452 recommendations) were included. TCM recommendations mainly considered the four key determinants of desirable anticipated effects, undesirable anticipated effects, balance between desirable and undesirable effects, certainty of evidence, with less than 20% of other dimensions. And TCM CPGs presented more strong recommendations (for or against) and inappropriate discordant recommendations than GRADE CPGs. GRADE CPGs were more comprehensive considered about the factors affecting the recommendations, and considered more than 70% of all factors in the evidence to recommendation. CONCLUSIONS: The TCM CPGs lack a comprehensive consideration of multiple influencing determinants from evidence to recommendations. In the future, the correct application of the GRADE approaches should be emphasized.

Distributed NN-Based Formation Control of Multi-Agent Systems: A Reduced-Order Appointed-Time Observer Approach.

Although the formation control of multi-agent systems has been widely investigated from various aspects, the problem is still not well resolved, especially for the case of distributed output-feedback formation controller design without input information exchange among neighboring agents. Using relative output information, this paper presents a novel distributed reduced-order estimation of the formation error at a predefined time. Based on the proposed distributed observer, a neural-network-based formation controller is then designed for multi-agent systems with connected graphs. The results are verified by both theoretical demonstration and simulation example.