Changes in planta K nutrient content altered the interaction pattern between Nicotiana benthamiana and Alternaria longipes.

Potassium (K) fertilisation has frequently been shown to enhance plant resistance against pathogens, though the mechanisms remain elusive. This study investigates the interaction dynamics between Nicotiana benthamiana and the pathogen Alternaria longipes under different planta K levels. On the host side, adding K activated the expressions of three NLR (nucleotide-binding domain and leucine-rich repeat-containing proteins) resistance genes, including NbRPM1, NbR1B23 and NbNBS12. Silencing these NLRs attenuated resistance in high-K (HK, 40.8 g/kg) plant, whereas their overexpression strengthened resistance in low-K (LK, 23.9 g/kg) plant. Typically, these NLRs mainly strengthened plant resistance via promoting the expression of pathogenesis-related genes (PRs), ROS burst and synthesis of antifungal metabolites in HK plant. On the pathogen side, the expression of effectors HKCSP1, HKCSP2 and LKCSP were shown to be related to planta K content. A. longipes mainly expressed effectors HKCSP1 and HKCSP2 in HK plant to interfere host resistance. HKCSP1 physically interacted with NbRPM1 to promote the degradation of NbRPM1, then attenuated related resistance in HK N. benthamiana. Meanwhile, HKCSP2 directly interacted with NbPR5 to suppress resistance in HK plant. In LK plant, A. longipes mainly deployed LKCSP that interacted with NbR1B23 to interfere reduce resistance in N. benthamiana. Overall, our research insights that both pathogen and host mobilise distinct strategies to outcompete each other during interactions in different K nutrient environments.

Opportunistic atrial fibrillation screening in primary care in Ireland: results of a pilot screening programme.

BACKGROUND: Atrial fibrillation (AF), a common, frequently asymptomatic cardiac arrhythmia, is a major risk factor for stroke. Identification of AF enables effective preventive treatment to be offered, potentially reducing stroke risk by up to two-thirds. There is international consensus that opportunistic AF screening is valuable though uncertainty remains about the optimum screening location and method. Primary care has been identified as a potential location for AF screening using one-lead ECG devices. METHODS: A pilot AF screening programme is in primary care in the south of Ireland. General practitioners (GPs) were recruited from Cork and Kerry. GPs invited patients ≥65 years to undergo AF screening. The screening comprised a one-lead ECG device, Kardia Mobile, blood pressure check and ascertainment of smoking status. Possible AF on one-lead ECG was confirmed with a 12-lead ECG. GPs also recorded information including medical history, current medication and onward referral. The Keele Decision Support tool was used to assess patients for oral anticoagulation (OAC). RESULTS: 3555 eligible patients, attending 52 GPs across 34 GP practices, agreed to undergo screening. 1720 (48%) were female, 1780 (50%) were hypertensive and 285 (8%) were current smokers. On the one-lead ECG, 3282 (92%) were in normal sinus rhythm, 101 (3%) had possible AF and among 124 (4%) the one-lead ECG was unreadable or unclassified. Of the 101 patients with possible AF, 45 (45%) had AF confirmed with 12-lead ECG, an incidence rate of AF of 1.3%. Among the 45 confirmed AF cases, 27 (60%) were commenced on OAC therapy by their GP. CONCLUSION: These findings suggest that AF screening in primary care may prove useful for early detection of AF cases that can be assessed for treatment. One-lead ECG devices may be useful in the detection of paroxysmal AF in this population and setting. Current OAC of AF may be suboptimal.

OsLCD3 interacts with OsSAMS1 to regulate grain size via ethylene/polyamine homeostasis control.

A fundamental question in developmental biology is how to regulate grain size to improve crop yields. Despite this, little is still known about the genetics and molecular mechanisms regulating grain size in crops. Here, we provide evidence that a putative protein kinase-like (OsLCD3) interacts with the S-adenosyl-L-methionine synthetase 1 (OsSAMS1) and determines the size and weight of grains. OsLCD3 mutation (lcd3) significantly increased grain size and weight by promoting cell expansion in spikelet hull, whereas its overexpression caused negative effects, suggesting that grain size was negatively regulated by OsLCD3. Importantly, lcd3 and OsSAMS1 overexpression (SAM1OE) led to large and heavy grains, with increased ethylene and decreased polyamines production. Based on genetic analyses, it appears that OsLCD3 and OsSAMS1 control rice grain size in part by ethylene/polyamine homeostasis. The results of this study provide a genetic and molecular understanding of how the OsLCD3-OsSAMS1 regulatory module regulates grain size, suggesting that ethylene/polyamine homeostasis is an appropriate target for improving grain size and weight.

Towards proactive palliative care in oncology: developing an explainable EHR-based machine learning model for mortality risk prediction.

BACKGROUND: Ex-ante identification of the last year in life facilitates a proactive palliative approach. Machine learning models trained on electronic health records (EHR) demonstrate promising performance in cancer prognostication. However, gaps in literature include incomplete reporting of model performance, inadequate alignment of model formulation with implementation use-case, and insufficient explainability hindering trust and adoption in clinical settings. Hence, we aim to develop an explainable machine learning EHR-based model that prompts palliative care processes by predicting for 365-day mortality risk among patients with advanced cancer within an outpatient setting. METHODS: Our cohort consisted of 5,926 adults diagnosed with Stage 3 or 4 solid organ cancer between July 1, 2017, and June 30, 2020 and receiving ambulatory cancer care within a tertiary center. The classification problem was modelled using Extreme Gradient Boosting (XGBoost) and aligned to our envisioned use-case: "Given a prediction point that corresponds to an outpatient cancer encounter, predict for mortality within 365-days from prediction point, using EHR data up to 365-days prior." The model was trained with 75% of the dataset (n = 39,416 outpatient encounters) and validated on a 25% hold-out dataset (n = 13,122 outpatient encounters). To explain model outputs, we used Shapley Additive Explanations (SHAP) values. Clinical characteristics, laboratory tests and treatment data were used to train the model. Performance was evaluated using area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC), while model calibration was assessed using the Brier score. RESULTS: In total, 17,149 of the 52,538 prediction points (32.6%) had a mortality event within the 365-day prediction window. The model demonstrated an AUROC of 0.861 (95% CI 0.856-0.867) and AUPRC of 0.771. The Brier score was 0.147, indicating slight overestimations of mortality risk. Explanatory diagrams utilizing SHAP values allowed visualization of feature impacts on predictions at both the global and individual levels. CONCLUSION: Our machine learning model demonstrated good discrimination and precision-recall in predicting 365-day mortality risk among individuals with advanced cancer. It has the potential to provide personalized mortality predictions and facilitate earlier integration of palliative care.

Pyruvate kinase M2 sustains cardiac mitochondrial integrity in septic cardiomyopathy by regulating PHB2-dependent mitochondrial biogenesis.

Previous studies have highlighted the protective effects of pyruvate kinase M2 (PKM2) overexpression in septic cardiomyopathy. In our study, we utilized cardiomyocyte-specific PKM2 knockout mice to further investigate the role of PKM2 in attenuating LPS-induced myocardial dysfunction, focusing on mitochondrial biogenesis and prohibitin 2 (PHB2). Our findings confirmed that the deletion of PKM2 in cardiomyocytes significantly exacerbated LPS-induced myocardial dysfunction, as evidenced by impaired contractile function and relaxation. Additionally, the deletion of PKM2 intensified LPS-induced myocardial inflammation. At the molecular level, LPS triggered mitochondrial dysfunction, characterized by reduced ATP production, compromised mitochondrial respiratory complex I/III activities, and increased ROS production. Intriguingly, the absence of PKM2 further worsened LPS-induced mitochondrial damage. Our molecular investigations revealed that LPS disrupted mitochondrial biogenesis in cardiomyocytes, a disruption that was exacerbated by the absence of PKM2. Given that PHB2 is known as a downstream effector of PKM2, we employed PHB2 adenovirus to restore PHB2 levels. The overexpression of PHB2 normalized mitochondrial biogenesis, restored mitochondrial integrity, and promoted mitochondrial function. Overall, our results underscore the critical role of PKM2 in regulating the progression of septic cardiomyopathy. PKM2 deficiency impeded mitochondrial biogenesis, leading to compromised mitochondrial integrity, increased myocardial inflammation, and impaired cardiac function. The overexpression of PHB2 mitigated the deleterious effects of PKM2 deletion. This discovery offers a novel insight into the molecular mechanisms underlying septic cardiomyopathy and suggests potential therapeutic targets for intervention.

DDX18 Facilitates the Tumorigenesis of Lung Adenocarcinoma by Promoting Cell Cycle Progression through the Upregulation of CDK4.

Lung adenocarcinoma (LUAD) is the most prevalent and aggressive subtype of lung cancer, exhibiting a dismal prognosis with a five-year survival rate below 5%. DEAD-box RNA helicase 18 (DDX18, gene symbol DDX18), a crucial regulator of RNA metabolism, has been implicated in various cellular processes, including cell cycle control and tumorigenesis. However, its role in LUAD pathogenesis remains elusive. This study demonstrates the significant upregulation of DDX18 in LUAD tissues and its association with poor patient survival (from public databases). Functional in vivo and in vitro assays revealed that DDX18 knockdown potently suppresses LUAD progression. RNA sequencing and chromatin immunoprecipitation experiments identified cyclin-dependent kinase 4 (CDK4), a cell cycle regulator, as a direct transcriptional target of DDX18. Notably, DDX18 depletion induced G1 cell cycle arrest, while its overexpression promoted cell cycle progression even in normal lung cells. Interestingly, while the oncogenic protein c-Myc bound to the DDX18 promoter, it did not influence its expression. Collectively, these findings establish DDX18 as a potential oncogene in LUAD, functioning through the CDK4-mediated cell cycle pathway. DDX18 may represent a promising therapeutic target for LUAD intervention.

Comparative effectiveness of myocardial patches and intramyocardial injections in treating myocardial infarction with a MitoQ/hydrogel system.

In cardiac tissue engineering, myocardial surface patches and hydrogel intramyocardial injections represent the two primary hydrogel-based strategies for myocardial infarction (MI) treatment. However, the comparative effectiveness of these two treatments remains uncertain. Therefore, this study aimed to compare the effects of the two treatment modalities by designing a simple and reproducible hydrogel cross-linked with γ-PGA and 4-arm-PEG-SG. To improve mitochondrial damage in cardiomyocytes (CMs) during early MI, we incorporated the mitochondria-targeting antioxidant MitoQ into the hydrogel network. The hydrogel exhibited excellent biodegradability, biocompatibility, adhesion, and injectability in vitro. The hydrogel was utilized for rat MI treatment through both patch adhesion and intramyocardial injections. In vivo results demonstrated that the slow release of MitoQ peptide from the hydrogel hindered ROS production in CM, alleviated mitochondrial damage, and enhanced CM activity within 7 days, effectively inhibiting MI progression. Both hydrogel intramyocardial injections and patches exhibited positive therapeutic effects, with intramyocardial injections demonstrating superior efficacy in terms of cardiac function and structure in equivalent treatment cycles. In conclusion, we developed a MitoQ/hydrogel system that is easily prepared and can serve as both a myocardial patch and an intramyocardial injection for MI treatment, showing significant potential for clinical applications.

Machine learning and deep learning to identifying subarachnoid haemorrhage macrophage-associated biomarkers by bulk and single-cell sequencing.

We investigated subarachnoid haemorrhage (SAH) macrophage subpopulations and identified relevant key genes for improving diagnostic and therapeutic strategies. SAH rat models were established, and brain tissue samples underwent single-cell transcriptome sequencing and bulk RNA-seq. Using single-cell data, distinct macrophage subpopulations, including a unique SAH subset, were identified. The hdWGCNA method revealed 160 key macrophage-related genes. Univariate analysis and lasso regression selected 10 genes for constructing a diagnostic model. Machine learning algorithms facilitated model development. Cellular infiltration was assessed using the MCPcounter algorithm, and a heatmap integrated cell abundance and gene expression. A 3 × 3 convolutional neural network created an additional diagnostic model, while molecular docking identified potential drugs. The diagnostic model based on the 10 selected genes achieved excellent performance, with an AUC of 1 in both training and validation datasets. The heatmap, combining cell abundance and gene expression, provided insights into SAH cellular composition. The convolutional neural network model exhibited a sensitivity and specificity of 1 in both datasets. Additionally, CD14, GPNMB, SPP1 and PRDX5 were specifically expressed in SAH-associated macrophages, highlighting its potential as a therapeutic target. Network pharmacology analysis identified some targeting drugs for SAH treatment. Our study characterised SAH macrophage subpopulations and identified key associated genes. We developed a robust diagnostic model and recognised CD14, GPNMB, SPP1 and PRDX5 as potential therapeutic targets. Further experiments and clinical investigations are needed to validate these findings and explore the clinical implications of targets in SAH treatment.

Therapeutic effects of orexin-A in sepsis-associated encephalopathy in mice.

BACKGROUND: Sepsis-associated encephalopathy (SAE) causes acute and long-term cognitive deficits. However, information on the prevention and treatment of cognitive dysfunction after sepsis is limited. The neuropeptide orexin-A (OXA) has been shown to play a protective role against neurological diseases by modulating the inflammatory response through the activation of OXR1 and OXR2 receptors. However, the role of OXA in mediating the neuroprotective effects of SAE has not yet been reported. METHODS: A mouse model of SAE was induced using cecal ligation perforation (CLP) and treated via intranasal administration of exogenous OXA after surgery. Mouse survival, in addition to cognitive and anxiety behaviors, were assessed. Changes in neurons, cerebral edema, blood-brain barrier (BBB) permeability, and brain ultrastructure were monitored. Levels of pro-inflammatory factors (IL-1ß, TNF-α) and microglial activation were also measured. The underlying molecular mechanisms were investigated by proteomics analysis and western blotting. RESULTS: Intranasal OXA treatment reduced mortality, ameliorated cognitive and emotional deficits, and attenuated cerebral edema, BBB disruption, and ultrastructural brain damage in mice. In addition, OXA significantly reduced the expression of the pro-inflammatory factors IL-1ß and TNF-α, and inhibited microglial activation. In addition, OXA downregulated the expression of the Rras and RAS proteins, and reduced the phosphorylation of P-38 and JNK, thus inhibiting activation of the MAPK pathway. JNJ-10,397,049 (an OXR2 blocker) reversed the effect of OXA, whereas SB-334,867 (an OXR1 blocker) did not. CONCLUSION: This study demonstrated that the intranasal administration of moderate amounts of OXA protects the BBB and inhibits the activation of the OXR2/RAS/MAPK pathway to attenuate the outcome of SAE, suggesting that OXA may be a promising therapeutic approach for the management of SAE.

Orexin-A mediates glioblastoma proliferation inhibition by increasing ferroptosis triggered by unstable iron pools and GPX4 depletion.

Glioblastoma (GBM) represents a prevalent form of primary malignant tumours in the central nervous system, but the options for effective treatment are extremely limited. Ferroptosis, as the most enriched programmed cell death process in glioma, makes a critical difference in glioma progression. Consequently, inducing ferroptosis has become an appealing strategy for tackling gliomas. Through the utilization of multi-omics sequencing data analysis, flow cytometry, MDA detection and transmission electron microscopy, the impact of orexin-A on ferroptosis in GBM was assessed. In this report, we provide the first evidence that orexin-A exerts inhibitory effects on GBM proliferation via the induction of ferroptosis. This induction is achieved by instigating an unsustainable increase in iron levels and depletion of GPX4. Moreover, the regulation of TFRC, FTH1 and GPX4 expression through the targeting of NFE2L2 appears to be one of the potential mechanisms underlying orexin-A-induced ferroptosis.

Postural behaviour in people with multiple sclerosis: A complexity paradox.

BACKGROUND: Balance deficits are a major concern for people with multiple sclerosis (pwMS). Measuring complexity of motor behaviour can offer an insight into MS-related changes in adaptability of the balance control system when dealing with increasingly complex tasks. QUESTION: Does postural behaviour complexity differ between pwMS at early stages of the disease and healthy controls (HC)? Does postural behaviour complexity change across increasingly complex tasks? METHODS: Forty-eight pwMS and 24 HC performed four increasingly complex postural tasks with eyes open (EO), eyes closed (EC), on firm (FS) and compliant surface (CS). Lumbar and sternum sensors recorded 3D acceleration, from which complexity index (CI) was calculated using multiscale sample entropy (MSE) in the frontal and sagittal planes. RESULTS: We found that only the complexity index in both planes during the eyes closed on compliant surface (EC-CS) task was significantly lower in pwMS compared to HC. We also found that complexity in pwMS was significantly lower during EC-CS compared to the other three tasks when using both lumbar and sternum sensors. SIGNIFICANCE: Increasing the complexity of postural tasks reduces the complexity of postural behaviour in pwMS. This paradox may reflect reduced adaptability of the sensorimotor integration processes at early stages of MS. CI can provide a different perspective on balance deficits and could potentially be a more sensitive biomarker of MS progression and an early indicator of balance deficit.

Clinicopathological characteristics and gene mutations in 11 patients with lipoprotein glomerulopathy.

OBJECTIVE: Lipoprotein glomerulopathy (LPG) is a rare disorder characterized by the development of glomerular lipoprotein thrombosis. LPG exhibits familial aggregation, with mutations in the apolipoprotein E (APOE) gene identified as the leading cause of this disease. This study aimed to investigate APOE gene mutations and the clinicopathological features in eleven LPG patients. METHODS: Clinicopathological and follow-up data were obtained by extracting DNA, followed by APOE coding region sequencing analysis. This study analyzed clinical and pathological manifestations, gene mutations, treatment and prognosis. RESULTS: The mean age of the eleven patients was 33.82 years. Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria. Dyslipidemia was identified in ten patients. In all renal specimens, there was evident dilation of glomerular capillary lumens containing lipoprotein thrombi, and positive oil red O staining was observed in frozen sections of all samples. APOE gene testing revealed that one patient had no mutations, while the remaining ten patients exhibited mutations in the APOE gene, with three patients presenting with multiple mutations simultaneously. Following the confirmation of LPG diagnosis, treatment with angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) was initiated, and the disease progressed slowly. CONCLUSION: LPG is histologically characterized by lamellated lipoprotein thrombi in glomeruli, and kidney biopsy is essential for diagnosis. Mutations in the APOE gene are the leading cause of LPG. This study revealed clinicopathological characteristics and APOE gene mutations in patients with LPG, which helps us better understand the disease.

Engagement of N6-methyladenisine methylation of Gng4 mRNA in astrocyte dysfunction regulated by CircHECW2.

The N6-methyladenosine (m6A) modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs. Accumulating evidence has suggested that m6A methylation may be involved in the pathological process of major depressive disorder (MDD), a common neuropsychiatric disorder with an unclear aetiology. Here, we found that the levels of the circular RNA HECW2 (circHECW2) were significantly increased in the plasma of both MDD patients and the chronic unpredictable stress (CUS) mouse model. Notably, the downregulation of circHECW2 attenuated astrocyte dysfunction and depression-like behaviors induced by CUS. Furthermore, we demonstrated that the downregulation of circHECW2 increased the expression of the methylase WTAP, leading to an increase in Gng4 expression via m6A modifications. Our findings provide functional insight into the correlation between circHECW2 and m6A methylation, suggesting that circHECW2 may represent a potential target for MDD treatment.

The Treatment of Tubal Inflammatory Infertility using Yinjia Tablets through EGFR/MEK/ERK Signaling Pathway based on Network Pharmacology.

Background: Salpingitis obstructive infertility (SOI) refers to infertility caused by abnormal conditions such as tubal adhesion and blockage caused by acute and chronic salpingitis. SOI has a serious impact on women's physical and mental health and family harmony, and it is a clinical problem that needs to be solved urgently.

Objective: The purpose of the present study was to explore the potential pharmacological mechanisms of the Yinjia tablets (Yin Jia Pian, YJP) on tubal inflammation.

Methods: Networks of YJP-associated targets and tubal inflammation-related genes were constructed through the STRING database. Potential targets and pathway enrichment analysis related to the therapeutic efficacy of YJP were identified using Cytoscape and Database for Annotation, Visualization, and Integrated Discovery (metascape). E. coli was used to establish a rat model of tubal inflammation and to validate the predictions of network pharmacology and the therapeutic efficacy of YJP. H&E staining was used to observe the pathological changes in fallopian tubes. TEM observation of the ultrastructure of the fallopian tubes. ELISA was used to detect the changes of IL-6 and TNF-α in fallopian tubes. Immunohistochemistry was used to detect the expression of ESR1. The changes of Bcl-2, ERK1/2, p-ERK1/2, MEK, p-MEK, EGFR, and p-EGFR were detected by western blot.

Results: Through database analysis, it was found that YJP shared 105 identical targets with the disease. Network pharmacology analysis showed that IL-6, TNF, and EGFR belong to the top 5 core proteins associated with salpingitis, and EGFR/MEK/ERK may be the main pathway involved. The E. coli-induced disease rat model of fallopian tube tissue showed damage, mitochondrial disruption, and increased levels of the inflammatory factors IL-6 and TNF-α. Tubal inflammatory infertility rats have increased expression of Bcl-2, p-ERK1/2, p-MEK, and p-EGFR, and decreased expression of ESR1. In vivo, experiments showed that YJP improved damage of tissue, inhibited shedding of tubal cilia, and suppressed the inflammatory response of the body. Furthermore, YJP inhibited EGFR/MEK/ERK signaling, inhibited the apoptotic protein Bcl-2, and upregulated ESR1.

Conclusion: This study revealed that YJP Reducing tubal inflammation and promoting tissue repair may be associated with inhibition of the EGFR/MEK/ERK signaling pathway.

Bio-functional hydroxyapatite-coated 3D porous polyetherketoneketone scaffold for enhanced osteogenesis and osteointegration in orthopedic applications.

Polyetherketoneketone (PEKK), a high-performance thermoplastic special engineering material, maintains bone-like mechanical properties and has received considerable attention in the biomedical field. The 3D printing technique enables the production of porous scaffolds with a honeycomb structure featuring precisely controlled pore size, porosity and interconnectivity, which holds significant potential for applications in tissue engineering. The ideal pore architecture of porous PEKK scaffolds has yet to be elucidated. Porous PEKK scaffolds with five pore sizes P200 (225 ± 9.8 µm), P400 (411 ± 22.1 µm), P600 (596 ± 23.4 µm), P800 (786 ± 24.2 µm) and P1000 (993 ± 26.0 µm) were produced by a 3D printer. Subsequently, the optimum pore size, the P600, for mechanical properties and osteogenesis was selected based on in vitro experiments. To improve the interfacial bioactivity of porous PEKK scaffolds, hydroxyapatite (HAp) crystals were generated via in situ biomimetic mineralization induced by the phase-transited lysozyme coating. Herein, a micro/nanostructured surface showing HAp crystals on PEKK scaffold was developed. In vitro and in vivo experiments confirmed that the porous PEKK-HAp scaffolds exhibited highly interconnected pores and functional surface structures that were favorable for biocompatibility and osteoinductivity, which boosted bone regeneration. Therefore, this work not only demonstrates that the pore structure of the P600 scaffold is suitable for PEKK orthopedic implants but also sheds light on a synergistic approach involving 3D printing and biomimetic mineralization, which has the potential to yield customized 3D PEKK-HAp scaffolds with enhanced osteoinductivity and osteogenesis, offering a promising strategy for bone tissue engineering.

B cell pathway dual inhibition for systemic lupus erythematosus: a prospective single-arm cohort study of telitacicept.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with B-cell hyperactivity. Telitacicept is a transmembrane activator, calcium modulator, and cyclophilin ligand interactor-Fc fusion protein, which can neutralize both B-cell lymphocyte stimulator and a proliferation-inducing ligand. Patients with active SLE who received telitacicept were prospectively followed at month 1, 3, 6, 9, and 12 after telitacicept initiation. Thirty-seven participants were involved and followed for 6.00 [3.00, 6.00] months. SRI-4 rate at month 6 was 44.7%. The median dosage of prednisone was decreased by 43.8% (from 10 to 5.62 mg/d) at month 6. The anti-dsDNA level was significantly decreased, while complement levels were significantly increased at month 6 from baseline. Continuously significant reductions in serum immunoglobin (Ig)G IgA, and IgM levels were also observed. Patients experienced significant decreases in the numbers of total and naive B cells, whereas memory B cells and T cell populations did not change. The number of NK cells was significantly increased during the follow-up. At month 6, 58.3% (14 out of 24) patients experienced improved fatigue accessed by FACIT-Fatigue score exceeding the minimum clinically important difference of 4. Most adverse events were mild, but one each case of severe hypogammaglobulinemia, psychosis with suicidal behavior, and B-cell lymphoma were occurred. In our first prospective real-world study, telitacicept treatment led to a significant clinical and laboratory improvement of disease activity, as well as fatigue amelioration in patients with SLE. Safety profile was favorable overall, but more studies are greatly needed.

Azobenzene-Based Conjugated Polymers: Synthesis, Properties, and Biological Applications.

Conjugated polymers (CPs) have been developed quickly as an emerging functional material with applications in optical and electronic devices, owing to their highly electron-delocalized backbones and versatile side groups for facile processibility, high mechanical strength, and environmental stability. CPs exhibit multistimuli responsive behavior and fluorescence quenching properties by incorporating azobenzene functionality into their molecular structures. Over the past few decades, significant progress has been made in developing functional azobenzene-based conjugated polymers (azo-CPs), utilizing diverse molecular design strategies and synthetic pathways. This article comprehensively reviews the rapidly evolving research field of azo-CPs, focusing on the structural characteristics and synthesis methods of general azo-CPs, as well as the applications of charged azo-CPs, specifically azobenzene-based conjugated polyelectrolytes (azo-CPEs). Based on their molecular structures, azo-CPs can be broadly categorized into three primary types: linear CPs with azobenzene incorporated into the side chain, linear CPs with azobenzene integrated into the main chain, and branched CPs containing azobenzene moieties. These systems are promising for biomedical applications in biosensing, bioimaging, targeted protein degradation, and cellular apoptosis.

PKM2 interacts with and phosphorylates PHB2 to sustain mitochondrial quality control against septic cerebral-cardiac injury.

Sepsis induces profound disruptions in cellular homeostasis, particularly impacting mitochondrial function in cardiovascular and cerebrovascular systems. This study elucidates the regulatory role of the Pyruvate Kinase M2 (PKM2)- Prohibitin 2 (PHB2) axis in mitochondrial quality control during septic challenges and its protective effects against myocardial and cerebral injuries. Employing LPS-induced mouse models, we demonstrate a significant downregulation of PKM2 and PHB2 in both heart and brain tissues post-sepsis, with corresponding impairments in mitochondrial dynamics, including fission, fusion, and mitophagy. Overexpression of PKM2 and PHB2 not only restores mitochondrial function, as evidenced by normalized ATP production and membrane potential but also confers resistance to oxidative stress by mitigating reactive oxygen species generation. These cellular mechanisms translate into substantial in vivo benefits, with transgenic mice overexpressing PKM2 or PHB2 displaying remarkable resistance to sepsis-induced cardiomyocyte and neuronal apoptosis, and organ dysfunction. Our findings highlight the PKM2-PHB2 interaction as a novel therapeutic target for sepsis, providing a foundation for future research into mitochondrial-based interventions to treat this condition. The study's insights into the molecular underpinnings of sepsis-induced organ failure pave the way for potential clinical applications in the management of sepsis and related pathologies.

Generative Upper-Level Policy Imitation Learning With Pareto-Improvement for Energy-Efficient Advanced Machining Systems.

The potential intelligence behind advanced machining systems (AMSs) offers positive contributions toward process improvement. Imitation learning (IL) offers an appealing approach to accessing this intelligence by observing demonstrations from skilled technologists. However, existing IL algorithms that implement single policy strategies have yet to consider realistic scenarios for complex AMS tasks, where the available demonstrations may have come from various experts. Moreover, most IL assumes that the expert's policy is optimal, preventing the learning from fulfilling the previously ignored green missions. This article introduces a novel three-phase policy search algorithm based on IL, enabling the learning of heterogeneous expert policies while balancing energy preferences. The first phase equips the agent with machining basics through upper-level policy learning, generating an imitation policy distribution with various decision-making principles. The second phase enhances energy conservation capabilities by employing Pareto-improvement learning and fine-tuning the agent's policies to a Pareto-policy manifold. The third phase produces outcomes and amplifies the efficacy of human feedback by utilizing ensemble policies. The experimental results indicate that the proposed method outperforms meta-heuristics, exhibiting superior solution quality and faster computation times compared to four diverse baseline methods, each with diverse samples.

Machine learning unveils immune-related signature in multicenter glioma studies.

In glioma molecular subtyping, existing biomarkers are limited, prompting the development of new ones. We present a multicenter study-derived consensus immune-related and prognostic gene signature (CIPS) using an optimal risk score model and 101 algorithms. CIPS, an independent risk factor, showed stable and powerful predictive performance for overall and progression-free survival, surpassing traditional clinical variables. The risk score correlated significantly with the immune microenvironment, indicating potential sensitivity to immunotherapy. High-risk groups exhibited distinct chemotherapy drug sensitivity. Seven signature genes, including IGFBP2 and TNFRSF12A, were validated by qRT-PCR, with higher expression in tumors and prognostic relevance. TNFRSF12A, upregulated in GBM, demonstrated inhibitory effects on glioma cell proliferation, migration, and invasion. CIPS emerges as a robust tool for enhancing individual glioma patient outcomes, while IGFBP2 and TNFRSF12A pose as promising tumor markers and therapeutic targets.