TLR2 reprograms glucose metabolism in CD4+ T cells of rheumatoid arthritis patients to mediate cell hyperactivation and TNF-α secretion.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease in which activated CD4+ T cells participate in the disease process by inducing inflammation. We aimed to investigate the role of Toll-like receptor 2 (TLR2) on CD4+ T cells in RA patients, and to elucidate the underlying mechanisms by which TLR2 contributes to the pathogenesis of RA. METHODS: Serum samples were collected from RA patients and healthy controls. Soluble TLR2 levels were quantified using an enzyme-linked immunosorbent assay (ELISA). Flow cytometry was employed to assess the TLR2 expression level, activation status, cytokine production, reactive oxygen species (ROS) levels, and glucose uptake capacity of CD4+ T cells. Quantitative polymerase chain reaction (qPCR) was used to measure the expression of enzymes associated with glucose and lipid metabolism. The concentration of lactic acid in the culture supernatant was determined using a dedicated detection kit. RESULTS: RA patients had higher levels of TLR2 in their serum, which positively correlated with C-reactive protein and rheumatoid factor. The expression level of TLR2 in CD4+ T cells of RA patients was increased, and TLR2+ cells showed higher activation levels than TLR2- cells. Activation of TLR2 in CD4+ T cells of RA patients promoted their activation, TNF-α secretion, and increased production of ROS. Furthermore, TLR2 activation led to changes in enzymes related to glucose metabolism, causing a shift in glucose metabolism towards the pentose phosphate pathway. Blocking oxidative phosphorylation and the pentose phosphate pathway had varying effects on CD4+ T cell function. CONCLUSION: TLR2 reprograms the glucose metabolism of CD4+ T cells in RA patients, contributing to the development of RA through ROS-mediated cell hyperactivation and TNF-α secretion. Key Points • TLR2 is upregulated in CD4+ T cells of RA patients and correlates with disease severity markers such as CRP and RF. • Activation of TLR2 in CD4+ T cells promotes cell activation, TNF-α secretion, and increased ROS production, contributing to the pathogenesis of RA. • TLR2 activates glucose metabolism in CD4+ T cells, shifting towards the pentose phosphate pathway, which may be a novel therapeutic target for RA treatment. • Blocking glucose metabolism and ROS production can reduce CD4 + T cell hyperactivation and TNF-α secretion, indicating potential therapeutic strategies for RA management.

An industrial perspective on metabolic responses of Penicillium chrysogenum to periodic dissolved oxygen feast-famine cycles in a scale-down system.

While traveling through different zones in large-scale bioreactors, microbes are most likely subjected to fluctuating dissolved oxygen (DO) conditions at the timescales of global circulation time. In this study, to mimic industrial-scale spatial DO gradients, we present a scale-down setup based on dynamic feast/famine regime (150 s) that leads to repetitive cycles with rapid changes in DO availability in glucose-limited chemostat cultures of Penicillium chrysogenum. Such DO feast/famine regime induced a stable and repetitive pattern with a reproducible metabolic response in time, and the dynamic response of intracellular metabolites featured specific differences in terms of both coverage and magnitude in comparison to other dynamic conditions, for example, substrate feast/famine cycles. Remarkably, intracellular sugar polyols were considerably increased as the hallmark metabolites along with a dynamic and higher redox state (NADH/NAD+) of the cytosol. Despite the increased availability of NADPH for penicillin production under the oscillatory DO conditions, this positive effect may be counteracted by the decreased ATP supply. Moreover, it is interesting to note that not only the penicillin productivity was reduced under such oscillating DO conditions, but also that of the unrecyclable byproduct ortho-hydroxyphenyl acetic acid and degeneration of penicillin productivity. Furthermore, dynamic flux profiles showed the most pronounced variations in central carbon metabolism, amino acid (AA) metabolism, energy metabolism and fatty acid metabolism upon the DO oscillation. Taken together, the metabolic responses of P. chrysogenum to DO gradients reported here are important for elucidating metabolic regulation mechanisms, improving bioreactor design and scale-up procedures as well as for constructing robust cell strains to cope with heterogenous industrial culture conditions.

Stoichiometric and bacterial eco-physiological insights into microbial resource availability in karst regions affected by clipping-and-burning.

Despite growing interest in soil microbial resource limitation (MRL), the impacts of clipping-and-burning on bacterial resource acquisition and its soil carbon, nitrogen, and phosphorous stoichiometry (C:N:P) remain unclear, yet are critical for nutrient cycling and SOC accumulation in vegetation restoration. We examined the soil C:N:P and eco-enzymatic stoichiometry, bacterial life-history strategies, and bacterial resource limitation under the influence of clipping-and-burning management practices: high-intensity fire (HIF), low-intensity fire (LIF), clipping-and-fire (CF), clipping (CP), and an undisturbed control (CK) in a Karst site in southwest China. The results showed that SOC, TN, and TP in HIF and LIF were significantly (p < 0.05) reduced (by 64%, 97%, and 99%) compared to CK. However, soil C:N, C:P, and N:P ratios were surprisingly higher (18.1, 56, and 3.08) in CF than in CK. The ratios of soil microbial biomass carbon (MBC) and nitrogen (MBN) were higher (4.8) under clipping. In contrast, their ratios with microbial biomass phosphorus (MBP) were observed to be higher (22.3 and 6.4) under high-intensity fire compared to CK. Moreover, results show that there is a higher percentage of species linked with oligotroph bacteria of Rickettsiales in CF treatments than CK. Soil bacterial communities in CF treatments exhibited co-limitation by C and P, whereas N limitation was more pronounced under low-intensity fire conditions. In conclusion, the evidence links MRL to soil C:N:P stoichiometry, underscoring the critical role of oligotrophic bacteria in mediating soil nutrient dynamics under clipping-and-burning disturbances. These findings improve our understanding of MRL over the Karst region under clipping-and-burning treatments, shedding light on its relationship with soil C:N:P, eco-enzymatic stoichiometry, and bacterial life-history strategies.

Gene Drive and Symbiont Technologies for Control of Mosquito-Borne Diseases.

Mosquito-borne diseases, such as dengue and malaria, pose a significant burden to global health. Current control strategies with insecticides are only moderately effective. Scalable solutions are needed to reduce the transmission risk of these diseases. Symbionts and genome engineering-based mosquito control strategies have been proposed to address these problems. Bacterial, fungal, and viral symbionts affect mosquito reproduction, reduce mosquito lifespan, and block pathogen transmission. Field tests of endosymbiont Wolbachia-based methods have yielded promising results, but there are hurdles to overcome due to the large-scale rearing and accurate sex sorting required for Wolbachia-based suppression approaches and the ecological impediments to Wolbachia invasion in replacement approaches. Genome engineering-based methods, in which mosquitoes are genetically altered for the modification or suppression of wild populations, offer an additional approach for control of mosquito-borne diseases. In particular, the use of gene drive alleles that bias inheritance in their favor is a potentially powerful approach. Several drives are frequency dependent, potentially giving them broadly similar population dynamics to Wolbachia. However, public acceptance and the behavior of released drives in natural mosquito populations remain challenges. We summarize the latest developments and discuss the knowledge gaps in both symbiont- and gene drive-based methods.

A NIR-II Organic Dendrimer with Superb Photothermal Performance Based on Electron-Donor Iteration for Photothermal Immunotherapy.

Organic photothermal materials have attracted extensive attention due to their designable molecular structure, tunable excited-state properties, and excellent biocompatibility, however, the development of near-infrared II (NIR-II) absorbing organic photothermal materials with high photothermal conversion efficiency (PTCE) and molar extinction coefficient (ɛ) remains challenging. Herein, a novel "electron-donor iteration" strategy is proposed to construct organic photothermal dendrimers (CR-DPA-T, CR-(DPA)2-T and CR-(DPA)3-T) with donor-π-acceptor-π-donor (D-π-A-π-D) features and diradical characteristics. Owing to the enhanced D-A effect and intramolecular motions, their absorption and photothermal capacity increase as the generation grows. Surprisingly, an excellent photothermal performance (ɛ1064 × PTCE1064) with a superb value of 2.85 × 104 in the NIR-II region is achieved for CR-(DPA)3-T nanoparticles (CR-(DPA)3-T NPs) compared to most reported counterparts. Besides, CR-(DPA)3-T NPs exhibit superior antitumor efficacy by the synergistic effect of photothermal therapy (PTT) and immunotherapy, efficiently inhibiting the growth of both primary and distant tumors. To the best knowledge, organic photothermal dendrimer is for the first time reported, and a universal donor engineering strategy is offered to develop NIR-II-absorbing organic photothermal materials for photothermal immunotherapy.

Magnetic response and bioaccessibility of toxic metal pollution in outdoor dustfall in Shanghai, China.

Toxic metal content testing, environmental magnetic monitoring and in vitro bioaccessibility experiments each have their own advantages and are often used independently for environmental monitoring, but there are few studies that combine the three to evaluate the hazards of toxic metals to humans. This paper investigated the total content, magnetic properties and bioaccessibility of nine potentially toxic metal elements (Zn, Sn, Pb, Cu, Fe, Ni, Cr, Sr, Mn) in dustfall from different functional zones in Shanghai, China, and systematically compared the related results. The results show that these nine metal elements have different degrees of contamination and enrichment in outdoor dustfall, and their content distribution shows the following trend: Zn > Sn > Pb > Cu > Fe > Ni > Cr > Sr > Mn. Magnetic characteristics χlf and SIRM are mostly positively correlated with the metal elements, indicating that the higher the content of magnetic minerals in the sample, the higher the concentration of metal elements. It was also found that χlf, SIRM, and χARM can well reflect the characteristics of dustfall pollution. The magnetic minerals have a certain degree of enrichment, and the particle size of the magnetic minerals is relatively coarse, mainly in the form of coarse multi-domain and pseudo-single-domain particles, which are largely derived from anthropogenic pollution. The χlf and PM10 concentrations in the precipitation show relatively similar spatial trends, so χlf, SIRM, and χARM can be used as air pollution indices to facilitate the evaluation of metal elements pollution in dustfall. The overall trend in gastric bioaccessibility is Pb > Zn > Mn > Cu > Cr. Due to the increase in the pH of digestive fluid, the bioavailability of toxic metals decreases significantly from the gastric stage to the intestinal stage. χlf, SIRM, and χARM/SIRM are all related to the bioaccessibility of toxic metals in the intestinal stage, so they can be used as toxicity indicators to evaluate the bioaccessibility of toxic metals in dustfall.

Nucleated red blood cell distribution in critically ill patients with acute pancreatitis: a retrospective cohort study.

OBJECTIVES: This study examined the potential association between nucleated red blood cell (NRBC) levels and mortality in critically ill patients with acute pancreatitis (AP) in the intensive care unit, due to limited existing research on this correlation. METHODS: This retrospective cohort study utilized data from the MIMIC-IV v2.0 and MIMIC-III v1.4 databases to investigate the potential relationship between NRBC levels and patient outcomes. The study employed restricted cubic splines (RCS) regression analysis to explore non-linear associations. The impact of NRBC on prognosis was assessed using a generalized linear model (GLM) with a logit link, adjusted for potential confounders. Furthermore, four machine learning models, including Gradient Boosting Classifier (GBC), Random Forest, Gaussian Naive Bayes, and Decision Tree Classifier model, were constructed using NRBC data to generate risk scores and evaluate the potential of NRBC in predicting patient prognosis. RESULTS: A total of 354 patients were enrolled in the study, with 162 (45.8%) individuals aged 60 years or older and 204 (57.6%) males. RCS regression analysis demonstrated a non-linear relationship between NRBC levels and 90-day mortality. Receiver Operating Characteristic (ROC) analysis identified a 1.7% NRBC cutoff to distinguish survivor from non-survivor patients for 90-day mortality, yielding an Area Under the Curve (AUC) of 0.599, with a sensitivity of 0.475 and specificity of 0.711. Elevated NRBC levels were associated with increased risks of 90-day mortality in both unadjusted and adjusted models (all Odds Ratios > 1, P < 0.05). Assessment of various machine learning models with nine variables, including NRBC, Sex, Age, Simplified Acute Physiology Score II, Acute Physiology Score III, Congestive Heart Failure, Vasopressin, Norepinephrine, and Mean Arterial Pressure, indicated that the GBC model displayed the highest predictive accuracy for 90-day mortality, with an AUC of 0.982 (95% CI 0.970-0.994). Post hoc power analysis showed a statistical power of 0.880 in the study. CONCLUSIONS: Elevated levels of NRBC are linked to an increased mortality risk in critically ill patients with AP, suggesting its potential for predicting mortality.

Configurational Paths of Preconditions to Transformational Leadership Among Core Hospital Leaders: A Fuzzy-Set Qualitative Comparative Analysis.

Purpose: Transformational leadership among core hospital leaders boosts medical organizations' competitiveness, adaptability, and sustainability, which is jointly affected by individual, organizational and environmental factors. This study aims to unpack its configurational framework and propose strategies to strengthen core hospital leaders' transformational leadership. Patients and Methods: Data were collected from an online questionnaire among 31 core hospital leaders. The fuzzy-set qualitative comparative analysis (fsQCA) was used to explore the causal mechanism of high-level transformational leadership. We enrich this mechanism by professional background, critical thinking, initiative spirit, family-work conflict, job satisfaction, subordinates' followership, and work pressure. Results: Result shows initiative spirit is the only necessary condition (consistency=0.911) for the formation of high-level transformational leadership among core hospital leaders. Three configurations are the sufficient conditions that lead to high-level transformational leadership among core hospital leaders with two different professional backgrounds (overall solution consistency= 0.952). Conclusion: Core hospital leaders' initiative spirit is an indispensable condition for improving high-level transformational leadership, emphasizing the necessity for core leaders to be proactive in order to develop such leadership. Besides, the study also uncovered three configurations are the sufficient conditions for core hospital leaders with diverse professional backgrounds to achieve high-level transformational leadership. This finding offers significant insights into hospital management practices, suggesting that core hospital leaders' work should be managed in a personalized manner based on their professional backgrounds, thereby fostering favorable conditions conducive to the development of their high-level transformational leadership capabilities. Furthermore, the central insight of this study is that the formation of high-level transformational leadership contingent upon the collaboration of professional background, critical thinking, initiative spirit, family-work conflict, job satisfaction, subordinates' followership, and work pressure, contributing to a holistic and more rigorous view for the development of transformational leadership.

Age-specific ASPECTS atlas of Chinese subjects across different age groups for assessing acute ischemic stroke.

The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is a valuable and easy-to-use method for assessing acute ischemic stroke. It aids in identifying suitable candidates for thrombolytic therapies and evaluating treatment effectiveness. However, ASPECTS evaluation primarily relies on visual observation in current clinical practice, lacking a common standardized space. Additionally, different doctors may have varying clinical experiences, leading to a poor inter-reader agreement and potential errors in the final ASPECTS scoring. To address these issues and fill in the absence of a publicly available ASPECTS atlas, this work constructs age-specific Chinese ASPECTS atlases based on non-contrast computed tomography images of 281 healthy subjects across different age groups. Images of different age groups are warped into respective common averaged spaces, where the average intensity atlases are computed. More importantly, 10 ASPECTS regions can be obtained during this process. We develop an automated ASPECTS region mapping pipeline and collect an independent dataset to validate our atlas. The results prove that the age-specific ASPECTS atlas is of great promise in clinical availability.

Prediction of Broadband and Highly-Efficient Electromagnetic Wave-Absorbing SiC@SiO2 Nanowire Aerogel by Genetic Algorithm.

Searching for lightweight and high-temperature stable electromagnetic wave-absorbing materials with broad absorbing bandwidth and high efficiency is of significance for applications in daily life and industry. Optimizing the dielectric properties of SiC nanowire aerogel by both compositional and structural designs is an efficient way to obtain simultaneous efficient wave-dissipation ability and good impendence matching and thus the desired properties. However, due to the complex effects of dielectric parameters on the wave-absorbing properties, rational design of high-performance electromagnetic wave-absorbing materials remains challenging. Herein, we propose a genetic algorithm-based approach to predict broadband and highly efficient electromagnetic wave-absorbing materials in a SiC@SiO2 nanowire aerogel-based system. The obtained SiC@SiO2 nanowire aerogels exhibit a gradient multilayered structure with a low dielectric outer layer, a medium layer with alternatively distributed electromagnetic wave transparent and attenuation layers, and an inner high attenuation layer, giving it a broadband electromagnetic wave-absorbing performance covering almost all the 2-18 GHz bandwidth and simultaneous high efficiency. The results show that the genetic algorithm-based approach is efficient in predicting high-performance electromagnetic wave-absorbing ceramic aerogels.

U-shaped nonlinear relationship between dietary copper intake and peripheral neuropathy.

BACKGROUND: Dietary copper intake is a promising predictor of peripheral neuropathy. There is no research exploring the potential link between dietary copper intake and peripheral neuropathy. METHODS: The information utilized in our research was collected from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004. The relationship between dietary copper intake and peripheral neuropathy was analyzed using a multivariate logistic regression model and restricted cubic spline (RCS). RESULTS: The RCS analysis results showed a U-shaped nonlinear relationship between dietary copper intake and peripheral neuropathy (P for nonlinearity < 0.001). The threshold effect analysis results indicated that when dietary copper intake was less than 0.889 mg/d, the risk of peripheral neuropathy decreased with increasing copper intake (OR: 0.388, 95% CI: 0.200-0.753). When dietary copper intake was ≥ 0.889 mg/d, the risk of peripheral neuropathy increased with increasing copper intake (OR: 1.129, 95% CI: 1.006-1.266). And the incidence rate of peripheral neuropathy in the first quantile (OR: 1.421, 95% CI: 1.143-1.766), the third quantile (OR: 1.358, 95% CI: 1.057-1.744), and the fourth quantile (OR: 1.676, 95% CI: 1.250-2.248) of dietary copper intake were significantly higher than that in the second quantile (where the inflection point was located). CONCLUSION: Our study suggests that both insufficient and excessive dietary copper intake may be associated with an increased incidence of peripheral neuropathy. However, further research is needed to provide definitive evidence and confirm these findings.

Three-dimensional reconstruction of insect chemosensory sensillum.

The olfactory system is involved in food and mate recognition in insects. However, 3D structures of chemosensory sensilla in insects are unexplored yet. Here, the internal structures of an olfactory sensillum on the antenna of the brown planthopper, Nilaparvata lugens (Hemiptera: Delphacidae), one of the most important rice pests, are examined and imaged using focused ion beam scanning electron microscopy. Based on these images, a 3D structure is reconstructed in this study. We find that the trichoid olfactory sensillum possesses a multiporous wall encircling a lumen with one sensory cell. Besides, there are three accessory cells (ACs) and a glia cell with different cell contents surrounding the sensory cell. The abundant tubular membrane structures in the tormogen cell suggest its role in secreting proteins like odorant binding proteins into the receptor lymph, while three auxiliary cells with simpler cellular content closely enfold the sensory cell, probably to prevent leaking of the receptor lymph into the surrounding epidermis. In the sensory cell, the microtubules and two tandem basal bodies at the base of the microtubules are also reconstructed. They are considered as a propulsive engine to ensure dendrite vibration or spinning in the receptor lymph, so that the proteins and odorant molecules move faster in the receptor lymph, which improves recognition of environmental odors and enables the insect to immediately respond to this information.

Photo-induced difluoroalkylation/cyclization of alkyne ketones: a novel strategy to access difluoroalkyl thiofavones.

A photo-induced electron donor-acceptor (EDA) complex enabled tandem reaction of alkyne ketones via a radical difluoroalkylation/cyclization cascade sequence is reported. The EDA complex plays a key role, and the C-Br bond homolysis process may also be involved for this transformation. Varieties of difluoroalkyl-substituted thiofavones can be smoothly assembled in moderate to good yields under photocatalyst-, metal- and oxidant-free conditions, thus offering potential applications for pharmaceutical research.

Novel nomogram for the prediction of sepsis-induced coagulopathy in the PICU: A multicentre retrospective study.

INTRODUCTION: Sepsis-induced coagulopathy (SIC) is a severe complication of sepsis, characterized by poor prognosis and high mortality. However, the predictors of SIC in pediatric patients have yet to be identified. Our aim was to develop a user-friendly and efficient nomogram for predicting SIC in sepsis patients admitted to the pediatric intensive care unit (PICU). MATERIALS AND METHODS: We screened 948 sepsis patients admitted to the PICU in three hospitals located in Shandong, China. Least absolute shrinkage and selector operation (LASSO) regression was used in the training cohort for variable selection and regularization. The selected variables were utilized to construct a nomogram for predicting the risk of SIC among sepsis patients admitted to the PICU. RESULTS: Overall, SIC was observed in 324 (40.3 %) patients. The morbidity of SIC in sepsis patients is associated with age, fibrinogen, prothrombin time, C-reactive protein, lactate and the pediatric sequential organ failure assessment score. We developed a nomogram for the early identification of SIC in the training cohort (area under the curve [AUC] 0.869, 95 % confidence interval [CI] 0.830-0.907, sensitivity 75.7 %, specificity 84.8 %) and validation cohorts (validation cohort 1: AUC 0.854, 95 % CI 0.805-0.903, sensitivity 72.0 %, specificity 86.9 %; validation cohort 2: AUC 0.853, 95 % CI 0.796-0.910, sensitivity 70.1 %, specificity 87.8 %). The calibration plots of the nomogram demonstrated a high level of concordance in the SIC probabilities between the observed and predicted values. CONCLUSIONS: The novel nomogram showed excellent predictive performance for the morbidity of SIC among sepsis patients admitted to the PICU, potentially assisting healthcare professionals in early identification and intervention for SIC.

Lysine methylation: A strategy to improve in-cell NMR spectroscopy of proteins.

BACKGROUND: In-cell NMR is a valuable technique for investigating protein structure and function in cellular environments. However, challenges arise due to highly crowded cellular environment, where nonspecific interactions between the target protein and other cellular components can lead to signals broadening or disappearance in NMR spectra. RESULTS: We implemented chemical reduction methylation to selectively modify lysine residues on protein surfaces aiming to weaken charge interactions and recover obscured NMR signals. This method was tested on six proteins varying in molecular size and lysine content. While methylation did not disrupt the protein's native conformation, it successful restored some previously obscured in-cell NMR signals, particularly for proteins with high isoelectric points that decreased post-methylation. SIGNIFICANCE: This study affirms lysine methylation as a feasible approach to enhance the sensitivity of in-cell NMR spectra for protein studies. By mitigating signal loss due to nonspecific interactions, this method expands the utility of in-cell NMR for investigating proteins in their natural cellular environment, potentially leading to more accurate structural and functional insights.

Overexpression of SLC2A1, ALDOC, and PFKFB4 in the glycolysis pathway drives strong drug resistance in 3D HeLa tumor cell spheroids.

The 3D multicellular tumor spheroid (MTS) model exhibits enhanced fidelity in replicating the tumor microenvironment and demonstrates exceptional resistance to clinical drugs compared to the 2D monolayer model. In this study, we used multiomics (transcriptome, proteomics, and metabolomics) tools to explore the molecular mechanisms and metabolic differences of the two culture models. Analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways revealed that the differentially expressed genes between the two culture models were mainly enriched in cellular components and biological processes associated with extracellular matrix, extracellular structural organization, and mitochondrial function. An integrated analysis of three omics data revealed 11 possible drug resistance targets. Among these targets, seven genes, AKR1B1, ALDOC, GFPT2, GYS1, LAMB2, PFKFB4, and SLC2A1, exhibited significant upregulation. Conversely, four genes, COA7, DLD, IFNGR1, and QRSL1, were significantly downregulated. Clinical prognostic analysis using the TCGA survival database indicated that high-expression groups of SLC2A1, ALDOC, and PFKFB4 exhibited a significant negative correlation with patient survival. We further validated their involvement in chemotherapy drug resistance, indicating their potential significance in improving prognosis and chemotherapy outcomes. These results provide valuable insights into potential therapeutic targets that can potentially enhance treatment efficacy and patient outcomes.

Self-Assembly of Nanovesicles for Enhanced Adsorption and Efficient Photodegradation of 2,4,6-Trichlorophenol.

The compound 2,4,6-trichlorophenol poses significant risks to both the aquatic environment and human health. Its inherent persistence and stability present challenges in achieving complete purification, thus warranting its inclusion as a priority pollutant. The present study reports the development of an amphiphilic small-molecule compound that self-assembles into nanovesicles exhibiting remarkable adsorption and photodegradation capabilities. Through the synergistic effects of hydrogen bonding, van der Waals forces, π-π interactions, and electrostatic interactions, these vesicles efficiently adsorb 2,4,6-trichlorophenol from aqueous solutions within 1 min while demonstrating exceptional environmental stability and broad applicability. Upon self-assembly into vesicles, not only are more adsorption sites exposed, but charge separation and migration within the vesicles are also facilitated. Through the synergistic effects of adsorption and photodegradation, complete removal of 2,4,6-trichlorophenol in aqueous solution can be achieved within 8 h while exhibiting excellent recycling capability. This approach offers a viable strategy for designing and synthesizing pure organic photodegradable materials.

Simulated microgravity-induced dysregulation of cerebrospinal fluid immune homeostasis by disrupting the blood-cerebrospinal fluid barrier.

BACKGROUND: The blood-cerebrospinal fluid barrier (BCSFB) comprises the choroid plexus epithelia. It is important for brain development, maintenance, function, and especially for maintaining immune homeostasis in the cerebrospinal fluid (CSF). Although previous studies have shown that the peripheral immune function of the body is impaired upon exposure to microgravity, no studies have reported changes in immune cells and cytokines in the CSF that reflect neuroimmune status. The purpose of this study is to investigate the alterations in cerebrospinal fluid (CSF) immune homeostasis induced by microgravity and its mechanisms. This research is expected to provide basic data for brain protection of astronauts during spaceflight. METHODS: The proportions of immune cells in the CSF and peripheral blood (PB) of SMG rats were analyzed using flow cytometry. Immune function was evaluated by measuring cytokine concentrations using the Luminex method. The histomorphology and ultrastructure of the choroid plexus epithelia were determined. The concentrations of intercellular junction proteins in choroid plexus epithelial cells, including vascular endothelial-cadherin (VE-cadherin), zonula occludens 1 (ZO-1), Claudin-1 and occludin, were detected using western blotting and immunofluorescence staining to characterize BCSFB injury. RESULTS: We found that SMG caused significant changes in the proportion of CD4 and CD8 T cells in the CSF and a significant increase in the levels of cytokines (GRO/KC, IL-18, MCP-1, and RANTES). In the PB, there was a significant decrease in the proportion of T cells and NKT cells and a significant increase in cytokine levels (GRO/KC, IL-18, MCP-1, and TNF-α). Additionally, we observed that the trends in immune markers in the PB and CSF were synchronized within specific SMG durations, suggesting that longer SMG periods (≥21 days) have a more pronounced impact on immune markers. Furthermore, 21d-SMG resulted in ultrastructural disruption and downregulated expression of intercellular junction proteins in rat choroid plexus epithelial cells. CONCLUSIONS: We found that SMG disrupts the BCSFB and affects the CSF immune homeostasis. This study provides new insights into the health protection of astronauts during spaceflight.

Update on JNK inhibitor patents: 2015 to present.

INTRODUCTION: c-Jun N-terminal kinase (JNK) regulates various biological processes through the phosphorylation cascade and is closely associated with numerous diseases, including inflammation, cardiovascular diseases, and neurological disorders. Therefore, JNKs have emerged as potential targets for disease treatment. AREAS COVERED: This review compiles the patents and literatures concerning JNK inhibitors through retrieving relevant information from the SciFinder, Google Patents databases, and PubMed from 2015 to the present. It summarizes the structure-activity relationship (SAR) and biological activity profiles of JNK inhibitors, offering valuable perspectives on their potential therapeutic applications. EXPERT OPINION: The JNK kinase serves as a novel target for the treatment of neurodegenerative disorders, pulmonary fibrosis, and other illnesses. A variety of small-molecule inhibitors targeting JNKs have demonstrated promising therapeutic potential in preclinical studies, which act upon JNK kinases via distinct mechanisms, encompassing traditional ATP competitive inhibition, covalent inhibition, and bidentate inhibition. Among them, several JNK inhibitors from PregLem SA, Celegene SA, and Xigen SA have accomplished the early stage of clinical trials, and their results will guide the development and indications of future JNK inhibitors.

Selective Covalent Inhibiting JNK3 by Small Molecules for Parkinson's Diseases.

c-Jun N-terminal kinases (JNKs) including JNK1/2/3 are key members of mitogen-activated protein kinase family. Wherein JNK3 is specifically expressed in brain and emerges as therapeutic target, especially for neurodegenerative diseases. However, developing JNK3 selective inhibitors as chemical probes to investigate its therapeutic potential in diseases remains challenging. Here, we adopted the covalent strategy for identifying JNK3-selective covalent inhibitor JC16I, with high inhibitory activity against JNK3. Despite targeting a conserved cysteine in the vicinity of ATP pocket in JNK family, JC16I exerted a greater than 160-fold selectivity for JNK3 over JNK1/2. Importantly, even at low concentration, JC16I showed enhanced and long-lasting inhibition against cellular JNK3. In addition, its alkyne-containing probe JC-P1 could label JNK3 in SH-SY5Y cell lysate and living cells, with good proteome-wide selectivity. JC16I selectively suppressed the abnormal activation of JNK3 signaling and sufficiently exhibited neuroprotective effect in Parkinson's diseases (PD) models. Overall, our findings highlight the potential of developing isoform-selective and cell-active JNK3 inhibitors by covalent drug design strategy targeting a conserved cysteine. This work not only provides a valuable chemical probe for JNK3-targeted investigations in vitro and in vivo but also opens new avenues for the treatment of PD.