Topical application of a BCL-2 inhibitor ameliorates imiquimod-induced psoriasiform dermatitis by eliminating senescent cells.

BACKGROUND: Psoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs. OBJECTIVE: To investigate the role of senescent CD4+ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis. METHODS: We explored the expression levels of p16INK4a and p21, classical markers of cellular senescence, in CD4+ T cells from human psoriatic lesions and imiquimod (IMQ)-induced psoriatic lesions. We prepared a senolytic gel using B-cell lymphoma 2 (BCL-2) inhibitor ABT-737 and evaluated its therapeutic efficacy in treating psoriasis. RESULTS: Using multispectrum immunohistochemistry (mIHC) staining, we detected increased expression levels of p16INK4a and p21 in CD4+ T cells from psoriatic lesions. After topical application of ABT-737 gel, significant alleviation of IMQ-induced psoriatic lesions was observed, with milder pathological alterations. Mechanistically, ABT-737 gel significantly decreased the percentage of senescent cells, expression of T cell receptor (TCR) α and ß chains, and expression of Tet methylcytosine dioxygenase 2 (Tet2) in IMQ-induced psoriatic lesions, as determined by mIHC, high-throughput sequencing of the TCR repertoire, and RT-qPCR, respectively. Furthermore, the severity of psoriatic lesions in CD4creTet2f/f mice was milder than that in Tet2f/f mice in the IMQ-induced psoriasis model. CONCLUSION: We revealed the roles of senescent CD4+ T cells in developing psoriasis and highlighted the therapeutic potential of topical ABT-737 gel in treating psoriasis through the elimination of senescent cells, modulation of the TCR αß repertoire, and regulation of the TET2-Th17 cell pathway.

One-to-Nine Single Spectroscopic Intelligent Probe for Risk Assessment of Multiple Metals in Drinking Water.

26% of the world's population lacks access to clean drinking water; clean water and sanitation are major global challenges highlighted by the UN Sustainable Development Goals, indicating water security in public water systems is at stake today. Water monitoring using precise instruments by skilled operators is one of the most promising solutions. Despite decades of research, the professionalism-convenience trade-off when monitoring ubiquitous metal ions remains the major challenge for public water safety. Thus, to overcome these disadvantages, an easy-to-use and highly sensitive visual method is desirable. Herein, an innovative strategy for one-to-nine metal detection is proposed, in which a novel thiourea spectroscopic probe with high 9-metal affinity is synthesized, acting as "one", and is detected based on the 9 metal-thiourea complexes within portable spectrometers in the public water field; this is accomplished by nonspecialized personnel as is also required. During the processing of multimetal analysis, issues arise due to signal overlap and reproducibility problems, leading to constrained sensitivity. In this innovative endeavor, machine learning (ML) algorithms were employed to extract key features from the composite spectral signature, addressing multipeak overlap, and completing the detection within 30-300 s, thus achieving a detection limit of 0.01 mg/L and meeting established conventional water quality standards. This method provides a convenient approach for public drinking water safety testing.

A Planar-Structured Dinuclear Cobalt(II) Complex with Indirect Synergy for Photocatalytic CO2-to-CO Conversion.

Dinuclear metal synergistic catalysis (DMSC) has been proved an effective approach to enhance catalytic efficiency in photocatalytic CO2 reduction reaction, while it remains challenge to design dinuclear metal complexes that can show DMSC effect. The main reason is that the influence of the microenvironment around dinuclear metal centres on catalytic activity has not been well recognized and revealed. Herein, we report a dinuclear cobalt complex featuring a planar structure, which displays outstanding catalytic efficiency for photochemical CO2-to-CO conversion. The turnover number (TON) and turnover frequency (TOF) values reach as high as 14457 and 0.40 s-1 respectively, 8.6 times higher than those of the corresponding mononuclear cobalt complex. Control experiments and DFT calculations revealed that the enhanced catalytic efficiency of the dinuclear cobalt complex is due to the indirect DMSC effect between two CoII ions, energetically feasible one step two-electron transfer process by Co2I,I intermediate to afford Co2II,II(CO22-) intermediate and fast mass transfer closely related with the planar structure.

Measurable residual disease testing by next generation sequencing is more accurate compared with multiparameter flow cytometry in adults with B-cell acute lymphoblastic leukemia.

Results of measurable residual disease (MRD)-testing by next-generation sequencing (NGS) correlate with relapse risk in adults with B-cell acute lymphoblastic leukemia (ALL) receiving chemotherapy or an allotransplant from a human leukocyte antigen (HLA)-identical relative or HLA-matched unrelated donor. We studied cumulative incidence of relapse (CIR) and survival prediction accuracy using a NGS-based MRD-assay targeting immunoglobulin genes after 2 courses of consolidation chemotherapy cycles in 93 adults with B-cell ALL most receiving HLA-haplotype-matched related transplants. Prediction accuracy was compared with MRD-testing using multi-parameter flow cytometry (MPFC). NGS-based MRD-testing detected residual leukemia in 28 of 65 subjects with a negative MPFC-based MRD-test. In Cox regression multi-variable analyses subjects with a positive NGS-based MRD-test had a higher 3-year CIR (Hazard Ratio [HR] = 3.37; 95 % Confidence Interval [CI], 1.34-8.5; P = 0.01) and worse survival (HR = 4.87 [1.53-15.53]; P = 0.007). Some data suggest a lower CIR and better survival in NGS-MRD-test-positive transplant recipients but allocation to transplant was not random. Our data indicate MRD-testing by NGS is more accurate compared with testing by MPFC in adults with B-cell ALL in predicting CIR and survival. (Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTROPC-14005546]).

[Lysine Succinylation:A New Perspective in the Treatment of Cardiovascular Diseases].

With the continuous development of identification technologies such as mass spectrometry,omics,and antibody technology,post-translational modification (PTM) has demonstrated increasing potential in medical research.PTM as a novel chemical modification method provides new perspectives for the research on diseases.Succinylation as a novel modification has aroused the interest of more and more researchers.The available studies about succinylation mainly focus on a desuccinylase named sirtuin 5.This enzyme plays a key role in modification and has been preliminarily explored in cardiovascular studies.This paper summarizes the influencing factors and regulatory roles of succinylation and the links between succinylation and other PTMs and reviews the research progress of PTMs in the cardiovascular field,aiming to deepen the understanding about the role of this modification and give new insights to the research in this field.

PRRX1-fused mesenchymal neoplasm: A novel PRRX1::NCOA1 fusion transcript.

PRRX1-fused mesenchymal neoplasm is a recently identified, rare subcutaneous soft tissue neoplasm that is characterized by fusion of PRRX1 (exon 1) with NCOA1 (exon 13) in the majority of reported cases. Although initially considered to be fibroblastic, a possibility of neural or neuroectodermal differentiation has been suggested in a subset of cases. We report a 26-year-old female with a 4.0 cm painless mass located in the subcutis of the left thigh. Microscopically, the tumor was well-circumscribed and multinodular and was composed of relatively monomorphic ovoid to spindle cells arranged in loose fascicles, trabeculae, and cords within alternating myxoid and fibrous matrix, and vascularized stroma. Mitotic figures were scarce and necrosis was not observed. By immunohistochemistry, the neoplastic cells demonstrated focal co-expression of S100 protein and SOX10 and were negative for epithelial membrane antigen, smooth muscle actin, desmin, CD34, STAT6, HMB45, Melan-A, and MUC4. The expression of Rb1 was retained. Targeted RNA-sequencing identified a novel transcript fusion of PRRX1 (exon 1)::NCOA1 (exon 15), which was further confirmed by reverse transcription polymerase chain reaction and Sanger sequencing. The tumor was narrowly excised and no tumor recurrence or metastasis was identified after 13 months of follow-up. In summary, we report a new case of PRRX1-fused mesenchymal neoplasm, expanding the molecular genetic spectrum and providing further support for possible neural or neuroectodermal differentiation of this emerging soft tissue tumor entity.

Investigation on the contaminate of hand washing activities on the surface of environmental objects in intensive care unit.

To detect the contaminate of faucets in hospitals and the splash during hand washing, and to explore the reasonable layout of hand washing pools. Two faucets with roughly the same spatial layout in the ICU of a third-class first-class general hospital were selected, and the farthest splashing distance and specific splashing points were measured by color paper. Samples were detected by ATP detection technology and routine microbial detection method, and the contaminate of faucets was analyzed. After 72 h of daily hand-washing activities, the furthest distance to the splash point was about 100 cm around the faucet, and the place 40-110 cm around the faucet was contaminated seriously. The farthest distance that the splash point reached was about 80 cm around the faucet with the center of the circle, and the area 40-60 cm around the faucet was heavily contaminated. The distance from the water outlet of the long handle and the short handle faucet to the detection point had a high negative correlation (r = - 0.811, P < 0.001) and a moderate negative correlation (r = - 0.475, P = 0.001) with the number of splash points, respectively. The qualified rates of ATP detection and microbial culture were 25% and 15%, respectively. Pseudomonas aeruginosa, Staphylococcus epidermidis, and other pathogenic bacteria were detected in the water outlet of the faucet and the surrounding environment. Safe hand hygiene facilities are one of the important guarantees of hand hygiene effect. Clean objects and objects related to patients should not be placed within 1 m range near the water outlet of faucet. Anti-splash baffle should be installed as much as possible when conditions permit to reduce the contaminate caused by splash during hand washing.

Development of a highly sensitive ultra-small ratiometric fluorescence nanosphere probe for Sunset Yellow detection.

A highly sensitive ultra-small ratiometric fluorescence nanosphere probe was successfully manufactured to detect Sunset Yellow (SY). The probe, CMCS@N, S-CDs/Rh6G, was formed through the encapsulation of N, S-CDs and Rh6G within carboxymethyl chitosan (CMCS) through in situ cross-linking. Remarkably, our nanosphere probe had an average grain diameter of 6.80 nm and exhibited excellent dispersibility without the need for additional solvents. The probe exhibited a strong linear relationship with SY concentration in the range of 0.26-100 µM, with a low detection limit of 0.078 µM. Furthermore, SY demonstrated strong fluorescence quenching capability on our nanosphere probe, with the fluorescence quenching mechanism involving a combined effects of inner filter effect (IFE) and static quenching. Notably, our nanosphere probe retained the bacteriostatic properties of CMCS, with a substantial bacteriostasis rate of 77.58 %, introducing novel potential applications.

Fresnel lens three-dimensionally printed on the facet of a single mode fiber for trapping, manipulation, and spectrum.

Fiber optical tweezers (FOTs) provide a functionality for micro-/nanoparticle manipulation with a slim and flexible optical fiber setup. An added in situ spectroscopic functionality can achieve characterization of the trapped particle, potentially useful for endoscopic, in-vivo studies in an inherently heterogeneous environment if the applicator end is all-fiber-built. Here, we demonstrate all-fiber optical tweezers (a-FOTs) for the trapping and in situ spectral measurement of a single, cell-sized microparticle. The key to ensure the simultaneous bifunctionality is a high numerical aperture (NA) Fresnel lens fabricated by two-photon direct laser writing (DLW) corrected by grid-correction methods. We demonstrate trapping and time-resolved, in situ spectroscopy of a single upconversion particle (UCP), a common fluorescent biomarker in biophotonics. The system achieves a 0.5-s time resolution in the in situ spectral measurement of a trapped UCP. The all-fiber designed system preserves the advantages of flexibility and robustness of the fiber, potentially useful for in-vivo biomedical studies such as cell-to-cell interactions, pH and temperature detection, and nucleic acids detection.

Monolayer directional metasurface for all-optical image classifier doublet: publisher's note.

This publisher's note contains a correction to Opt. Lett.49, 2505 (2024)10.1364/OL.520642.

Lipidomics and mass spectrometry imaging unveil alterations in mice hippocampus lipid composition exposed to hypoxia.

Lipids are components of cytomembranes that are involved in various biochemical processes. High-altitude hypoxic environments not only affect the body's energy metabolism, but these environments can also cause abnormal lipid metabolism involved in the hypoxia-induced cognitive impairment. Thus, comprehensive lipidomic profiling of the brain tissue is an essential step toward understanding the mechanism of cognitive impairment induced by hypoxic exposure. In the present study, mice showed reduced new-object recognition and spatial memory when exposed to hypobaric hypoxia for 1 day. Histomorphological staining revealed significant morphological and structural damage to the hippocampal tissue, along with prolonged exposure to hypobaric hypoxia. Dynamic lipidomics of the mouse hippocampus showed a significant shift in both the type and distribution of phospholipids, as verified by spatial lipid mapping. Collectively, a diverse and dynamic lipid composition in mice hippocampus was uncovered, which deepens our understanding of biochemical changes during sustained hypoxic exposure and could provide new insights into the cognitive decline induced by high-altitude hypoxia exposure.

Brain Short-Chain Fatty Acids Induce ACSS2 to Ameliorate Depressive-Like Behavior via PPARγ-TPH2 Axis.

Short-chain fatty acids (SCFAs) have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse psychiatric or neurological disorders via the microbiota-gut-brain axis. However, the precise mechanism by which brain SCFAs extert multiple beneficial effects is not completely understood. Our previous research has demonstrated that the acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is a novel target of the rapid and long-lasting antidepressant responses. Here, we show that micromolar SCFAs significantly augment both total cellular and nuclear ACSS2 to trigger tryptophan hydroxylase 2 (TPH2) promoter histone acetylation and its transcription in SH-SY5Y cells. In chronic-restraint-stress-induced depression mice, neuronal ACSS2 knockdown by stereotaxic injection of adeno-associated virus in the hippocampus abolished SCFA-mediated improvements in depressive-like behaviors of mice, supporting that ACSS2 is required for SCFA-mediated antidepressant responses. Mechanistically, the peroxisome-proliferator-activated receptor gamma (PPARγ) is identified as a novel partner of ACSS2 to activate TPH2 transcription. Importantly, PPARγ is also responsible for SCFA-mediated antidepressant-like effects via ACSS2-TPH2 axis. To further support brain SCFAs as a therapeutic target for antidepressant effects, d-mannose, which is a naturally present hexose, can significantly reverse the dysbiosis of gut microbiota in the chronic-restraint-stress-exposure mice and augment brain SCFAs to protect against the depressive-like behaviors via ACSS2-PPARγ-TPH2 axis. In summary, brain SCFAs can activate ACSS2-PPARγ-TPH2 axis to play the antidepressive-like effects, and d-mannose is suggested to be an inducer of brain SCFAs in resisting depression.

p53 lysine-lactylated modification contributes to lipopolysaccharide-induced proinflammatory activation in BV2 cell under hypoxic conditions.

p53 has diversity functions in regulation of transcription, cell proliferation, cancer metastasis, etc. Recent studies have shown that p53 and nuclear factor-κB (NF-κB) co-regulate proinflammatory responses in macrophages. However, the role of p53 lysine lactylation (p53Kla) in mediating proinflammatory phenotypes in microglia under hypoxic conditions remains unclear. In the current study, we investigated the proinflammatory activation exacerbated by hypoxia and the levels of p53Kla in microglial cells. BV2 cells, an immortalized mouse microglia cell line, were divided into control, lipopolysaccharide (LPS)-induced, hypoxia (Hy), and LPS-Hy groups. The protein expression levels of p53 and p53Kla and the activation of microglia were compared among the four groups. Sodium oxamate and mutant p53 plasmids were transfected into BV2 cells to detect the effect of p53Kla on microglial proinflammatory activation. LPS-Hy stimulation significantly upregulated p53Kla levels in both the nucleus and the cytoplasm of BV2 cells. In contrast, the p53 protein levels were downregulated. LPS-Hy stimulation upregulated phosphorylated p65 protein levels in nuclear and activated the NF-κB pathway in BV2 cells, resulting in increased expression of pro-inflammatory cytokines (iNOS, IL6, IL1ß, TNFα), enhanced cell viability, and concomitantly, increased cytotoxicity. In conclusion, p53 lysine-lactylated modification contributes to LPS-induced proinflammatory activation in BV2 cells under hypoxia through NF-κB pathway and inhibition of lactate production may alleviate neuroinflammatory injury.

Association between blood methylmalonic acid and chronic kidney disease in the general US population: insights from multi-cycle National Health and Nutrition Examination Survey (NHANES).

Background: Chronic kidney disease (CKD) is significantly influenced by mitochondrial dysfunction (MD). Previous research suggests that methylmalonic acid (MMA) is involved in MD. Consequently, we aimed to investigate associations between blood MMA level and the prevalence of CKD as well as mortality in patients with CKD. Methods: The study included 23,587 individuals from National Health and Nutrition Examination Survey (NHANES). The NHANES datasets from 1999-2004 and 2011-2014 were utilized as separate primary and validation subsets. There were 3,554 patients with CKD. The association of blood MMA level with the prevalence of CKD was investigated using weighted logistic regression. Meanwhile, we employed weighted Cox regression models to evaluate the association between blood MMA level and all-cause mortality in patients with CKD. Results: Blood MMA levels had a significant positive association with urinary albumin-to-creatinine ratio (ß=45.29, P=0.01) and negative association with estimated glomerular filtration rate (ß=-15.27, P<0.001) in CKD patients. Blood MMA level exhibited a significant increase in participants with CKD compared with those without CKD (7.60±0.86 vs. 7.03±0.62, P<0.001). The level of blood MMA was significantly associated with the prevalence of CKD [odds ratio (OR): 1.32, 95% confidence interval (CI): 1.05-1.64, P=0.01]. In addition, blood MMA level was significantly associated with all-cause mortality in CKD participants [hazard ratio (HR): 1.26, 95% CI: 1.11-1.43, P<0.001] after adjusting for other potential predictors. Conclusions: Increased blood MMA levels were associated with more severe kidney impairment and increased risk of both the prevalence of CKD and mortality in participants with CKD.

CFI-Net: A Choquet Fuzzy Integral based Ensemble Network with PSO-Optimized Fuzzy Measures for Diagnosing Multiple Skin Diseases Including Mpox.

In the domain of medical diagnostics, precise identification of various skin and oral diseases is vital for effective patient care. In particular, Mpox is a potentially dangerous viral disease with zoonotic origins, capable of human-to-human transmission, underscoring the urgency of precise diagnostic methods for timely intervention. This paper introduces a novel approach named the Choquet Fuzzy Integral-based Ensemble (CFI-Net) for accurate classification of skin diseases, with a specific emphasis on detecting Mpox, foot ulcers, and various mouth and oral diseases. Our methodology begins with Transfer Learning, enhancing the classification capabilities of base classifiers (DenseNet169, MobileNetV1 and DenseNet201) by incorporating additional layers. Subsequently, we aggregate the prediction scores from each base classifier using the Choquet fuzzy integral (CFI) to derive the final predicted labels, thus ensuring dynamic and robust predictions. Fuzzy measures, a crucial component of this fuzzy integral-based ensemble method, are typically determined through manual experimentation in previous approaches. However, in our study, we have tackled the challenge of manual tuning by employing meta-heuristic optimization algorithm to precisely configure the fuzzy measures for optimal performance. A rigorous evaluation is conducted on four publicly available datasets, encompassing two Mpox datasets, a foot ulcer dataset, and a mouth and oral disease dataset. The experiments reveal the remarkable effectiveness of CFI-Net in significantly improving disease classification accuracy. Additionally, we employ Grad-CAM analysis to provide insights into the decision-making processes of our models. Our findings underscore the exceptional performance of CFI-Net, achieving accuracy rates of 98.06% and 94.81% for Mpox detection, 99.06% for foot ulcer detection, and an impressive 99.61% for mouth and oral disease classification. This research not only contributes to the advancement of disease diagnosis but also demonstrates the effectiveness of ensemble learning techniques coupled with fuzzy integral-based fusion in enhancing diagnostic accuracy.

Crosstalk among Oxidative Stress, Autophagy, and Apoptosis in the Protective Effects of Ginsenoside Rb1 on Brain Microvascular Endothelial Cells: A Mixed Computational and Experimental Study.

OBJECTIVE: Brain microvascular endothelial cells (BMECs) were found to shift from their usually inactive state to an active state in ischemic stroke (IS) and cause neuronal damage. Ginsenoside Rb1 (GRb1), a component derived from medicinal plants, is known for its pharmacological benefits in IS, but its protective effects on BMECs have yet to be explored. This study aimed to investigate the potential protective effects of GRb1 on BMECs. METHODS: An in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model was established to mimic ischemia-reperfusion (I/R) injury. Bulk RNA-sequencing data were analyzed by using the Human Autophagy Database and various bioinformatic tools, including gene set enrichment analysis (GSEA), Gene Ontology (GO) classification and enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction network analysis, and molecular docking. Experimental validation was also performed to ensure the reliability of our findings. RESULTS: Rb1 had a protective effect on BMECs subjected to OGD/R injury. Specifically, GRb1 was found to modulate the interplay between oxidative stress, apoptosis, and autophagy in BMECs. Key targets such as sequestosome 1 (SQSTM1/p62), autophagy related 5 (ATG5), and hypoxia-inducible factor 1-alpha (HIF-1α) were identified, highlighting their potential roles in mediating the protective effects of GRb1 against IS-induced damage. CONCLUSION: GRbl protects BMECs against OGD/R injury by influencing oxidative stress, apoptosis, and autophagy. The identification of SQSTM1/p62, ATG5, and HIF-1α as promising targets further supports the potential of GRb1 as a therapeutic agent for IS, providing a foundation for future research into its mechanisms and applications in IS treatment.

Fibroblast: A Novel Target for Autoimmune and Inflammatory Skin Diseases Therapeutics.

Fibroblasts are crucial components of the skin structure. They were traditionally believed to maintain the skin's structure by producing extracellular matrix and other elements. Recent research illuminated that fibroblasts can respond to external stimuli and exhibit diverse functions, such as the secretion of pro-inflammatory factors, adipogenesis, and antigen presentation, exhibiting remarkable heterogeneity and plasticity. This revelation positions fibroblasts as active contributors to the pathogenesis of skin diseases, challenging the traditional perspective that views fibroblasts solely as structural entities. Based on their diverse functions, fibroblasts can be categorized into six subtypes: pro-inflammatory fibroblasts, myofibroblasts, adipogenic fibroblasts, angiogenic fibroblasts, mesenchymal fibroblasts, and antigen-presenting fibroblasts. Cytokines, metabolism, and epigenetics regulate functional abnormalities in fibroblasts. The dynamic changes fibroblasts exhibit in different diseases and disease states warrant a comprehensive discussion. We focus on dermal fibroblasts' aberrant manifestations and pivotal roles in inflammatory and autoimmune skin diseases, including psoriasis, vitiligo, lupus erythematosus, scleroderma, and atopic dermatitis, and propose targeting aberrantly activated fibroblasts as a potential therapeutic strategy for inflammatory and autoimmune skin diseases.