PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens.

The peripheral T cell repertoire of healthy individuals contains self-reactive T cells1,2. Checkpoint receptors such as PD-1 are thought to enable the induction of peripheral tolerance by deletion or anergy of self-reactive CD8 T cells3-10. However, this model is challenged by the high frequency of immune-related adverse events in patients with cancer who have been treated with checkpoint inhibitors11. Here we developed a mouse model in which skin-specific expression of T cell antigens in the epidermis caused local infiltration of antigen-specific CD8 T cells with an effector gene-expression profile. In this setting, PD-1 enabled the maintenance of skin tolerance by preventing tissue-infiltrating antigen-specific effector CD8 T cells from (1) acquiring a fully functional, pathogenic differentiation state, (2) secreting significant amounts of effector molecules, and (3) gaining access to epidermal antigen-expressing cells. In the absence of PD-1, epidermal antigen-expressing cells were eliminated by antigen-specific CD8 T cells, resulting in local pathology. Transcriptomic analysis of skin biopsies from two patients with cutaneous lichenoid immune-related adverse events showed the presence of clonally expanded effector CD8 T cells in both lesional and non-lesional skin. Thus, our data support a model of peripheral T cell tolerance in which PD-1 allows antigen-specific effector CD8 T cells to co-exist with antigen-expressing cells in tissues without immunopathology.

Spin-orbit exciton-induced phonon chirality in a quantum magnet.

The interplay of charge, spin, lattice, and orbital degrees of freedom in correlated materials often leads to rich and exotic properties. Recent studies have brought new perspectives to bosonic collective excitations in correlated materials. For example, inelastic neutron scattering experiments revealed non-trivial band topology for magnons and spin-orbit excitons (SOEs) in a quantum magnet CoTiO3 (CTO). Here, we report phonon properties resulting from a combination of strong spin-orbit coupling, large crystal field splitting, and trigonal distortion in CTO. Specifically, the interaction between SOEs and phonons endows chirality to two [Formula: see text] phonon modes and leads to large phonon magnetic moments observed in magneto-Raman spectra. The remarkably strong magneto-phononic effect originates from the hybridization of SOEs and phonons due to their close energy proximity. While chiral phonons have been associated with electronic topology in some materials, our work suggests opportunities may arise by exploring chiral phonons coupled to topological bosons.

Exotic Magnetism in Perovskite KOsO_{3}.

A new perovskite KOsO_{3} has been stabilized under high-pressure and high-temperature conditions. It is cubic at 500 K (Pm-3m) and undergoes subsequent phase transitions to tetragonal at 320 K (P4/mmm) and rhombohedral (R-3m) at 230 K as shown from refining synchrotron x-ray powder diffraction (SXRD) data. The larger orbital overlap integral and the extended wave function of 5d electrons in the perovskite KOsO_{3} allow to explore physics from the regime where Mott and Hund's rule couplings dominate to the state where the multiple interactions are on equal footing. We demonstrate an exotic magnetic ordering phase found by neutron powder diffraction along with physical properties via a suite of measurements including magnetic and transport properties, differential scanning calorimetry, and specific heat, which provide comprehensive information for a system at the crossover from localized to itinerant electronic behavior.

Base-Catalyzed One-Pot Synthesis of 2,3,6-Substituted Pyridines.

A three-component reaction catalyzed by base was established, which mainly consisted of ynals, isocyanates, amines and alcohols. This strategy provides a wide range of substrates and represents a simple process for the preparation of different pyridine derivatives in good yields with high regioselectivities.

Observation of Vector Spin Seebeck Effect in a Noncollinear Antiferromagnet.

Spintronic phenomena to date have been established in magnets with collinear moments, where the spin injection through the spin Seebeck effect (SSE) is always along the out-of-plane direction. Here, we report the observation of a vector SSE in a noncollinear antiferromagnet (AF) LuFeO_{3}, where temperature gradient along the out-of-plane and also the in-plane directions can both inject a pure spin current and generate a voltage in the heavy metal via the inverse spin Hall effect (ISHE). We show that the thermovoltages are due to the magnetization from canted spins in LuFeO_{3}. Furthermore, in contrast to the challenges of generating, manipulating, and detecting spin current in collinear AFs, the vector SSE in LuFeO_{3} is readily viable in zero magnetic field and can be controlled by a small magnetic field of about 150 Oe at room temperature. The noncollinear AFs expand new realms for exploring spin phenomena and provide a new route to low-field antiferromagnetic spin caloritronics and magnonics.

The Elevated Risk of Recurrent Clostridioides Difficile Infection in Patients with Inflammatory Bowel Disease: a Systematic Review and Meta-analysis.

BACKGROUND: The association between inflammatory bowel disease (IBD) and the risk of recurrent Clostridioides difficile infection (rCDI) is still controversial. This systematic review and meta-analysis aims to clarify whether the risk of rCDI is associated with IBD based on published data. METHODS: A systematic review and meta-analysis was conducted in English and Chinese databases, covering all available publications until date 01/01/2020. The statistical analysis was performed by RevMan 5.3 and odds ratios (ORs) combined with 95% confidence intervals (CI) were calculated to explore the IBD-rCDI association. RESULTS: A total of 4,417 IBD cases and 355,769 control cases in 14 independent studies from 2007 to 2019 were included. Compared with non-IBD, IBD was associated with an increased risk of rCDI (OR = 1.63, CI = 1.09 - 2.43, p = 0.02). In addition, the risk of rCDI was particularly and significantly increased in IBD patients at the young age (≤ 50, OR = 1.58, CI = 1.02 - 2.44, p = 0.04), but not in patients at the old age (> 50, OR = 2.08, CI = 0.65 - 6.61, p = 0.21). Compared with Crohn's disease (CD), no significant differences existed in the risk of rCDI in ulcerative colitis (UC) (OR = 1.22, CI = 0.81 - 1.85, p = 0.34). Additionally, the risk of rCDI was not significantly different between UC and CD, in patients receiving FMT (OR = 1.41, CI = 0.65 - 3.06, p = 0.38) or no FMT treatment (OR = 1.16, CI = 0.71 - 1.88, p = 0.56). CONCLUSIONS: The risk of rCDI was significantly increased in IBD patients, in particular in those age below 50. Compared with CD, no significant differences of the risk of rCDI was observed in UC.

Controllable Site-Selective Construction of 4- and 5-Hydroxyalkyl-Substituted Imidazoles from Amidines, Ynals, and Water.

The first example of controllable site-selective pathways to construct 4- and 5-hydroxyalkyl-substituted imidazoles through a three-component reaction of amidines, ynals, and water has been documented. Particularly, the high regioselectivity of the reaction was simply switched by changing the additives. In addition, further 18O-labeled experiments to probe a plausible mechanism and the gram-scale synthesis were studied.

Synthesis and Characterization of a Binuclear Copper(II)-dipyriamethyrin Complex: [Cu2(dipyriamethyrin)(µ2-1,1-acetato)2].

The reaction between dipyriamethyrin and copper(II) acetate [Cu(OAc)2] afforded what is, to our knowledge, the first transition metal-dipyriamethyrin complex. Molecular and electronic characterization of this binuclear Cu(II) complex via EPR, UV-vis, and single crystal X-ray diffraction analysis revealed marked differences between the present constructs and previously reported binuclear copper(II) hexaphyrin species. UV-vis titration analyses provided evidence for a homotropic positive allosteric effect, wherein the binuclear species is formed without significant intermediacy of a monomeric complex.

Transition-Metal-Free Three-Component Reaction: Additive Controlled Synthesis of Sulfonylated Imidazoles.

Two efficient transition-metal-free highly regioselective pathways for constructing sulfonylated imidazoles via three-component reactions of amidines, ynals, and sodium sulfonates have been developed. The generations of different sulfonylated imidazoles were simply controlled by additives. In addition, this method features environmental friendliness, good functional group tolerance, and high atom economy, which makes it practical.

Dimensional reduction and ionic gating induced enhancement of superconductivity in atomically thin crystals of 2H-TaSe2.

The effects of dimensional reduction and ion intercalation on superconductivity (SC) in the presence of charge density waves (CDWs) in two-dimensional crystals of 2H-TaSe2 were characterized. We prepared atomically thin crystals by mechanical exfoliation and performed electrical transport measurements on devices made by photolithography. The superconducting transition temperature (T c SC ) was found to increase monotonically as the thickness decreased, changing from 0.14 K in the bulk to higher than 1.4 K for a 3-nm-thick crystal. The temperature dependence of upper critical field was found to be anomalous. The CDW transition temperature (T c CDW ) was found to decrease, but to a less extent than T c SC , from 120 K in the bulk to around 113 K for the 3-nm-thick crystal. In addition, ion intercalation was found to increase T c SC and suppress T c CDW in an atomically thin crystal of 2H-TaSe2. The implications of these findings are discussed. We suggest that dimensional reduction and ion intercalation are potentially effective ways to engineer material properties for layered transition metal chalcogenides.

Integrating machine learning algorithms and single-cell analysis to identify gut microbiota-related macrophage biomarkers in atherosclerotic plaques.

Objective: The relationship between macrophages and the gut microbiota in patients with atherosclerosis remains poorly defined, and effective biological markers are lacking. This study aims to elucidate the interplay between gut microbial communities and macrophages, and to identify biomarkers associated with the destabilization of atherosclerotic plaques. The goal is to enhance our understanding of the underlying molecular pathways and to pave new avenues for diagnostic approaches and therapeutic strategies in the disease. Methods: This study employed Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis on atherosclerosis datasets to identify macrophage-associated genes and quantify the correlation between these genes and gut microbiota gene sets. The Random Forest algorithm was utilized to pinpoint PLEK, IRF8, BTK, CCR1, and CD68 as gut microbiota-related macrophage genes, and a nomogram was constructed. Based on the top five genes, a Non-negative Matrix Factorization (NMF) algorithm was applied to construct gut microbiota-related macrophage clusters and analyze their potential biological alterations. Subsequent single-cell analyses were conducted to observe the expression patterns of the top five genes and the interactions between immune cells. Finally, the expression profiles of key molecules were validated using clinical samples from atherosclerosis patients. Results: Utilizing the Random Forest algorithm, we ultimately identified PLEK, IRF8, CD68, CCR1, and BTK as gut microbiota-associated macrophage genes that are upregulated in atherosclerotic plaques. A nomogram based on the expression of these five genes was constructed for use as an auxiliary tool in clinical diagnosis. Single-cell analysis confirmed the specific expression of gut microbiota-associated macrophage genes in macrophages. Clinical samples substantiated the high expression of PLEK in unstable atherosclerotic plaques. Conclusion: Gut microbiota-associated macrophage genes (PLEK, IRF8, CD68, CCR1, and BTK) may be implicated in the pathogenesis of atherosclerotic plaques and could serve as diagnostic markers to aid patients with atherosclerosis.

Gallic Acid-Modified Polyethylenimine-Polypropylene Carbonate-Polyethylenimine Nanoparticles: Synthesis, Characterization, and Anti-Periodontitis Evaluation.

The aim of the research was to develop novel gallic acid (GA)-modified amphiphilic nanoparticles of polyethylenimine (PEI)-polypropylene carbonate (PPC)-PEI (PEPE) and comprehensively assess its properties as an antiperiodontitis nanoparticle targeting the Toll-like receptor (TLR). The first step is to evaluate the binding potential of GA to the core trigger receptors TLR2 and TLR4/MD2 for periodontitis using molecular docking techniques. Following this, we conducted NMR, transmission electron microscopy, and dynamic light scattering analyses on the synthesized PEPE nanoparticles. As the final step, we investigated the synthetic results and in vitro antiperiodontitis properties of GA-PEPE nanoparticles. The investigation revealed that GA exhibits potential for targeted binding to TLR2 and the TLR4/MD2 complex. Furthermore, we successfully developed 91.19 nm positively charged PEPE nanoparticles. Spectroscopic analysis indicated the successful synthesis of GA-modified PEPE. Additionally, CCK8 results demonstrated that GA modification significantly reduced the biotoxicity of PEPE. The in vitro antiperiodontitis properties assessment illustrated that 6.25 µM of GA-PEPE nanoparticles significantly reduced the expression of pro-inflammatory factors TNF-α, IL-1ß, and IL-6. The GA-PEPE nanoparticles, with their targeted TLR binding capabilities, were found to possess excellent biocompatibility and antiperiodontitis properties. GA-PEPE nanoparticles will provide highly innovative input into the development of anti- periodontitis nanoparticles.

Brusatol induces ferroptosis to inhibit hepatocellular carcinoma progression by targeting ATF3.

Ferroptosis is a novel form of programmed cell death that is triggered by iron-dependent lipid peroxidation. Brusatol (BRU), a natural nuclear factor erythroid 2-related factor 2 inhibitor, exhibits potent anticancer effects in various types of cancer. However, the exact mechanism of BRU in the treatment of hepatocellular carcinoma (HCC) remains unknown. The anticancer effects of BRU in HCC were detected using cell counting kit-8 and colony formation assays and a xenograft model. RNA sequencing (RNA-seq) and bioinformatics analyses of HCC cells were utilized to elucidate the mechanism underlying the effects of BRU in HCC. The levels of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and Fe2+ were measured using assay kits. The expression of activating transcription factor 3 (ATF3) was tested using RT-qPCR, western blotting, and immunofluorescence staining. The role of ATF3 in BRU-induced ferroptosis was examined using siATF3. BRU significantly inhibited HCC cell proliferation, both in vitro and in vivo. BRU activated the ferroptosis signaling pathway and increased ATF3 expression. Furthermore, ATF3 knockdown impeded BRU-induced ferroptosis. BRU suppressed HCC growth through ATF3-mediated ferroptosis, supporting BRU as a promising therapeutic agent for HCC.

Fusing WGCNA and Machine Learning for Immune-Related Gene Prognostic Index in Lung Adenocarcinoma: Precision Prognosis, Tumor Microenvironment Profiling, and Biomarker Discovery.

Background: The objective is to create an IRGPI (Immune-related genes prognostic index), which could predict the survival and effectiveness of immune checkpoint inhibitor (ICI) treatment for lung adenocarcinoma (LUAD). Methods: By applying weighted gene co-expression network analysis (WGCNA), we ascertained 13 genes associated with immune functions. An IRGPI was constructed using four genes through multicox regression, and its validity was assessed in the GEO dataset. Next, we explored the immunological and molecular attributes and advantages of ICI treatment in subcategories delineated by IRGPI. The model genes were also validated by the random forest tree, and functional experiments were conducted to validate it. Results: The IRGPI relied on the genes CD79A, IL11, CTLA-4, and CD27. Individuals categorized as low-risk exhibited significantly improved overall survival in comparison to those classified as high-risk. Extensive findings indicated that the low-risk category exhibited associations with immune pathways, significant infiltration of CD8 T cells, M1 macrophages, and CD4 T cells, a reduced rate of gene mutations, and improved sensitivity to ICI therapy. Conversely, the higher-risk group displayed metabolic signals, elevated frequencies of TP53, KRAS, and KEAP1 mutations, escalated levels of NK cells, M0, and M2 macrophage infiltration, and a diminished response to ICI therapy. Additionally, our study unveiled that the downregulation of IL11 effectively impedes the proliferation and migration of lung carcinoma cells, while also inducing cell cycle arrest. Conclusion: IRGPI is a biomarker with significant potential for predicting the effectiveness of ICI treatment in LUAD patients and is closely related to the microenvironment and clinicopathological characteristics.

Bloodletting cupping combined with conventional measures therapy for psoriasis: A systematic review and meta-analysis of randomized controlled trials.

Background: Psoriasis is an immune-mediated inflammatory disease prone to recurrence. Some studies indicated that bloodletting cupping combined with conventional measures therapy had been proposed as a treatment strategy for psoriasis. Therefore, we performed a systematic review and meta-analysis to assess the effectiveness of this combination therapy in reducing the severity of disease in patients with psoriasis. Methods: The following electronic databases were searched for articles from January 1, 2000 to March 1, 2022: PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Chinese Biomedical Literature Database (CBM), Chinese Scientific Journal Database (VIP database), Wan-Fang Database, and China National Knowledge Infrastructure (CNKI). The language was not restricted while performing the search. The quality of articles was evaluated using Rev. Man 5.4 software (provided by the Cochrane Collaboration), comparing bloodletting cupping combined with conventional measures therapy to conventional measures treatments. The studies obtained randomized controlled trials (RCTs) of bloodletting cupping combined with conventional standard treatment for treating psoriasis. Two trained researchers (Xiaoyu Ma and Jiaming He) independently reviewed the literature, extracted data based on exclusion and inclusion criteria, and assessed the quality of the included studies. We estimated the aggregate data using a random effects model. Findings: We identified 164 studies. Ten studies met the inclusion criteria for the meta-analysis. The primary outcome indicator was the total number of effective individuals. Secondary outcomes included the Psoriasis Area and Severity Index (PASI), adverse effects, and the Dermatology Life Quality Index (DLQI). Compared with conventional treatments, bloodletting cupping combined with conventional medicine yielded an improved total effective number of persons (RR = 1.15, 95%CI: 1.07 to 1.22, p < 0.00001), PASI (MD = -1.11, 95%CI: -1.40 to -0.82, p < 0.00001) and DLQI scores (MD = -0.99, 95%CI: -1.40 to -0.59, p < 0.0001). We found no significant difference in adverse reactions (RR = 0.93, 95%CI: 0.46 to 1.90, p = 0.85). The heterogeneity test showed the total effective numbers (p < 0.00001, I 2 = 43%) and PASI (p < 0.00001, I 2 = 44%) and DLQI scores (p < 0.00001, I 2 = 0%). Interpretation: Bloodletting cupping combined with conventional treatment can achieve the ideal treatment for psoriasis. However, the combined treatment in psoriasis needs to be further evaluated in high-quality RCTs with large sample sizes to enable future studies in clinical use.

The carbon reduction effects of stepped carbon emissions trading and carbon capture and storage on hybrid wind-PV-thermal- storage generation operating systems.

To accelerate the low-carbon transformation of the power industry, a range of carbon emission reduction policies and technologies have emerged. However, the current China's carbon emissions trading (CET) policy is inadequate in encouraging power generation enterprises to take proactive measures towards emission reduction due to challenges like fixed and low carbon prices. The high proportion of renewable energy in electricity consumption also faces significant challenges due to the unpredictable nature of wind and PV energy. Therefore, this paper applies stepped CET mechanism, energy storage system (ES) system and carbon capture and storage (CCS) mechanism together to hybrid renewable energy system, aiming to study their synergistic carbon emission reduction effect. Firstly, the paper constructs the stepped CET model considering incentives and penalties. Secondly, the stepped CET model, ES system and CCS are jointly introduced into the hybrid renewable energy system. Finally, a scenario analysis is conducted to investigate the synergistic effect of various carbon emissions reduction policies and technologies in the operation of power generation systems. The results show that: i) compared with traditional CET, the stepped CET increases renewable energy consumption by 0.12% and reduces carbon emissions by 0.6%; ii) the introduction of stepped CET and ES equipment together consumes an additional 36.1% of renewable energy and reduces carbon emissions by 32.4%; iii) based on stepped CET model and ES equipment, the introduction of CCS system reduces carbon emissions by 29.4%.

The role and application of three IFN-related reactions in psoriasis.

The pathophysiology of psoriasis is a highly complicated one. Due to the disease's specificity, it not only affects the patient's skin negatively but also manifests systemic pathological changes. These clinical symptoms seriously harm the patient's physical and mental health. IFN, a common immunomodulatory factor, has been increasingly demonstrated to have a significant role in the development of psoriatic skin disease. Psoriasis is connected with a variety of immunological responses. New targets for the therapy of autoimmune skin diseases may emerge from further research on the mechanics of the associated IFN upstream and downstream pathways. Different forms of IFNs do not behave in the same manner in psoriasis, and understanding how different types of IFNs are involved in psoriasis may provide a better notion for future research. This review focuses on the involvement of three types of IFNs in psoriasis and related therapeutic investigations, briefly describing the three IFNs' production and signaling, as well as the dual effects of IFNs on the skin. It is intended that it would serve as a model for future research.

Comprehensive Analysis of Necroptosis Landscape in Skin Cutaneous Melanoma for Appealing its Implications in Prognosis Estimation and Microenvironment Status.

PURPOSE: Due to poor prognosis and immunotherapy failure of skin cutaneous melanoma (SKCM), this study sought to find necroptosis-related biomarkers to predict prognosis and improve the situation with predicted immunotherapy drugs. EXPERIMENTAL DESIGN: The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression Program (GTEx) database were utilized to recognize the differential necroptosis-related genes (NRGs). Univariate Cox (uni-Cox) and least absolute shrinkage and selection operator (LASSO) Cox analysis were utilized for prognostic signature establishment. The signature was verified in the internal cohort. To assess the signature's prediction performance, the area under the curve (AUC) of receiver operating characteristic (ROC) curves, Kaplan-Meier (K-M) analyses, multivariate Cox (multi-Cox) regression, nomogram, and calibration curves were performed. The molecular and immunological aspects were also reviewed using single-sample gene set enrichment analysis (ssGSEA). Cluster analysis was performed to identify the different types of SKCM. Finally, the expression of the signature gene was verified by immunohistochemical staining. RESULTS: On basis of the 67 NRGs, 4 necroptosis-related genes (FASLG, PLK1, EGFR, and TNFRSF21) were constructed to predict SKCM prognosis. The area's 1-, 3-, and 5-year OS under the AUC curve was 0.673, 0.649, and 0.677, respectively. High-risk individuals had significantly lower overall survival (OS) compared to low-risk patients. Immunological status and tumor cell infiltration in high-risk groups were significantly lower, indicating an immune system that was suppressed. In addition, hot and cold tumors could be obtained by cluster analysis, which is helpful for accurate treatment. Cluster 1 was considered a hot tumor and more susceptible to immunotherapy. Immunohistochemical results were consistent with positive and negative regulation of coefficients in signature. CONCLUSION: The results of this finding supported that NRGs could predict prognosis and help make a distinction between the cold and hot tumors for improving personalized therapy for SKCM.

Clinical, polysomnographic, and heart rate variability in highland obstructive sleep apnea patients responding to one-night nocturnal oxygen supplementation: A post-hoc analysis from a randomized, crossover trial.

OBJECTIVE: /Background: This study aimed to explore the clinical, polysomnographic, and heart rate variability (HRV) characteristics of highland obstructive sleep apnea (OSA) patients receiving one-night nocturnal oxygen supplementation (NOS) and to identify factors predicting response. PATIENTS/METHODS: Thirty-four highland OSA patients living in Shangri-La were randomly assigned to receive NOS and sham oxygen in a randomized, placebo-controlled, crossover trial. Clinical assessments, polysomnography, and HRV were measured. A responder was defined as a ≥50% reduction in apnea-hypopnea index (AHI) with NOS compared with sham oxygen. RESULTS: Eighteen participants responded and 16 did not respond, with a median (interquartile range [IQR]) age of 46.5 (36.5-53.0) and 48.0 (44.3-53.3) years, respectively. The median treatment effect (95% CI) on total AHI was -23.2/h (-30.0 to -17.5) and -12.0/h (-16.6 to -7.6) in responders and non-responders (p = 0.004), with similar effects on oxygen desaturation index. The mean OAH duration was prolonged by 7 s in responders together with improved sleep quality and daytime blood pressure. The mean OAH duration at baseline predicted responses to NOS with a sensitivity and specificity of 88.9% and 68.7% (AUC 0.809) at a cut-off point of 24.9 s. Changes in HRV parameters were negatively correlated with changes in mean oxygen saturation and daytime systolic blood pressure only in responders. CONCLUSIONS: NOS significantly improved OSA severity and clinical outcomes in responders, which was related to improvements in parasympathetic activity. Highlanders with shorter mean OAH may be suitable candidates for NOS. These findings provide new information about tailored treatment strategies for highland OSA patients.