Observational study of microphysical and chemical characteristics of size-resolved fog in different regional backgrounds in China.

To investigate the relationship between microphysical and chemical characteristics of size-resolved fog droplets in different regional backgrounds, we conducted observational experiments in urban, mountainous, rainforest, and rural areas of China. Fog water samples across different diameter ranges (4-16 µm, 16-22 µm, and >22 µm) were collected, alongside fog droplet spectra data. Our findings reveal a close relationship between pH value, electrical conductivity (EC), total ion concentration (TIC) of droplets, and droplet sizes, with smaller droplets exhibiting stronger acidity and higher ion concentrations. Significant differences in chemical composition are observed across size ranges and regional backgrounds. Droplet number concentration (N) and liquid water content (LWC) distributions in different regional backgrounds are skewed, with peak diameters of LWC spectra similar to those of N spectra, yet overall spectral distributions varied significantly. Droplet number concentrations are highest in urban area, while large droplets contribute more to overall LWC in mountainous, rainforest, and rural areas. No direct evidence linked LWC or surface area (S) to LWC ratio to water-soluble ion concentrations of size-resolved fog droplets in different regional backgrounds. However, by adjusting the contributions of S and LWC proportions of different-sized droplets to the ion concentration proportions, we find that expanding the LWC proportion to 2.43 times and decreasing the S proportion to 0.2 times for large droplets, while decreasing the LWC ratio to 0.76 times for small droplets, provided a better explanation for the distribution of ion concentrations. This study advances our understanding of the intricate relationship between the microphysical and chemical characteristics of fog, helping to develop more robust and comprehensive models for fog prediction and management.

Akkermansia muciniphila: A promising probiotic against inflammation and metabolic disorders.

Metabolic disease is a worldwide epidemic that has become a public health problem. Gut microbiota is considered to be one of the important factors that maintain human health by regulating host metabolism. As an abundant bacterium in the host gut, A. muciniphila regulates metabolic and immune functions, and protects gut health. Multiple studies have indicated that alterations in the abundance of A. muciniphila are associated with various diseases, including intestinal inflammatory diseases, obesity, type 2 diabetes mellitus, and even parasitic diseases. Beneficial effects were observed not only in live A. muciniphila, but also in pasteurized A. muciniphila, A. muciniphila-derived extracellular vesicles, outer membrane, and secreted proteins. Although numerous studies have only proven the simple correlation between multiple diseases and A. muciniphila, an increasing number of studies in animal models and preclinical models have demonstrated that the beneficial impacts shifted from correlations to in-depth mechanisms. In this review, we provide a comprehensive view of the beneficial effects of A. muciniphila on different diseases and summarize the potential mechanisms of action of A. muciniphila in the treatment of diseases. We provide a comprehensive understanding of A. muciniphila for improving host health and discuss the perspectives of A. muciniphila in the future studies.

Metabolic labeling based methylome profiling enables functional dissection of histidine methylation in C3H1 zinc fingers.

Protein methylation is a functionally important post-translational modification that occurs on diverse amino acid residues. The current proteomics approaches are inefficient to discover the methylation on residues other than Arg and Lys, which hinders the deep understanding of the functional role of rare protein methylation. Herein, we present a methyl-specific metabolic labeling approach for global methylome mapping, which enable the acquisition of methylome dataset covering diverse methylation types. Interestingly, of the identified methylation events, His methylation is found to be preferably occurred in C3H1 zinc fingers (ZFs). These His methylation events are determined to be Nπ specific and catalyzed by CARNMT1. The His methylation is found to stabilize the structure of ZFs. U2AF1 is used as a proof-of-concept to highlight the functional importance of His methylation in ZFs in RNA binding and RNA metabolism. The results of this study enable novel understanding of how protein methylation regulates cellular processes.

Associations of sugar intake, high-sugar dietary pattern, and the risk of dementia: a prospective cohort study of 210,832 participants.

BACKGROUND: Limited evidence demonstrated the potential relationship between dietary sugar intake and dementia. This association demands further clarification in a large-scale population. METHODS: A total of 210,832 participants from the UK Biobank cohort were included in this prospective cohort study. Absolute and relative sugar intake and high-sugar dietary scores were utilized to reflect dietary sugar intake. Absolute sugar intake was identified by the Oxford WebQ in the UK Biobank. Relative sugar intake was calculated by dividing the absolute sugar intake by total diet energy. High-sugar dietary pattern was identified using the method of reduced rank regression. Cox proportional hazards regression analyses and restricted cubic splines were performed to examine the longitudinal associations between dietary sugar intake and all-cause dementia and its main subtype, Alzheimer's disease. Explorative mediation analyses were conducted to explore underlying mechanisms. RESULTS: Increased absolute sugar intake (g/day) was significantly associated with a higher risk of all-cause dementia (HR = 1.003, [95%CI: 1.002-1.004], p < 0.001) and Alzheimer's disease (1.002, [1.001-1.004], 0.005). Relative sugar intake (%g/kJ/day) also demonstrated significant associations with all-cause dementia (1.317, [1.173-1.480], p < 0.001) and Alzheimer's disease (1.249, [1.041-1.500], 0.017), while the high-sugar dietary score was only significantly associated with a higher risk of all-cause dementia (1.090, [1.045-1.136], p < 0.001). In addition, both sugar intake and high-sugar dietary score demonstrated significant non-linear relationships with all-cause dementia and Alzheimer's disease (all p values for non-linearity < 0.05). CONCLUSIONS: Our study provided evidence that excessive sugar intake was associated with dementia. Controlling the excess consumption of dietary sugar may be of great public health implications for preventing dementia.

Association of Autoimmune Diseases with the Risk of Parkinson's Disease.

INTRODUCTION: PD is a progressive neurodegeneration disease characterized by cardinal motor symptoms such as bradykinesia and tremor. The pathogenesis of PD remains unclear. It is hypothesized that immune system dysfunction may contribute to PD. Thus, autoimmune diseases may influence the risk of incident PD. METHODS: We included 398,329 participants without PD at the baseline from UK Biobank. The association between 20 autoimmune diseases with PD was examined using cox hazards regression analyses, adjusting covariates like age, sex, and smoking status in the statistical models. Sensitivity analyses were conducted, adjusting for polygenic risk score and the reported source of PD, to check the robustness. RESULTS: After an average follow-up of 13.1 ± 0.816 years, 2,245 participants were diagnosed with incident PD. After multiple comparison correction, only multiple sclerosis (MS) reached statistical significance and showed an increased risk for incident PD. Compared with non-MS patients, the risk of incident PD in MS patients was 2.57-fold with age and sex being adjusted (95% CI, 1.59-4.14; adjust p value = 0.002). After adjusting lifestyle and other factors, the hazard ratio of incident PD in MS patients was 2.49 (95% CI, 1.55-4.02; adjust p value = 0.004). Excluding the self-reported PD cases in the sensitivity analysis, MS was a detrimental factor for incident PD (HR, 2.06; 95% CI, 1.56-4.05; adjust p value = 0.004). The link between MS and PD did not reach the statistical significance in the sensitivity analysis adjusting the PRS (adjust p value = 0.95). CONCLUSION: Our study provided evidence from observational analyses that MS was associated with an increased risk of PD. Further investigations should be performed to determine the causal association and potential pathophysiology between MS and PD.

Unexpected response of terrestrial carbon sink to rural depopulation in China.

China is experiencing large-scale rural-urban migration and rapid urbanization, which have had significant impact on terrestrial carbon sink. However, the impact of rural-urban migration and its accompanying urban expansion on the carbon sink is unclear. Based on multisource remote sensing product data for 2000-2020, the soil microbial respiration equation, relative contribution rate, and threshold analysis, we explored the impact of rural depopulation on the carbon sink and its threshold. The results revealed that the proportion of the rural population in China decreased from 63.91 % in 2000 to 36.11 % in 2020. Human pressure decreased by 1.82% in rural depopulation areas, which promoted vegetation restoration in rural areas (+8.45 %) and increased the carbon sink capacity. The net primary productivity (NPP) and net ecosystem productivity (NEP) of the vegetation in the rural areas increased at rates of 2.95 g C m-2 yr-1 and 2.44 g C m-2 yr-1. Strong rural depopulation enhanced the carbon sequestration potential, and the NEP was 1.5 times higher in areas with sharp rural depopulation than in areas with mild rural depopulation. In addition, the rural depopulation was accompanied by urban expansion, and there was a positive correlation between the comprehensive urbanization level (CUL) and NEP in 75.29 % of urban areas. In the urban areas, the vegetation index increased by 88.42 %, and the urban green space partially compensated for the loss of carbon sink caused by urban expansion, with a growth rate of 4.96 g C m-2 yr-1. Changes in rural population have a nonlinear impact on the NEP. When the rural population exceeds 545.686 people/km2, an increase in the rural population will have a positive impact on the NEP. Our research shows that rural depopulation offers a potential opportunity to restore natural ecosystems and thus increase the carbon sequestration capacity.

Streptococcus suis Serotype 2 Type IV Secretion Effector SspA-1 Induces Proinflammatory Cytokine Production via TLR2 Endosomal and Type I Interferon Signaling.

The subtilisin-like protease-1 (SspA-1) plays an important role in the pathogenesis of a highly virulent strain of Streptococcus suis 2. However, the mechanism of SspA-1-triggered excessive inflammatory response is still unknown. In this study, we demonstrated that activation of type I IFN signaling is required for SspA-1-induced excessive proinflammatory cytokine production. Further experiments showed that the TLR2 endosomal pathway mediates SspA-1-induced type I IFN signaling and the inflammatory response. Finally, we mapped the major signaling components of the related pathway and found that the TIR adaptor proteins Mal, TRAM, and MyD88 and the downstream activation of IRF1 and IRF7 were involved in this pathway. These results explain the molecular mechanism by which SspA-1 triggers an excessive inflammatory response and reveal a novel effect of type I IFN in S. suis 2 infection, possibly providing further insights into the pathogenesis of this highly virulent S. suis 2 strain.

The impact of maternal smoking during pregnancy and the age of smoking initiation on incident dementia: A prospective cohort study.

INTRODUCTION: The impact of early-life tobacco exposure on dementia has remained unknown. METHODS: Using the UK Biobank, the associations of maternal smoking during pregnancy (MSDP) and age of smoking initiation (ASI) with the onset time of all-cause dementia were estimated with accelerated failure time models. The effects of MSDP and ASI on brain structure and their genetic correlation to Alzheimer's disease (AD) were analyzed. A Mendelian randomization (MR) analysis was conducted. RESULTS: The time ratios for smokers starting in childhood, adolescence, and adulthood (vs never smokers) were 0.87 (0.76 to 0.99), 0.92 (0.88 to 0.96), and 0.95 (0.89 to 1.01). MSDP and smoking in adolescence altered many brain regions, including the hippocampus. In genetic analysis, MSDP was genetically and causally linked to AD, and a younger ASI was genetically correlated to a higher AD risk. DISCUSSION: Early-life smoking accelerated dementia onset and was genetically correlated to AD. MSDP demonstrated genetic and causal linkage to AD risks. HIGHLIGHTS: Unlike the commonly used Cox proportional hazards model, this article uses a parametric survival analysis method - the accelerated failure model - to explore the relationship between exposure to onset time. It can be used as an alternative method when the proportional hazards assumption is not met. Genetic analyses including genetic correlation study and MR analysis and brain structure analyses were conducted to support our findings and explore the potential mechanisms. The study reveals the relationship between different smoking initiation periods and the onset time of dementia and shows that earlier smoking exposure has a more significant impact on dementia. It emphasizes the importance of preventing early smoking. In the future, more research focusing on the relationship between early exposure and dementia is called for to provide more detailed prevention measures for dementia that cover all age groups.

Latest advances on new promising molecular-based therapeutic approaches for Huntington's disease.

Huntington's disease (HD) is a devastating, autosomal-dominant inherited, neurodegenerative disorder characterized by progressive motor deficits, cognitive impairments, and neuropsychiatric symptoms. It is caused by excessive cytosine-adenine-guanine (CAG) trinucleotide repeats within the huntingtin gene (HTT). Presently, therapeutic interventions capable of altering the trajectory of HD are lacking, while medications for abnormal movement and psychiatric symptoms are limited. Numerous pre-clinical and clinical studies have been conducted and are currently underway to test the efficacy of therapeutic approaches targeting some of these mechanisms with varying degrees of success. In this review, we update the latest advances on new promising molecular-based therapeutic strategies for this disorder, including DNA-targeting techniques such as zinc-finger proteins, transcription activator-like effector nucleases, and CRISPR/Cas9; post-transcriptional huntingtin-lowering approaches such as RNAi, antisense oligonucleotides, and small-molecule splicing modulators; and novel methods to clear the mHTT protein, such as proteolysis-targeting chimeras. We mainly focus on the ongoing clinical trials and the latest pre-clinical studies to explore the progress of emerging potential HD therapeutics.

Nature of epigenetic aging from a single-cell perspective.

Age-related changes in DNA methylation (DNAm) form the basis of the most robust predictors of age-epigenetic clocks-but a clear mechanistic understanding of exactly which aspects of aging are quantified by these clocks is lacking. Here, to clarify the nature of epigenetic aging, we juxtapose the dynamics of tissue and single-cell DNAm in mice. We compare these changes during early development with those observed during adult aging in mice, and corroborate our analyses with a single-cell RNA sequencing analysis within the same multiomics dataset. We show that epigenetic aging involves co-regulated changes as well as a major stochastic component, and this is consistent with transcriptional patterns. We further support the finding of stochastic epigenetic aging by direct tissue and single-cell DNAm analyses and modeling of aging DNAm trajectories with a stochastic process akin to radiocarbon decay. Finally, we describe a single-cell algorithm for the identification of co-regulated and stochastic CpG clusters showing consistent transcriptomic coordination patterns. Together, our analyses increase our understanding of the basis of epigenetic clocks and highlight potential opportunities for targeting aging and evaluating longevity interventions.

The characteristic and prognostic role of blood inflammatory markers in patients with Huntington's disease from China.

Objectives: This study aims to elucidate the role of peripheral inflammation in Huntington's disease (HD) by examining the correlation of peripheral inflammatory markers with clinical manifestations and disease prognosis. Methods: This investigation involved 92 HD patients and 92 matched healthy controls (HCs). We quantified various peripheral inflammatory markers and calculated their derived metrics including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII). Clinical assessments spanning cognitive, motor, and disease severity were administered. Comparative analysis of inflammatory markers and clinical correlations between HD and controls was performed. Kaplan-Meier survival analysis and Cox regression model were used to assess the effect of inflammatory markers on survival. Results: The study revealed that HD patients had significantly reduced lymphocyte counts, and LMR. Conversely, NLR, PLR, and SII were elevated compared to HCs. Lymphocyte levels inversely correlated with the age of onset and monocyte levels inversely correlated with the UHDRS-total functional capacity (TFC) scores. After adjusting for age, sex, and CAG repeat length, lymphocyte count, NLR, PLR, and SII were significantly correlated with the progression rate of TFC scores. Elevated levels of white blood cells and monocytes were associated with an increased risk of disability and mortality in the HD cohort. Conclusion: Our findings indicate that HD patients display a distinct peripheral inflammatory profile with increased NLR, PLR, and SII levels compared to HCs. The peripheral inflammation appears to be linked with accelerated disease progression and decreased survival in HD.

Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation.

Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear. Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites. Using both transcriptomic and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.

The role of type VI secretion system genes in antibiotic resistance and virulence in Acinetobacter baumannii clinical isolates.

Introduction: The type VI secretion system (T6SS) is a crucial virulence factor in the nosocomial pathogen Acinetobacter baumannii. However, its association with drug resistance is less well known. Notably, the roles that different T6SS components play in the process of antimicrobial resistance, as well as in virulence, have not been systematically revealed. Methods: The importance of three representative T6SS core genes involved in the drug resistance and virulence of A. baumannii, namely, tssB, tssD (hcp), and tssM was elucidated. Results: A higher ratio of the three core genes was detected in drug-resistant strains than in susceptible strains among our 114 A. baumannii clinical isolates. Upon deletion of tssB in AB795639, increased antimicrobial resistance to cefuroxime and ceftriaxone was observed, alongside reduced resistance to gentamicin. The ΔtssD mutant showed decreased resistance to ciprofloxacin, norfloxacin, ofloxacin, tetracycline, and doxycycline, but increased resistance to tobramycin and streptomycin. The tssM-lacking mutant showed an increased sensitivity to ofloxacin, polymyxin B, and furazolidone. In addition, a significant reduction in biofilm formation was observed only with the ΔtssM mutant. Moreover, the ΔtssM strain, followed by the ΔtssD mutant, showed decreased survival in human serum, with attenuated competition with Escherichia coli and impaired lethality in Galleria mellonella. Discussion: The above results suggest that T6SS plays an important role, participating in the antibiotic resistance of A. baumannii, especially in terms of intrinsic resistance. Meanwhile, tssM and tssD contribute to bacterial virulence to a greater degree, with tssM being associated with greater importance.

Modulation of Dendritic Cell Function via Nanoparticle-Induced Cytosolic Calcium Changes.

Calcium nanoparticles have been investigated for applications, such as drug and gene delivery. Additionally, Ca2+ serves as a crucial second messenger in the activation of immune cells. However, few studies have systematically studied the effects of calcium nanoparticles on the calcium levels and functions within immune cells. In this study, we explore the potential of calcium nanoparticles as a vehicle to deliver calcium into the cytosol of dendritic cells (DCs) and influence their functions. We synthesized calcium hydroxide nanoparticles, coated them with a layer of silica to prevent rapid degradation, and further conjugated them with anti-CD205 antibodies to achieve targeted delivery to DCs. Our results indicate that these nanoparticles can efficiently enter DCs and release calcium ions in a controlled manner. This elevation in cytosolic calcium activates both the NFAT and NF-κB pathways, in turn promoting the expression of costimulatory molecules, antigen-presenting molecules, and pro-inflammatory cytokines. In mouse tumor models, the calcium nanoparticles enhanced the antitumor immune response and augmented the efficacy of both radiotherapy and chemotherapy without introducing additional toxicity. Our study introduces a safe nanoparticle immunomodulator with potential widespread applications in cancer therapy.

Hurdle or thruster: Glucose metabolism of T cells in anti-tumour immunity.

Glucose metabolism is essential for the activation, differentiation and function of T cells and proper glucose metabolism is required to maintain effective T cell immunity. Dysregulation of glucose metabolism is a hallmark of cancer, and the tumour microenvironment (TME2) can create metabolic barriers in T cells that inhibit their anti-tumour immune function. Targeting glucose metabolism is a promising approach to improve the capacity of T cells in the TME. The efficacy of common immunotherapies, such as immune checkpoint inhibitors (ICIs3) and adoptive cell transfer (ACT4), can be limited by T-cell function, and the treatment itself can affect T-cell metabolism. Therefore, understanding the relationship between immunotherapy and T cell glucose metabolism helps to achieve more effective anti-tumour therapy. In this review, we provide an overview of T cell glucose metabolism and how T cell metabolic reprogramming in the TME regulates anti-tumour responses, briefly describe the metabolic patterns of T cells during ICI and ACT therapies, which suggest possible synergistic strategies.

Streptococcus suis Serotype 2 Type IV Secretion Effector SspA-1 Induces Proinflammatory Cytokine Production via TLR2 Endosomal and Type I Interferon Signaling.

The subtilisin-like protease-1 (SspA-1) plays an important role in the pathogenesis of a highly virulent strain of Streptococcus suis 2. However, the mechanism of SspA-1-triggered excessive inflammatory response is still unknown. In this study, we demonstrated that activation of type I IFN signaling is required for SspA-1-induced excessive proinflammatory cytokine production. Further experiments showed that the TLR2 endosomal pathway mediates SspA-1-induced type I IFN signaling and the inflammatory response. Finally, we mapped the major signaling components of the related pathway and found that the TIR adaptor proteins Mal, TRAM, and MyD88 and the downstream activation of IRF1 and IRF7 were involved in this pathway. These results explain the molecular mechanism by which SspA-1 triggers an excessive inflammatory response and reveal a novel effect of type I IFN in S. suis 2 infection, possibly providing further insights into the pathogenesis of this highly virulent S. suis 2 strain.

Factors influencing cognitive function in patients with Huntington's disease from China: A cross-sectional clinical study.

BACKGROUND AND AIM: Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG repeats expansion. Cognitive decline contributes to the loss of daily activity in manifest HD. We aimed to examine the cognition status in a Chinese HD cohort and explore factors influencing the diverse cognitive domains. METHODS: A total of 205 participants were recruited in the study with the assessment by neuropsychological batteries, including the mini-mental state examination (MMSE), Stroop test, symbol digit modalities test (SDMT), trail making test (TMT), verbal fluency test (VFT), and Hopkins verbal learning test-revised, as well as motor and psychiatric assessment. Pearson correlation and multiple linear regression models were applied to investigate the correlation. RESULTS: Only 41.46% of patients had normal global function first come to our center. There was a significantly difference in MMSE, Stroop test, SDMT, TMT, and VFT across each stage of HD patients (p < .05). Apathy of PBA-s was correlated to MMSE, animal VFT and Stroop-interference tests performance. Severity of motor symptoms, functional capacity, age, and age of motor symptom onset were correlated to all neuropsychological scores, whereas education attainment and diagnostic delay were correlated to most neuropsychological scores except TMT. Severity of motor symptoms, functional capacity, and education attainment showed independent predicting effect (p < .05) in diverse cognitive domains. CONCLUSION: Cognitive impairment was very common in Chinese HD patients at the first visit and worse in the patients in advanced phase. The severity of motor symptoms and functional capacity were correlated to the diverse cognitive domains.

Neuro-11: a new questionnaire for the assessment of somatic symptom disorder in general hospitals.

Background: Somatic symptom disorder (SSD) commonly presents in general hospital settings, posing challenges for healthcare professionals lacking specialised psychiatric training. The Neuro-11 Neurosis Scale (Neuro-11) offers promise in screening and evaluating psychosomatic symptoms, comprising 11 concise items across three dimensions: somatic symptoms, negative emotions and adverse events. Prior research has validated the scale's reliability, validity and theoretical framework in somatoform disorders, indicating its potential as a valuable tool for SSD screening in general hospitals. Aims: This study aimed to establish the reliability, validity and threshold of the Neuro-11 by comparing it with standard questionnaires commonly used in general hospitals for assessing SSD. Through this comparative analysis, we aimed to validate the effectiveness and precision of the Neuro-11, enhancing its utility in clinical settings. Methods: Between November 2020 and December 2021, data were collected from 731 patients receiving outpatient and inpatient care at Shenzhen People's Hospital in China for various physical discomforts. The patients completed multiple questionnaires, including the Neuro-11, Short Form 36 Health Survey, Patient Health Questionnaire 15 items, Hamilton Anxiety Scale and Hamilton Depression Scale. Psychiatry-trained clinicians conducted structured interviews and clinical examinations to establish a gold standard diagnosis of SSD. Results: The Neuro-11 demonstrated strong content reliability and structural consistency, correlating significantly with internationally recognised and widely used questionnaires. Despite its brevity, the Neuro-11 exhibited significant correlations with other questionnaires. A test-retest analysis yielded a correlation coefficient of 1.00, Spearman-Brown coefficient of 0.64 and Cronbach's α coefficient of 0.72, indicating robust content reliability and internal consistency. Confirmatory factor analysis confirmed the validity of the three-dimensional structure (p<0.001, comparative fit index=0.94, Tucker-Lewis index=0.92, root mean square error of approximation=0.06, standardised root mean square residual=0.04). The threshold of the Neuro-11 is set at 10 points based on the maximum Youden's index from the receiver operating characteristic curve analysis. In terms of diagnostic efficacy, the Neuro-11 has an area under the curve of 0.67. Conclusions: (1) The Neuro-11 demonstrates robust associations with standard questionnaires, supporting its validity. It is applicable in general hospital settings, assessing somatic symptoms, negative emotions and adverse events. (2) The Neuro-11 exhibits strong content reliability and validity, accurately capturing the intended constructs. The three-dimensional structure demonstrates robust construct validity. (3) The threshold of the Neuro-11 is set at 10 points.

An Inflammatory Checkpoint Generated by IL1RN Splicing Offers Therapeutic Opportunity for KRAS-Mutant Intrahepatic Cholangiocarcinoma.

KRAS mutations are causally linked to protumor inflammation and are identified as driving factors in tumorigenesis. Here, using multiomics data gathered from a large set of patients, we showed that KRAS mutation was associated with a specific landscape of alternative mRNA splicing that connected to myeloid inflammation in intrahepatic cholangiocarcinoma (iCCA). Then, we identified a negative feedback mechanism in which the upregulation of interleukin 1 receptor antagonist (IL1RN)-201/203 due to alternative splicing confers vital anti-inflammatory effects in KRAS-mutant iCCA. In KRAS-mutant iCCA mice, both IL1RN-201/203 upregulation and anakinra treatment ignited a significant antitumor immune response by altering neutrophil recruitment and phenotypes. Furthermore, anakinra treatment synergistically enhanced anti-PD-1 therapy to activate intratumoral GZMB+ CD8+ T cells in KRAS-mutant iCCA mice. Clinically, we found that high IL1RN-201/203 levels in patients with KRAS-mutant iCCA were significantly associated with superior response to anti-PD-1 immunotherapy. SIGNIFICANCE: This work describes a novel inflammatory checkpoint mediated by IL1RN alternative splicing variants that may serve as a promising basis to develop therapeutic options for KRAS-mutant iCCA and other cancers. This article is featured in Selected Articles from This Issue, p. 2109.

Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation.

Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear. Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites. Using both transcriptomic and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.