Cells

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative condition characterized by the presence of intranuclear inclusions in neuronal and visceral cells. Patients with NIID can present respiratory symptoms; however, data on pulmonary functions in NIID are lacking. This study investigated the respiratory conditions in NIID patients diagnosed with histopathological and genetic studies. We conducted two spirometries before and after administrating the bronchodilator in NIID patients with asthmatic histories or symptoms. We statistically compared pre- and post-measured values including forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow (PEF). Before two spirometries, we also measured fractional concentration of exhaled nitric oxide (FeNO), if possible. Of the 51finally enrolled patients, 17 (33.3%, 95% CI 20.8% to 47.9%) patients had asthmatic histories or symptoms, and 14 patients received two spirometries. After administrating the bronchodilator, FEV1 and PEF significantly increased by 150 mL (6.01%, p = 0.002) and 260 mL/s (6.72%, p = 0.017), respectively. The median (interquartile range) of FeNO measured in nine patients was 15 (10-21) ppb. Patients with NIID have airflow reversibility like asthma. Airway inflammation is less associated with this condition; thus, immunomodulators such as corticosteroid may not improve respiratory symptoms in NIID.

BackgroundPlacenta accreta spectrum (PAS) is characterized by abnormal trophoblastic invasion into the uterine myometrium and is a cause of postpartum hemorrhage and maternal death. Protease-activated receptor-1 (PAR-1) promotes various cellular actions, including invasion. Here, we analyzed the expression of PAR-1, platelet antigen, and fibrin in PAS. MethodsWe analyzed 49 PAS cases (placenta accreta vera [accreta vera], 31 cases; placenta increta [increta], 8 cases; placenta percreta [percreta], 10 cases, classified by the degree of placental villous invasion) and 33 control cases. We immunohistochemically examined the expression of PAR-1, platelet glycoprotein (GP) IIb/IIIa, and fibrin. ResultsThe frequency of previous cesarean section was higher in the increta and percreta groups than in the control and accreta vera groups. PAR-1 expression in placental villi was weak and limited in extent in control cases, whereas immunoreactivity and staining density increased in increta and percreta. Immunofluorescence revealed PAR-1 expression in cytotrophoblasts of placental villi and in aggregated platelets. PAR-1 expression scores in cytotrophoblasts increased significantly with the degree of villous invasion (accreta vera, increta, percreta) compared with controls. The immunopositive areas for GPIIb/IIIa and fibrin were significantly larger in PAS groups than in controls. Furthermore, the immunopositive areas for platelets and fibrin were positively correlated with the PAR-1 expression score. ConclusionThese results indicate that PAR-1 may play a role in placental villous invasion and that a thrombogenic placental environment may influence PAR-1 activation.

Antimicrobial peptides (AMPs) are essential components of the innate immune system, exhibiting diverse mechanisms of action. This study investigates the roles of cathelicidin (LL-37), alpha-defensins, and the S100 proteins S100A8 and S100A9 in systemic inflammation associated with sepsis, severe COVID-19, and acute pancreatitis using whole-blood bulk RNA-sequencing data. Gene co-expression network analysis revealed that during septic shock and severe COVID-19, cathelicidin and alpha-defensins act synergistically in innate immune responses, while S100A8 and S100A9 function through distinct pathways related to mitochondrial metabolism and ubiquitin ligase binding. In contrast, the acute pancreatitis network displayed a different pattern, with CAMP co-expressed alongside S100A8 and S100A9, whereas alpha-defensins were downregulated and associated with inhibited mucosal immune responses. These findings suggest that antimicrobial peptides contribute variably to systemic inflammation depending on the underlying insult, underscoring their complex, context-dependent roles in critical illness.

Sinonasal squamous cell carcinoma (SNSCC) is an aggressive head and neck cancer of the sinonasal cavity which has not benefitted from therapeutic advances over decades1. Though historically attributed to inhaled carcinogens such as hardwood dust and tobacco smoking2, SNSCC is incidentally associated with human papillomavirus (HPV)3,4. Importantly, HPV is the primary oncogenic driver of >80% of anatomically adjacent oropharyngeal cancers5. While viral status drives clinical staging and treatment guidelines in these malignancies6,7, the potentially oncogenic consequences and prognostic value of host-virus interactions in SNSCC remain incompletely defined. Here, through paired host and viral whole-genome sequencing (WGS), we map the genomic footprint of HPV in SNSCC. Strikingly, lesser studied strains such as HPV45, 51, and 39 constitute driver infections in this rare but clinically credentialed cancer, where extrachromosomal DNA (ecDNA)-associated viral integration and APOBEC mutagenesis are shown to underpin somatic tumor evolution. Statement of SignificancePaired host viral and whole-genome sequencing of SNSCC nominates HPV as a primary oncogenic driver of SNSCC. HPV-human ecDNA amplicons harboring noncanonical strains such as HPV45, 51 mediate viral carcinogenesis. Routine clinical diagnostic HPV panels should be expanded to capture the activity of lesser studied strains.

Protein expression within oncogenic or suppressive pathways is a hallmark indicator of oncogenesis. While traditional AI models in digital pathology attempt to predict singular proteins, there is a need to predict the downstream expression of proteins to indicate the propagation of signals. RNA expression provides novel information, but does not provide information about the downstream propagation of protein signals or whether those signals are functional. Using Reverse Phase Protein Array (RPPA) data with whole-slide images (WSIs) from the publicly available Cancer Genome Atlas Breast Adenocarcinoma dataset (TCGA-BRCA), we predict the expression of five key proteins identified from the apoptosis cascade, using DNA damage and repair (DDR) cascades as a biological control. Furthermore, we examine the performance of patch-level Vision Transformers (ViT) on the regression task, which was tested against the designed cellular-level ViT, CellRPPA. Our results demonstrate that patch-level vision transformers were unable to obtain statistically significant predictive results, achieving R-squared values {inverted exclamation} 0.1 for all folds. In addition, CellViT obtained R-squared values {inverted question} 0.1 in all five test folds. We also show that morphologically indicative cascades, such as the apoptosis cascade, provide significantly higher performance compared to the DDR cascade.

BackgroundSinonasal malignancies frequently present with symptoms overlapping chronic inflammatory conditions such as chronic rhinosinusitis (CRS), complicating early detection and delaying treatment. A fast, scalable, non-invasive approach capable of resolving immune and epithelial cell states across inflammatory and malignant disease from routine nasal swabs could substantially improve clinical screening, leading to the initiation of appropriate treatment. MethodsWe developed a deep learning-enabled single-cell morpholomic framework using the REM-I platform to generate a reference atlas of >641K cell brightfield images from purified immune cell populations. This reference atlas was applied to >2.5 million images obtained from nasal swabs spanning a clinical spectrum of health, CRS, and sinonasal carcinoma. Embeddings were integrated using dimensionality reduction for differential feature testing and comparative feature enrichment across disease states. FindingsAcross the disease continuum, sinonasal carcinoma samples exhibited distinct immune remodeling, including increased myeloid-like cell abundance and elevated small dark pixel intensity consistent with enhanced granulocyte activity. Basophil/NK-enriched clusters contained tumor-associated cells with deep learning-derived morphologic signatures not observed in CRS or healthy samples. Tumor-associated epithelial cells were significantly smaller and displayed disease-specific morpholomic patterns distinct from chronic inflammation. ConclusionsThis study establishes a deep learning-enabled single-cell morpholomic atlas of nasal swabs spanning healthy epithelium, chronic inflammation and sinonasal malignancies. Morpholomic cytology reveals reproducible immune and epithelial states associated with inflammatory and malignant disease and provides a scalable, non-invasive framework for cellular stratification in sinonasal pathology, supporting future applications in early point-of-care diagnostics.

BackgroundCervical cancer is one of the most common malignant tumors of the female reproductive system. Existing treatments provide limited benefit for patients with advanced, recurrent or metastatic disease, and reliable prognostic markers are lacking. In this study we integrated multi-omic data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database. Protein-coding genes meeting the criteria of an adjusted P value < 0.05 and |log2 fold-change| > 5 were screened; 693 genes were identified. We further focused on three genes related to the tumor microenvironment--interleukin 21 (IL21), C-X-C motif chemokine ligand 9 (CXCL9) and cluster of differentiation 1A (CD1A)--and performed differential expression analysis, survival analysis, clinical stage analysis and immune infiltration correlation analysis to clarify their prognostic value and potential mechanisms in cervical cancer. Results(1) CXCL9 and CD1A were highly expressed in cervical cancer tissues, and all three genes showed high expression across different pathological stages without stage-dependent differences; (2) high expression of IL21, CXCL9 and CD1A improved patient prognosis and was positively associated with overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI); (3) expression of IL21, CXCL9 and CD1A was closely correlated with infiltration of multiple immune cells: IL21 correlated with total T cells, helper T cells and B cells, CXCL9 correlated with T cells and activated dendritic cells, and CD1A correlated with immature dendritic cells. ConclusionIL21, CXCL9 and CD1A are potential prognostic biomarkers and key immunomodulatory factors in cervical cancer. This study provides a new direction for immunotherapy and individualized precision treatment of cervical cancer.

ObjectiveWe reviewed the epidemiologic and genomic literature and performed genomic analyses to identify population burdens (Eating Disorders, ED and Parkinsons Disease, PD) and shared genetic risk (Anorexia Nervosa, AN and PD), after we previously demonstrated two-to four-fold relative risks of a family history of Parkinsons Disease in families of individuals with ED. MethodWe reviewed the epidemiology of both disorders and published genome-wide association studies (GWAS), searched PD GWAS findings with AN associated genome-wide significant SNPs and associated genes and regions, and performed conditional/conjunctional false discovery rate genomic analyses of AN and PD summary statistics to identify shared genetics. ResultsThe global population burden of ED and PD are similar despite differences in age of onset and sex ratio. GWAS review and linkage disequilibrium analysis showed that genome-wide significant variants from AN GWAS and PD GWAS in the chr3p21.31 region are correlated. We identified a chr3p21.31 variant with joint association with both disorders; this variant has functional linkages to 40 genes. ConclusionsED and PD share neuropsychological, neurobiological, and genetic risk factors, including association with the complex chr3p21.31 locus. Translational analyses leveraging disorder-specific research resources may benefit our understanding of the genetics and neuropsychiatric mechanisms of both disorders. HighlightsO_LIED and PD have similar age-standardized disability life years (AS-DALYS); the burden of both disorders are expected to increase in the future. C_LIO_LIGenomic epidemiology literature review reveals AN and PD genetic architectures are highly polygenic (AN >> PD), and, AN variant discoverability is less than PD variant discoverability. C_LIO_LIAN and PD are jointly associated at rs1352420 at chr3p21.31, a region with multiple AN and PD comorbid and genetically correlated trait associations. C_LIO_LICross-disorder research offers opportunities to identify shared variants and explore mechanistic hypotheses C_LI

PurposeSepsis-associated immunothrombosis significantly contributes to high mortality, yet the role of N-glycosylation in this process remains poorly understood. This study aimed to comprehensively profile the plasma N-glycosylation landscape in sepsis and elucidate how its specific reprogramming in the complement and coagulation cascades influences immunothrombotic balance and patient outcomes. MethodsWe performed in-depth 4D-DIA proteomic and N-glycomic analyses on plasma from 43 sepsis patients and 9 healthy controls. Differential expression, weighted gene co-expression network analysis (WGCNA), and protein-glycosylation correlation analyses were used to characterize molecular features. Clinical relevance was assessed via correlation and survival analyses. ResultsExtensive N-glycosylation reprogramming was observed in sepsis plasma,with marked enrichment in complement and coagulation pathways(KEGG p=7.76x10- {superscript 2}{superscript 1}).Pro-coagulant proteins(eg,vWF,fibrinogen)showed increased abundance together with enhanced site-specific glycosylation,potentially amplifying their activity.In contrast,key anticoagulant proteins(eg,SERPINC1)displayed unchanged glycosylation at critical sites despite abundance changes,which may impair function.Survival analysis revealed distinct prognostic values of glycoproteins and specific glycosylation sites.For instance,high vWF protein levels predicted mortality(HR=2.83),whereas elevated glycosylation at vWF N211 was associated with improved survival(HR=0.135),suggesting a negative regulatory role.These glycosylation markers correlated closely with disease severity and prognosis,representing potential early-warning biomarkers independent of current clinical coagulation indicators. ConclusionOur study demonstrates widespread reprogramming of the plasma proteome and N-glycome in sepsis.We propose that decoupling of protein function from abundance through N-glycosylation in the complement-coagulation network contributes to immunothrombotic imbalance.Specific N-glycosylation sites may serve as novel prognostic biomarkers,offering new perspectives for early risk stratification and glycosylation-targeted therapies in sepsis. Key PointsO_LISepsis plasma exhibits specific N-glycosylation reprogramming overwhelmingly focused on the complement and coagulation cascade. C_LIO_LIA dominant "glycosylation-dominated co-upregulation" mode in procoagulant factors, coupled with a "silent" glycosylation state in key anticoagulants, drives prothrombotic imbalance. C_LIO_LISite-specific N-glycosylation levels provide prognostic information distinct from, and often superior to, their carrier protein abundance, offering novel early-risk biomarkers. C_LI

A critical challenge in endocrine neurosurgery is intraoperative discrimination between normal pituitary tissue and pituitary neuroendocrine tumors (PitNETs). Suggesting the universal persistence of near-infrared autofluorescence (NIRAF) in endocrine organs and inspired by routine clinical use of NIRAF for parathyroid gland identification, we discovered that pituitary NIRAF can be employed for label-free transsphenoidal surgery guidance. Ex vivo confocal spectral imaging of 33 specimens identified secretory granules as the dominant long-wavelength fluorescence source and showed that normal pituitary had higher granule content than PitNETs. For the first time, we made use of the pituitary NIRAF during surgery and assessed its performance for pituitary/adenoma separation in vivo for 27 surgeries and showed near-perfect separability between pituitary and non-pituitary measurement sites with ROC-AUC of 0.98. The obtained results clearly demonstrate that the suggested method, based on the solid microscopic background, has the potential for clinical translation and paves the way for enhanced gland preservation during resection.

Major depressive disorder (MDD) involves dysregulated neuroimmune, metabolic, and oxidative stress (NIMETOX) pathways. Recently, it was shown that NIMETOX pathways should be evaluated in MDD patients stratified for metabolic syndrome (MetS). The current study aims to characterize the metabolic hormone and adipokine profiles of Chinese MDD patients stratified for MetS and to delineate their associations with overall severity of depression (OSOD), suicidal ideation (SI), recurrence of illness (ROI), and physiosomatic symptoms. We enrolled 125 MDD inpatients and 40 healthy controls and measured fasting serum insulin, glucose, glucagon, Glucose-dependent Insulinotropic Polypeptide (GIP), Glucagon-Like Peptide-1 (GLP-1), leptin, secretin, Plasminogen Activator Inhibitor-1 (PAI-1), resistin, ghrelin, and adiponectin, as well as the acute-phase inflammatory (API) response using albumin, transferrin (Tf), and monomeric CRP (mCRP). The results revealed a distinct metabolic hormone and adipokine signature in MDD with significantly lower insulin, glucagon, and PAI-1 levels, alongside an elevated API index (after adjusting for age, MetS, and body mass index). A composite GAP index (ghrelin, adiponectin, PAI-1) correlated negatively with OSOD, SI, ROI, physiosomatic symptoms, and adverse childhood experiences (ACEs). Integrative modeling combining the GAP index, API index, and ACEs achieved an area under the receiver operating characteristic (ROC) curve of 0.864 with an accuracy of 80% for discriminating MDD from controls. In conclusion, the findings delineated that many inpatients with severe MDD suffer from suppressed anabolic hormones and lower adipokine levels coupled with a mild, chronic inflammatory response. The deviations in this "hormonal-immune-metabolic" axis are components of the NIMETOX pathways in MDD and are not associated with MetS.

ObjectiveTo explore the application value of dual-staining for specific AT sequence binding protein 2 (SATB2) immunohistochemistry and elastic lamina in detecting elastic lamina invasion (ELI) in pT3 colon cancer, and to assess its association with clinicopathological characteristics, staging, and prognosis. MethodsThis retrospective cohort study enrolled 176 pT3 colon cancer patients who underwent radical resection at Affiliated Jinhua Hospital Zhejiang University School of Medicine. The deepest tumor-infiltrated paraffin blocks were collected for SATB2 immunohistochemistry and elastin dual-staining. Correlations between ELI status and clinicopathological characteristics and prognosis were analyzed. Survival data of 74 pT4a stage patients were collected for comparative analysis. ResultsELI (+) was positively associated with high tumor budding grade, vascular invasion, lymph node metastasis, and reduced tumor infiltrating lymphocytes (TILs) (all P < 0.001). No correlations were observed with age, gender, tumor location, histological subtype, tumor grade, or perineural invasion (all P > 0.05). The ELI (+) group exhibited significantly shorter disease-free survival (DFS) and overall survival (OS) compared to ELI (-) group (P < 0.05). Additionally, the ELI (+) group demonstrated inferior OS than the pT4a group, though DFS did not differ significantly. ConclusionDual-staining of SATB2 immunohistochemistry and elastic lamina provides a reproducible and objective method for assessing ELI. ELI correlates with key clinicopathological features and functions as an independent adverse prognostic indicator in pT3 colon cancer.

BackgroundGastroenteric tract requires robust tolerogenic mechanisms to tolerize foreign antigens like foods and microbiota. This is critical to establish the immune homeostasis, which upon disruption, might contribute to a plethora of atopic disorders, including food allergy and eosinophilic esophagitis (EOE). Recently, there was a new subset of tolerizing dendritic cells (tolDCs), PRDM16 tolDC, discovered in the gut of mice and humans, which confers protection against food allergy. Whether an analogous population of it exist in the esophagus is unknown, especially in the context of EOE, another atopic disease associated with dietary antigens. MethodsWe thoroughly analyzed the human esophagus cell atlas single cell RNA-seq dataset and the myeloid DC-VERSE dataset, in an attempt to identify and characterize the esophageal counterpart of the intestinal PRDM16 tolDC. ResultsWe identified the esophageal counterpart of intestinal PRDM16 tolDC as a conventional type II DC subtype expressing PRDM16, termed as cDC2C (PRDM16). We demonstrated the similarities between PRDM16 tolDC and cDC2C (PRDM16) regarding their transcriptomic and functional profiles. Importantly, we found that cDC2C (PRDM16) were expanded during EOE and exhibited an anti-inflammatory phenotype, suggesting their protective role in EOE. Notably, these tolerogenic DCs were not found in other atopic diseases beyond the gastroenteric tract. ConclusionsWe here defined a novel tolerogenic DC population in human esophagus and demonstrated their implications in the pathophysiology of EOE. These findings would provide novel insights towards the tolerogenic mechanisms along the gastroenteric tract and possess translational relevance for EOE diagnosis and interventions.

BackgroundAn adverse female sex-bias exists across many autoimmune disorders, yet its underlying mechanisms, particularly the role of sex hormones, remains poorly understood. Furthermore, the physiological influence of sex hormones in regulating T cell function remains undefined. We examined for the critical role of estrogen and progesterone, in regulating CD4+ T cell responses, specifically with respect to inflammation and their bone erosion potential in RA. MethodsInflammatory markers, circulating antibodies, sex hormone receptors, ER and PR levels were investigated in both RA patients and controls. Further, RA CD4+ T cells were stimulated in varying concentrations of estradiol and progesterone and assessed for modulation in cytokines, transcription factors, RANKL, and FasL expression. Subsequent ex-vivo studies were performed to examine the role of sex hormones in modulating T cell responses. ResultsRA patients displayed systemic inflammation and high circulating antibodies, with significantly higher expression in synovial fluid. Higher expression of ER and PR was evinced on RA CD4+ T cells. Upon hormone stimulation, two cohorts of patients namely responders and non-responders were observed with respect to modulation in cytokines, transcription factors, RANKL, and FasL expression. Our ex-vivo Th1 and Th17 cells demonstrated that sex hormones play a physiological role in modulating inflammation and have bone erosion potential. ConclusionOur findings demonstrate the pivotal significance of sex hormones in modulating TCR responses, thereby regulating inflammation and bone erosion in RA pathology. Further dissection of TCR signaling pathways with respect to sex hormone stimulation may provide promising targets for therapeutic implications. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/25342530v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@b74525org.highwire.dtl.DTLVardef@1cc01aorg.highwire.dtl.DTLVardef@1881e4forg.highwire.dtl.DTLVardef@17de2a8_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundTourette syndrome is a childhood-onset neuropsychiatric disorder characterised by recurrent motor and vocal tics. It shows a marked male predominance and is frequently associated with comorbid conditions such as attention-deficit/hyperactivity disorder (ADHD) and obsessive- compulsive disorder (OCD). Histaminergic dysregulation in the brain has been proposed as one of the mechanisms underlying Tourette syndrome. Vitamin B6, a key cofactor in histamine metabolism, may therefore play a contributory role in its pathophysiology. MethodThe clinical features of 25 children diagnosed with Tourette syndrome were assessed using the Yale Global Tic Severity Scale. Plasma vitamin B6 levels were measured using enzyme-linked immunosorbent assay (ELISA) and compared with those of a control group. ResultMost participants were males, and 16% had comorbid ADHD or OCD. The most common motor tics were eye blinking, shoulder shrugging, head jerking, and orofacial movements. Frequent vocal tics included throat clearing, sniffing, uttering syllables, and breathing-related tics. Coprolalia was observed in four children. The median plasma vitamin B6 level in the Tourette syndrome group was 25.01ng/ml, which was significantly lower than the 36.33ng/ml in the control group (Mann-Whitney U = 225, p = 0.03). The rank-biserial correlation indicated a moderate effect size (r = 0.35). ConclusionTourette syndrome in children predominantly affects males and is commonly associated with ADHD and OCD. Coprolalia-a clinically distressing symptom - was present only in a small subgroup. The lower plasma vitamin B6 levels observed in children with Tourette syndrome suggest a possible role for vitamin B6 in disease pathogenesis, potentially through its involvement in histaminergic and GABAergic neurotransmission, as well as in the modulation of neuroinflammatory processes.

Sjogrens disease (SjD) is a chronic autoimmune disorder characterized by inflammation of the exocrine glands, leading to dry mouth and dry eyes. This study investigates the role of interleukin-9 (IL-9) and T helper 9 (Th9) cells in the pathogenesis of SjD. We found that serum IL-9 levels were significantly elevated in SjD patients and correlated with clinical laboratory parameters, including autoantibody production. In a mouse model of SjD, IL-9 and Th9-associated cytokines were also elevated, and Th9 cells were enriched in the salivary glands. Our results suggest that IL-9 is produced by multiple cell types, including macrophages, CD4+ T cells, and NK cells, and that Th9 cells contribute to the development of SjD by promoting inflammation and autoantibody production. We also found that Th9 and Th17 polarization conditions increased Th2 and Th17 cells in SjD mice, indicating a shared epigenetic program that renders T cells permissive to multiple differentiation pathways. Anti-IL-9 treatment had a sex-dependent effect, reducing autoantibody production in male mice but worsening focal glandular infiltration in female mice. Our findings suggest that IL-9 plays a complex role in SjD pathobiology, contributing to both local immunoregulation and systemic autoantibody response. Overall, this study offers new insights into the role of IL-9 and Th9 cells in SjD, highlighting the potential for therapeutic targeting of the IL-9/Th9 axis in the treatment of this disease.

Background and HypothesisSchizophrenia is a disease characterized by various symptoms and has severe lifelong impacts on patients and their families. Despite various hypotheses and associated studies, the key mechanism in schizophrenia is not fully elucidated. In the present study, we focused on adropin, a peptide regulating energy metabolism, antioxidation, and neuroprotection. Study DesignIn both the group of healthy volunteers (HV) and the group of patients with some schizophrenia spectrum and other psychotic disorders (SZ), we evaluated adropin along with other variables such as anthropological factors, psychological well-being indicators, and laboratory test results. Study ResultsThe adropin levels in SZ were not significantly different from those in HV. Correlation analysis indicated five significant correlations beyond various natural correlations arising from fundamental proportional relationships and multifaceted psychological well-being indicators: (1) adropin versus right handgrip strength in the SZ group ({tau} = -0.82, P = 0.066); (2) adropin versus selenium in the total group ({tau} = 0.44, P = 0.053); (3) ferritin versus perceived stress in the total group ({tau} = -0.44, P = 0.053); (4) right versus left handgrip strength in the total group ({tau} = 0.70, P = 0.001) and in the SZ group ({tau} = 0.82, P = 0.075); and (5) selenium versus state anxiety in the total group ({tau} = 0.44, P = 0.053) and the SZ group ({tau} = 0.84, P = 0.066). ConclusionsThe present study provides a foundation for future studies and sheds light on the role of adropin in schizophrenia.

BackgroundMajor depressive disorder (MDD) severely impairs individual health and creates heavy societal burdens. Diagnostic and therapeutic research remains hindered by MDDs marked heterogeneity and the absence of valid biomarkers. As a neuro-immune, metabolic, and oxidative stress (NIMETOX) disorder, MDD exhibits metabolomic signatures as a final common pathway in the Chinese population. ObjectivesTo identify lipidomic profile differences between MDD patients and healthy controls and examine associations between lipidomic alterations and clinical phenotypes. MethodsWe recruited 125 MDD patients and 40 healthy controls, and measured serum lipidomic profiles using liquid chromatography-mass spectrometry. A rigorously controlled multistage machine learning pipeline with leakage-prevention measures was utilized to examine disparities between MDD and control groups and to predict phenome features. ResultsWe identified 43 differentially abundant lipids between the MDD and control groups. Subsequent factor analysis clustered the 43 lipids into 3 functional modules, namely the increased ceramide/GM3/LNAPE (CERLNAPE) module, the decreased mitochondrial fatty acid oxidation/acetyl-flux (CARSM) module, and the reduced lysophospholipid/ether-lysolipid (LYSOPE) module. The three lipidomic modules correlated with six previously reported metabolomic functional domains, establishing an integrated metabolomics-lipidomics architecture in MDD. A substantial portion of the variance in the overall severity of depression (74.0%), physiosomatic symptoms (58.5%), suicidal ideation (11.1%), and recurrence of illness (36.6%) was associated with the integrated metabolomics-lipidomics architecture. ConclusionThe MDD lipotype indicates a unified metabolic network linked to the NIMETOX pathophysiology of MDD. Lipidomics provides a robust foundation for subtyping and precision psychiatry. Ceramide, acetyl carnitine, lipotoxicity, and plasmalogens are potential drug targets to treat MDD.

Community-acquired pneumonia is a major cause of morbidity and mortality globally. Specific molecular endotypes are currently not well defined and different viral or bacterial pathogens may trigger specific host responses and pathogenic mechanisms. We performed longitudinal proteomic profiling of bronchoalveolar lavage fluid and plasma from bacterial, influenza and SARS-COV-2 driven pneumonia. Our analysis revealed highly pneumonia type specific proteomic signatures, including COVID-19 specific antibodies locally produced in the lung. These antibodies showed biased immunoglobulin V-domain usage, linked to a CD69/CD83 plasma cell state associated with disease severity and degree of autoimmunity. Using mass spectrometry driven autoantibody profiling in two independent COVID-19 cohorts, we identified 177 putative autoantibodies targeting extracellular matrix, nuclear, and immune-related proteins. Of note, temporal changes in autoantibody profiles correlated with clinical markers of inflammation, organ dysfunction, and duration of hospitalization. These findings highlight the autoimmune aspects of COVID-19 and provide potential biomarkers and therapeutic targets to help improve patient outcomes.

There is an unmet need to identify biomarkers of active thyroid eye disease (TED). scRNAseq revealed that orbital fibroblasts from orbital decompressions in people with TED express high levels of thyroid hormone receptors, growth factor receptors, including insulin-like growth factor 1 receptor (IGF1R), and extracellular matrix proteins including SPARC (osteonectin), whereas orbital fat endothelial cells expressed thyroid peroxidase (TPO). SPARC was significantly raised in the serum of people with thyroid disease compared to healthy controls. Furthermore, those with moderate, severe and sight threatening TED had higher SPARC levels than those with thyroid disease but free of TED or mild TED. Free-triiodothyronine (FT3) levels were positively correlated with SPARC in moderate-sight threatening TED. SPARC and IGF1 were positively correlated across people with thyroid disease alone, as well as TED. Thyroid stimulating hormone (TSH) levels were negatively correlated with SPARC in moderate-sight threatening TED. When participants were followed longitudinally, SPARC decreased after the active phase of TED. At the protein level, immunohistochemistry indicated that SPARC was heterogeneously expressed by fibroblasts in both control and TED orbital fat. SPARC is a key mediator of fibrosis and deposition of extracellular matrix and the correlation of SPARC serum levels to TED status and FT3 make it a promising biomarker of active TED.