Immune Proteins Research Articles

Combined plasma protein and memory T cell profiling discern IBD-patient-immunotypes related to intestinal disease and treatment outcomes

Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-naïve pediatric IBD (Crohn’s disease, CD: n = 62; ulcerative colitis, UC: n = 20; age-matched controls n = 43), and after 10–12 weeks’ induction therapy. At diagnosis, plasma protein profiles unveiled two UC and three CD clusters with distinct disease courses. UC patients displayed unchanged circulating Tmem, while CD exhibited increased frequencies of gut-homing ex-Th17, known for high IFN-γ production. UC#2 had elevated Th17/neutrophil-pathway-related proteins and severe disease, with higher endoscopic and histological damage and Th17/neutrophil infiltration. Although both UC#1 and UC#2 responded to therapy, UC#2 required earlier immunomodulation. CD#3 had lower plasma protein concentrations, especially IFN-γ pathway proteins, fewer gut-homing ex-Th17 and clinically milder disease, confirmed by intestinal gene expression. CD#1 and CD#2 had comparably high Th1-related immune profiles, but CD#1 exhibited higher concentrations of proteins previously associated with poorer prognosis. Both CD clusters responded to induction therapy, with similar one-year outcomes. This study highlights feasibility of discriminating patient-specific immunotypes in IBD, advancing our understanding of immune pathogenesis, needed for tailored treatment strategies.

Rumen-protected methionine supplementation during the transition period under artificially induced heat stress: Effects on cow-calf performance

This study aimed to evaluate the effects of rumen-protected Met on lactation performance, inflammation and immune response, and liver glutathione of lactating dairy cows during a subclinical mastitis challenge (SMC). Thirty-two Holstein cows (145 ± 51 DIM) were enrolled in a randomized complete block design. At -21 d relative to the SMC, cows were assigned to dietary treatments, and data were collected before and during the SMC. Cows were blocked according to parity, DIM, and milk yield and received a basal diet (17.4% CP; Lys 7.01% MP and Met 2.14% MP) plus 100 g/d of ground corn (CON; n = 16) or a basal diet plus 100 g/d of ground corn and rumen-protected Met (SM, Smartamine M at 0.09% of dietary DM; n = 16), fed as a top-dress. At 0 d, the mammary gland's rear right quarter was infused with 100,000 cfu of Streptococcus uberis (O140J). Milk yield was recorded twice daily from 0 until 3 d relative to SMC. Milk samples were collected during each milking from 0 to 3 d relative to SMC, blood samples were collected at 0, 6, 12, 24, 48, and 72 h relative to SMC. The mTOR pathway activation was assessed in immune cells in blood and milk samples by measuring quantity and phosphorylation status of mTOR-related proteins, including AKT, S6RP, and 4EBP1. For the ratio of phosphorylated to total AKT, S6RP, and 4EBP1, blood samples were collected at 0, 12, and 24 h, and milk samples at 24 h relative to SMC. Liver biopsies were performed at -10 d and 24 h relative to SMC for measurement of glutathione. Linear mixed models with repeated measures were used to analyze the results. There was a trend for greater milk yield per milking (+ 0.8 kg) and per day (+1.7 kg) after SMC in SM cows compared with CON. The DMI was not affected by dietary treatments. Reactive oxygen metabolites (ROM) were lower in SM cows than in CON. Milk somatic cell linear score was not affected by dietary treatments, and a score >4 at 24 h confirmed subclinical mastitis. The SM cows had greater milk fat percentage at 24 and 36 h post SMC, resulting in overall greater milk fat. Milk protein tended to be greater in SM cows than in CON. We observed greater liver glutathione in SM cows than in CON. Among inflammation biomarkers, ceruloplasmin was lower for SM cows compared with CON. In milk, greater pAKT:AKT and pS6RP:S6RP ratios were observed in immune cell populations from SM cows compared with CON. Blood neutrophils had a greater p4EBP1:4EBP1 ratio in SM cows compared with CON. Overall, our results show that Met supplementation during an SMC positively affected milk performance, lowered the risk of oxidative stress, and attenuated inflammation partially by increasing liver glutathione and immune cells' protein synthesis via mTOR signaling.

Tumor-induced natural killer cell dysfunction is a rapid and reversible process uncoupled from the expression of immune checkpoints.

Natural killer (NK) cells often become dysfunctional during tumor progression, but the molecular mechanisms underlying this phenotype remain unclear. To explore this phenomenon, we set up mouse lymphoma models activating or not activating NK cells. Both tumor types elicited type I interferon production, leading to the expression of a T cell exhaustion-like signature in NK cells, which included immune checkpoint proteins (ICPs). However, NK cell dysfunction occurred exclusively in the tumor model that triggered NK cell activation. Moreover, ICP-positive NK cells demonstrated heightened reactivity compared to negative ones. Furthermore, the onset of NK cell dysfunction was swift and temporally dissociated from ICPs induction, which occurred as a later event during tumor growth. Last, NK cell responsiveness was restored when stimulation was discontinued, and interleukin-15 had a positive impact on this reversion. Therefore, our data demonstrate that the reactivity of NK cells is dynamically controlled and that NK cell dysfunction is a reversible process uncoupled from the expression of ICPs.

Surface Immune Checkpoints as Potential Biomarkers in Physiological Pregnancy and Recurrent Pregnancy Loss.

Due to the genetic diversity between the mother and the fetus, heightened control over the immune system during pregnancy is crucial. Immunological parameters determined by clinicians in women with idiopathic recurrent spontaneous abortion (RSA) include the quantity and activity of Natural Killer (NK) and Natural Killer T (NKT) cells, the quantity of regulatory T lymphocytes, and the ratio of pro-inflammatory cytokines, which indicate imbalances in Th1 and Th2 cell response. The processes are controlled by immune checkpoint proteins (ICPs) expressed on the surface of immune cells. We aim to investigate differences in the expression of ICPs on T cells, T regulatory lymphocytes, NK cells, and NKT cells in peripheral blood samples collected from RSA women, pregnant women, and healthy multiparous women. We aim to discover new insights into the role of ICPs involved in recurrent pregnancy loss. Peripheral blood mononuclear cells (PBMCs) were isolated by gradient centrifugation from blood samples obtained from 10 multiparous women, 20 pregnant women (11-14th week of pregnancy), and 20 RSA women, at maximum of 72 h after miscarriage. The PBMCs were stained for flow cytometry analysis. Standard flow cytometry immunophenotyping of PBMCs was performed using antibodies against classical lymphocyte markers, including CD3, CD4, CD8, CD56, CD25, and CD127. Additionally, ICPs were investigated using antibodies against Programmed Death Protein-1 (PD-1, CD279), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3, CD366), V-domain Ig suppressor of T cell activation (VISTA), T cell immunoglobulin and ITIM domain (TIGIT), and Lymphocyte activation gene 3 (LAG-3). We observed differences in the surface expression of ICPs in the analyzed subpopulations of lymphocytes between early pregnancy and RSA, after miscarriage, and in women. We noted diminished expression of PD-1 on T lymphocytes (p = 0.0046), T helper cells (CD3CD4 positive cells, p = 0.0165), T cytotoxic cells (CD3CD8 positive cells, p = 0.0046), T regulatory lymphocytes (CD3CD4CD25CD127 low positive cells, p = 0.0106), and NKT cells (CD3CD56/CD16 positive cells, p = 0.0438), as well as LAG-3 on lymphocytes T (p = 0.0225) T helper, p = 0.0426), T cytotoxic cells (p = 0.0458) and Treg (p = 0.0293), and cells from RSA women. Impaired expression of TIM-3 (p = 0.0226) and VISTA (p = 0.0039) on CD8 cytotoxic T and NK (TIM3 p = 0.0482; VISTA p = 0.0118) cells was shown, with an accompanying increased expression of TIGIT (p = 0.0211) on NKT cells. The changes in the expression of surface immune checkpoints indicate their involvement in the regulation of pregnancy. The data might be utilized to develop specific therapies for RSA women based on the modulation of ICP expression.

TESC associated with poor prognosis enhances cancer stemness and migratory properties in liver cancer

Liver cancer stem cells (LCSCs) are responsible for recurrence, metastasis, and drug resistance in liver cancer. However, the genes responsible for inducing LCSCs have not been fully identified. Based on our previous study, we found that tescalcin (TESC), a calcium-binding EF hand protein that plays a crucial role in chromatin remodeling, transcriptional regulation, and epigenetic modifications, was up-regulated in LCSCs of spheroid cultures. By searching the Cancer Genome Atlas, International Cancer Genome Consortium, Human Protein Atlas, and Kaplan–Meier Plotter databases, we found that TESC expression was significantly elevated in liver cancer compared with that in normal liver tissue and was predictive of a decreased overall survival rate. Multivariate Cox analysis revealed TESC to be an independent prognostic factor for survival. High TESC expression was positively associated with cancer stem cell pathways, cancer stem cell surface markers, stemness transcription factors, epithelial–mesenchymal transition (EMT) factors, immune checkpoint proteins, and various cancer-related biological processes in liver cancer. Furthermore, TESC was implicated as promoting cancer stem cell properties through its influence on EMT. We demonstrated that TESC is a novel stemness-related gene that can serve as an independent prognostic factor for liver cancer.

Structural basis for mouse LAG3 interactions with the MHC class II molecule I-Ab

The immune checkpoint protein, Lymphocyte activation gene-3 (LAG3), binds Major Histocompatibility Complex Class II (MHC-II) and suppresses T cell activation. Despite the recent FDA approval of a LAG3 inhibitor for the treatment of melanoma, how LAG3 engages MHC-II on the cell surface remains poorly understood. Here, we determine the 3.84 Å-resolution structure of mouse LAG3 bound to the MHC-II molecule I-Ab, revealing that domain 1 (D1) of LAG3 binds a conserved, membrane-proximal region of MHC-II spanning both the α2 and β2 subdomains. LAG3 dimerization restricts the intermolecular spacing of MHC-II molecules, which may attenuate T cell activation by enforcing suboptimal signaling geometry. The LAG3-MHC-II interface overlaps with the MHC-II-binding site of the T cell coreceptor CD4, implicating disruption of CD4-MHC-II interactions as a mechanism for LAG3 immunosuppressive function. Lastly, antibody epitope analysis indicates that multiple LAG3 inhibitors do not recognize the MHC-II-binding interface of LAG3, suggesting a role for functionally distinct mechanisms of LAG3 antagonism in therapeutic development.

Nanoparticles targeting immune checkpoint protein VISTA induce potent antitumor immunity

BackgroundImmune checkpoint protein V-domain immunoglobulin suppressor of T cell activation (VISTA) controls antitumor immunity and is a valuable target for cancer immunotherapy. Previous mechanistic studies have indicated that VISTA impairs...

Application of Proteomics Technology Based on LC-MS Combined with Western Blotting and Co-IP in Antiviral Innate Immunity.

As an interferon-stimulating factor protein, STING plays a role in the response and downstream liaison in antiviral natural immunity. Upon viral invasion, the immediate response of STING protein leads to a series of changes in downstream proteins, which ultimately leads to an antiviral immune response in the form of proinflammatory cytokines and type I interferons, thus triggering an innate immune response, an adaptive immune response in vivo, and long-term protection of the host. In the field of antiviral natural immunity, it is particularly important to rigorously and sequentially probe the dynamic changes in the antiviral natural immunity connector protein STING caused by the entire anti-inflammatory and anti-pathway mechanism and the differences in upstream and downstream proteins. Traditionally, proteomics technology has been validated by detecting proteins in a 2D platform, for which it is difficult to sensitively identify changes in the nature and abundance of target proteins. With the development of mass spectrometry (MS) technology, MS-based proteomics has made important contributions to characterizing the dynamic changes in the natural immune proteome induced by viral infections. MS analytical techniques have several advantages, such as high throughput, rapidity, sensitivity, accuracy, and automation. The most common techniques for detecting complex proteomes are liquid chromatography (LC) and mass spectrometry (MS). LC-MS (Liquid Chromatography-Mass Spectrometry), which combines the physical separation capability of LC and the mass analysis capability of MS, is a powerful technique mainly used for analyzing the proteome of cells, tissues, and body fluids. To explore the combination of traditional proteomics techniques such as Western blotting, Co-IP (co-Immunoprecipitation), and the latest LC-MS methods to probe the anti-inflammatory pathway and the differential changes in upstream and downstream proteins induced by the antiviral natural immune junction protein STING.

Circulating miRNAs modulating systemic low-grade inflammation and affecting neurodegeneration

Objective and design: Inflammatory processes are an important part of the etiology of many chronic diseases across various medical domains, including neurodegeneration. Understanding their regulation on the molecular level represents a major challenge. Regulatory microRNAs (miRNAs), have been recognized for their role in post-transcriptionally modulating immune-related pathways serving as biomarkers for numerous diseases. Subjects and Methods: This study aims to investigate the association between 176 plasma-circulating miRNAs and the blood-based immune markers C-reactive protein and fibrinogen within the general population-based SHIP-TREND-0 cohort (N = 801) and assess their impact on neurodegeneration in linear regression and moderation analyses. Results: We provide strong evidence for miRNA-mediated regulation, particularly in relation to fibrinogen, identifying 48 significant miRNAs with a pronounced over-representation in chronic inflammatory and neurological diseases. Additional moderation analyses explored the influence of the APOE ε4 genotype and brain white matter neurodegeneration on the association between miRNAs and inflammation. Again, significant associations were observed for fibrinogen with special emphasize on hsa-miR-148a-3p, known to impact on neuroinflammation. Conclusions: Our study suggests the involvement of several plasma-circulating miRNAs in regulating immunological markers while also being linked to neurodegeneration. The strong interplay between miRNAs and inflammation holds promising potential for clinical application in many immune-related neurodegenerative diseases.

Impact of low-dose UV-A in Caenorhabditis elegans during candidate bacterial infections.

Ultraviolet radiation is a non-ionizing radiation produced by longer wavelength energy sources with lower frequency and is categorized into UV-A, UV-B, and UV-C. Minimal exposure to this radiation has several health benefits, which include treating microbial contaminations and skin therapies. However, the antimicrobial action of low-dose UV-A during pathogenic bacterial infections is still unrevealed. In this study, the impact of low-dose UV-A as pre- or post-treatment using the model organism, Caenorhabditis elegans with candidate pathogens (Acinetobacter baumannii and Staphylococcus aureus) mediated infections was investigated. The results indicated enrichment of metabolites, reduced level of antioxidants, increased expression of dopamine biosynthesis and transportation, and decrease in serotonin biosynthesis when the organism was exposed to low-dose UV-A for 5 min. This, in turn, elevated the expression of candidate regulatory proteins involved in lifespan determination, innate immunity, and cAMP-response element binding protein (CREB), which appear to increase the lifespan and brood size of C. elegans during A. baumannii and S. aureus infections. The findings suggested that the low-dose UV-A treatment during A. baumannii and S. aureus infections prolonged the lifespan and increased the egg-laying capacity of C. elegans.

A Bioinformatics Investigation of Hub Genes Involved in Treg Migration and Its Synergistic Effects, Using Immune Checkpoint Inhibitors for Immunotherapies.

This study aimed to identify hub genes involved in regulatory T cell (Treg) function and migration, offering insights into potential therapeutic targets for cancer immunotherapy. We performed a comprehensive bioinformatics analysis using three gene expression microarray datasets from the GEO database. Differentially expressed genes (DEGs) were identified to pathway enrichment analysis to explore their functional roles and potential pathways. A protein-protein interaction network was constructed to identify hub genes critical for Treg activity. We further evaluated the co-expression of these hub genes with immune checkpoint proteins (PD-1, PD-L1, CTLA4) and assessed their prognostic significance. Through this comprehensive analysis, we identified CCR8 as a key player in Treg migration and explored its potential synergistic effects with ICIs. Our findings suggest that CCR8-targeted therapies could enhance cancer immunotherapy outcomes, with breast invasive carcinoma (BRCA) emerging as a promising indication for combination therapy. This study highlights the potential of CCR8 as a biomarker and therapeutic target, contributing to the development of targeted cancer treatment strategies.

MicroRNA 29a alleviates mitochondrial stress in diet-induced NAFLD by inhibiting the MAVS pathway

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder characterized by fat accumulation in the liver. This leads to aggravated hepatocyte inflammation due to impaired mitochondrial function, mitochondrial double-stranded RNA (mt-dsRNA) release, elevated oxidative stress, and reactive oxygen species (ROS) production.MicroRNA-29a (miR-29a) is used to reduce hepatic fibrosis in cases of cholestatic liver damage and lessen the severity of non-alcoholic steatohepatitis in animal studies by influencing mitochondrial protein balance. However, the effectiveness of miR-29a in diminishing mt-dsRNA-induced exacerbation of NAFLD remains poorly understood, particularly in the context of a Western diet (WD). Our results have found that mice with increased miR-29a levels and fed a WD showed notably decreased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, and low-density lipoprotein cholesterol levels. They also experienced less weight gain and lower final body and liver weights. In addition, overexpression of miR-29a reduced the severity of fibrosis, alleviated hepatic oxidative stress, misfolded protein aggregates, and the release of mt-dsRNA. Moreover, miR-29a attenuated the innate immune mitochondrial antiviral-signaling protein (MAVS) pathway response. In vitro, the research using HepG2 cells confirmed that miR-29a reduces MAVS expression and decreases the release of mt-dsRNA and superoxide initiated by palmitic acid (PA). Analysis of luciferase activity further established that the specific binding of miR-29a to the 3′UTR of MAVS led to a repression of its expression. In conclusion, these groundbreaking findings underscore the potential of miR-29a in improving the treatment of NAFLD and liver steatofibrosis by inhibiting the MAVS signaling pathway.

Conservation of antiviral systems across domains of life reveals immune genes in humans

Deciphering the immune organization of eukaryotes is important for human health and for understanding ecosystems. The recent discovery of antiphage systems revealed that various eukaryotic immune proteins originate from prokaryotic antiphage systems. However, whether bacterial antiphage proteins can illuminate immune organization in eukaryotes remains unexplored. Here, we use a phylogeny-driven approach to uncover eukaryotic immune proteins by searching for homologs of bacterial antiphage systems. We demonstrate that proteins displaying sequence similarity with recently discovered antiphage systems are widespread in eukaryotes and maintain a role in human immunity. Two eukaryotic proteins of the anti-transposon piRNA pathway are evolutionarily linked to the antiphage system Mokosh. Additionally, human GTPases of immunity-associated proteins (GIMAPs) as well as two genes encoded in microsynteny, FHAD1 and CTRC, are respectively related to the Eleos and Lamassu prokaryotic systems and exhibit antiviral activity. Our work illustrates how comparative genomics of immune mechanisms can uncover defense genes in eukaryotes.

Multi-omics profiling reveals peripheral blood biomarkers of multiple sclerosis: implications for diagnosis and stratification.

Multiple sclerosis (MS), a chronic autoimmune disorder marked by demyelination in the central nervous system, is exceptionally uncommon in China, and remains poorly understood in terms of its peripheral blood manifestations. We conducted a cohort study comprising 39 MS patients and 40 normal controls (NC). High-dimensional mass cytometry, protein arrays, and targeted metabolomics were utilized to profile immune subsets, proteins, and metabolites in blood. Differences in multi-omics signatures were scrutinized across varying MS subtypes. Immune profiling demonstrated an elevation in various B cell subsets and monocytes, alongside a reduction in dendritic cells among MS patients. Proteomic data revealed a downregulation in neurotrophic and tissue repair proteins. Metabolomic assessment showed a noted decrease in anti-inflammatory molecules and sphingolipids. Integrated analysis identified distinct molecular patterns distinguishing MS from controls. Additionally, multi-omics differences among different MS subtypes were uncovered. Notably, hippuric acid levels was consistently lower in MS subgroups with greater disease severity. This study represents the pioneering exploration of multi-omics in Chinese MS patients, presenting a comprehensive view of the peripheral blood changes in MS. Our study underscores the robust capability of multi-omics assessments in identifying peripheral blood biomarkers that delineate the varied clinical presentation, and facilitates future development of biomarkers and targeted therapeutic interventions in MS.

Etoposide/unspecified immune checkpoint protein inhibitors/unspecified platinum complexes

Etoposide/unspecified immune checkpoint protein inhibitors/unspecified platinum complexes

Identification of gene and protein signatures associated with long-term effects of COVID-19 on the immune system after patient recovery by analyzing single-cell multi-omics data using a machine learning approach

Viral infections significantly impact the immune system, and impact will persist until recovery. However, the influence of severe acute respiratory syndrome coronavirus 2 infection on the homeostatic immune status and secondary immune response in recovered patients remains unclear. To investigate these persistent alterations, we employed five feature-ranking algorithms (LASSO, MCFS, RF, CATBoost, and XGBoost), incremental feature selection, synthetic minority oversampling technique and two classification algorithms (decision tree and k-nearest neighbors) to analyze multi-omics data (surface proteins and transcriptome) from coronavirus disease 2019 (COVID-19) recovered patients and healthy controls post-influenza vaccination. The single-cell multi-omics dataset was divided into five subsets corresponding to five immune cell subtypes: B cells, CD4+ T cells, CD8+ T cells, Monocytes, and Natural Killer cells. Each cell was represented by 28,402 scRNA-seq (RNA) features, 3 Hash Tag Oligo (HTO) features, 138 Cellular indexing of transcriptomes and epitopes by sequencing (CITE) features and 23,569 Single Cell Transform (SCT) features. Some multi-omics markers were identified and effective classifiers were constructed. Our findings indicate a distinct immune status in COVID-19 recovered patients, characterized by low expression of ribosomal protein (RPS26) and high expression of immune cell surface proteins (CD33, CD48). Notably, TMEM176B, a membrane protein, was highly expressed in monocytes of COVID-19 convalescent patients. These observations aid in discerning molecular differences among immune cell subtypes and contribute to understanding the prolonged effects of COVID-19 on the immune system, which is valuable for treating infectious diseases like COVID-19.

Fungal Extracellular Vesicle Proteins with Potential in Biological Interaction.

Extracellular vesicles (EVs) are vesicle-like structures composed of lipid bilayers, which can be divided into apoptotic bodies, microbubbles and exosomes. They are nanoparticles used for the exchange of information between cells. EVs contains many substances, including protein. With the development of proteomics, we know more about the types and functions of protein in vesicles. The potential functions of proteins in the envelope are mainly discussed, including cell wall construction, fungal virulence transmission, signal transmission and redox reactions, which provides a new perspective for studying the interaction mechanism between fungi and other organisms. The fungal protein markers of EVs are also summarized, which provided an exploration tool for studying the mechanism of vesicles. In addition, the possible role of immune protein in the EVs in the treatment of human diseases is also discussed, which provides new ideas for vaccine development.

Maternal immune activation accelerates pup reflex development and alters immune proteins in pup stomach contents and brain

Prenatal infection increases the risk for neurodevelopmental disorders including autism spectrum disorder and schizophrenia. To better understand this link, a number of maternal immune activation (MIA) rodent models have been studied. However, the majority of these studies focus on adult behavioural outcomes that mirror adult symptoms related to neurodevelopmental disorders. There is little research reporting the effects of MIA on early postnatal development and even fewer using outbred mouse strains. Here, we use a modified version of the Fox scale to assess the effects of two MIA models, a bacterial model (LPS) and a viral model (PolyIC), on overall mouse pup sensorimotor development in CD-1 mice. Surprisingly, both bacterial and viral MIA models resulted in early reflex development when compared with control pups. To better characterize potential factors related to these changes, we examined indicators of sickness/inflammation in the immune-activated dams and in their pups. Sickness behaviour in the dams resulting from immune activation was assessed using a telemetry implant that allowed for continuous recording of temperature and activity in dams exposed to bacterial or viral immune activation. Although MIA dams showed reduced activity on the day immediately following MIA compared to controls, there was no evidence of fever. All dams showed elevated cytokines/chemokines associated with parturition, but this resolved by day 10 post-parturition and was unaffected by previous immune activation. Although circulating cytokines/chemokines in the dams were similar across MIA treatments, there were differences in the amount of interleukin-12p70 and interleukin-13 present in milk taken from milk bands in MIA pups, and interleukin-4 was overall decreased in LPS pup brain. These findings demonstrate that bacterial and viral models of MIA can result in similar precocious development in mice but differing long-term effects on inflammatory markers in both the milk provided to the pups and in their brains.

Comprehensive landscapes of the causal network between immunity and sarcopenia.

Inflammaging, an immune status characterized by a sustained increase in pro-inflammatory markers and a decline in anti-inflammatory mechanisms, is a critical risk factor in the development of sarcopenia. Landscapes of the causal relationships between immunity and sarcopenia are needed to understand the mechanism of sarcopenia and provide novel treatments comprehensively. We used Mendelian Randomization (MR) as the basic method in this study. By setting immune proteins, immune cells, and sarcopenia as exposures and outcomes alternatively, and then combining them in different directions, we potentially estimated their causal relationships and directions and subsequently mapped the comprehensive causal landscape based on this information efficiently. To further understand the network, we developed a method based on rank-sums to integrate multiple algorithms and identify the key immune cells and proteins. More than 1,000 causal relationships were identified between immune cell phenotypes, proteins, and sarcopenia traits (p < 0.05), and the causal maps of these linkages were established. In the threshold of FDR < 0.05, hundreds of causal linkages were still significant. The final comprehensive map included 13 immune cell phenotypes and 8 immune proteins. The star factors in the final map included EM CD8br %CD8br, EM DN (CD4- CD8-) %DN, SIRT2, and so on. By reading the landscapes in this study, we may not only find the factors and the pathways that have been reported and proven but also identify multiple novel immunity cell phenotypes and proteins with enriched upstream and downstream pathways.

Identification of protein biomarkers in wastewater linked to the incidence of COVID-19

Wastewater-based epidemiological (WBE) surveillance is a viable disease surveillance technique capable of monitoring the spread of infectious disease agents in sewershed communities. In addition to detecting viral genomes in wastewater, WBE surveillance can identify other endogenous biomarkers that are significantly elevated and excreted in the saliva, urine, and/or stool of infected individuals. Human protein biomarkers allow the realization of real-time WBE surveillance using highly sensitive biosensors. In this study, we analyzed endogenous protein biomarkers present in wastewater influent through liquid chromatography–tandem mass spectrophotometry and scaffold data-independent acquisition to identify candidate target protein biomarkers for WBE surveillance of SARS-CoV-2. We found that out of the 1382 proteins observed in the wastewater samples, 44 were human proteins associated with infectious diseases. These included immune response substances such as immunoglobulins, cytokine–chemokines, and complements, as well as proteins belonging to antimicrobial and antiviral groups. A significant correlation was observed between the intensity of human infectious disease-related protein biomarkers in wastewater and COVID-19 case numbers. Real-time WBE surveillance using biosensors targeting immune response proteins, such as antibodies or immunoglobulins, in wastewater holds promise for expediting the implementation of relevant policies for the effective prevention of infectious diseases in the near future.