Search

Purpose: Human OX40 (hOX40/CD134), a member of the TNF receptor superfamily, is mainly expressed on activated T lymphocytes. Triggered by its ligand OX40L (CD252), it provides costimulatory signals that support the differentiation, proliferation and long-term survival of T cells. Besides being a relevant therapeutic target, hOX40 is also an important biomarker for monitoring the presence or infiltration of activated T cells within the tumor microenvironment (TME), the inflammatory microenvironment (IME) in immune-mediated diseases (IMIDs) and the lymphatic organs. Here, we developed novel single domain antibodies (nanobodies, Nbs) targeting hOX40 to monitor the activation status of T cells by in vivo molecular imaging. Methods: Nbs against hOX40 (hOX40-Nbs) were selected from an immunized Nb-library by phage display. The identified hOX40-Nbs were characterized in vitro, including determination of their specificity, affinity, stability, epitope recognition and their impact on OX40 signaling and T cell function. A lead candidate was site-specifically conjugated with a fluorophore via sortagging and applied for noninvasive in vivo optical imaging (OI) of hOX40-expressing cells in a xenograft mouse model. Results: Our selection campaign revealed four unique Nbs that exhibit strong binding affinities and high stabilities under physiological conditions. Epitope binning and domain mapping indicated the targeting of at least two different epitopes on hOX40. When analyzing their impact on OX40 signaling, an agonistic effect was excluded for all validated Nbs. Incubation of activated T cells with hOX40-Nbs did not affect cell viability or proliferation patterns, whereas differences in cytokine release were observed. In vivo OI with a fluorophoreconjugated lead candidate in experimental mice with hOX40-expressing xenografts demonstrated its specificity and functionality as an imaging probe. Conclusion: Considering the need for advanced probes for noninvasive in vivo monitoring of T cell activation dynamics, we propose, that our hOX40-Nbs have a great potential as imaging probes for noninvasive and longitudinal in vivo diagnostics. Quantification of OX40+ T cells in TME or IME will provide crucial insights into the activation state of infiltrating T cells, offering a valuable biomarker for assessing immune responses, predicting treatment efficacy, and guiding personalized immunotherapy strategies in patients with cancer or IMIDs. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases constitute a global health issue and a major economic burden. They significantly impair both cognitive and motor functions, and their prevalence is expected to rise due to ageing societies and continuous population growth. Conventional therapies provide symptomatic relief, nevertheless, disease-modifying treatments that reduce or halt neuron death and malfunction are still largely unavailable. Amongst the common hallmarks of neurodegenerative diseases are protein aggregation, oxidative stress, neuroinflammation and mitochondrial dysfunction. Transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2) constitutes a central regulator of cellular defense mechanisms, including the regulation of antioxidant, antiinflammatory and mitochondrial pathways, making it a highly attractive therapeutic target for disease modification in neurodegenerative disorders. Here, we describe the role of NRF2 in the common hallmarks of neurodegeneration, review the current pharmacological interventions and their challenges in activating the NRF2 pathway, and present alternative therapeutic approaches for disease modification. [ABSTRACT FROM AUTHOR]

Haemodialysis patients respond poorly to vaccination and continue to be at-risk for severe COVID-19. Therefore, dialysis patients were among the first for which a fourth COVID-19 vaccination was recommended. However, targeted information on how to bestmaintain immune protection after SARS-CoV-2 vaccinations in atrisk groups for severe COVID-19 remains limited. We provide, to the best of our knowledge, for the first time longitudinal vaccination response data in dialysis patients and controls after a triple BNT162b2 vaccination and in the latter after a subsequent fourth full-dose of mRNA-1273. We analysed systemic and mucosal humoral IgG responses against the receptor-binding domain (RBD) and ACE2-binding inhibition towards variants of concern including Omicron and Delta with multiplex-based immunoassays. In addition, we assessed Spike S1-specific T-cell responses by interferon γ release assay. After triple BNT162b2 vaccination, anti-RBD B.1 IgG and ACE2 binding inhibition reached peak levels in dialysis patients, but remained inferior compared to controls. Whilst we detected B.1-specific ACE2 binding inhibition in 84% of dialysis patients after three BNT162b2 doses, binding inhibition towards the Omicron variant was only detectable in 38% of samples and declining to 16% before the fourth vaccination. By using mRNA-1273 as fourth dose, humoral immunity against all SARS-CoV-2 variants tested was strongly augmented with 80% of dialysis patients having Omicron-specific ACE2 binding inhibition. Modest declines in T-cell responses in dialysis patients and controls after the second vaccination were restored by the third BNT162b2 dose and significantly increased by the fourth vaccination. Our data support current advice for a fourdose COVID-19 immunisation scheme for at-risk individuals such as haemodialysis patients. We conclude that administration of a fourth full-dose of mRNA-1273 as part of a mixed mRNA vaccination scheme to boost immunity and to prevent severe COVID-19 could also be beneficial in other immune impaired individuals. Additionally, strategic application of such mixed vaccine regimens may be an immediate response against SARS-CoV-2 variants with increased immune evasion potential. [ABSTRACT FROM AUTHOR]

Aims/Objectives: Wound healing in people with diabetes is delayed secondary to impaired nitric oxide generation, advanced glycation end products (AGE), and poor migration of epithelial cells. We developed a novel topical esmolol hydrochloride (Galnobax) and assessed its efficacy for wound healing in streptozocin-induced diabetic hairless rat. Methods: All experiments were performed at an animal laboratory and tertiarycare research facility. Ex vivo aldose reductase inhibition was assessed from enzymes obtained from a bacterial culture (spectrophotometer), sorbitol content in homogenized red blood cells, and AGE in glucose and bovine serum by fluorometry following the addition of esmolol in varying concentrations. A scratch assay of human fibroblasts, endothelial cells, and keratinocytes was assessed under a high-glucose environment and after esmolol by phase-contrast microscopy. The efficacy evaluation of the topical application of Galnobax (14 and 20%) or vehicle was conducted in streptozotocin-induced diabetic hairless rats, and endogenous nitrite and hydroxyproline from homogenized wound tissue were measured along with pharmacokinetic and dermal toxicity in Hanford miniature swine. Results: Esmolol inhibited the formation of sorbitol by 59% in erythrocytes in comparison to glucose-induced sorbitol levels. AGE generation in bovine serum albumin was reduced at 1 mM esmolol concentrations (2.6 ± 1.7) compared with control (p < 0.05) and similar to that of diclofenac (2.5 ± 1.3). Esmolol at 1 and 10 μM enhanced the migration of fibroblasts, epithelial cells, and keratinocytes compared with control. The nitric oxide levels (day 7) were 44 and 112% higher with Galnobax (14%) than those of the diabetic group (p < 0.05) and the vehicle control group (p < 0.05), respectively. The days 7 and 14 hydroxyproline in the wound was higher by 22 and 44% following Galnobax (14%) compared with the diabetic and vehicle control groups. The wound area exhibited better reduction with Galnobax at 14% up to day 10 follow-up compared with the controls. The pharmacokinetic and dermal toxicity in miniature swine suggested no significant adverse event with Galnobax. Conclusions: Topical esmolol hydrochloride is a novel, safe, and effective treatment modality that acts through pleotropic mechanisms to hasten wound healing in diabetes. [ABSTRACT FROM AUTHOR]

Recent developments in multiplex technologies enable the determination of a large nu\mber of soluble proteins such as cytokines in various biological samples. More than a one-by-one determination of the concentration of immune mediators, they permit the establishment of secretion profiles for a more accurate description of conditions related to infectious diseases or vaccination. Cytokine profiling has recently been made available for bovine species with the development of a Luminex® technology-based 15-plex assay. Independently from the manufacturer, we evaluated the bovine cytokine/chemokine multiplex assay for limits of detection, recovery rate, and reproducibility. Furthermore, we assessed cytokine secretion in blood samples from 107 cows upon stimulation with heat-killed bacteria and TLR2/4 ligands compared to a null condition. Secretion patterns were analyzed either using the absolute concentration of cytokines or using their relative concentration with respect to the overall secretion level induced by each stimulus. Using Partial Least Square-Discriminant Analysis, we show that the 15-cytokine profile is different under Escherichia coli , Staphylococcus aureus , and Streptococcus uberis conditions, and that IFN-γ, IL-1β, and TNF-α contribute the most to differentiate these conditions. LPS and E. coli induced largely overlapping biological responses, but S. aureus and S. uberis were associated with distinct cytokine profiles than their respective TLR ligands. Finally, results based on adjusted or absolute cytokine levels yielded similar discriminative power, but led to different stimuli-related signatures. [ABSTRACT FROM AUTHOR]

Recent advances in single-cell technologies, particularly single-cell RNA-sequencing (scRNA-seq), have permitted high throughput transcriptional profiling of a wide variety of biological systems. As scRNA-seq supports inference of cell-cell communication, this technology has and continues to anchor groundbreaking studies into the efficacy and mechanism of novel immunotherapies for cancer treatment. In this review, we will highlight methods developed to infer inter- and intracellular signaling from scRNA-seq and discuss how they have contributed to studies of immunotherapeutic intervention in the tumor microenvironment (TME). However, a central challenge remains in validating the hypothesized cell-cell interactions. Therefore, this review will also cover strategies for integration of these scRNA-seq-derived interaction networks with existing experimental and computational approaches. Integration of these networks with imaging, protein secretion measurements, and network analysis and mathematical modeling tools addresses challenges that remain with scRNA-seq to enhance studies of immunosuppressive and immunotherapy-altered signaling in the TME. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is widely considered to be a disabling neurodegenerative disorder, which has been ranked second worldwide just after Alzheimer's disease. Until present, a wide range of studies has focused on the role of circulating inflammatory cytokines in the development of PD. However, the causal relationship between circulating inflammatory cytokines and the risk and age at the onset of PD has not been elucidated. Hence, to evaluate the effects of circulating inflammatory cytokines on the risk or age at the onset of PD more accurately, we conducted this two-sample Mendelian randomization (MR) study involving summary statistics from genome-wide association studies (GWASs). Totally, we included a GWAS for inflammatory cytokines (8,293 participants), a meta-analysis of GWASs for PD risk (482,730 participants), and a GWAS dataset for age at the onset of PD (17,996 patients with PD). A total of 149 and 131 polymorphisms for exploring relationships between 19 inflammatory cytokines and the risk and age at the onset of PD were obtained as instrumental variants. Then, we used a total of five MR methods, including inverse-variance weighted (IVW), Wald ratio, MR Egger regression, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. Finally, we found a causal association between circulating levels of macrophage inflammatory protein-1 beta (MIP1b) and PD risk in the IVW method (OR: 1.06; 95% CI: 1.02–1.10; P = 0.001). Meanwhile, other MR estimates by weighted median and MR-PRESSO methods yielded similar effect estimates. Besides, we identified a suggestive association of interleukin-16 (IL-16) levels with PD risk (OR: 1.08; 95% CI: 1.00–1.17; P = 0.037). For age at PD onset, there was no evidence supporting its correlation with inflammatory cytokines. Our findings implied that MIP1b and IL-16 may be novel biomarkers and promising therapeutic targets for PD development. [ABSTRACT FROM AUTHOR]

Background: An involvement of the central-nervous and peripheral, innate and adaptive immune system in the pathogenesis of Parkinson's disease (PD) is nowadays well established. Objectives: We face several open questions in preparation of clinical trials aiming at disease-modification by targeting the immune system: Do peripheral (blood) inflammatory profiles reflect central (CSF) inflammatory processes? Are blood/CSF inflammatory markers associated with CSF levels of neurodegenerative/PD-specific biomarkers? Methods: Using a multiplex assay we assessed 41 inflammatory markers in CSF/serum pairs in 453 sporadic PD patients. We analyzed CSF/serum correlation as well as associations of inflammatory markers with clinical outcome measures (UPDRS-III, H&Y, MoCA) and with CSF levels of α-synuclein, Aβ1−42, t- Tau, p181-Tau and NFL. All analyses were stratified by sex as the immune system shows relevant sex-specific differences. Results: Correlations between CSF and serum were sparse and detected in only 25% (9 out of 36) of the analysable inflammatory markers in male PD patients and in only 38% (12 out of 32) of female PD patients. The most important pro-inflammatory mediators associated with motor and cognitive decline as well as with neurodegenerative/PD-specific biomarkers were FABP, ICAM-1, IL-8, MCP-1, MIP-1-beta, and SCF. Results were more robust for CSF than for serum. Interpretation: Levels of central-nervous and peripheral inflammatory markers might be regulated independently of each other with CSF inflammatory markers reflecting CNS pathology more accurately than peripheral markers. These findings along with sex-specific characteristics have to be considered when designing clinical trials aiming at disease-modification by targeting the immune system. [ABSTRACT FROM AUTHOR]

Recent increases in SARS-CoV-2 infections have led to questions about duration and quality of vaccine-induced immune protection. While numerous studies have been published on immune responses triggered by vaccination, these often focus on studying the impact of one or two immunisation schemes within subpopulations such as immunocompromised individuals or healthcare workers. To provide information on the duration and quality of vaccine-induced immune responses against SARS-CoV-2, we analyzed antibody titres against various SARS-CoV-2 antigens and ACE2 binding inhibition against SARS-CoV-2 wild-type and variants of concern in samples from a large German population-based seroprevalence study (MuSPAD) who had received all currently available immunisation schemes. We found that homologous mRNA-based or heterologous prime-boost vaccination produced significantly higher antibody responses than vector-based homologous vaccination. Ad26.CoV2S.2 performance was particularly concerning with reduced titres and 91.7% of samples classified as non-responsive for ACE2 binding inhibition, suggesting that recipients require a booster mRNA vaccination. While mRNA vaccination induced a higher ratio of RBD- and S1-targeting antibodies, vector-based vaccines resulted in an increased proportion of S2-targeting antibodies. Given the role of RBD- and S1-specific antibodies in neutralizing SARS-CoV-2, their relative over-representation after mRNA vaccination may explain why these vaccines have increased efficacy compared to vector-based formulations. Previously infected individuals had a robust immune response once vaccinated, regardless of which vaccine they received, which could aid future dose allocation should shortages arise for certain manufacturers. Overall, both titres and ACE2 binding inhibition peaked approximately 28 days post-second vaccination and then decreased. [ABSTRACT FROM AUTHOR]

Viruses play a key role in explaining the pathogenesis of various autoimmune disorders, whose underlying principle is defined by the activation of autoreactive T-cells. In many cases, T-cells escape self-tolerance due to the failure in encountering certain MHC-I self-peptide complexes at substantial levels, whose peptides remain invisible from the immune system. Over the years, contribution of unstable defective ribosomal products (DRiPs) in immunosurveillance has gained prominence. A class of unstable products emerge from non-canonical translation and processing of unannotated mammalian and viral ORFs and their peptides are cryptic in nature. Indeed, high throughput sequencing and proteomics have revealed that a substantial portion of our genomes comprise of non-canonical ORFs, whose generation is significantly modulated during disease. Many of these ORFs comprise short ORFs (sORFs) and upstream ORFs (uORFs) that resemble DRiPs and may hence be preferentially presented. Here, we discuss how such products, normally "hidden" from the immune system, become abundant in viral infections activating autoimmune T-cells, by discussing their emerging role in infection and disease. Finally, we provide a perspective on how these mechanisms can explain several autoimmune disorders in the wake of the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

The advancement of new immunotherapies necessitates appropriate probes to monitor the presence and distribution of distinct immune cell populations. Considering the key role of CD4+ cells in regulating immunological processes, we generated novel single-domain antibodies [nanobodies (Nbs)] that specifically recognize human CD4. After in-depth analysis of their binding properties, recognized epitopes, and effects on T-cell proliferation, activation, and cytokine release, we selected CD4-specific Nbs that did not interfere with crucial T-cell processes in vitro and converted them into immune tracers for noninvasive molecular imaging. By optical imaging, we demonstrated the ability of a high-affinity CD4-Nb to specifically visualize CD4+ cells in vivo using a xenograft model. Furthermore, quantitative high-resolution immune positron emission tomography (immunoPET)/MR of a human CD4 knock-in mouse model showed rapid accumulation of 64Cu-radiolabeled CD4-Nb1 in CD4+ T cell-rich tissues. We propose that the CD4-Nbs presented here could serve as versatile probes for stratifying patients and monitoring individual immune responses during personalized immunotherapy in both cancer and inflammatory diseases. [ABSTRACT FROM AUTHOR]

Sepsis is a complex syndrome promoted by pathogenic and host factors; it is characterized by dysregulated host responses and multiple organ dysfunction, which can lead to death. However, its underlying molecular mechanisms remain unknown. Proteomics, as a biotechnology research area in the post-genomic era, paves the way for large-scale protein characterization. With the rapid development of proteomics technology, various approaches can be used to monitor proteome changes and identify differentially expressed proteins in sepsis, which may help to understand the pathophysiological process of sepsis. Although previous reports have summarized proteomics-related data on the diagnosis of sepsis and sepsis-related biomarkers, the present review aims to comprehensively summarize the available literature concerning "sepsis", "proteomics", "cecal ligation and puncture", "lipopolysaccharide", and "post-translational modifications" in relation to proteomics research to provide novel insights into the molecular mechanisms of sepsis. [ABSTRACT FROM AUTHOR]

Introduction: Dermatophytes are a group of molds characterized by the ability to produce keratinases, thereby carving out for themselves specific ecological niches. Their traditional division into three genera, Trichophyton , Microsporum , and Epidermophyton has been expanded to nine and the species in each genus were modified. Dermatophytes are among the most prevalent causes of human and animal mycoses. Their epidemiology is influenced by various factors. These factors may be evolutive such as the predilected environment of the fungus, namely, humans (anthropophilic), animals (zoophilic), or environment (geophilic), is evolutionary and thus may require centuries to develop. Many other factors, however, result from a variety of causes, affecting the epidemiology of dermatophytoses within a shorter time frame. Objective: This review aims at summarizing the factors that have modified the epidemiology of dermatophytoses during the last decades. Results: Geographic and climatic conditions, demography such as age and gender, migration, socio-economic conditions, lifestyle, and the environment have had an impact on changes in the epidemiology of dermatophytoses, as have changes in the pattern of human interaction with animals, including pets, farm, and wild animals. A typical example of such changes is the increased prevalence of Trichophyton tonsurans , which spread from Latin America to the United States and subsequently becoming a frequent etiological agent of tinea capitis in Africa, Middle East, and other areas. Conclusion: The comprehension of the epidemiology of dermatophytoses has a major bearing on their prevention and treatment. Since it is undergoing continuous changes, periodic assessments of the most recent developments of this topic are required. This article aims at providing such an overview. [ABSTRACT FROM AUTHOR]

Purpose: In the tumor microenvironment, the functional differences among various tumor-associated macrophages (TAM) are not completely clear. Tumor-associated macrophages are thought to promote the progression of cancer. This article focuses on exploring M2 macrophage-related factors and behaviors of renal clear cell carcinoma. Method: We obtained renal clear cell carcinoma data from TCGA-KIRC-FPKM, GSE8050, GSE12606, GSE14762, and GSE3689. We used the "Cibersort" algorithm to calculate type M2 macrophage proportions among 22 types of immune cells. M2 macrophage-related co-expression module genes were selected using weighted gene co-expression network analysis (WGCNA). A renal clear cell carcinoma prognosis risk score was built based on M2 macrophage-related factors. The ROC curve and Kaplan–Meier analysis were performed to evacuate the risk score in various subgroups. The Pearson test was used to calculate correlations among M2 macrophage-related genes, clinical phenotype, immune phenotype, and tumor mutation burden (TMB). We measured differences in co-expression of genes at the protein level in clear renal cell carcinoma tissues. Results: There were six M2 macrophage co-expressed genes (F13A1, FUCA1, SDCBP, VSIG4, HLA-E, TAP2) related to infiltration of M2 macrophages; these were enriched in neutrophil activation and involved in immune responses, antigen processing, and presentation of exogenous peptide antigen via MHC class I. M2-related factor frequencies were robust biomarkers for predicting the renal clear cell carcinoma patient clinical phenotype and immune microenvironment. The Cox regression model, built based on M2 macrophage-related factors, showed a close prognostic correlation (AUC = 0.78). The M2 macrophage-related prognosis model also performed well in various subgroups. Using western blotting, we found that VSIG4 protein expression levels were higher in clear renal cell carcinoma tissues than in normal tissues. Conclusion: These co-expressed genes were most related to the M2 macrophage phenotype. They correlated with the immune microenvironment and predicted outcomes of renal clear cell carcinoma. These co-expressed genes and the biological processes associated with them might provide the basis for new strategies to intervene via chemotaxis of M2 macrophages. [ABSTRACT FROM AUTHOR]

Profiles of symbiotic microbial communities ("microbiomes") can provide insight into the natural history and ecology of their hosts. Using high throughput DNA sequencing of the 16S rRNA V4 region, microbiomes of five shark species in South Florida (nurse, lemon, sandbar, Caribbean reef, and tiger) have been characterized for the first time. The microbiomes show species specific microbiome composition, distinct from surrounding seawater. Shark anatomical location (gills, teeth, skin, cloaca) affected the diversity of microbiomes. An in-depth analysis of teeth communities revealed species specific microbial communities. For example, the genus Haemophilus , explained 7.0% of the differences of the teeth microbiomes of lemon and Caribbean reef sharks. Lemon shark teeth communities (n = 11) contained a high abundance of both Vibrio (10.8 ± 26.0%) and Corynebacterium (1.6 ± 5.1%), genera that can include human pathogenic taxa. The Vibrio (2.8 ± 6.34%) and Kordia (3.1 ± 6.0%) genera and Salmonella enterica (2.6 ± 6.4%) were the most abundant members of nurse shark teeth microbial communities. The Vibrio genus was highly represented in the sandbar shark (54.0 ± 46.0%) and tiger shark (5.8 ± 12.3%) teeth microbiomes. The prevalence of genera containing potential human pathogens could be informative in shark bite treatment protocols and future research to confirm or deny human pathogenicity. We conclude that South Florida sharks host species specific microbiomes that are distinct from their surrounding environment and vary due to differences in microbial community composition among shark species and diversity and composition among anatomical locations. Additionally, when considering the confounding effects of both species and location, microbial community diversity and composition varies. [ABSTRACT FROM AUTHOR]

There is currently a limited understanding of the morphological and functional organization of the olfactory system in cartilaginous fishes, particularly when compared to bony fishes and terrestrial vertebrates. In this fish group, there is a clear paucity of information on the characterization, density, and distribution of olfactory receptor neurons (ORNs) within the sensory olfactory epithelium lining the paired olfactory rosettes, and their functional implications with respect to the hydrodynamics of incurrent water flow into the nares. This imaging study examines the brownbanded bamboo shark Chiloscyllium punctatum (Elasmobranchii) and combines immunohistochemical labeling using antisera raised against five G-protein α-subunits (Gαs/olf, Gαq/11/14, Gαi–1/2/3, Gαi–3, Gα o ) with light and electron microscopy, to characterize the morphological ORN types present. Three main ORNs ("long", "microvillous" and "crypt-like") are confirmed and up to three additional microvilli-bearing types are also described; "Kappe-like" (potential or homologous "Kappe" as in teleosts), "pear-shaped" and "teardrop-shaped" cells. These morphotypes will need to be confirmed molecularly in the future. Using X-ray diffusible iodine-based contrast-enhanced computed tomography (diceCT), high-resolution scans of the olfactory rosettes, olfactory bulbs (OBs), peduncles, and telencephalon reveal a lateral segregation of primary olfactory inputs within the OBs, with distinct medial and lateral clusters of glomeruli, suggesting a potential somatotopic organization. However, most ORN morphotypes are found to be ubiquitously distributed within the medial and lateral regions of the olfactory rosette, with at least three microvilli-bearing ORNs labeled with anti-Gα o found in significantly higher densities in lateral lamellae [in lateral lamellae] and on the anterior portion of lamellae (facing the olfactory cavity). These microvilli-bearing ORN morphotypes (microvillous, "Kappe-like," "pear-shaped," and "teardrop-shaped") are the most abundant across the olfactory rosette of this species, while ciliated ORNs are less common and crypt cells are rare. Spatial simulations of the fluid dynamics of the incurrent water flow into the nares and within the olfactory cavities indicate that the high densities of microvilli-bearing ORNs located within the lateral region of the rosette are important for sampling incoming odorants during swimming and may determine subsequent tracking behavior. [ABSTRACT FROM AUTHOR]

Ras-associated binding (Rab) proteins are small GTPases that regulate the trafficking of membrane components during endocytosis and exocytosis including the release of extracellular vesicles (EVs). Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorder in the elderly population, where pathological proteins such as alpha-synuclein (α-Syn) are transmitted in EVs from one neuron to another neuron and ultimately across brain regions, thereby facilitating the spreading of pathology. We recently demonstrated fibroblast growth factor-2 (FGF2) to enhance the release of EVs and delineated the proteomic signature of FGF2-triggered EVs in cultured primary hippocampal neurons. Out of 235 significantly upregulated proteins, we found that FGF2 specifically enriched EVs for the two Rab family members Rab8b and Rab31. Consequently, we investigated the interactions of Rab8b and Rab31 using a network analysis approach in order to estimate the global influence of their enrichment in EVs. To achieve this, we have demarcated a protein–protein interaction network (PPiN) for these Rabs and identified the proteins associated with PD in various cellular components of the central nervous system (CNS), in different brain regions, and in the enteric nervous system (ENS). A total of 126 direct or indirect interactions were reported for two Rab candidates, out of which 114 are Rab8b interactions and 54 are Rab31 interactions, ultimately resulting in an individual interaction score (IS) of 90.48 and 42.86%, respectively. Conclusively, these results for the first time demonstrate the relevance of FGF2-induced Rab-enrichment in EVs and its potential to regulate PD pathophysiology. [ABSTRACT FROM AUTHOR]

Background: Non-motor symptoms are common in Parkinson's disease (PD) and can even be used as part of the supportive criteria for diagnosis. Chronic inflammation is involved in every stage of PD. Disorders of the immune system affect the peripheral blood. Whether the humoral immune response is associated with the non-motor symptoms of PD remains unknown. Methods: Mann–Whitney tests and Bonferroni correction were used to compare the serum levels of IgG, IgA, IgM, C3, and C4 between 180 sporadic PD patients and 187 healthy controls. Multiple regression models were conducted to assess the associations among these indicators of humoral immunity and the clinical features of PD patients. Results: Male PD patients had lower levels of C3 and C4 than healthy controls [0.87 (0.22) vs. 0.96 (0.19); 0.19 (0.06) vs. 0.22 (0.07), respectively, Pc < 0.01] and lower levels of C3 than female PD patients [0.87 (0.22) vs. 1.02 (0.23), Pc < 0.01]. Patients suffering from attention/memory problems had significantly lower levels of IgA and C3 than those without these problems [1.92 (1.21) vs. 2.57 (0.76); 0.89 (0.24) vs. 0.97 (0.24), respectively, Pc < 0.04]. In addition, serum IgG levels were negatively associated with mood/cognition problem scores and were positively associated with gastrointestinal tract problem scores (adjusted R 2 = 0.063, F = 1.805, p = 0.038). Serum C3 levels were negatively associated with being male, age, and sleep/fatigue problem scores (adjusted R 2 = 0.123, F = 2.678, p = 0.001). Conclusion: The peripheral humoral immune response might be correlated with the non-motor symptoms of PD. [ABSTRACT FROM AUTHOR]

Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi , is considered a neglected tropical disease by the World Health Organization. Congenital transmission of CD is an increasingly relevant public health problem. It progressively becomes the main transmission route over others and can occur in both endemic and non-endemic countries. Though most congenitally infected newborns are asymptomatic at birth, they display higher frequencies of prematurity, low birth weight, and lower Apgar scores compared to uninfected ones, and some suffer from severe symptoms. If not diagnosed and treated, infected newborns are at risk of developing disabling and life-threatening chronic pathologies later in life. The success or failure of congenital transmission depends on interactions between the parasite, the placenta, the mother, and the fetus. We review and discuss here the current knowledge about these parameters, including parasite virulence factors such as exovesicles, placental tropism, potential placental defense mechanisms, the placental transcriptome of infected women, gene polymorphism, and the maternal and fetal/neonatal immune responses, that might modulate the risk of T. cruzi congenital transmission. [ABSTRACT FROM AUTHOR]

There is growing evidence that ketone bodies, which are derived from fatty acid oxidation and usually produced in fasting state or on high-fat diets have broad neuroprotective effects. Although the mechanisms underlying the neuroprotective effects of ketone bodies have not yet been fully elucidated, studies in recent years provided abundant shreds of evidence that ketone bodies exert neuroprotective effects through possible mechanisms of anti-oxidative stress, maintaining energy supply, modulating the activity of deacetylation and inflammatory responses. Based on the neuroprotective effects, the ketogenic diet has been used in the treatment of several neurological diseases such as refractory epilepsy, Parkinson's disease, Alzheimer's disease, and traumatic brain injury. The ketogenic diet has great potential clinically, which should be further explored in future studies. It is necessary to specify the roles of components in ketone bodies and their therapeutic targets and related pathways to optimize the strategy and efficacy of ketogenic diet therapy in the future. [ABSTRACT FROM AUTHOR]

Neuroinflammation plays a critical role in the onset and progression of many neurological disorders, including Multiple Sclerosis, Alzheimer's and Parkinson's diseases. In these clinical conditions the underlying neuroinflammatory processes are significantly heterogeneous. Nevertheless, a common link is the chronic activation of innate immune responses and imbalanced secretion of pro and anti-inflammatory mediators. In light of this, the discovery of robust biomarkers is crucial for screening, early diagnosis, and monitoring of neurological diseases. However, the difficulty to investigate biochemical processes directly in the central nervous system (CNS) is challenging. In recent years, biomarkers of CNS inflammatory responses have been identified in different body fluids, such as blood, cerebrospinal fluid, and tears. In addition, progress in micro and nanotechnology has enabled the development of biosensing platforms capable of detecting in real-time, multiple biomarkers in clinically relevant samples. Biosensing technologies are approaching maturity where they will become deployed in community settings, at which point screening programs and personalized medicine will become a reality. In this multidisciplinary review, our goal is to highlight both clinical and recent technological advances toward the development of multiplex-based solutions for effective neuroinflammatory and neurodegenerative disease diagnostics and monitoring. [ABSTRACT FROM AUTHOR]