Search Results (13,881)

Autism Spectrum disorders (ASD) are diagnosed more often in males than in females, by a ratio of about 3:1; this is likely to be due to a difference in risk burden between the sexes and/or to “compensatory skills” in females, that may delay the diagnosis of ASD. Identifying specific risk factors for ASD in females may be important in facilitating early diagnosis. We investigated whether HLA- class I: -A, -B, -C and class II -DRB1 alleles, which have been suggested to play a role in the development of ASD, can be considered as sex-related risk/protective markers towards the ASD. We performed HLA allele genotyping in 178 Italian children with ASD, 94 healthy siblings, and their parents. HLA allele distribution was compared between children with ASD, sex-matched healthy siblings, and a cohort of healthy controls (HC) enrolled in the Italian bone marrow donor registry. Allele transmission from parents to children with ASD and their siblings was also assessed. Our findings suggest that HLA-A*02, B*38, and C*12 alleles are more frequently carried by females with ASD compared to both HC and healthy female siblings, indicating these alleles as potential risk factors for ASD in females. Conversely, the HLA-A*03 allele was more commonly transmitted to healthy female siblings, suggesting it might have a protective effect. Additionally, the HLA-B*44 allele was found to be more prevalent in boys with ASD, indicating it is a potential risk factor for male patients. This is the first Italian study of sex-related HLA association with ASD. If confirmed, these results could facilitate early ASD diagnosis in female patients, allowing earlier interventions, which are crucial in the management of neurodevelopmental disorders. Full article

This study examines the interactions between healthy target cells, infected target cells, virus particles, and immune cells within an HIV model. The model exhibits two equilibrium points: an infection-free equilibrium and an infection equilibrium. Stability analysis shows that the infection-free equilibrium is locally asymptotically stable when R0<1. Further, it is unstable when R0>1. The infection equilibrium is locally asymptotically stable when R0>1. The structural and practical identifiabilities of the within-host model for HIV infection dynamics were investigated using differential algebra techniques and Monte Carlo simulations. The HIV model was structurally identifiable by observing the total uninfected and infected target cells, immune cells, and viral load. Monte Carlo simulations assessed the practical identifiability of parameters. The production rate of target cells (λ), the death rate of healthy target cells (d), the death rate of infected target cells (δ), and the viral production rate by infected cells (π) were practically identifiable. The rate of infection of target cells by the virus (β), the death rate of infected cells by immune cells (Ψ), and antigen-driven proliferation rate of immune cells (b) were not practically identifiable. Practical identifiability was constrained by the noise and sparsity of the data. Analysis shows that increasing the frequency of data collection can significantly improve the identifiability of all parameters. This highlights the importance of optimal data sampling in HIV clinical studies, as it determines the best time points, frequency, and the number of sample points required to accurately capture the dynamics of the HIV infection within a host. Full article

The Varicella zoster virus (VZV), responsible for both varicella (chickenpox) and herpes zoster (shingles), presents significant global health challenges. While primary VZV infection primarily affects children, leading to chickenpox, reactivation in later life can result in herpes zoster and associated post-herpetic neuralgia, among other complications. Vaccination remains the most effective strategy for VZV prevention, with current vaccines largely based on the attenuated vOka strains. Although these vaccines are generally effective, they can induce varicella-like rashes and have sparked concerns regarding cell virulence. As a safer alternative, subunit vaccines circumvent these issues. In this study, we developed a nanoparticle-based vaccine displaying the glycoprotein E (gE) on ferritin particles using the SpyCatcher/SpyTag system, termed FR-gE. This FR-gE nanoparticle antigen elicited substantial gE-specific binding and VZV-neutralizing antibody responses in BALB/c and C57BL/6 mice—responses that were up to 3.2-fold greater than those elicited by the subunit gE while formulated with FH002C, aluminum hydroxide, or a liposome-based XUA01 adjuvant. Antibody subclass analysis revealed that FR-gE produced comparable levels of IgG1 and significantly higher levels of IgG2a compared to subunit gE, indicating a Th1-biased immune response. Notably, XUA01-adjuvanted FR-gE induced a significant increase in neutralizing antibody response compared to the live attenuated varicella vaccine and recombinant vaccine, Shingrix. Furthermore, ELISPOT assays demonstrated that immunization with FR-gE/XUA01 generated IFN-γ and IL-2 levels comparable to those induced by Shingrix. These findings underscore the potential of FR-gE as a promising immunogen for the development of varicella and herpes zoster vaccines. Full article

Vertically ordered mesoporous silica films (VMSF) are a class of porous materials composed of ultrasmall pores and ultrathin perpendicular nanochannels, which are attractive in the areas of electroanalytical sensors and molecular separation. However, VMSF easily falls off from the carbonaceous electrodes and thereby impacts their broad applications. Herein, carbon nitride nanosheets (CNNS) were served as an adhesive layer for stable growth of VMSF on the glassy carbon electrode (GCE). CNNS bearing plentiful oxygen-containing groups can covalently bind with silanol groups of VMSF, effectively promoting the stability of VMSF on the GCE surface. Benefiting from numerous open nanopores of VMSF, modification of VMSF’s external surface with carbohydrate antigen 15-3 (CA15-3)-specific antibody allows the target-controlled transport of electrochemical probes through the internal silica nanochannels, yielding sensitive quantitative detection of CA15-3 with a broad detection range of 1 mU/mL to 1000 U/mL and a low limit of detection of 0.47 mU/mL. Furthermore, the proposed VMSF/CNNS/GCE immunosensor is capable of highly selective and accurate determination of CA15-3 in spiked serum samples, which offers a simple and effective electrochemical strategy for detection of various practical biomarkers in complicated biological specimens. Full article

Over the past several decades, advancements in the treatment of BRAF-mutant melanoma have led to the development of BRAF inhibitors, BRAF/MEK inhibitor combinations, anti-PD-1 therapy, and anti-CTLA4 therapy. Although these therapies have shown substantial efficacy in clinical trials, their sustained effectiveness is often challenged by the tumor microenvironment, which is a highly heterogeneous and complex milieu of immunosuppressive cells that affect tumor progression. The era of personalized medicine holds substantial promise for the tailoring of treatments to individual genetic profiles. However, tumor heterogeneity and immune evasion mechanisms contribute to the resistance to immunotherapy. Despite these challenges, tumor-infiltrating lymphocyte (TIL) therapy, as exemplified by lifileucel, has demonstrated notable efficacy against BRAF V600-mutant melanoma. Additionally, early response biomarkers, such as COX-2 and MMP2, along with FDG-PET imaging, offer the potential to improve personalized immunotherapy by predicting patient responses and determining the optimal treatment duration. Future efforts should focus on reducing the T-cell harvesting periods and costs associated with TIL therapy to enhance efficiency and accessibility. Full article

Background: Microvascular flap surgery has become a routine option for defect correction. The role of von Willebrand factor antigen (VWF:Ag) in the pathophysiology of flap complications is not fully understood. We aim to investigate the predictive value of VWF:Ag for microvascular flap complications and explore the relationship between chronic inflammation and VWF:Ag. Methods: This prospective cohort study included 88 adult patients undergoing elective microvascular flap surgery. Preoperative blood draws were collected on the day of surgery before initiation of crystalloids. The plasma concentration of VWF:Ag as well as albumin, neutrophil-to-lymphocyte ratio (NLR), interleukin-6, and fibrinogen were determined. Results: The overall complication rate was 27.3%, and true flap loss occurred in 11.4%. VWF:Ag levels were higher in true flap loss when compared to patients without complications (217.94 IU/dL [137.27–298.45] vs. 114.14 [95.67–132.71], p = 0.001). Regression analysis revealed the association between VWF:Ag and true flap loss at the cutoff of 163.73 IU/dL (OR 70.22 [10.74–485.28], p = 0.043). Increased VWF:Ag concentrations were linked to increases in plasma fibrinogen (p < 0.001), C-reactive protein (p < 0.001), interleukin-6 (p = 0.032), and NLR (p = 0.019). Conclusions: Preoperative plasma VWF:Ag concentration is linked to biomarkers of inflammation and may be valuable in predicting complications in microvascular flap surgery. Full article

The original UT-1 transporter gene was initially identified in the spiny dogfish (Squalus acanthias), but localization of the UT-1 protein was not determined. Subsequent UT-1 expression was shown to localize to the collecting tubule (CT) of the shark nephron in other shark species, with expression in a closely related chimaera species also located additionally at a lower level in the intermediate-I segment (IS-I) of the nephron. In spiny dogfish, two UT-1 splice variants are known (UT-1 long and short), and there was also a second UT-1 gene described (here termed Brain UT). In this study, a second splice variant of the second Brain UT gene was discovered. Expression profiles (mRNA) of UT-1 long and short and Brain UT were determined in a number of spiny dogfish tissues. Quantitative PCR in kidney samples showed that the level of the short variant of UT-1 was around 100 times higher than the long variant, which was itself expressed around 10 times higher than Brain UT cDNA/mRNA (in kidney). For the long variant, there was a significantly higher level of mRNA abundance in fish acclimatized to 75% seawater. Ultimately, three UT-1 antibodies were made that could bind to both the UT-1 short and long variant proteins. The first two of these showed bands of appropriate sizes on Western blots of around 52.5 and 46 kDa. The second antibody had some additional lower molecular weight bands. The third antibody was mainly bound to the 46 kDa band with faint 52.5 kDa staining. Both the 52.5 and 46 kDa bands were absent when the antibodies were pre-blocked with the peptide antigens used to make them. Across the three antibodies, there were many similarities in localization but differences in subcellular localization. Predominantly, antibody staining was greatest in the intermediate segment 1 (IS-I) and proximal (PIb) segments of the first sinus zone loop of the nephron, with reasonably strong expression also found at the start and middle of the late distal tubule (LDT; second sinus zone loop). While some expression in the collecting tubule (CT) could not be ruled out, the level of staining seemed to be low or non-existent in convoluted bundle zone nephron segments such as the CT. Hence, this suggests that spiny dogfish have a fundamentally different mode of urea absorption in comparison to that found in other shark species, potentially focused more on the nephron sinus zone loops than the CT. Full article

Threonine phosphorylation promotes inflammatory functions of STAT1 while restricting its interferon (IFN) signaling in innate immune responses. However, it remains unclear whether the restriction of STAT1-mediated IFN signaling conferred by threonine phosphorylation is a ubiquitous mechanism or one that is context-dependent. To address this, we utilized pristane-induced lupus, a prototype IFN-driven systemic autoimmune disease model characterized by the production of high-titer autoantibodies against nucleic acid-associated antigens. Through genetic and biochemical assays, we demonstrate that Thr748 phosphorylation is dispensable for STAT1 functionality in pristane-induced lupus. Genetically engineered mice expressing the phospho-deficient threonine 748-to-alanine (T748A) mutant STAT1 exhibited similar survival rates, high titers of anti-dsDNA IgG, and nephritis compared to their wild-type littermates. In sharp contrast, STAT1 deficiency protected mice against pristane-induced lupus, as evidenced by increased survival, low titers of anti-dsDNA IgG, and less severe nephritis in the STAT1 knockout mice compared to their T748A littermates. Our study suggests a phosphorylation-dependent modularity that governs the spectrum of STAT1 functionality in inflammatory contexts: IFN phospho-tyrosine-dependent and inflammatory phospho-threonine-dependent, with Thr748 phosphorylation driving selective inflammatory activities, particularly those not driven by the canonical JAK pathway. From a broader perspective, our findings provide deeper insights into how distinct phosphorylation events shape the combinatorial logic of signaling cassettes, thereby regulating context-dependent responses. Full article

Autoimmune blistering diseases of the pemphigus and pemphigoid groups are immune-mediated disorders due to circulating pathogenetic autoantibodies. Multiple human leukocyte antigen (HLA) genes have been associated with predisposition to these disorders. HLA-Cw6 is involved in antigen presentation processes and has been linked to psoriasis. The aim of our study was to investigate the association between the presence of the HLA-Cw6 allele and susceptibility to pemphigus vulgaris and bullous pemphigoid. A genetic study in vitro with a cross-sectional design was performed enrolling forty patients with pemphigus vulgaris and forty patients with bullous pemphigoid. The detection of HLA-Cw6 was performed through the EUROArray test on DNA obtained from whole blood samples. The polymorphism was detected in 3/40 genotypes in the pemphigus vulgaris group and in 4/40 genotypes of patients with bullous pemphigoid, unveiling a non-statistically significant different frequency in pemphigus (p = 0.6368) and in pemphigoid (p = 0.62) compared to the reference frequency from the literature of 0.086. Further research is needed to better investigate the role of HLA-Cw6 in immune-mediated diseases and to identify novel genetic markers associated with susceptibility to autoimmune blistering diseases and with disease severity and response to immunosuppressive therapies. Full article

The prevalence of the highly pathogenic avian influenza virus H5N1 in wild birds that migrate all over the world has resulted in the dissemination of this virus across Asia, Europe, Africa, North and South America, the Arctic continent, and Antarctica. So far, H5N1 clade 2.3.4.4.b has reached an almost global distribution, with the exception of Australia and New Zealand for autochthonous cases. H5N1 clade 2.3.4.4.b, derived from the broad-host-range A/Goose/Guangdong/1/96 (H5N1) lineage, has evolved, adapted, and spread to species other than birds, with potential mammal-to-mammal transmission. Many public health agencies consider H5N1 influenza a real pandemic threat. In this sense, we analyzed H5N1 hemagglutinin sequences from recent outbreaks in animals, clinical samples, antigenic prototypes of candidate vaccine viruses, and licensed human vaccines for H5N1 with the aim of shedding light on the development of an H5N1 vaccine suitable for a pandemic response, should one occur in the near future. Full article

Sjögren’s syndrome (SS) is an autoimmune disease characterized by heterogeneous clinical presentation and the presence of various autoantibodies. This study aimed to determine the differences in clinical findings according to antibody positivity in patients with primary Sjögren syndrome (pSS) in the Turkish population. A retrospective study was conducted and 402 patients (378 women and 24 men) with pSS were analyzed. The patients were categorized into three subgroups based on serological tests. These were (1) quadruple seropositivity (positive for anti-Sjögren’s syndrome-related antigen A antibodies (anti-SSA; anti-Ro) and anti-Sjögren’s syndrome-related antigen B antibodies (anti-SSB; anti-La), rheumatoid factor (RF), and antinuclear antibody (ANA); (2) double seropositivity (positive for ANA and anti-SSA/Ro antibodies); and (3) quadruple seronegativity (negative for ANA, RF, anti-SSA/Ro and anti-SSB/La antibodies). The number of quadruple-seropositive patients was 72 (18.6%), double-seropositive 174 (43.2%), and quadruple-seronegative was 85 (21.1%). The age at diagnosis of quadruple-seropositive pSS was 42.4 ± 10.8, which was significantly younger than that of patients with double-seropositive and quadruple-seronegative pSS (p = 0.021, p = 0.112). In terms of organ involvement, salivary gland enlargement, arthralgia, arthritis, Raynaud’s phenomenon, lymphadenopathy, cutaneous vasculitis, interstitial lung disease, neurological involvement, autoimmune thyroiditis, renal interstitial disease, anemia, leukopenia, hypergammaglobulinemia, and hypocomplementemia were more common in quadruple-seropositive patients with pSS than in quadruple-seronegative patients (p < 0.0001). The results of this study confirmed the strong impact of immunological markers on the pSS phenotype at the time of diagnosis. Immunological patterns play a central role in the phenotypic expression of the disease, even during the initial diagnostic phase, and can guide physicians in designing personalized treatment plans for patients with pSS. Full article

Background: Some cases of classic Hodgkin lymphoma (CHL) display similarities to nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) in terms of architecture, leading to potential challenges in diagnosis. However, these difficulties can be overcome by conducting a thorough set of immunohistochemical examinations. Objective: To examine cases of T-cell-rich CHL that closely resemble the diagnosis of NLPHL, specifically pattern D, which can pose challenges in accurately determining the diagnosis even after conducting a thorough immunophenotypic assessment. Materials and methods: Histopathology slides of three cases of T-cell-rich CHL were retrieved and thoroughly examined to assess their clinical, immunomorphologic, and molecular features. Results: We present three cases containing cells that resembled lymphocyte predominant and Hodgkin Reed–Sternberg cells, expressing some B-cell antigens and CHL markers but all were lacking Epstein–Barr virus-encoded small RNA. All three cases were found in a background rich in T-cells with focal remaining follicular dendritic cell meshwork in one case. Only one case had few eosinophils while the other two had no background of eosinophils and plasma cells. Two patients presented with stage IIA and B-symptoms presented in one of them. Two patients were treated with four and six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), respectively. One patient planned to be treated with four cycles of ABVD plus Rituximab therapy. Conclusions: Some cases of Reed–Sternberg cells can show expression of both B-cell and CHL markers. This overlapping characteristic, which has not been extensively discussed in the existing literature, presents a unique challenge for treatment. Further research into these neoplasms may reveal valuable diagnostic and therapeutic implications. Full article

PRAME (PReferentially expressed Antigen in Melanoma) immunohistochemistry has proven helpful in distinguishing malignant from benign melanocytic tumors. We studied PRAME IHC expression in 46 thin melanomas and 39 melanocytic nevi, mostly dysplastic nevi. Twenty-six percent (26.09%) of the melanomas showed diffuse PRAME staining in over 76% of the tumor cells (4+), and 34.78% of the melanomas showed PRAME expression in over 51% of the tumor cells (3+ or 4+), while 8% were entirely negative for PRAME. No melanocytic nevi were PRAME 4+ or 3+. More than half of the nevi (64%) were entirely negative for PRAME staining, and 36% of the nevi showed staining expression in 1–25% (1+) or 26–50% of the cells (2+). No nevi were stained with a color intensity of 3, while 16.67% of the melanomas were stained with this color intensity. Most nevi (78.57%) were stained with an intensity of 1. With a lower positivity threshold, sensitivity increases with still reasonable specificity. The best accuracy was obtained for the 2+ positivity threshold. In conclusion, PRAME staining helps distinguish thin melanomas from dysplastic nevi. However, the threshold of positivity should be lowered in order not to miss thin melanomas. Full article

Chimeric antigen receptor (CAR)-T cell therapy represents a breakthrough in treating resistant hematologic cancers. It is based on genetically modifying T cells transferred from the patient or a donor. Although its implementation has increased over the last few years, CAR-T has many challenges to be addressed, for instance, the associated severe toxicities, such as cytokine release syndrome. To model CAR-T cell dynamics, focusing on their proliferation and cytotoxic activity, we developed a mathematical framework using ordinary differential equations (ODEs) with Bayesian parameter estimation. Bayesian statistics were used to estimate model parameters through Monte Carlo integration, Bayesian inference, and Markov chain Monte Carlo (MCMC) methods. This paper explores MCMC methods, including the Metropolis–Hastings algorithm and DEMetropolis and DEMetropolisZ algorithms, which integrate differential evolution to enhance convergence rates. The theoretical findings and algorithms were validated using Python and Jupyter Notebooks. A real medical dataset of CAR-T cell therapy was analyzed, employing optimization algorithms to fit the mathematical model to the data, with the PyMC library facilitating Bayesian analysis. The results demonstrated that our model accurately captured the key dynamics of CAR-T cell therapy. This conclusion underscores the potential of parameter estimation to improve the understanding and effectiveness of CAR-T cell therapy in clinical settings. Full article

Despite its medical relevance, there is no commercial vaccine that protects the population at risk from multidrug-resistant (MDR) Klebsiella pneumoniae infections. The availability of massive omic data and novel algorithms may improve antigen selection to develop effective prophylactic strategies. Up to 133 exposed proteins in the core proteomes, between 516 and 8666 genome samples, of the six most relevant MDR clonal groups (CGs) carried conserved B-cell epitopes, suggesting minimized future evasion if utilized for vaccination. Antigens showed a range of epitopicity, functional constraints, and potential side effects. Eleven antigens, including three sugar porins, were represented in all MDR-CGs, constitutively expressed, and showed limited reactivity with gut microbiota. Some of these antigens had important interactomic interactions and may elicit adhesion-neutralizing antibodies. Synergistic bivalent to pentavalent combinations that address expression conditions, interactome location, virulence activities, and clone-specific proteins may overcome the limiting protection of univalent vaccines. The combination of five central antigens accounted for 41% of all non-redundant interacting partners of the antigen dataset. Specific antigen mixtures represented in a few or just one MDR-CG further reduced the chance of microbiota interference. Rational antigen selection schemes facilitate the design of high-coverage and “magic bullet” multivalent vaccines against recalcitrant K. pneumoniae lineages. Full article