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Advanced bioinformatics analysis, such as systems biology (SysBio) and artificial intelligence (AI) approaches, including machine learning (ML) and deep learning (DL), is increasingly present in stem cell (SC) research. An approximate timeline on these developments and their global impact is still lacking. We conducted a scoping review on the contribution of SysBio and AI analysis to SC research and therapy development based on literature published in PubMed between 2000 and 2024. We identified an 8 to 10-fold increase in research output related to all 3 search terms between 2000 and 2021, with a 10-fold increase in AI-related production since 2010. Use of SysBio and AI still predominates in preclinical basic research with increasing use in clinically oriented translational medicine since 2010. SysBio- and AI-related research was found all over the globe, with SysBio output led by the (US, n = 1487), (UK, n = 1094), Germany (n = 355), The Netherlands (n = 339), Russia (n = 215), and France (n = 149), while for AI-related research the US (n = 853) and UK (n = 258) take a strong lead, followed by Switzerland (n = 69), The Netherlands (n = 37), and Germany (n = 19). The US and UK are most active in SCs publications related to AI/ML and AI/DL. The prominent use of SysBio in ESC research was recently overtaken by prominent use of AI in iPSC and MSC research. This study reveals the global evolution and growing intersection among AI, SysBio, and SC research over the past 2 decades, with substantial growth in all 3 fields and exponential increases in AI-related research in the past decade., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Major depressive disorder (MDD) is a leading global cause of disability, being more prevalent in females, possibly due to molecular and neuronal pathway differences between females and males. However, the connection between transcriptional changes and MDD remains unclear. We identified transcriptionally altered genes (TAGs) in MDD through gene and transcript expression analyses, focusing on sex-specific differences. Analyzing 263 brain samples from both sexes, we conducted differential gene expression, differential transcript expression, and differential transcript usage analyses, revealing 1169 unique TAGs, primarily in the prefrontal areas, with nearly half exhibiting transcript-level alterations. Females showed notable RNA splicing and export process disruptions in the orbitofrontal cortex, alongside altered DDX39B gene expression in five of the six brain regions in both sexes. Our findings suggest that disruptions in RNA processing pathways may play a vital role in MDD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Vaccination has played a critical role in mitigating COVID-19. Despite the availability of licensed vaccines, there remains a pressing need for improved vaccine platforms that provide high protection, safety, and versatility, while also reducing vaccine costs. In response to these challenges, our aim is to create a self-adjuvanted vaccine against SARS-CoV-2, utilizing Virus-Like Particles (VLPs) as the foundation. To achieve this, we produced bacteriophage (Qβ) VLPs in a prokaryotic system and purified them using a rapid and cost-effective strategy involving organic solvents. This method aims to solubilize lipids and components of the cell membrane to eliminate endotoxins present in bacterial samples. For vaccine formulation, Receptor Binding Domain (RBD) antigens were conjugated using chemical crosslinkers, a process compatible with Good Manufacturing Practice (GMP) standards. Transmission Electron Microscopy (TEM) confirmed the expected folding and spatial configuration of the QβVLPs vaccine. Additionally, vaccine formulation assessment involved SDS-PAGE stained with Coomassie Brilliant Blue, Western blotting, and stereomicroscopic experiments. In vitro and in vivo evaluations of the vaccine formulation were conducted to assess its capacity to induce a protective immune response without causing side effects. Vaccine doses of 20 µg and 50 µg stimulated the production of neutralizing antibodies. In in vivo testing, the group of animals vaccinated with 50 µg of vaccine formulation provided complete protection against virus infection, maintaining stable body weight without showing signs of disease. In conclusion, the QβVLPs-RBD vaccine has proven to be effective and safe, eliminating the necessity for supplementary adjuvants and offering a financially feasible approach. Moreover, this vaccine platform demonstrates flexibility in targeting Variants of Concern (VOCs) via established conjugation protocols with VLPs., (© 2024. The Author(s).)

Background : Typhoid fever caused by Salmonella enterica serovar Typhi (S. typhi) continues to pose a significant risk to public health in developing countries, including Pakistan. This study investigated the epidemiological factors linked to suspected and confirmed S. typhi infections in Peshawar's hospital population. Methodology : A total of 5735 blood samples of patients with suspected enteric fever were collected from September 2022 to November 2023. S. typhi infection was confirmed using microbiological culture of blood samples, biochemical-based tests, and DNA-sequencing methods. Drug sensitivity testing on cultures was conducted as per the CLSI guidelines. Chi-square tests were used to analyze the clinical and epidemiologic characteristics of 5735 samples stratified by S. typhi infection status, and risk factors were assessed by applying logistic regression models to estimate odds ratios (ORs). Results : The number of confirmed typhoid fever cases in this hospital-based study population was 691 (/5735, 12.0%), more prevalent in males (447/3235 13.8%) and children (0-11 years) (429/2747, 15.6%). Compared to children, the risk of S. typhi infection was lower in adolescence (adjusted OR = 0.52; 95% CI: 0.42-0.66), adulthood (19-59 years; aOR = 0.30; 95% CI: 0.25-0.38), and older adulthood (aOR = 0.08; 95% CI: 0.04-0.18) ( p < 0.001). Compared to males, the risk of S. typhi infection was lower in females (aOR = 0.67; 95% CI = 0.56-0.80; p = 0.002). Living in a rural residence (compared to urban) was associated with a higher risk of infection (aOR = 1.38; 95% CI: 1.16-1.63; p = 0.001), while access to a groundwater source (compared to municipal water supply) led to a lower risk (aOR = 0.56; 95% CI: 0.43-0.73; p = 0.002). Vaccination demonstrated a robust protective effect (aOR = 0.069; 95% CI = 0.04-0.11, p = 0.002). For those with typhoid infections, clinical biomarker analysis revealed the presence of leucopenia (65/691, 9.4%), thrombocytopenia (130/691, 18.8%), and elevated alanine aminotransferase (ALT) (402/691, 58.2%) and C-reactive protein (CRP) (690/691, 99.9%) levels. Worryingly, among the positive S. typhi isolates, there was a high prevalence of drug resistance (653/691), including multidrug-resistant (MDR 82/691, 11.9%) and extensively drug-resistant types (XDR, 571/691, 82.6%). Conclusions : This study highlights the importance of age, sex, locality, water source, and vaccination status in shaping the epidemiological landscape of S. typhi in the Peshawar district. It implies that expanding vaccination coverage to the broader population of Khyber Pakhtunkhwa province, particularly in the district of Peshawar, would be beneficial.

Tumor-associated myeloid-derived cells (MDCs) significantly impact cancer prognosis and treatment responses due to their remarkable plasticity and tumorigenic behaviors. Here, we integrate single-cell RNA-sequencing data from different cancer types, identifying 29 MDC subpopulations within the tumor microenvironment. Our analysis reveals abnormally expanded MDC subpopulations across various tumors and distinguishes cell states that have often been grouped together, such as TREM2+ and FOLR2+ subpopulations. Using deconvolution approaches, we identify five subpopulations as independent prognostic markers, including states co-expressing TREM2 and PD-1, and FOLR2 and PDL-2. Additionally, TREM2 alone does not reliably predict cancer prognosis, as other TREM2+ macrophages show varied associations with prognosis depending on local cues. Validation in independent cohorts confirms that FOLR2-expressing macrophages correlate with poor clinical outcomes in ovarian and triple-negative breast cancers. This comprehensive MDC atlas offers valuable insights and a foundation for futher analyses, advancing strategies for treating solid cancers., (© 2024. The Author(s).)

Competing Interests: None.

Immune checkpoint pathways, i.e., coinhibitory pathways expressed as feedback following immune activation, are crucial for controlling an excessive immune response. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) are the central classical checkpoint inhibitory (CPI) molecules used for the control of neoplasms and some infectious diseases, including some fungal infections. As the immunosuppression of severe paracoccidioidomycosis (PCM), a chronic granulomatous fungal disease, was shown to be associated with the expression of coinhibitory molecules, we hypothesized that the inhibition of CTLA-4 and PD-1 could have a beneficial effect on pulmonary PCM. To this end, C57BL/6 mice were infected with Paracoccidioides brasiliensis yeasts and treated with monoclonal antibodies (mAbs) α-CTLA-4, α-PD-1, control IgG, or PBS. We verified that blockade of CTLA-4 and PD-1 reduced the fungal load in the lungs and fungal dissemination to the liver and spleen and decreased the size of pulmonary lesions, resulting in increased survival of mice. Compared with PBS-treated infected mice, significantly increased levels of many pro- and anti-inflammatory cytokines were observed in the lungs of α-CTLA-4-treated mice, but a drastic reduction in the liver was observed following PD-1 blockade. In the lungs of α-CPI and IgG-treated mice, there were no changes in the frequency of inflammatory leukocytes, but a significant reduction in the total number of these cells was observed. Compared with PBS-treated controls, α-CPI- and IgG-treated mice exhibited reduced pulmonary infiltration of several myeloid cell subpopulations and decreased expression of costimulatory molecules. In addition, a decreased number of CD4+ and CD8+ T cells but sustained numbers of Th1, Th2, and Th17 T cells were detected. An expressive reduction in several Treg subpopulations and their maturation and suppressive molecules, in addition to reduced numbers of Treg, TCD4+, and TCD8+ cells expressing costimulatory and coinhibitory molecules of immunity, were also detected. The novel cellular and humoral profiles established in the lungs of α-CTLA-4 and α-PD-1-treated mice but not in control IgG-treated mice were more efficient at controlling fungal growth and dissemination without causing increased tissue pathology due to excessive inflammation. This is the first study demonstrating the efficacy of CPI blockade in the treatment of pulmonary PCM, and further studies combining the use of immunotherapy with antifungal drugs are encouraged., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Preite, Borges, Kaminski, Ayupe, Gonçalves, dos Santos, Fonseca, Filgueiras, Salgado, Muxel, Cabral-Marques, da Fonseca, Loures and Calich.)

Background: Diabetes Mellitus (DM) is an important chronic disease that occurs worldwide., Aims: This study aims to investigate how the use of the FreeStyle ® Libre system in Unified Health System (SUS) patients impacts diabetes parameters in patients who receive education on proper insulin administration and the use of the continuous monitoring device, as well as how this affects patients without any concomitant multidisciplinary support in Sergipe, Brazil., Methods: We conducted a prospective randomized study in a diabetes clinic in Sergipe, Brazil, using the flash method FreeStyle ® Libre (Abbott). The participants were divided into two groups: one receiving diabetes education on CGM (continuous glucose monitoring), while the other did not. Before the intervention, the patient's treatment motivation and quality of life were assessed using a questionnaire, and baseline levels of glycated hemoglobin were measured using high-performance liquid chromatography (HPLC) and the point of care Alere TM Afinion with boronate fixation. We compared first- and second-phase data with respect to glycated hemoglobin, mean interstitial blood glucose, time on and above target for hypoglycemic and hyperglycemic events, and mean hypoglycemic duration., Results: In group A, which received the diabetes education intervention, there was a significant reduction in average HbA1c levels from 8.6% to 7.9% after 3 months ( p = 0.001). However, there was no significant difference in average glycemic values. Time above target decreased significantly from 50.62% to 29.43% ( p = 0.0001), while time below target decreased from 22.90% to 20.21% ( p = 0.002). There was no significant change in the number of hypoglycemic events, but the duration of hypoglycemia decreased significantly from 130.35 min to 121.18 min after 3 months ( p = 0.0001). In Group B, there was no significant difference in mean HbA1c levels before (7.07%) and after (7.28%) sensor installation. This group maintained lower HbA1c levels compared to the other group. Average blood glucose levels also remained similar before (148.37 mg/dL) and after (154.65 mg/dL) the intervention. Although the time above the target glucose level increased significantly from 35.94% to 48.17%, the time at target decreased from 50.40% to 37.97%. No significant changes were observed in the time below target, the number of hypoglycemic events, or the duration of hypoglycemia., Conclusions: Our findings indicate that utilizing continuous glucose monitoring technology can enhance glycemic control, particularly in motivated, educated, low-income patients dependent on the SUS. To achieve positive results with FreeStyle Libre, it is imperative to allocate resources for multidisciplinary support.

Introduction: Dengue virus infection is a global health problem lacking specific therapy, requiring an improved understanding of DENV immunity and vaccine responses. Considering the recent emerging of new dengue vaccines, here we performed an integrative systems vaccinology characterization of molecular signatures triggered by the natural DENV infection (NDI) and attenuated dengue virus infection models (DVTs)., Methods and Results: We analyzed 955 samples of transcriptomic datasets of patients with NDI and attenuated dengue virus infection trials (DVT1, DVT2, and DVT3) using a systems vaccinology approach. Differential expression analysis identified 237 common differentially expressed genes (DEGs) between DVTs and NDI. Among them, 28 and 60 DEGs were up or downregulated by dengue vaccination during DVT2 and DVT3, respectively, with 20 DEGs intersecting across all three DVTs. Enriched biological processes of these genes included type I/II interferon signaling, cytokine regulation, apoptosis, and T-cell differentiation. Principal component analysis based on 20 common DEGs (overlapping between DVTs and our NDI validation dataset) distinguished dengue patients by disease severity, particularly in the late acute phase. Machine learning analysis ranked the ten most critical predictors of disease severity in NDI, crucial for the anti-viral immune response., Conclusion: This work provides insights into the NDI and vaccine-induced overlapping immune response and suggests molecular markers (e.g., IFIT5, ISG15, and HERC5 ) for anti-dengue-specific therapies and effective vaccination development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study received funding from IBM. The funder had the following involvement in the study: production of figures, revision, and manuscript editing. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Plaça, Fonseca, Marques, Zaki Pour, Usuda, Baiocchi, Prado, Salgado, Filgueiras, Freire, Rocha, Camara, Catar, Moll, Jurisica, Calich, Giil, Rivino, Ochs, Cabral-Miranda, Schimke and Cabral-Marques.)

MicroRNAs are small regulatory molecules that control gene expression. An emerging property of muscle miRNAs is the cooperative regulation of transcriptional and epitranscriptional events controlling muscle phenotype. miR-155 has been related to muscular dystrophy and muscle cell atrophy. However, the function of miR-155 and its molecular targets in muscular dystrophies remain poorly understood. Through in silico and in vitro approaches, we identify distinct transcriptional profiles induced by miR-155-5p in muscle cells. The treated myotubes changed the expression of 359 genes (166 upregulated and 193 downregulated). We reanalyzed muscle transcriptomic data from dystrophin-deficient patients and detected overlap with gene expression patterns in miR-155-treated myotubes. Our analysis indicated that miR-155 regulates a set of transcripts, including Aldh1l , Nek2 , Bub1b , Ramp3 , Slc16a4 , Plce1 , Dync1i1 , and Nr1h3 . Enrichment analysis demonstrates 20 targets involved in metabolism, cell cycle regulation, muscle cell maintenance, and the immune system. Moreover, digital cytometry confirmed a significant increase in M2 macrophages, indicating miR-155's effects on immune response in dystrophic muscles. We highlight a critical miR-155 associated with disease-related pathways in skeletal muscle disorders.

Arboviruses are a major threat to public health in tropical regions, encompassing over 534 distinct species, with 134 capable of causing diseases in humans. These viruses are transmitted through arthropod vectors that cause symptoms such as fever, headache, joint pains, and rash, in addition to more serious cases that can lead to death. Among the arboviruses, dengue virus stands out as the most prevalent, annually affecting approximately 16.2 million individuals solely in the Americas. Furthermore, the re-emergence of the Zika virus and the recurrent outbreaks of chikungunya in Africa, Asia, Europe, and the Americas, with one million cases reported annually, underscore the urgency of addressing this public health challenge. In this manuscript we discuss the epidemiology, viral structure, pathogenicity and integrated control strategies to combat arboviruses, and the most used tools, such as vaccines, monoclonal antibodies, treatment, etc., in addition to presenting future perspectives for the control of arboviruses. Currently, specific medications for treating arbovirus infections are lacking, and symptom management remains the primary approach. However, promising advancements have been made in certain treatments, such as Chloroquine, Niclosamide, and Isatin derivatives, which have demonstrated notable antiviral properties against these arboviruses in vitro and in vivo experiments. Additionally, various strategies within vector control approaches have shown significant promise in reducing arbovirus transmission rates. These encompass public education initiatives, targeted insecticide applications, and innovative approaches like manipulating mosquito bacterial symbionts, such as Wolbachia . In conclusion, combatting the global threat of arbovirus diseases needs a comprehensive approach integrating antiviral research, vaccination, and vector control. The continued efforts of research communities, alongside collaborative partnerships with public health authorities, are imperative to effectively address and mitigate the impact of these arboviral infections on public health worldwide., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Côrtes, Lira, Prates-Syed, Dinis Silva, Vuitika, Cabral-Miranda, Durães-Carvalho, Balan, Cabral-Marques and Cabral-Miranda.)

Non-HLA-directed regulatory autoantibodies (RABs) are known to target G-protein coupled receptors (GPCRs) and thereby contribute to kidney transplant vasculopathy and failure. However, the detailed underlying signaling mechanisms in human microvascular endothelial cells (HMECs) and immune cells need to be clarified in more detail. In this study, we compared the immune stimulatory effects and concomitant intracellular and extracellular signaling mechanisms of immunoglobulin G (IgG)-fractions from kidney transplant patients with allograft vasculopathy (KTx-IgG), to that from patients without vasculopathy, or matched healthy controls (Con-IgG). We found that KTx-IgG from patients with vasculopathy, but not KTx-IgG from patients without vasculopathy or Con-IgG, elicits HMEC activation and subsequent upregulation and secretion of tumor necrosis factor alpha (TNF-α) from HMECs, which was amplified in the presence of the protease-activated thrombin receptor 1 (PAR1) activator thrombin, but could be omitted by selectively blocking the PAR1 receptor. The amount and activity of the TNF-α secreted by HMECs stimulated with KTx-IgG from patients with vasculopathy was sufficient to induce subsequent THP-1 monocytic cell activation. Furthermore, AP-1/c-FOS, was identified as crucial transcription factor complex controlling the KTx-IgG-induced endothelial TNF-α synthesis, and mircoRNA-let-7f-5p as a regulatory element in modulating the underlying signaling cascade. In conclusion, exposure of HMECs to KTx-IgG from patients with allograft vasculopathy, but not KTx-IgG from patients without vasculopathy or healthy Con-IgG, triggers signaling through the PAR1-AP-1/c-FOS-miRNA-let7-axis, to control TNF-α gene transcription and TNF-α-induced monocyte activation. These observations offer a greater mechanistic understanding of endothelial cells and subsequent immune cell activation in the clinical setting of transplant vasculopathy that can eventually lead to transplant failure, irrespective of alloantigen-directed responses., Competing Interests: Author HH was employed by CellTrend GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Moll, Luecht, Gyamfi, da Fonseca, Wang, Zhao, Gong, Chen, Ashraf, Heidecke, Hackel, Dragun, Budde, Penack, Riemekasten, Cabral-Marques, Witowski and Catar.)

Rabies is an ancient neuroinvasive viral (genus Lyssavirus, family Rhabdoviridae) disease affecting approximately 59,000 people worldwide. The central nervous system (CNS) is targeted, and rabies has a case fatality rate of almost 100% in humans and animals. Rabies is entirely preventable through proper vaccination, and thus, the highest incidence is typically observed in developing countries, mainly in Africa and Asia. However, there are still cases in European countries and the United States. Recently, demographic, increasing income levels, and the coronavirus disease 2019 (COVID-19) pandemic have caused a massive raising in the animal population, enhancing the need for preventive measures (e.g., vaccination, surveillance, and animal control programs), postexposure prophylaxis, and a better understanding of rabies pathophysiology to identify therapeutic targets, since there is no effective treatment after the onset of clinical manifestations. Here, we review the neuroimmune biology and mechanisms of rabies. Its pathogenesis involves a complex and poorly understood modulation of immune and brain functions associated with metabolic, synaptic, and neuronal impairments, resulting in fatal outcomes without significant histopathological lesions in the CNS. In this context, the neuroimmunological and neurochemical aspects of excitatory/inhibitory signaling (e.g., GABA/glutamate crosstalk) are likely related to the clinical manifestations of rabies infection. Uncovering new links between immunopathological mechanisms and neurochemical imbalance will be essential to identify novel potential therapeutic targets to reduce rabies morbidity and mortality., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: COVID-19 led to the suspension academic activities worldwide, affecting millions of students and staff., Methods: In this study, we evaluated the presence of IgM and IgG anti-SARS-CoV-2 antibodies in an academic population during the return to classes after a one-year suspension. The study took place over five months at a Brazilian university and included 942 participants., Results: We found that most participants had reactive IgG and non-reactive IgM. All received at least one dose, and 940 received two or more doses, of different COVID-19 vaccines. We obtained a higher average of memory antibodies (IgG) in participants who received the CoronaVac/ChAdOx1 combination. IgG was consistently distributed for each vaccine group, but individuals who completed the vaccination schedule had higher levels. There were no differences between antibodies and gender, presence of symptoms, and previous COVID-19 infection, but older participants (>53 years) and contacts of infected individuals had higher IgM levels., Conclusion: This study makes significant contributions to the assessment of antibodies in the academic environment, allowing us to infer that most participants had memory immunity and low indications of recent infection when returning to face-to-face classes, as well as demonstrating the need to monitor immunity and update vaccinations.

Age is a significant risk factor for the coronavirus disease 2019 (COVID-19) severity due to immunosenescence and certain age-dependent medical conditions (e.g., obesity, cardiovascular disorder, and chronic respiratory disease). However, despite the well-known influence of age on autoantibody biology in health and disease, its impact on the risk of developing severe COVID-19 remains poorly explored. Here, we performed a cross-sectional study of autoantibodies directed against 58 targets associated with autoimmune diseases in 159 individuals with different COVID-19 severity (71 mild, 61 moderate, and 27 with severe symptoms) and 73 healthy controls. We found that the natural production of autoantibodies increases with age and is exacerbated by SARS-CoV-2 infection, mostly in severe COVID-19 patients. Multiple linear regression analysis showed that severe COVID-19 patients have a significant age-associated increase of autoantibody levels against 16 targets (e.g., amyloid β peptide, β catenin, cardiolipin, claudin, enteric nerve, fibulin, insulin receptor a, and platelet glycoprotein). Principal component analysis with spectrum decomposition and hierarchical clustering analysis based on these autoantibodies indicated an age-dependent stratification of severe COVID-19 patients. Random forest analysis ranked autoantibodies targeting cardiolipin, claudin, and platelet glycoprotein as the three most crucial autoantibodies for the stratification of severe COVID-19 patients ≥50 years of age. Follow-up analysis using binomial logistic regression found that anti-cardiolipin and anti-platelet glycoprotein autoantibodies significantly increased the likelihood of developing a severe COVID-19 phenotype with aging. These findings provide key insights to explain why aging increases the chance of developing more severe COVID-19 phenotypes., (© 2023. Springer Nature Limited.)

Dengue virus (DENV) infection manifests as a febrile illness with three distinct phases: early acute, late acute, and convalescent. Dengue can result in clinical manifestations with different degrees of severity, dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Interferons (IFNs) are antiviral cytokines central to the anti-DENV immune response. Notably, the distinct global signature of type I, II, and III interferon-regulated genes (the interferome) remains uncharacterized in dengue patients to date. Therefore, we performed an in-depth cross-study for the integrative analysis of transcriptome data related to DENV infection. Our systems biology analysis shows that the anti-dengue immune response is characterized by the modulation of numerous interferon-regulated genes (IRGs) enriching, for instance, cytokine-mediated signaling (e.g., type I and II IFNs) and chemotaxis, which is then followed by a transcriptional wave of genes associated with cell cycle, also regulated by the IFN cascade. The adjunct analysis of disease stratification potential, followed by a transcriptional meta-analysis of the interferome, indicated genes such as IFI27 , ISG15 , and CYBRD1 as potential suitable biomarkers of disease severity. Thus, this study characterizes the landscape of the interferome signature in DENV infection, indicating that interferome dynamics are a crucial and central part of the anti-dengue immune response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Usuda, Plaça, Fonseca, Marques, Filgueiras, Chaves, Adri, Torrentes-Carvalho, Hirata, Freire, Catar, Cabral-Miranda, Schimke, Moll and Cabral-Marques.)

Introduction: Despite the existing data on the Multisystem Inflammatory Syndrome in Children (MIS-C), the factors that determine these patients evolution remain elusive. Answers may lie, at least in part, in genetics. It is currently under investigation that MIS-C patients may have an underlying innate error of immunity (IEI), whether of monogenic, digenic, or even oligogenic origin., Methods: To further investigate this hypothesis, 30 patients with MIS-C were submitted to whole exome sequencing., Results: Analyses of genes associated with MIS-C, MIS-A, severe covid-19, and Kawasaki disease identified twenty-nine patients with rare potentially damaging variants (50 variants were identified in 38 different genes), including those previously described in IFNA21 and IFIH1 genes, new variants in genes previously described in MIS-C patients (KMT2D, CFB, and PRF1), and variants in genes newly associated to MIS-C such as APOL1, TNFRSF13B, and G6PD. In addition, gene ontology enrichment pointed to the involvement of thirteen major pathways, including complement system, hematopoiesis, immune system development, and type II interferon signaling, that were not yet reported in MIS-C., Discussion: These data strongly indicate that different gene families may favor MIS- C development. Larger cohort studies with healthy controls and other omics approaches, such as proteomics and RNAseq, will be precious to better understanding the disease dynamics., Competing Interests: The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Reis, Soares Faccion, de Carvalho, Moore, Zuma, Plaça, Salerno Filgueiras, Leandro Mathias Fonseca, Cabral-Marques, Bonomo, Savino, Freitas, Faoro, Passetti, Robaina, de Oliveira, Novaes Bellinat, Zeitel, Salú, de Oliveira, Rodrigues-Santos, Prata-Barbosa and Vasconcelos.)

During the pandemic of severe respiratory distress syndrome coronavirus 2 (SARS-CoV2), many novel therapeutic modalities to treat Coronavirus 2019 induced disease (COVID-19) were explored. This study summarizes 195 clinical trials of advanced cell therapies targeting COVID-19 that were registered over the two years between January 2020 to December 2021. In addition, this work also analyzed the cell manufacturing and clinical delivery experience of 26 trials that published their outcomes by July 2022. Our demographic analysis found the highest number of cell therapy trials for COVID-19 was in United States, China, and Iran (N=53, 43, and 19, respectively), with the highest number per capita in Israel, Spain, Iran, Australia, and Sweden (N=0.641, 0.232, 0,223, 0.194, and 0.192 trials per million inhabitants). The leading cell types were multipotent mesenchymal stromal/stem cells (MSCs), natural killer (NK) cells, and mononuclear cells (MNCs), accounting for 72%, 9%, and 6% of the studies, respectively. There were 24 published clinical trials that reported on infusions of MSCs. A pooled analysis of these MSC studies found that MSCs provide a relative risk reduction for all-cause COVID-19 mortality of RR=0.63 (95% CI 0.46 to 0.85). This result corroborates previously published smaller meta-analyses, which suggested that MSC therapy demonstrated a clinical benefit for COVID-19 patients. The sources of the MSCs used in these studies and their manufacturing and clinical delivery methods were remarkably heterogeneous, with some predominance of perinatal tissue-derived products. Our results highlight the important role that cell therapy products may play as an adjunct therapy in the management of COVID-19 and its related complications, as well as the importance of controlling key manufacturing parameters to ensure comparability between studies. Thus, we support ongoing calls for a global registry of clinical studies with MSC products that could better link cell product manufacturing and delivery methods to clinical outcomes. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the near future, preventing pathology through vaccination still remains the best protection to date. We conducted a systematic review and meta-analysis of advanced cell therapy clinical trials as potential novel treatment for COVID-19 (resulting from SARS-CoV-2 coronavirus infection), including analysis of the global clinical trial landscape, published safety/efficacy outcomes (RR/OR), and details on cell product manufacturing and clinical delivery. This study had a 2-year observation interval from start of January 2020 to end of December 2021, including a follow-up period until end of July to identify published outcomes, which covers the most vivid period of clinical trial activity, and is also the longest observation period studied until today. In total, we identified 195 registered advanced cell therapy studies for COVID-19, employing 204 individual cell products. Leading registered trial activity was attributed to the USA, China, and Iran. Through the end of July 2022, 26 clinical trials were published, with 24 out of 26 articles employing intravenous infusions (IV) of mesenchymal stromal/stem cell (MSC) products. Most of the published trials were attributed to China and Iran. The cumulative results from the 24 published studies employing infusions of MSCs indicated an improved survival (RR=0.63 with 95% Confidence Interval 0.46 to 0.85). Our study is the most comprehensive systematic review and meta-analysis on cell therapy trials for COVID-19 conducted to date, clearly identifying the USA, China, and Iran as leading advanced cell therapy trial countries for COVID-19, with further strong contributions from Israel, Spain, Australia and Sweden. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the future, preventing pathology through vaccination remains the best protection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Couto, Al-Arawe, Filgueiras, Fonseca, Hinterseher, Catar, Chinnadurai, Bersenev, Cabral-Marques, Moll and Verter.)

The historical and social vulnerability of quilombola communities in Brazil can make them especially fragile in the face of COVID-19, considering that several individuals have precarious health systems and inadequate access to water. This work aimed to characterize the frequency of SARS-COV-2 infections and the presence of IgM and IgG SARS-CoV-2 antibodies in quilombola populations and their relationship with the presence of risk factors or preexisting chronic diseases in the quilombola communities. We analyzed the sociodemographic and clinical characteristics, serological status, comorbidities, and symptoms of 1,994 individuals (478 males and 1,536 females) from 18 Brazilian municipalities in the State of Sergipe of quilombola communities, which were evaluated at different epidemiological weeks, starting at the 32nd (August 6th) and ending at the 40th (October 3rd) epidemiological week. More than 70% of studied families live in rural areas and they have an extreme poverty social status. Although we found a higher number of SARS-COV-2 infections in quilombola communities than in the local population, their SARS-CoV-2 reactivity and IgM and IgG positivity varied across the communities investigated. Arterial hypertension was the most risk factor, being found in 27.8% of the individuals (9.5% in stage 1, 10.8% in stage 2, and 7.5% in stage 3). The most common COVID-19 symptoms and comorbidities were headache, runny nose, flu, and dyslipidemia. However, most individuals were asymptomatic (79.9%). Our data indicate that mass testing must be incorporated into public policy to improve the health care system available to quilombola populations during a future pandemic or epidemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Martins, de Souza, de Rezende Neto, Santos, da Invenção, Matos, dos Santos, de Jesus, da Silva, de Almeida, do Vale, Fonseca, Schimke, Matos, Oliveira, Ferreira, de Paula Dias, dos Santos, Barbosa, de Carvalho Barreto, Moreno, Gonçalves, de Mello Silva, Cabral-Marques and Borges.)

Background: Acute ST-elevation myocardial infarction (STEMI) can lead to adverse cardiac remodeling, resulting in left ventricular systolic dysfunction (LVSd) and heart failure. Epigenetic regulators, such as microRNAs, may be involved in the physiopathology of LVSd., Objective: This study explored microRNAs in peripheral blood mononuclear cells (PBMC) of post-myocardial infarction patients with LVSd., Methods: Post-STEMI patients were grouped as having (LVSd, n  = 9) or not LVSd (non-LVSd, n  = 16). The expression of 61 microRNAs was analyzed in PBMC by RT-qPCR and the differentially expressed microRNAs were identified. Principal Component Analysis stratified the microRNAs based on the development of dysfunction. Predictive variables of LVSd were investigated through logistic regression analysis. A system biology approach was used to explore the regulatory molecular network of the disease and an enrichment analysis was performed., Results: The let-7b-5p (AUC: 0.807; 95% CI: 0.63-0.98; p  = 0.013), miR-125a-3p (AUC: 0.800; 95% CI: 0.61-0.99; p  = 0.036) and miR-326 (AUC: 0.783; 95% CI: 0.54-1.00; p  = 0.028) were upregulated in LVSd ( p  < 0.05) and discriminated LVSd from non-LVSd. Multivariate logistic regression analysis showed let-7b-5p (OR: 16.00; 95% CI: 1.54-166.05; p  = 0.020) and miR-326 (OR: 28.00; 95% CI: 2.42-323.70; p  = 0.008) as predictors of LVSd. The enrichment analysis revealed association of the targets of these three microRNAs with immunological response, cell-cell adhesion, and cardiac changes., Conclusion: LVSd alters the expression of let-7b-5p, miR-326, and miR-125a-3p in PBMC from post-STEMI, indicating their potential involvement in the cardiac dysfunction physiopathology and highlighting these miRNAs as possible LVSd biomarkers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Dantas-Komatsu, Cruz, Freire, Diniz, Bortolin, Cabral-Marques, Souza, Hirata, Hirata, Reis, Jurisica, Silbiger and Luchessi.)

G protein-coupled receptors (GPCR) are involved in various physiological and pathophysiological processes. Functional autoantibodies targeting GPCRs have been associated with multiple disease manifestations in this context. Here we summarize and discuss the relevant findings and concepts presented in the biennial International Meeting on autoantibodies targeting GPCRs (the 4th Symposium), held in Lübeck, Germany, 15-16 September 2022. The symposium focused on the current knowledge of these autoantibodies' role in various diseases, such as cardiovascular, renal, infectious (COVID-19), and autoimmune diseases (e.g., systemic sclerosis and systemic lupus erythematosus). Beyond their association with disease phenotypes, intense research related to the mechanistic action of these autoantibodies on immune regulation and pathogenesis has been developed, underscoring the role of autoantibodies targeting GPCRs on disease outcomes and etiopathogenesis. The observation repeatedly highlighted that autoantibodies targeting GPCRs could also be present in healthy individuals, suggesting that anti-GPCR autoantibodies play a physiologic role in modeling the course of diseases. Since numerous therapies targeting GPCRs have been developed, including small molecules and monoclonal antibodies designed for treating cancer, infections, metabolic disorders, or inflammatory conditions, anti-GPCR autoantibodies themselves can serve as therapeutic targets to reduce patients' morbidity and mortality, representing a new area for the development of novel therapeutic interventions., (Copyright © 2023. Published by Elsevier B.V.)

Several perturbations in the number of peripheral blood leukocytes, such as neutrophilia and lymphopenia associated with Coronavirus disease 2019 (COVID-19) severity, point to systemic molecular cell cycle alterations during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, the landscape of cell cycle alterations in COVID-19 remains primarily unexplored. Here, we performed an integrative systems immunology analysis of publicly available proteome and transcriptome data to characterize global changes in the cell cycle signature of COVID-19 patients. We found significantly enriched cell cycle-associated gene co-expression modules and an interconnected network of cell cycle-associated differentially expressed proteins (DEPs) and genes (DEGs) by integrating the molecular data of 1469 individuals (981 SARS-CoV-2 infected patients and 488 controls [either healthy controls or individuals with other respiratory illnesses]). Among these DEPs and DEGs are several cyclins, cell division cycles, cyclin-dependent kinases, and mini-chromosome maintenance proteins. COVID-19 patients partially shared the expression pattern of some cell cycle-associated genes with other respiratory illnesses but exhibited some specific differential features. Notably, the cell cycle signature predominated in the patients' blood leukocytes (B, T, and natural killer cells) and was associated with COVID-19 severity and disease trajectories. These results provide a unique global understanding of distinct alterations in cell cycle-associated molecules in COVID-19 patients, suggesting new putative pathways for therapeutic intervention., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with increased levels of autoantibodies targeting immunological proteins such as cytokines and chemokines. Reports further indicate that COVID-19 patients may develop a broad spectrum of autoimmune diseases due to reasons not fully understood. Even so, the landscape of autoantibodies induced by SARS-CoV-2 infection remains uncharted territory. To gain more insight, we carried out a comprehensive assessment of autoantibodies known to be linked to diverse autoimmune diseases observed in COVID-19 patients in a cohort of 231 individuals, of which 161 were COVID-19 patients (72 with mild, 61 moderate, and 28 with severe disease) and 70 were healthy controls. Dysregulated IgG and IgA autoantibody signatures, characterized mainly by elevated concentrations, occurred predominantly in patients with moderate or severe COVID-19 infection. Autoantibody levels often accompanied anti-SARS-CoV-2 antibody concentrations while stratifying COVID-19 severity as indicated by random forest and principal component analyses. Furthermore, while young versus elderly COVID-19 patients showed only slight differences in autoantibody levels, elderly patients with severe disease presented higher IgG autoantibody concentrations than young individuals with severe COVID-19. This work maps the intersection of COVID-19 and autoimmunity by demonstrating the dysregulation of multiple autoantibodies triggered during SARS-CoV-2 infection. Thus, this cross-sectional study suggests that SARS-CoV-2 infection induces autoantibody signatures associated with COVID-19 severity and several autoantibodies that can be used as biomarkers of COVID-19 severity, indicating autoantibodies as potential therapeutical targets for these patients., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

In patients with severe #COVID19, increased levels of autoantibodies against PAR1 were found. These might serve as allosteric agonists of PAR1 on endothelial cells and platelets, and thus might contribute to the pathogenesis of microthrombosis in COVID-19. https://bit.ly/3pqM9Vv., Competing Interests: Conflict of Interest: T. Bahmer reports grants from BMBF (unrestricted research grant for the German Center for Lung Research (DZL) and National Pandemic Cohort Network (NAPKON) – Coordinating Study Site for population-based cohort platform); lecture fees from Novartis, AstraZeneca, and Chiesi; support for attending the American Thoracic Society Conference from Chiesi; and advisory board participation with GlaxoSmithKline, Boehringer Ingelheim, Roche and AstraZeneca, outside the submitted work. D. Frank reports grants from DFG (467267736), BMBF and DZHK; consulting fees and support for attending meetings from Edwards Lifesciences and Medtronic; lecture honoraria from Edwards Lifesciences, Medtronic, Astra Zeneca, Pfizer, BMS, Novartis, Bayer and Abbott; and participation on advisory boards with BMS, Boehringer Ingelheim, Daiichi Sankyo, outside the submitted work. A.Z. Rosenberg reports grants from the NIH (NIDDK and NHLBI) outside the submitted work. CellTrend is owned by K. Schulze-Forster; CellTrend produces ELISA kits for the determination of antibodies against GPCR. G. Riemekasten reports consulting fees from CellTrend GmbH outside the submitted work. S. Schreiber reports consulting fees from Abbvie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, Prevention Bio, Protagonist and Falk, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2022.)

Brazil experienced one of the most prolonged periods of school closures, and reopening could have exposed students to high rates of SARS-CoV-2 infection. However, the infection status of students and school workers at the time of the reopening of schools located in Brazilian cities is unknown. Here we evaluated viral carriage by RT-PCR and seroprevalence of anti-SARS-CoV-2 antibodies (IgM and IgG) by immunochromatography in 2259 individuals (1139 students and 1120 school workers) from 28 schools in 28 Brazilian cities. We collected the samples within 30 days after public schools reopened and before the start of vaccination campaigns. Most students (n = 421) and school workers (n = 446) had active (qRT-PCR + IgM- IgG- or qRT-PCR + IgM + IgG-/+) SARS-CoV-2 infection. Regression analysis indicated a strong association between the infection status of students and school workers. Furthermore, while 45% (n = 515) of the students and 37% (n = 415) of the school workers were neither antigen nor antibody positive in laboratory tests, 16% of the participants (169 students and 193 school workers) were oligosymptomatic, including those reinfected. These individuals presented mild symptoms such as headache, sore throat, and cough. Notably, most of the individuals were asymptomatic (83.9%). These results indicate that many SARS-CoV-2 infections in Brazilian cities during school reopening were asymptomatic. Thus, our study highlights the need to promote a coordinated public health effort to guarantee a safe educational environment while avoiding exacerbating pre-existent social inequalities in Brazil, reducing social, mental, and economic losses for students, school workers, and their families., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

The kynurenine pathway is implicated in aging, longevity, and immune regulation, but longitudinal studies and assessment of the cerebrospinal fluid (CSF) are lacking. We investigated tryptophan (Trp) and downstream kynurenine metabolites and their associations with age and change over time in four cohorts using comprehensive, targeted metabolomics. The study included 1574 participants in two cohorts with repeated metabolite measurements (mean age at baseline 58 years ± 8 SD and 62 ± 10 SD), 3161 community-dwelling older adults (age range 71-74 years), and 109 CSF donors (mean age 73 years ± 7 SD). In the first two cohorts, age was associated with kynurenine (Kyn), quinolinic acid (QA), and the kynurenine to tryptophan ratio (KTR), and inversely with Trp. Consistent with these findings, Kyn, QA, and KTR increased over time, whereas Trp decreased. Similarly, QA and KTR were higher in community-dwelling older adults of age 74 compared to 71, whereas Trp was lower. Kyn and QA were more strongly correlated with age in the CSF compared to serum and increased in a subset of participants with repeated CSF sampling ( n = 33) over four years. We assessed associations with frailty and mortality in two cohorts. QA and KTR were most strongly associated with mortality and frailty. Our study provides robust evidence of changes in tryptophan and kynurenine metabolism with human aging and supports links with adverse health outcomes. Our results suggest that aging activates the inflammation and stress-driven kynurenine pathway systemically and in the brain, but we cannot determine whether this activation is harmful or adaptive. We identified a relatively stronger age-related increase of the potentially neurotoxic end-product QA in brain., Competing Interests: Per Magne Ueland is a member of the steering board of the nonprofit Foundation to Promote Research into Functional Vitamin B12 Deficiency, which owns Bevital, the company that did biochemical analyses. All the other authors, Stein-Erik H. Solvang, Allison Hodge, Leiv Otto Watne, Otavio Cabral-Marques, Jan Erik Nordrehaug, Graham G. Giles, Pierre-Antoine Dugué, Ottar Nygård, Adrian McCann, Ane-Victoria Idland, Øivind Midttun, Arve Ulvik, Nathalie B. Halaas, Grethe S. Tell, and Lasse M. Giil, report no conflicts of interest., (Copyright © 2022 Stein-Erik H. Solvang et al.)

Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protein coupled receptors (GPCR). In this exploratory study, we analyzed serum AAB levels against vaso- and immunoregulatory receptors, mostly GPCRs, in 80 PCS patients following mild-to-moderate COVID-19, with 40 of them fulfilling diagnostic criteria of ME/CFS. Healthy seronegative (n=38) and asymptomatic post COVID-19 controls (n=40) were also included in the study as control groups. We found lower levels for various AABs in PCS compared to at least one control group, accompanied by alterations in the correlations among AABs. Classification using random forest indicated AABs targeting ADRB2, STAB1, and ADRA2A as the strongest classifiers (AABs stratifying patients according to disease outcomes) of post COVID-19 outcomes. Several AABs correlated with symptom severity in PCS groups. Remarkably, severity of fatigue and vasomotor symptoms were associated with ADRB2 AAB levels in PCS/ME/CFS patients. Our study identified dysregulation of AAB against various receptors involved in the autonomous nervous system (ANS), vaso-, and immunoregulation and their correlation with symptom severity, pointing to their role in the pathogenesis of PCS., Competing Interests: The authors declare that HH and KS-F are managing directors of CellTrend. CellTrend holds together with Charité a patent for the diagnostic use of AABs against ADRB2. CS has a consulting agreement with CellTrend. FP reports grants from the Guthy Jackson Charitable Foundation, during the conduct of the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor MD declared a past co-authorship with the author YS., (Copyright © 2022 Sotzny, Filgueiras, Kedor, Freitag, Wittke, Bauer, Sepúlveda, Mathias da Fonseca, Baiocchi, Marques, Kim, Lange, Plaça, Luebber, Paulus, De Vito, Jurisica, Schulze-Forster, Paul, Bellmann-Strobl, Rust, Hoppmann, Shoenfeld, Riemekasten, Heidecke, Cabral-Marques and Scheibenbogen.)