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Background Evidence indicates a strong link between Zika virus (ZikV) and neurological complications. Acute myelitis, optic neuritis, polyneuropathy, and encephalomyelitis that mimic inflammatory idiopathic demyelination disorders (HDD) after ZikV infection have been reported in Brazil. Objective The present study aims to investigate the possible occurrence of molecular mimicry between ZikV antigens and Multiple Sclerosis (MS) autoantigens, the most frequent HDD of the central nervous system (CNS). Methods A retrospective cohort study with 305 patients admitted due to suspected arbovirus infection in Rio de Janeiro was performed, all subjects were submitted to neurological examination, and a biological sample was collected for serologic and molecular diagnostic. Bioinformatics tools were used to analyze the peptides shared between ZikV antigens and MS autoantigens. Results Of 305 patients, twenty-six were positive for ZikV and 4 presented IDD patterns found in MS cases. Sequence homology comparisons by bioinformatics approach between NS5 ZikV and PLP MS protein revealed a homology of 5/6 consecutive amino acids (CSSVPV/CSAVPV) with 83% identity, deducing a molecular mimicry. Analysis of the 3D structures revealed a similar conformation with alpha helix presentation. Conclusions Molecular mimicry between NS5 Zika virus antigen and PLP MS autoantigens emerge as a possible mechanism for IDD spectrum in genetically susceptible individuals. Resumo Antecedentes Evidências indicam uma forte ligação entre o vírus Zika (ZikV) e complicações neurológicas. Mielite aguda, neurite óptica, polineuropatia e encefalomielite que mimetizam distúrbios inflamatórios de desmielinização idiopáticos (DDII) após infecção por ZikV têm sido relatadas no Brasil. Obejtivo O presente estudo tem como objetivo investigar a possível ocorrência de mimetismo molecular entre antígenos do ZikV e autoantígenos da Esclerose Múltipla (EM), a DDII mais frequente do sistema nervoso central (SNC). Métodos Foi realizado um estudo de coorte retrospectivo com 305 pacientes internados por suspeita de infecção por arbovirus no Rio de Janeiro, todos os indivíduos foram submetidos a exame neurológico e coleta de amostra biológica para diagnóstico sorológico e molecular. Ferramentas de bioinformática foram usadas para analisar os peptídeos compartilhados entre antígenos do ZikV e autoantígenos da EM. Resultados Dos 305 pacientes, vinte e seis foram positivos para ZikV e 4 apresentaram padrão IDD encontrado em casos de EM. As comparações de homologia de sequência por abordagem de bioinformática entre a proteína NS5 ZikV e PLP EM revelaram uma homologia de 5/6 aminoácidos consecutivos (CSSVPV/CSAVPV) com 83% de identidade, deduzindo um mimetismo molecular. A análise das estruturas 3D revelou uma conformação semelhante com apresentação em alfa-hélice. Conclusões O mimetismo molecular entre o antígeno NS5 do vírus Zika e o autoantígeno PLP da EM surge como um possível mecanismo para o espectro IDD em indivíduos geneticamente suscetíveis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and caused the devastating global pandemic of coronavirus disease 2019 (COVID-19), in part because of its ability to effectively suppress host cell responses

Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift1 and suboptimal immune responses2. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses.

Cervical cancer is caused by infections of the human papillomavirus (HPV), which can be prevented by vaccinations. In Japan, although about 3000 people die of cervical cancer annually, the HPV vaccination rate has remained extremely low in the eligible population since many Japanese have been concerned that "diverse symptoms," such as chronic pain, movement disorders, and cognitive impairment, may occur as adverse reactions after HPV vaccination. The concern has been raised by media coverage of the ongoing HPV vaccine lawsuits, in which the plaintiffs complained of their symptoms caused by HPV vaccination. The claims have been based on the alleged pathogenic findings in research articles on HPV vaccines, summarized in the document prepared by the plaintiffs' attorneys. We critically evaluated these articles, in which the authors proposed the following findings/hypothesis: (i) molecular mimicry between HPV L1 and human proteins leads to the production of cross-reactive antibodies; and (ii) HPV vaccine injection in mice causes damage in the brain, a mouse model for HPV vaccine associated neuro-immunopathic syndrome (HANS). We found that these hypotheses were based mainly on the findings from a few research groups and that all the articles had flaws in the method, result, or discussion sections. Our current evaluation should help better understand the validity of the findings, which have been often misunderstood as the truth by the general public. We propose to accumulate high-quality data on potential adverse events following HPV vaccination and to continue critically evaluating them.

A long-established strategy for transcription regulation is the tethering of transcription factors to cellular membranes. In contrast, the principal effectors of Hedgehog signaling, the Gli transcription factors, are regulated by microtubules in the primary cilium and the cytoplasm. How Gli is tethered to microtubules remains unclear. We uncover DNA mimicry by the ciliary kinesin Kif7 as a mechanism for the recruitment of Gli to microtubules, wherein the coiled-coil dimerization domain of Kif7, characterized by striking shape, size and charge similarity to DNA, forms a complex with the DNA-binding zinc fingers in Gli, thus revealing a mode of tethering a DNA-binding protein to the cytoskeleton. Gli increases the Kif7-microtubule affinity and consequently modulates the localization of both proteins to microtubules and the cilium tip. Thus, the kinesin-microtubule system is not a passive Gli tether but a regulatable platform tuned by the kinesin-transcription factor interaction. We re-tooled the unique coiled-coil-based Gli-Kif7 interaction for inhibiting the nuclear and cilium localization of Gli. This strategy can be potentially exploited for downregulating erroneously activated Gli in human cancers.

Molecular mimicry: homology in the TCR facing residues and molecular interaction. The MAGE-A1278-286 peptide and the homologous peptide derived from Faecalibacterium prausnitzii (WP_158387495.1) are shown bound to the HLA-A*02:01 molecule. The identical residues K1, E4, Y5, I7 are presented to the TCR αβ chains with the same conformation (A – D). The contact areas in red between the two peptides and the TCR αβ chains are identical (E - H). The areas of contact between the HLA molecule and the TCR αβ chains are identical (yellow and dark blue areas) (I, J).

IntroductionVaccines have demonstrated protection against the morbidity and mortality of COVID-19, but concerns regarding the rare side effect of acute myocarditis have stymied immunization efforts. This review aims to describe the incidence and theorized mechanisms of COVID vaccine-associated myocarditis and review relevant principles for management of vaccine-associated myocarditis.Areas coveredEpidemiologic studies of myocarditis after COVID vaccination are reviewed, which show an incidence of approximately 20-30 per million patients. The vast majority of these cases are seen with mRNA vaccines especially in male patients under 30years of age. Mechanisms are largely theoretical, but molecular mimicry and dysregulated innate immune reactions have been proposed. While studies suggest that this subtype of myocarditis is mild and self-limited, long-term evidence is lacking. Principles of myocarditis treatment and surveillance are outlined as they apply to COVID vaccine-associated myocarditis.Expert opinionCOVID vaccine-associated myocarditis is rare but well described in certain at-risk groups. Better understanding of its pathogenesis is key to mitigating this complication and advancing vaccination efforts. Risk-benefit analyses demonstrate that individual- and population-level benefits of vaccination exceed the risks of this rare and mild form of myocarditis.

Previous studies have highlighted the potential role of Mycobacterium avium subspecies paratuberculosis (MAP) and human endogenous retrovirus W (HERV-W) in the pathogenesis of type 1 diabetes (T1DM) among Sardinian subjects. To better understand how antibody responses evolve during disease progression, a serological evaluation of IgG antibodies was performed in Sardinian children with T1DM collected at different time-points following the onset of the disease. It is known that anti-PI and anti-insulin (IAA) autoantibodies are the first to appear before the clinical onset of T1DM. In order to investigate the humoral responses, 69 children with T1DM were enrolled in the study, including 25 with new onset, 25 with T1DM at 1–5 years since diagnosis and 19 with T1DM at 6–12 years since diagnosis. Serum samples were tested for the presence of antibodies (Abs) against PI46–61, three MAP epitopes (including MAP 2404c, which has a homologous sequence with PI) and two HERV-W-derived epitopes via indirect enzyme-linked immunosorbent assay (ELISA). The data obtained from the analysis showed significantly higher IgG responses against all peptides detected in the new onset group compared to longer suffering (1–5 and 6–12 years) T1DM patients, also showing a robust correlation between the proinsulin autoantibody and anti-MAP/HERV antibodies, characterized by a progressive decline the first year after onset. Taken together, these findings support the hypothesis that MAP and HERV could act as risk factors for T1DM, suggesting that they may serve as potential biomarkers of disease progression in early-stage T1DM.

A laccase catalyzed colorimetric biosensing approach is promising for the detection of pheochromocytoma biomarkers, yet suffers from the poor stability of enzymes and high cost for production. Here we report for the first time an easy to produce, cheap, stable and reliable laccase-mimicking CuCoFe-LDHzyme, which can catalyze the oxidation of pheochromocytoma biomarkers to form a chromogenic product for smartphone-based colorimetric detection.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β-cells. One of the earliest aspects of this process is the development of autoantibodies and T cells directed at an epitope in the B-chain of insulin (insB:9–23). Analysis of microbial protein sequences with homology to the insB:9–23 sequence revealed 17 peptides showing >50% identity to insB:9–23. Of these 17 peptides, the hprt4–18 peptide, found in the normal human gut commensal Parabacteroides distasonis , activated both human T cell clones from T1D patients and T cell hybridomas from nonobese diabetic (NOD) mice specific to insB:9–23. Immunization of NOD mice with P. distasonis insB:9–23 peptide mimic or insB:9–23 peptide verified immune cross-reactivity. Colonization of female NOD mice with P. distasonis accelerated the development of T1D, increasing macrophages, dendritic cells, and destructive CD8 + T cells, while decreasing FoxP3 + regulatory T cells. Western blot analysis identified P. distasonis –reacting antibodies in sera of NOD mice colonized with P. distasonis and human T1D patients. Furthermore, adoptive transfer of splenocytes from P. distasonis –treated mice to NOD/SCID mice enhanced disease phenotype in the recipients. Finally, analysis of human children gut microbiome data from a longitudinal DIABIMMUNE study revealed that seroconversion rates (i.e., the proportion of individuals developing two or more autoantibodies) were consistently higher in children whose microbiome harbored sequences capable of producing the hprt4–18 peptide compared to individuals who did not harbor it. Taken together, these data demonstrate the potential role of a gut microbiota-derived insB:9–23-mimic peptide as a molecular trigger of T1D pathogenesis.

Urinary tract infection (UTI) is a disease of extremely high incidence in both community and nosocomial settings. UTIs cause significant morbidity and mortality, with approximately 150 million cases globally per year. Uropathogenic Escherichia coli (UPEC) is the primary cause of UTI and is generally treated empirically. However, the rapidly increasing incidence of UTIs caused by multidrug-resistant UPEC strains has led to limited available treatment options and highlights the urgent need to develop alternative treatment and prevention strategies. In this study, we performed a comprehensive analysis to define the regulation, structure, function, and immunogenicity of recently identified UPEC vaccine candidate C1275 (here referred to as IrmA). We showed that the irmA gene is highly prevalent in UPEC, is cotranscribed with the biofilm-associated antigen 43 gene, and is regulated by the global oxidative stress response OxyR protein. Localization studies identified IrmA in the UPEC culture supernatant. We determined the structure of IrmA and showed that it adopts a unique domain-swapped dimer architecture. The dimeric structure of IrmA displays similarity to those of human cytokine receptors, including the interleukin-2 receptor (IL-2R), interleukin-4 receptor (IL-4R), and interleukin-10 receptor (IL-10R) binding domains, and we showed that purified IrmA can bind to their cognate cytokines. Finally, we showed that plasma from convalescent urosepsis patients contains high IrmA antibody titers, demonstrating the strong immunogenicity of IrmA. Taken together, our results indicate that IrmA may play an important role during UPEC infection., IMPORTANCE Uropathogenic E. coli (UPEC) is the primary cause of urinary tract infection (UTI), a disease of major significance to human health. Globally, the incidence of UPEC-mediated UTI is strongly associated with increasing antibiotic resistance, making this extremely common infection a major public health concern. In this report, we describe the regulatory, structural, functional, and immunogenic properties of a candidate UPEC vaccine antigen, IrmA. We demonstrate that IrmA is a small UPEC protein that forms a unique domain-swapped dimer with structural mimicry to several human cytokine receptors. We also show that IrmA binds to IL-2, IL-4, and IL-10, is strongly immunogenic in urosepsis patients, and is coexpressed with factors associated with biofilm formation. Overall, this work suggests a potential novel contribution for IrmA in UPEC infection.

Autoimmune diseases affect 5–9% of the world’s population. It is now known that genetics play a relatively small part in the pathophysiology of autoimmune disorders in general, and that environmental factors have a greater role. In this review, we examine the role of the exposome, an individual’s lifetime exposure to external and internal factors, in the pathophysiology of autoimmune diseases. The most common of these environmental factors are toxic chemicals, food/diet, and infections. Toxic chemicals are in our food, drink, common products, the air, and even the land we walk on. Toxic chemicals can directly damage self-tissue and cause the release of autoantigens, or can bind to human tissue antigens and form neoantigens, which can provoke autoimmune response leading to autoimmunity. Other types of autoimmune responses can also be induced by toxic chemicals through various effects at the cellular and biochemical levels. The food we eat every day commonly has colorants, preservatives, or packaging-related chemical contamination. The food itself may be antigenic for susceptible individuals. The most common mechanism for food-related autoimmunity is molecular mimicry, in which the food’s molecular structure bears a similarity with the structure of one or more self-tissues. The solution is to detect the trigger, remove it from the environment or diet, then repair the damage to the individual’s body and health.

The design of high-affinity, RNA-binding ligands has proven very challenging. This is due to the unique structural properties of RNA, often characterized by polar surfaces and high flexibility. In addition, the frequent lack of well-defined binding pockets complicates the development of small molecule binders. This has triggered the search for alternative scaffolds of intermediate size. Among these, peptide-derived molecules represent appealing entities as they can mimic structural features also present in RNA-binding proteins. However, the application of peptidic RNA-targeting ligands is hampered by a lack of design principles and their inherently low bio-stability. Here, the structure-based design of constrained α-helical peptides derived from the viral suppressor of RNA silencing, TAV2b, is described. We observe that the introduction of two inter-side chain crosslinks provides peptides with increased α-helicity and protease stability. One of these modified peptides (B3) shows high affinity for double-stranded RNA structures including a palindromic siRNA as well as microRNA-21 and its precursor pre-miR-21. Notably, B3 binding to pre-miR-21 inhibits Dicer processing in a biochemical assay. As a further characteristic this peptide also exhibits cellular entry. Our findings show that constrained peptides can efficiently mimic RNA-binding proteins rendering them potentially useful for the design of bioactive RNA-targeting ligands.

Viruses require multifunctional structured RNAs to hijack their host’s biochemistry, but their mechanisms can be obscured by the difficulty of solving conformationally dynamic RNA structures. Using cryo–electron microscopy (cryo-EM), we visualized the structure of the mysterious viral transfer RNA (tRNA)–like structure (TLS) from the brome mosaic virus, which affects replication, translation, and genome encapsidation. Structures in isolation and those bound to tyrosyl-tRNA synthetase (TyrRS) show that this ~55-kilodalton purported tRNA mimic undergoes large conformational rearrangements to bind TyrRS in a form that differs substantially from that of tRNA. Our study reveals how viral RNAs can use a combination of static and dynamic RNA structures to bind host machinery through highly noncanonical interactions, and we highlight the utility of cryo-EM for visualizing small, conformationally dynamic structured RNAs.

Off-target drug release and insufficient drug delivery are the main obstacles for effective anticancer chemotherapy. Prodrug-based self-assembled nanoparticles bioactivated under tumor-specific conditions are one of the effective strategies to achieve on-demand drug release and effective tumor accumulation. Herein, stimuli-activable prodrugs are designed yielding smart tumor delivery by combination of the triglyceride-mimic (TG-mimetic) prodrug structure and disulfide bond. Surprisingly, these prodrugs can self-assemble into uniform nanoparticles (NPs) with a high drug loading (over 40%) and accumulate in tumor sites specifically. The super hydrophobic TG structure can act as a gate that senses lipase to selectively control over NP dissociation and affect the glutathione-triggered prodrug activation. In addition, the impacts of the double bonds in the prodrug NPs on parent drug release and the following cytotoxicity, pharmacokinetics, and antitumor efficiency are further demonstrated. Our findings highlight the promising potential of TG-mimetic structure-gated prodrug nanoparticles for tumor-specific drug delivery.

The discovery of a new class of small molecule compounds that target the BCL-2 family of anti-apoptotic proteins is one of the great success stories of basic science leading to translational outcomes in the last 30 years. The eponymous BCL-2 protein was identified over 30 years ago due to its association with cancer. However, it was the unveiling of the biochemistry and structural biology behind it and its close relatives’ mechanism(s)-of-action that provided the inspiration for what are now known as ‘BH3-mimetics’, the first clinically approved drugs designed to specifically inhibit protein–protein interactions. Herein, we chart the history of how these drugs were discovered, their evolution and application in cancer treatment.

Background and Objectives Whether exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may predispose to the risk of cancer in individuals with no prior cancers is a crucial question that remains unclear. To confirm/refute possible relationships between exposure to the virus and ex novo insurgence of tumors, this study analyzed molecular mimicry and the related cross-reactive potential between SARS-CoV-2 spike glycoprotein (gp) antigen and human tumor-suppressor proteins. Materials and Methods Tumor-associated proteins were retrieved from UniProt database and analyzed for pentapeptide sharing with SARS-CoV-2 spike gp by using publicly available databases. Results An impressively high level of molecular mimicry exists between SARS-CoV-2 spike gp and tumor-associated proteins. Numerically, 294 tumor-suppressor proteins share 308 pentapeptides with the viral antigen. Crucially, the shared peptides have a relevant immunologic potential by repeatedly occurring in experimentally validated epitopes. Such immunologic potential is of further relevancy in that most of the shared peptides are also present in infectious pathogens to which, in general, human population has already been exposed, thus indicating the possibility of immunologic imprint phenomena. Conclusion This article described a vast peptide overlap between SARS-CoV-2 spike gp and tumor-suppressor proteins, and supports autoimmune cross-reactivity as a potential mechanism underlying prospective cancer insurgence following exposure to SARS-CoV-2. Clinically, the findings call for close surveillance of tumor sequelae that possibly could result from the current coronavirus pandemic.

Background People living with HIV/AIDS (PLWHA) show a reduced incidence for three cancer types, namely breast, prostate and colon cancers. In the present study, we assessed whether a molecular mimicry between HIV epitopes and tumor associated antigens and, consequently, a T cell cross-reactivity could provide an explanation for such an epidemiological evidence. Methods Homology between published TAAs and non-self HIV-derived epitopes have been assessed by BLAST homology. Structural analyses have been performed by bioinformatics tools. Immunological validation of CD8+ T cell cross-reactivity has been evaluated ex vivo by tetramer staining. Findings Sequence homologies between multiple TAAs and HIV epitopes have been found. High structural similarities between the paired TAAs and HIV epitopes as well as comparable patterns of contact with HLA and TCR α and β chains have been observed. Furthermore, cross-reacting CD8+ T cells have been identified. Interpretation This is the first study showing a molecular mimicry between HIV antigens an TAAs identified in breast, prostate and colon cancers. Therefore, it is highly reasonable that memory CD8+ T cells elicited during the HIV infection may play a key role in controlling development and progression of such cancers in the PLWHA lifetime. This represents the first demonstration ever that a viral infection may induce a natural “preventive” anti-cancer memory T cells, with highly relevant implications beyond the HIV infection.

Carbon nitride (C

Campylobacter jejuni is a major foodborne pathogen causing enteritis in humans and is also known as an antecedent infectious factor for Guillain-Barre syndrome (GBS). The onset of GBS after C. jejuni infection results from molecular mimicry between human neuronal ganglioside and C. jejuni lipooligosaccharide (LOS). C. jejuni HS:19 has been previously reported to be isolated from GBS cases more frequently than other serotypes in Japan. Therefore, in this study, we performed molecular analysis of 88 HS:19 isolates from GBS cases, sporadic diarrheal patients, and poultry meats using multi-locus sequence typing and LOS class analysis. As a result, 87 of the 88 HS:19 isolates were typed as ST22 / CC22 and LOS class A1, while one was typed as ST1947 / CC22 and LOS class A1. Furthermore, the analysis of other 331 isolates from sporadic enteritis cases shows that only 34 (10.3%) were typed as LOS class A, including HS:19 (25 isolates), HS:2 (8 isolates), and HS:4c (1 isolate). In conclusion, C. jejuni HS:19 had high clonality, regardless of its origin, over other capsule types in Japan.

Neurological complications are increasingly being reported in dengue fever, and the dengue virus is now recognized as a neurotrophic virus. The damage caused by inflammatory cytokines in the febrile phase and molecular mimicry in the recovery phase is responsible for these neurological manifestations. We report such an unusual neurological complication occurring in a 27-year-old female in the recovery phase of dengue fever, who developed an acute onset of ascending symmetric weakness of all four limbs without any sensory, autonomic, cerebellar, or cranial nerve involvement. She was diagnosed as having an acute motor axonal neuropathy (AMAN) variant of Guillain-Barre syndrome (GBS) based on a nerve conduction study (NCS) showing axonal neuropathy and contrast-enhanced magnetic resonance imaging (CE-MRI) showing root enhancement at the region of the cauda equina. She was treated with intravenous immunoglobulin (IVIG) and showed full recovery from symptoms with treatment. Our case highlights the importance of being aware of such rare neurological complications in dengue fever. Early detection and rapid initiation of treatment can lead to the complete reversal of neurological deficits.

Helicobacter pylori (H. pylori) is an infectious agent influencing as much as 50% of the world’s population. It is the causative agent for several diseases, most especially gastric and duodenal peptic ulcer, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma of the stomach. A number of other, extragastric manifestations also are associated with H. pylori infection. These include neurological disorders, such as Alzheimer’s disease, demyelinating multiple sclerosis and Parkinson’s disease. There is also evidence for a relationship between H. pylori infection and such dermatological diseases as psoriasis and rosacea as well as a connection with infection and open-angle glaucoma. Generally little is known about the relationship between H. pylori infection and diseases of the pancreas. Most evidence about H. pylori and its potential role in the development of pancreatic diseases concerns pancreatic adenocarcinoma and autoimmune forms of chronic pancreatitis. There is data (albeit not fully consistent) indicating modestly increased pancreatic cancer risk in H. pylori-positive patients. The pathogenetic mechanism of this increase is not yet fully elucidated, but several theories have been proposed. Reduction of antral D-cells in H. pylori-positive patients causes a suppression of somatostatin secretion that, in turn, stimulates increased secretin secretion. That stimulates pancreatic growth and thus increases the risk of carcinogenesis. Alternatively, H. pylori, as a part of microbiome dysbiosis and the so-called oncobiome, is proven to be associated with pancreatic adenocarcinoma development via the promotion of cellular proliferation. The role of H. pylori in the inflammation characteristic of autoimmune pancreatitis seems to be explained by a mechanism of molecular mimicry among several proteins (mostly enzymes) of H. pylori and pancreatic tissue. Patients with autoimmune pancreatitis often show positivity for antibodies against H. pylori proteins. H. pylori, as a part of microbiome dysbiosis, also is viewed as a potential trigger of autoimmune inflammation of the pancreas. It is precisely these relationships (and associated equivocal conclusions) that constitute a center of attention among pancreatologists, immunologists and pathologists. In order to obtain clear and valid results, more studies on sufficiently large cohorts of patients are needed. The topic is itself sufficiently significant to draw the interest of clinicians and inspire further systematic research. Next-generation sequencing could play an important role in investigating the microbiome as a potential diagnostic and prognostic biomarker for pancreatic cancer.

While repurposed drugs came in handy earlier in the wake of the coronavirus disease 2019 (COVID-19) pandemic, vaccination has been considered a more sustainable approach. The recent spikes have been linked to “double,” “triple,” and even multi-mutant variants, thus renewing calls for deeper structural and functional insights of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a lead to rationale design of therapeutics, vaccines, and point-of-care diagnostics. There is a repertoire of findings from the earliest SARS-CoV-2 molecular mimicry to evade host immunity cum host immune responses to the role of the viral glycocalyx in modulating the susceptibility and severity of infection through attraction and repulsive interactions. Recently, molecular studies of some viral components that aid infection in the face of vaccination seem unending. In addition, the wave of infections and the attendant case fatality ratios have necessitated the need for emergency use authorizations for COVID-19 vaccines and in vitro diagnostics. This review provides key updates of SARS-CoV-2, current antigenic and formulation strategies, with emergency use authorizations considerations for future vaccine candidates and diagnostics. We also premise that despite the difficulty in modeling and analyzing glycans, understanding and exploiting their roles in the SARS-CoV-2 architecture is fundamental to glycan-based COVID-19 vaccines devoid of inconsistent clinical outcomes.

Supplemental Digital Content is available in the text., Myocarditis has been recognized as a rare complication of coronavirus disease 2019 (COVID-19) mRNA vaccinations, especially in young adult and adolescent males. According to the US Centers for Disease Control and Prevention, myocarditis/pericarditis rates are ≈12.6 cases per million doses of second-dose mRNA vaccine among individuals 12 to 39 years of age. In reported cases, patients with myocarditis invariably presented with chest pain, usually 2 to 3 days after a second dose of mRNA vaccination, and had elevated cardiac troponin levels. ECG was abnormal with ST elevations in most, and cardiac MRI was suggestive of myocarditis in all tested patients. There was no evidence of acute COVID-19 or other viral infections. In 1 case, a cardiomyopathy gene panel was negative, but autoantibody levels against certain self-antigens and frequency of natural killer cells were increased. Although the mechanisms for development of myocarditis are not clear, molecular mimicry between the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and self-antigens, trigger of preexisting dysregulated immune pathways in certain individuals, immune response to mRNA, and activation of immunologic pathways, and dysregulated cytokine expression have been proposed. The reasons for male predominance in myocarditis cases are unknown, but possible explanations relate to sex hormone differences in immune response and myocarditis, and also underdiagnosis of cardiac disease in women. Almost all patients had resolution of symptoms and signs and improvement in diagnostic markers and imaging with or without treatment. Despite rare cases of myocarditis, the benefit-risk assessment for COVID-19 vaccination shows a favorable balance for all age and sex groups; therefore, COVID-19 vaccination is recommended for everyone ≥12 years of age.

Membranous nephropathy (MN) is an organ-restricted autoimmune disease mainly caused by circulating autoantibodies against podocyte antigens, including the M-type phospholipase A2 receptor (PLA2R) and thrombospondin domain-containing 7A (THSD7A). Antibodies against PLA2R are present in 70%–80% and against THSD7A in 2% of adult patients, which provides a paradigm shift in molecular diagnosis and management monitoring. Both antigens share some similar characteristics: they are expressed by podocytes and have wide tissue distributions; they are bound by autoantibodies only under nonreducing conditions, and the subtype of most autoantibodies is IgG4. However, the factors triggering autoantibody production as well as the association among air pollution, malignancy, and the pathogenesis of MN remain unclear. In this review, we discuss the similarity between the pathological mechanisms triggered by disparate antigens and their associated diseases. Furthermore, we demonstrated the possibility that PM2.5, malignancy, and gene expression specifically induce exposure of these antigens through conformational changes, molecular mimicry, or increased expression eliciting autoimmune responses. Thus, this review provides novel insights into the pathological mechanism of MN.

Autoimmune encephalitis (AE) is an increasingly recognized inflammatory disorder of the central nervous system and is most often characterized by antibodies against intracellular and neuronal surface antigens. AE is a devastating disease that may result in developmental delay or regression in children. However, the pathogenesis of AE is not clear, and immune system disorders after infection likely play an important role in AE. Many studies have reported that patients with herpes simplex virus encephalitis develop anti-N-methyl-d-aspartate receptor encephalitis after antiviral treatment. It is critical to recognize pediatric AE early and to distinguish it from infectious forms because AE is treatable and responsive to immunotherapies. In this review, we discuss the clinical features of pediatric AE and focus on the relationship between AE and postinfection status. In addition, we review the probable mechanisms underlying infection-triggered AE, which include molecular mimicry, bystander activation, epitope spreading, immune system disorder, and genetic susceptibility.

Recent studies identified specific gut microbial species linked to various human diseases, and gut-brain axis is currently attracting much attention in the field of microbiome science clinically and biologically. Research on multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis is one of the most active research subjects. Notably, recent achievements established the bidirectional causality between MS and gut microbiome. The reduction of gut microbiome-derived short chain fatty acids and the enrichment of gut-associated oxidative stress appear to be promoting for neurodegenerative processes. Also, researchers are trying to elucidate the mechanisms by which the microbiome regulates the onset and progression of MS. The new findings achieved by the analysis of the causal relationship between MS and the gut microbiome will provide a new therapeutic strategy for MS. These results will contribute to our understanding of the cause, prevention, and treatment of MS, and will lead to a complete cure for this disease in the future. In MS, for which no curative treatment has yet to be established, the unmet needs may be overcome through the analysis of gut microbiome.

Molecular mimicry is one of the evolutionary strategies that parasites use to manipulate the host metabolism and perform an effective infection. This phenomenon has been observed in several animal and plant pathosystems. Despite the relevance of this mechanism in pathogenesis, little is known about it in fungus–plant interactions. For that reason, we performed an in silico method to select plausible mimicry candidates for the Ustilago maydis–maize interaction. Our methodology used a tripartite sequence comparison between the parasite, the host, and nonparasitic organisms’ genomes. Furthermore, we used RNA sequencing information to identify gene coexpression, and we determined subcellular localization to detect potential cases of colocalization in the imitator-imitated pairs. With these approximations, we found a putative extracellular formin in U. maydis with the potential to rearrange the host cell cytoskeleton. In parallel, we detected at least two maize genes involved in the cytoskeleton rearrangement differentially expressed under U. maydis infection; thus, this find increases the expectation for the potential mimicry role of the fungal protein. The use of several sources of data led us to develop a strict and replicable in silico methodology to detect molecular mimicry in pathosystems with enough information available. Furthermore, this is the first time that a genomewide search has been performed to detect molecular mimicry in a U. maydis–maize system. Additionally, to allow the reproducibility of this experiment and the use of this pipeline, we created a Web server called Molecular Mimicry Finder. [Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

The etiological complexity of multiple sclerosis, an immune-mediated, neurodegenerative disease with multifactorial etiology is still elusive because of an incomplete understanding of the complex synergy between contributing factors such as genetic susceptibility and aberrant immune response. Recently, the disease phenotypes have also been shown to be associated with dysbiosis of the gut microbiome, a dynamic reservoir of billions of microbes, their proteins and metabolites capable of mimicring the autoantigens. Microbial factors could potentially trigger the neuroinflammation and symptoms of MS. In this perspective article, we discussed how microbial molecules resulting from a leaky gut might mimic a host’s autoantigen, potentially contributing to the disease disequilibrium. It further highlights the importance of targeting the gut microbiome for alternate therapeutic options for the treatment of MS.

The use of innovative approaches to elucidate the pathophysiological mechanisms of autoimmune diseases, as well as to further study of the factors which can have either a positive or negative effect on the course of the disease, is essential. In this line, the development of new molecular techniques and the creation of the Human Genome Program have allowed access to many more solutions to the difficulties that exist in the identification and characterization of the microbiome, as well as changes due to various factors. Such innovative technologies can rekindle older hypotheses, such as molecular mimicry, allowing us to move from hypothesis to theory and from correlation to causality, particularly regarding autoimmune diseases and dysbiosis of the microbiota. For example, Prevotella copri appears to have a strong association with rheumatoid arthritis; it is expected that this will be confirmed by several scientists, which, in turn, will make it possible to identify other mechanisms that may contribute to the pathophysiology of the disease. This article seeks to identify new clues regarding similar correlations between autoimmune activity and the human microbiota, particularly in relation to qualitative and quantitative microbial variations therein.

SummaryLate-onset Alzheimer’s Disease (LOAD) pathology is rare in our closest living evolutionary relatives (chimpanzees), which also express much lower microglial levels of CD33(Siglec-3)–a myelomonocytic receptor inhibiting innate immune reactivity by extracellular V-set domain recognition of sialic acid(Sia)-containing “self-associated molecular patterns” (SAMPs). We earlier showed that V-set domain-deficient CD33-variant allele, protective against LOAD, is derived and specific to hominin-lineage. We now report that CD33 also harbors multiple hominin-specific V-set domain mutations and explore selection forces that may have favored such genomic changes. N-glycolylneuraminic acid (Neu5Gc), the preferred Sia-ligand of ancestral CD33 is absent in humans, due to hominin-specific, fixed loss-of-function mutation in CMAH, which generates CMP-Neu5Gc from its precursor, CMP-N-acetylneuraminic acid (Neu5Ac). Extensive mutational analysis and MD-simulations indicate that fixed change in amino acid 21 of hominin V-set domain and conformational changes related to His45 corrected for Neu5Gc-loss by switching to Neu5Ac-recognition. Considering immune-evasive “molecular mimicry” of SAMPs by pathogens, we found that human-specific pathogens Neisseria gonorrhoeae and Group B Streptococcus (affecting fertility and fetuses/neonates respectively) selectively bind huCD33 and this binding is significantly impacted by amino acid 21 modification. Alongside LOAD-protective CD33 alleles, humans harbor additional, derived, population-universal, cognition-protective variants absent in “great ape” genomes. Interestingly, 11 of 13 SNPs in these human genes (including CD33), that protect the cognitive health of elderly populations, are not shared by genomes of archaic hominins: Neanderthals and Denisovans. Finally, we present a plausible evolutionary scenario to compile, correlate and comprehend existing knowledge about huCD33 evolution and suggest that grandmothering emerged in humans.

Aberrant extravascular expression of VE-cadherin has been observed in metastasis associated with vasculogenic mimicry (VM); we have recently shown that in VM prone cells VE-cadherin (mainly in the form of phospho-VE-cadherin in Y658) is in part located in the cell nucleus, which associates with p120-catenin and the transcription factor kaiso allowing increased plasticity that potentiates VM development in malignant cells. In this chapter, we describe the protocol to analyze protein-protein interactions in subcellular fractions with particular focus in VE-cadherin. The verification of the subcellular interactome of VE-cadherin and other key proteins involved in VM shed light to novel functions of endothelial proteins aberrantly expressed in tumor cells and their consequences in cell plasticity during VM development.

Background The gut microbiota profile is unique for each individual and are composed by different bacteria species according to individual birth-to-infant transitions. In the last years, the local and systemic effects of microbiota on cancer onset, progression and response to treatments, such as immunotherapies, has been extensively described. Here we offer a new perspective, proposing a role for the microbiota based on the molecular mimicry of tumor associated antigens by microbiome-associated antigens. Methods In the present study we looked for homology between published TAAs and non-self microbiota-derived epitopes. Blast search for sequence homology was combined with extensive bioinformatics analyses. Results Several evidences for homology between TAAs and microbiota-derived antigens have been found. Strikingly, three cases of 100% homology between the paired sequences has been identified. The predicted average affinity to HLA molecules of microbiota-derived antigens is very high ( Conclusions The data reported in the present study show for the first time the high homology in the linear sequence as well as in structure and conformation between TAAs and peptides derived from microbiota species of the Firmicutes and the Bacteroidetes phyla, which together account for 90% of gut microbiota. Cross-reacting CD8+ T cell responses are very likely induced. Therefore, the anti-microbiota T cell memory may turn out to be an anti-cancer T cell memory, able to control the growth of a cancer developed during the lifetime if the expressed TAA is similar to the microbiota epitope. This may ultimately represent a relevant selective advantage for cancer patients and may lead to a novel preventive anti-cancer vaccine strategy.

We present a unique case of biopsy-proven syphilitic hepatitis which presented as severe acute liver injury with significant elevation in aminotransferases and bilirubin, and improved with antibiotic therapy. However, the patient returned weeks after initial presentation with new-onset acute liver injury and had developed hypergammaglobulinemia, positive autoantibody titers, and repeat liver biopsy demonstrating interface hepatitis, supporting a diagnosis of autoimmune hepatitis. He had an otherwise unrevealing etiologic workup, and responded to glucocorticoid therapy. We believe that syphilitic hepatitis and its treatment subsequently triggered an immunogenic response, leading to autoimmune hepatitis. Autoimmune hepatitis is a chronic liver disease thought to manifest as a result of predisposing genetic factors in combination with environmental insults, especially hepatotropic pathogens. Syphilis is a sexually transmitted disease caused by Treponema pallidum that has been associated with autoimmunity and the development of autoantibodies. We propose that in the setting of syphilitic hepatitis, a molecular mimicry event resulting from structural similarities between T. pallidum and liver antigens, as well as impaired regulatory T-cell function, led to the breakdown of immune tolerance and the onset of autoimmune hepatitis. To support this hypothesis, further molecular analyses and case series are necessary to determine if syphilitic hepatitis and its treatment are risk factors for the onset of autoimmune hepatitis. Autoimmune hepatitis should be considered early as the cause of acute liver injury in susceptible patients with risk factors for the disease, as prompt recognition and appropriate treatment may prevent progression of liver injury and result in improved outcomes.

The recent outbreak of Zika virus infection increased the incidence of Guillain–Barré syndrome (GBS). Following the first reported case of GBS after Zika virus infection in 2013, there has been a considerable increase in the incidence of GBS in endemic countries, such as French Polynesia and Latin American countries. The association between coronavirus disease 2019 (COVID‐19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), and GBS is another emerging research hotspot. Electrophysiological studies have suggested that GBS patients associated with Zika virus infection or COVID‐19 tend to manifest acute inflammatory demyelinating polyneuropathy, rather than acute motor axonal neuropathy (AMAN). Causative autoantibodies, such as anti‐ganglioside antibodies in AMAN associated with Campylobacter jejuni infection, have not been identified in GBS associated with these emerging infectious diseases. Nevertheless, recent studies suggested molecular mimicry between these viruses and human proteins related to GBS. Recent studies have shown the efficacy of new vaccines, containing artificial messenger RNA encoding the spike protein of SARS‐CoV‐2, against. These vaccines are now available in many countries and massive vaccination campaigns are currently ongoing. Although there are long‐standing concerns about the increased risk of GBS after inoculation of conventional vaccines, the risk of GBS is not considered a legitimate reason to limit administration of currently available vaccines, because the benefits outweigh the risks., In this article, we review the evidence regarding the relationship between emerging infectious diseases (such as Zika virus infection and coronavirus disease 2019) and Guillain–Barré syndrome. The contemporary knowledge about post‐vaccination Guillain–Barré syndrome is also summarized.

Proteomics, i.e. the study of the set of proteins produced in a cell, tissue, organism, or biological entity, has made possible analyses and contextual comparisons of proteomes/proteins and biological functions among the most disparate entities, from viruses to the human being. In this way, proteomic scrutiny of tumor-associated proteins, autoantigens, and pathogen antigens offers the tools for fighting cancer, autoimmunity, and infections. Comparative proteomics and immunoproteomics, the new scientific disciplines generated by proteomics, are the main themes of the present review that describes how comparative analyses of pathogen and human proteomes led to re-modulate the molecular mimicry concept of the pre-proteomic era. I.e. before proteomics, molecular mimicry – the sharing of peptide sequences between two biological entities – was considered as intrinsically endowed with immunologic properties and was related to cross-reactivity. Proteomics allowed to redefine such an assumption using physicochemical parameters according to which frequency and hydrophobicity preferentially confer an immunologic potential to shared peptide sequences. Proteomics is outlining peptide platforms to be used for the diagnostics and management of human diseases. A Molecular Medicine targeted to obtain healing without paying the price for adverse events is on the horizon. The next step is to take up the challenge and operate the paradigm shift that the current proteomic era requires.

The bottom-up construction of enzyme-based artificial cells is generating increasing interest, but achieving artificial cells for "all artificial modules" remains challenging in synthetic biology. Here, we introduce a fully synthetic cell system by integration of biomimetic nanozymes into giant unilamellar vesicles (GUVs). To mimic native peroxidase for free radical generation by taking advantage of Fenton catalysis reactions, we designed and prepared a de novo artificial nanozyme composed of ferritin heavy-chain scaffold protein and catalytic Fe3O4 nanoparticles as the active center. As two examples in bioapplications, we showed this nanozyme-powered GUV system not only mimics intracellular oxidative stress pathways but also induces tumor cell death by sensing and responding to external chemical signals. Specifically, we recreated intracellular biochemical events, including DNA damage and lipid peroxidation, in the compartmentalized GUVs by taking advantage of nanozyme induction of defined catalytic reactions. Additionally, the GUV system also actively induced DNA double-strand breakage and lipid damage of tumor cells, in response to the high expression of H2O2 within the tumor microenvironment. This concept-of-proof study offers a promising option for defining catalysis in biological systems and gives new insights into the de novo creation of artificial cells in a fully synthetic manner.

Tumour neoantigens arising from cancer-specific mutations generate a molecular fingerprint that has a definite specificity for cancer. Although this fingerprint perfectly discriminates cancer from healthy somatic and germline cells, and is therefore therapeutically exploitable using immune checkpoint blockade, gut and extra-gut microbial species can independently produce epitopes that resemble tumour neoantigens as part of their natural gene expression programmes. Such tumour molecular mimicry is likely not only to influence the quality and strength of the body’s anti-cancer immune response, but could also explain why certain patients show favourable long-term responses to immune checkpoint blockade while others do not benefit at all from this treatment. This article outlines the requirement for tumour neoantigens in successful cancer immunotherapy and draws attention to the emerging role of microbiome-mediated tumour neoantigen mimicry in determining checkpoint immunotherapy outcome, with far-reaching implications for the future of cancer immunotherapy.

Several landmark preclinical studies have shown an association between the gut microbiota and the effectiveness of immunotherapy for cancer. These studies have sparked clinical trials aimed at modulating the gut microbiota in order to improve clinical response rates to immunotherapy. Despite this, the mechanisms through which the gut microbiota influences the effectiveness of immunotherapy are still incompletely characterized. Preclinical and preliminary clinical findings from numerous types of gut microbiota modulation studies, including fecal transplantation, probiotics, consortia, and diet, demonstrate that favorable microbiota modulation is associated with increased intratumoral infiltration of CD8+ effector T cells. This CD8+ T-cell infiltration is often associated with enhanced intratumoral activity of T-helper type 1 cells and dendritic cells and a lower density of immunosuppressive cells. Herein, we discuss how gut microbiota may affect the activity of immune cells by at least three interlacing mechanisms: activation of pattern recognition receptors, molecular mimicry, and impact of metabolites. We also discuss the therapeutic potential and limitations of the different gut microbiota modulation techniques and their putative mechanisms of immune activation.

Cells sense and respond to the external environment, mainly through proteins presented on the membrane where their expression and conformation are dynamically regulated via intracellular programs. Here, we engineer a cell-surface nanoarchitecture that realizes molecular-recognition-initiated DNA assembly to mimic the dynamic behavior of membrane proteins, enabling the manipulation of cellular interaction in response to environmental changes. Our results show that this membrane-anchored DNA nanoarchitecture can be specifically activated by cell-responsive signals to external stimulation. Accordingly, multiple functional modules can be assembled onto the membrane to equip the cell with cell-type-specific binding and killing. This system is expected to offer a new paradigm for engineering therapeutic cells with customized sensing/response pathways.

Autoimmune diseases are thought to develop as a consequence of various environmental and genetic factors, each of which contributes to dysfunctional immune responses and/or a breakdown in immunological tolerance towards native structures. Molecular mimicry by microbial components is among the environmental factors thought to promote a breakdown in immune tolerance, particularly through the presence of cross-reactive epitopes shared with the human host. While resident members of the microbiota are essential promoters of human health through immunomodulation, defence against pathogenic colonisation and conversion of dietary fibre into nutritional resources for host tissues, there may be an underappreciated role of these microbes in the aetiology and/or progression of autoimmune disease. An increasing number of molecular mimics are being identified amongst the anaerobic microbiota which structurally resemble endogenous components and, in some cases, for example the human ubiquitin mimic of Bacteroides fragilis and DNA methyltransferase of Roseburia intestinalis, have been associated with promoting antibody profiles characteristic of autoimmune diseases. The persistent exposure of molecular mimics from the microbiota to the human immune system is likely to be involved in autoantibody production that contributes to the pathologies associated with immune-mediated inflammatory disorders. Here-in, examples of molecular mimics that have been identified among resident members of the human microbiota and their ability to induce autoimmune disease through cross-reactive autoantibody production are discussed. Improved awareness of the molecular mimics that exist among human colonisers will help elucidate the mechanisms involved in the breakdown of immune tolerance that ultimately lead to chronic inflammation and downstream disease.

Although peptide assemblies have been explored extensively, the self-assembly of negatively charged peptides (NCPs) received little attention. Stimulated by the fact that acidic stretch is a common feature in the intrinsically disordered regions of histone chaperones, we explored the use of the assemblies of NCPs for trafficking histone proteins. Our results show that the peptides that contain glutamic acid (E)-repeat, at neutral or basic pH, self-assemble to form micelles in solution. Circular dichroism indicates that increasing pH favor the peptides to populate more in disordered and alpha-helix conformations. Being innocuous to cells, the assemblies of these NCPs traffic histone 2B (H2B) to mitochondria. Structural-activity study indicates that self-assembly, proper stereochemistry, and acidic repeats are necessary for trafficking H2B. This work, as the first example of peptide assemblies for protein trafficking, illustrates a supramolecular approach for controlling cellular processes and provides insights for mimicking chaperones and controlling protein-protein interactions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the novel pathogen responsible for the coronavirus disease 19 (COVID-19) outbreak. Researchers and clinicians are exploring the pathogenetic mechanisms of the viral-induced damage and growing interest is focusing on the short-term and long-term immune-mediated consequences triggered by the infection. We will focus on post-SARS-CoV2 infection arthritis which may arise as a new pathological condition associated with COVID-19. In this article, we describe a case of acute oligoarthritis occurring 13 days after a SARS-CoV2 severe pneumonia in a middle-aged Caucasian man and we go over a brief review of the current available literature. We hypothesize that molecular mimicry might be the basic immunological mechanism responsible for the onset of COVID-19-related arthritis based on the current knowledge of SARS-CoV2 and on the known pathogenetic mechanism of viral-induced arthritis.

Graves' ophthalmopathy is an inflammatory disease with primary involvement of the extraocular muscles and the orbit. It encompasses the most common extra-thyroid manifestation in patients with Graves-Basedow disease. The underlying cause is molecular mimicry with the TSH receptor in ocular fibroblasts, leading to an immuno-mediated pathogenesis. Glucocorticoids at high doses are the cornerstone in moderate-severe cases. However, some patients are corticorresistant or intolerant. In recent years, therapeutic novelties have been described in terms of the dosage of the immunosuppressive treatments used, as well as the emergence of biological therapy in this field. The objective of this review is to update the treatment of Graves' ophthalmopathy, as well as to present alternative options in patients resistant or intolerant to glucocorticoids.

Chikungunya virus (CHIKV) infection is caused by an arbovirus prevalent in various parts of the world. The virus can induce autoantibodies and rheumatic diseases, such as rheumatoid arthritis and spondylarthritis. However, until now, no case of Sjögren syndrome (SS) was described associated with CHIKV. In this article, we describe a 49-year-old female with polyarthralgia and a temporary rash on her trunk and arms. Her physical examination showed polyarthritis of her ankles and wrists. Serologies for CHIKV were interpreted as positive with IgM 6.5 (normal range < 0.8) and negative for IgG. Antinuclear antibodies were positive at a titer of 1:640 as well as anti-Ro/SS-A. The diagnosis of subacute CHIKV infection was determined. The Schirmer test, Rose Bengal, and salivary scintigraphy were positive and the diagnosis of SS was confirmed. She was treated with hydroxychloroquine, methotrexate, and a single dose of betamethasone depot. This is the first report on CHIKV associated with SS. Sequence analysis of the CHIKV proteome versus SS autoantigens showed an extensive peptide sharing between the virus and numerous SS autoantigens, thus supporting the hypothesis that autoimmune cross-reactivity might causally link CHIKV to SS.

BACKGROUND: Damage to the renal microvasculature is a hallmark of renal ischemia-reperfusion injury (IRI)–mediated AKI. The miR-17∼92 miRNA cluster (encoding miR-17, -18a, -19a, -20a, -19b-1, and -92a-1) regulates angiogenesis in multiple settings, but no definitive role in renal endothelium during AKI pathogenesis has been established. METHODS: Antibodies bound to magnetic beads were utilized to selectively enrich for renal endothelial cells from mice. Endothelial-specific miR-17∼92 knockout (miR-17∼92(endo−/−)) mice were generated and given renal IRI. Mice were monitored for the development of AKI using serum chemistries and histology and for renal blood flow using magnetic resonance imaging (MRI) and laser Doppler imaging. Mice were treated with miRNA mimics during renal IRI, and therapeutic efficacies were evaluated. RESULTS: miR-17, -18a, -20a, -19b, and pri–miR-17∼92 are dynamically regulated in renal endothelial cells after renal IRI. miR-17∼92(endo−/−) exacerbates renal IRI in male and female mice. Specifically, miR-17∼92(endo−/−) promotes renal tubular injury, reduces renal blood flow, promotes microvascular rarefaction, increases renal oxidative stress, and promotes macrophage infiltration to injured kidneys. The potent antiangiogenic factor thrombospondin 1 (TSP1) is highly expressed in renal endothelium in miR-17∼92(endo−/−) after renal IRI and is a target of miR-18a and miR-19a/b. miR-17∼92 is critical in the angiogenic response after renal IRI, which treatment with miR-18a and miR-19b mimics can mitigate. CONCLUSIONS: These data suggest that endothelial-derived miR-17∼92 stimulates a reparative response in damaged renal vasculature during renal IRI by regulating angiogenic pathways.

Background: Congenital anomalies are increasingly becoming a global pediatric health concern, which requires immediate attention to its early diagnosis, preventive strategies, and efficient treatments. Guanine nucleotide binding protein, alpha inhibiting activity polypeptide 3 (Gnai3) gene mutation has been demonstrated to cause congenital small jaw deformity, but the functions of Gnai3 in the disease-specific microRNA (miRNA) upregulations and their downstream signaling pathways during osteogenesis have not yet been reported. Our previous studies found that the expression of Mir24-2-5p was significantly downregulated in the serum of young people with overgrowing mandibular, and bioinformatics analysis suggested possible binding sites of Mir24-2-5p in the Gnai3 3'UTR region. Therefore, this study was designed to investigate the mechanism of Mir24-2-5p-mediated regulation of Gnai3 gene expression and explore the possibility of potential treatment strategies for bone defects. Methods: Synthetic miRNA mimics and inhibitors were transduced into osteoblast precursor cells to regulate Mir24-2-5p expression. Dual-luciferase reporter assay was utilized to identify the direct binding of Gnai3 and its regulator Mir24-2-5p. Gnai3 levels in osteoblast precursor cells were downregulated by shRNA (shGnai3). Agomir, Morpholino Oligo (MO), and mRNA were microinjected into zebrafish embryos to control mir24-2-5p and gnai3 expression. Relevant expression levels were determined by the qRT-PCR and Western blotting. CCK-8 assay, flow cytometry, and transwell migration assays were performed to assess cell proliferation, apoptosis, and migration. ALP, ARS and Von Kossa staining were performed to observe osteogenic differentiation. Alcian blue staining and calcein immersions were performed to evaluate the embryonic development and calcification of zebrafish. Results: The expression of Mir24-2-5p was reduced throughout the mineralization process of osteoblast precursor cells. miRNA inhibitors and mimics were transfected into osteoblast precursor cells. Cell proliferation, migration, osteogenic differentiation, and mineralization processes were measured, which showed a reverse correlation with the expression of Mir24-2-5p. Dual-luciferase reporter gene detection assay confirmed the direct interaction between Mir24-2-5p and Gnai3 mRNA. Moreover, in osteoblast precursor cells treated with Mir24-2-5p inhibitor, the expression of Gnai3 gene was increased, suggesting that Mir24-2-5p negatively targeted Gnai3. Silencing of Gnai3 inhibited osteoblast precursor cells proliferation, migration, osteogenic differentiation, and mineralization. Promoting effects of osteoblast precursor cells proliferation, migration, osteogenic differentiation, and mineralization by low expression of Mir24-2-5p was partially rescued upon silencing of Gnai3. In vivo, mir24-2-5p Agomir microinjection into zebrafish embryo resulted in shorter body length, smaller and retruded mandible, decreased cartilage development, and vertebral calcification, which was partially rescued by microinjecting gnai3 mRNA. Notably, quite similar phenotypic outcomes were observed in gnai3 MO embryos, which were also partially rescued by mir24-2-5p MO. Besides, the expression of phospho-JNK (p-JNK) and p-p38 were increased upon Mir24-2-5p inhibitor treatment and decreased upon shGnai3-mediated Gnai3 downregulation in osteoblast precursor cells. Osteogenic differentiation and mineralization abilities of shGnai3-treated osteoblast precursor cells were promoted by p-JNK and p-p38 pathway activators, suggesting that Gnai3 might regulate the differentiation and mineralization processes in osteoblast precursor cells through the MAPK signaling pathway. Conclusions: In this study, we investigated the regulatory mechanism of Mir24-2-5p on Gnai3 expression regulation in osteoblast precursor cells and provided a new idea of improving the prevention and treatment strategies for congenital mandibular defects and mandibular protrusion.