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Notably during the Yuan period of Chinese history, Korean Buddhists had a curious custom of making arduous trips to Buddhist centers in mainland China, by sea or overland. To the extent that monks made this trip despite the possible dangers of this long journey, Yuan Buddhism in the practice of Korean Buddhism was conceived as an important hub of monastic certification and the source of new Buddhist developments. In addition, the Chinese masters were seen as essential figures in the monastic careers of the Korean monks. Although there would have been qualified masters in Korea to lead the practice of kanhua chan and to verify the enlightened states of the Korean monks, traveling to China continued up to the end of the Koryŏ period. This continued because the Korean monks obtained obvious benefits after having traveled to China and received their certification of enlightenment 印可. On their return, these monks were given recognition for their spiritual attainment and assigned to high positions in the saṃgha bureaucracy, in many cases, as either a royal or state preceptor. This custom of visiting China was all the more heightened due to Yuan's domination over Koryŏ from the late-13th to the mid-14th centuries. [ABSTRACT FROM AUTHOR]

Dengue virus infection (DVI) is a mosquito-borne disease that can lead to serious morbidity and mortality. Dengue fever (DF) is a major public health concern that affects approximately 3.9 billion people each year globally. However, there is no vaccine or drug available to deal with DVI. Dengue virus consists of four distinct serotypes (DENV1-4), each raising a different immunological response. In the present study, we designed a tetravalent subunit multi-epitope vaccine, targeting proteins including the structural protein envelope domain III (EDIII), precursor membrane proteins (prM), and a non-structural protein (NS1) from each serotype by employing an immunoinformatic approach. Only conserved sequences obtained through a multiple sequence alignment were used for epitope mapping to ensure efficacy against all serotypes. The epitopes were shortlisted based on an IC50 value <50, antigenicity, allergenicity, and a toxicity analysis. In the final vaccine construct, overall, 11 B-cell epitopes, 10 HTL epitopes, and 10 CTL epitopes from EDIII, prM, and NS1 proteins targeting all serotypes were selected and joined via KK, AAY, and GGGS linkers, respectively. We incorporated a 45-amino-acid-long B-defensins adjuvant in the final vaccine construct for a better immunogenic response. The vaccine construct has an antigenic score of 0.79 via VaxiJen and is non-toxic and non-allergenic. Our refined vaccine structure has a Ramachandran score of 96.4%. The vaccine has shown stable interaction with TLR3, which has been validated by 50 ns of molecular dynamics (MD) simulation. Our findings propose that a designed multi-epitope vaccine has substantial potential to elicit a strong immune response against all dengue serotypes without causing any adverse effects. Furthermore, the proposed vaccine can be experimentally validated as a probable vaccine, suggesting it may serve as an effective preventative measure against dengue virus infection. [ABSTRACT FROM AUTHOR]

The epidemic of corona virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome Coronavirus 2 and its variants of concern (VOCs) has been ongoing for over 3 years. Antibody therapies encompassing convalescent plasma, hyperimmunoglobulin, and neutralizing monoclonal antibodies (mAbs) applied in passive immunotherapy have yielded positive outcomes and played a crucial role in the early COVID-19 treatment. In this review, the development path, action mechanism, clinical research results, challenges, and safety profile associated with the use of COVID-19 convalescent plasma, hyperimmunoglobulin, and mAbs were summarized. In addition, the prospects of applying antibody therapy against VOCs was assessed, offering insights into the coping strategies for facing new infectious disease outbreaks. [ABSTRACT FROM AUTHOR]

Human leukocyte immunoglobulin (Ig)-like receptors (LILR) are a family of 11 innate immunomodulatory receptors, primarily expressed on lymphoid and myeloid cells. LILRs are either activating (LILRA) or inhibitory (LILRB) depending on their associated signalling domains (D). With the exception of the soluble LILRA3, LILRAs mediate immune activation, while LILRB1-5 primarily inhibit immune responses and mediate tolerance. Abnormal expression and function of LILRs is associated with a range of pathologies, including immune insufficiency (infection and malignancy) and overt immune responses (autoimmunity and alloresponses), suggesting LILRs may be excellent candidates for targeted immunotherapies. This review will discuss the biology and clinical relevance of this extensive family of immune receptors and will summarise the recent developments in targeting LILRs in disease settings, such as cancer, with an update on the clinical trials investigating the therapeutic targeting of these receptors. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) NK and T cell therapy are promising immunotherapeutic approaches for the treatment of cancer. However, the efficacy of CAR NK/T cell therapy is often hindered by various factors, including the phenomenon of trogocytosis, which involves the bidirectional exchange of membrane fragments between cells. In this review, we explore the role of trogocytosis in CAR NK/T cell therapy and highlight potential strategies for its modulation to improve therapeutic efficacy. We provide an in-depth analysis of trogocytosis as it relates to the fate and function of NK and T cells, focusing on its effects on cell activation, cytotoxicity, and antigen presentation. We discuss how trogocytosis can mediate transient antigen loss on cancer cells, thereby negatively affecting the effector function of CAR NK/T cells. Additionally, we address the phenomenon of fratricide and trogocytosis-associated exhaustion, which can limit the persistence and effectiveness of CAR-expressing cells. Furthermore, we explore how trogocytosis can impact CAR NK/T cell functionality, including the acquisition of target molecules and the modulation of signaling pathways. To overcome the negative effects of trogocytosis on cellular immunotherapy, we propose innovative approaches to modulate trogocytosis and augment CAR NK/T cell therapy. These strategies encompass targeting trogocytosis-related molecules, engineering CAR NK/T cells to resist trogocytosis-induced exhaustion and leveraging trogocytosis to enhance the function of CAR-expressing cells. By overcoming the limitations imposed by trogocytosis, it may be possible to unleash the full potential of CAR NK/T therapy against cancer. The knowledge and strategies presented in this review will guide future research and development, leading to improved therapeutic outcomes in the field of immunotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Although environmental and human behavioral factors in countries with Zika virus (ZIKV) outbreaks are also common in Nigeria, such an outbreak has not yet been reported probably due to misdiagnosis. The atypical symptoms of malaria and ZIKV infections at the initial phase could leverage their misdiagnosis. This study randomly recruited 496 malaria-suspected patients who visited selected health institutions in Adamawa, Bauchi, and Borno states for malaria tests. These patients' sera were analyzed for ZIKV antibodies using ELISA and plaque reduction neutralization tests (PRNT) at 90% endpoint. About 13.8% of Zika virus-neutralizing antibodies (nAb) did not cross-react with dengue, yellow fever, and West Nile viruses suggesting possible monotypic infections. However, 86% of the sera with ZIKV nAb also neutralized other related viruses at varied degrees: dengue viruses (60.7%), West Nile viruses (23.2%), yellow fever virus (7.1%) and 39.3% were co-infections with chikungunya viruses. Notably, the cross-reactions could also reflect co-infections as these viruses are also endemic in the country. The serum dilution that neutralized 90–100% ZIKV infectivity ranged from 1:8 to 1:128. Also, our findings suggest distinct protection against the ZIKV between different collection sites studied. As indicated by nAb, acute ZIKV infection was detected in 1.7% of IgM-positive patients while past infections occurred in 8.5% of IgM-negatives in the three states. In Borno State, 9.4% of IgG neutralized ZIKV denoting past infections while 13.5% were non-neutralizing IgM and IgG indicating other related virus infections. The age, gender, and occupation of the patients and ZIKV nAb were not significantly different. ZIKV nAb from samples collected within 1–7 days after the onset of symptoms was not significantly different from those of 7–10 days. A wider interval with the same techniques in this study may probably give better diagnostic outcomes. ZIKV nAb was significantly distinct among recipients and non-recipients of antibiotic/antimalaria treatments before seeking malaria tests. The inhibiting effect of these drugs on ZIKV infection progression may probably contribute to the absence of neurological disorders associated with the virus despite being endemic in the environment for several decades. Also, protection against ZIKV as marked by the nAb was different among the vaccinated and unvaccinated YF vaccine recipients. Thus, the YF vaccine may be a good alternative to the Zika vaccine in resource-constrained countries. Conclusion: The cryptic ZIKV infections underscore the need for differential diagnosis of malaria-suspected febrile patients for arboviruses, especially the Zika virus. The absence of systemic surveillance for the virus is worrisome because of its association with neurological disorders in newborns. Co-infections with other arboviruses may impact adversely on the management of these diseases individually. [ABSTRACT FROM AUTHOR]

Purpose: Worldwide, the incidence of chronic fungal rhinosinusitis (CFRS) has increased. Although ageing leads to weakening of the immune system, which increases susceptibility to CFRS, the CFRS characteristics in geriatric patients are unclear. Therefore, we comparatively analysed the clinical characteristics of CFRS in geriatric and non-geriatric patients. Methods: This retrospective analysis compared the demographics, rhinologic symptoms, multiple allergen simultaneous tests, olfactory function tests, paranasal sinus computed tomography findings, and outcomes of 131 patients with CFRS who underwent functional endoscopic sinus surgery and 131 enrolled patients were divided in geriatric (> 65 years) and non-geriatric (≤ 65 years) groups. Results: Among the geriatric and non-geriatric participants (n = 65, 49.6% and n = 66, 50.4%, respectively), hypertension and diabetes mellitus were more common in the geriatric group. Demographics, including symptoms, showed no significant intergroup differences. Normosmia and hyposmia were significantly less prevalent, whereas phantosmia and parosmia were more prevalent in the geriatric group than in the non-geriatric group (p = 0.03 and p = 0.01, respectively). Sphenoidal sinus involvement was significantly higher in geriatric patients than in non-geriatric patients (p = 0.02). Conclusion: Based on greater sphenoidal sinus involvement, a deeper anatomical area is more vulnerable to fungal infection in the geriatric group than in the non-geriatric group. Increasing clinicians' awareness of CFRS in geriatric patients with olfactory dysfunction, including phantosmia and parosmia, is important for early intervention. [ABSTRACT FROM AUTHOR]

Background: Long COVID is a debilitating chronic condition that has affected over 100 million people globally. It is characterized by a diverse array of symptoms, including fatigue, cognitive dysfunction and respiratory problems. Studies have so far largely failed to identify genetic associations, the mechanisms behind the disease, or any common pathophysiology with other conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that present with similar symptoms. Methods: We used a combinatorial analysis approach to identify combinations of genetic variants significantly associated with the development of long COVID and to examine the biological mechanisms underpinning its various symptoms. We compared two subpopulations of long COVID patients from Sano Genetics' Long COVID GOLD study cohort, focusing on patients with severe or fatigue dominant phenotypes. We evaluated the genetic signatures previously identified in an ME/CFS population against this long COVID population to understand similarities with other fatigue disorders that may be triggered by a prior viral infection. Finally, we also compared the output of this long COVID analysis against known genetic associations in other chronic diseases, including a range of metabolic and neurological disorders, to understand the overlap of pathophysiological mechanisms. Results: Combinatorial analysis identified 73 genes that were highly associated with at least one of the long COVID populations included in this analysis. Of these, 9 genes have prior associations with acute COVID-19, and 14 were differentially expressed in a transcriptomic analysis of long COVID patients. A pathway enrichment analysis revealed that the biological pathways most significantly associated with the 73 long COVID genes were mainly aligned with neurological and cardiometabolic diseases. Expanded genotype analysis suggests that specific SNX9 genotypes are a significant contributor to the risk of or protection against severe long COVID infection, but that the gene-disease relationship is context dependent and mediated by interactions with KLF15 and RYR3. Comparison of the genes uniquely associated with the Severe and Fatigue Dominant long COVID patients revealed significant differences between the pathways enriched in each subgroup. The genes unique to Severe long COVID patients were associated with immune pathways such as myeloid differentiation and macrophage foam cells. Genes unique to the Fatigue Dominant subgroup were enriched in metabolic pathways such as MAPK/JNK signaling. We also identified overlap in the genes associated with Fatigue Dominant long COVID and ME/CFS, including several involved in circadian rhythm regulation and insulin regulation. Overall, 39 SNPs associated in this study with long COVID can be linked to 9 genes identified in a recent combinatorial analysis of ME/CFS patient from UK Biobank. Among the 73 genes associated with long COVID, 42 are potentially tractable for novel drug discovery approaches, with 13 of these already targeted by drugs in clinical development pipelines. From this analysis for example, we identified TLR4 antagonists as repurposing candidates with potential to protect against long term cognitive impairment pathology caused by SARS-CoV-2. We are currently evaluating the repurposing potential of these drug targets for use in treating long COVID and/or ME/CFS. Conclusion: This study demonstrates the power of combinatorial analytics for stratifying heterogeneous populations in complex diseases that do not have simple monogenic etiologies. These results build upon the genetic findings from combinatorial analyses of severe acute COVID-19 patients and an ME/CFS population and we expect that access to additional independent, larger patient datasets will further improve the disease insights and validate potential treatment options in long COVID. [ABSTRACT FROM AUTHOR]

Background: Arthropod-borne flaviviruses like dengue virus (DENV) and yellow fever virus (YFV) are major human pathogens. In Latin America, YFV is maintained in sylvatic cycles involving non-human primates (NHP) and forest-dwelling mosquitos. YFV supposedly does not circulate north of Panama. Methods: We conducted a serologic study for flaviviruses and other emerging viruses in NHP from southeastern Mexico. A total of thirty sera of black-handed spider monkeys (Ateles geoffroyi, n = 25), black howler monkeys (Alouatta pigra, n = 3), and mantled howler monkeys (Al. palliata, n = 2) sampled in 2012 and 2018 were screened by an indirect immunofluorescence assay (IFA) to detected IgG antibodies against DENV, YFV, Zika virus (ZIKV), West Nile virus (WNV), Rift Valley fever virus, Crimean-Congo hemorrhagic fever virus, Middle East respiratory syndrome coronavirus, and Zaire Ebola virus, and confirmed by plaque reduction neutralization tests (PRNT90) representing all mosquito-borne flavivirus serocomplexes circulating in the Americas. Results: A total of 16 sera (53.3%; 95% CI, 34.3–71.7) showed IFA reactivity to at least one tested flavivirus with end-point titers ranging from 1:100 to 1:1000. No serum reacted with other viruses. Monotypic and high mean PRNT90 endpoint YFV titers of 1:246 were found in 3 black-handed spider monkey sera (10.0%; 95% CI, 2.1–26.5) sampled in 2018 in Tabasco, compared to all other flaviviruses tested. Monotypic endpoint PRNT90 titers of 1:28 for Ilheus virus and 1:22 for WNV in serum of black howler monkeys sampled in 2018 in Tabasco suggested additional flavivirus exposure. Conclusions: Our findings may suggest unnoticed YFV circulation. Intensification of YFV surveillance in NHP and vectors is warranted in Mexico and potentially other areas considered free of yellow fever. [ABSTRACT FROM AUTHOR]

Introduction: Zika virus (ZIKV) infection during pregnancy results in a spectrum of birth defects and neurodevelopmental deficits in prenatally exposed infants, with no clear understanding of why some pregnancies are more severely affected. Differential control of maternal ZIKV infection may explain the spectrum of adverse outcomes. Methods: Here, we investigated whether the magnitude and breadth of the maternal ZIKV-specific antibody response is associated with better virologic control using a rhesus macaque model of prenatal ZIKV infection. We inoculated 18 dams with an Asian-lineage ZIKV isolate (PRVABC59) at 30-45 gestational days. Plasma vRNA and infectious virus kinetics were determined over the course of pregnancy, as well as vRNA burden in the maternal-fetal interface (MFI) at delivery. Binding and neutralizing antibody assays were performed to determine the magnitude of the ZIKV-specific IgM and IgG antibody responses throughout pregnancy, along with peptide microarray assays to define the breadth of linear ZIKV epitopes recognized. Results: Dams with better virologic control (n= 9) cleared detectable infectious virus and vRNA from the plasma by 7 days post-infection (DPI) and had a lower vRNA burden in the MFI at delivery. In comparison, dams with worse virologic control (n= 9) still cleared detectable infectious virus from the plasma by 7 DPI but had vRNA that persisted longer, and had higher vRNA burden in the MFI at delivery. The magnitudes of the ZIKV-specific antibody responses were significantly lower in the dams with better virologic control, suggesting that higher antibody titers are not associated with better control of ZIKV infection. Additionally, the breadth of the ZIKV linear epitopes recognized did not differ between the dams with better and worse control of ZIKV infection. Discussion: Thus, the magnitude and breadth of the maternal antibody responses do not seem to impact maternal virologic control. This may be because control of maternal infection is determined in the first 7 DPI, when detectable infectious virus is present and before robust antibody responses are generated. However, the presence of higher ZIKV-specific antibody titers in dams with worse virologic control suggests that these could be used as a biomarker of poor maternal control of infection and should be explored further. [ABSTRACT FROM AUTHOR]

Fc gamma receptors (FcγRs) are a family of receptors that bind IgG antibodies and interface at the junction of humoral and innate immunity. Precise regulation of receptor expression provides the necessary balance to achieve healthy immune homeostasis by establishing an appropriate immune threshold to limit autoimmunity but respond effectively to infection. The underlying genetics of the FCGR gene family are central to achieving this immune threshold by regulating affinity for IgG, signaling efficacy, and receptor expression. The FCGR gene locus was duplicated during evolution, retaining very high homology and resulting in a genomic region that is technically difficult to study. Here, we review the recent evolution of the gene family in mammals, its complexity and variation through copy number variation and single-nucleotide polymorphism, and impact of these on disease incidence, resolution, and therapeutic antibody efficacy. We also discuss the progress and limitations of current approaches to study the region and emphasize how new genomics technologies will likely resolve much of the current confusion in the field. This will lead to definitive conclusions on the impact of genetic variation within the FCGR gene locus on immune function and disease., (© 2024 The Author(s). Immunological Reviews published by John Wiley & Sons Ltd.)

Advances in antibody technologies have resulted in the development of potent antibody-based therapeutics with proven clinical efficacy against infectious diseases. Several monoclonal antibodies (mAbs), mainly against viruses such as SARS-CoV-2, HIV-1, Ebola virus, influenza virus, and hepatitis B virus, are currently undergoing clinical testing or are already in use. Although these mAbs exhibit potent neutralizing activity that effectively blocks host cell infection, their antiviral activity results not only from Fab-mediated virus neutralization, but also from the protective effector functions mediated through the interaction of their Fc domains with Fcγ receptors (FcγRs) on effector leukocytes. Fc-FcγR interactions confer pleiotropic protective activities, including the clearance of opsonized virions and infected cells, as well as the induction of antiviral T-cell responses. However, excessive or inappropriate activation of specific FcγR pathways can lead to disease enhancement and exacerbated pathology, as seen in the context of dengue virus infections. A comprehensive understanding of the diversity of Fc effector functions during infection has guided the development of engineered antiviral antibodies optimized for maximal effector activity, as well as the design of targeted therapeutic approaches to prevent antibody-dependent enhancement of disease., (© 2024 The Author(s). Immunological Reviews published by John Wiley & Sons Ltd.)

Objectives: Tick-borne encephalitis (TBE) is an infection caused by the tick-borne encephalitis virus (TBEV) that can lead to symptoms of central nervous system inflammation. There are five subtypes of TBEV, three of which - European, Siberian and Far Eastern - occur in Europe. As it is thought that different subtype infections exhibit varying clinical courses and outcomes, serological differentiation of the virus subtypes is clearly important. However, to date, this has proved difficult to achieve., Methods: An ELISA format was developed based on TBE virus NS1 antigen against the European, Siberian and Far Eastern subtype. The three NS1 antigens were biotechnologically produced in a human cell line and used for ELISA coating. Sera from German (European subtype) and Russian (Siberian and/or Far Eastern subtypes) TBE patients with positive TBEV IgG were used to test the reactivity against these three NS1 antigens., Results: Testing of 23 German and 32 Russian TBEV IgG-positive sera showed that the ELISA was able to differentiate between TBEV European subtype and TBEV Siberian and Far Eastern subtype infections., Conclusions: In geographical areas where two or more TBEV subtype infections can occur, the NS1-IgG ELISA developed here constitutes an important diagnostic tool to differentiate between European subtype infections and Siberian/Far Eastern subtype infections and to use the new assay for epidemiological studies to clarify the importance of particular subtype infections in an area. Consequently, it may help to better describe and anticipate the clinical courses and outcomes of particular TBEV subtype infections., (© 2024. The Author(s).)

Clinical manifestation of dengue disease ranges from asymptomatic, febrile fever without warning sign (DOS) to serious outcome dengue with warning sign (DWS) and severe disease (SD) leading to shock syndrome and death. The role of antibody response in natural dengue infection is complex and not completely understood. Here, we aimed to assess serological marker for disease severity. Antibody response of dengue-confirmed pediatric patients with acute secondary infection were evaluated against infecting virus, immature virus, and recombinant envelop protein. Immature virus antibody titers were significantly higher in DWS as compared to DOS (p = 0.0006). However, antibody titers against recombinant envelop protein were higher in DOS as compared to DWS, and antibody avidity was significantly higher against infecting virus in DOS. Serum samples of DOS patients displayed higher in vitro neutralization potential in plaque assay as compared to DWS, whereas DWS serum samples showed higher antibody-dependent enhancement in the in vitro enhancement assays. Thus, antibodies targeting immature virus can predict disease severity and could be used in early forecast of disease outcome using an enzyme-linked immunoassay assay system which is less laborious and cheaper than plaque assay system for correlates of protection and could help optimize medical care and resources., (© 2024 Wiley Periodicals LLC.)

Introduction: dengue cases occur frequently in Kenya, although the trend is not uniform across the country, making this infectious disease a major public health problem that is transmitted without detection. The purpose of this review study was to determine the seroprevalence of dengue virus (DENV) infection in the Kenyan population during the last ten years to reveal geographical areas with unreported dengue fever activity. For that purpose, this review describes the recent (2010 to 2020) DENV incidences, methods of detection, and the circulating genotypes in Kenya. Methods: studies were identified to summarize reported dengue fever infections and epidemic activities in Kenya using a search approach (terms "Dengue", "Dengue Virus" and "DENV" in combination with "Infection in Kenya"). All published studies between 2010 and 2020 retrieved through search engines PubMed, Google Scholar, Research4life, and ScienceDirect were screened for eligibility. Results: a total of 21 eligible articles containing 24 studies, covering five general geographic regions and 39 sampling sites, were included in this review. The results indicate a surveillance gap in dengue fever infection serosurvey in Kenya. There was transmission between epidemics in the reported areas. Seroprevalence ranged from 0.4% to 100% during outbreaks. Coast region was the most studied region with Mombasa being the most sampled site. Conclusion: about 76.6% of Kenyan Counties' DENV seroprevalence status was found to be unknown or unreported. In addition, DENV infection was unrecognized and/or unreported in most areas of the country, especially rural Kenya. This information may serve as a basis for better awareness and detection of DENV infection during outbreaks and in establishing appropriate prevention and control measures to further avoid outbreaks. [ABSTRACT FROM AUTHOR]

Dengue represents a growing public health burden worldwide, accounting for approximately 100 million symptomatic cases and tens of thousands of fatalities yearly. Prior infection with one serotype of dengue virus (DENV) is the greatest known risk factor for severe disease upon secondary infection with a heterologous serotype, a risk which increases as serotypes co-circulate in endemic regions. This disease risk is thought to be mediated by IgG-isotype antibodies raised during a primary infection, which poorly neutralize heterologous DENV serotypes and instead opsonize virions for uptake by FcγR-bearing cells. This antibody-dependent enhancement (ADE) of infection leads to a larger proportion of susceptible cells infected, higher viremia and greater immunopathology. We have previously characterized the induction of a serum IgA response, along with the typical IgM and IgG responses, during dengue infection, and have shown that DENV-reactive IgA can neutralize DENV and competitively antagonize IgG-mediated ADE. Here, we evaluate the potential for IgA itself to cause ADE. We show that IgG, but not IgA, mediated ADE of infection in cells expressing both FcαR and FcγRs. IgG-mediated ADE stimulated significantly higher pro-inflammatory cytokine production by primary human macrophages, while IgA did not affect, or slightly suppressed, this production. Mechanistically, we show that DENV/IgG immune complexes bind susceptible cells significantly more efficiently than DENV/IgA complexes or virus alone. Finally, we show that over the course of primary dengue infection, the expression of FcγRI (CD64) increases during the period of acute viremia, while FcγRIIa (CD32) and FcαR (CD89) expression decreases, thereby further limiting the ability of IgA to facilitate ADE in the presence of DENV. Overall, these data illustrate the distinct protective role of IgA during ADE of dengue infection and highlight the potential therapeutic and prognostic value of DENV-specific IgA. Author summary: Dengue virus is a widespread and growing public health challenge, causing an estimated 100 million symptomatic infections every year. A unique feature of dengue is that sub-neutralizing levels of virion-specific antibodies generated by a prior infection can increase the severity of a subsequent infection through a mechanism known as antibody-dependent enhancement (ADE). This is thought to be mediated by IgG isotype antibodies that bind the virus and facilitate its uptake via antibody receptors expressed on immune cells. However, IgG is not the only antibody isotype elicited by dengue virus. Our group and others have described a significant IgA response following dengue infection, especially following primary infections and mild secondary infections. It is currently unclear how dengue virus specific IgA contributes to the anti-dengue immune response. Our results here demonstrate that IgA is incapable of facilitating ADE due to the low affinity of IgA for its cognate Fc receptor. This positions IgA as a potential biomarker of dengue severity and highlights the potential therapeutic value of DENV-specific IgA. [ABSTRACT FROM AUTHOR]

The immune system is strictly regulated by glycosylation through the addition of highly diverse and dynamically changing sugar structures (glycans) to the majority of immune cell receptors. Although knowledge in the field of glycoimmunology is still limited, numerous studies point to the key role of glycosylation in maintaining homeostasis, but also in reflecting its disruption. Changes in oligosaccharide patterns can lead to impairment of both innate and acquired immune responses, with important implications in the pathogenesis of diseases, including autoimmunity. B cells appear to be unique within the immune system, since they exhibit both innate and adaptive immune activity. B cell surface is rich in glycosylated proteins and lectins which recognise glycosylated ligands on other cells. Glycans are important in the development, selection, and maturation of B cells. Changes in sialylation and fucosylation of cell surface proteins affect B cell signal transduction through BCRs, CD22 inhibitory coreceptor and Siglec-G. Plasmocytes, as the final stage of B cell differentiation, produce and secrete immunoglobulins (Igs), of which IgGs are the most abundant N-glycosylated proteins in human serum with the conserved Nglycosylation site at Asn297. N-oligosaccharide composition of the IgG Fc region affects its secretion, structure, half-life and effector functions (ADCC, CDC). IgG N-glycosylation undergoes little change during homeostasis, and may gradually be modified with age and during ongoing inflammatory processes. Hyperactivated B lymphocytes secrete autoreactive antibodies responsible for the development of autoimmunity. The altered profile of IgG N-glycans contributes to disease progression and remission and is sensitive to the application of therapeutic substances and immunosuppressive agents. In this review, we focus on the role of N-glycans in B-cell biology and IgG activity, the rearrangement of IgG oligosaccharides in aging, autoimmunity and immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

A novel surface plasmon resonance-based biosensor for SARS-CoV-2 virus is proposed in this article. The biosensor is a Kretschmann configuration-based structure that consists of CaF2 prism as base, at which silver (Ag), TiO2, and MXene nanolayers are used to enhance the performance. Theoretically, the performance parameters have been investigated by means of Fresnel equations and transfer matrix method (TMM). The TiO2 nanolayer not only prevents oxidation of Ag layer but also enhances the evanescent field in its vicinity. The sensor provides an ultrahigh angular sensitivity of 346°/RIU for the detection of SARS-CoV-2 virus. Some other performance parameters, including FWHM (full width at half maxima), detection accuracy (DA), limit of detection (LOD), and quality factor (QF) have also been calculated for proposed SPR biosensor with their optimized values 2.907°, 0.3439 deg−1, 1.445 × 10−5, and 118.99 RIU−1, respectively. The obtained results designate that the proposed surface plasmon resonance (SPR) based biosensor has notably enhanced angular sensitivity as compared to previous results reported in the literatures till date. This work may facilitate a significant biological sample sensing device for fast and accurate diagnosis at early stage of SARS-CoV-2 virus. [ABSTRACT FROM AUTHOR]

Background: Severe dengue often leads to poor clinical outcomes and high mortality; as a result, it is of vital importance to find prognostic factors associated with the severe form of dengue. Obesity is known to deteriorate many infectious diseases due to impaired immune responses. Several studies have suggested that obese patients with dengue infection tend to have more severe manifestations with poorer prognosis. However, a firm conclusion could not be drawn due to the varied results of these studies. Here, we aimed to conduct a systematic review and meta-analysis to investigate the association between obesity and dengue severity. Methods: A literature search for relevant studies was conducted in PubMed, Embase, Ovid Medline and Cochrane from inception to September 9, 2022. The two main keywords were "dengue" and "obesity". Mantel-Haenszel method and random effects model was used to analyze the pooled odds ratio with 95% confidence intervals. Results: A total of 15 article involving a total of 6,508 patients were included in the meta-analysis. Included patients in most studies were hospitalized pediatric patients. Only one study included adulthood data. Three cohort studies, four case-control studies, and one cross-sectional studies found a significant association between obesity and dengue severity. In contrast, three cohort studies, three case-control studies, and one cross-sectional study reported no significant relationship between obesity and dengue severity. Our analysis results showed that patient with obesity is 50% (OR = 1.50; 95%CI: 1.15–1.97) more likely to develop severe manifestation of dengue. Conclusion: This meta-analysis revealed that overweight could be a clinical predictor for severe disease for pediatric patients with dengue infection. [ABSTRACT FROM AUTHOR]

Over the past several decades, mRNA vaccines have evolved from a theoretical concept to a clinical reality. These vaccines offer several advantages over traditional vaccine techniques, including their high potency, rapid development, low-cost manufacturing, and safe administration. However, until recently, concerns over the instability and inefficient distribution of mRNA in vivo have limited their utility. Fortunately, recent technological advancements have mostly resolved these concerns, resulting in the development of numerous mRNA vaccination platforms for infectious diseases and various types of cancer. These platforms have shown promising outcomes in both animal models and humans. This study highlights the potential of mRNA vaccines as a promising alternative approach to conventional vaccine techniques and cancer treatment. This review article aims to provide a thorough and detailed examination of mRNA vaccines, including their mechanisms of action and potential applications in cancer immunotherapy. Additionally, the article will analyze the current state of mRNA vaccine technology and highlight future directions for the development and implementation of this promising vaccine platform as a mainstream therapeutic option. The review will also discuss potential challenges and limitations of mRNA vaccines, such as their stability and in vivo distribution, and suggest ways to overcome these issues. By providing a comprehensive overview and critical analysis of mRNA vaccines, this review aims to contribute to the advancement of this innovative approach to cancer treatment. [ABSTRACT FROM AUTHOR]

Dengue is the most common viral infection spread by mosquitoes, prevalent in tropical countries. The acute dengue virus (DENV) infection is a benign and primarily febrile illness. However, secondary infection with alternative serotypes can worsen the condition, leading to severe and potentially fatal dengue. The antibody raised by the vaccine or the primary infections are frequently cross-reactive; however, weakly neutralizing, and during subsequent infection, they may increase the odds of antibody-dependent enhancement (ADE). Despite that, many neutralizing antibodies have been identified against the DENV, which are thought to be useful in reducing dengue severity. Indeed, an antibody must be free from ADE for therapeutic application, as it is pretty common in dengue infection and escalates disease severity. Therefore, this review has described the critical characteristics of DENV and the potential immune targets in general. The primary emphasis is given to the envelope protein of DENV, where potential epitopes targeted for generating serotype-specific and cross-reactive antibodies have critically been described. In addition, a novel class of highly neutralizing antibodies targeted to the quaternary structure, similar to viral particles, has also been described. Lastly, we have discussed different aspects of the pathogenesis and ADE, which would provide significant insights into developing safe and effective antibody therapeutics and equivalent protein subunit vaccines. [ABSTRACT FROM AUTHOR]

Myeloid cells form an essential component of initial responses to environmental hazards and toxic exposures. The ability to model these responses in vitro is central to efforts tasked with identifying hazardous materials and understanding mechanisms of injury and disease. Induced pluripotent stem cell (iPSC) derived cells have been suggested as alternatives to more established primary cell testing systems for these purposes. iPSC derived macrophage and dendritic like cells were compared to CD34+ haematopoietic stem cell derived populations using transcriptomic analysis. Using single cell sequencing-based characterisation of iPSC derived myeloid cells, we identified transitional, mature and M2 like macrophages as well as dendritic like antigen presenting cells and fibrocytes. Direct transcriptomic comparisons between iPSC and CD34+ cell derived populations revealed higher expression of myeloid differentiation genes such as MNDA, CSF1R and CSF2RB in CD34+ cells, while iPSC populations had higher fibroblastic and proliferative markers. Exposure of differentiated macrophage populations to nanoparticle alone or in combination with dust mite, resulted in differential gene expression on combination only, with responses markedly absent in iPSC compared to CD34+ derived cells. The lack of responsiveness in iPSC derived cells may be attributable to lower levels of dust mite component receptors CD14, TLR4, CLEC7A and CD36. In summary, iPSC derived myeloid cells display typical characteristics of immune cells but may lack a fully mature phenotype to adequately respond to environmental exposures. [ABSTRACT FROM AUTHOR]

Presence of Japanese encephalitis (JE) have not been documented in Saudi Arabia. There has been no systemic screening of JE in both vectors (Mosquito) and vulnerable populations. In the current study for the first time in southern Saudi Arabia, JE virus specific IgM and IgG antibodies were evaluated in blood samples from children attending emergency room, Abha Maternity and Children hospital. The results showed 20% seropositivity for JE with 19 (17.7%) IgM and 2(1.8%) IgG. There was no double positivity of IgM or IgG reported. The mean age for JE seropositive were 3 and 2 for male and female respectively. Convulsion was one single statistically significant clinical presentation that was observed in JE seropositive cases compared to the un-known viral etiology group. Paralysis and altered consciousness were only observed in JE seropositive individuals with majority of cases showing JE positivity from 1 to 3 days' date of illness compared to 1 day to 4 weeks among un-known viral etiology individuals. From the results it is evident that there is presence of JE among the community causing febrile illness and can be escalated to be screened in suspected viral meningitis and encephalitis cases. Further investigation including cerebrospinal fluid (CSF) and larger seroprevalence study can throw light on the incidence and prevalence of the JE in this part of the Kingdom. [ABSTRACT FROM AUTHOR]

Dengue is a viral infection caused by one of four serotypes of dengue virus (DENV), which is responsible for causing potentially life-threatening disease and substantial public health as well as economic burden worldwide. The non-structural and structural proteins of DENV are essential to its viral activity and pathogenesis. Unfortunately, despite numerous efforts, there is still no cure for dengue. Most of the available therapeutic options only provide symptomatic treatment. Since there is a lack of cure and dengue-related substantial economic and public health burden, a safe and effective dengue vaccine is urgently required. Currently, there is only one approved dengue vaccine available that provides suboptimal protection; however, a range of other dengue vaccines are under development to lower the infection burden and decrease dengue morbidities. In addition, numerous dengue therapeutics are also being developed, which have great potential in dengue treatment. These therapeutics mostly act by decreasing viral replication, vascular pathologies, and/or inflammation. This review comprehensively summarizes the latest update on dengue vaccines and therapeutics. Moreover, various other important aspects of DENV, including molecular biology, pathogenesis, and control strategies, have also been discussed. [ABSTRACT FROM AUTHOR]

Dengue fever is a global health threat caused by the dengue virus (DENV), a vector-borne and single-stranded RNA virus. Development of a safe and efficacious vaccine against DENV is a demanding challenge. The greatest pitfall in the development of vaccines is antibody-dependent enhancement (ADE), which is closely associated with disease exacerbation. We displayed the modified envelope proteins from the four serotypes of the DENV on a 24-mer ferritin nanoparticle, respectively. This tetravalent nanoparticle vaccine induced potent humoral and cellular immunity in mice without ADE and conferred efficient protection against the lethal challenge of DENV-2 and DENV-3 in AG6 mice. Further exploration of immunization strategies showed that even single-dose vaccination could reduce pathologic damage in BALB/c mice infected with high doses of DENV-2. Treatment with cyclic-di-guanosine monophosphate facilitated a higher titer of neutralizing antibodies and a stronger type-1 T-helper cell-biased immune response, thereby revealing it to be an effective adjuvant for dengue nanoparticle vaccines. These data suggest that a promising tetravalent nanoparticle vaccine could be produced to prevent DENV infection. [ABSTRACT FROM AUTHOR]

Mosquito-borne viral diseases are a group of viral illnesses that are predominantly transmitted by mosquitoes, including viruses from the Togaviridae and Flaviviridae families. In recent years, outbreaks caused by Dengue and Zika viruses from the Flaviviridae family, and Chikungunya virus from the Togaviridae family, have raised significant concerns for public health. However, there are currently no safe and effective vaccines available for these viruses, except for CYD-TDV, which has been licensed for Dengue virus. Efforts to control the transmission of COVID-19, such as home quarantine and travel restrictions, have somewhat limited the spread of mosquito-borne viral diseases. Several vaccine platforms, including inactivated vaccines, viral-vector vaccines, live attenuated vaccines, protein vaccines, and nucleic acid vaccines, are being developed to combat these viruses. This review analyzes the various vaccine platforms against Dengue, Zika, and Chikungunya viruses and provides valuable insights for responding to potential outbreaks. [ABSTRACT FROM AUTHOR]

Mammalian orthoreovirus (reovirus) infects most mammals and is associated with celiac disease in humans. In mice, reovirus infects the intestine and disseminates systemically to cause serotype-specific patterns of disease in the brain. To identify receptors conferring reovirus serotype-dependent neuropathogenesis, we conducted a genome-wide CRISPRa screen and identified paired immunoglobulin-like receptor B (PirB) as a receptor candidate. Ectopic expression of PirB allowed reovirus binding and infection. PirB extracelluar D3D4 region is required for reovirus attachment and infectivity. Reovirus binds to PirB with nM affinity as determined by single molecule force spectroscopy. Efficient reovirus endocytosis requires PirB signaling motifs. In inoculated mice, PirB is required for maximal replication in the brain and full neuropathogenicity of neurotropic serotype 3 (T3) reovirus. In primary cortical neurons, PirB expression contributes to T3 reovirus infectivity. Thus, PirB is an entry receptor for reovirus and contributes to T3 reovirus replication and pathogenesis in the murine brain. Mammalian orthoreovirus causes serotype-specific disease in the brain. Here, Shang et al. identify and characterise the role of paired immunoglobulin-like receptor B in reovirus attachment, entry and infectivity in the brain. [ABSTRACT FROM AUTHOR]

Copyright of Rare Metals is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The mechanism of pH-dependent hydrogen oxidation and evolution kinetics is still a matter of significant debate. To make progress, we study the Volmer step kinetics on platinum (111) using classical molecular dynamics simulations with an embedded Anderson-Newns Hamiltonian for the redox process and constant potential electrodes. We investigate how negative electrode electrostatic potential affects Volmer step kinetics. We find that the redox solvent reorganization energy is insensitive to changes in interfacial field strength. The negatively charged surface attracts adsorbed H as well as H+, increasing hydrogen binding energy, but also trapping H+ in the double layer. While more negative electrostatic potential in the double layer accelerates the oxidation charge transfer, it becomes difficult for the proton to move to the bulk. Conversely, reduction becomes more difficult because the transition state occurs farther from equilibrium solvation polarization. Our results help to clarify how the charged surface plays a role in hydrogen electrocatalysis kinetics. Excess free charges on electrode surfaces drive changes in hydrogen electrocatalysis kinetics. Here, the authors show how redox solvent reorganization energy is insensitive to interfacial electric field strength; instead, the charged surface directly modulates proton electrochemical potential. [ABSTRACT FROM AUTHOR]

Background: Typical symptoms of uncomplicated dengue fever (DF) include headache, muscle pains, rash, cough, and vomiting. A proportion of cases progress to severe dengue hemorrhagic fever (DHF), associated with increased vascular permeability, thrombocytopenia, and hemorrhages. Progression to severe dengue is difficult to diagnose at the onset of fever, which complicates patient triage, posing a socio-economic burden on health systems. Methods: To identify parameters associated with protection and susceptibility to DHF, we pursued a systems immunology approach integrating plasma chemokine profiling, high-dimensional mass cytometry and peripheral blood mononuclear cell (PBMC) transcriptomic analysis at the onset of fever in a prospective study conducted in Indonesia. Results: After a secondary infection, progression to uncomplicated dengue featured transcriptional profiles associated with increased cell proliferation and metabolism, and an expansion of ICOS+CD4+ and CD8+ effector memory T cells. These responses were virtually absent in cases progressing to severe DHF, that instead mounted an innate-like response, characterised by inflammatory transcriptional profiles, high circulating levels of inflammatory chemokines and with high frequencies of CD4low non-classical monocytes predicting increased odds of severe disease. Conclusions: Our results suggests that effector memory T cell activation might play an important role ameliorating severe disease symptoms during a secondary dengue infection, and in the absence of that response, a strong innate inflammatory response is required to control viral replication. Our research also identified discrete cell populations predicting increased odds of severe disease, with potential diagnostic value. [ABSTRACT FROM AUTHOR]

Metabolic processes play a critical role in immune regulation. Metabolomics is the systematic analysis of small molecules (metabolites) in organisms or biological samples, providing an opportunity to comprehensively study interactions between metabolism and immunity in physiology and disease. Integrating metabolomics into systems immunology allows the exploration of the interactions of multilayered features in the biological system and the molecular regulatory mechanism of these features. Here, we provide an overview on recent technological developments of metabolomic applications in immunological research. To begin, two widely used metabolomics approaches are compared: targeted and untargeted metabolomics. Then, we provide a comprehensive overview of the analysis workflow and the computational tools available, including sample preparation, raw spectra data preprocessing, data processing, statistical analysis, and interpretation. Third, we describe how to integrate metabolomics with other omics approaches in immunological studies using available tools. Finally, we discuss new developments in metabolomics and its prospects for immunology research. This review provides guidance to researchers using metabolomics and multiomics in immunity research, thus facilitating the application of systems immunology to disease research. [ABSTRACT FROM AUTHOR]

Since the discovery of the human respiratory syncytial virus (hRSV), multiple research efforts have been conducted to develop vaccines and treatments capable of reducing the risk of severe disease, hospitalization, long-term sequelae, and death from this pathogen in susceptible populations. In this sense, therapies specifically directed against hRSV are mainly based on monoclonal and polyclonal antibodies such as intravenous IgG (IVIG)-RSV and the monoclonal antibody palivizumab. However, these therapies are associated with significant limitations, including the need for the recruitment of a high number of convalescent volunteers who donate blood to procure IVIG-RSV and the costs associated with the need for repeated administrations of palivizumab. These limitations render this product not cost-effective for populations other than high-risk patients. These problems have underscored that it is still necessary to identify new safe and effective therapies for human use. However, these new therapies must benefit from a comparatively cheap production cost and the opportunity to be available to the high-risk population and anyone who requires treatment. Here, we review the different antibodies used to prevent the pathology caused by hRSV infection, highlighting therapies currently approved for human use and their clinical value. Also, the new, most promising candidates based on preclinical studies and clinical trial results are revised. [ABSTRACT FROM AUTHOR]

Coronaviruses have been identified as pathogens of gastrointestinal and respiratory diseases in humans and various animal species. In recent years, the global spread of new coronaviruses has had profound influences for global public health and economies worldwide. As highly pathogenic zoonotic viruses, coronaviruses have become the focus of current research. Porcine Deltacoronavirus (PDCoV), an enterovirus belonging to the family of coronaviruses, has emerged on a global scale in the past decade and significantly influenced the swine industry. Moreover, PDCoV infects not only pigs but also other species, including humans, chickens and cattles, exhibiting a broad host tropism. This emphasizes the need for in-depth studies on coronaviruses to mitigate their potential threats. In this review, we provided a comprehensive summary of the current studies on PDCoV. We first reviewed the epidemiological investigations on the global prevalence and distribution of PDCoV. Then, we delved into the studies on the pathogenesis of PDCoV to understand the mechanisms how the virus impacts its hosts. Furthermore, we also presented some exploration studies on the immune evasion mechanisms of the virus to enhance the understanding of host-virus interactions. Despite current limitations in vaccine development for PDCoV, we highlighted the inhibitory effects observed with certain substances, which offers a potential direction for future research endeavors. In conclusion, this review summarized the scientific findings in epidemiology, pathogenesis, immune evasion mechanisms and vaccine development of PDCoV. The ongoing exploration of potential vaccine candidates and the insights gained from inhibitory substances have provided a solid foundation for future vaccine development to prevent and control diseases associated with PDCoV., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Case: In this report, a rare case of primary cutaneous adenoid cystic carcinoma (PCACC) localized in the subcutaneous tissue of the scapular region that grew after BNT162b2 corona virus disease of 2019 (COVID-19) vaccination is presented and may be explained by CD4 and CD8 cell infiltration. The BNT162b2 mRNA vaccine has been associated with a multisystem inflammatory syndrome (MIS-V). A comparable immune reaction could potentially enhance tumor growth rate., Conclusion: Primary cutaneous adenoid cystic carcinomas are rare tumors with unique locations. Further studies with case series are required to establish management algorithms for PCACC and investigate the potential effect of vaccination., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C323)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Dengue is a mosquito-borne infection caused by dengue virus (DENV) of the Flaviviridae family. In another paediatric cohort, high anti-DENV antibody levels, >1:320 titres, protected against symptomatic dengue, whereas individuals with anti-DENV antibody titres between 1:21 and 1:80 were more susceptible to severe dengue [[2]]. Furthermore, in early disease phase, higher afucosylated IgG1 abundance was observed in secondary DENV infection compared to primary infection, and these antibodies were predictive of severe dengue [[21]]. [Extracted from the article]

Antibody-antigen interaction–at antigenic local environments called B-cell epitopes–is a prominent mechanism for neutralization of infection. Effective mimicry, and display, of B-cell epitopes is key to vaccine design. Here, a physical approach is evaluated for the discovery of epitopes which evolve slowly over closely related pathogens (conserved epitopes). The approach is 1) protein flexibility-based and 2) demonstrated with clinically relevant enveloped viruses, simulated via molecular dynamics. The approach is validated against 1) seven structurally characterized enveloped virus epitopes which evolved the least (out of thirty-nine enveloped virus-antibody structures), 2) two structurally characterized non-enveloped virus epitopes which evolved slowly (out of eight non-enveloped virus-antibody structures), and 3) eight preexisting epitope and peptide discovery algorithms. Rationale for a new benchmarking scheme is presented. A data-driven epitope clustering algorithm is introduced. The prediction of five Zika virus epitopes (for future exploration on recombinant vaccine technologies) is demonstrated. For the first time, protein flexibility is shown to outperform solvent accessible surface area as an epitope discovery metric. [ABSTRACT FROM AUTHOR]

Background The reactogenicity and immunogenicity of coronavirus disease 2019 (COVID-19) vaccines are well studied. Little is known regarding the relationship between immunogenicity and reactogenicity of COVID-19 vaccines. Methods This study assessed the association between immunogenicity and reactogenicity after 2 mRNA-1273 (100 µg) injections in 1671 total adolescent and adult participants (≥12 years) from the primary immunogenicity sets of the blinded periods of the Coronavirus Efficacy (COVE) and TeenCOVE trials. Associations between immunogenicity through day 57 and solicited adverse reactions (ARs) after the first and second injections of mRNA-1273 were evaluated among participants with and without solicited ARs using linear mixed-effects models. Results mRNA-1273 reactogenicity in this combined analysis set was similar to that reported for these trials. The vaccine elicited high neutralizing antibody (nAb) geometric mean titers (GMTs) in evaluable participants. GMTs at day 57 were significantly higher in participants who experienced solicited systemic ARs after the second injection (1227.2 [1164.4–1293.5]) than those who did not (980.1 [886.8–1083.2], P =.001) and were associated with fever, chills, headache, fatigue, myalgia, and arthralgia. Significant associations with local ARs were not found. Conclusions These data show an association of systemic ARs with increased nAb titers following a second mRNA-1273 injection. While these data indicate systemic ARs are associated with increased antibody titers, high nAb titers were observed in participants after both injections, consistent with the immunogenicity and efficacy in these trials. These results add to the body of evidence regarding the relationship of immunogenicity and reactogenicity and can contribute toward the design of future mRNA vaccines. [ABSTRACT FROM AUTHOR]

Bispecific antibodies (BsAbs) form an exciting class of bio-therapeutics owing to their multispecificity. Although numerous formats have been developed, generation of hetero-tetrameric IgG1-like BsAbs having acceptable safety and pharmacokinetics profiles from a single cell culture system remains challenging due to the heterogeneous pairing between the four chains. Herein, we employed a structure-guided approach to engineer mutations in the constant domain interfaces (CH1-CL and CH3-CH3) of heavy and k light chains to prevent heavy-light mispairing in the antigen binding fragment (Fab) region and heavy-heavy homodimerization in the Fc region. Transient co-transfection of mammalian cells with heavy and light chains of pre-existing antibodies carrying the engineered constant domains generates BsAbs with percentage purity ranging from 78% to 85%. The engineered BsAbs demonstrate simultaneous binding of both antigens, while retaining the thermal stability, Fc-mediated effector properties and FcRn binding properties of the parental antibodies. Importantly, since the variable domains were not modified, the mutations may enable BsAb formation from antibodies belonging to different germline origins and isotypes. The rationally designed mutations reported in this work could serve as a starting point for generating optimized solutions required for large scale production. [ABSTRACT FROM AUTHOR]

Background: There is still insufficient knowledge with regard to the potential involvement of mast cells (MCs) and their mediators in the pathology of coronavirus disease-2019 (COVID-19). Therefore, our study aimed to investigate the role of MCs, their activation and protease profiles in the pathogenesis of early and late lung damage in COVID-19 patients. Methods: Formalin-fixed and paraffin embedded lung specimens from 30 patients who died from COVID-19 and 9 controls were used for histological detection of MCs and their proteases (tryptase, chymase) followed by morphometric quantification. Results: Our results demonstrated increased numbers of MCs at early stage and further augmentation of MCs number during the late stage of alveolar damage in COVID-19 patients, as compared to the control group. Importantly, the percentage of degranulated (activated) MCs was higher during both stages of alveolar lesions in comparison to the controls. While there was no prominent alteration in the profile of tryptase-positive MCs, our data revealed a significant elevation in the number of chymase-positive MCs in the lungs of COVID-19 patients, compared to the controls. Conclusions: MCs are characterized by dysregulated accumulation and increased activation in the lungs of patients suffering from COVID-19. However, future profound studies are needed for precise analysis of the role of these immune cells in the context of novel coronavirus disease. [ABSTRACT FROM AUTHOR]

Fc gamma receptors (FcγRs) are critical effector receptors for immunoglobulin G (IgG) antibodies. On macrophages, FcγRs mediate multiple effector functions, including phagocytosis, but the individual contribution of specific FcγRs to phagocytosis has not been fully characterized. Primary human macrophage populations, such as splenic macrophages, can express FcγRI, FcγRIIA, and FcγRIIIA. However, there is currently no widely available monocyte or macrophage cell line expressing all these receptors. Common sources of monocytes for differentiation into macrophages, such as human peripheral blood monocytes and the monocytic leukemia cell line THP-1, generally lack the expression of FcγRIIIA (CD16A). Here, we utilized a lentiviral system to generate THP-1 cells stably expressing human FcγRIIIA (CD16F158). THP-1-CD16A cells treated with phorbol 12-myristate 13-acetate for 24 hours phagocytosed anti-D-opsonized human red blood cells primarily utilizing FcγRI with a lesser but significant contribution of IIIA while phagocytosis of antibody-opsonized human platelets equally utilized FcγRI and Fcγ IIIA. Despite the well-known ability of FcγRIIA to bind IgG in cell free systems, this receptor did not appear to be involved in either RBC or platelet phagocytosis. These transgenic cells may constitute a valuable tool for studying macrophage FcγR utilization and function. [ABSTRACT FROM AUTHOR]

The duration of protection after a single dose of yellow fever vaccine is a matter of debate. To summarize the current knowledge, we performed a systematic literature review and meta-analysis. Studies on the duration of protection after 1 and ≥2 vaccine doses were reviewed. Data were stratified by time since vaccination. In our meta-analysis, we used random-effects models. We identified 36 studies from 20 countries, comprising more than 17 000 participants aged 6 months to 85 years. Among healthy adults and children, pooled seroprotection rates after single vaccination dose were close to 100% by 3 months and remained high in adults for 5 to 10 years. In children vaccinated before age 2 years, the seroprotection rate was 52% within 5 years after primary vaccination. For immunodeficient persons, data indicate relevant waning. The extent of waning of seroprotection after yellow fever vaccination depends on age and immune status at primary vaccination. [ABSTRACT FROM AUTHOR]

Obesity is a global health problem that affects 650 million people worldwide and leads to diverse changes in host immunity. Individuals with obesity experience an increase in the size and the number of adipocytes, which function as an endocrine organ and release various adipocytokines such as leptin and adiponectin that exert wide ranging effects on other cells. In individuals with obesity, macrophages account for up to 40% of adipose tissue (AT) cells, three times more than in adipose tissue (10%) of healthy weight individuals and secrete several cytokines and chemokines such as interleukin (IL)-1b, chemokine C-C ligand (CCL)-2, IL-6, CCL5, and tumor necrosis factor (TNF)-a, leading to the development of inflammation. Overall, obesity-derived cytokines strongly affect immune responses and make patients with obesity more prone to severe symptoms than patients with a healthy weight. Several epidemiological studies reported a strong association between obesity and severe arthropod-borne virus (arbovirus) infections such as dengue virus (DENV), chikungunya virus (CHIKV), West Nile virus (WNV), and Sindbis virus (SINV). Recently, experimental investigations found that DENV, WNV, CHIKV and Mayaro virus (MAYV) infections cause worsened disease outcomes in infected diet induced obese (DIO) mice groups compared to infected healthy-weight animals. The mechanisms leading to higher susceptibility to severe infections in individuals with obesity remain unknown, though a better understanding of the causes will help scientists and clinicians develop host directed therapies to treat severe disease. In this review article, we summarize the effects of obesity on the host immune response in the context of arboviral infections. We have outlined that obesity makes the host more susceptible to infectious agents, likely by disrupting the functions of innate and adaptive immune cells. We have also discussed the immune response of DIO mouse models against some important arboviruses such as CHIKV, MAYV, DENV, and WNV. We can speculate that obesity-induced disruption of innate and adaptive immune cell function in arboviral infections ultimately affects the course of arboviral disease. Therefore, further studies are needed to explore the cellular and molecular aspects of immunity that are compromised in obesity during arboviral infections or vaccination, which will be helpful in developing specific therapeutic/prophylactic interventions to prevent immunopathology and disease progression in individuals with obesity. [ABSTRACT FROM AUTHOR]

The amount of aluminium sheets in future body-in-white concepts is still on the rise. There is a need for optimizing the joining techniques, caused by the different characteristics compared to the established steel components. Especially the electrode life for resistance spot welding as a reliable and established process needs to be improved. One reason for the short electrode life when welding aluminium is the insulating effect of the aluminium oxide layer. One possibility to reduce the electrode wear is the mechanical destruction of the oxide layer before the welding. This paper describes the influence of a translational and rotational electrode movement on the electrode wear. The oxide layer destruction is detected by resistance measurement. It could be shown that the destruction of the oxide layer already occurs at low movements. However, a homogeneous, large-area destruction is necessary for a wear reduction. [ABSTRACT FROM AUTHOR]

Copyright of Revista Mexicana de Pediatria is the property of Sociedad Mexicana de Pediatria and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Leukocyte immunoglobulin (Ig)‐like receptors (LILR) LILRB1 and LILRB2 may play a pivotal role in maintaining self‐tolerance and modulating the immune response through interaction with classical and nonclassical HLA molecules. Although both diversity and natural selection patterns over HLA genes have been extensively evaluated, little information is available concerning the genetic diversity and selection signatures on the LILRB1/2 regions. Therefore, we identified the LILRB1/2 genetic diversity using next‐generation sequencing in a population sample from São Paulo State, Brazil. We identified 58 LILRB1 Single Nucleotide Variants (SNVs), which gave rise to 13 haplotypes, and 41 LILRB2 SNVs arranged into 11 haplotypes. Although we may not exclude as a possible effect of population structure, we found evidence of either positive or purifying selection on LILRB1/2 coding regions. Some residues in both proteins showed to be under the effect of positive selection, suggesting that amino acid replacements in these proteins resulted in beneficial functional changes. Finally, we have revealed that allelic variation (six and five amino acid exchanges in LILRB1 and LILRB2, respectively) affects the structure and/or stability of both molecules. Nonetheless, LILRB2 has shown higher average stability, with no D1/D2 residue affecting protein structure. Overall, our findings demonstrate that LILRB1 and LILRB2 are as polymorphic as HLA class Ib genes and provide strong evidence supporting the directional selection regime hypothesis. [ABSTRACT FROM AUTHOR]