Neutrophil trapping and nexocytosis, mast cell-mediated processes for inflammatory signal relay.

Neutrophils are sentinel immune cells with essential roles for antimicrobial defense. Most of our knowledge on neutrophil tissue navigation derived from wounding and infection models, whereas allergic conditions remained largely neglected. Here, we analyzed allergen-challenged mouse tissues and discovered that degranulating mast cells (MCs) trap living neutrophils inside them. MCs release the attractant leukotriene B4 to re-route neutrophils toward them, thus exploiting a chemotactic system that neutrophils normally use for intercellular communication. After MC intracellular trap (MIT) formation, neutrophils die, but their undigested material remains inside MC vacuoles over days. MCs benefit from MIT formation, increasing their functional and metabolic fitness. Additionally, they are more pro-inflammatory and can exocytose active neutrophilic compounds with a time delay (nexocytosis), eliciting a type 1 interferon response in surrounding macrophages. Together, our study highlights neutrophil trapping and nexocytosis as MC-mediated processes, which may relay neutrophilic features over the course of chronic allergic inflammation.

Human Immunodeficiency Virus-Induced Interferon-Stimulated Gene Expression Is Associated With Monocyte Activation and Predicts Viral Load.

Background: Chronic immune activation is one of the hallmarks of human immunodeficiency virus (HIV) pathogenesis. Persistent upregulation of interferons (IFNs) and interferon-stimulated genes (ISGs) has previously been associated with chronic immune activation and HIV progression. Here a longitudinal analysis of the IFN and ISG response during HIV infection was performed to gain insights into the ongoing immune activation during HIV infection. Methods: IFN and ISG levels were determined using quantitative polymerase chain reaction in peripheral blood mononuclear cells of people with HIV at pre-seroconversion, during acute and chronic HIV infection, and during suppressive antiretroviral therapy (ART). Results: HIV infection induced the expression of a set of 4 ISGs-RSAD2, ISG15, IFI44L, and IFI27-which remained upregulated during chronic infection. This set of ISGs showed no clear correlations with T-cell activation as determined by co-expression of CD38 and HLA-DR. However, a strong correlation with monocyte activation marker soluble CD163 in serum was found. Furthermore, the expression of this ISG cluster was predictive of viral load before ART initiation and, on ART, expression levels normalized to pre-seroconversion levels. Conclusions: The results presented here suggests that ISG expression is linked to monocyte activation, possibly driven by viral replication.

Cyclic GMP-AMP synthase recognizes the physical features of DNA.

Cyclic GMP-AMP synthase (cGAS) is a major cytosolic DNA sensor that plays a significant role in innate immunity. Upon binding to double stranded DNA (dsDNA), cGAS utilizes GTP and ATP to synthesize the second messenger cyclic GMP-AMP (cGAMP). The cGAMP then binds to the adapter protein stimulator of interferon genes (STING) in the endoplasmic reticulum, resulting in the activation of the transcription factor interferon regulatory factor 3 (IRF3) and subsequent induction of type I interferon. An important question is how cGAS distinguishes between self and non-self DNA. While cGAS binds to the phosphate backbone of DNA without discrimination, its activation is influenced by physical features such as DNA length, inter-DNA distance, and mechanical flexibility. This suggests that the recognition of DNA by cGAS may depend on these physical features. In this article we summarize the recent progress in research on cGAS-STING pathway involved in antiviral defense, cellular senescence and anti-tumor response, and focus on DNA recognition mechanisms based on the physical features.

Involvement of mitochondrial fatty acid ß-oxidation in the antiviral innate immune response in head kidney macrophages of large yellow croaker (Larimichthys crocea).

As a vital pathway for cellular energy production, mitochondrial fatty acid ß-oxidation (FAO) is essential in regulating immune responses to bacterial pathogens and maintaining intracellular homeostasis in vertebrates. However, the specific role of FAO in antiviral innate immune response in macrophages remains insufficiently understood. In this study, virus infection simulated by poly(I:C) inhibited FAO, as indicated by the reduced expression of FAO-related genes and proteins in the head kidney of large yellow croaker, with similar results observed in poly(I:C)-stimulated macrophages. Then, inhibition of FAO by supplementary mildronate in vivo and etomoxir treatment in vitro revealed varying increases in the mRNA expression of antiviral innate immune response genes after stimulated by poly(I:C) in the head kidney and macrophages. Notably, etomoxir significantly facilitated the transcriptional up-regulation of the IFNh promoter by IRF3. Moreover, inhibiting FAO by knockdown of cpt1b promoted antiviral innate immune response triggered by poly(I:C) in macrophages. Conversely, activating FAO through overexpression of cpt1b or cpt2 significantly reduced the mRNA levels of antiviral response genes in macrophages stimulated by poly(I:C). Unlike etomoxir, cpt1b overexpression inhibited the transcriptional up-regulation of the IFNh promoter by IRF3. Furthermore, in vivo dietary palm oil feeding and in vitro exposure to palmitic acid inhibited the antiviral innate immune response triggered by poly(I:C) in the head kidney and macrophages, respectively. These effects were partly associated with FAO activation, as evidenced by etomoxir. In summary, this study elucidates FAO's critical role in regulating antiviral innate immune response in head kidney macrophages. These findings not only deepen insights into the interaction between metabolic remodeling and host immune responses, but also offer valuable guidance for developing nutritional strategies to improve antiviral immunity in aquaculture.

The Fusicoccin story revisited.

In plant biology Fusicoccin (FC) is one of the most studied fungal metabolites to date. Since the structural identification in 1964, much has been learned about its effects on the physiology of plants, about the interference with the action of plant hormones, the molecular nature of the plant receptor(s) for FC and the biosynthetic pathway for FC in the fungus. The finding that the plasma membrane H+-ATPase in combination with 14-3-3 proteins acts as high-affinity receptor for FC was a breakthrough in the field. Ever since, the binding of FC to the ATPase|14-3-3 receptor has taken center stage in explaining all FC induced physiological effects. However, a more critical review shows that this is not at all evident for a number of FC induced effects. Examples of this are: the inhibition of outward rectifying K+-channels in guard cells, the phosphorylation/activation of PEP-carboxylase and malate accumulation, the antagonism with ABA induced production of H2O2 / NO and the effect on ethylene production. In addition, recently two other physiological processes were shown to be targeted by FC, viz. the activation of TORC1 and the interference of FC with the immune response to fungal elicitors. In this review, the notion will be challenged that all FC affected processes start with the binding to and activation of the PM-ATPase and the question is raised whether may be other proteins with a key role in the respective processes are directly targeted by FC. A second unresolved question is whether FC may be another example of a fungal molecule turning out to be a 'copy' of an as yet unknown plant molecule; in analogy to the fungal product and plant hormone gibberellic acid. A relevant question in this respect is whether it is a coincidence that proteins that act in a coordinated fashion during stomatal opening (the ATPases and K+-channels) are targeted by FC? Or are the sites where FC binds in the plant, conserved during evolution because they serve a physiological role, namely the accommodation of a plant produced molecule? In view of the evidence, albeit not conclusive, that plants indeed produce 'FC-like ligands', it is worthwhile to make a renewed attempt with current day improved technology to answer this question and may be upgrade FC or structural analogue(s) to a new level, the level of plant hormone.

Association between a past history of nausea and vomiting during pregnancy and fever after the BNT162b2 COVID-19 vaccination.

PURPOSE: Nausea and vomiting during pregnancy (NVP) are common among pregnant women and can be severe enough to require hospitalization. However, the mechanism underlying NVP pathogenesis remains unclear. This study examined factors associated with adverse events after vaccination, including a past history of NVP. METHODS: A questionnaire-based survey was completed by non-pregnant women working at Nagasaki University Hospital who received two doses of the BNT162b2 coronavirus disease 2019 (COVID-19) vaccine. This study primarily examined the association between a past history of NVP and post-vaccination fever, as fever was determined to be the most objective and reliable indicator of the surveyed adverse events. RESULTS: Multivariate logistic regression analysis showed that post-vaccination fever was more strongly associated with a past history of NVP (odds ratio, 1.88; 95% confidence interval, 1.16-3.07) than either age (0.73; 0.56-0.96) or weight (0.85; 0.70-1.15), which were previously considered to be highly associated with the incidence of adverse events following COVID-19 vaccination. CONCLUSION: These results suggest an involvement of a similar pathological condition in developing NVP and post-vaccination fever.

Coexistence of nonfluorescent chromoproteins and fluorescent proteins in massive Porites spp. corals manifesting a pink pigmentation response.

Introduction: Several fluorescent proteins (FPs) and chromoproteins (CPs) are present in anthozoans and play possible roles in photoprotection. Coral tissues in massive corals often display discoloration accompanied by inflammation. Incidences of the pink pigmentation response (PPR) in massive Porites, described as inflammatory pink lesions of different shapes and sizes, has recently increased worldwide. FPs are reported to be present in PPR lesions, wherein a red fluorescent protein (RFP) appears to play a role in reducing reactive oxygen species. However, to date, the biochemical characterization and possible roles of the pigments involved are poorly understood. The present study aimed to identify and characterize the proteins responsible for pink discoloration in massive Porites colonies displaying PPRs, as well as to assess the differential distribution of pigments and the antioxidant properties of pigmented areas. Method: CPs were extracted from PPR lesions using gel-filtration chromatography and identified via genetic analysis using liquid chromatography-tandem mass spectrometry. The coexistence of CPs and RFP in coral tissues was assessed using microscopic observation. Photosynthetic antivity and hydrogen peroxide-scavenging activitiy were measured to assess coral stress conditions. Results: The present study revealed that the same CP (plut2.m8.16902.m1) isolated from massive Porites was present in both the pink spot and patch morphologies of the PPR. CPs were also found to coexist with RFP in coral tissues that manifested a PPR, with a differential distribution (coenosarc or tip of polyps' tentacles). High hydrogen peroxide-scavenging rates were found in tissues affected by PPR. Discussion and Conclusion: The coexistence of CPs and RFP suggests their possible differential role in coral immunity. CPs, which are specifically expressed in PPR lesions, may serve as an antioxidant in the affected coral tissue. Overall, this study provides new knowledge to our understanding of the role of CPs in coral immunity.

Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response.

Pseudomonas aeruginosa is a highly adaptable opportunistic pathogen capable of exploiting barriers and immune defects to cause chronic lung infections in conditions such as cystic fibrosis. In these contexts, host immune responses are ineffective at clearing persistent bacterial infection, instead driving a cycle of inflammatory lung damage. This review outlines key components of the host immune response to chronic P. aeruginosa infection within the lung, beginning with initial pathogen recognition, followed by a robust yet maladaptive innate immune response, and an ineffective adaptive immune response that propagates lung damage while permitting bacterial persistence. Untangling the interplay between host immunity and chronic P. aeruginosa infection will allow for the development and refinement of strategies to modulate immune-associated lung damage and potentiate the immune system to combat chronic infection more effectively.

Common virulence factors between Histoplasma and Paracoccidioides: Recognition of Hsp60 and Enolase by CR3 and plasmin receptors in host cells.

Over the last two decades, the incidence of Invasive Fungal Infections (IFIs) globally has risen, posing a considerable challenge despite available antifungal therapies. Addressing this, the World Health Organization (WHO) prioritized research on specific fungi, notably Histoplasma spp. and Paracoccidioides spp. These dimorphic fungi have a mycelial life cycle in soil and a yeast phase associated with tissues of mammalian hosts. Inhalation of conidia and mycelial fragments initiates the infection, crucially transforming into the yeast form within the host, influenced by factors like temperature, host immunity, and hormonal status. Survival and multiplication within alveolar macrophages are crucial for disease progression, where innate immune responses play a pivotal role in overcoming physical barriers. The transition to pathogenic yeast, triggered by increased temperature, involves yeast phase-specific gene expression, closely linked to infection establishment and pathogenicity. Cell adhesion mechanisms during host-pathogen interactions are intricately linked to fungal virulence, which is critical for tissue colonization and disease development. Yeast replication within macrophages leads to their rupture, aiding pathogen dissemination. Immune cells, especially macrophages, dendritic cells, and neutrophils, are key players during infection control, with macrophages crucial for defense, tissue integrity, and pathogen elimination. Recognition of common virulence molecules such as heat- shock protein-60 (Hsp60) and enolase by pattern recognition receptors (PRRs), mainly via the complement receptor 3 (CR3) and plasmin receptor pathways, respectively, could be pivotal in host-pathogen interactions for Histoplasma spp. and Paracoccidioides spp., influencing adhesion, phagocytosis, and inflammatory regulation. This review provides a comprehensive overview of the dynamic of these two IFIs between host and pathogen. Further research into these fungi's virulence factors promises insights into pathogenic mechanisms, potentially guiding the development of effective treatment strategies.

The complex interplay between encephalomyocarditis virus and the host defence system.

A variety of animals can be infected by encephalomyocarditis virus (EMCV). EMCV is the established causative agent of myocarditis and encephalitis in some animals. EMCV causes high fatality in suckling and weaning piglets, making pigs the most susceptible domestic animal species. Importantly, EMCV has zoonotic potential to infect the human population. The ability of the pathogen to avoid and undermine the initial defence mechanism of the host contributes to its virulence and pathogenicity. A large body of literature highlights the intricate strategies employed by EMCV to escape the innate immune machinery to suit its "pathogenic needs." Here, we also provide examples on how EMCV interacts with certain host proteins to dampen the infection process. Hence, this concise review aims to summarize these findings in a compendium of decades of research on this exciting yet underappreciated topic.

Effects of dam metabolic profile and seasonality (Spring vs. Winter) on their offspring' metabolism, health, and immunity: maternal factors in dairy calves' analytes.

Maternal status during the transition period can significantly impact the health and performance of Holstein dairy calves, with lasting effects on various variables. However, the relationship between maternal late gestation metabolic status, seasonality, and their impact on offspring remains unclear. This study aimed to assess the influence of maternal variables at calving on the performance, metabolism, and immunity of 28 dairy calves during their first month of life. Blood samples were collected from 28 Holstein cows at calving. Median results for maternal variables including non-esterified fatty acids (NEFA), ß-hydroxybutyrate (BHB), glucose, total protein (TP), albumin, triglycerides (TG), total cholesterol (TC), haptoglobin (Hp), body weight (BW), and body condition score (BCS) were determined. These median values served as a basis for categorizing the offspring into two groups based on their dams' high or low degree of each maternal variable. Additionally, calves were categorized by the season of birth (Spring vs. Winter), with 14 in each. Blood samples were collected from the calves at birth and on days 1, 7, 14, and 28 to assess IgG, biochemical parameters, and haptoglobin concentration. Reactive oxygen species (ROS) production by polymorphonuclear cells stimulated by various agents was also evaluated. Clinical assessments were conducted for diarrhea and bovine respiratory disease frequencies. Despite the overall health of the cows, differences were observed in the calves between maternal groups. Heavier cows with high maternal BCS tended to have larger offspring, while high maternal BCS was associated with increased diarrhea prevalence. Low maternal BCS resulted in a stronger innate immune response, indicated by higher ROS production. Calves from cows experiencing metabolic changes during calving displayed elevated Hp concentrations. Spring-born calves were larger but had lower serum IgG concentration and reduced innate immune response compared to winter-born calves. Additionally, spring-born calves exhibited higher Hp and increased diarrhea prevalence on day 28. These findings underscore the importance of the prenatal period in determining neonatal health and suggest further research to elucidate the long-term clinical implications of maternal effects on offspring health and growth. Investigating offspring constituents later in life can provide insight into the persistence of maternal effects over time.

Physicochemical and structural insights into lyophilized mRNA-LNP from lyoprotectant and buffer screenings.

The surge in RNA therapeutics has revolutionized treatments for infectious diseases like COVID-19 and shows the potential to expand into other therapeutic areas. However, the typical requirement for ultra-cold storage of mRNA-LNP formulations poses significant logistical challenges for global distribution. Lyophilization serves as a potential strategy to extend mRNA-LNP stability while eliminating the need for ultra-cold supply chain logistics. Although recent advancements have demonstrated the promise of lyophilization, the choice of lyoprotectant is predominately focused on sucrose, and there remains a gap in comprehensive evaluation and comparison of lyoprotectants and buffers. Here, we aim to systematically investigate the impact of a diverse range of excipients including oligosaccharides, polymers, amino acids, and various buffers, on the quality and performance of lyophilized mRNA-LNPs. From the screening of 45 mRNA-LNP formulations under various lyoprotectant and buffer conditions for lyophilization, we identified previously unexplored formulation compositions, e.g., polyvinylpyrrolidone (PVP) in Tris or acetate buffers, as promising alternatives to the commonly used oligosaccharides to maintain the physicochemical stability of lyophilized mRNA-LNPs. Further, we delved into how physicochemical and structural properties influence the functionality of lyophilized mRNA-LNPs. Leveraging high-throughput small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM), we showed that there is complex interplay between mRNA-LNP structural features and cellular translation efficacy. We also assessed innate immune responses of the screened mRNA-LNPs in human peripheral blood mononuclear cells (PBMCs), and showed minimal alterations of cytokine secretion profiles induced by lyophilized formulations. Our results provide valuable insights into the structure-activity relationship of lyophilized formulations of mRNA-LNP therapeutics, paving the way for rational design of these formulations. This work creates a foundation for a comprehensive understanding of mRNA-LNP properties and in vitro performance change resulting from lyophilization.

Metabolism and immune memory in invertebrates: are they dissociated?

Since the discovery of specific immune memory in invertebrates, researchers have investigated its immune response to diverse microbial and environmental stimuli. Nevertheless, the extent of the immune system's interaction with metabolism, remains relatively enigmatic. In this mini review, we propose a comprehensive investigation into the intricate interplay between metabolism and specific immune memory. Our hypothesis is that cellular endocycles and epigenetic modifications play pivotal roles in shaping this relationship. Furthermore, we underscore the importance of the crosstalk between metabolism and specific immune memory for understanding the evolutionary costs. By evaluating these costs, we can gain deeper insights into the adaptive strategies employed by invertebrates in response to pathogenic challenges. Lastly, we outline future research directions aimed at unraveling the crosstalk between metabolism and specific immune memory. These avenues of inquiry promise to illuminate fundamental principles governing host-pathogen interactions and evolutionary trade-offs, thus advancing our understanding of invertebrate immunology.

Comparison of Antiviral Immune Responses in Healthy Cats Induced by Two Immune Therapeutics.

BACKGROUND: Effective immunotherapeutic agents for use in cats are needed to aid in the management of intractable viral diseases, including feline infectious peritonitis (FIP) infection. The objectives of this study were to compare two different immune stimulants for antiviral activity in cats: (1) TLR 2/6-activating compound polyprenyl immunostimulant; (PI) and (2) liposome Toll-like receptor 3/9 agonist complexes (LTCs) to determine relative abilities to stimulate the induction of type I (IFN-α, IFN-ß) and type II (IFN-γ) interferon immune responses in vitro and to study the effects of treatment on immune responses in healthy cats. METHODS: Cytokine and cellular immune responses to PI and LTC were evaluated using peripheral blood mononuclear cells (PBMCs) from healthy cats incubated with LTC and PI at indicated concentrations using reverse transcriptase polymerase chain reaction assays and ELISA assays. The effects of the immune stimulants on inhibiting FIPV replication were assessed using a feline macrophage cell line (fcwf-4). Cytokine and cellular immune responses to PI and LTC were evaluated in blood samples from healthy cats treated with PI and LTC, using reverse transcriptase polymerase chain reaction (RT-PCR) and ELISA assays. RESULTS: In the in vitro studies, both compounds triggered the upregulated expression of IFN-α, IFN-γ, and IL-1ß genes in cat PBMC, whereas treatment with LTC induced significantly greater expression of IFN-α and IFN-γ on Day 1 and IL-1b on Day 3. There was significant protection from FIPV-induced cytopathic effects when fcwf-4 cells were treated with conditioned medium from LTC-activated leukocytes. In the healthy cat study (in vivo), both PI and LTC increased the mRNA signal for IFN-α, IFN-γ, and IL-1ß above baseline at multiple time points with statistically greater increases in the LTC group on either Day 1 (IFN-α, IFN-γ) or Day 3 (IL-1ß). In addition, RANTES increased over time in cats treated with the LTC. CONCLUSIONS: Both LTC and PI protocols induced immune-enhancing effects, suggesting a possible clinical use for the management of chronic infectious diseases like FIP. Activating the TLR 3 and 9 pathways (LTC) induced superior broad interferon production in vitro than the activation of the TLR 2 and 6 pathways (PI).

Adjuvant system AS01: from mode of action to effective vaccines.

INTRODUCTION: The use of novel adjuvants in human vaccines continues to expand as their contribution to preventing disease in challenging populations and caused by complex pathogens is increasingly understood. AS01 is a family of liposome-based vaccine Adjuvant Systems containing two immunostimulants: 3-O-desacyl-4'-monophosphoryl lipid A and the saponin QS-21. AS01-containing vaccines have been approved and administered to millions of individuals worldwide. AREAS COVERED: Here, we report advances in our understanding of the mode of action of AS01 that contributed to the development of efficacious vaccines preventing disease due to malaria, herpes zoster, and respiratory syncytial virus. AS01 induces early innate immune activation that induces T cell-mediated and antibody-mediated responses with optimized functional characteristics and induction of immune memory. AS01-containing vaccines appear relatively impervious to baseline immune status translating into high efficacy across populations. Currently licensed AS01-containing vaccines have shown acceptable safety profiles in clinical trials and post-marketing settings. EXPERT OPINION: Initial expectations that adjuvantation with AS01 could support effective vaccine responses and contribute to disease control have been realized. Investigation of the utility of AS01 in vaccines to prevent other challenging diseases, such as tuberculosis, is ongoing, together with efforts to fully define its mechanisms of action in different vaccine settings.

Adjuvants are added to vaccines to increase the immune response produced after vaccination. Adjuvant Systems contain two or more molecules that stimulate the immune system. AS01 is an Adjuvant System that contains two components, MPL and QS-21, that stimulate the immune system. AS01 is included in three approved vaccines: a malaria vaccine for children, a herpes zoster vaccine for older adults, and a respiratory syncytial virus vaccine also for older adults. Vaccines containing AS01 have been extensively evaluated in clinical trials and administered to millions of individuals during market use. These vaccines are effective in preventing disease and have acceptable safety in different age groups. Experiments have been done to investigate how AS01 works in vaccines to produce an efficient immune response that helps to protect against the disease being targeted. A key effect of AS01 is to encourage specific immune cells to produce chemicals that stimulate the immune system. We now know that this effect is due to co-operation between MPL and QS-21. Experiments have shown that AS01 induces a sophisticated immune 'gene signature' in blood within 24 h after vaccination, and people who developed this 'gene signature' had a stronger response to vaccination. AS01 seems to be able to stimulate the immune system of most people ­ even if they are older or have a weakened immune system. This means that AS01 could be included in other vaccines against other challenging diseases, such as tuberculosis, or could be used in the treatment of some disease, such as chronic hepatitis B.

The cGAS/STING Pathway-A New Potential Biotherapeutic Target for Gastric Cancer?

Gastric cancer ranks among the top five deadliest tumors worldwide, both in terms of prevalence and mortality rates. Despite mainstream treatments, the efficacy in treating gastric cancer remains suboptimal, underscoring the urgency for novel therapeutic approaches. The elucidation of tumor immunosuppressive microenvironments has shifted focus towards cancer biotherapeutics, which leverage the patient's immune system or biologics to target tumor cells. Biotherapy has emerged as a promising alternative for tumors resistant to traditional chemotherapy, radiation, and immunotherapy. Central to this paradigm is the cGAS-STING pathway, a pivotal component of the innate immune system. This pathway recognizes aberrant DNA, such as that from viral infections or tumor cells, and triggers an immune response, thereby reshaping the immunosuppressive tumor microenvironment into an immune-stimulating milieu. In the context of gastric cancer, harnessing the cGAS-STING pathway holds significant potential for biotherapeutic interventions. This review provides a comprehensive overview of the latest research on cGAS-STING in gastric cancer, including insights from clinical trials involving STING agonists. Furthermore, it assesses the prospects of targeting the cGAS-STING pathway as a novel biotherapeutic strategy for gastric cancer.

Assessment of serum proprotein convertase subtilisin/kexin type 9 in pediatric sepsis syndrome.

Sepsis is a life-threatening condition that arises when the body's response to infection causes injury to its tissues and organs. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme released in response to the drop in cholesterol level occurring in sepsis. Our study aimed to evaluate the prognostic role of serum Proprotein convertase subtilisin/kexin type 9 (PCSK9) level in children with sepsis and severe sepsis. Sixty children were included in this study. They were divided into two groups: 30 children in the sepsis group and 30 in the severe sepsis group. Another 30 apparently healthy children were included as a control group. Blood samples were withdrawn from all included children for complete blood count (CBC), renal function tests (RFT), liver function tests (LFT), LDL-cholesterol (LDL-C), blood culture, and serum PCSK9. In this study, PCSK9 and LDL-C were higher in the two sepsis groups than in the control group (p < 0.05). They were also higher in the severe sepsis group than the sepsis group and in the non-survivors than in the survivors (p < 0.05). PCSK9 was positively correlated with length of hospital stay in surviving children (r = 0.67, p = 0.001) and had predicted significant hematological dysfunction (adjusted B = - 96.95, p = 0.03). In conclusion, the PCSK9 assay can be used as a biomarker for bad prognosis in children suffering from clinical sepsis.

Exploring the midgut physiology of the non-haematophagous mosquito Toxorhynchites theobaldi.

Toxorhynchites mosquitoes have an exclusively phytophagous feeding habit as adults, which leads to significant differences in their morphophysiology compared with haematophagous mosquitoes. However, the molecular mechanisms of digestion in this mosquito are not well understood. In this study, RNA sequencing of the posterior midgut (PMG) of the mosquito Toxorhynchites theobaldi was undertaken, highlighting its significance in mosquito digestion. Subsequently, a comparison was made between the differential gene expression of the PMG and that of the anterior midgut. It was found that the most abundant proteases in the PMG were trypsin and chymotrypsin, and the level of gene expression for enzymes essential for digestion (such as serine protease, α-amylase and pancreatic triacylglycerol lipase) and innate immune response (including catalase, cecropin-A2 and superoxide dismutase) was like that of haematophagous mosquitoes. Peritrophin-1 was detected in the entire midgut, with an elevated expression level in the PMG. Based on our findings, it is hypothesized that a non-haematophagic habit might have been exhibited by the ancestor of Tx. theobaldi, and this trait may have been retained. This study represents a pioneering investigation at the molecular level of midgut contents in a non-haematophagous mosquito. The findings offer valuable insights into the evolutionary aspects of feeding habits in culicids.

Cap-related modifications of RNA regulate binding to IFIT proteins.

All cells in our body are equipped with receptors to recognize pathogens and trigger a rapid defense response. As a result, foreign molecules are blocked and cells are alerted to the danger. Among the many molecules produced in response to viral infection are interferon-induced proteins with tetratricopeptide repeats (IFITs). Their role is to recognize foreign mRNA and eliminate it from the translational pool of transcripts. In the present study, we used biophysical methods to characterize the interactions between IFIT1 protein and its partners IFIT2 and IFIT3. IFIT1 interacts with IFIT3 with nanomolar binding affinity, which did not change significantly in the presence of the preformed IFIT2/3 complex. The interactions between IFIT2 and IFIT3 and IFIT1 and IFIT2 were one order of magnitude weaker. We also present kinetic data of the interactions between the IFIT protein complex and short RNA bearing various modifications at the 5' end. We show kinetic parameters for interaction between IFIT complex and RNA with m6Am modification. The results show that the cap adjacent m6Am modification is a stronger signature than cap1 alone. It blocks the formation of a complex between IFIT proteins and m7Gpppm6Am-RNA much more effectively than other cap modifications. In contrast, m6A in the 5'UTR is not recognized by IFIT proteins and does not contribute to translation repression by IFIT proteins. The data obtained are important for understanding the regulation of expression of genetic information. They indicate that 2'-O and m6Am modifications modulate the availability of mRNA molecules for proteins of innate immune response.

The Influence of Metabolic Risk Factors on the Inflammatory Response Triggered by Myocardial Infarction: Bridging Pathophysiology to Treatment.

Myocardial infarction (MI) sets off a complex inflammatory cascade that is crucial for effective cardiac healing and scar formation. Yet, if this response becomes excessive or uncontrolled, it can lead to cardiovascular complications. This review aims to provide a comprehensive overview of the tightly regulated local inflammatory response triggered in the early post-MI phase involving cardiomyocytes, (myo)fibroblasts, endothelial cells, and infiltrating immune cells. Next, we explore how the bone marrow and extramedullary hematopoiesis (such as in the spleen) contribute to sustaining immune cell supply at a cardiac level. Lastly, we discuss recent findings on how metabolic cardiovascular risk factors, including hypercholesterolemia, hypertriglyceridemia, diabetes, and hypertension, disrupt this immunological response and explore the potential modulatory effects of lifestyle habits and pharmacological interventions. Understanding how different metabolic risk factors influence the inflammatory response triggered by MI and unraveling the underlying molecular and cellular mechanisms may pave the way for developing personalized therapeutic approaches based on the patient's metabolic profile. Similarly, delving deeper into the impact of lifestyle modifications on the inflammatory response post-MI is crucial. These insights may enable the adoption of more effective strategies to manage post-MI inflammation and improve cardiovascular health outcomes in a holistic manner.