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The first layer of plant immunity is activated by cell surface receptor‐like kinases (RLKs) and proteins (RLPs) that detect infectious pathogens. Constitutive interaction with the SUPPRESSOR OF BIR1 (SOBIR1) RLK contributes to RLP stability and kinase activity. As RLK activation requires transphosphorylation with a second associated RLK, it remains elusive how RLPs initiate downstream signaling. We employed live‐cell imaging, gene silencing and coimmunoprecipitation to investigate the requirement of associated kinases for functioning and ligand‐induced subcellular trafficking of Cf RLPs that mediate immunity of tomato against Cladosporium fulvum. Our research shows that after elicitation with matching effector ligands Avr4 and Avr9, BRI1‐ASSOCIATED KINASE 1/SOMATIC EMBRYOGENESIS RECEPTOR KINASE 3 (BAK1/SERK3) associates with Cf‐4 and Cf‐9. BAK1/SERK3 is required for the effector‐triggered hypersensitive response and resistance of tomato against C. fulvum. Furthermore, Cf‐4 interacts with SOBIR1 at the plasma membrane and is recruited to late endosomes upon Avr4 trigger, also depending on BAK1/SERK3. These observations indicate that RLP‐mediated resistance and endocytosis require ligand‐induced recruitment of BAK1/SERK3, reminiscent of BAK1/SERK3 interaction and subcellular fate of the FLAGELLIN SENSING 2 (FLS2) RLK. This reveals that diverse classes of cell surface immune receptors share common requirements for initiation of resistance and endocytosis.

A major barrier to human immunodeficiency virus (HIV-1) cure is the latent viral reservoir, which persists despite antiretroviral therapy (ART), including across the non-dividing myeloid reservoir which is found systemically in sanctuary sites across tissues and the central nervous system (CNS). Unlike activated CD4+ T cells that undergo rapid cell death during initial infection (due to rapid viral replication kinetics), viral replication kinetics are delayed in non-dividing myeloid cells, resulting in long-lived survival of infected macrophages and macrophage-like cells. Simultaneously, persistent inflammation in macrophages confers immune dysregulation that is a key driver of co-morbidities including cardiovascular disease (CVD) and neurological deficits in people living with HIV-1 (PLWH). Macrophage activation and dysregulation is also a key driver of disease progression across other viral infections including SARS-CoV-2, influenza, and chikungunya viruses, underscoring the interplay between macrophages and disease progression, pathogenesis, and comorbidity in the viral infection setting. This review discusses the role of macrophages in persistence and pathogenesis of HIV-1 and related comorbidities, SARS-CoV-2 and other viruses. A special focus is given to novel immunomodulatory targets for key events driving myeloid cell dysregulation and reservoir maintenance across a diverse array of viral infections.

Inflammation-induced thrombosis is a common consequence of bacterial infections, such as those caused by Salmonella Typhimurium (STm). The presentation of multi-organ thrombosis post-infection that develops and resolves with organ-specific kinetics raises significant challenges for its therapeutic control. Here, we identify specific inflammatory events driving thrombosis in the spleens and livers of STm-infected mice. IFN-γ or platelet expression of C-type lectin-like receptor CLEC-2, key drivers of thrombosis in liver, are dispensable for thrombosis in the spleen. Platelets, monocytes, and neutrophils are identified as core constituents of thrombi in both organs. Depleting either neutrophils or monocytic cells abrogates thrombus formation. Neutrophils and monocytes secrete TNF and blocking TNF diminishes both thrombosis and inflammation, which correlates with reduced endothelial expression of E-selectin and leukocyte infiltration. Moreover, inhibiting tissue factor and P-selectin glycoprotein ligand-1 pathways impairs thrombosis in both spleen and liver. Therefore, we identify organ-specific, and shared mechanisms driving thrombosis within a single infection. This may inform on tailoring treatments towards infection-induced inflammation, and single- or multi-organ thrombosis, based on the clinical need. Infection may induce multi-organ thrombosis, but the underlying inflammatory mechanism remains elusive. Here, using Salmonella Typhimurium infectious mouse model, the authors reveal organ specific and broad inflammatory events like TNF for thrombosis in liver and spleen.

Background Clinical ethics consultations (CEC) can be complex interventions, involving multiple methods, stakeholders, and competing ethical values. Despite longstanding calls for rigorous evaluation in the field, progress has been limited. The Medical Research Council (MRC) proposed guidelines for evaluating the effectiveness of complex interventions. The evaluation of CEC may benefit from application of the MRC framework to advance the transparency and methodological rigor of this field. A first step is to understand the outcomes measured in evaluations of CEC in healthcare settings. Objective The primary objective of this review was to identify and map the outcomes reported in primary studies of CEC. The secondary objective was to provide a comprehensive overview of CEC structures, processes, and roles to enhance understanding and to inform standardization. Methods We searched electronic databases to identify primary studies of CEC involving patients, substitute decision-makers and/or family members, clinicians, healthcare staff and leaders. Outcomes were mapped across five conceptual domains as identified a priori based on our clinical ethics experience and preliminary literature searches and revised based on our emerging interpretation of the data. These domains included personal factors, process factors, clinical factors, quality, and resource factors. Results Forty-eight studies were included in the review. Studies were highly heterogeneous and varied considerably regarding format and process of ethical intervention, credentials of interventionist, population of study, outcomes reported, and measures employed. In addition, few studies used validated measurement tools. The top three outcome domains that studies reported on were quality (n = 31), process factors (n = 23), and clinical factors (n = 19) . The majority of studies examined multiple outcome domains. All five outcome domains were multidimensional and included a variety of subthemes. Conclusions This scoping review represents the initial phase of mapping the outcomes reported in primary studies of CEC and identifying gaps in the evidence. The confirmed lack of standardization represents a hindrance to the provision of high quality intervention and CEC scientific progress. Insights gained can inform the development of a core outcome set to standardize outcome measures in CEC evaluation research and enable scientifically rigorous efficacy trials of CEC.

CHARGE syndrome is a developmental disorder that affects 1 in 10,000 births, and patients exhibit both physical and behavioral characteristics. De novo variants in chromodomain helicase DNA binding protein 7 (CHD7) cause 67% of CHARGE syndrome cases. CHD7 is a DNA-binding chromatin remodeler with thousands of predicted binding sites in the genome, making it challenging to define molecular pathways linking loss of CHD7 to CHARGE syndrome phenotypes. To address this problem, here, we used a previously characterized zebrafish model of CHARGE syndrome to generate transcriptomic and proteomic datasets from larval zebrafish head tissue at two developmental time points. By integrating these datasets with differential expression, pathway and upstream regulator analyses, we identified multiple consistently dysregulated pathways and defined a set of candidate genes that link loss of chd7 with disease-related phenotypes. Finally, we identified that CRISPR/Cas9-mediated knockdown of capgb, nefla or rdh5 phenocopies behavioral defects seen in chd7 mutants, functionally validating the roles of these genes. Our data provide a resource for further investigation of molecular mediators of CHD7 and a template to reveal functionally relevant therapeutic targets to alleviate specific aspects of CHARGE syndrome.

Bacterial infections remain a significant global challenge, further complicated by the growing issue of antimicrobial resistance (AMR). In this context, vaccination provides a cost-effective means of preventing infections and combating the emergence of AMR strains. Antibodies are key mediators of vaccine-induced protection. However, their mechanisms of action in vivo are not fully understood. In this study, we demonstrate how antibodies enhance the capture of Salmonella by macrophages. Although these cells may be dispensable for controlling bacterial numbers, they are crucial for limiting the spread of bacterial antigens. Additionally, we find that the classical complement cascade is not necessary for bacterial clearance but does facilitate bacterial capture by macrophages. Overall, our findings reveal that multiple antibody-mediated pathways operate in vivo , exhibiting some redundancy in their combined efforts to control infection, underscoring the importance of antibody functions in limiting bacterial spread.

Abstract Background The original equine sepsis score provided a method of identifying foals with sepsis. New variables associated with sepsis have been evaluated, but the sepsis score has not been updated. Objectives To evaluate the sensitivity and specificity of 2 updated sepsis scores and the systemic inflammatory response syndrome (SIRS) criteria in regard to detecting sepsis in foals. Animals Two-hundred and seventy-three ill foals and 25 healthy control foals. Methods Historical, physical examination, and clinicopathologic findings were used to calculate the original sepsis score and 2 updated sepsis scores. SIRS criteria were also evaluated. Sepsis scores and positive SIRS scores were statistically compared to foals with sepsis. Results One-hundred and twenty-six foals were septic and 147 sick-nonseptic. The original and updated sepsis scores were significantly higher in septic foals as compared to sick-nonseptic and healthy foals. The sensitivity and specificity of the updated sepsis scores to predict sepsis were not significantly better than those of the original sepsis score. One-hundred and twenty-seven of 273 (46.5%) foals met the original SIRS criteria and 88/273 (32%) foals met the equine neonatal SIRS criteria. The original SIRS criteria had similar sensitivity and specificity for predicting sepsis as did the 3 sepsis scores in our study. Conclusions and Clinical Importance The updated sepsis scores did not provide improved ability in predicting sepsis. Fulfilling the original SIRS criteria provided similar sensitivity and specificity in predicting sepsis as the modified sepsis score and might serve as a diagnostic aid in identifying foals at risk for sepsis.

The sources of stress (academics, financial, family, social, and daily hassles) and coping strategies (self-help, approach, accommodation, avoidance, and self-punishment) of 166 college students were examined. The relationship between sex, specific sources of stress, and coping strategies was also investigated. Students completed a stress assessment inventory and a stress coping inventory based on a 5-factor revised COPE model (Zuckerman and Gagne Journal of Research in Personality, 37:169–204, 2003). Results found that college women reported a higher overall level of stress and greater use of emotion-focused coping strategies than college men. College men and women also reported different coping strategies for different stressors; however the use of emotion-focused coping strategies dominated over problem-solving strategies for both men and women. These results have implications for designing stress reduction workshops that build on the existing adaptive emotion-focused strategies of college students.

Vaccination with Vi capsular polysaccharide (Vi-PS) or protein-Vi typhoid conjugate vaccine (TCV) can protect adults against Typhi infections. TCVs offer better protection than Vi-PS in infants and may offer better protection in adults. Potential reasons for why TCV may be superior in adults are not fully understood. Here, we immunized wild-type (WT) mice and mice deficient in IgG or IgM with Vi-PS or TCVs (Vi conjugated to tetanus toxoid or CRM197) for up to seven months, with and without subsequent challenge with Vi-expressing Typhimurium. Unexpectedly, IgM or IgG alone were similarly able to reduce bacterial burdens in tissues, and this was observed in response to conjugated or unconjugated Vi vaccines and was independent of antibody being of high affinity. Only in the longer-term after immunization (>5 months) were differences observed in tissue bacterial burdens of mice immunized with Vi-PS or TCV. These differences related to the maintenance of antibody responses at higher levels in mice boosted with TCV, with the rate of fall in IgG titres induced to Vi-PS being greater than for TCV. Therefore, Vi-specific IgM or IgG are independently capable of protecting from infection and any superior protection from vaccination with TCV in adults may relate to responses being able to persist better rather than from differences in the antibody isotypes induced. These findings suggest that enhancing our understanding of how responses to vaccines are maintained may inform on how to maximize protection afforded by conjugate vaccines against encapsulated pathogens such as . Typhi.

Aneurysmal subarachnoid hemorrhage (aSAH) is caused by abnormal blood vessel dilation and subsequent rupture, resulting in blood pooling in the subarachnoid space. This neurological insult results in the activation of the inflammasome, a multiprotein complex that processes pro-inflammatory interleukin (IL)-1 cytokines leading to morbidity and mortality. Moreover, increases in inflammasome proteins are associated with clinical deterioration in many neurological diseases. Limited studies have investigated inflammasome protein expression following aSAH. Reliable markers of the inflammatory response associated with aSAH may allow for earlier detection of patients at risk for complications and aid in the identification of novel pharmacologic targets. Here, we investigated whether inflammasome signaling proteins may serve as potential biomarkers of the inflammatory response in aSAH. Serum and cerebrospinal fluid (CSF) from fifteen aSAH subjects and healthy age-matched controls and hydrocephalus (CSF) no-aneurysm controls were evaluated for levels of inflammasome signaling proteins and downstream pro-inflammatory cytokines. Protein measurements were carried out using Simple Plex and Single-Molecule Array (Simoa) technology. The area under the curve (AUC) was calculated using receiver operating characteristics (ROCs) to obtain information on biomarker reliability, specificity, sensitivity, cut-off points, and likelihood ratio. In addition, a Spearman r correlation matrix was performed to determine the correlation between inflammasome protein levels and clinical outcome measures. aSAH subjects demonstrated elevated caspase-1, apoptosis-associated speck-like protein with a caspase recruiting domain (ASC), IL-18 and IL-1β levels in serum, and CSF when compared to controls. Each of these proteins was found to be a promising biomarker of inflammation in aSAH in the CSF. In addition, ASC, caspase-1, and IL-1β were found to be promising biomarkers of inflammation in aSAH in serum. Furthermore, we found that elevated levels of inflammasome proteins in serum are useful to predict worse functional outcomes following aSAH. Thus, the determination of inflammasome protein levels in CSF and serum in aSAH may be utilized as reliable biomarkers of inflammation in aSAH and used clinically to monitor patient outcomes.