The rockefeller university

Parasites can have important detrimental effects on host fitness, thereby influencing their ecology and evolution. Hosts can, in turn, exert strong selective pressures on their parasites, affecting eco-evolutionary dynamics. Although the reciprocal pressures that hosts and parasites exert on each other have long been recognized, the mechanisms are insufficiently understood. Here, we discuss the role of host cognition in host-parasite eco-evolutionary dynamics. Theoretical advances have acknowledged the importance of behavior in shaping these dynamics, but how and why host cognition should affect and/or be affected by parasites is less clear. We propose three scenarios that may create causal and non-causal links between cognition and the richness, prevalence and intensity of parasites. First, host cognition may change the probability of exposure to parasites, either increasing (e.g., altering the relationship with the environment via innovative behaviors) or decreasing (e.g., influencing decision-making to avoid infected conspecifics) exposure. Second, parasites may change host cognitive performance, for example, by reducing host condition. Finally, host cognition and parasites can be associated via common causal factors (e.g., shared molecular pathways), energetic constraints generating trade-offs between cognition and immunocompetence, or trait co-evolution with life history, ecological, or social strategies. The existence of such a variety of non-mutually exclusive mechanisms suggests that host cognition has a great potential to affect and be affected by parasites. However, it also implies that progress in understanding these effects will only be possible if we distinguish between causal and non-causal links.

CD4(+) T cells integrate well-defined signals from the T-cell receptor (TCR) (signal 1) and a host of costimulatory molecules (signal 2) to initiate clonal expansion and differentiation into diverse functional T helper (Th) subsets. However, our ability to guide the expansion of context-appropriate Th subsets by deploying these signals in vaccination remains limited. Using cell-based vaccines, we selectively amplified signal 1 by exclusive presentation of an optimized peptide:MHC II (pMHC II) complex in the absence of classic costimulation. Contrary to expectations, amplified signal 1 alone was strongly immunogenic and selectively expanded high-affinity TCR clonotypes, despite delivering intense TCR signals. In contrast to natural infection or standard vaccines, amplified signal 1, presented by a variety of professional and nonprofessional antigen-presenting cells (APCs), induced exclusively polyfunctional Th1 effector and memory cells, which protected against retroviral infection and tumor challenge, and expanded tumor-reactive CD4(+) T cells otherwise rendered unresponsive in tumor-bearing hosts. Together, our findings uncover a default Th1 response to ample signal 1 and offer a means to selectively prime such protective responses by vaccination.

Objective Survivors of prolonged (>2 weeks) post-cardiac arrest (CA) coma are expected to remain permanently disabled. We aimed to investigate 3 outlier patients who ultimately achieved independent functional outcomes after prolonged post-CA coma to identify electroencephalographic (EEG) markers of their recovery potential. For validation purposes, we also aimed to evaluate these markers in an independent cohort of post-CA patients. Methods We identified 3 patients with late recovery from coma (17-37 days) following CA who recovered to functionally independent behavioral levels. We performed spectral power analyses of available EEGs during prominent burst suppression patterns (BSP) present in all 3 patients. Using identical methods, we also assessed the relationship of intraburst spectral power and outcomes in a prospectively enrolled cohort of post-CA patients. We performed chart reviews of common clinical, imaging, and EEG prognostic variables and clinical outcomes for all patients. Results All 3 patients with late recovery from coma lacked evidence of overwhelming cortical injury but demonstrated prominent BSP on EEG. Spectral analyses revealed a prominent theta (similar to 4-7Hz) feature dominating the bursts during BSP in these patients. In the prospective cohort, similar intraburst theta spectral features were evident in patients with favorable outcomes; patients with BSP and unfavorable outcomes showed either no features, transient burst features, or decreasing intraburst frequencies with time. Interpretation BSP with theta (similar to 4-7Hz) peak intraburst spectral power after CA may index a recovery potential. We discuss our results in the context of optimizing metabolic substrate availability and stimulating the corticothalamic system during recovery from prolonged post-CA coma. ANN NEUROL 2020

Chordomas are highly recurrent tumors of the midline skeleton that arise from the remnants of the notochord. The development of systemic therapy is critically important to ultimately managing this tumor. Several ongoing trials are attempting to use molecular targeted therapies for mutated pathways in recurrent and advanced chordomas and have shown promise. In addition, immunotherapies, including brachyury-directed vaccination and checkpoint inhibition, have also been attempted with encouraging results. This article discusses the major pathways that have been implicated in the pathogenesis of chordoma with an emphasis on molecular vulnerabilities that future therapies are attempting to exploit.

STARD4, a member of the evolutionarily conserved START gene family, is a soluble sterol transport protein implicated in cholesterol sensing and maintenance of cellular homeostasis. STARD4 is widely expressed and has been shown to transfer sterol between liposomes as well as organelles in cells. However, STARD4 knockout mice lack an obvious phenotype, so the overall role of STARD4 is unclear. To model long term depletion of STARD4 in cells, we use short hairpin RNA technology to stably decrease STARD4 expression in human U2OS osteosarcoma cells (STARD4-KD). We show that STARD4-KD cells display increased total cholesterol, slower cholesterol trafficking between the plasma membrane and the endocytic recycling compartment, and increased plasma membrane fluidity. These effects can all be rescued by transient expression of a short hairpin RNA-resistant STARD4 construct. Some of the cholesterol increase was due to excess storage in late endosomes or lysosomes. To understand the effects of reduced STARD4, we carried out transcriptional and lipidomic profiling of control and STARD4-KD cells. Reduction of STARD4 activates compensatory mechanisms that alter membrane composition and lipid homeostasis. Based on these observations, we propose that STARD4 functions as a critical sterol transport protein involved in sterol sensing and maintaining lipid homeostasis.

Buruli ulcer, caused by Mycobacterium ulcerans and characterized by devastating necrotizing skin lesions, is the third mycobacterial disease worldwide. The role of host genetics in susceptibility to Buruli ulcer has long been suggested. We conduct the first genome-wide association study of Buruli ulcer on a sample of 1524 well characterized patients and controls from rural Benin. Two-stage analyses identify two variants located within LncRNA genes: rs9814705 in ENSG00000240095.1 (P = 2.85 x 10(-7); odds ratio = 1.80 [1.43-2.27]), and rs76647377 in LINC01622 (P = 9.85 x 10(-8); hazard ratio = 0.41 [0.28-0.60]). Furthermore, we replicate the protective effect of allele G of a missense variant located in ATG16L1, previously shown to decrease bacterial autophagy (rs2241880, P = 0.003; odds ratio = 0.31 [0.14-0.68]). Our results suggest LncRNAs and the autophagy pathway as critical factors in the development of Buruli ulcer. Jeremy Manry, Quentin Vincent et al. report a genome-wide association study for susceptibility to Buruli ulcer in a rural population from the West African country of Benin. They identify two independently associated variants within LncRNA genes and confirm the protective effect of a missense variant in the bacterial autophagy gene ATG16L1.

BACKGROUND: Evidence of T(H)1/IFN-gamma overactivation as a major pathogenic driver somewhat conflicts with data supporting robust allergic background in patients with alopecia areata (AA). Previous investigations of immunological dysregulations show that both T(H)1- and T(H)2-related markers are overexpressed in AA. Clinical correlations in large populations may shed light on the immune pathways most likely to result in the clinical phenotype of AA. OBJECTIVE: To investigate the atopic comorbidities among patients with AA in a large population-based study. METHODS: This is a cross-sectional retrospective study of patients with AA and a matched comparison group, analyzing the associations between AA and 4 atopic comorbidities: asthma, atopic dermatitis (AD), allergic rhinitis, and allergic conjunctivitis. chi(2) and t tests were used for univariate analysis, and logistic regression model was used for multivariate analysis. The study was performed using the computerized database of the Clalit Health Services, encompassing more than 4.4 million subjects. RESULTS: The study population included 51,561 patients with AA and 51,410 matched control subjects. The prevalence of asthma (7.8% vs 6.5%; odds ratio [OR], 1.22; 95% CI, 1.17-1.28; P < .001), AD (3.9% vs 2.6%; OR, 1.55; 95% CI, 1.44-1.66; P < .001), allergic rhinitis (16.0% vs 12.8%; OR, 1.29; 95% CI, 1.25-1.34; P < .001), and allergic conjunctivitis (23.5% vs 19.6%; OR, 1.27; 95% CI, 1.23-1.30; P < .001) was significantly higher among patients with AA as compared with matched control subjects. Patients with AA also had a significantly higher probability of having more than 1 atopic comorbidity, with increasing OR as the number of concomitant atopic conditions increased. CONCLUSIONS: Our analysis supports the previous literature and provides strong generalizability of significant atopy in patients with AA, suggesting T(H)2 pathogenicity in AA, and challenging the traditional view of AA as a single-axis, T(H)1-centered disease. (C) 2020 American Academy of Allergy, Asthma & Immunology

Editor Keloids are benign growths representing a disrupted wound healing process involving abnormal collagen proliferation. Keloids are most prevalent in African American (AA)1 and Asian populations,2 and greatly impact quality of life.3 Keloids show high recurrence rates and current therapies (intralesional steroids, bleomycin, surgical excision, etc.) have limited efficacy,4 thus, presenting a high unmet need for better treatments. Genetic studies have identified chromosome variants associated with keloid formation in AAs and Asians.1, 5 A genomic profiling study on lesional and non‐lesional keloid skin from three AA patients identified bone/cartilage abnormalities,6 but did not assess inflammatory pathways. Recently, atopic dermatitis (AD) has been indicated as an independent risk factor for developing keloids.7 Increases in IL‐4 and IL‐13 receptors have been detected through laser capture microdissection in lesional keloid skin, but increases in cognate ligands were not detected.

Mixed lineage kinase 3 (MLK3), also known as MAP3K11, was initially identified in a megakaryocytic cell line and is an emerging therapeutic target in cancer, yet its role in immune cells is not known. Here, we report that loss or pharmacological inhibition of MLK3 promotes activation and cytotoxicity of T cells. MLK3 is abundantly expressed in T cells, and its loss alters serum chemokines, cytokines, and CD28 protein expression on T cells and its subsets. MLK3 loss or pharmacological inhibition induces activation of T cells in in vitro, ex vivo, and in vivo conditions, irrespective of T cell activating agents. Conversely, overexpression of MLK3 decreases T cell activation. Mechanistically, loss or inhibition of MLK3 down-regulates expression of a prolyl-isomerase, Ppia, which is directly phosphorylated by MLK3 to increase its isomerase activity. Moreover, MLK3 also phosphorylates nuclear factor of activated T cells 1 (NFATc1) and regulates its nuclear translocation via interaction with Ppia, and this regulates T cell effector function. In an immune-competent mouse model of breast cancer, MLK3 inhibitor increases Granzyme B-positive CD8(+) T cells and decreases MLK3 and Ppia gene expression in tumor-infiltrating T cells. Likewise, the MLK3 inhibitor in pan T cells, isolated from breast cancer patients, also increases cytotoxic CD8(+) T cells. These results collectively demonstrate that MLK3 plays an important role in T cell biology, and targeting MLK3 could serve as a potential therapeutic intervention via increasing T cell cytotoxicity in cancer.