Dynamic adoption of anergy by antigen-exhausted CD4+ T cells

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A quaternary anti-cholinesterase probe for determining the integrity of the blood--brain barrier

7-(Methylethoxyphosphinyloxy)-1-methyl quinolinium iodide (MEPQ), a new quaternary anti-cholinesterase (anti-ChE) compound was prepared and evaluated as a potential probe for assessing changes in the blood-brain barrier (B-BB) permeability. MEPQ was found to be 170 times more potent in its cholinesterase inhibitory activity than phospholine iodide, a previously reported anti-ChE probe in B-BB research. In rats and mice with impaired B-BB induced by osmotic opening, MEPQ readily penetrated through the damaged site as demonstrated by considerable reduction of ChE activity. In controls, brain ChE activity remained unaffected. It is suggested that MEPQ is a useful probe for both qualitative (histological staining) and quantitative (brain homogenated) assessment of permeability changes in the B-BB.     

Deciphering the Palimpsest: Studying the Relationship Between Morphological Integration and Phenotypic Covariation

Organisms represent a complex arrangement of anatomical structures and individuated parts that must maintain functional associations through development. This integration of variation between functionally related body parts and the modular organization of development are fundamental determinants of their evolvability. This is because integration results in the expression of coordinated variation that can create preferred directions for evolutionary change, while modularity enables variation in a group of traits or regions to accumulate without deleterious effects on other aspects of the organism. Using our own work on both model systems (e.g., lab mice, avians) and natural populations of rodents and primates, we explore in this paper the relationship between patterns of phenotypic covariation and the developmental determinants of integration that those patterns are assumed to reflect. We show that integration cannot be reliably studied through phenotypic covariance patterns alone and argue that the relationship between phenotypic covariation and integration is obscured in two ways. One is the superimposition of multiple determinants of covariance in complex systems and the other is the dependence of covariation structure on variances in covariance-generating processes. As a consequence, we argue that the direct study of the developmental determinants of integration in model systems is necessary to fully interpret patterns of covariation in natural populations, to link covariation patterns to the processes that generate them, and to understand their significance for evolutionary explanation.     

A COMPARISON OF COVARIANCE STRUCTURE IN WILD AND LABORATORY MUROID CRANIA

Mutations have the ability to produce dramatic changes to covariance structure by altering the variance of covariance-generating developmental processes. Several evolutionary mechanisms exist that may be acting interdependently to stabilize covariance structure, despite this developmental potential for variation within species. We explore covariance structure in the crania of laboratory mouse mutants exhibiting mild-to-significant developmental perturbations of the cranium, and contrast it with covariance structure in related wild muroid taxa. Phenotypic covariance structure is conserved among wild muroidea, but highly variable and mutation-dependent within the laboratory group. We show that covariance structures in natural populations of related species occupy a more restricted portion of covariance structure space than do the covariance structures resulting from single mutations of significant effect or the almost nonexistent genetic differences that separate inbred mouse strains. Our results suggest that developmental constraint is not the primary mechanism acting to stabilize covariance structure, and imply a more important role for other mechanisms.     

Biomechanical adaptation of ulnar cross-sectional morphology in brachiating primates

The forelimbs of hylobatids (gibbons and siamang) are distinctive among tetrapods in that they are loaded in overall tension during normal locomotion. While hylobatid ulnae must also encounter bending stresses in the course of their full range of locomotor behavior, their loading regime differs from that of quadrupedal anthropoids in that these bending stresses are distributed evenly along the bone, are not exerted in a preferred plane, and are probably of generally lower magnitude. This study examines the degree to which hylobatid ulnae are adapted to this suspensory loading regime. We obtained cross-sections of ulnae at various increments along the length of the bone using CAT scans. The sample comprises 476 cross-sections representing the ulnae of 25 individuals from five species of comparable body size. We show that in gibbons and siamang, the patterning of ulnar cross-sectional area and resistance to bending in the dorsoventral plane along the ulnar diaphysis differ from that of similarly sized quadrupedal anthropoids in the manner predicted by a suspensory loading regime. We also find the same pattern for the ulnae of Ateles, whose loading regime may be fairly similar to that of hylobatids. However, we find that the cross-sectional shape of the ulnar diaphysis in hylobatids and Ateles does not differ from that of quadrupedal monkeys in the manner predicted by a suspensory loading regime. © 1995 Wiley-Liss, Inc.     

Primidone blocks RIPK1-driven cell death and inflammation

The receptor-interacting serine/threonine protein kinase 1 (RIPK1) is a key mediator of regulated cell death and inflammation. Recent studies suggest that RIPK1 inhibition would fundamentally improve the therapy of RIPK1-dependent organ damage in stroke, myocardial infarction, kidney failure, and systemic inflammatory response syndrome. Additionally, it could ameliorate or prevent multi-organ failure induced by cytokine release in the context of hyperinflammation, as seen in COVID-19 patients. Therefore, we searched for a RIPK1 inhibitor and present the aromatic antiepileptic and FDA-approved drug primidone (Liskantin®) as a potent inhibitor of RIPK1 activation in vitro and in a murine model of TNFα-induced shock, which mimics the hyperinflammatory state of cytokine release syndrome. Furthermore, we detected for the first time RIPK1 activation in the respiratory tract epithelium of hospitalized patients who tested positive for SARS-CoV-2 infection. Our data provide a strong rationale for evaluating the drug primidone in conditions of hyperinflammation in humans.Subject terms: Cell death and immune response, Translational research     

The dominantly expressed class II molecule from a resistant MHC haplotype presents only a few Marek’s disease virus peptides by using an unprecedented binding motif

Viral diseases pose major threats to humans and other animals, including the billions of chickens that are an important food source as well as a public health concern due to zoonotic pathogens. Unlike humans and other typical mammals, the major histocompatibility complex (MHC) of chickens can confer decisive resistance or susceptibility to many viral diseases. An iconic example is Marek’s disease, caused by an oncogenic herpesvirus with over 100 genes. Classical MHC class I and class II molecules present antigenic peptides to T lymphocytes, and it has been hard to understand how such MHC molecules could be involved in susceptibility to Marek’s disease, given the potential number of peptides from over 100 genes. We used a new in vitro infection system and immunopeptidomics to determine peptide motifs for the 2 class II molecules expressed by the MHC haplotype B2, which is known to confer resistance to Marek’s disease. Surprisingly, we found that the vast majority of viral peptide epitopes presented by chicken class II molecules arise from only 4 viral genes, nearly all having the peptide motif for BL2*02, the dominantly expressed class II molecule in chickens. We expressed BL2*02 linked to several Marek’s disease virus (MDV) peptides and determined one X-ray crystal structure, showing how a single small amino acid in the binding site causes a crinkle in the peptide, leading to a core binding peptide of 10 amino acids, compared to the 9 amino acids in all other reported class II molecules. The limited number of potential T cell epitopes from such a complex virus can explain the differential MHC-determined resistance to MDV, but raises questions of mechanism and opportunities for vaccine targets in this important food species, as well as providing a basis for understanding class II molecules in other species including humans.

This study shows that chicken MHC class II molecules present peptides from only a handful of the more than 100 genes of the oncogenic herpesvirus Marek’s disease virus, explaining the strong genetic association of chicken MHC with resistance and susceptibility to this and other economically-important pathogens.