HLA A*24:02-restricted T cell receptors cross-recognize bacterial and preproinsulin peptides in type 1 diabetes.

CD8+ T cells destroy insulin-producing pancreatic β cells in type 1 diabetes through HLA class I-restricted presentation of self-antigens. Combinatorial peptide library screening was used to produce a preferred peptide recognition landscape for a patient-derived T cell receptor (TCR) that recognized the preproinsulin-derived (PPI-derived) peptide sequence LWMRLLPLL in the context of disease risk allele HLA A*24:02. Data were used to generate a strong superagonist peptide, enabling production of an autoimmune HLA A*24:02-peptide-TCR structure by crystal seeding.

High-affinity CD8 variants enhance the sensitivity of pMHCI antigen recognition via low-affinity TCRs.

CD8 T cell-mediated recognition of peptide-major histocompatibility complex class I (pMHCI) molecules involves cooperative binding of the T cell receptor (TCR), which confers antigen specificity, and the CD8 coreceptor, which stabilizes the TCR/pMHCI complex. Earlier work has shown that the sensitivity of antigen recognition can be regulated in vitro by altering the strength of the pMHCI/CD8 interaction. Here, we characterized two CD8 variants with moderately enhanced affinities for pMHCI, aiming to boost antigen sensitivity without inducing non-specific activation.

Albumin-mediated extracellular zinc speciation drives cellular zinc uptake.

The role of the extracellular medium in influencing metal uptake into cells has not been described quantitatively. In a chemically-defined model system containing albumin, zinc influx into endothelial cells correlates with the extracellular free zinc concentration. Allosteric inhibition of zinc-binding to albumin by free fatty acids increased zinc flux.

CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor.

CD8 T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8.

GPU-Accelerated Discovery of Pathogen-Derived Molecular Mimics of a T-Cell Insulin Epitope.

The strong links between (Human Leukocyte Antigen) HLA, infection and autoimmunity combine to implicate T-cells as primary triggers of autoimmune disease (AD). T-cell crossreactivity between microbially-derived peptides and self-peptides has been shown to break tolerance and trigger AD in experimental animal models. Detailed examination of the potential for T-cell crossreactivity to trigger human AD will require means of predicting which peptides might be recognised by autoimmune T-cell receptors (TCRs).

Beholding the cosmos: Huygens' and the latter-day Copernicans.

Christiaan Huygens, a founding father of modern physics and astronomy, speculated on extraterrestrial life toward the end of his life. Some of his speculations now seem quaint or naïve, but in other respects, Huygens was admirably enlightened. Huygens' thought was permeated by Copernicanism and the associated way of thinking that may be termed the principle of indifference.

Computational physiology of uterine smooth muscle.

Pregnancy can be accompanied by serious health risks to mother and child, such as pre-eclampsia, premature birth and postpartum haemorrhage. Understanding of the normal physiology of uterine function is essential to an improved management of such risks. Here we focus on the physiology of the smooth muscle fibres which make up the bulk of the uterine wall and which generate the forceful contractions that accompany parturition.

On a general theoretical foundation for endocrinology.

Hormones are messenger molecules that distribute across all tissues and thus operate on the whole-organism level. Moreover, a given hormone typically affects a number of different biological processes. As such, hormones coordinate concerted cooperation between the cells and tissues of an organism, a phenomenon that has been termed 'organismal harmony'.

Occam's razor: from Ockham's to modern data science.

The principle of parsimony, also known as 'Occam's razor', is a heuristic dictum that is thoroughly familiar to virtually all practitioners of science: Aristotle, Newton, and many others have enunciated it in some form or other. Even though the principle is not difficult to comprehend as a general heuristic guideline, it has proved surprisingly resistant to being put on a rigorous footing - a difficulty that has become more pressing and topical with the 'big data' explosion. We review the significance of Occam's razor in the philosophical and theological writings of William of Ockham, and survey modern developments of parsimony in data science.

Identification of uterine pacemaker regions at the myometrial-placental interface in the rat.

Key Points: Coordinated contraction of the uterine smooth muscle is essential to parturition. Histologically and physiologically defined pacemaker structures have not been identified in uterine smooth muscle. Here we report combined electrophysiological and histological evidence of zones associated with pacemaker activity in the rat myometrium.

Darwin endures, despite disparagement.

Evolution lies at the heart of the life sciences, and Charles Darwin is a towering historical figure within evolutionary science. One testimony to his lasting influence is that declaring Darwin to have been wrong all along remains a provocative way to command attention. The present paper discusses various strands of 'Darwin was wrong' partisans and their divergent views and motives: some are looking to Darwin to justify or condemn the political ideologies that they support or reject; others are concerned with the corrupting influence that the bleak cosmic outlook of evolution is deemed to exert on the moral or religious rectitude of impressionable minds, or regard Darwinism as a direct assault on religion; philosophers question the very coherence of the entire enterprise; and certain biologists aspire to go down in history as even greater than Darwin.

Mathematical models of microbial growth and metabolism: a whole-organism perspective.

We review the principles underpinning the development of mathematical models of the metabolic activities of micro-organisms. Such models are important to understand and chart the substantial contributions made by micro-organisms to geochemical cycles, and also to optimise the performance of bioreactors that exploit the biochemical capabilities of these organisms. We advocate an approach based on the principle of dynamic allocation.

X makes nine: a distant ice giant in the solar system.

Ever since Pluto lost its status as one of the main planets of our solar system and was demoted to just another frozen denizen of the Kuiper belt, we have had to make do with eight, albeit in a pleasing symmetry, with four rocky ones this side of the asteroid belt and four giants on the far side. Now it looks like number nine is back on the slate: the existence of a large planet, about ten times as massive as Earth and hundreds of times more distant from the Sun than Earth itself, has been postulated to explain the curiously bunched-up orbits of several small celestial bodies, far beyond the orbit of Neptune. To date, we have only "proof by simulation" and we are yet to observe this massive planet in the backyard of our solar system by more direct means.

Beyond the Discovery Void: New targets for antibacterial compounds.

Antibiotics save many lives, but their efficacy is under threat: overprescription, population growth, and global travel all contribute to the rapid origination and spread of resistant strains. Exacerbating this threat is the fact that no new major classes of antibiotics have been discovered in the last 30 years: this is the "discovery void." We discuss the traditional molecular targets of antibiotics as well as putative novel targets.

Inceptions of biomathematics from Lotka to Thom.

Mathematical biology occupies a special place at the interface between the physical, mathematical and life sciences. Is this interface merely a meeting point for dabblers venturing out of their own proper domains to work on problems of mutual interest? Or is it an incipient science in its own right, with its own particular character, principles, and practices? The past century has seen vast advances in the application of mathematical and physical ideas and techniques to biological problems, in the process transforming many of them almost beyond recognition. Nonetheless, the question of a biomathematics as a new kind of science remains open, despite several fascinating, if sometimes problematic, attempts.

Optimal management of nutrient reserves in microorganisms under time-varying environmental conditions.

Intracellular reserves are a conspicuous feature of many bacteria; such internal stores are often present in the form of inclusions in which polymeric storage compounds are accumulated. Such reserves tend to increase in times of plenty and be used up in times of scarcity. Mathematical models that describe the dynamical nature of reserve build-up and use are known as "cell quota," "dynamic energy/nutrient budget," or "variable-internal-stores" models.

A computational method for three-dimensional reconstruction of the microarchitecture of myometrial smooth muscle from histological sections.

Background: The fibrous structure of the myometrium has previously been characterised at high resolutions in small tissue samples (< 100 mm3) and at low resolutions (∼500 μm per voxel edge) in whole-organ reconstructions. However, no high-resolution visualisation of the myometrium at the organ level has previously been attained.

Methods And Results: We have developed a technique to reconstruct the whole myometrium from serial histological slides, at a resolution of approximately 50 μm per voxel edge.

Structural Mechanism Underpinning Cross-reactivity of a CD8+ T-cell Clone That Recognizes a Peptide Derived from Human Telomerase Reverse Transcriptase.

T-cell cross-reactivity is essential for effective immune surveillance but has also been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focused antigen binding involving contact with more peptide residues.

Targeted suppression of autoreactive CD8 T-cell activation using blocking anti-CD8 antibodies.

CD8 T-cells play a role in the pathogenesis of autoimmune diseases such as multiple sclerosis and type 1 diabetes. However, drugs that target the entire CD8 T-cell population are not desirable because the associated lack of specificity can lead to unwanted consequences, most notably an enhanced susceptibility to infection. Here, we show that autoreactive CD8 T-cells are highly dependent on CD8 for ligand-induced activation via the T-cell receptor (TCR).

CD8 T-cell specificity is compromised at a defined MHCI/CD8 affinity threshold.

The CD8 co-receptor engages peptide-major histocompatibility complex class I (pMHCI) molecules at a largely invariant site distinct from the T-cell receptor (TCR)-binding platform and enhances the sensitivity of antigen-driven activation to promote effective CD8 T-cell immunity. A small increase in the strength of the pMHCI/CD8 interaction (~1.5-fold) can disproportionately amplify this effect, boosting antigen sensitivity by up to two orders of magnitude.

Variable-Internal-Stores models of microbial growth and metabolism with dynamic allocation of cellular resources.

Variable-Internal-Stores models of microbial metabolism and growth have proven to be invaluable in accounting for changes in cellular composition as microbial cells adapt to varying conditions of nutrient availability. Here, such a model is extended with explicit allocation of molecular building blocks among various types of catalytic machinery. Such an extension allows a reconstruction of the regulatory rules employed by the cell as it adapts its physiology to changing environmental conditions.

Reconstruction of Cell Surface Densities of Ion Pumps, Exchangers, and Channels from mRNA Expression, Conductance Kinetics, Whole-Cell Calcium, and Current-Clamp Voltage Recordings, with an Application to Human Uterine Smooth Muscle Cells.

Uterine smooth muscle cells remain quiescent throughout most of gestation, only generating spontaneous action potentials immediately prior to, and during, labor. This study presents a method that combines transcriptomics with biophysical recordings to characterise the conductance repertoire of these cells, the 'conductance repertoire' being the total complement of ion channels and transporters expressed by an electrically active cell. Transcriptomic analysis provides a set of potential electrogenic entities, of which the conductance repertoire is a subset.

Identification of human viral protein-derived ligands recognized by individual MHCI-restricted T-cell receptors.

Evidence indicates that autoimmunity can be triggered by virus-specific CD8(+) T cells that crossreact with self-derived peptide epitopes presented on the cell surface by major histocompatibility complex class I (MHCI) molecules. Identification of the associated viral pathogens is challenging because individual T-cell receptors can potentially recognize up to a million different peptides. Here, we generate peptide length-matched combinatorial peptide library (CPL) scan data for a panel of virus-specific CD8(+) T-cell clones spanning different restriction elements and a range of epitope lengths.