Gene and protein sequence features augment HLA class I ligand predictions.

The sensitivity of malignant tissues to T cell-based immunotherapies depends on the presence of targetable human leukocyte antigen (HLA) class I ligands. Peptide-intrinsic factors, such as HLA class I affinity and proteasomal processing, have been established as determinants of HLA ligand presentation. However, the role of gene and protein sequence features as determinants of epitope presentation has not been systematically evaluated. We perform HLA ligandome mass spectrometry to evaluate the contribution of 7,135 gene and protein sequence features to HLA sampling. This analysis reveals that a number of predicted modifiers of mRNA and protein abundance and turnover, including predicted mRNA methylation and protein ubiquitination sites, inform on the presence of HLA ligands. Importantly, integration of such "hard-coded" sequence features into a machine learning approach augments HLA ligand predictions to a comparable degree as experimental measures of gene expression. Our study highlights the value of gene and protein features for HLA ligand predictions.

Collagen Induces Anisotropy in Fingertip Subcutaneous Tissues During Contact.

The subcutaneous mechanical response of the fingertip is highly anisotropic due to the presence of a network of collagen fibers linking the outer skin layer to the bone. The impact of this anisotropy on the fingerpad deformation, which had not been studied until now, is here demonstrated using a two-dimensional finite element model of a transverse section of the finger. Different distributions of fiber orientations are considered: radial (physiologic), circumferential, and random (isotropic). The three variants of the model are assessed using experimental observations of a finger pressed on a flat surface. Predictions relying on the physiological orientation of fibers best reproduce experimental trends. Our results show that the orientation of fibers significantly influences the distribution of internal strains and stresses. This leads to a sudden change in the profile of contact pressure when transitioning from sticking to slipping. Interpreted in terms of tactile perception or sensation, these variations might represent important sensory cues for partial slip detection. This is also valuable information for the development of haptic devices.

Magnetic anisotropy engineering in onion-structured metal oxide nanoparticles combining dual exchange coupling and proximity effects.

A series of exchange-coupled magnetic nanoparticles combining several magnetic phases in an onion-type structure were synthesized by performing a three-step seed-mediated growth process. Iron and cobalt precursors were alternatively decomposed in high-boiling-temperature solvents (288-310 °C) to successively grow CoO and Fe3-δO4 shells (the latter in three stages) on the surface of Fe3-δO4 seeds. The structure and chemical composition of these nanoparticles were investigated in depth by combining a wide panel of advanced techniques, such as scanning transmission electron microscopy (STEM), electron energy-loss spectroscopy-spectrum imaging (EELS-SI), 57Fe Mössbauer spectrometry, and X-ray circular magnetic dichroism (XMCD) techniques. The size of the nanoparticles increased progressively after each thermal decomposition step, but the crystal structure of core-shell nanoparticles was significantly modified during the growth of the second shell. Indeed, the antiferromagnetic CoO phase was progressively replaced by the CoFe2O4 ferrimagnet due to the concomitant processes of partial solubilization/crystallization and the interfacial cationic diffusion of iron. A much more complex chemical structure than that suggested by a simple size variation of the nanoparticles is thus proposed, namely Fe3-δO4@CoO-CoFe2O4@Fe3-δO4, where an intermediate Co-based layer was shown to progressively become a single, hybrid magnetic phase (attributed to proximity effects) with a reduction in the CoO amount. In turn, the dual exchange-coupling of this hybrid Co-based intermediate layer (with high anisotropy and ordering temperature) with the surrounding ferrite (core and outer shells) stabilized the particle moment well above room temperature. These effects allow for the production of Fe oxide-based magnetic nanoparticles with high effective anisotropy, thus revealing the potential of this strategy to design rare-earth-free permanent nanomagnets at room temperature.

Open-Source Instrumented Object to Study Dexterous Object Manipulation.

Humans use tactile feedback to perform skillful manipulation. When tactile sensory feedback is unavailable, for instance, if the fingers are anesthetized, dexterity is severely impaired. Imaging the deformation of the finger pad skin when in contact with a transparent plate provides information about the tactile feedback received by the central nervous system. Indeed, skin deformations are transduced into neural signals by the mechanoreceptors of the finger pad skin. Understanding how this feedback is used for active object manipulation would improve our understanding of human dexterity. In this paper, we present a new device for imaging the skin of the finger pad of one finger during manipulation performed with a precision grip. The device's mass (300 g) makes it easy to use during unconstrained dexterous manipulation. Using this device, we reproduced the experiment performed in Delhaye et al. (2021) We extracted the strains aligned with the object's movement, i.e., the vertical strains in the ulnar and radial parts of the fingerpad, to see how correlated they were with the grip force (GF) adaptation. Interestingly, parts of our results differed from those in Delhaye et al. (2021) due to weight and inertia differences between the devices, with average GF across participants differing significantly. Our results highlight a large variability in the behavior of the skin across participants, with generally low correlations between strain and GF adjustments, suggesting that skin deformations are not the primary driver of GF adaptation in this manipulation scenario.

Fast grip force adaptation to friction relies on localized fingerpad strains.

During object manipulation, humans adjust the grip force to friction, such that slippery objects are squeezed more firmly than sticky ones. This essential mechanism to keep a stable grasp relies on feedback from tactile afferents innervating the fingertips, that are sensitive to local skin strains. To test if this feedback originates from the skin-object interface, we asked participants to perform a grip-lift task with an instrumented object able to monitor skin strains at the contact through transparent plates of different frictions. We observed that, following an unbeknown change in plate across trials, participants adapted their grip force to friction. After switching from high to low friction, we found a significant increase in strain inside the contact arising ~100 ms before the modulation of grip force, suggesting that differences in strain patterns before lift-off are used by the nervous system to quickly adjust the force to the frictional properties of manipulated objects.

The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function.

2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in cluster of differentiation (CD)8+ T cell biology, where we find they have highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific α-ketoglutarate (αKG)-dependent enzymes. Treatment of CD8+ T cells with exogenous S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo and enhanced anti-tumor activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.

A haptic illusion created by gravity.

Human dexterity requires very fine and efficient control of fingertip forces, which relies on the integration of cutaneous and proprioceptive feedback. Here, we examined the influence of gravity on isometric force control. We trained participants to reproduce isometric vertical forces on a dynamometer held between the thumb and the index finger in normal gravity and tested them during parabolic flight creating phases of microgravity and hypergravity, thereby strongly influencing the motor commands and the proprioceptive feedback. We found that gravity creates the illusion that upward forces are larger than downward forces of the same magnitude. The illusion increased under hypergravity and was abolished under microgravity. Gravity also affected the control of the grip force employed to secure the grasp. These findings suggest that gravity biases the haptic estimation of forces, which has implications for the design of haptic devices to be used during flight or space activities.

Re-use of laboratory utensils reduces CO2 equivalent footprint and running costs.

Laboratory-based research is resource intensive in terms of financial costs and its carbon footprint. Research laboratories require immense amounts of energy to power equipment, as well as large volumes of materials, particularly of single-use item consumption. In fact, many laboratories have essentially become reliant on single-use plastics. Understanding the full carbon footprint of consumable usage is increasingly important as many research institutes commit to carbon neutrality. To date, no carbon footprint assessment has been conducted to detail the differences between single-use plastics, and reusable glass in a laboratory setting. Here, we analyse the CO2 equivalent (CO2e) footprint of utilising single-use plastics, and re-use of glass or plastic items within laboratory environments. We focused our assessment on four commonly utilised consumables for mammalian cell and bacterial culture, and found that re-use scenarios resulted in substantial reduction in CO2e footprint up to 11-fold. In addition, we estimated the long-term financial costs of re-use and single-use scenarios, and found that re-use had either similar or much lower running costs even when including technical staff wage. We concluded that research facilities must foster re-use in laboratory consumables, while reserving single-use items for select, defined cases. Our study highlights the need to account for indirect CO2e footprint in designing a carbon-neutral lab and promotes circular economy principles.

Biomechanics of the finger pad in response to torsion.

Surface skin deformation of the finger pad during partial slippage at finger-object interfaces elicits firing of the tactile sensory afferents. A torque around the contact normal is often present during object manipulation, which can cause partial rotational slippage. Until now, studies of surface skin deformation have used stimuli sliding rectilinearly and tangentially to the skin. Here, we study surface skin dynamics under pure torsion of the right index finger of seven adult participants (four males). A custom robotic platform stimulated the finger pad with a flat clean glass surface, controlling the normal forces and rotation speeds applied while monitoring the contact interface using optical imaging. We tested normal forces between 0.5 N and 10 N at a fixed angular velocity of 20° s-1 and angular velocities between 5° s-1 and 100° s-1 at a fixed normal force of 2 N. We observe the characteristic pattern by which partial slips develop, starting at the periphery of the contact and propagating towards its centre, and the resulting surface strains. The 20-fold range of normal forces and angular velocities used highlights the effect of those parameters on the resulting torque and skin strains. Increasing normal force increases the contact area, the generated torque, strains and the twist angle required to reach full slip. On the other hand, increasing angular velocity causes more loss of contact at the periphery and higher strain rates (although it has no impact on resulting strains after the full rotation). We also discuss the surprisingly large inter-individual variability in skin biomechanics, notably observed in the twist angle the stimulus needs to rotate before reaching full slip.

Time-dependent regulation of cytokine production by RNA binding proteins defines T cell effector function.

Potent T cell responses against infections and malignancies require a rapid yet tightly regulated production of toxic effector molecules. Their production level is defined by post-transcriptional events at 3' untranslated regions (3' UTRs). RNA binding proteins (RBPs) are key regulators in this process. With an RNA aptamer-based capture assay, we identify >130 RBPs interacting with IFNG, TNF, and IL2 3' UTRs in human T cells. RBP-RNA interactions show plasticity upon T cell activation. Furthermore, we uncover the intricate and time-dependent regulation of cytokine production by RBPs: whereas HuR supports early cytokine production, ZFP36L1, ATXN2L, and ZC3HAV1 dampen and shorten the production duration, each at different time points. Strikingly, even though ZFP36L1 deletion does not rescue the dysfunctional phenotype, tumor-infiltrating T cells produce more cytokines and cytotoxic molecules, resulting in superior anti-tumoral T cell responses. Our findings thus show that identifying RBP-RNA interactions reveals key modulators of T cell responses in health and disease.

The relationship of mRNA with protein expression in CD8+ T cells associates with gene class and gene characteristics.

T cells are key players in our defence against infections and malignancies. When T cells differentiate or become activated, they undergo substantial alterations in gene expression. Even though RNA expression levels are now well documented throughout different stages of T cells, it is not well understood how mRNA expression translates into the protein landscape. By combining paired RNA sequencing and mass spectrometry data of primary human CD8+ T cells, we report that mRNA expression is a poor proxy for the overall protein output, irrespective of the differentiation or activation status. Yet, gene class stratification revealed a function-specific correlation of mRNA with protein expression. This gene class-specific expression pattern associated with differences in gene characteristics such as sequence conservation and untranslated region (UTR) lengths. In addition, the presence of AU-rich elements in the 3'UTR associated with alterations in mRNA and protein abundance T cell activation dependent, gene class-specific manner. In conclusion, our study highlights the role of gene characteristics as a determinant for gene expression in T cells.

Crossover From Individual to Collective Magnetism in Dense Nanoparticle Systems: Local Anisotropy Versus Dipolar Interactions.

Dense systems of magnetic nanoparticles may exhibit dipolar collective behavior. However, two fundamental questions remain unsolved: i) whether the transition temperature may be affected by the particle anisotropy or it is essentially determined by the intensity of the interparticle dipolar interactions, and ii) what is the minimum ratio of dipole-dipole interaction (Edd ) to nanoparticle anisotropy (Kef V, anisotropy⋅volume) energies necessary to crossover from individual to collective behavior. A series of particle assemblies with similarly intense dipolar interactions but widely varying anisotropy is studied. The Kef  is tuned through different degrees of cobalt-doping in maghemite nanoparticles, resulting in a variation of nearly an order of magnitude. All the bare particle compacts display collective behavior, except the one made with the highest anisotropy particles, which presents "marginal" features. Thus, a threshold of Kef V/Edd  ≈ 130 to suppress collective behavior is derived, in good agreement with Monte Carlo simulations. This translates into a crossover value of ≈1.7 for the easily accessible parameter TMAX (interacting)/TMAX (non-interacting) (ratio of the peak temperatures of the zero-field-cooled magnetization curves of interacting and dilute particle systems), which is successfully tested against the literature to predict the individual-like/collective behavior of any given interacting particle assembly comprising relatively uniform particles.

Circular RNAs exhibit limited evidence for translation, or translation regulation of the mRNA counterpart in terminal hematopoiesis.

Each day, about 1012 erythrocytes and platelets are released into the bloodstream. This substantial output from hematopoietic stem cells is tightly regulated by transcriptional and epigenetic factors. Whether and how circular RNAs (circRNAs) contribute to the differentiation and/or identity of hematopoietic cells is to date not known. We recently reported that erythrocytes and platelets contain the highest levels and numbers of circRNAs among hematopoietic cells. Here, we provide the first detailed analysis of circRNA expression during erythroid and megakaryoid differentiation. CircRNA expression not only significantly increased upon enucleation, but also had limited overlap between progenitor cells and mature cells, suggesting that circRNA expression stems from regulated processes rather than resulting from mere accumulation. To study circRNA function in hematopoiesis, we first compared the expression levels of circRNAs with the translation efficiency of their mRNA counterpart. We found that only one out of 2531 (0.04%) circRNAs associated with mRNA-translation regulation. Furthermore, irrespective of thousands of identified putative open reading frames, deep ribosome-footprinting sequencing, and mass spectrometry analysis provided little evidence for translation of endogenously expressed circRNAs. In conclusion, circRNAs alter their expression profile during terminal hematopoietic differentiation, yet their contribution to regulate cellular processes remains enigmatic.

Grip Force is Adjusted at a Level That Maintains an Upper Bound on Partial Slip Across Friction Conditions During Object Manipulation.

Dexterous manipulation of objects heavily relies on the feedback provided by the tactile afferents innervating the fingertips. Previous studies have suggested that humans might take advantage of partial slip, localized loss of grip between the skin and the object, to gauge the stability of a contact and react appropriately when it is compromised, that is, when slippage is about to happen. To test this hypothesis, we asked participants to perform point-to-point movements using a manipulandum. Through optical imaging, the device monitored partial slip at the contact interface, and at the same time, the forces exerted by the fingers. The level of friction of the contact material was changed every five trials. We found that the level of grip force was systematically adjusted to the level of friction, and thus partial slip was limited to an amount similar across friction conditions. We suggest that partial slip is a key signal for dexterous manipulation and that the grip force is regulated to continuously maintain an upper bound on partial slip across friction conditions.

RNA-Binding Protein Expression Alters Upon Differentiation of Human B Cells and T Cells.

B cells and T cells are key players in the defence against infections and malignancies. To exert their function, B cells and T cells differentiate into effector and memory cells. Tight regulation of these differentiation processes is key to prevent their malfunction, which can result in life-threatening disease. Lymphocyte differentiation relies on the appropriate timing and dosage of regulatory molecules, and post-transcriptional gene regulation (PTR) is a key player herein. PTR includes the regulation through RNA-binding proteins (RBPs), which control the fate of RNA and its translation into proteins. To date, a comprehensive overview of the RBP expression throughout lymphocyte differentiation is lacking. Using transcriptome and proteome analyses, we here catalogued the RBP expression for human B cells and T cells. We observed that even though the overall RBP expression is conserved, the relative RBP expression is distinct between B cells and T cells. Differentiation into effector and memory cells alters the RBP expression, resulting into preferential expression of different classes of RBPs. For instance, whereas naive T cells express high levels of translation-regulating RBPs, effector T cells preferentially express RBPs that modulate mRNA stability. Lastly, we found that cytotoxic CD8+ and CD4+ T cells express a common RBP repertoire. Combined, our study reveals a cell type-specific and differentiation-dependent RBP expression landscape in human lymphocytes, which will help unravel the role of RBPs in lymphocyte function.

CD29 Enriches for Cytotoxic Human CD4+ T Cells.

CD4+ T cells are key contributors in the induction of adaptive immune responses against pathogens. Even though CD4+ T cells are primarily classified as noncytotoxic helper T cells, it has become appreciated that a subset of CD4+ T cells is cytotoxic. However, tools to identify these cytotoxic CD4+ T cells are lacking. We recently showed that CD29 (integrin ß1, ITGB1) expression on human CD8+ T cells enriches for the most potent cytotoxic T cells. In this study, we questioned whether CD29 expression also associates with cytotoxic CD4+ T cells. We show that human peripheral blood-derived CD29hiCD4+ T cells display a cytotoxic gene expression profile, which closely resembles that of CD29hi cytotoxic CD8+ T cells. This CD29hi cytotoxic phenotype was observed ex vivo and was maintained in in vitro cultures. CD29 expression enriched for CD4+ T cells, which effectively produced the proinflammatory cytokines IFN-γ, IL-2, and TNF-α, and cytotoxic molecules. Lastly, CD29-expressing CD4+ T cells transduced with a MART1-specific TCR showed target cell killing in vitro. In conclusion, we demonstrate in this study that CD29 can be employed to enrich for cytotoxic human CD4+ T cells.

Sequence determinants as key regulators in gene expression of T cells.

T cell homeostasis, T cell differentiation, and T cell effector function rely on the constant fine-tuning of gene expression. To alter the T cell state, substantial remodeling of the proteome is required. This remodeling depends on the intricate interplay of regulatory mechanisms, including post-transcriptional gene regulation. In this review, we discuss how the sequence of a transcript influences these post-transcriptional events. In particular, we review how sequence determinants such as sequence conservation, GC content, and chemical modifications define the levels of the mRNA and the protein in a T cell. We describe the effect of different forms of alternative splicing on mRNA expression and protein production, and their effect on subcellular localization. In addition, we discuss the role of sequences and structures as binding hubs for miRNAs and RNA-binding proteins in T cells. The review thus highlights how the intimate interplay of post-transcriptional mechanisms dictate cellular fate decisions in T cells.

Measuring fingerpad deformation during active object manipulation.

During active object manipulation, the finger-object interactions give rise to complex fingertip skin deformations. These deformations are in turn encoded by the local tactile afferents and provide rich and behaviorally relevant information to the central nervous system. Most of the work studying the mechanical response of the finger to dynamic loading has been performed under a passive setup, thereby precisely controlling the kinematics or the dynamics of the loading. However, to identify aspects of the deformations that are relevant to online control during object manipulation, it is desirable to measure the skin response in an active setup. To that end, we developed a device that allows us to monitor finger forces, skin deformations, and kinematics during fine manipulation. We describe the device in detail and test it to precisely describe how the fingertip skin in contact with the object deforms during a simple vertical oscillation task. We show that the level of grip force directly influences the fingerpad skin strains and that the strain rates are substantial during active manipulation (norm up to 100%/s). The developed setup will enable us to causally relate sensory information, i.e. skin deformation, to online control, i.e. grip force adjustment, in future studies.NEW & NOTEWORTHY We present a novel device, a manipulandum, that enables to image the contact between the finger and the contact surface during active manipulation of the device. The device is tested in a simple vertical oscillation task involving 18 participants. We demonstrate that substantial surface skin strains take place at the finger-object interface and argue that those deformations provide essential information for grasp stability during object manipulation.

Climate signals in river flood damages emerge under sound regional disaggregation.

Climate change affects precipitation patterns. Here, we investigate whether its signals are already detectable in reported river flood damages. We develop an empirical model to reconstruct observed damages and quantify the contributions of climate and socio-economic drivers to observed trends. We show that, on the level of nine world regions, trends in damages are dominated by increasing exposure and modulated by changes in vulnerability, while climate-induced trends are comparably small and mostly statistically insignificant, with the exception of South & Sub-Saharan Africa and Eastern Asia. However, when disaggregating the world regions into subregions based on river-basins with homogenous historical discharge trends, climate contributions to damages become statistically significant globally, in Asia and Latin America. In most regions, we find monotonous climate-induced damage trends but more years of observations would be needed to distinguish between the impacts of anthropogenic climate forcing and multidecadal oscillations.