Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery.

G protein-coupled receptors (GPCRs) are the largest human membrane protein family that transduce extracellular signals into cellular responses. They are major pharmacological targets, with approximately 26% of marketed drugs targeting GPCRs, primarily at their orthosteric binding site. Despite their prominence, predicting the pharmacological effects of novel GPCR-targeting drugs remains challenging due to the complex functional dynamics of these receptors.

Adaptive hip exoskeleton control using heart rate feedback reduces oxygen cost during ecological locomotion.

Despite their potential, exoskeletons have not reached widespread adoption in daily life, partly due to the challenge of seamlessly adapting assistance across various tasks and environments. Task-specific designs, reliance on complex sensing and extensive data-driven training often limit the practicality of the existing control strategies. To address this challenge, we introduce an adaptive control strategy for hip exoskeletons, emphasizing minimal sensing and ease of implementation.

GEMLI: Gene Expression Memory-Based Lineage Inference from Single-Cell RNA-Sequencing Datasets.

Gene expression memory-based lineage inference (GEMLI) is a computational tool allowing to predict cell lineages solely from single-cell RNA-sequencing (scRNA-seq) datasets and is publicly available as an R package on GitHub. GEMLI is based on the occurrence of gene expression memory, i.e.

Characterization of Machine Learning-Based Surrogate Models of Neural Activation Under Electrical Stimulation.

Electrical stimulation of peripheral nerves via implanted electrodes has been shown to be a promising approach to restore sensation, movement, and autonomic functions across a wide range of illnesses and injuries. While in principle computational models of neuromodulation can allow the exploration of large parameter spaces and the automatic optimization of stimulation devices and strategies, their high time complexity hinders their use on a large scale. We recently proposed the use of machine learning-based surrogate models to estimate the activation of nerve fibers under electrical stimulation, producing a considerable speed-up with respect to biophysically accurate models of fiber excitation while retaining good predictivity.

Virus adaptation to heparan sulfate comes with capsid stability tradeoff.

Because of high mutation rates, viruses constantly adapt to new environments. When propagated in cell lines, certain viruses acquire positively charged amino acids on their surface proteins, enabling them to utilize negatively charged heparan sulfate (HS) as an attachment receptor. In this study, we used enterovirus A71 (EV-A71) as model and demonstrated that unlike the parental MP4 variant, the cell-adapted strong HS-binder MP4-97R/167G does not require acidification for uncoating and releases its genome in the neutral or weakly acidic environment of early endosomes.

Photo-Cross-linked DNA Structures Greatly Improves Their Serum Nuclease Resistances and Gene Knock-In Efficiencies.

The stabilization and structural integrity of DNA architectures remain significant challenges in their biomedical applications, particularly when inserting functional units into the genome using long single-stranded DNA (lssDNA). To address these challenges, a site-specific photo-cross-linking method is employed. Single-stranded oligonucleotides, containing one or two photosensitive cyanovinylcarbazole nucleoside (K) molecules, are precisely incorporated and cross-linked at the specific sites of ssDNA through base-pairing, followed by rapid UV irradiation at 365 nm.

Off-the-Shelf Implant to Bridge a Urethral Defect: Multicenter 8-Year Journey From Bench to Bed.

Objective: To engineer an acellular mesh to reconstruct the urethra to replace the current surgical practice of using autologous tissue grafts. Cell based approaches have shown progress. However, these have been associated with high costs and logistical challenges.

Bridging Wright-Fisher and Moran models.

The Wright-Fisher model and the Moran model are both widely used in population genetics. They describe the time evolution of the frequency of an allele in a well-mixed population with fixed size. We propose a simple and tractable model which bridges the Wright-Fisher and the Moran descriptions.

Metabolic immunoengineering approaches to enhance CD8 T cell-based cancer immunotherapy.

Many cancer immunotherapies rely on robust CD8 T cells capable of eliminating cancer cells and establishing long-term tumor control. Recent insights into immunometabolism highlight the importance of nutrients and metabolites in T cell activation and differentiation. Within the tumor microenvironment (TME), CD8 tumor-infiltrating lymphocytes (TILs) undergo metabolic adaptations to survive but compromise their effector function and differentiation.

Collagen signaling and matrix stiffness regulate multipotency in glandular epithelial stem cells in mice.

Glandular epithelia, including mammary gland (MG) and prostate, are composed of luminal and basal cells. During embryonic development, glandular epithelia arise from multipotent stem cells (SCs) that are replaced after birth by unipotent basal and unipotent luminal SCs. Different conditions, such as basal cell transplantation, luminal cell ablation, and oncogene expression can reinduce adult basal SC (BaSCs) multipotency in different glandular epithelia.

The physiological landscape and specificity of antibody repertoires are consolidated by multiple immunizations.

Diverse antibody repertoires spanning multiple lymphoid organs (i.e., bone marrow, spleen, lymph nodes) form the foundation of protective humoral immunity.

Continuous Biosensing to Monitor Acute Systemic Inflammation, a Diagnostic Need for Therapeutic Guidance.

Continuous monitoring of acute inflammation can become a very important next step for guiding therapeutic interventions in severely ill patients. This Perspective discusses the current medical need for patients with acute inflammatory diseases and the potential of continuous biosensing technologies. First, we discuss biomarkers that could help to monitor the state of a patient with acute systemic inflammation based on theoretical studies and empirical data.

A modular toolbox for the optogenetic deactivation of transcription.

Light-controlled transcriptional activation is a commonly used optogenetic strategy that allows researchers to regulate gene expression with high spatiotemporal precision. The vast majority of existing tools are, however, limited to light-triggered induction of gene expression. Here, we inverted this mode of action and created optogenetic systems capable of efficiently terminating transcriptional activation in response to blue light.

Spotlight on cytochrome b561 and DOMON domain proteins.

Biotic and abiotic stresses constrain plant growth worldwide. Therefore, understanding the molecular mechanisms contributing to plant resilience is key to achieving food security. In recent years, proteins containing dopamine β-monooxygenase N-terminal (DOMON) and/or cytochrome b561 domains have been identified as important regulators of plant responses to multiple stress factors.

DiffPaSS-high-performance differentiable pairing of protein sequences using soft scores.

Motivation: Identifying interacting partners from two sets of protein sequences has important applications in computational biology. Interacting partners share similarities across species due to their common evolutionary history, and feature correlations in amino acid usage due to the need to maintain complementary interaction interfaces. Thus, the problem of finding interacting pairs can be formulated as searching for a pairing of sequences that maximizes a sequence similarity or a coevolution score.

OXA β-lactamases from spp. are membrane bound and secreted into outer membrane vesicles.

β-lactamases from Gram-negative bacteria are generally regarded as soluble, periplasmic enzymes. NDMs have been exceptionally characterized as lipoproteins anchored to the outer membrane. A bioinformatics study on all sequenced β-lactamases was performed that revealed a predominance of putative lipidated enzymes in the Class D OXAs.

Direct Monomer Recovery from Ring-Closing Depolymerization of Thermosets.

Recovering monomers from the depolymerization of thermosets presents a significant challenge, which becomes even more daunting if one sets the goal of doing it directly, i.e., without complex chemical separation steps.

Epitope-focused immunogens targeting the hepatitis C virus glycoproteins induce broadly neutralizing antibodies.

Hepatitis C virus (HCV) infection causes ~290,000 annual human deaths despite the highly effective antiviral treatment available. Several viral immune evasion mechanisms have hampered the development of an effective vaccine against HCV, among them the remarkable conformational flexibility within neutralization epitopes in the HCV antigens. Here, we report the design of epitope-focused immunogens displaying two distinct HCV cross-neutralization epitopes.

Amino acids modulate liquid-liquid phase separation in vitro and in vivo by regulating protein-protein interactions.

Liquid-liquid phase separation (LLPS) is an intracellular process widely used by cells for many key biological functions. It occurs in complex and crowded environments, where amino acids (AAs) are vital components. We have found that AAs render the net interaction between proteins more repulsive.

Physical exercise impacts bone remodeling around bio-resorbable magnesium implants.

Physical exercise has been shown to induce positive reactions in bone healing but next to nothing is known about how it affects the nanostructure, in particular around implants. In this study, we established this link by using small-angle X-ray scattering tensor tomography (SASTT) to investigate nanostructural parameters in 3D such as mineral particle orientation and thickness. As a model system, rat femoral bone with a bio-resorbable implant (ultra-high purity magnesium) was used.

Patterned gastrointestinal monolayers with bilateral access as observable models of parasite gut infection.

Organoids for modelling the physiology and pathology of gastrointestinal tissues are constrained by a poorly accessible lumen. Here we report the development and applicability of bilaterally accessible organoid-derived patterned epithelial monolayers that allow the independent manipulation of their apical and basal sides. We constructed gastric, small-intestinal, caecal and colonic epithelial models that faithfully reproduced their respective tissue geometries and that exhibited stem cell regionalization and transcriptional resemblance to in vivo epithelia.

A computational model to design wide field-of-view optic nerve neuroprostheses.

Retinal stimulation (RS) allows restoring vision in blind patients, but it covers only a narrow region of the visual field. Optic nerve stimulation (ONS) has the potential to produce visual perceptions spanning the whole visual field, but it produces very irregular phosphenes. We introduced a geometrical model converting retinal and optic nerve firing rates into visual perceptions and vice versa and a method to estimate the best perceptions elicitable through an electrode configuration.