Rapid affinity optimization of an anti-TREM2 clinical lead antibody by cross-lineage immune repertoire mining.

We describe a process for rapid antibody affinity optimization by repertoire mining to identify clones across B cell clonal lineages based on convergent immune responses where antigen-specific clones with the same heavy (V) and light chain germline segment pairs, or parallel lineages, bind a single epitope on the antigen. We use this convergence framework to mine unique and distinct V lineages from rat anti-triggering receptor on myeloid cells 2 (TREM2) antibody repertoire datasets with high diversity in the third complementarity-determining loop region (CDR H3) to further affinity-optimize a high-affinity agonistic anti-TREM2 antibody while retaining critical functional properties. Structural analyses confirm a nearly identical binding mode of anti-TREM2 variants with subtle but significant structural differences in the binding interface.

Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism.

Introduction: Triggering receptor expressed on myeloid cells 2 (TREM2) agonists are being clinically evaluated as disease-modifying therapeutics for Alzheimer's disease. Clinically translatable pharmacodynamic (PD) biomarkers are needed to confirm drug activity and select the appropriate therapeutic dose in clinical trials.

Methods: We conducted multi-omic analyses on paired non-human primate brain and cerebrospinal fluid (CSF), and stimulation of human induced pluripotent stem cell-derived microglia cultures after TREM2 agonist treatment, followed by validation of candidate fluid PD biomarkers using immunoassays.

Neutral or Detrimental Effects of TREM2 Agonist Antibodies in Preclinical Models of Alzheimer's Disease and Multiple Sclerosis.

Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia.

De-imFAR phase II project: a study protocol for a cluster randomised implementation trial to evaluate the effectiveness of de-implementation strategies to reduce low-value statin prescribing in the primary prevention of cardiovascular disease.

Introduction: This study aims to reduce potentially inappropriate prescribing (PIP) of statins and foster healthy lifestyle promotion in cardiovascular disease (CVD) primary prevention in low-risk patients. To this end, we will compare the effectiveness and feasibility of several de-implementation strategies developed following the structured design process of the Behaviour Change Wheel targeting key determinants of the clinical decision-making process in CVD prevention.

Methods And Analysis: A cluster randomised implementation trial, with an additional control group, will be launched, involving family physicians (FPs) from 13 Integrated Healthcare Organisations (IHOs) of Osakidetza-Basque Health Service with non-zero incidence rates of PIP of statins in 2021.

A Single Amino Acid Able to Promote High-Temperature Ring-Opening Polymerization by Dual Activation.

Amino acids are indispensable compounds in the body, performing several biological processes that enable proper functioning. In this work, it is demonstrated that a single amino acid, taurine, is also able to promote the ring-opening polymerization (ROP) of several cyclic monomers under industrially relevant conditions. It is shown that the unique zwitterionic structure of taurine, where the negatively charged sulfonic acid group and the protonated amine group are separated by two methylene groups, not only provides high thermal stability but also leads to a dual activation mechanism, which is corroborated by quantum mechanical calculations.

Dual-Cross-Linked Magnetic Hydrogel with Programmed Release of Parathyroid Hormone Promotes Bone Healing.

Intermittent delivery of parathyroid hormone (PTH) could effectively promote bone regeneration, but the need for daily injection administration has limited its further clinical applications. Exposure to magnetic stimulation could regulate cell fate to promote osteogenesis. Herein, we developed a magnetized hydrogel with programmed PTH release and simultaneous magnetic actuation to promote osteogenic commitment.

Lactide and Ethylene Brassylate-Based Thermoplastic Elastomers and Their Nanocomposites with Carbon Nanotubes: Synthesis, Mechanical Properties and Interaction with Astrocytes.

Polylactide (PLA) is among the most commonly used polymers for biomedical applications thanks to its biodegradability and cytocompatibility. However, its inherent stiffness and brittleness are clearly inappropriate for the regeneration of soft tissues (e.g.

3D-Printed Hybrid Collagen/GelMA Hydrogels for Tissue Engineering Applications.

Bioprinting is an emerging technology involved in the fabrication of three-dimensional tissue constructs for the repair and regeneration of various tissues and organs. Collagen, a natural protein found abundantly in the extracellular matrix of several tissues, can be extracted from collagen-rich tissues of animals such as sheep, cows, rats, pigs, horses, birds, and marine animals. However, due to the poor printability of collagen bioinks, biocompatible collagen scaffolds that mimic the extracellular matrix (ECM) are difficult to fabricate using bioprinting techniques.

A communication procedure between community pharmacists and primary care professionals resolves medication errors and other administrative issues.

Objectives: The aim of this study was to implement a communication procedure, with agreed-upon protocols, to resolve daily medication errors and other administrative issues that require communication between community pharmacists (CPs) and primary healthcare professionals (PHCPs).

Methods: A 6-month pilot study followed by a year-length principal study was carried out in the Donostialdea Integrated Healthcare Organisation (IHO). Afterwards, the project was extended to other IHOs.

Modulating the Crystallinity of a Circular Plastic towards Packaging Material with Outstanding Barrier Properties.

Chemically recyclable polymers have attracted increasing attention since they are promising materials in a circular economy, but such polymers appropriate for packaging applications are scarce. Here a combined thermal, mechanical, and transport (permeability and sorption) study is presented of a circular polymer system based on biobased trans-hexahydrophthalide which, upon polymerization, can lead to amorphous, homochiral crystalline, and nanocrystalline stereocomplex materials. This study uncovers their largely different transport properties of the same polymer but with different stereochemical arrangements and synergistic or conflicting effects of crystallinity on transport properties versus thermal and mechanical properties.

Lactide-Valerolactone Copolymers for Packaging Applications.

Lactide-valerolactone copolymers have potential application in the packaging sector. Different copolymers were synthesized, and the kinetics of the copolymerization reactions and the microstructure of the copolymers were analysed. Lactide showed higher reactivity than valerolactone which leads to composition drift through the reaction.

Pregnant Females as Historical Individuals: An Insight From the Philosophy of Evo-Devo.

Criticisms of the "container" model of pregnancy picturing female and embryo as separate entities multiply in various philosophical and scientific contexts during the last decades. In this paper, we examine how this model underlies received views of pregnancy in evolutionary biology, in the characterization of the transition from oviparity to viviparity in mammals and in the selectionist explanations of pregnancy as an evolutionary strategy. In contrast, recent evo-devo studies on eutherian reproduction, including the role of inflammation and new maternal cell types, gather evidence in favor of considering pregnancy as an evolved relational novelty.

[Evaluation of the collaboration between Primary and Hospital Care in order to improve inappropriate prescription].

Introduction And Objectives: To evaluate the implementation of a collaborative experience between Primary (PC) and Hospital Care (HC) aimed at reducing potentially inappropriate prescribing (PIP) in patients with polypharmacy.

Materials And Methods: Collaborative experience including a controlled before-after intervention study, carried out in the Donostialdea Integrated Health Organization (IHO), with Bilbao Basurto IHO as control group, Osakidetza, Basque Health Service. Participant were 227 PC physicians and physicians from 7 hospital services, and patients with 5 or more drugs meeting at least one PIP criteria.

Alzheimer's Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation.

Damage-associated microglia (DAM) profiles observed in Alzheimer's disease (AD)-related mouse models reflect an activation state that could modulate AD risk or progression. To learn whether human AD microglia (HAM) display a similar profile, we develop a method for purifying cell types from frozen cerebrocortical tissues for RNA-seq analysis, allowing better transcriptome coverage than typical single-nucleus RNA-seq approaches. The HAM profile we observe bears little resemblance to the DAM profile.

Nanoantioxidants: Recent Trends in Antioxidant Delivery Applications.

Antioxidants interact with free radicals, terminating the adverse chain reactions and converting them to harmless products. Antioxidants thus minimize the oxidative stress and play a crucial role in the treatment of free radicals-induced diseases. However, the effectiveness of natural and/or synthetic antioxidants is limited due to their poor absorption, difficulties to cross the cell membranes, and degradation during delivery, hence contributing to their limited bioavailability.

A 3D printed chitosan-pectin hydrogel wound dressing for lidocaine hydrochloride delivery.

A chitosan-pectin (CS-PEC) biopolymeric hydrogel wound dressing was investigated for lidocaine delivery. Here we demonstrate for the first time the feasibility of three-dimensional (3D) printed CS-PEC hydrogel incorporating the local anaesthetic drug lidocaine hydrochloride (LDC) as a potential wound dressing candidate. The hydrogels were prepared by physical crosslinking of CS and PEC polysaccharides.

Packaging materials with desired mechanical and barrier properties and full chemical recyclability.

Plastics have become indispensable in modern life and the material of choice in packaging applications, but they have also caused increasing plastic waste accumulation in oceans and landfills. Although there have been continuous efforts to develop biodegradable plastics, the mechanical and/or transport properties of these materials still need to be significantly improved to be suitable for replacing conventional plastic packaging materials. Here we report a class of biorenewable and degradable plastics, based on copolymers of γ-butyrolactone and its ring-fused derivative, with competitive permeability and elongation at break compared to commodity polymers and superior mechanical and transport properties to those of most promising biobased plastics.

Elaboration and Characterization of Conductive Polymer Nanocomposites with Potential Use as Electrically Driven Membranes.

In this work, a general, facile, and relatively low-cost method to produce electrically driven non-porous membranes by revalorization of recycled polyolefins is proposed. The polymer matrices are poly(propylene) (PP) and poly(ethylene) (PE) and their corresponding recycled samples, which are respectively mixed with carbon nanotubes (CNT). The performances of the elaborated nanocomposites are studied by morphological, rheological, and electrical conductivity tests.

Development of a Long-Term Drug Delivery System with Levonorgestrel-Loaded Chitosan Microspheres Embedded in Poly(vinyl alcohol) Hydrogel.

This study reports on the fabrication of a controlled release system for the delivery of levonorgestrel (LNG) for long-term contraception. LNG was encapsulated in chemically cross-linked chitosan (CS) microspheres, and microspheres presented a spherical geometry with a good particle size distribution (polydispersity index (PDI) < 0.1).

Initiation of CNS Myelination in the Optic Nerve Is Dependent on Axon Caliber.

Emerging evidence suggests that neuronal signaling is important for oligodendrocyte myelination; however, the necessity of this signaling during development is unclear. By eliminating dynamic neuronal signaling along the developing optic nerve, we find that oligodendrocyte differentiation is not dependent on neuronal signaling and that the initiation of myelination is dependent on a permissive substrate, namely supra-threshold axon caliber. Furthermore, we show that loss of dynamic neuronal signaling results in hypermyelination of axons.

Lack of correlation between surface expression and currents in epileptogenic AB-calmodulin binding domain Kv7.2 potassium channel mutants.

Heteromers of Kv7.2/Kv7.3 subunits constitute the main substrate of the neuronal M-current that limits neuronal hyper-excitability and firing frequency.

[Evaluation of an educational intervention and a structured review of polypharmacy in elderly patients in Primary Care].

Background And Objective: Several interventions have been shown to reduce polypharmacy and potentially inappropriate prescription (PIP). The objective of the study was to evaluate the number of drugs and PIP before and after an educational intervention with the Primary Care physician (PCP), with electronic identification of PIP and structured medication review, in elderly patients with excessive polypharmacy (≥10 drugs).

Material And Methods: A before-after intervention study was conducted in the Gipuzkoa district of Osakidetza (Basque Country Health System), in a random sample of patients older than 80 years taking ≥ 10 drugs, and whose PCP attended training sessions.