Axin1 and Axin2 regulate the WNT-signaling landscape to promote distinct mesoderm programs.

How distinct mesodermal lineages - extraembryonic, lateral, intermediate, paraxial and axial - are specified from pluripotent epiblast during gastrulation is a longstanding open question. By investigating AXIN, a negative regulator of the WNT/β-catenin pathway, we have uncovered new roles for WNT signaling in the determination of mesodermal fates. We undertook complementary approaches to dissect the role of WNT signaling that augmented a detailed analysis of ; mutant mouse embryos, including single-cell and single-embryo transcriptomics, with pluripotent Epiblast-Like Cell differentiation assays.

STAT: schema therapy for addiction treatment, a proposal for the integrative treatment of addictive disorders.

The nature and origins of addictions and of their adjunctive behaviors, as well as their chronicity, call for treatments that conceptualize and treat them as the long-term and complex processes that they are. Addictions are often comorbid with personality problems and with trauma histories. Patients suffering from these disorders often show poor engagement with treatment and high rates of relapse, possibly because available treatments have yet to address the patient suffering from addiction in a more integrated or holistic manner.

Prehospital Needle Decompression of Suspected Tension Pneumothorax: Outcomes and Consequences.

Tension pneumothorax (TPT) identified in the prehospital setting requires prehospital needle decompression (PHND). This study aimed to evaluate complications from PHND when it was performed without meeting clinical criteria. A retrospective review was performed of patients undergoing (PHND) from 2016 through 2022 at a level 1 trauma center.

Effectiveness of BNT162b2 mRNA vaccine third doses and previous infection in protecting against SARS-CoV-2 infections during the Delta and Omicron variant waves; the UK SIREN cohort study September 2021 to February 2022.

Third doses of COVID-19 vaccines were widely deployed following the primary vaccine course waning and the emergence of the Omicron-variant. We investigated protection from third-dose vaccines and previous infection against SARS-CoV-2 infection during Delta-variant and Omicron-variant (BA.1 & BA.

"Stapling" scFv for multispecific biotherapeutics of superior properties.

Single-chain fragment variable (scFv) domains play an important role in antibody-based therapeutic modalities, such as bispecifics, multispecifics and chimeric antigen receptor T cells or natural killer cells. However, scFv domains exhibit lower stability and increased risk of aggregation due to transient dissociation ("breathing") and inter-molecular reassociation of the two domains (VL and VH). We designed a novel strategy, referred to as stapling, that introduces two disulfide bonds between the scFv linker and the two variable domains to minimize scFv breathing.

Enhanced delivery of antibodies across the blood-brain barrier via TEMs with inherent receptor-mediated phagocytosis.

Background: The near impermeability of the blood-brain barrier (BBB) and the unique neuroimmune environment of the CNS prevents the effective use of antibodies in neurological diseases. Delivery of biotherapeutics to the brain can be enabled through receptor-mediated transcytosis via proteins such as the transferrin receptor, although limitations such as the ability to use Fc-mediated effector function to clear pathogenic targets can introduce safety liabilities. Hence, novel delivery approaches with alternative clearance mechanisms are warranted.

A hypomorphic mutation in Pold1 disrupts the coordination of embryo size expansion and morphogenesis during gastrulation.

Formation of a properly sized and patterned embryo during gastrulation requires a well-coordinated interplay between cell proliferation, lineage specification and tissue morphogenesis. Following transient physical or pharmacological manipulations of embryo size, pre-gastrulation mouse embryos show remarkable plasticity to recover and resume normal development. However, it remains unclear how mechanisms driving lineage specification and morphogenesis respond to defects in cell proliferation during and after gastrulation.

XRCC3 loss leads to midgestational embryonic lethality in mice.

RAD51 paralogs are key components of the homologous recombination (HR) machinery. Mouse mutants have been reported for four of the canonical RAD51 paralogs, and each of these mutants exhibits embryonic lethality, although at different gestational stages. However, the phenotype of mice deficient in the fifth RAD51 paralog, XRCC3, has not been reported.

Discovery and Functional Characterization of hPT3, a Humanized Anti-Phospho Tau Selective Monoclonal Antibody.

Background: As a consequence of the discovery of an extracellular component responsible for the progression of tau pathology, tau immunotherapy is being extensively explored in both preclinical and clinical studies as a disease modifying strategy for the treatment of Alzheimer's disease.

Objective: Describe the characteristics of the anti-phospho (T212/T217) tau selective antibody PT3 and its humanized variant hPT3.

Methods: By performing different immunization campaigns, a large collection of antibodies has been generated and prioritized.

A qualitative study of e-cigarette emergence and the potential for renormalisation of smoking in UK youth.

Background: Growth of e-cigarette use among smokers has raised concerns over uptake by non-smokers, particularly young people. Legislative changes aimed in part at reducing youth exposure to e-cigarettes include the EU Tobacco Products Directive (TPD). A core justification for such measures is the belief that e-cigarettes can lead to tobacco smoking through mechanisms of renormalisation including: mimicking and normalizing the act of smoking; increasing product acceptability via marketing; nicotine exposure.

Pharmacological Profile of JNJ-64179375: A Novel, Long-Acting Exosite-1 Thrombin Inhibitor.

JNJ-64179375 (JNJ-9375) is a recombinant human IgG4 monoclonal antibody engineered to mimic an IgA antibody that was identified in a patient who exhibited markedly prolonged clotting times but without spontaneous bleeding episodes over several years of follow-up. The crystal structure of the JNJ-9375 antigen-binding fragment/thrombin complex showed an almost identical binding mode to that of the patient IgA. In the current study, we characterized the in vitro and in vivo properties of JNJ-9375.

Anti-Tau Monoclonal Antibodies Derived from Soluble and Filamentous Tau Show Diverse Functional Properties in vitro and in vivo.

The tau spreading hypothesis provides rationale for passive immunization with an anti-tau monoclonal antibody to block seeding by extracellular tau aggregates as a disease-modifying strategy for the treatment of Alzheimer's disease (AD) and potentially other tauopathies. As the biochemical and biophysical properties of the tau species responsible for the spatio-temporal sequences of seeding events are poorly defined, it is not yet clear which epitope is preferred for obtaining optimal therapeutic efficacy. Our internal tau antibody collection has been generated by immunizations with different tau species: aggregated- and non-aggregated tau and human postmortem AD brain-derived tau fibrils.

Nup133 Is Required for Proper Nuclear Pore Basket Assembly and Dynamics in Embryonic Stem Cells.

Nup133 belongs to the Y-complex, a key component of the nuclear pore complex (NPC) scaffold. Studies on a null mutation in mice previously revealed that Nup133 is essential for embryonic development but not for mouse embryonic stem cell (mESC) proliferation. Using single-pore detection and average NE-fluorescence intensity, we find that Nup133 is dispensable for interphase and postmitotic NPC scaffold assembly in pluripotent mESCs.

Human IgG subclass cross-species reactivity to mouse and cynomolgus monkey Fcγ receptors.

In therapeutic antibody discovery and early development, mice and cynomolgus monkey are used as animal models to assess toxicity, efficacy and other properties of candidate molecules. As more candidate antibodies are based on human immunoglobulin (IgG) subclasses, many strategies are pursued to simulate the human system in the test animal. However, translation rate from a successful preclinical trial to an approved drug is extremely low.

Unique pharmacology of a novel allosteric agonist/sensitizer insulin receptor monoclonal antibody.

Objective: Insulin resistance is a key feature of Type 2 Diabetes (T2D), and improving insulin sensitivity is important for disease management. Allosteric modulation of the insulin receptor (IR) with monoclonal antibodies (mAbs) can enhance insulin sensitivity and restore glycemic control in animal models of T2D.

Methods: A novel human mAb, IRAB-A, was identified by phage screening using competition binding and surface plasmon resonance assays with the IR extracellular domain.

Cross-sectional study examining the prevalence, correlates and sequencing of electronic cigarette and tobacco use among 11-16-year olds in schools in Wales.

Objectives: To examine the prevalence and frequency of electronic (e)-cigarette use among young people in Wales, associations with socio-demographic characteristics, smoking and other substances and the sequencing of e-cigarette and tobacco use.

Design: A cross-sectional survey of school students in Wales undertaken in 2015.

Setting: 87 secondary schools in Wales.

Novel Monoclonal Antibody Is an Allosteric Insulin Receptor Antagonist That Induces Insulin Resistance.

A hallmark of type 2 diabetes is impaired insulin receptor (IR) signaling that results in dysregulation of glucose homeostasis. Understanding the molecular origins and progression of diabetes and developing therapeutics depend on experimental models of hyperglycemia, hyperinsulinemia, and insulin resistance. We present a novel monoclonal antibody, IRAB-B, that is a specific, potent IR antagonist that creates rapid and long-lasting insulin resistance.

Symmetric BMPs on the Developmental Road.

The signaling pathways and cellular mechanisms that achieve alignment of dorsal and ventral midline structures remain a poorly understood aspect of vertebrate development. In this issue of Developmental Cell, Arraf et al. (2016) find a requisite role for bilaterally symmetrical BMP signaling in coordinating dorsal and ventral tissue morphogenesis.

Monoclonal antibodies targeting ST2L Domain 1 or Domain 3 differentially modulate IL-33-induced cytokine release by human mast cell and basophilic cell lines.

The cell-surface receptor ST2L triggers cytokine release by immune cells upon exposure to its ligand IL-33. To study the effect of ST2L-dependent signaling in different cell types, we generated antagonist antibodies that bind different receptor domains. We sought to characterize their activities in vitro using both transfected cells as well as basophil and mast cell lines that endogenously express the ST2L receptor.