Discovery and Preclinical Characterization of Fulacimstat (BAY 1142524), a Potent and Selective Chymase Inhibitor As a New Profibrinolytic Approach for Safe Thrombus Resolution.

Chymase is a serine-protease produced by mast cells. In the past few decades, its role in fibrotic diseases triggered the search for orally available chymase inhibitors. Aiming at reducing adverse cardiac remodeling after myocardial infarction, our research efforts resulted in the discovery of fulacimstat (BAY 1142524).

eIF1 and eIF5 dynamically control translation start site fidelity.

Translation initiation defines the identity of a synthesized protein through selection of a translation start site on a messenger RNA. This process is essential to well-controlled protein synthesis, modulated by stress responses, and dysregulated in many human diseases. The eukaryotic initiation factors eIF1 and eIF5 interact with the initiator methionyl-tRNA on the 40S ribosomal subunit to coordinate start site selection.

Intermetallics with sp-d orbital hybridisation: morphologies, stabilities and work functions of In-Pd particles at the nanoscale.

The field of intermetallic catalysts, alloying a p-block and a transition metal to form a pM-TM bimetallic alloy, is experiencing robust growth, emerging as a vibrant frontier in catalysis research. Although such materials are increasingly used in the form of nanoparticles, a precise description of their atomic arrangements at the nanoscale remains scarce. Based on the In-Pd binary as a typical pM-TM system, we performed density functional theory calculations to investigate the morphologies, relative stabilities and electronic properties of 24 Å and 36 Å nanoparticles built from the InPd, InPd and InPd compounds.

WindCline: Sloping wind tunnel for characterizing flame behavior under variable inclines and wind conditions.

Developing accurate computational models of wildfire dynamics is increasingly important due to the substantial and expanding negative impacts of wildfire events on human health, infrastructure, and the environment. Wildfire spread and emissions depend on a number of factors, including fuel type, environmental conditions (moisture, wind speed, etc.), and terrain/location.

Universal features of Nsp1-mediated translational shutdown by coronaviruses.

Nonstructural protein 1 (Nsp1) produced by coronaviruses inhibits host protein synthesis. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp1 C-terminal domain was shown to bind the ribosomal mRNA channel to inhibit translation, but it is unclear whether this mechanism is broadly used by coronaviruses, whether the Nsp1 N-terminal domain binds the ribosome, or how Nsp1 allows viral RNAs to be translated. Here, we investigated Nsp1 from SARS-CoV-2, Middle East respiratory syndrome coronavirus (MERS-CoV), and Bat-Hp-CoV coronaviruses using structural, biophysical, and biochemical experiments, revealing a conserved role for the C-terminal domain.

Real-time detection of human telomerase DNA synthesis by multiplexed single-molecule FRET.

Genomic stability in proliferating cells critically depends on telomere maintenance by telomerase reverse transcriptase. Here we report the development and proof-of-concept results of a single-molecule approach to monitor the catalytic activity of human telomerase in real time and with single-nucleotide resolution. Using zero-mode waveguides and multicolor FRET, we recorded the processive addition of multiple telomeric repeats to individual DNA primers.

Universal features of Nsp1-mediated translational shutdown by coronaviruses.

Nonstructural protein 1 (Nsp1) produced by coronaviruses shuts down host protein synthesis in infected cells. The C-terminal domain of SARS-CoV-2 Nsp1 was shown to bind to the small ribosomal subunit to inhibit translation, but it is not clear whether this mechanism is broadly used by coronaviruses, whether the N-terminal domain of Nsp1 binds the ribosome, or how Nsp1 specifically permits translation of viral mRNAs. Here, we investigated Nsp1 from three representative - SARS-CoV-2, MERS-CoV, and Bat-Hp-CoV - using structural, biophysical, and biochemical assays.

Segmental stiff skin syndrome treated with secukinumab.

Segmental stiff skin syndrome is a rare fibrosing scleroderma-like disorder characterized by progressive indurations of the skin leading to joint contractures, decreased mobility, and pain. Treatment options are limited; we report a patient that showed improvement with anti-IL17 biologic therapy.

Genomic Sequence of Canadian : A North American Wild Relative of Quinoa.

(pitseed goosefoot) is a widespread native North American plant, which was cultivated and consumed by indigenous peoples prior to the arrival of European colonists. is closely related to, and freely hybridizes with the domesticated South American food crop . As such it is a potential source of wild germplasm for breeding with , for improved quinoa production in North America.

Chymase Inhibition Resolves and Prevents Deep Vein Thrombosis Without Increasing Bleeding Time in the Mouse Model.

Background Deep vein thrombosis (DVT) is the primary cause of pulmonary embolism and the third most life-threatening cardiovascular disease in North America. Post-DVT anticoagulants, such as warfarin, heparin, and direct oral anticoagulants, reduce the incidence of subsequent venous thrombi. However, all currently used anticoagulants affect bleeding time at various degrees, and there is therefore a need for improved therapeutic regimens in DVT.

Repurposing alpelisib, an anti-cancer drug, for the treatment of severe TIE2-mutated venous malformations: Preliminary pharmacokinetics and pharmacodynamic data.

Extensive venous malformations involving limbs severely impact quality of life, mostly due to chronic pain and functional limitations. But patients can also display coagulopathy with associated risks of life-threatening thromboembolism and bleeding. Available pharmacological treatments (e.

Pediatric Lymphedema: Study of 180 Patients Referred to a Tertiary Lymphedema Clinic.

Background: Lymphedema is due to dysfunction of the lymphatic system. It can be primary or secondary. Pediatric lymphedema is more often primary and is a chronic disease with a heavy burden on quality of life.

eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining.

Translation initiation defines the identity and quantity of a synthesized protein. The process is dysregulated in many human diseases. A key commitment step is when the ribosomal subunits join at a translation start site on a messenger RNA to form a functional ribosome.

Patient safety and quality care for children with intellectual disability: An action research study.

Children with intellectual disability experience significant challenges in accessing and receiving high-quality healthcare leading to poorer health outcomes and negative patient experiences. Families of these children often report a need for healthcare staff to better understand, communicate, and collaborate for better care while staff acknowledge a lack of training. To address this, we utilised an action research framework with a pre- and post- survey to evaluate an integrated continuing professional development and quality improvement program combining strategies from education, behavioural psychology and quality improvement that was delivered in two departments within a tertiary children's Hospital in Metropolitan Sydney in 2019-2020.

Development of Self-Efficacy Tools for Parents and Professionals Caring for Children and Young People with Lymphedema (ILF Parent SE and ILF Professional SE).

Self-management is a key aspect of lymphedema treatment and self-efficacy is a key factor linked to long-term adherence to treatment. The study aimed to generate self-efficacy scales to support the care of children and adolescents with lymphedema to support self-management. Parents of children with lymphedema and the professionals caring for them were recruited during a lymphedema educational camp.

Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta-CoV that recently emerged as a human pathogen and is the causative agent of the COVID-19 pandemic. A molecular framework of how the virus manipulates host cellular machinery to facilitate infection remains unclear. Here, we focus on SARS-CoV-2 NSP1, which is proposed to be a virulence factor that inhibits protein synthesis by directly binding the human ribosome.

Mast Cell Degranulation Increases Mouse Mast Cell Protease 4-Dependent Vasopressor Responses to Big Endothelin-1 But Not Angiotensin I.

Mouse mast cell protease 4 (mMCP-4), the murine functional analog to the human chymase, is a serine protease synthesized and stored in mast cell secretory granules. Our previous studies reported physiologic and pathologic roles for mMCP-4 in the maturation and synthesis of the vasoactive peptide endothelin-1 (ET-1) from its precursor, big ET-1. The aim of this study was to investigate the impact of mast cell degranulation or stabilization on mMCP-4-dependent pressor responses after the administration of big ET-1 or angiotensin I (Ang I).

Reinforcing materials modelling by encoding the structures of defects in crystalline solids into distortion scores.

This work revises the concept of defects in crystalline solids and proposes a universal strategy for their characterization at the atomic scale using outlier detection based on statistical distances. The proposed strategy provides a generic measure that describes the distortion score of local atomic environments. This score facilitates automatic defect localization and enables a stratified description of defects, which allows to distinguish the zones with different levels of distortion within the structure.

Records of RNA locations in living yeast revealed through covalent marks.

RNA movements and localization pervade biology, from embryonic development to disease. To identify RNAs at specific locations, we developed a strategy in which a uridine-adding enzyme is anchored to subcellular sites, where it directly marks RNAs with 3' terminal uridines. This localized RNA recording approach yields a record of RNA locations, and is validated through identification of RNAs localized selectively to the endoplasmic reticulum (ER) or mitochondria.

Extrapolating Unconverged GW Energies up to the Complete Basis Set Limit with Linear Regression.

The GW approximation to the electronic self-energy is now a well-recognized approach to obtain the electron quasiparticle energies of molecules and, in particular, their ionization potential and electron affinity. Though much faster than the corresponding wavefunction methods, the GW energies are still affected by slow convergence with respect to the basis completeness. This limitation hinders a wider application of the GW approach.

A memory of eS25 loss drives resistance phenotypes.

In order to maintain cellular protein homeostasis, ribosomes are safeguarded against dysregulation by myriad processes. Remarkably, many cell types can withstand genetic lesions of certain ribosomal protein genes, some of which are linked to diverse cellular phenotypes and human disease. Yet the direct and indirect consequences from these lesions are poorly understood.

Inter-dependent Centrosomal Co-localization of the cen and ik2 cis-Natural Antisense mRNAs in Drosophila.

Overlapping genes are prevalent in most genomes, but the extent to which this organization influences regulatory events operating at the post-transcriptional level remains unclear. Studying the cen and ik2 genes of Drosophila melanogaster, which are convergently transcribed as cis-natural antisense transcripts (cis-NATs) with overlapping 3' UTRs, we found that their encoded mRNAs strikingly co-localize to centrosomes. These transcripts physically interact in a 3' UTR-dependent manner, and the targeting of ik2 requires its 3' UTR sequence and the presence of cen mRNA, which serves as the main driver of centrosomal co-localization.

eIF5B gates the transition from translation initiation to elongation.

Translation initiation determines both the quantity and identity of the protein that is encoded in an mRNA by establishing the reading frame for protein synthesis. In eukaryotic cells, numerous translation initiation factors prepare ribosomes for polypeptide synthesis; however, the underlying dynamics of this process remain unclear. A central question is how eukaryotic ribosomes transition from translation initiation to elongation.