TRIM9 controls growth cone responses to netrin through DCC and UNC5C.

The guidance cue netrin-1 promotes both growth cone attraction and growth cone repulsion. How netrin-1 elicits these diverse axonal responses, beyond engaging the attractive receptor DCC and repulsive receptors of the UNC5 family, remains elusive. Here we demonstrate that murine netrin-1 induces biphasic axonal responses in cortical neurons: attraction at lower concentrations and repulsion at higher concentrations using both a microfluidic-based netrin-1 gradient and bath application of netrin-1.

BOLD v4: A Centralized Bioinformatics Platform for DNA-Based Biodiversity Data.

BOLD, the Barcode of Life Data System, supports the acquisition, storage, validation, analysis, and publication of DNA barcodes, activities requiring the integration of molecular, morphological, and distributional data. Its pivotal role in curating the reference library of DNA barcodes, coupled with its data management and analysis capabilities, makes it a central resource for biodiversity science. It enables rapid, accurate identification of specimens and also reveals patterns of genetic diversity and evolutionary relationships among taxa.

A genetic atlas for the butterflies of continental Canada and United States.

Multi-locus genetic data for phylogeographic studies is generally limited in geographic and taxonomic scope as most studies only examine a few related species. The strong adoption of DNA barcoding has generated large datasets of mtDNA COI sequences. This work examines the butterfly fauna of Canada and United States based on 13,236 COI barcode records derived from 619 species.

IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial.

Toll-like receptor-driven and interleukin-1 (IL-1) receptor-driven inflammation mediated by IL-1 receptor-associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD.

Erinacine S from Hericium erinaceus mycelium promotes neuronal regeneration by inducing neurosteroids accumulation.

Erinacines derived from Hericium erinaceus have been shown to possess various health benefits including neuroprotective effect against neurodegenerative diseases, yet the underlying mechanism remains unknown. Here we found that erinacine S enhances neurite outgrowth in a cell autonomous fashion. It promotes post-injury axon regeneration of PNS neurons and enhances regeneration on inhibitory substrates of CNS neurons.

Cytoskeleton: Septin wreaths regulate actin in neuritogenesis.

The shape of a neuron changes dramatically during development. New work reports a novel septin cytoskeleton network that is important in establishing proper neuronal morphology.

Machine Learning Assisted Handheld Confocal Raman Micro-Spectroscopy for Identification of Clinically Relevant Atopic Eczema Biomarkers.

Atopic dermatitis (AD) is a common chronic inflammatory skin dermatosis condition due to skin barrier dysfunction that causes itchy, red, swollen, and cracked skin. Currently, AD severity clinical scores are subjected to intra- and inter-observer differences. There is a need for an objective scoring method that is sensitive to skin barrier differences.

Computationally driven discovery of SARS-CoV-2 M inhibitors: from design to experimental validation.

We report a fast-track computationally driven discovery of new SARS-CoV-2 main protease (M) inhibitors whose potency ranges from mM for the initial non-covalent ligands to sub-μM for the final covalent compound (IC = 830 ± 50 nM). The project extensively relied on high-resolution all-atom molecular dynamics simulations and absolute binding free energy calculations performed using the polarizable AMOEBA force field. The study is complemented by extensive adaptive sampling simulations that are used to rationalize the different ligand binding poses through the explicit reconstruction of the ligand-protein conformation space.

A molecular-based identification resource for the arthropods of Finland.

To associate specimens identified by molecular characters to other biological knowledge, we need reference sequences annotated by Linnaean taxonomy. In this study, we (1) report the creation of a comprehensive reference library of DNA barcodes for the arthropods of an entire country (Finland), (2) publish this library, and (3) deliver a new identification tool for insects and spiders, as based on this resource. The reference library contains mtDNA COI barcodes for 11,275 (43%) of 26,437 arthropod species known from Finland, including 10,811 (45%) of 23,956 insect species.

The TRIM9/TRIM67 neuronal interactome reveals novel activators of morphogenesis.

TRIM9 and TRIM67 are neuronally enriched E3 ubiquitin ligases essential for appropriate morphogenesis of cortical and hippocampal neurons and fidelitous responses to the axon guidance cue netrin-1. Deletion of murine or results in neuroanatomical defects and striking behavioral deficits, particularly in spatial learning and memory. TRIM9 and TRIM67 interact with cytoskeletal and exocytic proteins, but the full interactome is not known.

PARG has a robust endo-glycohydrolase activity that releases protein-free poly(ADP-ribose) chains.

Poly(ADP-ribosyl)ation (PARylation) regulates DNA damage response, chromatin structure, and cell-fate. Dynamic regulation of cellular PAR levels is crucial for the maintenance of genomic integrity and excessive cellular PAR activates a PAR-dependent cell death pathway. Thus, PAR serves as a cell-death signal; however, it has been debated how the protein-free PAR is generated.

Fast pulsatile blood flow measurement in deep tissue through a multimode detection fiber.

Significance: Noninvasive in vivo fast pulsatile blood flow measurement in deep tissue is important because the blood flow waveform is correlated with physiological parameters, such as blood pressure and elasticity of blood vessels. Compromised blood flow may cause diseases, such as stroke, foot ulcer, and myocardial ischemia. There is great clinical demand for a portable and cost-effective device for noninvasive pulsatile blood flow measurement.

Actin waves transport RanGTP to the neurite tip to regulate non-centrosomal microtubules in neurons.

Microtubules (MTs) are the most abundant cytoskeleton in neurons, and control multiple facets of their development. While the MT-organizing center (MTOC) in mitotic cells is typically located at the centrosome, the MTOC in neurons switches to non-centrosomal sites. A handful of cellular components have been shown to promote non-centrosomal MT (ncMT) formation in neurons, yet the regulation mechanism remains unknown.

Handheld confocal Raman spectroscopy (CRS) for objective assessment of skin barrier function and stratification of severity in atopic dermatitis (AD) patients.

Background: We developed the first-of-its-kind handheld confocal Raman spectroscopy (CRS) system to quantify the concentration of natural moisturizing factors in the skin.

Objective: To evaluate the feasibility of our handheld CRS system and propose a novel quantitative index to measure skin barrier function.

Methods: This prospective study included 30 atopic dermatitis (AD) patients and 14 healthy volunteers.

A reference library for Canadian invertebrates with 1.5 million barcodes, voucher specimens, and DNA samples.

The reliable taxonomic identification of organisms through DNA sequence data requires a well parameterized library of curated reference sequences. However, it is estimated that just 15% of described animal species are represented in public sequence repositories. To begin to address this deficiency, we provide DNA barcodes for 1,500,003 animal specimens collected from 23 terrestrial and aquatic ecozones at sites across Canada, a nation that comprises 7% of the planet's land surface.

Visualizing Alzheimer's Disease Mouse Brain with Multispectral Optoacoustic Tomography using a Fluorescent probe, CDnir7.

Alzheimer's disease (AD) is now clinically considered as a chronic inflammation-based neurodegenerative disease. The CDnir7 probe was previously developed as an optical imaging probe to target macrophages in order to image mouse inflammation using in vivo optical imaging modalities such as In Vivo imaging system (IVIS) and fluorescent molecular tomography (FMT). Here, we demonstrate the application of CDnir7 in AD mouse brain imaging via multispectral optoacoustic tomography (MSOT).

Nanoimprinted Anisotropic Topography Preferentially Guides Axons and Enhances Nerve Regeneration.

Surface topography has a profound effect on the development of the nervous system, such as neuronal differentiation and morphogenesis. While the interaction of neurons and the surface topography of their local environment is well characterized, the neuron-topography interaction during the regeneration process remains largely unknown. To address this question, an anisotropic surface topography resembling linear grooves made from poly(ethylene-vinyl acetate) (EVA), a soft and biocompatible polymer, using nanoimprinting, is established.

Noninvasive Anatomical and Functional Imaging of Orthotopic Glioblastoma Development and Therapy using Multispectral Optoacoustic Tomography.

Purpose: Here we demonstrate the potential of multispectral optoacoustic tomography (MSOT), a new non-invasive structural and functional imaging modality, to track the growth and changes in blood oxygen saturation (sO) in orthotopic glioblastoma (GBMs) and the surrounding brain tissues upon administration of a vascular disruptive agent (VDA).

Methods: Nude mice injected with U87MG tumor cells were longitudinally monitored for the development of orthotopic GBMs up to 15 days and observed for changes in sO upon administration of combretastatin A4 phosphate (CA4P, 30 mg/kg), an FDA approved VDA for treating solid tumors. We employed a newly-developed non-negative constrained approach for combined MSOT image reconstruction and unmixing in order to quantitatively map sO in whole mouse brains.

Design, synthesis, and biological evaluation of stable β-Helices: Discovery of non-hemolytic antibacterial peptides.

Gramicidin A, a topical antibiotic made from alternating L and D amino acids, is characterized by its wide central pore; upon insertion into membranes, it forms channels that disrupts ion gradients. We present helical peptidomimetics with this characteristic wide central pore that have been designed to mimic gramicidin A channels. Mimetics were designed using molecular modeling focused on oligomers of heterochiral dipeptides of proline analogs, in particular azaproline (AzPro).

Noninvasive real-time characterization of non-melanoma skin cancers with handheld optoacoustic probes.

Currently, imaging technologies that enable dermsurgeons to visualize non-melanoma skin cancers (NMSC) preoperatively are lacking, resulting in excessive or incomplete removal. Multispectral optoacoustic tomography (MSOT) is a volumetric imaging tool to differentiate tissue chromophores and exogenous contrast agents, based on differences in their spectral signatures and used for high-resolution imaging of functional and molecular contrast at centimeter scale depth. We performed MSOT imaging with two- and three-dimensional handheld scanners on 21 Asian patients with NMSC.

Investigating the effect of forestry on leaf-litter arthropods (Algonquin Park, Ontario, Canada).

Arthropods are the most diverse taxonomic group of terrestrial eukaryotes and are sensitive to physical alterations in their environment such as those caused by forestry. With their enormous diversity and physical omnipresence, arthropods could be powerful indicators of the effects of disturbance following forestry. When arthropods have been used to measure the effects of disturbance, the total diversity of some groups is often found to increase following forestry.

Designing small molecules to target cryptic pockets yields both positive and negative allosteric modulators.

Allosteric drugs, which bind to proteins in regions other than their main ligand-binding or active sites, make it possible to target proteins considered "undruggable" and to develop new therapies that circumvent existing resistance. Despite growing interest in allosteric drug discovery, rational design is limited by a lack of sufficient structural information about alternative binding sites in proteins. Previously, we used Markov State Models (MSMs) to identify such "cryptic pockets," and here we describe a method for identifying compounds that bind in these cryptic pockets and modulate enzyme activity.

A mechanism for lipid binding to apoE and the role of intrinsically disordered regions coupled to domain-domain interactions.

Relative to the apolipoprotein E (apoE) E3 allele of the gene, apoE4 strongly increases the risk for the development of late-onset Alzheimer's disease. However, apoE4 differs from apoE3 by only a single amino acid at position 112, which is arginine in apoE4 and cysteine in apoE3. It remains unclear why apoE3 and apoE4 are functionally different.