Azasugar inhibitors as pharmacological chaperones for Krabbe disease

Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.     

Calculated coupling constants 1J(X–Y) and 1K(X–Y), and fundamental relationships among the reduced coupling constants for molecules HmX–YHn,with X,Y ═ 1H, 7Li, 9Be, 11B, 13C, 15N, 17O, 19F, 31P, 33S,and 35Cl

Equation-of-motion coupled-cluster singles and doubles (EOM-CCSD) calculations have been performed to determine coupling constants ¹J(X–Y) for 65 molecules H_mX–YH_n, with X,Y ═ ¹H, ⁷Li, ⁹Be, ¹¹B, ¹³C, ¹⁵N, ¹⁷O, ¹⁹F, ³¹P, ³³S, and ³⁵Cl. The computed ¹J(X–Y) values are in good agreement with available experimental data. The reduced coupling constants ¹K(X–Y) have been derived from ¹J(X–Y) by removing the dependence on the magnetogyric ratios of X and Y. Patterns are found for the reduced coupling constants on a ¹K(X–Y) surface that are related to the positions of X and Y in the periodic table.     

The Impact of Research Culture on Mental Health & Diversity in STEM

The onset of COVID-19, coupled with the finer lens placed on systemic racial disparities within our society, has resulted in increased discussions around mental health. Despite this, mental health struggles in research are still often viewed as individual weaknesses and not the result of a larger dysfunctional research culture. Mental health interventions in the science, technology, engineering, and mathematics (STEM) academic community often focus on what individuals can do to improve their mental health instead of focusing on improving the research environment. In this paper, we present four aspects of research that may heavily impact mental health based on our experiences as research scientists: bullying and harassment; precarity of contracts; diversity, inclusion, and accessibility; and the competitive research landscape. Based on these aspects, we propose systemic changes that institutions must adopt to ensure their research culture is supportive and allows everyone to thrive.     

Duality for Koszul homology over Gorenstein rings

We study Koszul homology over local Gorenstein rings. It is well known that if an ideal is strongly Cohen–Macaulay the Koszul homology algebra satisfies Poincaré duality. We prove a version of this duality which holds for all ideals and allows us to give two criteria for an ideal to be strongly Cohen–Macaulay. The first can be compared to a result of Hartshorne and Ogus; the second is a generalization of a result of Herzog, Simis, and Vasconcelos using sliding depth.     

(2‐Aminopyrimidine‐κN1)aqua(pyridine‐2,6‐dicarboxylato‐κ3O2,N,O6)copper(II): X‐ray and DFT calculated structure

In the title compound, [Cu(C₇H₃N₂O₄)(C₄H₅N₂)(H₂O)], (I), pyridine‐2,6‐dicarboxylate (pydc²⁻), 2‐aminopyrimidine and aqua ligands coordinate the Cu^II centre through two N atoms, two carboxylate O atoms and one water O atom, respectively, to give a nominally distorted square‐pyramidal coordination geometry, a common arrangement for copper complexes containing the pydc²⁻ ligand. Because of the presence of Cu...X_bridged contacts (X = N or O) between adjacent molecules in the crystal structures of (I) and three analogous previously reported compounds, and the corresponding uncertainty about the effective coordination number of the Cu^II centre, density functional theory (DFT) calculations were used to elucidate the degree of covalency in these contacts. The calculated Wiberg and Mayer bond‐order indices reveal that the Cu...O contact can be considered as a coordination bond, whereas the amine group forming a Cu...N contact is not an effective participant in the coordination environment.     

A Statewide Implementation of the Critical Features of Professional Development: Impact on Teacher Outcomes

This study is focused on a statewide implementation of the core conceptual framework for effective professional development in the United States. and associated impact on teacher quality and attitudes. The framework included content focus, active learning, coherence, duration, and collective participation. There were 252 participants in the study, who were involved in one of the five science or six mathematics programs. Findings indicated a significant impact on teacher quality for all participating programs. Teacher attitudes were positive at the baseline, and remained positive with some improvement at the end of the program. However, teacher perceived preparedness increased significantly across the duration of the program. Discussion of the findings and implications for professional development programs internationally are shared.     

Bjarni Jónsson’s contributions in algebra: an addendum

Normal categories are pointed categorical counterparts of 0-regular varieties, i.e., varieties where each congruence is uniquely determined by the equivalence class of a fixed constant 0. In this paper, we give a new axiomatic approach to normal categories, which uses self-dual axioms on a functor defined using subobjects of objects in the category. We also show that a similar approach can be developed for 0-regular varieties, if we replace subobjects with subsets of algebras containing 0.     

Ce-promoted Fe–Cu–ZSM-5 catalyst: SCR-NO activity and hydrothermal stability

Research on Chemical Intermediates - Fe–Cu–ZSM-5 and Ce–Fe–Cu–ZSM-5 solids prepared using solid-state ion exchange method (SSIE) were tested in the NH3–SCR of NO...