Discovery of potent SARS-CoV-2 nsp3 macrodomain inhibitors uncovers lack of translation to cellular antiviral response.

A strategy for pandemic preparedness is the development of antivirals against a wide set of viral targets with complementary mechanisms of action. SARS-CoV-2 nsp3-mac1 is a viral macrodomain with ADP-ribosylhydrolase activity, which counteracts host immune response. Targeting the virus' immunomodulatory functionality offers a differentiated strategy to inhibit SARS-CoV-2 compared to approved therapeutics, which target viral replication directly.

Interplay of coulomb and exciton-phonon coupling controls singlet fission dynamics in two pentacene polymorphs.

Pentacene is an important model organic semiconductor in both the singlet exciton fission (SF) and organic electronics communities. We have investigated the effect of changing crystal structure on the SF process, generating multiple triplet excitons from an initial singlet exciton, and subsequent triplet recombination. Unlike for similar organic semiconductors that have strong SF sensitive to polymorphism, we find almost no quantitative difference between the kinetics of triplet pair (TT) formation in the two dominant polymorphs of pentacene.

Phonon-Driven Femtosecond Dynamics of Excitons in Crystalline Pentacene from First Principles.

Nonradiative exciton relaxation processes are critical for energy transduction and transport in optoelectronic materials, but how these processes are connected to the underlying crystal structure and the associated electron, exciton, and phonon band structures, as well as the interactions of all these particles, is challenging to understand. Here, we present a first-principles study of exciton-phonon relaxation pathways in pentacene, a paradigmatic molecular crystal and optoelectronic semiconductor. We compute the momentum- and band-resolved exciton-phonon interactions, and use them to analyze key scattering channels.

Unique Patterns of Eye Movements Characterizing Inattentive Reading in ADHD.

Objective: We aimed to identify unique patterns of eye-movements measures reflecting inattentive reading among adults with and without ADHD.

Method & Results: We recorded eye-movements during uninterrupted text reading of typically developed (TD) and ADHD adults. First, we found significantly longer reading time for the ADHD group than the TD group.

Near and Far Transfer Effects of Computerized Progressive Attention Training (CPAT) Versus Mindfulness Based Stress Reduction (MBSR) Practice Among Adults With ADHD.

Objective: The present study evaluated the near (attention) and far (reading, ADHD symptoms, learning, and quality of life) transfer effects of a Computerized Progressive Attention Training (CPAT) versus Mindfulness Based Stress Reduction (MBSR) practice among adults with ADHD compared to a passive group.

Method: Fifty-four adults participated in a non-fully randomized controlled trial. Participants in the intervention groups completed eight 2-hr weekly training sessions.

Optimization of Covalent MKK7 Inhibitors Crude Nanomole-Scale Libraries.

High-throughput nanomole-scale synthesis allows for late-stage functionalization (LSF) of compounds in an efficient and economical manner. Here, we demonstrated that copper-catalyzed azide-alkyne cycloaddition could be used for the LSF of covalent kinase inhibitors at the nanoscale, enabling the synthesis of hundreds of compounds that did not require purification for biological assay screening, thus reducing experimental time drastically. We generated crude libraries of inhibitors for the kinase MKK7, derived from two different parental precursors, and analyzed them the high-throughput In-Cell Western assay.

Signatures of Dimensionality and Symmetry in Exciton Band Structure: Consequences for Exciton Dynamics and Transport.

Exciton dynamics, lifetimes, and scattering are directly related to the exciton dispersion or band structure. Here, we present a general theory for exciton band structure within both and model Hamiltonian approaches. We show that contrary to common assumption, the exciton band structure contains nonanalytical discontinuities-a feature which is impossible to obtain from the electronic band structure alone.

Non-quaternary oximes detoxify nerve agents and reactivate nerve agent-inhibited human butyrylcholinesterase.

Government-sanctioned use of nerve agents (NA) has escalated dramatically in recent years. Oxime reactivators of organophosphate (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) serve as antidotes toward poisoning by OPNAs. The oximes used as therapeutics are quaternary compounds that cannot penetrate the blood-brain barrier (BBB).

Ubiquitous selection for mecA in community-associated MRSA across diverse chemical environments.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is threatening public health as it spreads worldwide across diverse environments. Its genetic hallmark, the mecA gene, confers resistance to many β-lactam antibiotics. Here, we show that, in addition, mecA provides a broad selective advantage across diverse chemical environments.

PRMT1 inhibition induces differentiation of colon cancer cells.

Differentiation therapy has been recently revisited as a prospective approach in cancer therapy by targeting the aberrant growth, and repairing the differentiation and cell death programs of cancer cells. However, differentiation therapy of solid tumors is a challenging issue and progress in this field is limited. We performed High Throughput Screening (HTS) using a novel dual multiplex assay to discover compounds, which induce differentiation of human colon cancer cells.

A network of cytosolic factors targets SRP-independent proteins to the endoplasmic reticulum.

Translocation into the endoplasmic reticulum (ER) is an initial and crucial biogenesis step for all secreted and endomembrane proteins in eukaryotes. ER insertion can take place through the well-characterized signal recognition particle (SRP)-dependent pathway or the less-studied route of SRP-independent translocation. To better understand the prevalence of the SRP-independent pathway, we systematically defined the translocational dependence of the yeast secretome.

The E3 ubiquitin-ligase Bmi1/Ring1A controls the proteasomal degradation of Top2alpha cleavage complex - a potentially new drug target.

Background: The topoisomerases Top1, Top2alpha and Top2beta are important molecular targets for antitumor drugs, which specifically poison Top1 or Top2 isomers. While it was previously demonstrated that poisoned Top1 and Top2beta are subject to proteasomal degradation, this phenomena was not demonstrated for Top2alpha.

Methodology/principal Findings: We show here that Top2alpha is subject to drug induced proteasomal degradation as well, although at a lower rate than Top2beta.

A survey of pain, pressure, and discomfort induced by commonly used oral local anesthesia injections.

Intraoral local anesthesia is essential for delivering dental care. However, it is often perceived by some patients as the most painful and in some instances as the only painful part of the treatment, leading in extreme cases to avoidance of dental care. The present study measured the variables of pain, pressure, and discomfort caused by 4 commonly used local anesthesia injections: local infiltration, mental nerve block, inferior alveolar nerve block, and periodontal ligament injections.