Competing mechanisms for the buckling of an epithelial monolayer identified using multicellular simulation.

A model using the rigid body multi-cellular framework (RBMCF) is implemented to investigate the mechanisms of buckling of an epithelial monolayer. Specifically, the deformation of a monolayer of epithelial cells which are attached to a basement membrane and the surrounding stromal tissue. The epithelial monolayer, supporting basement membrane and stromal tissue are modelled using two separate vertex dynamics models (one for the epithelial monolayer layer and one for the basement membrane and stromal tissue combined) and interactions between the two are considered using the RBMCF to ensure biologically realistic interactions.

Identification of Inhibitors of virus nsP2 ATPase.

Non-structural protein 2 (nsP2), which plays an essential role in replication of CHIKV, contains a protease, helicase, and methyltransferase-like domain. We executed a simple a screen using malachite green to detect compounds that decreased ATP hydrolysis and tested a library of diverse compounds to find inhibitors of CHIKV nsP2 helicase.

Toward target 2035: EUbOPEN - a public-private partnership to enable & unlock biology in the open.

Target 2035 is a global initiative that seeks to identify a pharmacological modulator of most human proteins by the year 2035. As part of an ongoing series of annual updates of this initiative, we summarise here the efforts of the EUbOPEN project whose objectives and results are making a strong contribution to the goals of Target 2035. EUbOPEN is a public-private partnership with four pillars of activity: (1) chemogenomic library collections, (2) chemical probe discovery and technology development for hit-to-lead chemistry, (3) profiling of bioactive compounds in patient-derived disease assays, and (4) collection, storage and dissemination of project-wide data and reagents.

A Covalent Chemical Probe for nsP2 Cysteine Protease with Antialphaviral Activity and Proteome-wide Selectivity.

RA-0003022 () was identified as a high-quality covalent chemical probe for nsP2 cysteine protease (nsP2pro). Isoxazole covalently captured the active site C478 and inactivated the enzyme with a / ratio of 6000 Ms. A negative control analog RA-0025453 () retained the covalent warhead but demonstrated >100-fold decrease in enzyme inhibition.

A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.

Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays.

18 F-FDG PET/CT in the Evaluation of Polyarteritis Nodosa.

A 61-year-old man with a medical history of human immunodeficiency virus well controlled on antiretroviral therapy presented for distal sensorimotor symptoms, fatigue, and recurrent fevers. Erythrocyte sedimentation rate and C-reactive protein were both elevated. Antineutrophilic cytoplasmic antibody and antinuclear antibodies were negative.

LD-transpeptidation is crucial for fitness and polar growth in Agrobacterium tumefaciens.

Peptidoglycan (PG), a mesh-like structure which is the primary component of the bacterial cell wall, is crucial to maintain cell integrity and shape. While most bacteria rely on penicillin binding proteins (PBPs) for crosslinking, some species also employ LD-transpeptidases (LDTs). Unlike PBPs, the essentiality and biological functions of LDTs remain largely unclear.

Enhancing Photogenerated Radical Pair Properties in Donor-Chromophore-Acceptor Systems for Quantum Information Applications.

We report on new donor-chromophore-acceptor triads and where the BDX donor is 2,2,6,6-tetramethylbenzo[1,2-;4,5-]bis[1,3]dioxole, the ANI chromophore is 4-(-piperidinyl)naphthalene-1,8-dicarboximide, the NDI acceptor is naphthalene-1,8:4,5-bis(dicarboximide), and xy is a 2,5-xylyl spacer. The results on these compounds are compared to the analogous derivatives having a -methoxyaniline (MeOAn) as the donor. BDX has no nitrogen atoms and only a single hydrogen atom coupled to its unpaired electron spin, and therefore has significantly decreased hyperfine interactions compared to MeOAn.

Luminescent Organic Triplet Diradicals as Optically Addressable Molecular Qubits.

Optical-spin interfaces that enable the photoinitialization, coherent microwave manipulation, and optical read-out of ground state spins have been studied extensively in solid-state defects such as diamond nitrogen vacancy (NV) centers and are promising for quantum information science applications. Molecular quantum bits (qubits) offer many advantages over solid-state spin centers through synthetic control of their optical and spin properties and their scalability into well-defined multiqubit arrays. In this work, we report an optical-spin interface in an organic molecular qubit consisting of two luminescent tris(2,4,6-trichlorophenyl)methyl (TTM) radicals connected via the -positions of a phenyl linker.

The cell division protein FzlA performs a conserved function in diverse alphaproteobacteria.

In almost all bacteria, the tubulin-like GTPase FtsZ polymerizes to form a "Z-ring" that marks the site of division. FtsZ recruits other proteins, collectively known as the divisome, that together remodel and constrict the envelope. Constriction is driven by peptidoglycan (PG) cell wall synthesis by the glycosyltransferase FtsW and the transpeptidase FtsI (FtsWI), but these enzymes require activation to function.

Declining Medicare reimbursement in spinal imaging: a 15-year review.

Objective: To analyze and quantify the change in United States of America Medicare reimbursement rates for the 30 most commonly performed spinal imaging procedures.

Materials And Methods: The Physician Fee Schedule Look-Up Tool from the Centers for Medicare & Medicaid Services was utilized to find and extract the 28 most billed spinal imaging procedures. All data was adjusted for inflation and listed in 2020 US dollars.

Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of nsP2 Cysteine Protease with Antialphavirus Activity.

Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 () is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad-spectrum antiviral activity. Analogs of that varied each of the three regions of the molecule were synthesized to establish structure-activity relationships for the inhibition of (CHIKV) nsP2 protease and viral replication.

Poor Sleep is Common in Treatment-Resistant Late-life Depression and Associated With Poorer Antidepressant Response: Findings From the OPTIMUM Clinical Trial.

Background: Adults with treatment-resistant late-life depression (TRLLD) have high rates of sleep problems; however, little is known about the occurrence and change in sleep during pharmacotherapy of TRLLD. This analysis examined: (1) the occurrence of insufficient sleep among adults with TRLLD; (2) how sleep changed during pharmacotherapy; and (3) whether treatment outcomes differed among participants with persistent insufficient sleep, worsened sleep, improved sleep, or persistent sufficient sleep.

Methods: Secondary analysis of data from 634 participants age 60+ years in the OPTIMUM clinical trial for TRLLD.

Light-Induced H NMR Hyperpolarization in Solids at 9.4 and 21.1 T.

The inherently low sensitivity of nuclear magnetic resonance (NMR) spectroscopy is the major limiting factor for its application to elucidate structure and dynamics in solids. In the solid state, nuclear spin hyperpolarization methods based on microwave-induced dynamic nuclear polarization (DNP) provide a versatile platform to enhance the bulk NMR signal of many different sample formulations, leading to significant sensitivity improvements. Here we show that H NMR hyperpolarization can also be generated in solids at high magnetic fields by optical irradiation of the sample.

Relationship between Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores in older adults with major depressive disorder: An analysis of the OPTIMUM clinical trial.

Background: The Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) are commonly used scales to measure depression severity in older adults.

Methods: We utilized data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) clinical trial to produce conversion tables relating PHQ-9 and MADRS total scores. We split the sample into training (N = 555) and validation samples (N = 187).

Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of nsP2 Cysteine Protease with Anti-alphavirus Activity.

Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 () is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad spectrum antiviral activity. Analogs of that varied each of three regions of the molecule were synthesized to establish structure-activity relationships for inhibition of (CHIKV) nsP2 protease and viral replication.

Alcohol and substance use in older adults with treatment-resistant depression.

Introduction: Alcohol and substance use are increasing in older adults, many of whom have depression, and treatment in this context may be more hazardous. We assessed alcohol and other substance use patterns in older adults with treatment-resistant depression (TRD). We examined patient characteristics associated with higher alcohol consumption and examined the moderating effect of alcohol on the association between clinical variables and falls during antidepressant treatment.

Anomalous origin of the circumflex artery from the right pulmonary artery.

Anomalous origin of the circumflex artery from the pulmonary artery (ACxAPA) is a rare but clinically significant condition in which the circumflex artery arises from either the main pulmonary artery or one of its main branches. Untreated patients with ACxAPA may develop severe heart failure or sudden cardiac death. Diagnosis is established with either catheter or CT angiography.

Magic Angle Spinning Solid-State C Photochemically Induced Dynamic Nuclear Polarization by a Synthetic Donor-Chromophore-Acceptor System at 9.4 T.

Solid-state photochemically induced dynamic nuclear polarization (photo-CIDNP) is a nuclear magnetic resonance spectroscopy technique in which nuclear spin hyperpolarization is generated upon optical irradiation of an appropriate donor-acceptor system. Until now, solid-state photo-CIDNP at high magnetic fields has been observed only in photosynthetic reaction centers and flavoproteins. In the present work, we show that the effect is not limited to such biomolecular samples, and solid-state C photo-CIDNP can be observed at 9.

A 2D chiral microcavity based on apparent circular dichroism.

Engineering asymmetric transmission between left-handed and right-handed circularly polarized light in planar Fabry-Pérot (FP) microcavities would enable a variety of chiral light-matter phenomena, with applications in spintronics, polaritonics, and chiral lasing. Such symmetry breaking, however, generally requires Faraday rotators or nanofabricated polarization-preserving mirrors. We present a simple solution requiring no nanofabrication to induce asymmetric transmission in FP microcavities, preserving low mode volumes by embedding organic thin films exhibiting apparent circular dichroism (ACD); an optical phenomenon based on 2D chirality.

Getting to the point: unipolar growth of Hyphomicrobiales.

The governing principles and suites of genes for lateral elongation or incorporation of new cell wall material along the length of a rod-shaped cell are well described. In contrast, relatively little is known about unipolar elongation or incorporation of peptidoglycan at one end of the rod. Recent work in three related model systems of unipolar growth (Agrobacterium tumefaciens, Brucella abortus, and Sinorhizobium meliloti) has clearly established that unipolar growth in the Hyphomicrobiales order relies on a set of genes distinct from the canonical elongasome.

Discovery of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach.

Unlabelled: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has been responsible for numerous large-scale outbreaks in the last twenty years. Currently, there are no FDA-approved therapeutics for any alphavirus infection. CHIKV non-structural protein 2 (nsP2), which contains a cysteine protease domain, is essential for viral replication, making it an attractive target for a drug discovery campaign.