Off-label dermatologic uses of IL-23 inhibitors.

Background: While IL-23 inhibitors, which include guselkumab, tildrakizumab, and risankizumab, are currently FDA-approved solely for the treatment of psoriasis, several other inflammatory skin conditions have been associated with elevated IL-23 levels. The purpose of this review is to summarize and interpret the literature surrounding the off-label uses of IL-23 inhibitors in dermatologic practice.

Methods: We conducted searches on PubMed and for clinical trials, observational studies, case series, and case reports assessing use of the three IL-23 inhibitors for non-psoriatic dermatologic conditions.

Dramatic improvement in the "Bulk" hyperpolarization of Xe via spin exchange optical pumping probed using in situ low-field NMR.

We report on hyperpolarization of quadrupolar (I=3/2) Xe via spin-exchange optical pumping. Observations of the Xe polarization dynamics via in situ low-field NMR show that the estimated alkali-metal/Xe spin-exchange rates can be large enough to compete with Xe spin relaxation. Xe polarization up to 7.

Does the Doctor-Patient Relationship Affect Enrollment in Clinical Research?

Purpose: Recruiting patients for clinical research is challenging, especially for underrepresented populations, and may be influenced by patients' relationships with their physicians, care experiences, and engagement with care. This study sought to understand predictors of enrollment in a research study among socioeconomically diverse participants in studies of care models that promote continuity in the doctor-patient relationship.

Method: A study of the effects of vitamin D levels and supplementation on COVID-19 risk and outcomes was implemented from 2020 to 2022 within 2 studies of care models at the University of Chicago that promoted continuity of inpatient and outpatient care from the same physician.

Revisiting the Time Needed to Provide Adult Primary Care.

Background: Many patients do not receive guideline-recommended preventive, chronic disease, and acute care. One potential explanation is insufficient time for primary care providers (PCPs) to provide care.

Objective: To quantify the time needed to provide 2020 preventive care, chronic disease care, and acute care for a nationally representative adult patient panel by a PCP alone, and by a PCP as part of a team-based care model.

A cryptic pocket in Ebola VP35 allosterically controls RNA binding.

Protein-protein and protein-nucleic acid interactions are often considered difficult drug targets because the surfaces involved lack obvious druggable pockets. Cryptic pockets could present opportunities for targeting these interactions, but identifying and exploiting these pockets remains challenging. Here, we apply a general pipeline for identifying cryptic pockets to the interferon inhibitory domain (IID) of Ebola virus viral protein 35 (VP35).

Naturally Occurring Genetic Variants in the Oxytocin Receptor Alter Receptor Signaling Profiles.

The hormone oxytocin is commonly administered during childbirth to initiate and strengthen uterine contractions and prevent postpartum hemorrhage. However, patients have wide variation in the oxytocin dose required for a clinical response. To begin to uncover the mechanisms underlying this variability, we screened the 11 most prevalent missense genetic variants in the oxytocin receptor () gene.

SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome.

SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression and replication that depend on the structure and dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate 0.

SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome.

SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression, and replication, which depend on the structure and dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate an unprecedented 0.

Conformational distributions of isolated myosin motor domains encode their mechanochemical properties.

Myosin motor domains perform an extraordinary diversity of biological functions despite sharing a common mechanochemical cycle. Motors are adapted to their function, in part, by tuning the thermodynamics and kinetics of steps in this cycle. However, it remains unclear how sequence encodes these differences, since biochemically distinct motors often have nearly indistinguishable crystal structures.

Antagonism between substitutions in β-lactamase explains a path not taken in the evolution of bacterial drug resistance.

CTX-M β-lactamases are widespread in Gram-negative bacterial pathogens and provide resistance to the cephalosporin cefotaxime but not to the related antibiotic ceftazidime. Nevertheless, variants have emerged that confer resistance to ceftazidime. Two natural mutations, causing P167S and D240G substitutions in the CTX-M enzyme, result in 10-fold increased hydrolysis of ceftazidime.

Cooperative Changes in Solvent Exposure Identify Cryptic Pockets, Switches, and Allosteric Coupling.

Proteins are dynamic molecules that undergo conformational changes to a broad spectrum of different excited states. Unfortunately, the small populations of these states make it difficult to determine their structures or functional implications. Computer simulations are an increasingly powerful means to identify and characterize functionally relevant excited states.

Choice of Adaptive Sampling Strategy Impacts State Discovery, Transition Probabilities, and the Apparent Mechanism of Conformational Changes.

Interest in atomically detailed simulations has grown significantly with recent advances in computational hardware and Markov state modeling (MSM) methods, yet outstanding questions remain that hinder their widespread adoption. Namely, how do alternative sampling strategies explore conformational space and how might this influence predictions generated from the data? Here, we seek to answer these questions for four commonly used sampling methods: (1) a single long simulation, (2) many short simulations run in parallel, (3) adaptive sampling, and (4) our recently developed goal-oriented sampling algorithm, FAST. We first develop a theoretical framework for analytically calculating the probability of discovering select states on simple landscapes, where we uncover the drastic effects of varying the number and length of simulations.

Selection and Clonal Propagation of High Artemisinin Genotypes of .

Artemisinin, produced in the glandular trichomes of L. is a vital antimalarial drug effective against resistant to quinine-derived medicines. Although work has progressed on the semi-synthetic production of artemisinin, field production of remains the principal commercial source of the compound.

Electron Cryo-microscopy Structure of Ebola Virus Nucleoprotein Reveals a Mechanism for Nucleocapsid-like Assembly.

Ebola virus nucleoprotein (eNP) assembles into higher-ordered structures that form the viral nucleocapsid (NC) and serve as the scaffold for viral RNA synthesis. However, molecular insights into the NC assembly process are lacking. Using a hybrid approach, we characterized the NC-like assembly of eNP, identified novel regulatory elements, and described how these elements impact function.

Emission of volatile organic compounds from petunia flowers is facilitated by an ABC transporter.

Plants synthesize a diversity of volatile molecules that are important for reproduction and defense, serve as practical products for humans, and influence atmospheric chemistry and climate. Despite progress in deciphering plant volatile biosynthesis, their release from the cell has been poorly understood. The default assumption has been that volatiles passively diffuse out of cells.

A Framework to Simplify Combined Sampling Strategies in Rosetta.

A core task in computational structural biology is the search of conformational space for low energy configurations of a biological macromolecule. Because conformational space has a very high dimensionality, the most successful search methods integrate some form of prior knowledge into a general sampling algorithm to reduce the effective dimensionality. However, integrating multiple types of constraints can be challenging.

Blockade of CD40 ligand for intercellular communication reduces hypertension, placental oxidative stress, and AT1-AA in response to adoptive transfer of CD4+ T lymphocytes from RUPP rats.

Preeclampsia (PE) is associated with altered immune activation during pregnancy. We have previously shown that adoptive transfer of CD4(+) T cells from the reduced uterine perfusion pressure (RUPP) rat model of PE increases blood pressure, oxidative stress (ROS), and inflammation in normal pregnant recipient rats. The objective of this study was to determine if blockade of communication via the CD40-CD40 ligand (CD40L) interaction between placental ischemia-induced CD4(+) T cells with endogenous normal pregnant (NP) cells would improve pathophysiology that was previously observed in NP recipient rats of RUPP CD4(+) T cells.

Simplified technique for injection of Botulinum Toxin to Obturator Internus muscle using ultrasound-guided nerve stimulation for persistent pelvic pain.

Botulinum toxin (BoNT) injections have been used to reduce muscle spasm in the presence of severe pelvic pain. However, while pubococcygeus is easily accessed vaginally, injection to obturator internus is more complex - with variation in operative technique and needle placement confounding the ability to assess outcomes. We describe a simplified technique for BoNT injection to obturator internus using neurostimulation under ultrasound guidance.

Access to Cα backbone dynamics of biological solids by 13C T1 relaxation and molecular dynamics simulation.

We introduce a labeling scheme for magic angle spinning (MAS) solid-state NMR that is based on deuteration in combination with dilution of the carbon spin system. The labeling strategy achieves spectral editing by simplification of the HαCα and aliphatic side chain spectral region. A reduction in both proton and carbon spin density in combination with fast spinning (≥50 kHz) is essential to retrieve artifact-free (13)C-R1 relaxation data for aliphatic carbons.

Enodthelin 1 is elevated in plasma and explants from patients having uterine leiomyomas.

Objective: To determine a role for endothelin (ET) in progression of uterine fibroids.

Design: An in vitro model of fibroid and myometrium cultivation.

Patients: A total of 32 women undergoing hysterectomies for uterine fibroids and 11 women undergoing hysterectomies for abnormal uterine bleeding (control population).

Site-specific analysis of heteronuclear Overhauser effects in microcrystalline proteins.

Relaxation parameters such as longitudinal relaxation are susceptible to artifacts such as spin diffusion, and can be affected by paramagnetic impurities as e.g. oxygen, which make a quantitative interpretation difficult.

Robust and highly accurate automatic NOESY assignment and structure determination with Rosetta.

We have developed a novel and robust approach for automatic and unsupervised simultaneous nuclear Overhauser effect (NOE) assignment and structure determination within the CS-Rosetta framework. Starting from unassigned peak lists and chemical shift assignments, autoNOE-Rosetta determines NOE cross-peak assignments and generates structural models. The approach tolerates incomplete and raw NOE peak lists as well as incomplete or partially incorrect chemical shift assignments, and its performance has been tested on 50 protein targets ranging from 50 to 200 residues in size.

Flower morphology and floral sequence in Artemisia annua (Asteraceae)1.

Unlabelled: •

Premise Of The Study: Artemisia annua produces phytochemicals possessing antimalarial, antitumor, anti-inflammatory, and anthelmintic activities. The main active ingredient, artemisinin, is extremely effective against malaria. Breeding to develop cultivars producing high levels of artemisinin can help meet worldwide demand for artemisinin and its derivatives.