N1-Methylpseudouridine and pseudouridine modifications modulate mRNA decoding during translation.

The ribosome utilizes hydrogen bonding between mRNA codons and aminoacyl-tRNAs to ensure rapid and accurate protein production. Chemical modification of mRNA nucleobases can adjust the strength and pattern of this hydrogen bonding to alter protein synthesis. We investigate how the N1-methylpseudouridine (mΨ) modification, commonly incorporated into therapeutic and vaccine mRNA sequences, influences the speed and fidelity of translation.

Disease related changes in ATAC-seq of iPSC-derived motor neuron lines from ALS patients and controls.

Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing.

Discovery of Group II Intron RNA Splicing Inhibitors.

Here, we describe the discovery of compounds that inhibit self-splicing in group II introns. Using docking calculations, we targeted the catalytic active site within the group IIC intron and virtually screened a library of lead-like compounds. From this initial virtual screen, we identified three unique scaffolds that inhibit splicing .

Collaborative Learning Communities With Medical Students as Teachers.

In recent years, peer-assisted learning has emerged as a new and effective medical education modality. Near-peer tutoring utilizes a senior student serving as an instructor to a junior student. In 2019, the University of California, Irvine, School of Medicine (UCISOM) implemented a near-peer tutoring model beginning with first-year anatomy and physiology curricula.

Lifetime of ground conformational state determines the activity of structured RNA.

Biomolecules continually sample alternative conformations. Consequently, even the most energetically favored ground conformational state has a finite lifetime. Here, we show that, in addition to the 3D structure, the lifetime of a ground conformational state determines its biological activity.

Structural basis for control of bacterial RNA polymerase pausing by a riboswitch and its ligand.

Folding of nascent transcripts can be modulated by the RNA polymerase (RNAP) that carries out their transcription, and vice versa. A pause of RNAP during transcription of a preQ riboswitch (termed que-PEC) is stabilized by a previously characterized template consensus sequence and the ligand-free conformation of the nascent RNA. Ligand binding to the riboswitch induces RNAP pause release and downstream transcription termination; however, the mechanism by which riboswitch folding modulates pausing is unclear.

Per- and polyfluoroalkyl substances fate and transport at a wastewater treatment plant with a collocated sewage sludge incinerator.

This study aims to understand the fate and transport of per- and polyfluoroalkyl substances (PFAS) and inorganic fluoride (IF) at an undisclosed municipal wastewater treatment plant (WWTP) operating a sewage sludge incinerator (SSI). A robust statistical analysis characterized concentrations and mass flows at all WWTP and SSI primary influents/effluents, including thermal-treatment derived airborne emissions. WWTP-level net mass flows (NMFs) of total PFAS were not statistically different from zero.

Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects.

Using induced pluripotent stem cells (iPSCs) to understand the mechanisms of neurological disease holds great promise; however, there is a lack of well-curated lines from a large array of participants. Answer ALS has generated over 1,000 iPSC lines from control and amyotrophic lateral sclerosis (ALS) patients along with clinical and whole-genome sequencing data. The current report summarizes cell marker and gene expression in motor neuron cultures derived from 92 healthy control and 341 ALS participants using a 32-day differentiation protocol.

Using Selectively Scaled Molecular Dynamics Simulations to Assess Ligand Poses in RNA Aptamers.

Predicting the structure (or pose) of RNA-ligand complexes is an important problem in RNA structural biology. Although one could use computational docking to rapidly sample putative poses of RNA-ligand complexes, accurately discriminating the native-like poses from non-native, decoy poses remains a formidable challenge. Here, we started from the assumption that native-like RNA-ligand poses are less likely to dissociate during molecular dynamics simulations, and then we used enhanced simulations to promote ligand unbinding for diverse poses of a handful of RNA aptamer-ligand complexes.

Using Unassigned NMR Chemical Shifts to Model RNA Secondary Structure.

NMR-derived chemical shifts are sensitive probes of RNA structure. However, the need to assign NMR spectra hampers their utility as a direct source of structural information. In this report, we describe a simple method that uses unassigned 2D NMR spectra to model the secondary structure of RNAs.

Answer ALS, a large-scale resource for sporadic and familial ALS combining clinical and multi-omics data from induced pluripotent cell lines.

Answer ALS is a biological and clinical resource of patient-derived, induced pluripotent stem (iPS) cell lines, multi-omic data derived from iPS neurons and longitudinal clinical and smartphone data from over 1,000 patients with ALS. This resource provides population-level biological and clinical data that may be employed to identify clinical-molecular-biochemical subtypes of amyotrophic lateral sclerosis (ALS). A unique smartphone-based system was employed to collect deep clinical data, including fine motor activity, speech, breathing and linguistics/cognition.

An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients.

Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in .

Navigating Chemical Space by Interfacing Generative Artificial Intelligence and Molecular Docking.

Here, we report the implementation and application of a simple, structure-aware framework to generate target-specific screening libraries. Our approach combines advances in generative artificial intelligence (AI) with conventional molecular docking to explore chemical space on the unique physicochemical properties of the active site of a biomolecular target. As a demonstration, we used our framework, which we refer to as sample-and-dock, to construct focused libraries for cyclin-dependent kinase type-2 (CDK2) and the active site of the main protease (M) of the SARS-CoV-2 virus.

Probabilistic Modeling of RNA Ensembles Using NMR Chemical Shifts.

NMR-derived chemical shifts are structural fingerprints that are sensitive to the underlying conformational distributions of molecules. Thus, chemical shift data are now routinely used to infer the dynamical or conformational ensembles of peptides and proteins. However, for RNAs, techniques for inferring their conformational ensembles from chemical shift data have received less attention.

Quantum Mechanics Helps Uncover Atypical Recognition Features in the Flavin Mononucleotide Riboswitch.

Estimating the binding energies of small molecules to RNA could help uncover their molecular recognition characteristics and be used to rationally design RNA-targeting chemical probes. Here, we leveraged the ability of the fragment molecular orbital (FMO) method to provide detailed pairwise energetic information to examine the interactions between the aptamer domain of the flavin mononucleotide (FMN)-responsive riboswitch and small-molecule ligands. After developing an efficient protocol for executing high-level FMO calculations on RNA-ligand complexes, we applied our protocol to nine FMN-aptamer-ligand complexes.

Mining for Ligandable Cavities in RNA.

Identifying potential ligand binding cavities is a critical step in structure-based screening of biomolecular targets. Cavity mapping methods can detect such binding cavities; however, for ribonucleic acid (RNA) targets, determining which of the detected cavities are "ligandable" remains an unsolved challenge. In this study, we trained a set of machine learning classifiers to distinguish ligandable RNA cavities from decoy cavities.

Correction: Paszkiewicz et al. A Peripheral CB1R Antagonist Increases Lipolysis, Oxygen Consumption Rate, and Markers of Beiging in 3T3-L1 Adipocytes Similar to RIM, Suggesting That Central Effects Can Be Avoided. 2020, , 6639.

The authors wish to make the following corrections to this paper [...

RNA Ensembles from Solvent Accessibility Data: Application to the SAM-I Riboswitch Aptamer Domain.

Riboswitches are regulatory ribonucleic acid (RNA) elements that act as ligand-dependent conformational switches that recognize their cognate ligand via a binding pocket located in their aptamer domain. In the apo form, the aptamer domain is dynamic, requiring an ensemble representation of its structure. Here, as a proof-of-concept, we used solvent accessibility information to construct a pair of dynamical ensembles of the aptamer domain of the well-studied -adenosylmethionine (SAM) class-I riboswitch in the absence (-SAM) and presence (+SAM) of SAM.

CS-Annotate: A Tool for Using NMR Chemical Shifts to Annotate RNA Structure.

Here, we introduce CS-Annotate, a tool that uses assigned NMR chemical shifts to annotate structural features in RNA. At its core, CS-Annotate is a deployment of a multitask deep learning model that simultaneously classifies the solvent exposure, base-stacking and -pairing status, and conformation of individual RNA residues from their chemical shift fingerprint. Here, we briefly describe how we trained and tested the classifier and demonstrate its application to a model RNA system.

Endocannabinoid Receptor-1 and Sympathetic Nervous System Mediate the Beneficial Metabolic Effects of Gastric Bypass.

The exact mechanisms underlying the metabolic effects of bariatric surgery remain unclear. Here, we demonstrate, using a combination of direct and indirect calorimetry, an increase in total resting metabolic rate (RMR) and specifically anaerobic RMR after Roux-en-Y gastric bypass (RYGB), but not sleeve gastrectomy (SG). We also show an RYGB-specific increase in splanchnic sympathetic nerve activity and "browning" of visceral mesenteric fat.

A Peripheral CB1R Antagonist Increases Lipolysis, Oxygen Consumption Rate, and Markers of Beiging in 3T3-L1 Adipocytes Similar to RIM, Suggesting that Central Effects Can Be Avoided.

With the increased prevalence of obesity and related co-morbidities, such as type 2 diabetes (T2D), worldwide, improvements in pharmacological treatments are necessary. The brain- and peripheral-cannabinoid receptor 1 (CB1R) antagonist rimonabant (RIM) has been shown to induce weight loss and improve glucose homeostasis. We have previously demonstrated that RIM promotes adipose tissue beiging and decreased adipocyte cell size, even during maintenance on a high-fat diet.

RNAPosers: Machine Learning Classifiers for Ribonucleic Acid-Ligand Poses.

Determining the three-dimensional (3D) structures of ribonucleic acid (RNA)-small molecule ligand complexes is critical to understanding molecular recognition in RNA. Computer docking can, in principle, be used to predict the 3D structure of RNA-small molecule complexes. Unfortunately, retrospective analysis has shown that the scoring functions that are typically used for pose prediction tend to misclassify non-native poses as native and vice versa.

Chemical characterization of marijuana blunt smoke by non-targeted chemical analysis.

Marijuana blunts, which are tobacco cigar wrappers filled with marijuana, are commonly smoked in the US as a means of cannabis use. The use of marijuana blunts presents toxicity concerns because the smoke contains both marijuana-related and tobacco-related chemicals. Thus, it is important to understand the chemical composition of mainstream smoke (MSS) from marijuana blunts.

Effects of ERβ and ERα on OVX-induced changes in adiposity and insulin resistance.

Loss of ovarian hormones leads to increased adiposity and insulin resistance (IR), increasing the risk for cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the molecular mechanism behind the adverse systemic and adipose tissue-specific metabolic effects of ovariectomy requires loss of signaling through estrogen receptor alpha (ERα) or estrogen receptor β (ERβ). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ERα-null (αKO), and ERβ-null (βKO) female mice (age ~49 weeks; n = 7-12/group).

PyShifts: A PyMOL Plugin for Chemical Shift-Based Analysis of Biomolecular Ensembles.

Here, we present PyShifts-a PyMOL plugin for chemical shift-based analysis of biomolecular ensembles. With PyShifts, users can compare and visualize differences between experimentally measured and computationally predicted chemical shifts. When analyzing multiple conformations of a biomolecule with PyShifts, users can also sort a set of conformations based on chemical shift differences and identify the conformers that exhibit the best agreement between measured and predicted chemical shifts.