INDIVIDUAL ARTICLE: Real-World Cases of Clascoterone Topical Treatment for Acne and Related Disorders.

Acne vulgaris affects approximately 80% of young adults and adolescents in the world. Acne presents as comedones, pustules, papules, and nodules on the face, chest, shoulders, or back. It can lead to a significant decrease in quality of life with a high risk of associated depression and anxiety.

Use of a small molecule microarray screen to identify inhibitors of the catalytic RNA subunit of Methanobrevibacter smithii RNase P.

Despite interest in developing therapeutics that leverage binding pockets in structured RNAs-whose dysregulation leads to diseases-such drug discovery efforts are limited. Here, we have used a small molecule microarray (SMM) screen to find inhibitors of a large ribozyme: the Methanobrevibacter smithii RNase P RNA (Msm RPR, ∼300 nt). The ribonucleoprotein form of RNase P, which catalyzes the 5'-maturation of precursor tRNAs, is a suitable drug target as it is essential, structurally diverse across life domains, and present in low copy.

Widespread 3'UTR capped RNAs derive from G-rich regions in proximity to AGO2 binding sites.

The 3' untranslated region (3'UTR) plays a crucial role in determining mRNA stability, localisation, translation and degradation. Cap analysis of gene expression (CAGE), a method for the detection of capped 5' ends of mRNAs, additionally reveals a large number of apparently 5' capped RNAs derived from locations within the body of the transcript, including 3'UTRs. Here, we provide direct evidence that these 3'UTR-derived RNAs are indeed capped and widespread in mammalian cells.

Bioorthogonal cyclopropenones for investigating RNA structure.

RNA sequences encode secondary and tertiary structures that impact protein production and other cellular processes. Misfolded RNAs can also potentiate disease, but the complete picture is lacking. To establish more comprehensive and accurate RNA structure-function relationships, new methods are needed to interrogate RNA and trap native conformations in cellular environments.

Decoding complexity in biomolecular recognition of DNA i-motifs with microarrays.

DNA i-motifs (iMs) are non-canonical C-rich secondary structures implicated in numerous cellular processes. Though iMs exist throughout the genome, our understanding of iM recognition by proteins or small molecules is limited to a few examples. We designed a DNA microarray containing 10976 genomic iM sequences to examine the binding profiles of four iM-binding proteins, mitoxantrone and the iMab antibody.

Distinct neuroinflammatory signatures exist across genetic and sporadic amyotrophic lateral sclerosis cohorts.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. ALS is on a pathogenetic disease spectrum with frontotemporal dementia, referred to as ALS-frontotemporal spectrum disorder (ALS-FTSD). For mutations associated with ALS-FTSD, such as the C9orf72 hexanucleotide repeat expansion, the molecular factors associated with heterogeneity along this spectrum require further characterization.

Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice.

RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein 2 (RBFOX2) in maintaining cholesterol homeostasis in a lipogenic environment in the liver.

Random forest modelling demonstrates microglial and protein misfolding features to be key phenotypic markers in C9orf72-ALS.

Clinical heterogeneity observed across patients with amyotrophic lateral sclerosis (ALS) is a known complicating factor in identifying potential therapeutics, even within cohorts with the same mutation, such as C9orf72 hexanucleotide repeat expansions (HREs). Thus, further understanding of pathways underlying this heterogeneity is essential for appropriate ALS trial stratification and the meaningful assessment of clinical outcomes. It has been shown that both inflammation and protein misfolding can influence ALS pathogenesis, such as the manifestation or severity of motor or cognitive symptoms.

Heterobifunctional molecules tackle targeted protein dephosphorylation.

Recently, Chen and colleagues reported the development of phosphatase-targeting chimeric molecules (PhosTACs), heterobifunctional small molecules that promote targeted, proximity-induced protein dephosphorylation. This strategy represents an innovative approach to selectively manipulate phosphoprotein function and provides proof-of-concept for a new class of bifunctional small molecules in the chemical biologist's toolbox.

Astrocytes display cell autonomous and diverse early reactive states in familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a rapidly progressive and fatal disease. Although astrocytes are increasingly recognized contributors to the underlying pathogenesis, the cellular autonomy and uniformity of astrocyte reactive transformation in different genetic forms of amyotrophic lateral sclerosis remain unresolved. Here we systematically examine these issues by using highly enriched and human induced pluripotent stem cell-derived astrocytes from patients with VCP and SOD1 mutations.

A flexible microfluidic system for single-cell transcriptome profiling elucidates phased transcriptional regulators of cell cycle.

Single cell transcriptome profiling has emerged as a breakthrough technology for the high-resolution understanding of complex cellular systems. Here we report a flexible, cost-effective and user-friendly droplet-based microfluidics system, called the Nadia Instrument, that can allow 3' mRNA capture of ~ 50,000 single cells or individual nuclei in a single run. The precise pressure-based system demonstrates highly reproducible droplet size, low doublet rates and high mRNA capture efficiencies that compare favorably in the field.

Elucidating the cellular dynamics of the brain with single-cell RNA sequencing.

Single-cell RNA-sequencing (scRNA-seq) has emerged in recent years as a breakthrough technology to understand RNA metabolism at cellular resolution. In addition to allowing new cell types and states to be identified, scRNA-seq can permit cell-type specific differential gene expression changes, pre-mRNA processing events, gene regulatory networks and single-cell developmental trajectories to be uncovered. More recently, a new wave of multi-omic adaptations and complementary spatial transcriptomics workflows have been developed that facilitate the collection of even more holistic information from individual cells.

Lipophilic tail modifications of 2-(hydroxymethyl)pyrrolidine scaffold reveal dual sphingosine kinase 1 and 2 inhibitors.

The sphingosine 1-phosphate (S1P) signaling pathway is an attractive target for pharmacological manipulation due to its involvement in cancer progression and immune cell chemotaxis. The synthesis of S1P is catalyzed by the action of sphingosine kinase 1 or 2 (SphK1 or SphK2) on sphingosine and ATP. While potent and selective inhibitors of SphK1 or SphK2 have been reported, development of potent dual SphK1/SphK2 inhibitors are still needed.

Granulomatous and systemic inflammatory reactions from tattoo ink: Case report and concise review.

Tattoo pigment can precipitate numerous inflammatory states, and granulomatous tattoo reactions are a diagnostically challenging form. The skin is the most common site of inflammation, but systemic inflammation can occur. Reactions to black tattoo ink have a broad differential of cutaneous and systemic conditions.

Coronary CT Angiography and Carotid MRI Improve Phenotyping of Disease Extent Compared with ACC/AHA Risk Score Alone.

Purpose: To determine the relationship between the American College of Cardiology/American Heart Association (ACC/AHA) risk score and plaque phenotype of the coronary and carotid arteries assessed directly using CT angiography and MRI.

Materials And Methods: Asymptomatic subjects eligible for statin therapy by risk score were enrolled in a prospective study of disease burden using coronary artery calcium (CAC) scoring, coronary CT angiography, and MRI of the carotid arteries. Quartiles were calculated for noncalcified plaque, CAC, and average carotid wall volume and were compared with ACC/AHA risk quartiles.

Author Correction: A systems view of spliceosomal assembly and branchpoints with iCLIP.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Discovery of a Small Side Cavity in Sphingosine Kinase 2 that Enhances Inhibitor Potency and Selectivity.

The sphingosine-1-phosphate (S1P) signaling pathway is an attractive drug target due to its involvement in immune cell chemotaxis and vascular integrity. The formation of S1P is catalyzed by sphingosine kinase 1 or 2 (SphK1 or SphK2) from sphingosine (Sph) and ATP. Inhibition of SphK1 and SphK2 to attenuate levels of S1P has been reported to be efficacious in animal models of diseases such as cancer, sickle cell disease, and renal fibrosis.

A systems view of spliceosomal assembly and branchpoints with iCLIP.

Studies of spliceosomal interactions are challenging due to their dynamic nature. Here we used spliceosome iCLIP, which immunoprecipitates SmB along with small nuclear ribonucleoprotein particles and auxiliary RNA binding proteins, to map spliceosome engagement with pre-messenger RNAs in human cell lines. This revealed seven peaks of spliceosomal crosslinking around branchpoints (BPs) and splice sites.

Route to Air and Moisture Stable β-Difluoroboryl Acrylamides.

A method for the preparation of air stable difluoroboryl acrylamides is reported. In contrast to the ubiquitous organotrifluoroborate salts, difluoroboryl acrylamides are relatively nonpolar and are readily purified by silica chromatography. Difluoroboryl acrylamides serve as efficient substrates in cross-coupling reactions to afford the corresponding trisubstituted acrylamides in good to excellent yields.