Inhibition of the Rho/MRTF pathway improves the response of BRAF-resistant melanoma to PD1/PDL1 blockade.

Metastatic cutaneous melanoma is a fatal skin cancer. Resistance to targeted and immune therapies limits the benefits of current treatments. Identifying and adding anti-resistance agents to current treatment protocols can potentially improve clinical responses.

Role of Rho/MRTF in Aggressive Vemurafenib-Resistant Murine Melanomas and Immune Checkpoint Upregulation.

Cutaneous melanoma is the deadliest skin cancer. Most have Ras-MAPK pathway (BRAF or NRAS) mutations and highly effective targeted therapies exist; however, they and immune therapies are limited by resistance, in part driven by small GTPase (Rho and Rac) activation. To facilitate preclinical studies of combination therapies to provide durable responses, we describe the first mouse melanoma lines resistant to BRAF inhibitors.

ILEE: Algorithms and toolbox for unguided and accurate quantitative analysis of cytoskeletal images.

The eukaryotic cytoskeleton plays essential roles in cell signaling and trafficking, broadly associated with immunity and diseases in humans and plants. To date, most studies describing cytoskeleton dynamics and function rely on qualitative/quantitative analyses of cytoskeletal images. While state-of-the-art, these approaches face general challenges: the diversity among filaments causes considerable inaccuracy, and the widely adopted image projection leads to bias and information loss.

BRAF Inhibitor Resistance Confers Increased Sensitivity to Mitotic Inhibitors.

Single agent and combination therapy with BRAF and MEK inhibitors have remarkable efficacy against melanoma tumors with activating BRAF mutations, but in most cases BRAF inhibitor (BRAFi) resistance eventually develops. One resistance mechanism is reactivation of the ERK pathway. However, only about half of BRAFi resistance is due to ERK reactivation.

Dynamic disequilibrium-based pathogenicity model in mutated pyrin's B30.2 domain-Casp1/p20 complex.

Background: The B30.2 variants lead to most relevant severity forms of familial Mediterranean fever (FMF) manifestations. The B30.

Self-Renewing Islet TCF1 CD8 T Cells Undergo IL-27-Controlled Differentiation to Become TCF1 Terminal Effectors during the Progression of Type 1 Diabetes.

In type 1 diabetes (T1D) autoreactive CD8 T cells infiltrate pancreatic islets and destroy insulin-producing β cells. Progression to T1D onset is a chronic process, which suggests that the effector activity of β-cell autoreactive CD8 T cells needs to be maintained throughout the course of disease development. The mechanism that sustains diabetogenic CD8 T cell effectors during the course of T1D progression has not been completely defined.

Mutational analysis of Aurora kinase C gene in Egyptian patients with macrozoospermia.

Macrozoospermia is a rare syndrome. The key marker of the disease is a high percentage of spermatozoa with abnormal phenotypes namely enlarged head and multiple tails. The presence of at least 70% of spermatozoa with a large head is usually associated with Aurora kinase C gene (AURKC) mutations.

The CD137 Ligand Is Important for Type 1 Diabetes Development but Dispensable for the Homeostasis of Disease-Suppressive CD137 FOXP3 Regulatory CD4 T Cells.

CD137 modulates type 1 diabetes (T1D) progression in NOD mice. We previously showed that CD137 expression in CD4 T cells inhibits T1D, but its expression in CD8 T cells promotes disease development by intrinsically enhancing the accumulation of β-cell-autoreactive CD8 T cells. CD137 is expressed on a subset of FOXP3 regulatory CD4 T cells (Tregs), and CD137 Tregs are the main source of soluble CD137.

Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjögren Syndrome-like Inflammation.

Human genetic studies implicate interleukin-27 (IL-27) in the pathogenesis of type 1 diabetes (T1D), but the underlying mechanisms remain largely unexplored. To further define the role of IL-27 in T1D, we generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27Rα. In contrast to wild-type NOD mice, both NOD.

Combined congenic mapping and nuclease-based gene targeting for studying allele-specific effects of Tnfrsf9 within the Idd9.3 autoimmune diabetes locus.

Rodent complex trait genetic studies involving a cross between two inbred strains are usually followed by congenic mapping to refine the loci responsible for the phenotype. However, progressing from a chromosomal region to the actual causal gene remains challenging because multiple polymorphic genes are often closely linked. The goal of this study was to develop a strategy that allows candidate gene testing by allele-specific expression without prior knowledge of the credible causal variant.

Technical advances in trigger-induced RNA interference gene silencing in the parasite Entamoeba histolytica.

Entamoeba histolytica has a robust endogenous RNA interference (RNAi) pathway. There are abundant 27 nucleotide (nt) anti-sense small RNAs (AS sRNAs) that target genes for silencing and the genome encodes many genes involved in the RNAi pathway such as Argonaute proteins. Importantly, an E.

A Single RNaseIII Domain Protein from Entamoeba histolytica Has dsRNA Cleavage Activity and Can Help Mediate RNAi Gene Silencing in a Heterologous System.

Dicer enzymes process double-stranded RNA (dsRNA) into small RNAs that target gene silencing through the RNA interference (RNAi) pathway. Dicer enzymes are complex, multi-domain RNaseIII proteins, however structural minimalism of this protein has recently emerged in parasitic and fungal systems. The most minimal Dicer, Saccharomyces castellii Dicer1, has a single RNaseIII domain and two double stranded RNA binding domains.

Dimethylated H3K27 Is a Repressive Epigenetic Histone Mark in the Protist Entamoeba histolytica and Is Significantly Enriched in Genes Silenced via the RNAi Pathway.

RNA interference (RNAi) is a fundamental biological process that plays a crucial role in regulation of gene expression in many organisms. Transcriptional gene silencing (TGS) is one of the important nuclear roles of RNAi. Our previous data show that Entamoeba histolytica has a robust RNAi pathway that links to TGS via Argonaute 2-2 (Ago2-2) associated 27-nucleotide small RNAs with 5'-polyphosphate termini.

Multifunctional G-rich and RRM-containing domains of TbRGG2 perform separate yet essential functions in trypanosome RNA editing.

Efficient editing of Trypanosoma brucei mitochondrial RNAs involves the actions of multiple accessory factors. T. brucei RGG2 (TbRGG2) is an essential protein crucial for initiation and 3'-to-5' progression of editing.

TbRGG2 facilitates kinetoplastid RNA editing initiation and progression past intrinsic pause sites.

TbRGG2 is an essential kinetoplastid RNA editing accessory factor that acts specifically on pan-edited RNAs. To understand the mechanism of TbRGG2 action, we undertook an in-depth analysis of edited RNA populations in TbRGG2 knockdown cells and an in vitro examination of the biochemical activities of the protein. We demonstrate that TbRGG2 down-regulation more severely impacts editing at the 5' ends of pan-edited RNAs than at their 3' ends.