Comparison of Immunotherapy versus Targeted Therapy Effectiveness in BRAF-Mutant Melanoma Patients and Use of cGAS Expression and Aneuploidy as Potential Prognostic Biomarkers.

BRAF-mutant melanoma patients can be treated with targeted therapy or immunotherapies, and it is not clear which should be provided first. Targeted treatments do not work in up to one-third of cases, while immunotherapies may only be effective in up to 60% and come with a high risk of immune-related side effects. Determining which treatment to provide first is thus of critical importance.

Optimization of Tissue Digestion Methods for Characterization of Photoaged Skin by Single Cell RNA Sequencing Reveals Preferential Enrichment of T Cell Subsets.

Healthy human skin tissue is often used as a control for comparison to diseased skin in patients with skin pathologies, including skin cancers or other inflammatory conditions such as atopic dermatitis or psoriasis. Although non-affected skin from these patients is a more appropriate choice for comparison, there is a paucity of studies examining such tissue. This lack is exacerbated by the difficulty of processing skin tissue for experimental analysis.

Advances in Early Detection of Melanoma and the Future of At-Home Testing.

The past decade has seen numerous advancements in approaches to melanoma detection, each with the common goal to stem the growing incidence of melanoma and its mortality rate. These advancements, while well documented to increase early melanoma detection, have also garnered considerable criticism of their efficacy for improving survival rates. In this review, we discuss the current state of such early detection approaches that do not require direct dermatologist intervention.

AKAP95 Organizes a Nuclear Microdomain to Control Local cAMP for Regulating Nuclear PKA.

Contrary to the classic model of protein kinase A (PKA) residing outside of the nucleus, we identify a nuclear signaling complex that consists of AKAP95, PKA, and PDE4D5 and show that it forms a functional cyclic AMP (cAMP) signaling microdomain. Locally generated cAMP can accumulate within the vicinity of this complex; however, when cAMP is generated at the plasma membrane, PDE4 serves as a local sink and PDE3 as a barrier to prevent accumulation of cAMP within the microdomain as a means of controlling activation of tethered nuclear PKA.

Mouse Spermatogenesis Requires Classical and Nonclassical Testosterone Signaling.

Testosterone acts though the androgen receptor in Sertoli cells to support germ cell development (spermatogenesis) and male fertility, but the molecular and cellular mechanisms by which testosterone acts are not well understood. Previously, we found that in addition to acting through androgen receptor to directly regulate gene expression (classical testosterone signaling pathway), testosterone acts through a nonclassical pathway via the androgen receptor to rapidly activate kinases that are known to regulate spermatogenesis. In this study, we provide the first evidence that nonclassical testosterone signaling occurs in vivo as the MAP kinase cascade is rapidly activated in Sertoli cells within the testis by increasing testosterone levels in the rat.

Dynamic Visualization of mTORC1 Activity in Living Cells.

The mechanistic target of rapamycin complex 1 (mTORC1) senses diverse signals to regulate cell growth and metabolism. It has become increasingly clear that mTORC1 activity is regulated in time and space inside the cell, but direct interrogation of such spatiotemporal regulation is challenging. Here, we describe a genetically encoded mTORC1 activity reporter (TORCAR) that exhibits a change in FRET in response to phosphorylation by mTORC1.

Single-cell analysis of G-protein signal transduction.

The growing use of fluorescent biosensors to directly probe the spatiotemporal dynamics of biochemical processes in living cells has revolutionized the study of intracellular signaling. In this review, we summarize recent developments in the use of biosensors to illuminate the molecular details of G-protein-coupled receptor (GPCR) signaling pathways, which have long served as the model for our understanding of signal transduction, while also offering our perspectives on the future of this exciting field. Specifically, we highlight several ways in which biosensor-based single-cell analyses are being used to unravel many of the enduring mysteries that surround these diverse signaling pathways.

Sockeye salmon retain immunoglobulin-secreting plasma cells throughout their spawning journey and post-spawning.

Antibody-producing plasma cells are a major source of protective immunity in vertebrates, including salmon. During the spawning phase, salmon undergo drastic, hormonally driven changes in their physiology, including elevated levels of cortisol, which are known to suppress the immune system. As adult fish need to survive their long journey to the spawning grounds, we hypothesized that humoral immunity, in the form of IgM-secreting plasma cells, remains functional until post-spawning.