Probes for INS

Myeloid lineage cells suppress T cell viability through arginine depletion via arginase 1 (ARG1). Despite numerous studies exploring the mechanisms by which ARG1 perturbs lymphocyte function, the cellular populations responsible for its generation and release remain poorly understood. Here, we showed that neutrophil lineage cells and not monocytes or macrophages expressed ARG1 in human non-small cell lung cancer (NSCLC). Importantly, we showed that approximately 40% of tumor-associated neutrophils (TANs) actively transcribed ARG1 mRNA. To determine the mechanism by which ARG1 mRNA is induced in TANs, we utilized FPLC followed by MS/MS to screen tumor-derived factors capable of inducing ARG1 mRNA expression in neutrophils. These studies identified ANXA2 as the major driver of ARG1 mRNA expression in TANs. Mechanistically, ANXA2 signaled through the TLR2/MYD88 axis in neutrophils to induce ARG1 mRNA expression. The current study describes what we believe to be a novel mechanism by which ARG1 mRNA expression is regulated in neutrophils in cancer and highlights the central role that neutrophil lineage cells play in the suppression of tumor-infiltrating lymphocytes.

Amyotrophic lateral sclerosis or ALS is a devastating and fatal neurodegenerative disease of motor neurons with very few treatment options. We had previously found that motor neuron degeneration in a mouse model of ALS can be delayed by deleting the axon damage sensor MAP3K12 or Dual Leucine Zipper Kinase (DLK)1. However, DLK is also involved in axon regeneration2-5, prompting us to ask whether combining DLK deletion with a way to promote axon regeneration would result in greater motor neuron protection. To achieve this, we used a mouse line that constitutively expresses ATF3, a master regulator of regeneration in neurons6,7. Although there is precedence for each individual strategy in the SOD1G93A mouse model of ALS1,8, these have not previously been combined. By several lines of evidence including motor neuron electrophysiology, histology and behavior, we observed a powerful synergy when combining DLK deletion with ATF3 expression. The combinatorial strategy resulted in significant protection of motor neurons with fewer undergoing cell death, reduced axon degeneration, and preservation of motor function and connectivity to muscle. This study provides a demonstration of the power of combinatorial therapy to treat neurodegenerative disease.

The Planar cell polarity (PCP) pathway is known to mediate the function of the Wnt proteins in growth cone guidance. Here, we show that the PCP pathway may directly influence local protein synthesis within the growth cones. We found that FMRP interacts with Fzd3. This interaction is negatively regulated by Wnt5a, which induces FMRP phosphorylation. Knocking down FMRP via electroporating shRNAs into the dorsal spinal cord lead to a randomization of anterior-posterior turning of commissural axons, which could be rescued by a FMRP rescue construct. Using RNAscope, we found that some of the FMRP target mRNAs encoding PCP components, PRICKLE2 and Celsr2, as well as regulators of cytoskeletal dynamics and components of cytoskeleton, APC, Cfl1, Map1b, Tubb3 and Actb, are present in the commissural neuron growth cones. Our results suggest that PCP signaling may regulate growth cone guidance, at least in part, by regulating local protein synthesis in the growth cones through via an interaction between Frizzled3 and FMRP.

Star polymers are structures composed of multiple functional linear arms covalently connected through a central core. The unique conformation of star polymers, with their tunable side arms and architectural plasticity, makes them well equipped to deliver pharmaceutical drugs and biologicals (peptides, nucleic acids), and design imaging agents. A great deal has been reported on the design and synthesis of star polymers, with several studies demonstrating the possibility for future translation. In this work, we have for the first time performed a review on research published over the last 5-years, focused on the translation of star polymer nanoparticles toward therapeutic application. We discuss all the important potential translational breakthroughs in the field as well as offering a perspective on how the addition of cutting-edge in vitro and in vivo models could provide us with the tools for the successful future clinical translation of star polymer nanoparticles.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, but its root cause may lie in neurodevelopment. PSEN1 mutations cause the majority of familial AD, potentially by disrupting proper Notch signaling, causing early unnoticed cellular changes that affect later AD progression. While rodent models are useful for modeling later stages of AD, human induced pluripotent stem cell-derived cortical spheroids (hCSs) allow access to studying the human cortex at the cellular level over the course of development. Here, we show that the PSEN1 L435F heterozygous mutation affects hCS development, increasing size, increasing progenitors, and decreasing post-mitotic neurons as a result of increased Notch target gene expression during early hCS development. We also show altered Aβ expression and neuronal activity at later hCS stages. These results contrast previous findings, showing how individual PSEN1 mutations may differentially affect neurodevelopment and may give insight into fAD progression to provide earlier time points for more effective treatments.