Potent antitumor activity of a designed interleukin-21 mimic.

Long-standing goals of cancer immunotherapy are to activate cytotoxic antitumor T cells across a broad range of affinities while dampening suppressive regulatory T (Treg) cell responses, but current approaches achieve these goals with limited success. Here, we report a IL-21 mimic, 21h10, designed to have augmented stability and high signaling potency in both humans and mice. In multiple animal models and in human melanoma patient derived organotypic tumor spheroids (PDOTS), 21h10 showed robust antitumor activity.

SMAC mimetics induce human macrophages to phagocytose live cancer cells.

Macrophages engulf apoptotic bodies and cellular debris as part of homeostasis, but they can also phagocytose live cells such as aged red blood cells. Pharmacologic reprogramming with the SMAC mimetic LCL161 in combination with T cell-derived cytokines can induce macrophages to phagocytose live cancer cells in mouse models. Here we extend these findings to encompass a wide range of monovalent and bivalent SMAC mimetic compounds, demonstrating that live cell phagocytosis is a class effect of these agents.

Structurally targeted mutagenesis identifies key residues supporting -synuclein misfolding in multiple system atrophy.

Multiple system atrophy (MSA) and Parkinson's disease (PD) are caused by misfolded -synuclein spreading throughout the central nervous system. While familial PD is linked to several point mutations in -synuclein, there are no known mutations associated with MSA. Our previous work investigating differences in -synuclein misfolding between the two disorders showed that the familial PD mutation E46K inhibits replication of MSA prions both and providing key evidence to support the hypothesis that -synuclein adopts unique strains in patients.

NAPRT Silencing in FH-Deficient Renal Cell Carcinoma Confers Therapeutic Vulnerabilities via NAD+ Depletion.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by loss of function mutations in fumarate hydratase (FH) and results in an aggressive subtype of renal cell carcinoma with limited treatment options. Loss of FH leads to accumulation of fumarate, an oncometabolite that disrupts multiple cellular processes and drives tumor progression. High levels of fumarate inhibit alpha ketoglutarate-dependent dioxygenases, including the ten-eleven translocation (TET) enzymes, and can lead to global DNA hypermethylation.

The ER membrane protein complex restricts mitophagy by controlling BNIP3 turnover.

Lysosomal degradation of autophagy receptors is a common proxy for selective autophagy. However, we find that two established mitophagy receptors, BNIP3 and BNIP3L/NIX, are constitutively delivered to lysosomes in an autophagy-independent manner. This alternative lysosomal delivery of BNIP3 accounts for nearly all its lysosome-mediated degradation, even upon mitophagy induction.

Impact of a high sensitivity troponin accelerated diagnostic protocol on the safety and emergency department length of stay of chest pain in an academic tertiary hospital: a quality improvement study.

Purpose: High-sensitivity troponin (hsTn) accelerated diagnostic protocols are highly recommended for evaluating acute coronary syndromes. Our goal was to improve care for chest pain patients through the safe adoption of an accelerated diagnostic protocol in our academic Emergency Department (ED) with an aim to reduce mean ED length of stay for chest pain patients by 1 h over 1.5 years.

In vitro flow cytometry assay to assess primary human and mouse macrophage phagocytosis of live cells.

Although tumor-associated macrophages are generally immunosuppressive, macrophages may also promote tumor clearance via phagocytosis of live tumor cells. Here, we present a protocol for assessing macrophage engulfment of tumor cells in vitro using flow cytometry. We describe steps for cell preparation, reseeding macrophages, and setting up phagocytosis.

The ER membrane protein complex governs lysosomal turnover of a mitochondrial tail-anchored protein, BNIP3, to restrict mitophagy.

Lysosomal degradation of autophagy receptors is a common proxy for selective autophagy. However, we find that two established mitophagy receptors, BNIP3 and BNIP3L/NIX, violate this assumption. Rather, BNIP3 and NIX are constitutively delivered to lysosomes in an autophagy-independent manner.

An Analysis of SNAP Online Purchasing Behavior in California: A Review of the First 7 Months of Program Implementation and Lessons Learned.

Purpose: The Supplemental Nutrition Assistance Program (SNAP) Online Purchasing Pilot (OPP) allows for the online purchase of groceries using SNAP benefits. First implemented in California in late April 2020, little is known about program usage. This study assessed initial implementation of SNAP Online in California using SNAP OPP transaction data from April - October 2020.

Disparities in SNAP online grocery delivery and implementation: Lessons learned from California during the 2020-21 COVID pandemic.

During the COVID-19 pandemic in 2020, the Supplemental Nutrition Assistance Program (SNAP) Online Purchasing Pilot (OPP) was rapidly expanded across the US. This program, enabling direct-to-home grocery delivery, could be a transformative step towards improving fresh-food access. However, lack of information on which areas are serviced by SNAP OPP hinders the identification of potential demographic and regional disparities in access.

Discerning Fact From Fiction: An Assessment of Coronavirus-19 Misinformation Among Patients in Rural Michigan.

Coronavirus-19 misinformation poses a unique challenge for public health communication efforts. In rural communities, COVID-19 misinformation is not well studied. We investigate patients' ability to discriminate COVID-19 fact from fiction from their news sources, as well as general COVID-19 knowledge, perceptions, public health practices, and their primary news sources in 258 adult patients at a primary health clinic in rural Michigan.

Consequences of variability in α-synuclein fibril structure on strain biology.

Synucleinopathies are a group of clinically and neuropathologically distinct protein misfolding diseases caused by unique α-synuclein conformations, or strains. While multiple atomic resolution cryo-electron microscopy structures of α-synuclein fibrils are now deposited in Protein Data Bank, significant gaps in the biological consequences arising from each conformation have yet to be unraveled. Mutations in the α-synuclein gene (SNCA), cofactors, and the solvation environment contribute to the formation and maintenance of each disease-causing strain.

Inter- and intra-mouse variability in odor preferences revealed in an olfactory multiple-choice test.

Animals choose between sensory stimuli, a highly complex behavior which includes detection, discrimination, preference, and memory processes. Rodents are reported to display robust preferences for some odors, for instance, in the context of choosing among possible mates or food items. In contrast to the apparent robustness of responses toward these and other "ethologically relevant" odors, little is known about the robustness of behaviors toward odors which have no overt role in the rodent ecological niche, so-called "nonethologically relevant" odors.