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MSTPublications: May 2020

Posted by on Wednesday, May 20, 2020 in New Publications.

Cerebrospinal fluid biomarkers of neurodegeneration, synaptic dysfunction, and axonal injury relate to atrophy in structural brain regions specific to Alzheimer’s disease.
Moore EE, Gifford KA, Khan OA, Liu D, Pechman KR, Acosta LMY, Bell SP, Turchan M, Landman BA, Blennow K, Zetterberg H, Hohman TJ, Jefferson AL.
Alzheimers Dement. 2020 May 6. doi: 10.1002/alz.12087. [Epub ahead of print]

INTRODUCTION: Patterns of atrophy can distinguish normal cognition from Alzheimer’s disease (AD), but neuropathological drivers of this pattern are unknown. This study examined associations between cerebrospinal fluid biomarkers of AD pathology, synaptic dysfunction, and neuroaxonal injury with two AD imaging signatures.
METHODS: Signatures were calculated using published guidelines. Linear regressions related each biomarker to both signatures, adjusting for demographic factors. Bootstrapped analyses tested if associations were stronger with one signature versus the other.
RESULTS: Increased phosphorylated tau (p-tau), total tau, and neurofilament light (P-values <.045) related to smaller signatures (indicating greater atrophy). Diagnosis and sex modified associations between p-tau and neurogranin (P-values<.05) and signatures, such that associations were stronger among participants with mild cognitive impairment and female participants. The strength of associations did not differ between signatures.
DISCUSSION: Increased evidence of neurodegeneration, axonopathy, and tau phosphorylation relate to greater AD-related atrophy. Tau phosphorylation and synaptic dysfunction may be more prominent in AD-affected regions in females.

 

Host deficiency in ephrin-A1 inhibits breast cancer metastasis.
Shiuan E, Inala A, Wang S, Song W, Youngblood V, Chen J, Brantley-Sieders DM.
F1000Res. 2020 Mar 30;9:217. doi: 10.12688/f1000research.22689.1. eCollection 2020.

Background: The conventional dogma of treating cancer by focusing on the elimination of tumor cells has been recently refined to include consideration of the tumor microenvironment, which includes host stromal cells. Ephrin-A1, a cell surface protein involved in adhesion and migration, has been shown to be tumor suppressive in the context of the cancer cell. However, its role in the host has not been fully investigated. Here, we examine how ephrin-A1 host deficiency affects cancer growth and metastasis in a murine model of breast cancer. Methods: 4T1 cells were orthotopically implanted into the mammary fat pads or injected into the tail veins of ephrin-A1 wild-type ( Efna1 +/+), heterozygous ( Efna1 +/-), or knockout ( Efna1 -/-) mice. Tumor growth, lung metastasis, and tumor recurrence after surgical resection were measured. Flow cytometry and immunohistochemistry (IHC) were used to analyze various cell populations in primary tumors and tumor-bearing lungs. Results: While primary tumor growth did not differ between Efna1 +/+, Efna1 +/-, and Efna1 -/- mice, lung metastasis and primary tumor recurrence were significantly decreased in knockout mice. Efna1 -/- mice had reduced lung colonization of 4T1 cells compared to Efna1 +/+ littermate controls as early as 24 hours after tail vein injection. Furthermore, established lung lesions in Efna1 -/- mice had reduced proliferation compared to those in Efna1 +/+ controls. Conclusions: Our studies demonstrate that host deficiency of ephrin-A1 does not impact primary tumor growth but does affect metastasis by providing a less favorable metastatic niche for cancer cell colonization and growth. Elucidating the mechanisms by which host ephrin-A1 impacts cancer relapse and metastasis may shed new light on novel therapeutic strategies.

 

Neuronal modeling of alternating hemiplegia of childhood reveals transcriptional compensation and replicates a trigger-induced phenotype.
Snow JP, Westlake G, Klofas LK, Jeon S, Armstrong LC, Swoboda KJ, George AL Jr, Ess KC.
Neurobiol Dis. 2020 Apr 26:104881. doi: 10.1016/j.nbd.2020.104881. [Epub ahead of print]

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disease caused by heterozygous de novo missense mutations in the ATP1A3 gene that encodes the neuronal specific α3 subunit of the Na,K-ATPase (NKA) pump. Mechanisms underlying patient episodes including environmental triggers remain poorly understood, and there are no empirically proven treatments for AHC. In this study, we generated patient-specific induced pluripotent stem cells (iPSCs) and isogenic controls for the E815K ATP1A3 mutation that causes the most phenotypically severe form of AHC. Using an in vitro iPSC-derived cortical neuron disease model, we found elevated levels of ATP1A3 mRNA in AHC lines compared to controls, without significant perturbations in protein expression. Microelectrode array analyses demonstrated that in cortical neuronal cultures, ATP1A3+/E815K iPSC-derived neurons displayed less overall activity than neurons differentiated from isogenic mutation-corrected and unrelated control cell lines. However, induction of cellular stress by elevated temperature revealed a hyperactivity phenotype following heat stress in ATP1A3+/E815K neurons compared to control lines. Treatment with flunarizine, a drug commonly used to prevent AHC episodes, did not impact this stress-triggered phenotype. These findings support the use of iPSC-derived neuronal cultures for studying complex neurodevelopmental conditions such as AHC and provide a platform for mechanistic discovery in a human disease model.

 

Integrated human pseudoislet system and microfluidic platform demonstrates differences in G-protein-coupled-receptor signaling in islet cells.
Walker JT, Haliyur R, Nelson HA, Ishahak M, Poffenberger G, Aramandla R, Reihsmann C, Luchsinger JR, Saunders DC, Wang P, Garcia-Ocana A, Bottino R, Agarwal A, Powers AC, Brissova M.
JCI Insight. 2020 Apr 30. pii: 137017. doi: 10.1172/jci.insight.137017. [Epub ahead of print]

Pancreatic islets secrete insulin from β cells and glucagon from α cells and dysregulated secretion of these hormones is a central component of diabetes. Thus, an improved understanding of the pathways governing coordinated β and α cell hormone secretion will provide insight into islet dysfunction in diabetes. However, the three-dimensional multicellular islet architecture, essential for coordinated islet function, presents experimental challenges for mechanistic studies of intracellular signaling pathways in primary islet cells. Here, we developed an integrated approach to study the function of primary human islet cells using genetically modified pseudoislets that resemble native islets across multiple parameters. Further, we developed a microperifusion system that allowed synchronous acquisition of GCaMP6f biosensor signal and hormone secretory profiles. We demonstrate the utility of this experimental approach by studying the effects of Gi and Gq GPCR pathways on insulin and glucagon secretion by expressing the designer receptors exclusively activated by designer drugs (DREADDs) hM4Di or hM3Dq. Activation of Gi signaling reduced insulin and glucagon secretion, while activation of Gq signaling stimulated glucagon secretion but had both stimulatory and inhibitory effects on insulin secretion which occur through changes in intracellular Ca2+. The experimental approach of combining pseudoislets with a microfluidic system, allowed the co-registration of intracellular signaling dynamics and hormone secretion and demonstrated differences in GPCR signaling pathways between human β and α cells.

 

The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy.
Lim AR, Rathmell WK, Rathmell JC.
Elife. 2020 May 5;9. pii: e55185. doi: 10.7554/eLife.55185.

Breakthroughs in anti-tumor immunity have led to unprecedented advances in immunotherapy, yet it is now clear that the tumor microenvironment (TME) restrains immunity. T cells must substantially increase nutrient uptake to mount a proper immune response and failure to obtain sufficient nutrients or engage the appropriate metabolic pathways can alter or prevent effector T cell differentiation and function. The TME, however, can be metabolically hostile due to insufficient vascular exchange and cancer cell metabolism that leads to hypoxia, depletion of nutrients, and accumulation of waste products. Further, inhibitory receptors present in the TME can inhibit T cell metabolism and alter T cell signaling both directly and through release of extracellular vesicles such as exosomes. This review will discuss the metabolic changes that drive T cells into different stages of their development and how the TME imposes barriers to the metabolism and activity of tumor infiltrating lymphocytes.

 

Balancing Expediency and Scientific Rigor in SARS-CoV-2 Vaccine Development.
Graepel KW, Kochhar S, Clayton EW, Edwards KE.
J Infect Dis. 2020 May 4. pii: jiaa234. doi: 10.1093/infdis/jiaa234. [Epub ahead of print] No abstract available.

 

 

 

 

 

Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive Staphylococcus aureus infection.
Potter AD, Butrico CE, Ford CA, Curry JM, Trenary IA, Tummarakota SS, Hendrix AS, Young JD, Cassat JE.
Proc Natl Acad Sci U S A. 2020 May 15. pii: 201922211. doi: 10.1073/pnas.1922211117. [Epub ahead of print]

A modified lysosomal organelle mediates nonlytic egress of reovirus.
Fernández de Castro I, Tenorio R, Ortega-González P, Knowlton JJ, Zamora PF, Lee CH, Fernández JJ, Dermody TS, Risco C.
J Cell Biol. 2020 Jul 6;219(7). pii: e201910131. doi: 10.1083/jcb.201910131.

Human Herpesvirus 6 Detection during the Evaluation of Sepsis in Infants Using the FilmArray Meningitis/Encephalitis Panel.
Dantuluri KL, Konvinse KC, Crook J, Thomsen IP, Banerjee R.
J Pediatr. 2020 May 13. pii: S0022-3476(20)30351-6. doi: 10.1016/j.jpeds.2020.03.023. [Epub ahead of print]

Discovery of Widespread Host Protein Interactions with the Pre-replicated Genome of CHIKV Using VIR-CLASP.
Kim B, Arcos S, Rothamel K, Jian J, Rose KL, McDonald WH, Bian Y, Reasoner S, Barrows NJ, Bradrick S, Garcia-Blanco MA, Ascano M.
Mol Cell. 2020 May 3. pii: S1097-2765(20)30255-0. doi: 10.1016/j.molcel.2020.04.013. [Epub ahead of print]

New insights into abasic site repair and tolerance.
Thompson PS, Cortez D.
DNA Repair (Amst). 2020 Apr 30;90:102866. doi: 10.1016/j.dnarep.2020.102866. [Epub ahead of print]