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MSTPublications: June 2021

Posted by on Friday, June 25, 2021 in New Publications .

Western-style diet consumption impairs maternal insulin sensitivity and glucose metabolism during pregnancy in a Japanese macaque model.
Elsakr JM, Zhao SK, Ricciardi V, Dean TA, Takahashi DL, Sullivan E, Wesolowski SR, McCurdy CE, Kievit P, Friedman JE, Aagaard KM, Edwards DRV, Gannon M.
Sci Rep. 2021 Jun 21;11(1):12977. doi: 10.1038/s41598-021-92464-w.

The prevalence of maternal obesity is increasing in the United States. Offspring born to women with obesity or poor glycemic control have greater odds of becoming obese and developing metabolic disease later in life. Our group has utilized a macaque model to study the metabolic effects of consumption of a calorically-dense, Western-style diet (WSD; 36.3% fat) during pregnancy. Here, our objective was to characterize the effects of WSD and obesity, alone and together, on maternal glucose tolerance and insulin levels in dams during each pregnancy. Recognizing the collinearity of maternal measures, we adjusted for confounding factors including maternal age and parity. Based on intravenous glucose tolerance tests, dams consuming a WSD showed lower glucose area under the curve during first study pregnancies despite increased body fat percentage and increased insulin area under the curve. However, with (1) prolonged WSD feeding, (2) multiple diet switches, and/or (3) increasing age and parity, WSD was associated with increasingly higher insulin levels during glucose tolerance testing, indicative of insulin resistance. Our results suggest that prolonged or recurrent calorically-dense WSD and/or increased parity, rather than obesity per se, drive excess insulin resistance and metabolic dysfunction. These observations in a highly relevant species are likely of clinical and public health importance given the comparative ease of maternal dietary modifications relative to the low likelihood of successfully reversing obesity in the course of any given pregnancy.

NMDA Receptors Require Multiple Pre-opening Gating Steps for Efficient Synaptic Activity
Amin JB*, Gochman A*, He M, Certain N, Wollmuth LP. Neuron. 2021 Feb 3;109(3):488-501.e4. doi: 10.1016/j.neuron.2020.11.009. Epub 2020 Dec 1.

NMDA receptors (NMDARs) are glutamate-gated ion channels that mediate fast excitatory synaptic transmission in the nervous system. Applying glutamate to outside-out patches containing a single NMDAR, we find that agonist-bound receptors transition to the open state via two conformations, an “unconstrained pre-active” state that contributes to fast synaptic events and a “constrained pre-active” state that does not. To define how glutamate drives these conformations, we decoupled the ligand-binding domains from specific transmembrane segments for GluN1 and GluN2A. Displacements of the pore-forming M3 segments define the energy of fast opening. However, to enter the unconstrained conformation and contribute to fast signaling, the GluN2 pre-M1 helix must be displaced before the M3 segments move. This pre-M1 displacement is facilitated by the flexibility of the S2-M4 of GluN1 and GluN2A. Thus, outer structures-pre-M1 and S2-M4-work in concert to remove constraints and prime the channel for rapid opening, facilitating fast synaptic transmission.

Genome-Wide Association Study Identifies Genetic Risk Factors for Spastic Cerebral Palsy.
Hale AT, Akinnusotu O, He J, Wang J, Hibshman N, Shannon CN, Naftel RP.
Neurosurgery. 2021 Jun 7:nyab184. doi: 10.1093/neuros/nyab184. Online ahead of print.

Background: Although many clinical risk factors of spastic cerebral palsy (CP) have been identified, the genetic basis of spastic CP is largely unknown. Here, using whole-genome genetic information linked to a deidentified electronic health record (BioVU) with replication in the UK Biobank and FinnGen, we perform the first genome-wide association study (GWAS) for spastic CP.
Objective: To define the genetic basis of spastic CP.
Methods: Whole-genome data were obtained using the multi-ethnic genotyping array (MEGA) genotyping array capturing single-nucleotide polymorphisms (SNPs), minor allele frequency (MAF) > 0.01, and imputation quality score (r2) > 0.3, imputed based on the 1000 genomes phase 3 reference panel. Threshold for genome-wide significance was defined after Bonferroni correction for the total number of SNPs tested (P < 5.0 × 10-8). Replication analysis (defined as P < .05) was performed in the UK Biobank and FinnGen.
Results: We identify 1 SNP (rs78686911) reaching genome-wide significance with spastic CP. Expression quantitative trait loci (eQTL) analysis suggests that rs78686911 decreases expression of GRIK4, a gene that encodes a high-affinity kainate glutamatergic receptor of largely unknown function. Replication analysis in the UK Biobank and FinnGen reveals additional SNPs in the GRIK4 loci associated with CP.
Conclusion: To our knowledge, we perform the first GWAS of spastic CP. Our study indicates that genetic variation contributes to CP risk.

Sunitinib and Axitinib increase secretion and glycolytic activity of small extracellular vesicles in renal cell carcinoma.
Lim AR, Vincent BG, Weaver AM, Rathmell WK.
Cancer Gene Ther. 2021 Jun 4. doi: 10.1038/s41417-021-00345-1. Online ahead of print.

Extracellular vesicles (EVs) encompass a wide range of vesicles that are released by all cell types. They package protein, nucleic acids, metabolites, and other cargo that can be delivered to recipient cells and affect their phenotypes. However, little is known about how pharmaceutical agents can alter EV secretion, protein and metabolic cargo, and the active biological processes taking place in these vesicles. In this study, we isolated EVs from human renal cell carcinoma (RCC) cells treated with tyrosine kinase inhibitors (TKIs) Sunitinib and Axitinib. We found these TKIs increase the number of large (lEVs) and small extracellular vesicles (sEVs) secreted from RCC cells in a dose-dependent manner. In addition, quantitative proteomics revealed that metabolic proteins are enriched in sEVs secreted from Sunitinib-treated cells. In particular, the glucose transporter GLUT1 was enriched in sEVs purified from TKI-treated cells. These sEVs displayed increased glucose uptake and glycolytic metabolism compared to sEVs released from vehicle-treated cells. Overexpression of GLUT1 in RCC cells augmented GLUT1 levels in sEVs, which subsequently displayed higher glucose uptake and glycolytic activity. Together, these findings suggest that these TKIs alter metabolic cargo and activity in RCC sEVs.

Cdk1 phosphorylation of fission yeast paxillin inhibits its cytokinetic ring localization.
Mangione MC, Chen JS, Gould KL.
Mol Biol Cell. 2021 Jun 16:mbcE20120807. doi: 10.1091/mbc.E20-12-0807. Online ahead of print.

Divisions of the genetic material and cytoplasm are coordinated spatially and temporally to ensure genome integrity. This coordination is mediated in part by the major cell cycle regulator cyclin-dependent kinase (Cdk1). Cdk1 activity peaks during mitosis, but during mitotic exit/cytokinesis Cdk1 activity is reduced, and phosphorylation of its substrates is reversed by various phosphatases including Cdc14, PP1, PP2A and PP2B. Cdk1 is known to phosphorylate several components of the actin- and myosin-based cytokinetic ring (CR) that mediates division of yeast and animal cells. Here we show that Cdk1 also phosphorylates the Schizosaccharomyces pombe CR-component paxillin Pxl1. We determined that both the Cdc14 phosphatase Clp1 and the PP1 phosphatase Dis2 contribute to Pxl1 dephosphorylation at mitotic exit, but PP2B/calcineurin does not. Preventing Pxl1 phosphorylation by Cdk1 results in increased Pxl1 levels, precocious Pxl1 recruitment to the division site, and increases the duration of CR constriction. In vitro, Cdk1-mediated phosphorylation of Pxl1 inhibits its interaction with the F-BAR domain of the cytokinetic scaffold Cdc15, thereby disrupting a major mechanism of Pxl1 recruitment. Thus, Pxl1 is a novel substrate through which S. pombe Cdk1 and opposing phosphatases coordinate mitosis and cytokinesis.

Association of Aortic Stiffness With Biomarkers of Neuroinflammation, Synaptic Dysfunction, and Neurodegeneration.
Moore EE, Liu D, Li J, Schimmel SJ, Cambronero FE, Terry JG, Nair S, Pechman KR, Moore ME, Bell SP, Beckman JA, Gifford KA, Hohman TJ, Blennow K, Zetterberg H, Carr JJ, Jefferson AL.
Neurology. 2021 May 24:10.1212/WNL.0000000000012257. doi: 10.1212/WNL.0000000000012257. Online ahead of print.

Objectives: To test the hypothesis that increased aortic stiffening is associated with greater cerebrospinal fluid (CSF) evidence of core Alzheimer’s disease pathology (Aβ, phosphorylated tau (p-tau)), neurodegeneration (total tau (t-tau)), synaptic dysfunction (neurogranin), neuroaxonal injury (neurofilament light (NFL)), and neuroinflammation (YKL-40, sTREM2), we analyzed pulse wave velocity (PWV) data and CSF data among older adults.
Methods: Participants free of stroke and dementia from the Vanderbilt Memory and Aging Project, an observational community-based study, underwent cardiac magnetic resonance to assess aortic pulse wave velocity (PWV, m/sec) and lumbar puncture to obtain CSF. Linear regressions related aortic PWV to CSF Aβ, p-tau, t-tau, neurogranin, NFL, YKL-40, and sTREM2 concentrations adjusting for age, race/ethnicity, education, apolipoprotein (APOE) ε4 status, Framingham Stroke Risk Profile, and cognitive diagnosis. Models were repeated testing PWV interactions with age, diagnosis, APOE-ε4, and hypertension on each biomarker.
Results: 146 participants were examined (72±6 years). Aortic PWV interacted with age on p-tau (β=0.31, p=0.04), t-tau, (β=2.67, p=0.05), neurogranin (β=0.94, p=0.04), and sTREM2 (β=20.4, p=0.05). Among participants over age 73 years, higher aortic PWV related to higher p-tau (β=2.4, p=0.03), t-tau (β=19.3, p=0.05), neurogranin (β=8.4, p=0.01), and YKL-40 concentrations (β=7880, p=0.005). Aortic PWV had modest interactions with diagnosis on neurogranin (β=-10.76, p=0.03) and hypertension status on YKL-40 (β=-18020, p<0.001).
Conclusions: Among our oldest participants, age 74 years and older, greater aortic stiffening is associated with in vivo biomarker evidence of neuroinflammation, tau phosphorylation, synaptic dysfunction, and neurodegeneration, but not amyloidosis. Central arterial stiffening may lead to cumulative cerebral microcirculatory damage and blood flow delivery to tissue, resulting in neuroinflammation and neurodegeneration in more advanced age.

Genome-wide approach to measure variant-based heritability of drug outcome phenotypes.
Muhammad A, Aka IT, Birdwell KA, Gordon AS, Roden DM, Wei WQ, Mosley JD, Van Driest SL.
Clin Pharmacol Ther. 2021 Jun 20. doi: 10.1002/cpt.2323. Online ahead of print.

Pharmacogenomic studies have successfully identified variants – typically with large effect sizes in drug target and metabolism enzymes – that predict drug outcome phenotypes. However, these variants may account for a limited proportion of phenotype variability attributable to the genome. Using genome-wide common variation, we measured the narrow-sense heritability [ h2SNP ] of 7 pharmacodynamic and 5 pharmacokinetic phenotypes across 3 cardiovascular drugs, 2 antibiotics, and 3 immunosuppressants. We used a Bayesian Hierarchical Mixed Model, BayesR, to model the distribution of genome-wide variant effect sizes for each drug phenotype as a mixture of 4 normal distributions of fixed variance (0, 0.01%, 0.1% and 1% of the total additive genetic variance). This model allowed us to parse h2SNP into bins representing contributions of no-, small-, moderate- and large-effect size variants respectively. For the 12 phenotypes, a median of 969 (range 235-6,304) unique individuals of European ancestry and a median of 1,201,626 (range 777,427-1,514,275) variants were included in our analyses. The number of variants contributing to h2SNP ranged from 2,791 to 5,356 (median 3,347). Estimates for h2SNP ranged from 0.05 (ACE-inhibitor induced cough) to 0.59 (gentamicin concentration). Small- and moderate-effect variants contributed a majority to h2SNP for every phenotype (range 61-95%). We conclude that drug outcome phenotypes are highly polygenic. Thus, larger genome-wide association studies of drug phenotypes are needed both to discover novel variants and to determine how genome-wide approaches may improve clinical prediction of drug outcomes.

Investigating the structure of trait rumination in autistic adults: A network analysis.
Williams ZJ, McKenney EE, Gotham KO.
Autism. 2021 May 31:13623613211012855. doi: 10.1177/13623613211012855. Online ahead of print.

Autistic adults are substantially more likely to develop depression than individuals in the general population, and recent research has indicated that certain differences in thinking styles associated with autism may play a role in this association. Rumination, the act of thinking about the same thing over and over without a functional outcome, is a significant risk factor for depression in both autistic and non-autistic adults. However, little is known about how different kinds of rumination relate to each other and to depressive symptoms in the autistic population specifically. To fill this gap in knowledge, we recruited a large online sample of autistic adults, who completed questionnaire measures of both the tendency to ruminate and symptoms of depression. By examining the interacting network of rumination and depression symptoms, this study was able to identify particular aspects of rumination-such as thinking repetitively about one’s guilty feelings or criticizing oneself-that may be particularly important in maintaining these harmful thought patterns in autistic adults. Although further study is needed, it is possible that the symptoms identified as most “influential” in the network may be particularly good targets for future interventions for mood and anxiety disorders in the autistic population.

RNA-Sequencing Reveals a Distinct Transcriptomic Signature for Giant Cell Myocarditis and Identifies Novel Druggable Targets.
Amancherla K, Qin J, Wang Y, Axelrod ML, Balko JM, Schlendorf KH, Hoffman RD, Xu Y, Lindenfeld J, Moslehi JJ.
Circ Res. 2021 Jun 14. doi: 10.1161/CIRCRESAHA.121.319317. Online ahead of print.

Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial.
Rajasingham R, Bangdiwala AS, Nicol MR, Skipper CP, Pastick KA, Axelrod ML, Pullen MF, Nascene AA, Williams DA, Engen NW, Okafor EC, Rini BI, Mayer IA, McDonald EG, Lee TC, Li P, MacKenzie LJ, Balko JM, Dunlop SJ, Hullsiek KH, Boulware DR, Lofgren SM; COVID PREP team.
Clin Infect Dis. 2021 Jun 1;72(11):e835-e843. doi: 10.1093/cid/ciaa1571.

Unsupervised logic-based mechanism inference for network-driven biological processes.
Prugger M, Einkemmer L, Beik SP, Wasdin PT, Harris LA, Lopez CF.
PLoS Comput Biol. 2021 Jun 2;17(6):e1009035. doi: 10.1371/journal.pcbi.1009035. Online ahead of print.

Contemporary clinical isolates of Staphylococcus aureus from pediatric osteomyelitis patients display unique characteristics in a mouse model of hematogenous osteomyelitis.
Roper PM, Eichelberger KR, Cox L, O’Connor L, Shao C, Ford CA, Fritz SA, Cassat JE, Veis DJ.
Infect Immun. 2021 Jun 7:IAI0018021. doi: 10.1128/IAI.00180-21. Online ahead of print.

Detection of Atrial Fibrillation After Central Retinal Artery Occlusion.
Mac Grory B, Landman SR, Ziegler PD, Boisvert CJ, Flood SP, Stretz C, Madsen TE, Reznik ME, Cutting S, Moore EE, Hewitt H, Closser JB, Torres J, Lavin PJ, Furie KL, Xian Y, Feng W, Biousse V, Schrag M, Yaghi S.
Stroke. 2021 Jun 7:STROKEAHA120033934. doi: 10.1161/STROKEAHA.120.033934. Online ahead of print.

Psychometric validation and refinement of the Interoception Sensory Questionnaire (ISQ) in adolescents and adults on the autism spectrum.
Suzman E, Williams ZJ, Feldman JI, Failla M, Cascio CJ, Wallace MT, Niarchou M, Sutcliffe JS, Wodka E, Woynaroski TG.
Mol Autism. 2021 Jun 7;12(1):42. doi: 10.1186/s13229-021-00440-y.

Intrauterine Devices as an Exposure Risk for Urinary Tract Infections: a Scoping Review.
Lo CT, Abraham A, Lipworth L, Aronoff DM.
Am J Reprod Immunol. 2021 May 30:e13476. doi: 10.1111/aji.13476. Online ahead of print.

Western lifestyle as a driver of dysbiosis in colorectal cancer.
Foegeding NJ, Jones ZS, Byndloss MX.
Dis Model Mech. 2021 May 1;14(5):dmm049051. doi: 10.1242/dmm.049051. Epub 2021 Jun 1.

Commentary: The construct validity of ‘camouflaging’ in autism: psychometric considerations and recommendations for future research – reflection on Lai et al. (2020).
Williams ZJ.
J Child Psychol Psychiatry. 2021 Jun 17. doi: 10.1111/jcpp.13468. Online ahead of print


Sulfation of glycosaminoglycans depends on catalytic activity of a lithium-inhibited phosphatase
Brynna S. EiseleZigmund A. LukaAlice J. WuFei YangAndrew T. HaleJohn D. York

A Family of Glycosylated Macrolides Selectively Target Energetic Vulnerabilities in Leukemia
Benjamin J. ReismanHui GuoHaley E. RamseyMadison T. WrightBradley I. ReinfeldP. Brent FerrellGary A. SulikowskiW. Kimryn RathmellMichael R. SavonaLars PlateJohn L. RubinsteinBrian O. Bachmann