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MSTPublications: May 2019

Posted by on Thursday, May 30, 2019 in New Publications.

Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors.
DiCarlo GE, Aguilar JI, Matthies HJ, Harrison FE, Bundschuh KE, West A, Hashemi P, Herborg F, Rickhag M, Chen H, Gether U, Wallace MT, Galli A.
J Clin Invest. 2019 May 16;130. pii: 127411. doi: 10.1172/JCI127411.

The precise regulation of synaptic dopamine (DA) content by the dopamine transporter (DAT) ensures the phasic nature of the DA signal, which underlies the ability of DA to encode reward prediction error, thereby driving motivation, attention, and behavioral learning. Disruptions to the DA system are implicated in a number of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and, more recently, Autism Spectrum Disorder (ASD). An ASD-associated de novo mutation in the SLC6A3 gene resulting in a threonine to methionine substitution at site 356 (DAT T356M) was recently identified and has been shown to drive persistent reverse transport of DA (i.e. anomalous DA efflux) in transfected cells and to drive hyperlocomotion in Drosophila melanogaster. A corresponding mutation in the leucine transporter, a DAT-homologous transporter, promotes an outward-facing transporter conformation upon substrate binding, a conformation possibly underlying anomalous dopamine efflux. Here we investigated in vivo the impact of this ASD-associated mutation on DA signaling and ASD-associated behaviors. We found that mice homozygous for this mutation display impaired striatal DA neurotransmission and altered DA-dependent behaviors that correspond with some of the behavioral phenotypes observed in ASD.

Maternal Western-style diet affects offspring islet composition and function in a non-human primate model of maternal over-nutrition.
Elsakr JM, Dunn JC, Tennant K, Zhao SK, Kroeten K, Pasek RC, Takahashi DL, Dean TA, Velez Edwards DR, McCurdy CE, Aagaard KM, Powers AC, Friedman JE, Kievit P, Gannon M.
Mol Metab. 2019 Apr 12. pii: S2212-8778(19)30142-5. doi: 10.1016/j.molmet.2019.03.010. [Epub ahead of print]

OBJECTIVE: In humans, offspring of women who are overweight or obese are more likely to develop metabolic disease later in life. Studies in lower animal species reveal that a calorically-dense maternal diet is associated with alterations in islet cell mass and function. The long-term effects of maternal diet on the structure and function of offspring islets with characteristics similar to humans are unknown. We used a well-established non-human primate (NHP) model to determine the consequences of exposure to Western-Style Diet (WSD) in utero and during lactation on islet cell mass and function in the offspring. METHODS: Female Japanese Macaques (Macaca fuscata) were fed either control (CTR) or WSD before and throughout pregnancy and lactation. Offspring were weaned onto CTR or WSD to generate four different groups based on maternal/offspring diets: CTR/CTR, WSD/CTR, CTR/WSD, and WSD/WSD. Offspring were analyzed at three years of age. Pancreatic tissue sections were immunolabelled to measure α- and β-cell mass and proliferation as well as islet vascularization. Live islets were also isolated to test the effects of WSD-exposure on islet function ex vivo. Offspring glucose tolerance was correlated with various maternal characteristics. RESULTS: α-cell mass was reduced as a result of maternal WSD exposure. α-cell proliferation was reduced in response to offspring WSD. Islet vasculature did not differ among the diet groups. Islets from WSD/CTR offspring secreted a greater amount of insulin in response to glucose ex vivo. We also found that maternal glucose tolerance and parity correlated with offspring glucose tolerance. CONCLUSIONS: Maternal WSD exposure results in persistently decreased α-cell mass in the three-year old offspring. WSD/CTR islets secreted greater amounts of insulin ex vivo, suggesting that these islets are primed to hyper-secrete insulin under certain metabolic stressors. Although WSD did not induce overt impaired glucose tolerance in dams or offspring, offspring born to mothers with higher glucose excursions during a glucose tolerance test were more likely to also show higher glucose excursions.

Brainstem Functional Connectivity Disturbances in Epilepsy may Recover After Successful Surgery.
González HFJ, Goodale SE, Jacobs ML, Haas KF, Landman BA, Morgan VL, Englot DJ.
Neurosurgery. 2019 May 16. pii: nyz128. doi: 10.1093/neuros/nyz128. [Epub ahead of print]

BACKGROUND: Focal seizures in temporal lobe epilepsy (TLE) are associated with widespread brain network perturbations and neurocognitive problems. OBJECTIVE: To determine whether brainstem connectivity disturbances improve with successful epilepsy surgery, as recent work has demonstrated decreased brainstem connectivity in TLE that is related to disease severity and neurocognitive profile. METHODS: We evaluated 15 adult TLE patients before and after (>1 yr; mean, 3.4 yr) surgery, and 15 matched control subjects using magnetic resonance imaging to measure functional and structural connectivity of ascending reticular activating system (ARAS) structures, including cuneiform/subcuneiform nuclei (CSC), pedunculopontine nucleus (PPN), and ventral tegmental area (VTA). RESULTS: TLE patients who achieved long-term postoperative seizure freedom (10 of 15) demonstrated increases in functional connectivity between ARAS structures and fronto-parietal-insular neocortex compared to preoperative baseline (P = .01, Kruskal-Wallis), with postoperative connectivity patterns resembling controls’ connectivity. No functional connectivity changes were detected in 5 patients with persistent seizures after surgery (P = .9, Kruskal-Wallis). Among seizure-free postoperative patients, larger increases in CSC, PPN, and VTA functional connectivity were observed in individuals with more frequent seizures before surgery (P < .05 for each, Spearman’s rho). Larger postoperative increases in PPN functional connectivity were seen in patients with lower baseline verbal IQ (P = .03, Spearman’s rho) or verbal memory (P = .04, Mann-Whitney U). No changes in ARAS structural connectivity were detected after successful surgery. CONCLUSION: ARAS functional connectivity disturbances are present in TLE but may recover after successful epilepsy surgery. Larger increases in postoperative connectivity may be seen in individuals with more severe disease at baseline.

miR-21 is required for hematopoietic cell viability following radiation exposure.
Puccetti MV, Adams CM, Dan TD, Palagani A, Simone BA, DeAngelis T, Eischen CM, Simone NL.
Int J Radiat Oncol Biol Phys. 2019 Apr 27. pii: S0360-3016(19)30652-2. doi: 10.1016/j.ijrobp.2019.04.020. [Epub ahead of print]

Radiation therapy is an essential intervention used in the treatment plan of more than half of cancer patients. With the increasing use of hypofractionated radiation regimens, concurrent use of radiation and chemotherapy, targeted agents and immunotherapy, the risk of radiation-induced toxicities is increased. Hematopoietic toxicity caused by radiation limits a patient’s options for subsequent systemic therapy. However, much remains unknown about the molecular underpinnings responsible for radiation-induced hematopoietic toxicity. MicroRNA (miRNA) are small, non-coding RNA involved in post-transcriptional regulation of gene expression and are associated with essential cellular processes. miR-21 is a potent oncomiR that is dysregulated in a significant fraction of human malignancies, and its overexpression is linked to poor overall survival, chemoresistance, and radioresistance in several human cancers. However, the contribution of miR-21 in governing radiation sensitivity in normal, untransformed cells, and the impact of silencing this miRNA in normal tissues remains largely unexplored. We determined ionizing radiation significantly increased miR-21 levels in radio-sensitive tissues, but not in radio- insensitive tissues, suggesting it may have a critical function in the normal tissue response to radiation. To test this concept, we generated miR-21 knockout mice. Mice lacking one or both alleles of miR-21 showed reduced numbers of hematopoietic stem and progenitor cells (HSPCs) and increased sensitivity to an LD50/30 dose of total body irradiation (TBI) with evidence of bone marrow failure compared to wild-type mice. Transplantation of wild-type bone marrow into irradiated miR-21-deficient mice rescued the mice from death. Thus, our data identify miR-21 as a critical component of HSPC viability and essential for bone marrow recovery following irradiation. Further investigation is warranted to determine if miR-21 can be used to stratify patients at risk for hematopoietic toxicity following irradiation.

Adaptive Immune Cells in Calcific Aortic Valve Disease.
Raddatz MA, Madhur MS, Merryman WD.
Am J Physiol Heart Circ Physiol. 2019 May 3. doi: 10.1152/ajpheart.00100.2019. [Epub ahead of print]

Comparative Analysis of Subventricular Zone Glioblastoma Contact and Ventricular Entry During Resection in Predicting Dissemination, Hydrocephalus, and Survival.
Mistry AM, Kelly PD, Gallant JN, Mummareddy N, Mobley BC, Thompson RC, Chambless LB.
Neurosurgery. 2019 May 6. pii: nyz144. doi: 10.1093/neuros/nyz144. [Epub ahead of print]

Direct Activation of Human MLKL by a Select Repertoire of Inositol Phosphate Metabolites.
McNamara DE, Dovey CM, Hale AT, Quarato G, Grace CR, Guibao CD, Diep J, Nourse A, Cai CR, Wu H, Kalathur RC, Green DR, York JD, Carette JE, Moldoveanu T.
Cell Chem Biol. 2019 Mar 29. pii: S2451-9456(19)30106-0. doi: 10.1016/j.chembiol.2019.03.010. [Epub ahead of print]

On the accuracy of optically tracked transducers for image-guided transcranial ultrasound.
Chaplin V, Phipps MA, Jonathan SV, Grissom WA, Yang PF, Chen LM, Caskey CF.
Int J Comput Assist Radiol Surg. 2019 May 8. doi: 10.1007/s11548-019-01988-0. [Epub ahead of print]

Monophosphoryl Lipid A Attenuates Multiorgan Dysfunction During Post-Burn Pseudomonas Aeruginosa Pneumonia In Sheep.
Fukuda S, Ihara K, Bohannon JK, Hernandez A, Patil NK, Luan L, Stothers C, Stark R, Prough DS, Herndon DN, Sherwood ER, Enkhbaatar P.
Shock. 2019 Apr 26. doi: 10.1097/SHK.0000000000001364. [Epub ahead of print]