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MSTPublications: October 2023

Posted by on Tuesday, October 31, 2023 in New Publications .

Spatiospectral image processing workflow considerations for advanced MR spectroscopy of the brain.
Cai LY, Del Tufo SN, Barquero L, D’Archangel M, Sachs L, Cutting LE, Glaser N, Ghetti S, Jaser SS, Anderson AW, Jordan LC, Landman BA.
bioRxiv. 2023 Sep 12:2023.09.07.556701. doi: 10.1101/2023.09.07.556701. Preprint. PMID: 37745381

Magnetic resonance spectroscopy (MRS) is one of the few non-invasive imaging modalities capable of making neurochemical and metabolic measurements in vivo. Traditionally, the clinical utility of MRS has been narrow. The most common use has been the “single-voxel spectroscopy” variant to discern the presence of a lactate peak in the spectra in one location in the brain, typically to evaluate for ischemia in neonates. Thus, the reduction of rich spectral data to a binary variable has not classically necessitated much signal processing. However, scanners have become more powerful and MRS sequences more advanced, increasing data complexity and adding 2 to 3 spatial dimensions in addition to the spectral one. The result is a spatially- and spectrally-variant MRS image ripe for image processing innovation. Despite this potential, the logistics for robustly accessing and manipulating MRS data across different scanners, data formats, and software standards remain unclear. Thus, as research into MRS advances, there is a clear need to better characterize its image processing considerations to facilitate innovation from scientists and engineers. Building on established neuroimaging standards, we describe a framework for manipulating these images that generalizes to the voxel, spectral, and metabolite level across space and multiple imaging sites while integrating with LCModel, a widely used quantitative MRS peak-fitting platform. In doing so, we provide examples to demonstrate the advantages of such a workflow in relation to recent publications and with new data. Overall, we hope our characterizations will lower the barrier of entry to MRS processing for neuroimaging researchers.


Utility of iliac crest tetracycline-labelled bone biopsy in osteoporosis and metabolic bone disease: An evaluation of 95 cases over a period of 25 years.
Colazo JM, Quirion J, Judice AD, Halpern J, Schwartz HS, Tanner SB, Lawrenz JM, Dahir KM, Holt GE.
Bone Rep. 2023 Sep 24;19:101715. doi: 10.1016/j.bonr.2023.101715. eCollection 2023 Dec.

Background: Metabolic bone diseases (MBD) are typically diagnosed by non-invasive imaging and clinical biomarkers. However, imaging does not provide structural information, and biomarkers can be transiently affected by many systemic factors. Bone biopsy and pathologic evaluation is the gold standard for diagnosis of MBD, however, it is rarely utilized. We describe our technique for iliac crest tetracycline-labelled bone using a cannulated drill and assess the utility of bone biopsies to provide diagnostic and therapeutic guidance.
Methods: In the 25-year period between March 1998 and January 2023, a total of 95 bone biopsies were performed on 94 patients for an osteological indication at Vanderbilt University Medical Center (VUMC). Patient demographics, bone biopsy indications, complications, diagnostic utility, and subsequent therapeutic guidance were retrospectively reviewed and analyzed.
Results: The procedure had minimal complications and was well tolerated by patients. This technique provided good quality specimens for pathology, which helped establish a diagnosis and treatment change in most patients. Patients that had biopsy-guided treatment alterations showed significant increases in Dual-Energy X-ray Absorptiometry (DEXA) bone mineral density (BMD) scores post-biopsy and subsequent treatment.
Conclusion: Despite scientific and technological progress in non-invasive diagnostic imaging, clinical biomarkers, and procedures for MBD, there remains a small but significant subset of patients who may benefit from inclusion of tetracycline-labelled bone biopsy into the diagnostic and therapeutic picture. Future prospective comparison studies are warranted.


Tissue-Specific Dependence of Th1 Cells on the Amino Acid Transporter SLC38A1 in Inflammation.
Sugiura A, Beier KL, Chi C, Heintzman DR, Ye X, Wolf MM, Patterson AR, Cephus JY, Hong HS, Lyssiotis CA, Newcomb DC, Rathmell JC.
bioRxiv. 2023 Sep 13:2023.09.13.557496. doi: 10.1101/2023.09.13.557496. Preprint.

Amino acid (AA) uptake is essential for T cell metabolism and function, but how tissue sites and inflammation affect CD4+ T cell subset requirements for specific AA remains uncertain. Here we tested CD4+ T cell AA demands with in vitro and multiple in vivo CRISPR screens and identify subset- and tissue-specific dependencies on the AA transporter SLC38A1 (SNAT1). While dispensable for T cell persistence and expansion over time in vitro and in vivo lung inflammation, SLC38A1 was critical for Th1 but not Th17 cell-driven Experimental Autoimmune Encephalomyelitis (EAE) and contributed to Th1 cell-driven inflammatory bowel disease. SLC38A1 deficiency reduced mTORC1 signaling and glycolytic activity in Th1 cells, in part by reducing intracellular glutamine and disrupting hexosamine biosynthesis and redox regulation. Similarly, pharmacological inhibition of SLC38 transporters delayed EAE but did not affect lung inflammation. Subset- and tissue-specific dependencies of CD4+ T cells on AA transporters may guide selective immunotherapies.


Biomimetic proteoglycans as a tool to engineer the structure and mechanics of porcine bioprosthetic heart valves.
Petrovic M, Kahle ER, Han L, Marcolongo MS.
J Biomed Mater Res B Appl Biomater. 2023 Oct 11. doi: 10.1002/jbm.b.35336. Online ahead of print.

The utility of bioprosthetic heart valves (BHVs) is limited to certain patient populations because of their poor durability compared to mechanical prosthetic valves. Histological analysis of failed porcine BHVs suggests that degeneration of the tissue extracellular matrix (ECM), specifically the loss of proteoglycans and their glycosaminoglycans (GAGs), may lead to impaired mechanical performance, resulting in nucleation and propagation of tears and ultimately failure of the prosthetic. Several strategies have been proposed to address this deterioration, including novel chemical fixatives to stabilize ECM constituents and incorporation of small molecule inhibitors of catabolic enzymes implicated in the degeneration of the BHV ECM. Here, biomimetic proteoglycans (BPGs) were introduced into porcine aortic valves ex vivo and were shown to distribute throughout the valve leaflets. Incorporation of BPGs into the heart valve leaflet increased tissue overall GAG content. The presence of BPGs also significantly increased the micromodulus of the spongiosa layer within the BHV without compromising the chemical fixation process used to sterilize and strengthen the tissue prior to implantation. These findings suggest that a targeted approach for molecularly engineering valve leaflet ECM through the use of BPGs may be a viable way to improve the mechanical behavior and potential durability of BHVs.


Immune profiling of murine cardiac leukocytes identifies triggering receptor expressed on myeloid cells 2 as a novel mediator of hypertensive heart failure.
Smart CD, Fehrenbach DJ, Wassenaar JW, Agrawal V, Fortune NL, Dixon DD, Cottam MA, Hasty AH, Hemnes AR, Doran AC, Gupta DK, Madhur MS.
Cardiovasc Res. 2023 Oct 24;119(13):2312-2328. doi: 10.1093/cvr/cvad093.

Aims: Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction, and myocardial fibrosis with recent evidence implicating the immune system in orchestrating cardiac remodelling.
Methods and results: Here, we show the mouse model of deoxycorticosterone acetate (DOCA)-salt hypertension induces key elements of HFpEF, including diastolic dysfunction, exercise intolerance, and pulmonary congestion in the setting of preserved ejection fraction. A modified single-cell sequencing approach, cellular indexing of transcriptomes and epitopes by sequencing, of cardiac immune cells reveals an altered abundance and transcriptional signature in multiple cell types, most notably cardiac macrophages. The DOCA-salt model results in differential expression of several known and novel genes in cardiac macrophages, including up-regulation of Trem2, which has been recently implicated in obesity and atherosclerosis. The role of Trem2 in hypertensive heart failure, however, is unknown. We found that mice with genetic deletion of Trem2 exhibit increased cardiac hypertrophy, diastolic dysfunction, renal injury, and decreased cardiac capillary density after DOCA-salt treatment compared to wild-type controls. Moreover, Trem2-deficient macrophages have impaired expression of pro-angiogenic gene programmes and increased expression of pro-inflammatory cytokines. Furthermore, we found that plasma levels of soluble TREM2 are elevated in DOCA-salt treated mice and humans with heart failure.
Conclusions: Together, our data provide an atlas of immunological alterations that can lead to improved diagnostic and therapeutic strategies for HFpEF. We provide our dataset in an easy to explore and freely accessible web application making it a useful resource for the community. Finally, our results suggest a novel cardioprotective role for Trem2 in hypertensive heart failure.


Spatially non-overlapping Ca2+ signals drive distinct forms of neurotransmission.
Wang CS, Monteggia LM, Kavalali ET.
Cell Rep. 2023 Sep 30;42(10):113201. doi: 10.1016/j.celrep.2023.113201. Online ahead of print. PMID: 37777959

Calcium (Ca2+) signaling is tightly regulated within a presynaptic bouton. Here, we visualize Ca2+ signals within hippocampal presynaptic boutons using GCaMP8s tagged to synaptobrevin, a synaptic vesicle protein. We identify evoked presynaptic Ca2+ transients (ePreCTs) that derive from synchronized voltage-gated Ca2+ channel openings, spontaneous presynaptic Ca2+ transients (sPreCTs) that originate from ryanodine sensitive Ca2+ stores, and a baseline Ca2+ signal that arises from stochastic voltage-gated Ca2+ channel openings. We find that baseline Ca2+, but not sPreCTs, contributes to spontaneous glutamate release. We employ photobleaching as a use-dependent tool to probe nano-organization of Ca2+ signals and observe that all three occur in non-overlapping domains within the synapse at near-resting conditions. However, increased depolarization induces intermixing of these Ca2+ domains via both local and non-local synaptic vesicle turnover. Our findings reveal nanosegregation of Ca2+ signals within a presynaptic terminal that derive from multiple sources and in turn drive specific modes of neurotransmission.


Whole-brain, gray, and white matter time-locked functional signal changes with simple tasks and model-free analysis.
Schilling KG, Li M, Rheault F, Gao Y, Cai L, Zhao Y, Xu L, Ding Z, Anderson AW, Landman BA, Gore JC.
Proc Natl Acad Sci U S A. 2023 Oct 17;120(42):e2219666120. doi: 10.1073/pnas.2219666120. Epub 2023 Oct 12.

White matter tract microstructure, macrostructure, and associated cortical gray matter morphology across the lifespan.
Schilling KG, Chad JA, Chamberland M, Nozais V, Rheault F, Archer D, Li M, Gao Y, Cai L, Del’Acqua F, Newton A, Moyer D, Gore JC, Lebel C, Landman BA.
bioRxiv. 2023 Sep 26:2023.09.25.559330. doi: 10.1101/2023.09.25.559330. Preprint.

Reducing uncertainty in cancer risk estimation for patients with indeterminate pulmonary nodules using an integrated deep learning model.
Gao R, Li T, Tang Y, Xu K, Khan M, Kammer M, Antic SL, Deppen S, Huo Y, Lasko TA, Sandler KL, Maldonado F, Landman BA.
Comput Biol Med. 2022 Nov;150:106113. doi: 10.1016/j.compbiomed.2022.106113. Epub 2022 Sep 29.

The USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling.
Ng VH, Spencer Z, Neitzel LR, Nayak A, Loberg MA, Shen C, Kassel SN, Kroh HK, An Z, Anthony CC, Bryant JM, Lawson A, Goldsmith L, Benchabane H, Hansen AG, Li J, D’Souza S, Lebensohn AM, Rohatgi R, Weiss WA, Weiss VL, Williams C, Hong CC, Robbins DJ, Ahmed Y, Lee E.
Nat Commun. 2023 Oct 5;14(1):6173. doi: 10.1038/s41467-023-41836-z.

Tumor-reactive CD8+ T cells enter a TCF1+PD1- dysfunctional state.
Roetman JJ, Erwin MM, Rudloff MW, Favret NR, Detres Roman CR, Apostolova MKI, Murray KA, Lee TF, Lee YA, Philip M.
Cancer Immunol Res. 2023 Oct 16. doi: 10.1158/2326-6066.CIR-22-0939. Online ahead of print.

Clinical consequences of a genetic predisposition toward higher benign prostate-specific antigen levels.
Shi M, Shelley JP, Schaffer KR, Tosoian JJ, Bagheri M, Witte JS, Kachuri L, Mosley JD.
EBioMedicine. 2023 Oct 19;97:104838. doi: 10.1016/j.ebiom.2023.104838. Online ahead of print.

Physician-scientist trainees with parenting responsibilities need financial and childcare support.
Jansen CS, Sugiura A, Stalbow L, Nguyen C, Lever JP, Peiper A, Plaza-Jennings A, Varvel L, Williams MA, Zarrinpar A, Swartz TH.
Nat Med. 2023 Oct 18. doi: 10.1038/s41591-023-02606-y. Online ahead of print.

Updates to the Autism Intervention Research Network on Physical Health (AIR-P) Research Agenda.
Hotez E, Haley M, Martinez-Agosto JA, Anderson J, Brown H, Choi K, Croen LA, Dwyer P, Fernandes P, Gassner D, Giwa Onaiwu M, Gragnani CM, Graham Holmes L, Kapp S, Kim D, Massolo M, Montgomery B, Natri HM, Rava JA, Rosenau KA, Roth J, Rudolph D, Ryan JG, Shattuck P, Shea L, Williams ZJ, Wilson RB, Kuo A.
Cureus. 2023 Aug 30;15(8):e44388. doi: 10.7759/cureus.44388. eCollection 2023 Aug. PMID: 37779815

Synaptic BMAL1 phosphorylation controls circadian hippocampal plasticity. 
Barone I, Gilette NM, Hawks-Mayer H, Handy J, Zhang KJ, Chifamba FF, Mostafa E, Johnson-Venkatesh EM, Sun Y, Gibson JM, Rotenberg A, Umemori H, Tsai PT, Lipton JO.
Sci Adv. 2023 Oct 27;9(43):eadj1010. doi: 10.1126/sciadv.adj1010. Epub 2023 Oct 25. PMID: 37878694

Drug repurposing for Alzheimer’s disease from 2012-2022-a 10-year literature review.
Grabowska ME, Huang A, Wen Z, Li B, Wei WQ.
Front Pharmacol. 2023 Sep 7;14:1257700. doi: 10.3389/fphar.2023.1257700. eCollection 2023. PMID: 37745051 Review.

Evolving approaches in paediatric thyroid cytopathology: A review.
Loberg MA, Tigue ML, Gallant JN, Wang H, Canberk S, Weiss VL.
Cytopathology. 2023 Sep 27. doi: 10.1111/cyt.13311. Online ahead of print. PMID: 37759375 Review.