Member (Student), Cardiovascular Institute
Education & Certifications
BS, University of Pittsburgh, Neuroscience (2020)
Exome-wide association study of treatment-resistant depression suggests novel treatment targets.
2023; 13 (1): 12467
Treatment-resistant depression (TRD) is a severe form of major depressive disorder (MDD) with substantial public health impact and poor treatment outcome. Treatment outcome in MDD is significantly heritable, but genome-wide association studies have failed to identify replicable common marker alleles, suggesting a potential role for uncommon variants. Here we investigated the hypothesis that uncommon, putatively functional genetic variants are associated with TRD. Whole-exome sequencing data was obtained from 182 TRD cases and 2021 psychiatrically healthy controls. After quality control, the remaining 149 TRD cases and 1976 controls were analyzed with tests designed to detect excess burdens of uncommon variants. At the gene level, 5 genes, ZNF248, PRKRA, PYHIN1, SLC7A8, and STK19 each carried exome-wide significant excess burdens of variants in TRD cases (q < 0.05). Analysis of 41 pre-selected gene sets suggested an excess of uncommon, functional variants among genes involved in lithium response. Among the genes identified in previous TRD studies, ZDHHC3 was also significant in this sample after multiple test correction. ZNF248 and STK19 are involved in transcriptional regulation, PHYIN1 and PRKRA are involved in immune response, SLC7A8 is associated with thyroid hormone transporter activity, and ZDHHC3 regulates synaptic clustering of GABA and glutamate receptors. These results implicate uncommon, functional alleles in TRD and suggest promising novel targets for future research.
View details for DOI 10.1038/s41598-023-38984-z
View details for PubMedID 37528149
View details for PubMedCentralID 6065213
Spectrally Resolved Fiber Photometry for In Vivo Multi-Color Fluorescence Measurements.
2022; 2 (11): e587
This article describes how to assemble and operate a spectrometer-based fiber photometry system for in vivo simultaneous measurements of multiple fluorescent biosensors in freely moving mice. The first section of the article describes the step-by-step procedure to assemble a basic single-spectrometer fiber photometry system and how to expand it into a dual-spectrometer system that allows for simultaneous recordings from two sites. The second part describes the steps for a typical fiber probe implantation surgery. The last section describes how to acquire and analyze the time-lapsed spectral data. This article is intended for teaching labs how to build their own fiber photometry systems (with a video tutorial) from commercially available parts and perform in vivo recordings in behaving mice. © Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Basic Protocol 1: Assembling a dual-laser, single-spectrometer fiber photometry system Support Protocol: Dual-spectrometer fiber photometry assembly Basic Protocol 2: Optical fiber probe implantation Basic Protocol 3: Data acquisition and analysis.
View details for DOI 10.1002/cpz1.587
View details for PubMedID 36373979
View details for PubMedCentralID PMC10018997
Neurological Prognostication After Hypoglycemic Coma: Role of Clinical and EEG Findings
2022; 37 (1): 273-280
Hypoglycemic coma (HC) is an uncommon but severe clinical condition associated with poor neurological outcome. There is a dearth of robust neurological prognostic factors after HC. On the other hand, there is an increasing body of literature on reliable prognostic markers in the postanoxic coma, a similar-albeit not identical-situation. The objective of this study was thus to investigate the use and predictive value of these markers in HC.We conducted a retrospective, multicenter, cohort study within five centers of the Critical Care EEG Monitoring Research Consortium. We queried our electroencephalography (EEG) databases to identify all patients undergoing continuous EEG monitoring after admission to an intensive care unit with HC (defined as Glasgow Coma Scale < 8 on admission and a first blood glucose level < 50 mg/dL or not documented but in an obvious clinical context) between 01/01/2010 and 12/31/2020. We studied the association of findings at neurological examination (Glasgow Coma Scale motor subscale, pupillary light and corneal reflexes) and at continuous EEG monitoring(highly malignant patterns, reactivity, periodic discharges, seizures) with best neurological outcome within 3 months after hospital discharge, defined by the Cerebral Performance Category as favorable (1-3: recovery of consciousness) versus unfavorable (4-5: lack of recovery of consciousness).We identified 60 patients (30 [50%] women; age 62 [51-72] years). Thirty-one and 29 patients had a favorable and unfavorable outcome, respectively. The presence of pupillary reflexes (24 [100%] vs. 17 [81%]; p value 0.04) and a motor subscore > 2 (22 [92%] vs. 12 [63%]; p value 0.03) at 48-72 h were associated with a favorable outcome. A highly malignant EEG pattern was observed in 7 of 29 (24%) patients with unfavorable outcome versus 0 of 31 (0%) with favorable outcome, whereas the presence of EEG reactivity was observed in 28 of 31 (90%) patients with favorable outcome versus 13 of 29 (45%) with unfavorable outcome (p < 0.001 for comparison of all background categories).This preliminary study suggests that highly malignant EEG patterns might be reliable prognostic markers of unfavorable outcome after HC. Other EEG findings, including lack of EEG reactivity and seizures and clinical findings appear less accurate. These findings should be replicated in a larger multicenter prospective study.
View details for DOI 10.1007/s12028-022-01495-2
View details for Web of Science ID 000784052000001
View details for PubMedID 35437670
Cobalt-induced oxidative stress contributes to alveolar/bronchiolar carcinogenesis in B6C3F1/N mice
ARCHIVES OF TOXICOLOGY
2021; 95 (10): 3171-3190
Rodent alveolar/bronchiolar carcinomas (ABC) that arise either spontaneously or due to chemical exposure are similar to a subtype of lung adenocarcinomas in humans. B6C3F1/N mice and F344/NTac rats exposed to cobalt metal dust (CMD) by inhalation developed ABCs in a dose dependent manner. In CMD-exposed mice, the incidence of Kras mutations in ABCs was 67% with 80% of those being G to T transversions on codon 12 suggesting a role of oxidative stress in the pathogenesis. In vitro studies, such as DMPO (5,5-dimethyl-1-pyrroline N-oxide) immune-spin trapping assay, and dihydroethidium (DHE) fluorescence assay on A549 and BEAS-2B cells demonstrated increased oxidative stress due to cobalt exposure. In addition, significantly increased 8-oxo-dG adducts were demonstrated by immunohistochemistry in lungs from mice exposed to CMD for 90 days. Furthermore, transcriptomic analysis on ABCs arising spontaneously or due to chronic CMD-exposure demonstrated significant alterations in canonical pathways related to MAPK signaling (IL-8, ErbB, Integrin, and PAK pathway) and oxidative stress (PI3K/AKT and Melatonin pathway) in ABCs from CMD-exposed mice. Oxidative stress can stimulate PI3K/AKT and MAPK signaling pathways. Nox4 was significantly upregulated only in CMD-exposed ABCs and NOX4 activation of PI3K/AKT can lead to increased ROS levels in human cancer cells. The gene encoding Ereg was markedly up-regulated in CMD-exposed mice. Oncogenic KRAS mutations have been shown to induce EREG overexpression. Collectively, all these data suggest that oxidative stress plays a significant role in CMD-induced pulmonary carcinogenesis in rodents and these findings may also be relevant in the context of human lung cancers.
View details for DOI 10.1007/s00204-021-03146-5
View details for Web of Science ID 000691924600002
View details for PubMedID 34468815
View details for PubMedCentralID PMC9418869
Spectrally Resolved Fiber Photometry for Multi-component Analysis of Brain Circuits
2018; 98 (4): 707-+
To achieve simultaneous measurement of multiple cellular events in molecularly defined groups of neurons in vivo, we designed a spectrometer-based fiber photometry system that allows for spectral unmixing of multiple fluorescence signals recorded from deep brain structures in behaving animals. Using green and red Ca2+ indicators differentially expressed in striatal direct- and indirect-pathway neurons, we were able to simultaneously monitor the neural activity in these two pathways in freely moving animals. We found that the activities were highly synchronized between the direct and indirect pathways within one hemisphere and were desynchronized between the two hemispheres. We further analyzed the relationship between the movement patterns and the magnitude of activation in direct- and indirect-pathway neurons and found that the striatal direct and indirect pathways coordinately control the dynamics and fate of movement. VIDEO ABSTRACT.
View details for DOI 10.1016/j.neuron.2018.04.012
View details for Web of Science ID 000432474200008
View details for PubMedID 29731250
View details for PubMedCentralID PMC5957785