I am a translational physician-scientist focused on studying the role of the immune system in patients with schizophrenia. My work spans careful clinical characterization of patients to understanding mechanisms in basic science model systems, allowing to provide mechanistic understanding to observations in clinical samples. Currently, I'm focused on deciphering the role of the complement system and how the known genetic risk translates into pathophysiological disease mechanisms. I hope that this work will pave the way to novel treatment strategies.
- 22q11 Deletion Syndrome
Clinical Instructor, Psychiatry and Behavioral Sciences
Honors & Awards
Ruth L. Kirschstein National Research Service Award F30, National Institutes of Health (2008-2013)
Outstanding Resident Award- Honorable Mention, National Institutes of Health (2017)
T32 Postdoctoral Research Training in Psychiatric Research, National Institutes of Health (2017-2019)
Translational Research and Applied Medicine Scholar, Stanford University School of Medicine (2018-2020)
Advanced Fellow in Mental Illness Research, Sierra Pacific Mental Illness Research Education and Clinical Center (MIRECC), VA Palo Alto (2019-present)
Board Certification: American Board of Psychiatry and Neurology, Psychiatry (2018)
Residency: Stanford University Adult Psychiatry Residency (2017) CA
Medical Education: University of Pittsburgh School of Medicine (2013) PA
Doctor of Philosophy, Carnegie Mellon University (2011)
Doctor of Medicine, University of Pittsburgh (2013)
Elizabeth Mellins, Postdoctoral Research Mentor
Increased activation product of complement 4 protein in plasma of individuals with schizophrenia.
2021; 11 (1): 486
Structural variation in the complement 4 gene (C4) confers genetic risk for schizophrenia. The variation includes numbers of the increased C4A copy number, which predicts increased C4A mRNA expression. C4-anaphylatoxin (C4-ana) is a C4 protein fragment released upon C4 protein activation that has the potential to change the blood-brain barrier (BBB). We hypothesized that elevated plasma levels of C4-ana occur in individuals with schizophrenia (iSCZ). Blood was collected from 15 iSCZ with illness duration < 5 years and from 14 healthy controls (HC). Plasma C4-ana was measured by radioimmunoassay. Other complement activation products C3-ana, C5-ana, and terminal complement complex (TCC) were also measured. Digital-droplet PCR was used to determine C4 gene structural variation state. Recombinant C4-ana was added to primary brain endothelial cells (BEC) and permeability was measured in vitro. C4-ana concentration was elevated in plasma from iSCZ compared to HC (mean=654±16ng/mL, 557±94 respectively, p=0.01). The patients also carried more copies of the C4AL gene and demonstrated a positive correlation between plasma C4-ana concentrations and C4A gene copy number. Furthermore, C4-ana increased the permeability of a monolayer of BEC in vitro. Our findings are consistent with a specific role for C4A protein in schizophrenia and raise the possibility that its activation product, C4-ana, increases BBB permeability. Exploratory analyses suggest the novel hypothesis that the relationship between C4-ana levels and C4A gene copy number could also be altered in iSCZ, suggesting an interaction with unknown genetic and/or environmental risk factors.
View details for DOI 10.1038/s41398-021-01583-5
View details for PubMedID 34552056
Machine learning reveals bilateral distribution of somatic L1 insertions in human neurons and glia.
Retrotransposons can cause somatic genome variation in the human nervous system, which is hypothesized to have relevance to brain development and neuropsychiatric disease. However, the detection of individual somatic mobile element insertions presents a difficult signal-to-noise problem. Using a machine-learning method (RetroSom) and deep whole-genome sequencing, we analyzed L1 and Alu retrotransposition in sorted neurons and glia from human brains. We characterized two brain-specific L1 insertions in neurons and glia from a donor with schizophrenia. There was anatomical distribution of the L1 insertions in neurons and glia across both hemispheres, indicating retrotransposition occurred during early embryogenesis. Both insertions were within the introns of genes (CNNM2 and FRMD4A) inside genomic loci associated with neuropsychiatric disorders. Proof-of-principle experiments revealed these L1 insertions significantly reduced gene expression. These results demonstrate that RetroSom has broad applications for studies of brain development and may provide insight into the possible pathological effects of somatic retrotransposition.
View details for DOI 10.1038/s41593-020-00767-4
View details for PubMedID 33432196
Low C4 Copy Number of Total C4 Gene, C4B Gene and C4BL Gene in Children with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS)
WILEY. 2020: 254–55
View details for Web of Science ID 000542687800145
Teaching Practice-Based Learning on Inpatient Psychiatric Services.
Academic psychiatry : the journal of the American Association of Directors of Psychiatric Residency Training and the Association for Academic Psychiatry
OBJECTIVE: Psychiatry residents must learn to incorporate new information into clinical practice as the field quickly evolves. The authors developed a practice-based workshop grounded in active learning principles on the inpatient psychiatric unit.METHODS: Residents rotating on inpatient services observed a patient interview, then brainstormed learner-driven learning objectives. They each independently researched selected topics, then utilized peer instruction and discussion grounded in the clinical case. Topic areas covered over a year were tracked and residents' experiences were surveyed.RESULTS: The material covered included evidence-based treatments, neuroscience, cultural, and systems psychiatry. Residents rated the workshop as highly effective and engaging (91% and 96%, respectively, on Likert Scale) and positively on the Tutorial Group Effectiveness Instrument (3.8±0.6 for cognitive aspects, 3.2±0.7 for motivational aspects, and 2.7±0.6 for demotivational aspects).CONCLUSIONS: This case-based and learner-driven peer teaching model based on an active learning model allows for quick integration of new material into the curriculum with resident satisfaction.
View details for DOI 10.1007/s40596-019-01113-y
View details for PubMedID 31642050
- MACHINE LEARNING REVEALS BILATERAL DISTRIBUTION OF SOMATIC L1 INSERTIONS IN HUMAN NEURONS AND GLIA ELSEVIER. 2019: S68
- Medical Workup for First-Episode Psychosis Intervening Early in Psychosis American Psychiatric Association Publishing. 2019; 1: 133–150
Medical Workup for First-Episode Psychosis
INTERVENING EARLY IN PSYCHOSIS: A TEAM APPROACH
View details for Web of Science ID 000549765400010
- Neuroscience in Clinical Supervision: Toward a Neurobiopsychosocial Approach Supervision in Psychiatric Practice Practical Approaches Across Venues and Providers American Psychiatric Association Publishing. 2019
Governmental standard drink definitions and low-risk alcohol consumption guidelines in 37 countries
2016; 111 (7): 1293-1298
One of the challenges of international alcohol research and policy is the variability in and lack of knowledge of how governments in different nations define a standard drink and low-risk drinking. This study gathered such information from governmental agencies in 37 countries.A pool of 75 countries that might have definitions was created using World Health Organization (WHO) information and the authors' own judgement. Structured internet searches of relevant terms for each country were supplemented by efforts to contact government agencies directly and to consult with alcohol experts in the country.Most of the 75 national governments examined were not identified as having adopted a standard drink definition. Among the 37 that were so identified, the modal standard drink size was 10 g pure ethanol, but variation was wide (8-20 g). Significant variability was also evident for low-risk drinking guidelines, ranging from 10-42 g per day for women and 10-56 g per day for men to 98-140 g per week for women and 150-280 g per week for men.Researchers working and communicating across national boundaries should be sensitive to the substantial variability in 'standard' drink definitions and low-risk drinking guidelines. The potential impact of guidelines, both in general and in specific national cases, remains an important question for public health research.
View details for DOI 10.1111/add.13341
View details for Web of Science ID 000379951700027
View details for PubMedID 27073140
The tail domain of lamin B1 is more strongly modulated by divalent cations than lamin A.
Nucleus (Austin, Tex.)
2015; 6 (3): 203–11
The nucleoskeleton contains mainly nuclear intermediate filaments made of lamin proteins. Lamins provide nuclear structure and also play a role in various nuclear processes including signal transduction, transcription regulation and chromatin organization. The disparate functions of lamins may be related to the intrinsic disorder of the tail domains, which allows for altered and promiscuous binding. Here, we show modulation of lamin tail domain structures in the presence of divalent cations. We utilize changes in fluorescence of tryptophan residues within the Ig-fold flanked by disordered regions to experimentally measure protein thermodynamics. Using spectroscopy experiments and molecular dynamics simulations, we show that the tail domain of lamin B1 shows enhanced association with both Ca(2+) and Mg(2+) compared to the tail domain of lamin A. Binding curves show a similar KD between protein and ion (250-300 μM) for both proteins with both ions. However, we observe a maximum binding of ions to lamin B1 tail domain which is 2-3 times greater than that for lamin A tail domain by both experiment and simulation. Using simulations, we show that divalent ion association alters the Ig-fold by pinning flanking regions. With cells in culture, we observe altered lamin B1 organization in the presence of excess Mg(2+) more so than for lamin A. We suggest that the differential sensitivity to divalent cations contributes to the vastly different functionalities and binding of the 2 proteins.
View details for DOI 10.1080/19491034.2015.1031436
View details for PubMedID 25807068
View details for PubMedCentralID PMC4615889
Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson-Gilford progeria syndrome.
2014; 195: 43–48
Hutchinson-Gilford progeria syndrome is a premature aging disorder associated with the expression of ∆50 lamin A (∆50LA), a mutant form of the nuclear structural protein lamin A (LA). ∆50LA is missing 50 amino acids from the tail domain and retains a C-terminal farnesyl group that is cleaved from the wild-type LA. Many of the cellular pathologies of HGPS are thought to be a consequence of protein-membrane association mediated by the retained farnesyl group. To better characterize the protein-membrane interface, we quantified binding of purified recombinant ∆50LA tail domain (∆50LA-TD) to tethered bilayer membranes composed of phosphatidylserine and phosphocholine using surface plasmon resonance. Farnesylated ∆50LA-TD binds to the membrane interface only in the presence of Ca(2+) or Mg(2+) at physiological ionic strength. At extremely low ionic strength, both the farnesylated and non-farnesylated forms of ∆50LA-TD bind to the membrane surface in amounts that exceed those expected for a densely packed protein monolayer. Interestingly, the wild-type LA-TD with no farnesylation also associates with membranes at low ionic strength but forms only a single layer. We suggest that electrostatic interactions are mediated by charge clusters with a net positive charge that we calculate on the surface of the LA-TDs. These studies suggest that the accumulation of ∆50LA at the inner nuclear membrane observed in cells is due to a combination of aggregation and membrane association rather than simple membrane binding; electrostatics plays an important role in mediating this association.
View details for DOI 10.1016/j.bpc.2014.08.005
View details for PubMedID 25194277
View details for PubMedCentralID PMC4212650
Calcium causes a conformational change in lamin A tail domain that promotes farnesyl-mediated membrane association.
2013; 104 (10): 2246–53
Lamin proteins contribute to nuclear structure and function, primarily at the inner nuclear membrane. The posttranslational processing pathway of lamin A includes farnesylation of the C-terminus, likely to increase membrane association, and subsequent proteolytic cleavage of the C-terminus. Hutchinson Gilford progeria syndrome is a premature aging disorder wherein a mutant version of lamin A, Δ50 lamin A, retains its farnesylation. We report here that membrane association of farnesylated Δ50 lamin A tail domains requires calcium. Experimental evidence and molecular dynamics simulations collectively suggest that the farnesyl group is sequestered within a hydrophobic region in the tail domain in the absence of calcium. Calcium binds to the tail domain with an affinity KD ≈ 250 μM where it alters the structure of the Ig-fold and increases the solvent accessibility of the C-terminus. In 2 mM CaCl2, the affinity of the farnesylated protein to a synthetic membrane is KD ≈ 2 μM, as measured with surface plasmon resonance, but showed a combination of aggregation and binding. Membrane binding in the absence of calcium could not be detected. We suggest that a conformational change induced in Δ50 lamin A with divalent cations plays a regulatory role in the posttranslational processing of lamin A, which may be important in disease pathogenesis.
View details for DOI 10.1016/j.bpj.2013.04.016
View details for PubMedID 23708364
View details for PubMedCentralID PMC3660631
- Nucleoskeleton mechanics at a glance. Journal of cell science 2011; 124 (Pt 5): 675–78
Computational image analysis of nuclear morphology associated with various nuclear-specific aging disorders.
Nucleus (Austin, Tex.)
2011; 2 (6): 570–79
Computational image analysis is used in many areas of biological and medical research, but advanced techniques including machine learning remain underutilized. Here, we used automated segmentation and shape analyses, with pre-defined features and with computer generated components, to compare nuclei from various premature aging disorders caused by alterations in nuclear proteins. We considered cells from patients with Hutchinson-Gilford progeria syndrome (HGPS) with an altered nucleoskeletal protein; a mouse model of XFE progeroid syndrome caused by a deficiency of ERCC1-XPF DNA repair nuclease; and patients with Werner syndrome (WS) lacking a functional WRN exonuclease and helicase protein. Using feature space analysis, including circularity, eccentricity, and solidity, we found that XFE nuclei were larger and significantly more elongated than control nuclei. HGPS nuclei were smaller and rounder than the control nuclei with features suggesting small bumps. WS nuclei did not show any significant shape changes from control. We also performed principle component analysis (PCA) and a geometric, contour based metric. PCA allowed direct visualization of morphological changes in diseased nuclei, whereas standard, feature-based approaches required pre-defined parameters and indirect interpretation of multiple parameters. Both methods yielded similar results, but PCA proves to be a powerful pre-analysis methodology for unknown systems.
View details for DOI 10.4161/nucl.2.6.17798
View details for PubMedID 22127259
View details for PubMedCentralID PMC3324345
Structure and stability of the lamin A tail domain and HGPS mutant.
Journal of structural biology
2011; 175 (3): 425–33
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging syndrome caused by the expression and accumulation of a mutant form of lamin A, Δ50 lamin A. As a component of the cell's nucleoskeleton, lamin A plays an important role in the mechanical stabilization of the nuclear envelope and in other nuclear functions. It is largely unknown how the characteristic 50 amino acid deletion affects the conformation of the mostly intrinsically disordered tail domain of lamin A. Here we perform replica exchange molecular dynamics simulations of the tail domain and determine an ensemble of semi-stable structures. Based on these structures we show that the ZMPSTE 24 cleavage site on the precursor form of the lamin A tail domain orients itself in such a way as to facilitate cleavage during the maturation process. We confirm our simulated structures by comparing the thermodynamic properties of the ensemble structures to in vitro stability measurements. Using this combination of experimental and computational techniques, we compare the size, heterogeneity of size, thermodynamic stability of the Ig-fold, as well as the mechanisms of force-induced denaturation. Our data shows that the Δ50 lamin A tail domain is more compact and displays less heterogeneity than the mature lamin A tail domain. Altogether these results suggest that the altered structure and stability of the tail domain can explain changed protein-protein and protein-DNA interactions and may represent an etiology of the disease. Also, this study provides the first molecular structure(s) of the lamin A tail domain, which is confirmed by thermodynamic tests in experiment.
View details for DOI 10.1016/j.jsb.2011.05.015
View details for PubMedID 21635954
View details for PubMedCentralID PMC3150306
Mechanobiology and the microcirculation: cellular, nuclear and fluid mechanics.
Microcirculation (New York, N.Y. : 1994)
2010; 17 (3): 179–91
Endothelial cells are stimulated by shear stress throughout the vasculature and respond with changes in gene expression and by morphological reorganization. Mechanical sensors of the cell are varied and include cell surface sensors that activate intracellular chemical signaling pathways. Here, possible mechanical sensors of the cell including reorganization of the cytoskeleton and the nucleus are discussed in relation to shear flow. A mutation in the nuclear structural protein lamin A, related to Hutchinson-Gilford progeria syndrome, is reviewed specifically as the mutation results in altered nuclear structure and stiffer nuclei; animal models also suggest significantly altered vascular structure. Nuclear and cellular deformation of endothelial cells in response to shear stress provides partial understanding of possible mechanical regulation in the microcirculation. Increasing sophistication of fluid flow simulations inside the vessel is also an emerging area relevant to the microcirculation as visualization in situ is difficult. This integrated approach to study--including medicine, molecular and cell biology, biophysics and engineering--provides a unique understanding of multi-scale interactions in the microcirculation.
View details for DOI 10.1111/j.1549-8719.2009.00016.x
View details for PubMedID 20374482
View details for PubMedCentralID PMC2881226
Stabilization of the spectrin-like domains of nesprin-1α by the evolutionarily conserved "adaptive" domain.
Cellular and molecular bioengineering
2010; 3 (2): 139–50
Nesprins are located at the outer and inner membranes of the nuclear envelope and help link the cytoskeleton to the nucleoskeleton. Nesprin-1α, located at the inner nuclear membrane, binds to A-type lamins and emerin and has homology to spectrin-repeat proteins. However, the mechanical and thermodynamic properties of the spectrin-like repeats (SLRs) of nesprin-1α and the potential structural contributions of the unique central domain were untested. In other spectrin superfamily proteins, tandem spectrin-repeat domains undergo cooperatively coupled folding and unfolding. We hypothesized that the large central domain, which interrupts SLRs and is conserved in other nesprin isoforms, might confer unique structural properties. To test this model we measured the thermal unfolding of nesprin-1α fragments using circular dichroism and dynamic light scattering. The SLRs in nesprin-1α were found to have structural and thermodynamic properties typical of spectrins. The central domain had relatively little secondary structure as an isolated fragment, but significantly stabilized larger SLR-containing molecules by increasing their overall helicity, thermal stability and cooperativity of folding. We suggest this domain, now termed the 'adaptive' domain (AD), also strengthens dimerization and inhibits unfolding. Further engineering of the isolated AD, and AD-containing nesprin molecules, may yield new information about the higher-order association of cooperative protein motifs.
View details for DOI 10.1007/s12195-010-0121-3
View details for PubMedID 20563238
View details for PubMedCentralID PMC2885798
Dynamical response of nanomechanical oscillators in immiscible viscous fluid for in vitro biomolecular recognition.
Physical review letters
2006; 96 (18): 186105
Dynamical response of nanomechanical cantilever structures immersed in a viscous fluid is important to in vitro single-molecule force spectroscopy, biomolecular recognition of disease-specific proteins, and the study of microscopic protein dynamics. Here we study the stochastic response of biofunctionalized nanomechanical cantilever beams in a viscous fluid. Using the fluctuation-dissipation theorem we derive an exact expression for the spectral density of displacement and a linear approximation for resonance frequency shift. We find that in a viscous solution the frequency shift of the nanoscale cantilever is determined by surface stress generated by biomolecular interaction with negligible contributions from mass loading due to the biomolecules.
View details for DOI 10.1103/PhysRevLett.96.186105
View details for PubMedID 16712378