Jeffrey Nirschl
@profiles.stanford.edu
Pathology
Stanford University
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
James Burgess, Jeffrey J. Nirschl, Maria-Clara Zanellati, Alejandro Lozano, Sarah Cohen, and Serena Yeung-Levy
Springer Science and Business Media LLC
AbstractCell and organelle shape are driven by diverse genetic and environmental factors and thus accurate quantification of cellular morphology is essential to experimental cell biology. Autoencoders are a popular tool for unsupervised biological image analysis because they learn a low-dimensional representation that maps images to feature vectors to generate a semantically meaningful embedding space of morphological variation. The learned feature vectors can also be used for clustering, dimensionality reduction, outlier detection, and supervised learning problems. Shape properties do not change with orientation, and thus we argue that representation learning methods should encode this orientation invariance. We show that conventional autoencoders are sensitive to orientation, which can lead to suboptimal performance on downstream tasks. To address this, we develop O2-variational autoencoder (O2-VAE), an unsupervised method that learns robust, orientation-invariant representations. We use O2-VAE to discover morphology subgroups in segmented cells and mitochondria, detect outlier cells, and rapidly characterise cellular shape and texture in large datasets, including in a newly generated synthetic benchmark.
Ryan M. Jamiolkowski, Quynh-Anh Nguyen, Jordan S. Farrell, Ryan J. McGinn, David A. Hartmann, Jeff J. Nirschl, Mateo I. Sanchez, Vivek P. Buch, and Ivan Soltesz
Springer Science and Business Media LLC
AbstractTargeted tissue ablation involving the anterior hippocampus is the standard of care for patients with drug-resistant mesial temporal lobe epilepsy. However, a substantial proportion continues to suffer from seizures even after surgery. We identified the fasciola cinereum (FC) neurons of the posterior hippocampal tail as an important seizure node in both mice and humans with epilepsy. Genetically defined FC neurons were highly active during spontaneous seizures in epileptic mice, and closed-loop optogenetic inhibition of these neurons potently reduced seizure duration. Furthermore, we specifically targeted and found the prominent involvement of FC during seizures in a cohort of six patients with epilepsy. In particular, targeted lesioning of the FC in a patient reduced the seizure burden present after ablation of anterior mesial temporal structures. Thus, the FC may be a promising interventional target in epilepsy.
Ragini Phansalkar, Vanessa S. Goodwill, Jeffrey J. Nirschl, Chiara De Lillo, Jihee Choi, Elizabeth Spurlock, David G. Coughlin, Donald Pizzo, Christina J. Sigurdson, Annie Hiniker,et al.
Springer Science and Business Media LLC
AbstractChronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head trauma. Brain pathology in CTE is characterized by neuronal loss, gliosis, and a distinctive pattern of neuronal accumulation of hyper-phosphorylated tau (p-tau) and phospho-TDP43 (p-TDP43). Visual anomalies have been reported by patients with CTE, but the ocular pathology underlying these symptoms is unknown. We evaluated retinal pathology in post-mortem eyes collected from 8 contact sport athletes with brain autopsy-confirmed stage IV CTE and compared their findings to retinas from 8 control patients without CTE and with no known history of head injury. Pupil-optic nerve cross sections were prepared and stained with hematoxylin and eosin (H&E), p-tau, p-TDP43, and total TDP43 by immunohistochemistry. No significant retinal degeneration was observed in CTE eyes compared to control eyes by H&E. Strong cytoplasmic p-TDP43 and total TDP43 staining was found in 6/8 CTE eyes in a subset of inner nuclear layer interneurons (INL) of the retina, while only 1/8 control eyes showed similar p-TDP43 pathology. The morphology and location of these inner nuclear layer interneurons were most compatible with retinal horizontal cells, although other retinal cell types present in INL could not be ruled out. No p-tau pathology was observed in CTE or control retinas. These findings identify novel retinal TDP43 pathology in CTE retinas and support further investigation into the role of p-TDP43 in producing visual deficits in patients with CTE.
Edgar E Nollet, Inez Duursma, Anastasiya Rozenbaum, Moritz Eggelbusch, Rob C I Wüst, Stephan A C Schoonvelde, Michelle Michels, Mark Jansen, Nicole N van der Wel, Kenneth C Bedi,et al.
Oxford University Press (OUP)
AbstractAimsGenetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mitochondrial respiratory function and specific disease-modifying treatment options in patients with HCM are scarce.Methods and resultsRespirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of mitochondria relative to myofibrils (expressed as a percentage of disorganized mitochondria) was strongly associated with mitochondrial dysfunction. Pre-incubation with the cardiolipin-stabilizing drug elamipretide and raising mitochondrial NAD+ levels both boosted NADH-linked respiration.ConclusionMitochondrial dysfunction is explained by cardiomyocyte architecture disruption and is linked to septal hypertrophy in genotype-negative HCM. Despite severe myocardial remodelling mitochondria were responsive to treatments aimed at restoring respiratory function, eliciting the mitochondria as a drug target to prevent and ameliorate cardiac disease in HCM. Mitochondria-targeting therapy may particularly benefit genotype-negative patients with HCM, given the tight link between mitochondrial impairment and septal thickening in this subpopulation.
Rebecca Rojansky, Iny Jhun, Alex M. Dussaq, Steven M. Chirieleison, Jeffrey J. Nirschl, Don Born, Jennifer Fralick, William Hetherington, Alison M. Kerr, Jonathan Lavezo,et al.
Archives of Pathology and Laboratory Medicine
Context.—Stanford Pathology began stepwise subspecialty implementation of whole slide imaging (WSI) in 2018 soon after the first US Food and Drug Administration approval. In 2020, during the COVID-19 pandemic, the Centers for Medicare & Medicaid Services waived the requirement for pathologists to perform diagnostic tests in Clinical Laboratory Improvement Amendments (CLIA)–licensed facilities. This encouraged rapid implementation of WSI across all surgical pathology subspecialties.Objective.—To present our experience with validation and implementation of WSI at a large academic medical center encompassing a caseload of more than 50 000 cases per year.Design.—Validation was performed independently for 3 subspecialty services with a diagnostic concordance threshold above 95%. Analysis of user experience, staffing, infrastructure, and information technology was performed after department-wide expansion.Results.—Diagnostic concordance was achieved in 96% of neuropathology cases, 100% of gynecologic pathology cases, and 98% of immunohistochemistry cases. After full implementation, 8 high-capacity scanners were operational, with whole slide images generated on greater than 2000 slides per weekday, accounting for approximately 80% of histologic slides at Stanford Medicine. Multiple modifications in workflow and information technology were needed to improve performance. Within months of full implementation, most attending pathologists and trainees had adopted WSI for primary diagnosis.Conclusions.—WSI across all surgical subspecialities is achievable at scale at an academic medical center; however, adoption required flexibility to adjust workflows and develop tailored solutions. WSI at scale supported the health and safety of medical staff while facilitating high-quality patient care and education during COVID-19 restrictions.
Patrick J. Cimino, Courtney Ketchum, Rust Turakulov, Omkar Singh, Zied Abdullaev, Caterina Giannini, Peter Pytel, Giselle Yvette Lopez, Howard Colman, MacLean P. Nasrallah,et al.
Springer Science and Business Media LLC
David S Rogawski, Jeffrey J Nirschl, Jamie McDonald, Esther Nie, Nicholas U Schwartz, Hannes Vogel, Brian J Scott, Carl A Gold, and Lucas B Kipp
SAGE Publications
Primary central nervous system (CNS) histiocytic sarcoma is a rare hematolymphoid malignancy with features of mature histiocytes and carries a poor prognosis. We describe a unique case in which a 50-year-old woman presented with recurrent acute brainstem syndrome, area postrema syndrome, and myelitis with corresponding magnetic resonance imaging (MRI) lesions meeting diagnostic criteria for seronegative neuromyelitis optica spectrum disorder (NMOSD). Despite initial improvement with steroids and plasma exchange, she experienced recurrent symptoms over 10 months referable to new and persistently enhancing lesions. At autopsy, neuropathology revealed a diffusely infiltrative primary CNS histiocytic sarcoma. This case represents a rare clinicoradiologic mimic of NMOSD, underscoring the importance of evaluation for infiltrative diseases in cases of atypical seronegative NMOSD.
Douwe van der Wal, Iny Jhun, Israa Laklouk, Jeff Nirschl, Lara Richer, Rebecca Rojansky, Talent Theparee, Joshua Wheeler, Jörg Sander, Felix Feng,et al.
Springer Science and Business Media LLC
AbstractBiology has become a prime area for the deployment of deep learning and artificial intelligence (AI), enabled largely by the massive data sets that the field can generate. Key to most AI tasks is the availability of a sufficiently large, labeled data set with which to train AI models. In the context of microscopy, it is easy to generate image data sets containing millions of cells and structures. However, it is challenging to obtain large-scale high-quality annotations for AI models. Here, we present HALS (Human-Augmenting Labeling System), a human-in-the-loop data labeling AI, which begins uninitialized and learns annotations from a human, in real-time. Using a multi-part AI composed of three deep learning models, HALS learns from just a few examples and immediately decreases the workload of the annotator, while increasing the quality of their annotations. Using a highly repetitive use-case—annotating cell types—and running experiments with seven pathologists—experts at the microscopic analysis of biological specimens—we demonstrate a manual work reduction of 90.60%, and an average data-quality boost of 4.34%, measured across four use-cases and two tissue stain types.
Adam M. Wawro, Chandresh R. Gajera, Steven A. Baker, Jeffrey J. Nirschl, Hannes Vogel, and Thomas J. Montine
Wiley
AbstractThe severe impact on brain function and lack of effective therapy for patients with creatine (Cr) transporter deficiency motivated the generation of three ubiquitous Slc6a8 deficient mice (−/y). While each mouse knock‐out line has similar behavioral effects at 2 to 3 months of age, other features critical to the efficient use of these mice in drug discovery are unclear or lacking: the concentration of Cr in brain and heart differ widely between mouse lines, there are limited data on histopathologic changes, and no data on Cr uptake. Here, we determined survival, measured endogenous Cr and uptake of its deuterium‐labeled analogue Cr‐d3 using a liquid chromatography coupled with tandem mass spectrometry assay, and performed comprehensive histopathologic examination on the Slc6a8−/y mouse developed by Skelton et al. Our results show that Slc6a8−/y mice have widely varying organ‐specific uptake of Cr‐d3, significantly diminished growth with the exception of brain, progressive vacuolar myopathy, and markedly shortened lifespan.
Andrew S. Moore, Stephen M. Coscia, Cory L. Simpson, Fabian E. Ortega, Eric C. Wait, John M. Heddleston, Jeffrey J. Nirschl, Christopher J. Obara, Pedro Guedes-Dias, C. Alexander Boecker,et al.
Springer Science and Business Media LLC
John L Robinson, Hayley Richardson, Sharon X Xie, EunRan Suh, Vivianna M Van Deerlin, Brian Alfaro, Nicholas Loh, Matias Porras-Paniagua, Jeffrey J Nirschl, David Wolk,et al.
Oxford University Press (OUP)
Abstract Cerebral amyloid angiopathy (CAA), limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) and Lewy bodies occur in the absence of clinical and neuropathological Alzheimer’s disease, but their prevalence and severity dramatically increase in Alzheimer’s disease. To investigate how plaques, tangles, age and apolipoprotein E ε4 (APOE ε4) interact with co-pathologies in Alzheimer’s disease, we analysed 522 participants ≥50 years of age with and without dementia from the Center for Neurodegenerative Disease Research (CNDR) autopsy program and 1340 participants in the National Alzheimer's Coordinating Center (NACC) database. Consensus criteria were applied for Alzheimer’s disease using amyloid phase and Braak stage. Co-pathology was staged for CAA (neocortical, allocortical, and subcortical), LATE-NC (amygdala, hippocampal, and cortical), and Lewy bodies (brainstem, limbic, neocortical, and amygdala predominant). APOE genotype was determined for all CNDR participants. Ordinal logistic regression was performed to quantify the effect of independent variables on the odds of having a higher stage after checking the proportional odds assumption. We found that without dementia, increasing age associated with all pathologies including CAA (odds ratio 1.63, 95% confidence interval 1.38–1.94, P < 0.01), LATE-NC (1.48, 1.16–1.88, P < 0.01), and Lewy bodies (1.45, 1.15–1.83, P < 0.01), but APOE ε4 only associated with CAA (4.80, 2.16–10.68, P < 0.01). With dementia, increasing age associated with LATE-NC (1.30, 1.15–1.46, P < 0.01), while Lewy bodies associated with younger ages (0.90, 0.81–1.00, P = 0.04), and APOE ε4 only associated with CAA (2.36, 1.52–3.65, P < 0.01). A longer disease course only associated with LATE-NC (1.06, 1.01–1.11, P = 0.01). Dementia in the NACC cohort associated with the second and third stages of CAA (2.23, 1.50–3.30, P < 0.01), LATE-NC (5.24, 3.11–8.83, P < 0.01), and Lewy bodies (2.41, 1.51–3.84, P < 0.01). Pathologically, increased Braak stage associated with CAA (5.07, 2.77–9.28, P < 0.01), LATE-NC (5.54, 2.33–13.15, P < 0.01), and Lewy bodies (4.76, 2.07–10.95, P < 0.01). Increased amyloid phase associated with CAA (2.27, 1.07–4.80, P = 0.03) and Lewy bodies (6.09, 1.66–22.33, P = 0.01). In summary, we describe widespread distributions of CAA, LATE-NC and Lewy bodies that progressively accumulate alongside plaques and tangles in Alzheimer’s disease dementia. CAA interacted with plaques and tangles especially in APOE ε4 positive individuals; LATE-NC associated with tangles later in the disease course; most Lewy bodies associated with moderate to severe plaques and tangles.
Hong Xu, Mia O’Reilly, Garrett S. Gibbons, Lakshmi Changolkar, Jennifer D. McBride, Dawn M. Riddle, Bin Zhang, Anna Stieber, Jeffrey Nirschl, Soo-Jung Kim,et al.
Springer Science and Business Media LLC
AbstractThe microtubule-associated protein tau (tau) forms hyperphosphorylated aggregates in the brains of tauopathy patients that can be pathologically and biochemically defined as distinct tau strains. Recent studies show that these tau strains exhibit strain-specific biological activities, also referred to as pathogenicities, in the tau spreading models. Currently, the specific pathogenicity of human-derived tau strains cannot be fully recapitulated by synthetic tau preformed fibrils (pffs), which are generated from recombinant tau protein. Reproducing disease-relevant tau pathology in cell and animal models necessitates the use of human brain-derived tau seeds. However, the availability of human-derived tau is extremely limited. Generation of tau variants that can mimic the pathogenicity of human-derived tau seeds would significantly extend the scale of experimental design within the field of tauopathy research. Previous studies have demonstrated that in vitro seeding reactions can amplify the beta-sheet structure of tau protein from a minute quantity of human-derived tau. However, whether the strain-specific pathogenicities of the original, human-derived tau seeds are conserved in the amplified tau strains has yet to be experimentally validated. Here, we used biochemically enriched brain-derived tau seeds from Alzheimer’s disease (AD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) patient brains with a modified seeding protocol to template the recruitment of recombinant 2N4R (T40) tau in vitro. We quantitatively interrogated efficacy of the amplification reactions and the pathogenic fidelity of the amplified material to the original tau seeds using recently developed sporadic tau spreading models. Our data suggest that different tau strains can be faithfully amplified in vitro from tau isolated from different tauopathy brains and that the amplified tau variants retain their strain-dependent pathogenic characteristics.
Pedro Guedes-Dias, Jeffrey J. Nirschl, Nohely Abreu, Mariko K. Tokito, Carsten Janke, Maria M. Magiera, and Erika L.F. Holzbaur
Elsevier BV
Jeffrey J. Nirschl, Andrew Janowczyk, Eliot G. Peyster, Renee Frank, Kenneth B. Margulies, Michael D. Feldman, and Anant Madabhushi
Public Library of Science (PLoS)
Over 26 million people worldwide suffer from heart failure annually. When the cause of heart failure cannot be identified, endomyocardial biopsy (EMB) represents the gold-standard for the evaluation of disease. However, manual EMB interpretation has high inter-rater variability. Deep convolutional neural networks (CNNs) have been successfully applied to detect cancer, diabetic retinopathy, and dermatologic lesions from images. In this study, we develop a CNN classifier to detect clinical heart failure from H&E stained whole-slide images from a total of 209 patients, 104 patients were used for training and the remaining 105 patients for independent testing. The CNN was able to identify patients with heart failure or severe pathology with a 99% sensitivity and 94% specificity on the test set, outperforming conventional feature-engineering approaches. Importantly, the CNN outperformed two expert pathologists by nearly 20%. Our results suggest that deep learning analytics of EMB can be used to predict cardiac outcome.
Jeffrey J. Nirschl, Amy E. Ghiretti, and Erika L. F. Holzbaur
Springer Science and Business Media LLC
Pallavi P. Gopal, Jeffrey J. Nirschl, Eva Klinman, and Erika L. F. Holzbaur
Proceedings of the National Academy of Sciences
Significance Mutations in TAR-DNA binding protein 43 (TDP-43), an RNA-binding protein (RBP) with multiple functions in RNA metabolism, cause amyotrophic lateral sclerosis (ALS), but it is uncertain how defects in RNA biology cause disease. Purified RNA-binding protein FUS and heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) form liquid droplets in vitro through liquid–liquid phase separation. However, the biophysical properties of ribonucleoprotein (RNP) granules composed of wild-type (WT) or ALS-linked TDP-43 have not been studied in primary neurons. We show that TDP-43 WT RNP granules exhibit distinct biophysical properties depending on their axonal location, whereas granules formed by ALS-linked mutant TDP-43 are more viscous and show disrupted axonal transport dynamics. We propose the distinct biophysical properties of these neuronal RNP granules may reflect different maturational states and differential propensity for pathological transformation.
Jeffrey J. Nirschl, Andrew Janowczyk, Eliot G. Peyster, Renee Frank, Kenneth B. Margulies, Michael D. Feldman, and Anant Madabhushi
Elsevier
Jeffrey J. Nirschl, Amy E. Ghiretti, and Erika L.F. Holzbaur
Elsevier BV
Jeffrey J. Nirschl, Maria M. Magiera, Jacob E. Lazarus, Carsten Janke, and Erika L.F. Holzbaur
Elsevier BV
Jeffrey J. Nirschl and Erika L.F. Holzbaur
Elsevier
Meng-meng Fu, Jeffrey J. Nirschl, and Erika L.F. Holzbaur
Elsevier BV
Atulya Iyengar, Jordan Imoehl, Atsushi Ueda, Jeffery Nirschl, and Chun-Fang Wu
Informa UK Limited
Automated tracking methods facilitate screening for and characterization of abnormal locomotion or more complex behaviors in Drosophila. We developed the Iowa Fly Locomotion and Interaction Tracker (IowaFLI Tracker), a MATLAB-based video analysis system, to identify and track multiple flies in a small arena. We report altered motor activity in the K+ and Na+ channel mutants, Hk1 and parats1, which had previously been shown to display abnormal larval locomotion. Environmental factors influencing individual behavior, such as available “social space,” were studied by using IowaFLI Tracker to simultaneously track multiple flies in the same arena. We found that crowding levels affect individual fly activity, with the total movement of individual flies attenuated around a particular density. This observation may have important implications in the design of activity chambers for studying particular kinds of social interactions. IowaFLI Tracker also directly quantifies social interactions by tracking the amount of time individuals are in proximity to one another—visualized as an “interactogram.” This feature enables the development of a “target-preference” assay to study male courtship behavior where males are presented with a choice between two immobilized, decapitated females, and their locomotion and interactions quantified. We used this assay to study the chemosensory mutants olf D (paraolf D, sbl 2) and Gr32a and their preferences towards virgin or mated females. Male olf D flies showed reduced courtship levels, with no clear preference towards either, whereas Gr32a males preferentially courted with virgin females over mated females in this assay. These initial results demonstrate that IowaFLI Tracker can be employed to explore motor coordination and social interaction phenomena in behavioral mutants of Drosophila.