Richard Perez, MD

All Publications

• Translatome profiling of spinal cord astrocytes reveals distinct gene signatures associated with acute and chronic pain. iScience Siliezar-Doyle, J., Perez, R. K., Stauffenberg, E., Nippert, A. R., Tawfik, V. L. 2026; 29 (5): 115719

  Abstract

  Astrocytes coordinate neuronal signaling in physiological conditions but can also drive neuroinflammation in pathophysiologic conditions, such as chronic pain. How and when astrocyte molecular pathways change in response to pain-inducing peripheral injury is key to understanding the acute-to-chronic pain transition. Here, we utilize translating ribosome affinity purification technology in a mouse model of complex regional pain syndrome to uncover the functional molecular signature of spinal astrocytes early and late post-injury. We find that astrocytes exhibit a temporally distinct translatome with most significant gene expression changes occurring acutely after injury. We further identify astrocyte lipid metabolism as altered after injury and demonstrate that lipid droplets (marked by PLIN2) accumulate in the spinal dorsal horn in the chronic post-injury phase. Overall, this work provides an astrocyte-specific translatome resource for understanding spinal astrocyte contributions to pain and highlights spinal cord lipid metabolism as a pathway of interest in pain pathophysiology.

  View details for DOI 10.1016/j.isci.2026.115719

  View details for PubMedID 42095095

  View details for PubMedCentralID PMC13141037

• Comparative transcriptomic meta-analysis reveals elevated TCL1A expression in human circulating immune cells across chronic pain conditions. British journal of anaesthesia Perez, R. K., Tawfik, V. L. 2025

  Abstract

  Chronic pain affects millions worldwide. Its management is complicated by diverse risk factors, symptom variability, and the lack of biomarkers. Research often explores pain through the lens of the human immune system, as immune dysregulation may contribute to pain. However, most studies analyse both sexes together despite known sex differences in immune responses, with women facing higher risks of autoimmunity and chronic pain. Pooling data and adjusting for sex could obscure sex-specific immune signatures linked to chronic pain, limiting our understanding of its origins.Using transcriptomic meta-analysis, we reprocessed several bulk RNA-sequencing studies of human circulating immune cells across multiple chronic pain conditions to examine both common and previously overlooked sex-specific transcriptomic signatures.Our meta-analysis included bulk RNA-sequencing data from circulating immune cells of 142 patients with chronic pain and 154 control subjects across six chronic pain conditions. Combined-sex analysis revealed differential expression of 19 genes in chronic pain. Stratification by sex identified 34 altered genes in women, including TCL1A, which is implicated in autoimmunity. Notably, TCL1A expression correlated with neuropathic symptom severity (P<0.05). Protein-level validation in an independent cohort confirmed these findings in women with neuropathic pain.Through transcriptomic meta-analysis of open-access data, we identified genes conserved across pain conditions and uncovered sex-specific signatures, including increased expression of TCL1A as a potential biomarker for neuropathic pain in a subset of women.

  View details for DOI 10.1016/j.bja.2025.09.014

  View details for PubMedID 41206280

• Transcriptomic Meta-Analysis of Human Circulating Immune Cells Across Chronic Pain Syndromes Reveals Shared Genetic Signatures Perez, R., Tawfik, V. LIPPINCOTT WILLIAMS & WILKINS. 2025: 657-658

  View details for Web of Science ID 001551889100255

• Deciphering the Translatomic Perturbations Associated with Acute and Chronic Pain in Mouse Spinal Cord Astrocytes Perez, R., Siliezar-Doyle, J., Tawfik, V. LIPPINCOTT WILLIAMS & WILKINS. 2024: 505

  View details for Web of Science ID 001349531300198

• Coordinated, multicellular patterns of transcriptional variation that stratify patient cohorts are revealed by tensor decomposition NATURE BIOTECHNOLOGY Mitchel, J., Gordon, M., Perez, R. K., Biederstedt, E., Bueno, R., Ye, C., Kharchenko, P. V. 2025; 43 (7): 1192-1201

  Abstract

  Tissue-level and organism-level biological processes often involve the coordinated action of multiple distinct cell types. The recent application of single-cell assays to many individuals should enable the study of how donor-level variation in one cell type is linked to that in other cell types. Here we introduce a computational approach called single-cell interpretable tensor decomposition (scITD) to identify common axes of interindividual variation by considering joint expression variation across multiple cell types. scITD combines expression matrices from each cell type into a higher-order matrix and factorizes the result using the Tucker tensor decomposition. Applying scITD to single-cell RNA-sequencing data on 115 persons with lupus and 83 persons with coronavirus disease 2019, we identify patterns of coordinated cellular activity linked to disease severity and specific phenotypes, such as lupus nephritis. scITD results also implicate specific signaling pathways likely mediating coordination between cell types. Overall, scITD offers a tool for understanding the covariation of cell states across individuals, which can yield insights into the complex processes that define and stratify disease.

  View details for DOI 10.1038/s41587-024-02411-z

  View details for Web of Science ID 001318996300003

  View details for PubMedID 39313646

  View details for PubMedCentralID 6300015

• Neuronal and behavioral responses to naturalistic texture im-ages in macaque monkeys. The Journal of neuroscience : the official journal of the Society for Neuroscience Ziemba, C. M., Goris, R. L., Stine, G. M., Perez, R. K., Simoncelli, E. P., Movshon, J. A. 2024

  Abstract

  The visual world is richly adorned with texture, which can serve to delineate important elements of natural scenes. In anes-thetized macaque monkeys, selectivity for the statistical features of natural texture is weak in V1, but substantial in V2, sug-gesting that neuronal activity in V2 might directly support texture perception. To test this, we investigated the relation between single cell activity in macaque V1 and V2 and simultaneously measured behavioral judgments of texture. We generated stim-uli along a continuum between naturalistic texture and phase-randomized noise and trained two macaque monkeys to judge whether a sample texture more closely resembled one or the other extreme. Analysis of responses revealed that individual V1 and V2 neurons carried much less information about texture naturalness than behavioral reports. However, the sensitivity of V2 neurons, especially those preferring naturalistic textures, was significantly closer to that of behavior compared with V1. The firing of both V1 and V2 neurons predicted perceptual choices in response to repeated presentations of the same ambiguous stimulus in one monkey, despite low individual neural sensitivity. However, neither population predicted choice in the second monkey. We conclude that neural responses supporting texture perception likely continue to develop downstream of V2. Fur-ther, combined with neural data recorded while the same two monkeys performed an orientation discrimination task, our results demonstrate that choice-correlated neural activity in early sensory cortex is unstable across observers and tasks, untethered from neuronal sensitivity, and thus unlikely to reflect a critical aspect of the formation of perceptual decisions.Significance statement As visual signals propagate along the cortical hierarchy, they encode increasingly complex aspects of the sensory environment and likely have a more direct relationship with perceptual experience. We replicate and extend previous results from anes-thetized monkeys differentiating the selectivity of neurons along the first step in cortical vision from area V1 to V2. However, our results further complicate efforts to establish neural signatures that reveal the relationship between perception and the neu-ronal activity of sensory populations. We find that choice-correlated activity in V1 and V2 is unstable across different observers and tasks, and also untethered from neuronal sensitivity and other features of nonsensory response modulation.

  View details for DOI 10.1523/JNEUROSCI.0349-24.2024

  View details for PubMedID 39197942

• Profound Coronary Vasospasm Associated with Intraoperative Ketamine Administration: A Case Report. A&A practice Perez, R. K., Lighthall, G. 2024; 18 (5): e01786

  Abstract

  We report a case of a 62-year-old woman with a decade-long history of atypical chest pain resulting in a largely negative cardiac workup, who developed significant angiographically demonstrated coronary vasospasm thought to be due to a small dose of intravenous ketamine. In patients with a history of atypical chest pain despite a reassuring cardiac evaluation, providers should carefully consider medications that may precipitate coronary vasospasm and be prepared to treat it accordingly.

  View details for DOI 10.1213/XAA.0000000000001786

  View details for PubMedID 38708942

• Deciphering the Mouse Spinal Cord Astrocyte Translatome at Acute and Chronic Timepoints of Complex Regional Pain Syndrome Lugo, J., Perez, R. K., Nippert, A. R., Wu, S., Tawfik, V. L. CHURCHILL LIVINGSTONE. 2024: 11

  View details for Web of Science ID 001282167300049

• SURGE: uncovering context-specific genetic-regulation of gene expression from single-cell RNA sequencing using latent-factor models GENOME BIOLOGY Strober, B. J., Tayeb, K., Popp, J., Qi, G., Gordon, M., Perez, R., Ye, C., Battle, A. 2024; 25 (1): 28

  Abstract

  Genetic regulation of gene expression is a complex process, with genetic effects known to vary across cellular contexts such as cell types and environmental conditions. We developed SURGE, a method for unsupervised discovery of context-specific expression quantitative trait loci (eQTLs) from single-cell transcriptomic data. This allows discovery of the contexts or cell types modulating genetic regulation without prior knowledge. Applied to peripheral blood single-cell eQTL data, SURGE contexts capture continuous representations of distinct cell types and groupings of biologically related cell types. We demonstrate the disease-relevance of SURGE context-specific eQTLs using colocalization analysis and stratified LD-score regression.

  View details for DOI 10.1186/s13059-023-03152-z

  View details for Web of Science ID 001148280600001

  View details for PubMedID 38254214

  View details for PubMedCentralID PMC10801966

• A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling ISCIENCE Hackney, J. A., Shivram, H., Heiden, J., Overall, C., Orozco, L., Gao, X., Kim, E., West, N., Qamra, A., Chang, D., Chakrabarti, A., Choy, D. F., Combes, A. J., Courau, T., Fragiadakis, G. K., Rao, A., Ray, A., Tsui, J., Hu, K., Kuhn, N. F., Krummel, M. F., Erle, D. J., Kangelaris, K., Sarma, A., Lyon, Z., Calfee, C. S., Woodruff, P. G., Ghale, R., Mick, E., Byrne, A., Zha, B., Langelier, C., Hendrickson, C. M., Wijst, M., Hartoularos, G. C., Grant, T., Bueno, R., Lee, D. S., Greenland, J. R., Sun, Y., Perez, R., Ogorodnikov, A., Ward, A., Ye, C., Ramalingam, T., Mcbride, J. M., Cai, F., Teterina, A., Bao, M., Tsai, L., Rosas, I. O., Regev, A., Kapadia, S. B., Bauer, R. N., Rosenberger, C. M., UCSF COMET Consortium 2023; 26 (10): 107813

  Abstract

  Altered myeloid inflammation and lymphopenia are hallmarks of severe infections. We identified the upregulated EN-RAGE gene program in airway and blood myeloid cells from patients with acute lung injury from SARS-CoV-2 or other causes across 7 cohorts. This program was associated with greater clinical severity and predicted future mechanical ventilation and death. EN-RAGEhi myeloid cells express features consistent with suppressor cell functionality, including low HLA-DR and high PD-L1. Sustained EN-RAGE program expression in airway and blood myeloid cells correlated with clinical severity and increasing expression of T cell dysfunction markers. IL-6 upregulated many EN-RAGE program genes in monocytes in vitro. IL-6 signaling blockade by tocilizumab in a placebo-controlled clinical trial led to rapid normalization of EN-RAGE and T cell gene expression. This identifies IL-6 as a key driver of myeloid dysregulation associated with worse clinical outcomes in COVID-19 patients and provides insights into shared pathophysiological mechanisms in non-COVID-19 ARDS.

  View details for DOI 10.1016/j.isci.2023.107813

  View details for Web of Science ID 001086992400001

  View details for PubMedID 37810211

  View details for PubMedCentralID PMC10551843

• Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus SCIENCE Perez, R. K., Gordon, M., Subramaniam, M., Kim, M., Hartoularos, G. C., Targ, S., Sun, Y., Ogorodnikov, A., Bueno, R., Lu, A., Thompson, M., Rappoport, N., Dahl, A., Lanata, C. M., Matloubian, M., Maliskova, L., Kwek, S. S., Li, T., Slyper, M., Waldman, J., Dionne, D., Rozenblatt-Rosen, O., Fong, L., Dall'Era, M., Balliu, B., Regev, A., Yazdany, J., Criswell, L. A., Zaitlen, N., Ye, C. 2022; 376 (6589): 153-+

  Abstract

  Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Knowledge of circulating immune cell types and states associated with SLE remains incomplete. We profiled more than 1.2 million peripheral blood mononuclear cells (162 cases, 99 controls) with multiplexed single-cell RNA sequencing (mux-seq). Cases exhibited elevated expression of type 1 interferon-stimulated genes (ISGs) in monocytes, reduction of naïve CD4+ T cells that correlated with monocyte ISG expression, and expansion of repertoire-restricted cytotoxic GZMH+ CD8+ T cells. Cell type-specific expression features predicted case-control status and stratified patients into two molecular subtypes. We integrated dense genotyping data to map cell type-specific cis-expression quantitative trait loci and to link SLE-associated variants to cell type-specific expression. These results demonstrate mux-seq as a systematic approach to characterize cellular composition, identify transcriptional signatures, and annotate genetic variants associated with SLE.

  View details for DOI 10.1126/science.abf1970

  View details for Web of Science ID 000783316500040

  View details for PubMedID 35389781

  View details for PubMedCentralID PMC9297655

• Author Correction: CSC software corrects off-target mediated gRNA depletion in CRISPR-Cas9 essentiality screens. Nature communications Perez, A. R., Sala, L., Perez, R. K., Vidigal, J. A. 2022; 13 (1): 1893

  View details for DOI 10.1038/s41467-022-29598-6

  View details for PubMedID 35365673

• CloudPred: Predicting Patient Phenotypes From Single-cell RNA-seq. Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing He, B., Thomson, M., Subramaniam, M., Perez, R., Ye, C. J., Zou, J. 2022; 27: 337-348

  Abstract

  Single-cell RNA sequencing (scRNA-seq) has the potential to provide powerful, high-resolution signatures to inform disease prognosis and precision medicine. This paper takes an important first step towards this goal by developing an interpretable machine learning algorithm, CloudPred, to predict individuals' disease phenotypes from their scRNA-seq data. Predicting phenotype from scRNA-seq is challenging for standard machine learning methods-the number of cells measured can vary by orders of magnitude across individuals and the cell populations are also highly heterogeneous. Typical analysis creates pseudo-bulk samples which are biased toward prior annotations and also lose the single cell resolution. CloudPred addresses these challenges via a novel end-to-end differentiable learning algorithm which is coupled with a biologically informed mixture of cell types model. CloudPred automatically infers the cell subpopulation that are salient for the phenotype without prior annotations. We developed a systematic simulation platform to evaluate the performance of CloudPred and several alternative methods we propose, and find that CloudPred outperforms the alternative methods across several settings. We further validated CloudPred on a real scRNA-seq dataset of 142 lupus patients and controls. CloudPred achieves AUROC of 0.98 while identifying a specific subpopulation of CD4 T cells whose presence is highly indicative of lupus. CloudPred is a powerful new framework to predict clinical phenotypes from scRNA-seq data and to identify relevant cells.

  View details for PubMedID 34890161

• CSC software corrects off-target mediated gRNA depletion in CRISPR-Cas9 essentiality screens. Nature communications Perez, A. R., Sala, L., Perez, R. K., Vidigal, J. A. 2021; 12 (1): 6461

  Abstract

  Off-target effects are well established confounders of CRISPR negative selection screens that impair the identification of essential genomic loci. In particular, non-coding regulatory elements and repetitive regions are often difficult to target with specific gRNAs, effectively precluding the unbiased screening of a large portion of the genome. To address this, we developed CRISPR Specificity Correction (CSC), a computational method that corrects for the effect of off-targeting on gRNA depletion. We benchmark CSC with data from the Cancer Dependency Map and show that it significantly improves the overall sensitivity and specificity of viability screens while preserving known essentialities, particularly for genes targeted by highly promiscuous gRNAs. We believe this tool will further enable the functional annotation of the genome as it represents a robust alternative to the traditional filtering strategy of discarding unspecific guides from the analysis. CSC is an open-source software that can be seamlessly integrated into current CRISPR analysis pipelines.

  View details for DOI 10.1038/s41467-021-26722-w

  View details for PubMedID 34753924

• Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19 SCIENCE TRANSLATIONAL MEDICINE van der Wijst, M. G. P., Vazquez, S. E., Hartoularos, G. C., Bastard, P., Grant, T., Bueno, R., Lee, D. S., Greenland, J. R., Sun, Y., Perez, R., Ogorodnikov, A., Ward, A., Mann, S. A., Lynch, K. L., Yun, C., Havlir, D., Chamie, G., Marquez, C., Greenhouse, B., Lionakis, M. S., Norris, P. J., Dumont, L. J., Kelly, K., Zhang, P., Zhang, Q., Gervais, A., Le Voyer, T., Whatley, A., Si, Y., Byrne, A., Combes, A. J., Rao, A., Song, Y. S., Fragiadakis, G. K., Kangelaris, K., Calfee, C. S., Erle, D. J., Hendrickson, C., Krummel, M. F., Woodruff, P. G., Langelier, C. R., Casanova, J., Derisi, J. L., Anderson, M. S., Ye, C., UCSF COMET Consortium 2021; 13 (612): eabh2624

  Abstract

  Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN–specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non–COVID-19 controls revealed a lack of type I IFN–stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN–specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN–specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.

  View details for DOI 10.1126/scitranslmed.abh2624

  View details for Web of Science ID 000699896400005

  View details for PubMedID 34429372

  View details for PubMedCentralID PMC8601717

• Optimized design of single-cell RNA sequencing experiments for cell-type-specific eQTL analysis NATURE COMMUNICATIONS Mandric, I., Schwarz, T., Majumdar, A., Hou, K., Briscoe, L., Perez, R., Subramaniam, M., Hafemeister, C., Satija, R., Ye, C., Pasaniuc, B., Halperin, E. 2020; 11 (1): 5504

  Abstract

  Single-cell RNA-sequencing (scRNA-Seq) is a compelling approach to directly and simultaneously measure cellular composition and state, which can otherwise only be estimated by applying deconvolution methods to bulk RNA-Seq estimates. However, it has not yet become a widely used tool in population-scale analyses, due to its prohibitively high cost. Here we show that given the same budget, the statistical power of cell-type-specific expression quantitative trait loci (eQTL) mapping can be increased through low-coverage per-cell sequencing of more samples rather than high-coverage sequencing of fewer samples. We use simulations starting from one of the largest available real single-cell RNA-Seq data from 120 individuals to also show that multiple experimental designs with different numbers of samples, cells per sample and reads per cell could have similar statistical power, and choosing an appropriate design can yield large cost savings especially when multiplexed workflows are considered. Finally, we provide a practical approach on selecting cost-effective designs for maximizing cell-type-specific eQTL power which is available in the form of a web tool.

  View details for DOI 10.1038/s41467-020-19365-w

  View details for Web of Science ID 000588063600027

  View details for PubMedID 33127880

  View details for PubMedCentralID PMC7599215

• Anaesthesiologists as translational scientists BRITISH JOURNAL OF ANAESTHESIA Castellanos, J. G., Perez, A. R., Perez, R. K. 2020; 124 (4): 373-376

  View details for DOI 10.1016/j.bja.2019.12.035

  View details for Web of Science ID 000519986700011

  View details for PubMedID 32000974

• Laminar Differences in Responses to Naturalistic Texture in Macaque V1 and V2 JOURNAL OF NEUROSCIENCE Ziemba, C. M., Perez, R. K., Pai, J., Kelly, J. G., Hallum, L. E., Shooner, C., Movshon, J. 2019; 39 (49): 9748-9756

  Abstract

  Most single units recorded from macaque secondary visual cortex (V2) respond with higher firing rates to synthetic texture images containing "naturalistic" higher-order statistics than to spectrally matched "noise" images lacking these statistics. In contrast, few single units in V1 show this property. We explored how the strength and dynamics of response vary across the different layers of visual cortex by recording multiunit (defined as high-frequency power in the local field potential) and gamma-band activity evoked by brief presentations of naturalistic and noise images in V1 and V2 of anesthetized macaque monkeys of both sexes. As previously reported, recordings in V2 showed consistently stronger responses to naturalistic texture than to spectrally matched noise. In contrast to single-unit recordings, V1 multiunit activity showed a preference for images with naturalistic statistics, and in gamma-band activity this preference was comparable across V1 and V2. Sensitivity to naturalistic image structure was strongest in the supragranular and infragranular layers of V1, but weak in granular layers, suggesting that it might reflect feedback from V2. Response timing was consistent with this idea. Visual responses appeared first in V1, followed by V2. Sensitivity to naturalistic texture emerged first in V2, followed by the supragranular and infragranular layers of V1, and finally in the granular layers of V1. Our results demonstrate laminar differences in the encoding of higher-order statistics of natural texture, and suggest that this sensitivity first arises in V2 and is fed back to modulate activity in V1.SIGNIFICANCE STATEMENT The circuit mechanisms responsible for visual representations of intermediate complexity are largely unknown. We used a well validated set of synthetic texture stimuli to probe the temporal and laminar profile of sensitivity to the higher-order statistical structure of natural images. We found that this sensitivity emerges first and most strongly in V2 but soon after in V1. However, sensitivity in V1 is higher in the laminae (extragranular) and recording modalities (local field potential) most likely affected by V2 connections, suggesting a feedback origin. Our results show how sensitivity to naturalistic image structure emerges across time and circuitry in the early visual cortex.

  View details for DOI 10.1523/JNEUROSCI.1743-19.2019

  View details for Web of Science ID 000502250500007

  View details for PubMedID 31666355

  View details for PubMedCentralID PMC6891061

• Advent of CRISPR Based Immunotherapy in Hematologic Malignancies. Journal of oncopathology and clinical research Perez, R. K., Chen, R., Kang, R., Perez, A. R. 2018; 2 (1)

  View details for PubMedID 29953127

• Computational Oncology. Journal of oncopathology and clinical research Perez, R. K., Kang, R., Chen, R., Castellanos, J. G., Milewski, A. R., Perez, A. R. 2018; 2 (1)

  View details for PubMedID 29953114