Mrinalini Kala

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Scholarly Contributions

Journals/Publications

• Bixby, B., Vrba, L., Lenka, J., Oshiro, M. M., Watts, G. S., Hughes, T., Erickson, H., Chopra, M., Knepler, J. L., Knox, K. S., Jarnagin, L., Alalawi, R., Kala, M., Bernert, R., Routh, J., Roe, D. J., Garland, L. L., Futscher, B. W., & Nelson, M. A. (2024). Cell-free DNA methylation analysis as a marker of malignancy in pleural fluid. Scientific reports, 14(1), 2939.
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  Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology for the diagnosis of malignant pleural effusion is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion. This was a blind, prospective case-control biomarker study. We recruited 104 patients with pleural effusion for the study. We collected pleural fluid from patients with: MPE (n = 48), indeterminate pleural effusion in subjects with known malignancy or IPE (n = 28), and benign PE (n = 28), and performed the Sentinel-MPE liquid biopsy assay. The methylation level of Sentinel-MPE was markedly higher in the MPE samples compared to BPE control samples (p 
• Kala, M. (2024). Measurement of circulating viral antigens post-SARS-CoV-2 infection in a multicohort study. . Clin Microbiol Infect.
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  Recover consortium authors
• Kala, M. (2024). Update of the RECOVER-Adult Long COVID Research Index. JAMA.
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  As Recover consortium
• Kala, M. (2024). RECOVER-Adult Cohort. Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort. . Ann Intern Med, 177(9), 1209-1221.
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  Contribution as Biorepositry consortium
• Liu, B., Yi, D., Li, S., Ramirez, K., Xia, X., Cao, Y., Zhao, H., Tripathi, A., Qiu, S., Kala, M., Rafikov, R., Gu, H., de Jesus Perez, V., Lemay, S. E., Glembotski, C. C., Knox, K. S., Bonnet, S., Kalinichenko, V. V., Zhao, Y. Y., , Fallon, M. B., et al. (2024). Single-cell and Spatial Transcriptomics Identified Fatty Acid-binding Proteins Controlling Endothelial Glycolytic and Arterial Programming in Pulmonary Hypertension. bioRxiv : the preprint server for biology.
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  Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Single-cell RNA sequencing (scRNAseq) analysis found that both FABP4 and FABP5 were highly induced in endothelial cells (ECs) of (CKO) mice, which was also observed in pulmonary arterial ECs (PAECs) from idiopathic PAH (IPAH) patients, and in whole lungs of pulmonary hypertension (PH) rats. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters using plasma proteome analysis. Genetic deletion of both and 5 in CKO mice ( ,TKO) caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure assessed by echocardiography, hemodynamic and histological analysis. Employing bulk RNA-seq and scRNA-seq, and spatial transcriptomic analysis, we showed that deletion also inhibited EC glycolysis and distal arterial programming, reduced ROS and HIF-2α expression in PH lungs. Thus, PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced ECs glycolysis and distal arterial programming, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.
• Schippel, N., Wei, J., Ma, X., Kala, M., Qiu, S., Stoilov, P., & Sharma, S. (2024). Erythropoietin-dependent Acquisition of CD71 CD105 Phenotype within CD235a Early Erythroid Progenitors. bioRxiv : the preprint server for biology.
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  The development of committed erythroid progenitors and their continued maturation into mature erythrocytes requires the cytokine erythropoietin (Epo). Here, we describe the immunophenotypic identification of a unique Epo-dependent colony-forming unit-erythroid (CFU-E) cell subtype that forms during early erythropoiesis (EE). This previously undescribed CFU-E subtype, termed late-CFU-E (lateC), lacks surface expression of the characteristic erythroid marker CD235a (glycophorin A) but has high levels of CD71 and CD105. LateCs could be prospectively detected in human bone marrow (BM) cells and, upon isolation and reculture, exhibited the potential to form CFU-E colonies in medium containing only Epo (no other cytokines) and continued differentiation along the erythroid trajectory. Analysis of cultures of BM CD34 cells showed that acquisition of the CD7 CD105 phenotype in lateCs is gradual and occurs through the formation of four EE cell subtypes. Of these, two are CD34 burst-forming unit-erythroid (BFU-E) cells, distinguishable as CD7 CD105 early BFU-E and CD7 CD105 late BFU-E, and two are CD34 CFU-Es, also distinguishable as CD71 CD105 early CFU-E and CD7 CD105 mid-CFU-E. The transition of these EE populations is accompanied by a rise in CD36 expression, such that all lateCs are CD36 . Single cell RNA-sequencing analysis confirmed Epo-dependent formation of a CFU-E cluster that exhibits high coexpression of CD71, CD105, and CD36 transcripts. Gene set enrichment analysis revealed the involvement of genes specific to fatty acid and cholesterol metabolism in lateC formation. Overall, in addition to identifying a key Epo-dependent EE cell stage, this study provides a framework for investigation into mechanisms underlying other erythropoiesis-stimulating agents.
• Bixby, B., Vrba, L., Lenka, J., Oshiro, M., Watts, G. S., Hughes, T., Erickson, H., Chopra, M., Knepler, J. L., Knox, K. S., Jarnagin, L., Alalawi, R., Kala, M., Bernert, R., Routh, J., Roe, D. J., Garland, L. L., Futscher, B. W., & Nelson, M. A. (2023). Cell-Free DNA Methylation Analysis as a Marker of Malignancy in Pleural Fluid. Research square.
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  Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology malignant pleural effusion diagnosis is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion.
• Feng, A., Caro, Y. M., Gardner, C., Grischo, G., Liang, Y., Wickremasinghe, P. D., Polmann, M., Kala, M., Marlowe, T., Black, S. M., Knox, K. S., & Wang, T. (2023). PTK2-associated gene signature could predict the prognosis of IPF. Respiratory research, 24(1), 304.
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  Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with a poor prognosis. Current/available clinical prediction tools have limited sensitivity and accuracy when evaluating clinical outcomes of IPF. Research has shown that focal adhesion kinase (FAK), produced by the protein tyrosine kinase 2 (PTK2) gene, is crucial in IPF development. FAK activation is a characteristic of lesional fibroblasts; Thus, FAK may be a valuable therapeutic target or prognostic biomarker for IPF. This study aimed to create a gene signature based on PTK2-associated genes and microarray data from blood cells to predict disease prognosis in patients with IPF. PTK2 levels were found to be higher in lung tissues of IPF patients compared to healthy controls, and PTK2 inhibitor Defactinib was found to reduce TGFβ-induced FAK activation and increase α-smooth muscle actin. Although the blood PTK2 levels were higher in IPF patients, blood PTK level alone could not predict IPF prognosis. From 196 PTK2-associated genes, 11 genes were prioritized to create a gene signature (PTK2 molecular signature) and a risk score system using univariate and multivariate Cox regression analysis. Patients were divided into high-risk and low-risk groups using PTK2 molecular signature. Patients in the high-risk group experienced decreased survival rates compared to patients in the low-risk group across all discovery and validation cohorts. Further functional enrichment and immune cell proportion analyses revealed that the PTK2 molecular signature strongly reflected the activation levels of immune pathways and immune cells. These findings suggested that PTK2 is a molecular target of IPF and the PTK2 molecular signature is an effective IPF prognostic biomarker.
• Jergović, M., Watanabe, M., Bhat, R., Coplen, C. P., Sonar, S. A., Wong, R., Castaneda, Y., Davidson, L., Kala, M., Wilson, R. C., Twigg, H. L., Knox, K., Erickson, H. E., Weinkauf, C. C., Bime, C., Bixby, B. A., Parthasarathy, S., Mosier, J. M., LaFleur, B. J., , Bhattacharya, D., et al. (2023). T-cell cellular stress and reticulocyte signatures, but not loss of naïve T lymphocytes, characterize severe COVID-19 in older adults. GeroScience, 45(3), 1713-1728.
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  In children and younger adults up to 39 years of age, SARS-CoV-2 usually elicits mild symptoms that resemble the common cold. Disease severity increases with age starting at 30 and reaches astounding mortality rates that are ~330 fold higher in persons above 85 years of age compared to those 18-39 years old. To understand age-specific immune pathobiology of COVID-19, we have analyzed soluble mediators, cellular phenotypes, and transcriptome from over 80 COVID-19 patients of varying ages and disease severity, carefully controlling for age as a variable. We found that reticulocyte numbers and peripheral blood transcriptional signatures robustly correlated with disease severity. By contrast, decreased numbers and proportion of naïve T-cells, reported previously as a COVID-19 severity risk factor, were found to be general features of aging and not of COVID-19 severity, as they readily occurred in older participants experiencing only mild or no disease at all. Single-cell transcriptional signatures across age and severity groups showed that severe but not moderate/mild COVID-19 causes cell stress response in different T-cell populations, and some of that stress was unique to old severe participants, suggesting that in severe disease of older adults, these defenders of the organism may be disabled from performing immune protection. These findings shed new light on interactions between age and disease severity in COVID-19.
• Kala, M., Casanova, N. G., Feng, A., Jacobsen, J. R., Grischo, G., Liang, Y., Moreno, Y., Wang, T., & Knox, K. S. (2023). Carbon nanotube stimulation of human mononuclear cells to model granulomatous inflammation. American journal of translational research, 15(3), 1704-1714.
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  Sarcoidosis is a multisystem inflammatory granulomatous disease of unknown etiology. The disease most often affects the lung and leads to death in 5% of patients. Patients who die often succumb due to progressive fibrotic lung disease. Translational research in sarcoidosis is significantly limited by a paucity of available experimental models. Carbon nanotubes are released into the environment during fuel combustion, manufacturing, and natural fires. Exposed individuals are at risk for cancer, lung inflammation and other chronic pulmonary disorders, including diseases resembling sarcoidosis and pulmonary fibrosis. In this study, we developed and characterized an experimental model relevant to sarcoidosis using human peripheral blood mononuclear cells (PBMCs) exposed to multiwalled carbon nanotubes (MWCNTs).
• Yi, D., Liu, B., Ding, H., Li, S., Li, R., Pan, J., Ramirez, K., Xia, X., Kala, M., Ye, Q., Lee, W. H., Frye, R. E., Wang, T., Zhao, Y., Knox, K. S., Glembotski, C. C., Fallon, M. B., & Dai, Z. (2023). E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension. Hypertension (Dallas, Tex. : 1979), 80(11), 2357-2371.
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  Rare genetic variants and genetic variation at loci in an enhancer in SOX17 (SRY-box transcription factor 17) are identified in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH with congenital heart disease. However, the exact role of genetic variants or mutations in SOX17 in PAH pathogenesis has not been reported.
• Bapat, A., N Schippel, N., Shi, X., Jasbi, P., Gu, H., Kala, M., Sertil, A., & Sharma, S. (2021). Hypoxia promotes erythroid differentiation through the development of multiple progenitors and proerythroblasts. Experimental Hematology, 97, 32-46.
• Shi, X., Sharma, S., Sertil, A. R., Schippel, N., Kala, M., Jasbi, P., Gu, H., & Bapat, A. (2021). Hypoxia promotes erythroid differentiation through the development of progenitors and proerythroblasts.. Experimental hematology, 97, 32-46.e35. doi:10.1016/j.exphem.2021.02.012
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  Oxygen is a critical noncellular component of the bone marrow microenvironment that plays an important role in the development of hematopoietic cell lineages. In this study, we investigated the impact of low oxygen (hypoxia) on ex vivo myeloerythroid differentiation of human cord blood-derived CD34+ hematopoietic stem and progenitor cells. We characterized the culture conditions to demonstrate that low oxygen inhibits cell proliferation and causes a metabolic shift in the stem and progenitor populations. We found that hypoxia promotes erythroid differentiation by supporting the development of progenitor populations. Hypoxia also increases the megakaryoerythroid potential of the common myeloid progenitors and the erythroid potential of megakaryoerythroid progenitors and significantly accelerates maturation of erythroid cells. Specifically, we determined that hypoxia promotes the loss of CD71 and the appearance of the erythroid markers CD235a and CD239. Further, evaluation of erythroid populations revealed a hypoxia-induced increase in proerythroblasts and in enucleation of CD235a+ cells. These results reveal the extensive role of hypoxia at multiple steps during erythroid development. Overall, our work establishes a valuable model for further investigations into the relationship between erythroid progenitors and/or erythroblast populations and their hypoxic microenvironment.
• Bomprezzi, R., Schaefer, R., Reese, V., Misra, A., Vollmer, T. L., & Kala, M. (2011). Glatiramer acetate-specific antibody titres in patients with relapsing / remitting multiple sclerosis and in experimental autoimmune encephalomyelitis.. Scandinavian journal of immunology, 74(3), 219-226. doi:10.1111/j.1365-3083.2011.02581.x
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  Glatiramer acetate (GA) is an immunomodulatory drug approved for the treatment of clinically isolated syndrome (CIS) and relapsing/remitting multiple sclerosis (RRMS). As an antigen-based therapy, GA induces GA-specific antibodies in treated patients and animals. GA-specific antibodies do not neutralize therapeutic effects on relapses and disability. Rather, it has been suggested that GA-specific antibodies may be associated with improved clinical outcomes. We evaluated antibody responses in eight patients with RRMS treated with GA for 15 months and antibody responses in GA-treated C57BL/6 mice before and after induction of experimental autoimmune encephalomyelitis (EAE). There were no significant differences from pretreatment levels of total IgE or GA-specific IgE in patients with RRMS. Total IgG1, IgG3 and GA-specific IgG4 were significantly increased at 15 months of GA treatment. Antibody type and titre were not associated with clinical outcomes, i.e. expanded disability status scale (EDSS) score, disease burden on magnetic resonance images (MRI) or clinical relapses. In contrast, mice with EAE showed a marked increase in GA-specific IgE and GA-specific IgG1 antibody responses. GA-treated mice demonstrated improved clinical symptoms and lower mortality than untreated controls. Our results suggest that antibody responses to GA are heterogeneous among patients with RRMS, with no apparent association between antibody response and clinical outcomes. Clinical improvements in EAE-induced GA-treated mice suggest that GA-specific IgE and IgG1 may contribute to GA treatment effects in EAE.
• Kala, M., Miravalle, A., & Vollmer, T. (2011). Recent insights into the mechanism of action of glatiramer acetate.. Journal of neuroimmunology, 235(1-2), 9-17. doi:10.1016/j.jneuroim.2011.01.009
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  Glatiramer acetate (GA, Copaxone®, co-polymer 1) is an immunomodulatory therapy approved in 1996 by the United States Food and Drug Administration for treatment of relapsing-remitting multiple sclerosis. GA has a good safety profile, moderate efficacy, and a unique mode of action. Recent evidence in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), suggests that GA effects on NK cells and B cells may contribute to therapeutic efficacy. We review the mechanism of action of GA, with particular focus on recent data suggesting a role for regulatory B cells.
• Miravalle, A., Hendin, B., Vollmer, T. L., & Kala, M. (2011). Glatiramer Acetate in the Reduction of Relapse Frequency in Multiple sclerosis. Clinical Medicine Insights: Therapeutics, 2011(3), 151-158. doi:10.4137/cmt.s2057
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  Glatiramer acetate (GA; Copaxone®) is a heterogeneous polymer of four amino acids. It is one of the therapies approved by the Food and Drug Administration in 1996 for treatment of relapsing remitting multiple sclerosis (RRMS). GA reduces the relapse rate for RRMS, and has a good safety profile and moderate efficacy. Preclinical and clinical studies reveal that GA plays a role in modulating the cells of the immune system as well as in neuroprotection. In this article, we review the role of GA in reducing the frequency of relapses in MS, as well as its efficacy, safety, and current place in therapy.
• Kala, M., Rhodes, S. N., Piao, W., Shi, F., Campagnolo, D. I., & Vollmer, T. L. (2010). B cells from glatiramer acetate-treated mice suppress experimental autoimmune encephalomyelitis.. Experimental neurology, 221(1), 136-45. doi:10.1016/j.expneurol.2009.10.015
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  Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) thought to be primarily mediated by T cells. However, emerging evidence supports an important role for B cells in the pathogenesis and inhibition of MS. Glatiramer acetate (GA), a Food and Drug Administration-approved drug for the treatment of MS, has a good safety profile. But GA's mechanism of action in MS is still elusive. In this study, we showed that B cells from GA-treated mice increased production of IL-10 and reduced expression of co-stimulatory molecules viz.: CD80 and CD86. B cells from GA-treated mice also diminished proliferation of myelin oligodendrocyte glycoprotein (MOG(35-55)) specific T cells. Purified B cells transferred from GA-treated mice suppressed experimental autoimmune encephalomyelitis (EAE) in recipient mice compared with B cells transferred from mice treated with PBS or ovalbumin. The treatment effect of GA in EAE was abrogated in B cell-deficient mice. Transfer of B cells from GA-treated mice inhibited the proliferation of autoreactive T cells as well as the development of Th1 and Th17 cells but promoted IL-10 production in recipient mice. The number of peripheral CD11b(+) macrophages in recipient mice also decreased after transfer of B cells from GA-treated mice; however, the number of dendritic cells and regulatory T cells remained unaltered. These results suggest that B cells are important to the protective effects of GA in EAE.
• Jee, Y. H., Liu, R. L., Coons, S. W., Kala, M., Collins, M., Young, D. A., Campagnolo, D. I., Vollmer, T. L., Shi, F. D., Piao, W. H., Cava, A. L., & Bai, X. F. (2008). IL-21 modulates CD4+ CD25+ regulatory T-cell homeostasis in experimental autoimmune encephalomyelitis.. Scandinavian journal of immunology, 67(1), 37-46. doi:10.1111/j.1365-3083.2007.02035.x
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  The homeostasis of CD4+ CD25+ regulatory T cells (Tregs) depends on the cytokine interleukin (IL)-2. As IL-21 shares sequence homology with IL-2 and the IL-21 receptors contain a gamma-chain common to IL-2, we hypothesized that IL-21 could also affect the homeostasis of Tregs. We tested this hypothesis in experimental autoimmune encephalomyelitis (EAE), an animal model of relapsing-remitting human multiple sclerosis. We show that blockade of IL-21 in SJL/J mice before and after the induction of EAE enhances the influx of inflammatory cells into the central nervous system (CNS). The blockade of IL-21 leads to proliferation of proteolipid peptide (PLP(139-151))-autoreactive CD4+ T cells, which are capable to cause severe EAE in adoptively transferred recipient mice. Conversely, Tregs from mice where IL-21 was blocked, lose their capacity to prevent EAE induced PLP(139-151)-reactive T cells. Notably, direct effects of IL-21 on Tregs are confirmed by studies of blockade of IL-21 in mice expressing a green fluorescent protein 'knocked' into a Foxp3 allele, in which a reduction of the number of Tregs and a downregulation of their frequency and expression of Foxp3 are observed. These data suggest a role of the IL-21/IL-21R axis in the homeostasis of Tregs in CNS autoimmunity.

Presentations

• Kala, M. (2023, December). Ideas/Proposals for local plasma sample cohort. Annual Recover Retreat. Tempe, AZ: Aegis Consortium.
• Kala, M. (2022). Flow Cytometry Core Open House. Open house. UACOM-P: RO.
• Kala, M. (2022, May). Novel Non-Catalytic FAK Inhibition Downregulates Lung Fibroblast Matrix Production. ATS. SanFrancisco.

Poster Presentations

• Kala, M. (2024, April). Identification of Cocci specific Immunoreactive peptides and the assocaited immune response.. Cocci Study Group. San Antonio, TX.
• Kala, M., & Knox, K. S. (2024, May).

  Optimizing 9 color panel for valley fever flow cytometry Assay

                                       . International Society of Advanced Cytometry/Cyto2024. Edinburgh, UK.
• Kala, M. (2024, May). T cell Responses in Valley Fever. American Thoracic Society. San Diego, CA.
• Kala, M., & Chakraborty, U. (2023, May/Summer). Global challenges of social infrastructure, its effects and outcome on SRL sustainability: THE WAY AHEAD. Cyto 2023. Montreal: International Society of Advanced Cytometry.
• Kala, M. (2022, April). COCCIDIOIDOMYCOSIS EX VIVO CYTOKINE RELEASE ASSAY USING RECOMBINANT COCCIDIOIDES ANTIGENS. 66th Annual Coccidioidomycosis Study Group Meeting. Buck Owens’ Crystal Palace, Bakersfield, CA.
• Kala, M. (2022, May). Transcriptomic Profiling to Validate an In-Vitro Nanotube-InducedSarcoid Model. ATS. San Francisco.
• Kala, M. (2021, Jan/Winter). Key role of focal adhesion kinase in idiopathic pulmonary fibrosis. 3rd Annual Reimagine Health: Intervention and Prevention. UACOM-P: ABRC, Flinn Foundation, UACOM-P.
• Kala, M. (2021, May/Summer). An in vitro Model for Studying Sarcoidosis.. American Thoracic Society International Conference 2021. San Diego, CA: American Thoracic Society.
• Kala, M. (2021, Oct/fall). Department of Medicine Biospecimen Core. Wells Commons. Phoenix: ASU.
• Kala, M. (2021, October/fall). Flow Cytometry Core: Collaboartion/services/training. Wells Commons, ASU. Phoenix: ASU.
• Kala, M. (2021, Spring). Lung on a Leaf" in vitro Model to Study Pulmonary Granulomatous Diseases. 6th Annula ABRC-Flinn Research Conference 2021. Phoenix: ABRC/Flinn.

Others

• Kala, M. (2020, December). Biobank Annual Quality Control Presentation to advisory committee. Biobank Advisory Committee.