Publications by authors named "Sara Mirali"

19 Publications

  • Page 1 of 1

Clinical manifestations and treatment outcomes in prurigo pigmentosa (Nagashima disease): A systematic review of the literature.

JAAD Int 2021 Jun 10;3:79-87. Epub 2021 Apr 10.

Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Background: Prurigo pigmentosa (PP) is a rare inflammatory dermatosis characterized by pruritic erythematous papules that coalesce to form a reticulate pattern. PP is often misdiagnosed, and patients are treated with ineffective therapies. Although the majority of reports about PP are from East Asia, patients of all backgrounds can be affected.

Objectives: To perform a systematic review of reported PP cases with the purpose of summarizing the clinical presentation and treatment of PP.

Methods: MEDLINE and Embase were searched for original articles describing PP. We identified 115 studies from 24 countries representing 369 patients to include in the analysis.

Results: Of the 369 patients included in the analysis, the mean age was 25.6 years (range: 13-72 years) with 72.1% (266 of 369) female. Risk factors or aggravating factors were described in 52.3% (193 of 369) of patients and included dietary changes (25.5%, 94 of 369), friction (8.4%, 31 of 369), sweat (7.6%, 28 of 369), and ketonuria (5.1%, 19 of 369). Of those patients who experienced PP following dietary changes, 40.4% (38 of 94) started a ketogenic diet. Minocycline monotherapy was the most frequently prescribed treatment for PP (20.9%, 77 of 369), achieving complete resolution in 48.1% (37 of 77) of patients.

Conclusions: PP is sometimes associated with ketogenic diets and can be effectively managed with oral tetracyclines.
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http://dx.doi.org/10.1016/j.jdin.2021.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362297PMC
June 2021

Moisturizers and Cleansers in the Management of Skin Conditions Caused by Personal Protective Equipment and Frequent Handwashing.

Skin Therapy Lett 2021 07;26(4):9-13

Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

During the COVID-19 pandemic, prolonged usage of personal protective equipment (PPE) and frequent handwashing has exacerbated or caused skin diseases, particularly amongst frontline workers. Skin conditions, such as atopic dermatitis, irritant contact dermatitis, and hand eczema, affect patients’ quality of life and their ability to work. These conditions can be managed by frequent moisturization and washing with gentle cleansers. In this review, we discuss the properties of effective moisturizers and cleansers for patients with skin diseases related to enhanced infection control procedures.
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July 2021

Venetoclax enhances T cell-mediated antileukemic activity by increasing ROS production.

Blood 2021 07;138(3):234-245

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent azacytidine, achieves complete remission with or without count recovery in ∼70% of treatment-naive elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug combination is not fully understood. We discovered that venetoclax directly activated T cells to increase their cytotoxicity against acute myeloid leukemia (AML) in vitro and in vivo. Venetoclax enhanced T-cell effector function by increasing reactive oxygen species generation through inhibition of respiratory chain supercomplexes formation. In addition, azacytidine induced a viral mimicry response in AML cells by activating the STING/cGAS pathway, thereby rendering the AML cells more susceptible to T cell-mediated cytotoxicity. Similar findings were seen in patients treated with venetoclax, as this treatment increased reactive oxygen species generation and activated T cells. Collectively, this study presents a new immune-mediated mechanism of action for venetoclax and azacytidine in the treatment of AML and highlights a potential combination of venetoclax and adoptive cell therapy for patients with AML.
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http://dx.doi.org/10.1182/blood.2020009081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310428PMC
July 2021

Drugs Associated With the Development of Palmoplantar Keratoderma: A Systematic Review.

J Cutan Med Surg 2021 Sep 28;25(5):553-554. Epub 2021 Mar 28.

12366 Division of Dermatology, Department of Medicine, University of Toronto, Canada.

Background: Palmoplantar keratoderma (PPK) are a heterogenous group of hereditary and acquired disorders that are characterized by excessive epidermal thickening of the palms and/or soles. PPK has been described as a rare adverse event for some medications. The aim of this systematic review was to summarize outcomes in PPK associated with various medications. This data will assist dermatologists and other healthcare providers treating patients with drug-induced PPK.

Methods: EMBASE and MEDLINE databases were searched in accordance with PRISMA guidelines using the keyword "palmoplantar keratoderma." 40 studies met the inclusion criteria.

Results: A total of 247 patients (mean age: 57.0 years) were included in the analysis. Among patients whose sex was reported, 60.3% ( = 35/58) were male. PPK most frequently developed after treatment with BRAF inhibitors (73.7%, = 182/247), BRAF inhibitors combined with MEK1/2 inhibitors (15.4%, = 38/247), tyrosine kinase inhibitors (TKIs) (3.2%, = 8/247), or chemotherapy (2.4%, = 6/247). The mean latency period between initiation of the drug and onset of PPK was 7.6 months (range: 0.25-90 months). Improvement of PPK was reported in 24 cases, with 50% ( = 12/24) achieving complete resolution and 50% ( = 12/24) achieving partial resolution. All patients who achieved complete resolution stopped the suspected drug, with a mean resolution period of 2.4 months (range: 2 weeks-6 months). The most common treatments for PPK were keratolytic treatments ( = 10) and topical corticosteroids ( = 4).

Conclusions: PPK was most frequently associated with targeted kinase inhibitors, specifically BRAF, MEK1/2, and tyrosine kinase inhibitors.
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http://dx.doi.org/10.1177/12034754211004560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474319PMC
September 2021

Mitochondrial and Metabolic Pathways Regulate Nuclear Gene Expression to Control Differentiation, Stem Cell Function, and Immune Response in Leukemia.

Cancer Discov 2021 05 27;11(5):1052-1066. Epub 2021 Jan 27.

Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Mitochondria are involved in many biological processes including cellular homeostasis, energy generation, and apoptosis. Moreover, mitochondrial and metabolic pathways are interconnected with gene expression to regulate cellular functions such as cell growth, survival, differentiation, and immune recognition. Metabolites and mitochondrial enzymes regulate chromatin-modifying enzymes, chromatin remodeling, and transcription regulators. Deregulation of mitochondrial pathways and metabolism leads to alterations in gene expression that promote cancer development, progression, and evasion of the immune system. This review highlights how mitochondrial and metabolic pathways function as a central mediator to control gene expression, specifically on stem cell functions, differentiation, and immune response in leukemia. SIGNIFICANCE: Emerging evidence demonstrates that mitochondrial and metabolic pathways influence gene expression to promote tumor development, progression, and immune evasion. These data highlight new areas of cancer biology and potential new therapeutic strategies.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1227DOI Listing
May 2021

Development of chronic cutaneous lupus erythematosus during biologic therapy: A systematic review.

J Am Acad Dermatol 2021 Mar 3;84(3):835-838. Epub 2020 Oct 3.

Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Canada; Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Women's College Hospital, Toronto, Ontario, Canada; Probity Medical Research Inc, Waterloo, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.09.087DOI Listing
March 2021

Targeting neurolysin in acute myeloid leukemia.

Mol Cell Oncol 2020 23;7(4):1761243. Epub 2020 May 23.

Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

We recently identified the mitochondrial peptidase, neurolysin (NLN), as a top hit in an acute myeloid leukemia (AML) viability screen. Using chemical and genetic approaches, we demonstrated that loss of NLN disrupted respiratory chain supercomplex assembly and impaired oxidative metabolism in AML. Moreover, inhibition of NLN and reduced the growth of AML cells.
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http://dx.doi.org/10.1080/23723556.2020.1761243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469488PMC
May 2020

The role of mitochondrial proteases in leukemic cells and leukemic stem cells.

Stem Cells Transl Med 2020 12 5;9(12):1481-1487. Epub 2020 Aug 5.

Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

The biological function of most mitochondrial proteases has not been well characterized. Moreover, most of the available information on the normal function of these proteases has been derived from studies in model organisms. Recently, the mitochondrial proteases caseinolytic protease P (CLPP) and neurolysin (NLN) have been identified as therapeutic targets in acute myeloid leukemia (AML). Both proteases are overexpressed in approximately 40% of AML patients. Mechanistically, CLPP and NLN maintain the integrity of the mitochondrial respiratory chain: CLPP cleaves defective respiratory chain proteins, while NLN promotes the formation of respiratory chain supercomplexes. In this review, we highlight the functional consequences of inhibiting and activating mitochondrial proteases and discuss their potential as therapeutic targets in AML.
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http://dx.doi.org/10.1002/sctm.20-0142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695628PMC
December 2020

Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal.

Cell Stem Cell 2020 06 15;26(6):926-937.e10. Epub 2020 May 15.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Electronic address:

Leukemic stem cells (LSCs) rely on oxidative metabolism and are differentially sensitive to targeting mitochondrial pathways, which spares normal hematopoietic cells. A subset of mitochondrial proteins is folded in the intermembrane space via the mitochondrial intermembrane assembly (MIA) pathway. We found increased mRNA expression of MIA pathway substrates in acute myeloid leukemia (AML) stem cells. Therefore, we evaluated the effects of inhibiting this pathway in AML. Genetic and chemical inhibition of ALR reduces AML growth and viability, disrupts LSC self-renewal, and induces their differentiation. ALR inhibition preferentially decreases its substrate COX17, a mitochondrial copper chaperone, and knockdown of COX17 phenocopies ALR loss. Inhibiting ALR and COX17 increases mitochondrial copper levels which in turn inhibit S-adenosylhomocysteine hydrolase (SAHH) and lower levels of S-adenosylmethionine (SAM), DNA methylation, and chromatin accessibility to lower LSC viability. These results provide insight into mechanisms through which mitochondrial copper controls epigenetic status and viability of LSCs.
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http://dx.doi.org/10.1016/j.stem.2020.04.010DOI Listing
June 2020

The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability.

Sci Transl Med 2020 04;12(538)

Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada.

Neurolysin (NLN) is a zinc metallopeptidase whose mitochondrial function is unclear. We found that NLN was overexpressed in almost half of patients with acute myeloid leukemia (AML), and inhibition of NLN was selectively cytotoxic to AML cells and stem cells while sparing normal hematopoietic cells. Mechanistically, NLN interacted with the mitochondrial respiratory chain. Genetic and chemical inhibition of NLN impaired oxidative metabolism and disrupted the formation of respiratory chain supercomplexes (RCS). Furthermore, NLN interacted with the known RCS regulator, LETM1, and inhibition of NLN disrupted LETM1 complex formation. RCS were increased in patients with AML and positively correlated with NLN expression. These findings demonstrate that inhibiting RCS formation selectively targets AML cells and stem cells and highlights the therapeutic potential of pharmacologically targeting NLN in AML.
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http://dx.doi.org/10.1126/scitranslmed.aaz8264DOI Listing
April 2020

Piloting a long distance clinician scientist trainee mentorship match in Canada.

Clin Invest Med 2020 04 5;43(1):E5-E8. Epub 2020 Apr 5.

Faculty of Medicine, University of Toronto, Toronto, ON.

Clinician scientists are physicians who are uniquely trained to bridge the gap between scientific discovery and clinical practice. However, the challenges of integrating research and medicine are often not directly addressed in the clinician scientist training programs. Furthermore, the demanding training path is financially and personally daunting. Previous studies have shown that MD/PhD trainees value the advice and expertise of senior mentors in navigating their academic career path. Despite this demand for mentors, there is a lack of formal mentorship initiatives at the institutional level across Canada. Recently, MD/PhD trainees have attempted to address this issue by implementing a nationwide mentorship match, with the aim of making mentorship more accessible to trainees across Canada.
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http://dx.doi.org/10.25011/cim.v43i1.33649DOI Listing
April 2020

Inhibition of mitochondrial translation overcomes venetoclax resistance in AML through activation of the integrated stress response.

Sci Transl Med 2019 10;11(516)

Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada.

Venetoclax is a specific B cell lymphoma 2 (BCL-2) inhibitor with promising activity against acute myeloid leukemia (AML), but its clinical efficacy as a single agent or in combination with hypomethylating agents (HMAs), such as azacitidine, is hampered by intrinsic and acquired resistance. Here, we performed a genome-wide CRISPR knockout screen and found that inactivation of genes involved in mitochondrial translation restored sensitivity to venetoclax in resistant AML cells. Pharmacologic inhibition of mitochondrial protein synthesis with antibiotics that target the ribosome, including tedizolid and doxycycline, effectively overcame venetoclax resistance. Mechanistic studies showed that both tedizolid and venetoclax suppressed mitochondrial respiration, with the latter demonstrating inhibitory activity against complex I [nicotinamide adenine dinucleotide plus hydrogen (NADH) dehydrogenase] of the electron transport chain (ETC). The drugs cooperated to activate a heightened integrated stress response (ISR), which, in turn, suppressed glycolytic capacity, resulting in adenosine triphosphate (ATP) depletion and subsequent cell death. Combination treatment with tedizolid and venetoclax was superior to either agent alone in reducing leukemic burden in mice engrafted with treatment-resistant human AML. The addition of tedizolid to azacitidine and venetoclax further enhanced the killing of resistant AML cells in vitro and in vivo. Our findings demonstrate that inhibition of mitochondrial translation is an effective approach to overcoming venetoclax resistance and provide a rationale for combining tedizolid, azacitidine, and venetoclax as a triplet therapy for AML.
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http://dx.doi.org/10.1126/scitranslmed.aax2863DOI Listing
October 2019

Global Interactome Mapping of Mitochondrial Intermembrane Space Proteases Identifies a Novel Function for HTRA2.

Proteomics 2019 12;19(24):e1900139

Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada.

A number of unique proteases localize to specific sub-compartments of the mitochondria, but the functions of these enzymes are poorly defined. Here, in vivo proximity-dependent biotinylation (BioID) is used to map the interactomes of seven proteases localized to the mitochondrial intermembrane space (IMS). In total, 802 high confidence proximity interactions with 342 unique proteins are identified. While all seven proteases co-localized with the IMS markers OPA1 and CLPB, 230 of the interacting partners are unique to just one or two protease bait proteins, highlighting the ability of BioID to differentiate unique interactomes within the confined space of the IMS. Notably, high-temperature requirement peptidase 2 (HTRA2) interacts with eight of 13 components of the mitochondrial intermembrane space bridging (MIB) complex, a multiprotein assembly essential for the maintenance of mitochondrial cristae structure. Knockdown of HTRA2 disrupts cristae in HEK 293 and OCI-AML2 cells, and leads to increased intracellular levels of the MIB subunit IMMT. Using a cell-free assay it is demonstrated that HTRA2 can degrade recombinant IMMT but not two other core MIB complex subunits, SAMM50 and CHCHD3. The IMS protease interactome thus represents a rich dataset that can be mined to uncover novel IMS protease biology.
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http://dx.doi.org/10.1002/pmic.201900139DOI Listing
December 2019

Male-Specific Conditioned Pain Hypersensitivity in Mice and Humans.

Curr Biol 2019 01 10;29(2):192-201.e4. Epub 2019 Jan 10.

Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC H3A 1B1, Canada; Department of Anesthesia, McGill University, Montreal, QC H3G 1Y6, Canada. Electronic address:

Pain memories are hypothesized to be critically involved in the transition of pain from an acute to a chronic state. To help elucidate the underlying neurobiological mechanisms of pain memory, we developed novel paradigms to study context-dependent pain hypersensitivity in mouse and human subjects, respectively. We find that both mice and people become hypersensitive to acute, thermal nociception when tested in an environment previously associated with an aversive tonic pain experience. This sensitization persisted for at least 24 hr and was only present in males of both species. In mice, context-dependent pain hypersensitivity was abolished by castrating male mice, pharmacological blockade of the hypothalamic-pituitary-adrenal axis, or intracerebral or intrathecal injections of zeta inhibitory peptide (ZIP) known to block atypical protein kinase C (including the protein kinase Mζ isoform). In humans, men, but not women, self-reported higher levels of stress when tested in a room previously associated with tonic pain. These models provide a new, completely translatable means for studying the relationship between memory, pain, and stress.
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http://dx.doi.org/10.1016/j.cub.2018.11.030DOI Listing
January 2019

Publications Are Not the Finish Line: Focusing on Societal Rather Than Publication Impact.

Front Med (Lausanne) 2018 12;5:314. Epub 2018 Nov 12.

Department of Psychiatry, College of Medicine, University of Arizona, Tucson, AZ, United States.

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http://dx.doi.org/10.3389/fmed.2018.00314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240663PMC
November 2018

Scientific overview on CSCI-CITAC Annual General Meeting and 2017 Young Investigators' Forum.

Clin Invest Med 2018 10 5;41(3):E156-E164. Epub 2018 Oct 5.

Cumming School of Medicine, University of Calgary, Calgary, AB.

The 2017 Annual General Meeting of the Canadian Society of Clinician Investigators (CSCI) and Clinician Investigator Trainee Association of Canada/Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was a national Annual General Meeting (AGM) held in Toronto, Ontario November 20-22, 2017, in conjunction with the University of Toronto Clinician Investigator Program Research Day. The theme for this year's meeting was "Roll up your sleeves-How to manage your physician scientist career", emphasizing lectures and workshops that were designed to provide tools for being proactive and successful in career planning. The keynote speakers were Dr. Rod McInnes (McGill University and Canadian Institutes of Health Research Acting President), who was the Distinguished Scientist Award recipient, Dr. David Goltzman (McGill University), who was the 2017 Henry Friesen Award recipient, Dr. Gillian Hawker (University of Toronto), Dr. Mike Sapieha (Université de Montréal), who was the 2017 Joe Doupe Award recipient, and Dr. Alex MacKenzie (Children's Hospital of Eastern Ontario Research Institute, University of Ottawa). The workshops, focusing on career development for clinician scientists, were hosted by Dr. Lisa Robinson, Dr. Nicola Jones, Kevin Vuong, Fran Brunelle, Dr. Jason Berman and Dr. Alan Underhill. Further to this, the Young Investigators' Forum encompasses presentations from scientist-clinician trainees from across the country. All scientific abstracts are summarized in this review. There were over 100 abstracts showcased at this year's meeting during the highlighted poster sessions, with six outstanding abstracts selected for oral presentations during the President's Forum.
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http://dx.doi.org/10.25011/cim.v41i3.31020DOI Listing
October 2018

Scientific Overview on CSCI-CITAC Annual General Meeting and 2016 Young Investigators' Forum.

Clin Invest Med 2017 10 19;40(5):E211-E217. Epub 2017 Oct 19.

CITAC/ACCFC Executive Committee; MD/PhD Program, McGill University.

The 2016 Annual General Meeting of the Canadian Society of Clinician Investigators (CSCI) and Clinician Investigator Trainee Association of Canada/Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was a national conference held in Toronto November 21-23, 2016, in conjunction with The University of Toronto Clinician Investigator Program Research Day. The theme for this year's meeting was "Mapping Your Career as a Clinician-Scientist"; emphasizing essential skills for developing a fruitful career as clinician-scientist. The meeting featured an opening presentation by Dr. Alan Underhill, Dr. Nicola Jones and Alexandra Kuzyk. The keynote speakers were Dr. Nada Jabado (McGill University), who discussed the association between cancer and histones, Dr. Norman Rosenblum (University of Toronto), who addressed the career path and the "calling" of the Clinician Scientist, Dr. Martin Schmeing (McGill University), who was the 2016 Joe Doupe Award recipient, and Dr. Linda Rabeneck (Cancer Care Ontario and University of Toronto), who received the Friends of CIHR lectureship. The workshops, focusing on career development for clinician scientists, were hosted by Drs. Alan Underhill, Nicola Jones, Lynn Raymond, Michael Schlossmacher and Norman Rosenblum, as well as University of Toronto communication specialists, Caitlin Johannesson and Suzanne Gold. In addition, the Young Investigators' Forum included presentations from clinician investigator trainees from across the country. The research topics were diverse and comprehensive: from basic sciences to clinical practice; from epidemiology to medical engineering. All scientific abstracts are summarized in this review. Over 70 abstracts were showcased at this year's meeting during two poster sessions, with six outstanding abstracts selected for oral presentations during the President's Forum.
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http://dx.doi.org/10.25011/cim.v40i5.28626DOI Listing
October 2017

Reducing social stress elicits emotional contagion of pain in mouse and human strangers.

Curr Biol 2015 Feb 15;25(3):326-332. Epub 2015 Jan 15.

Department of Psychology, McGill University, Montreal, QC H3A 1B1, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC H3A 0G1, Canada. Electronic address:

Empathy for another's physical pain has been demonstrated in humans [1] and mice [2]; in both species, empathy is stronger between familiars. Stress levels in stranger dyads are higher than in cagemate dyads or isolated mice [2, 3], suggesting that stress might be responsible for the absence of empathy for the pain of strangers. We show here that blockade of glucocorticoid synthesis or receptors for adrenal stress hormones elicits the expression of emotional contagion (a form of empathy) in strangers of both species. Mice and undergraduates were tested for sensitivity to noxious stimulation alone and/or together (dyads). In familiar, but not stranger, pairs, dyadic testing was associated with increased pain behaviors or ratings compared to isolated testing. Pharmacological blockade of glucocorticoid synthesis or glucocorticoid and mineralocorticoid receptors enabled the expression of emotional contagion of pain in mouse and human stranger dyads, as did a shared gaming experience (the video game Rock Band) in human strangers. Our results demonstrate that emotional contagion is prevented, in an evolutionarily conserved manner, by the stress of a social interaction with an unfamiliar conspecific and can be evoked by blocking the endocrine stress response.
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http://dx.doi.org/10.1016/j.cub.2014.11.028DOI Listing
February 2015
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