Nicole Fernandes

Centro Hospitalar de Vila Nova de Gaia

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Uma Sriram

Temple University

Raghava Potula

Temple University

Adam M. Staffaroni

University of California, San Francisco

Joel H. Kramer

University of California, San Francisco

Fanny M. Elahi

Icahn School of Medicine at Mount Sinai

Bruce L. Miller

University of California, San Francisco

Kaitlin B. Casaletto

University of California, San Francisco

Nivetha Brathaban

University of California, San Francisco

Viviana Zuluaga‐Ramirez

Temple University

Yuri Persidsky

Temple University

Cooperative Institutions

University of California, San Francisco

University of Cape Town

Temple University

University Memory and Aging Center

Groote Schuur Hospital

University College London

Alzheimer’s Disease Neuroimaging Initiative

Universidade Federal do Rio de Janeiro

Cairo University

University of Birmingham

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Relative Role of Akt, ERK and CREB in Alcohol-Induced Microglia P2X4R Receptor Expression

Alcohol and Alcoholism (2016)

Larisa Gofman Nicole Fernandes Raghava Potula

Previously we have demonstrated altered microglia P2X4R expression in response to alcohol and pharmacological blockade with a selective P2X4R antagonist can reverse the action, suggesting that P2X4R play a role in mediating alcohol-induced effects on microglia. In the present study, we investigated the underlying signaling mediators, which may play a role in modulating P2X4R expression in microglia cells in response to alcohol. Embryonic stem cell-derived microglia (ESdM) cells were used to investigate the potential mechanisms involved in the regulation of P2X4R in response to alcohol. Selective P2X4R antagonist and kinase inhibitors were used to further corroborate the signal transduction pathway through which alcohol modulates P2X4R expression in microglia. Alcohol (100 mM) suppressed phosphorylated AKT and ERK cascades in native ESdM cells. This alcohol-induced suppression was confirmed to be P2X4R-dependent through the use of a selective P2X4R antagonist and knockdown of P2XR4 by siRNA. Alcohol increased transcriptional activity of CREB. P2X4R antagonist blocked alcohol-induced effects on CREB, suggesting a P2X4R-mediated effect. These findings provide important clues to the underlying mechanism of purinoceptors in alcohol-induced microglia immune suppression.

10.1093/alcalc/agw009

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The impact of the COVID-19 pandemic on sleep and mood disturbances of healthcare professionals

Sara Catarina Dias Bruno Malta Nicole Fernandes Márcia Araújo Joana Lourenço

Introduction: The COVID-19 pandemic was associated with depression, anxiety and sleep disorders. Healthcare professionals (HCPs), due to their frontline position, may have an increased risk of mood and sleep disorders. Aim: To assess sleep and mood disturbances in HCPs related to COVID-19 pandemic. Methods: Observational study conducted through a questionnaire answered by HCPs from 2 healthcare institutions in Portugal. Results: A total of 1382 HCPs participated, most females (84.3%), in the 30-39 age group (31.8%) and nurses (41.2%). Age (p=0.03), professional class (p<0.05), working in shifts (p=0.003) and night shifts (p=0.08) were significantly related to quality of sleep, which was bad or very bad in 37.8% of HCPs. 641 (46.4%) HCPs contacted with COVID-19 patients and 53.6% reported that the 3rd pandemic wave worsened the quality of their sleep. Most HCPs slept 6 hours or less (62.4%), had at least 1 awakening per night (87.3%) and difficulty falling back asleep (87.3%). Beyond this, 46.6% also reported taking more than 30 minutes to fall asleep. These were reflected in daytime sleepiness in 70.3% of HCPs. Some HCPs reported the need for sleeping medication at least once a week (34.2%), mainly anxiolytics, and 10.1% started alternative sleep therapies. Regarding mood disorders, most participants reported sadness (57.7%), less patience (75.0%) and distress (59.7%), the latter related to contact with covid-19 patients (p=0.022). Discussion: The quality of sleep and mood of HCPs was significantly impaired during the COVID-19 pandemic, highlighting insomnia, daytime sleepiness and use of sleep medication. It is important to implement measures to improve sleep and mental health of HCPs.

Depression

Sadness

Pandemic

Health Professionals

10.1183/23120541.sleepandbreathing-2023.61

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Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation

Frontiers in Immunology (2018)

Alecia Seliga Michael H. Lee Nicole Fernandes Viviana Zuluaga‐Ramirez Marta Didukh

The Kallikrein-Kinin System (KKS), comprised of kallikreins (klks), bradykinins (BKs) angiotensin converting enzyme (ACE) and many other molecules, regulates a number of physiological processes, including inflammation, coagulation, angiogenesis and control of blood pressure. In this report, we show that KKS regulates Type I IFN responses, thought to be important in lupus pathogenesis. We used CpG (TLR9 ligand), R848 (TLR7 ligand) or recombinant IFN-α to induce Interferon Stimulated Genes (ISGs) and proteins, and observed that this response was markedly diminished by BKs, klk1 (tissue kallikrein) or captopril (an ACE inhibitor). BKs significantly decreased the ISGs induced by TLRs in vitro and in vivo (in normal and lupus-prone mice), and in human PBMCs, especially the induction of Irf7 gene (p<0.05), the master regulator of Type I IFNs. ISGs induced by IFN-α were also suppressed by the KKS. MHC Class I up regulation, a classic response to Type I IFNs, was reduced by BKs in murine dendritic cells (DCs). BKs decreased phosphorylation of STAT2 molecules that mediate IFN signaling. Among the secreted pro-inflammatory cytokines/chemokines analyzed (IL-6, IL12p70 and CXCL10), the strongest suppressive effect was on CXCL10, a highly Type I IFN-dependent cytokine, upon CpG stimulation, both in normal and lupus-prone DCs. Klks that break down into BKs, also suppressed CpG-induced ISGs in murine DCs. Captopril, a drug that inhibits ACE and increases BK, suppressed ISGs, both in mouse DCs and human PBMCs. The effects of BK were reversed with indomethacin (compound that inhibits production of PGE2), suggesting that BK suppression of IFN responses may be mediated via prostaglandins. These results highlight a novel regulatory mechanism in which members of the KKS control the type I IFN response and suggest a role for modulators of IFNs in the pathogenesis of lupus and interferonopathies.

10.3389/fimmu.2018.00156

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Citations (34)

Reliability of the Robinson classification for displaced comminuted midshaft clavicular fractures

Clinical Imaging (2014)

Sylvia A. Stegeman Nicole Fernandes Pieta Krijnen Inger B. Schipper

Observer (physics)

10.1016/j.clinimag.2014.07.012

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Parks, people, and partnerships

Joshua W. R. Baur Laura Diprizio Nicole Fernandes Zachary Fried Jennifer Sellers

National Park Service (NPS) units across the U.S. receive hundreds of thousands of visitors annually, but visitor demographics have generally not matched the increasing diversity of the U.S. population. The purpose of this study is to provide the NPS and community-based organizations (CBOs) with useful information and tools to improve their outreach efforts through partnerships. This study focuses on the Los Angeles metropolitan area because of its diverse population and relative proximity to several national park sites. In addition to the review of relevant literature and examination of model partnership programs, the study is based on interviews with NPS staff and 15 CBOs representing faith-based organizations, female organizations, urban nature centers, and youth organizations. While our interviews covered multiple topics, the primary focus was on the challenges and benefits to partnerships. Despite recognition of perceived barriers, all interviewees were interested in building partnerships. Furthermore, both NPS and CBO participants saw common benefits afforded by such arrangements. Our recommendations focus on three domains of effort for NPS focus: improving information exchange, strengthening logistical support, and enhancing cultural awareness and staff diversity. By addressing these areas, we believe that the NPS will facilitate partnerships with community-based organizations and meaningfully engage underserved audiences not currently visiting national parks.

Outreach

Visitor pattern

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Kallikrein-Kinin System suppresses Type I Interferon (IFN) responses: a novel mechanism of IFN regulation.

The Journal of Immunology (2016)

Uma Sriram Nicole Fernandes Michael H. Lee Marta Didukh Viviana Zuluaga‐Ramirez

Abstract Kallikrein-Kinin System (KKS) that comprises of kallikreins (klks), bradykinins (bk), angiotensin converting enzyme (ACE), and many other molecules, have classically known to be involved in a variety of physiological processes, including coagulation, angiogenesis and control of blood pressure. The role of KKS in regulating immune responses has come to light recently. Recent reports indicate that KKS is involved in lupus and giving exogenous klks can ameliorate lupus in mice. We have reported earlier the expression of a Type I IFN signature by dendritic cells (DCs) from the B6.Sle1, 2, 3 congenic model of lupus-prone mice. In this study, we directly asked the question if exogenous KKS regulates IFN induced responses. We used Flt3L induced bone-marrow-derived DCs from normal C57BL/6 (B6) mice and PBMC from normal human donors for in vitro studies. We stimulated the cells with recombinant IFN-α, IFN-β, CpG (TLR9 ligand), or R848 (TLR7 ligand) to induce IFN responses, and further treated with KKS candidates [Lys-bk, Hyp-bk, klk]. We analyzed the IFN induced responses by Interferon Stimulated Gene (ISG) expression and cytokine production. KKS candidates suppressed IFN or TLR induced IRF7 gene expression and CXCL10 production in both mouse DCs and human PBMCs. KKS candidates also suppressed IFN or TLR induced IL-6. We also used HOE140, a bk receptor 2 antagonist, and observed that blocking bk signaling increased the IFN responses in vitro. In vivo administration of Hyp-bk after IFN induction with CpG strongly decreased IRF7 and CXCL10 gene expression in B6 splenocytes, confirming our in vitro observations. Our results suggest a novel pathway of Type I IFN regulation by the KKS and opens up a new direction for designing drug targets for lupus.

TLR9

10.4049/jimmunol.196.supp.210.3

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Kallikrein-kinin system and Type I Interferons in Neurolupus

The Journal of Immunology (2017)

Uma Sriram Viviana Zuluaga‐Ramirez Steven F. Merkel Malika Winfield Nicole Fernandes

Abstract Neuropsychiatric lupus is one of the most common manifestations of human systemic lupus erythematosus (SLE), causing depression in many. SLE is an autoimmune disease characterized by multi-organ damage including the brain and Interferon-α (IFN-α) is a central mediator in disease pathogenesis. Excessive production/response to Type I IFNs in SLE (called the “IFN signature”) is a hallmark of the disease. The mechanism of how IFN causes depression remain poorly understood; however, it is known that administration of IFN-α in certain chronic viral infections and some cancers causes the development of depressive symptoms in a high percentage of patients. The Kallikrein-Kinin System (KKS) that is comprised of kallikreins (klks), bradykinins (bk), angiotensin converting enzyme (ACE), and many other molecules, has classically known to be involved in a variety of physiological processes, including coagulation, angiogenesis and control of blood pressure. The KKS has been explored recently for their regulation of brain functions. We hypothesize that IFN-α may cause some of the symptoms in neurolupus patients and the KKS can ameliorate these effects. In this study, we used the MRL/lpr lupus-prone mouse model and showed that exposing MRL mice to IFN-α (a) increased depressive-like behavior, (b) decreased klk expression, and (c) enhanced ACE expression in the brain. Administering captopril (a commonly prescribed ACE inhibitor) decreased IFN-induced gene expression in the brain. It is also known that ACE activity decreases BK levels. The role of key KKS effectors and their interactions with the IFN pathway may provide a rationale for therapeutic use of KKS molecules for treatment of neurolupus.

Pathogenesis

Captopril

10.4049/jimmunol.198.supp.224.4

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THE ROLE OF P2X7R IN METHAMPHETAMINE-INDUCED BEHAVIORAL CHANGES AND MICROGLIAL EFFECTOR FUNCTIONS

Nicole Fernandes

Methamphetamine

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Patient care and clinical outcomes for patients with COVID-19 infection admitted to African high-care or intensive care units (ACCCOS): a multicentre, prospective, observational cohort study

The Lancet (2021)

Bruce Biccard PD Gopalan Malcolm Miller W L Michell David Thomson

10.1016/s0140-6736(21)00441-4

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Citations (174)

Impaired Subset Progression and Polyfunctionality of T Cells in Mice Exposed to Methamphetamine during Chronic LCMV Infection

PLoS ONE (2016)

Uma Sriram Beth L. Hill Jonathan Cenna Larisa Gofman Nicole Fernandes

Methamphetamine (METH) is a widely used psychostimulant that severely impacts the host's innate and adaptive immune systems and has profound immunological implications. T cells play a critical role in orchestrating immune responses. We have shown recently how chronic exposure to METH affects T cell activation using a murine model of lymphocytic choriomeningitis virus (LCMV) infection. Using the TriCOM (trinary state combinations) feature of GemStone™ to study the polyfunctionality of T cells, we have analyzed how METH affected the cytokine production pattern over the course of chronic LCMV infection. Furthermore, we have studied in detail the effects of METH on splenic T cell functions, such as cytokine production and degranulation, and how they regulate each other. We used the Probability State Modeling (PSM) program to visualize the differentiation of effector/memory T cell subsets during LCMV infection and analyze the effects of METH on T cell subset progression. We recently demonstrated that METH increased PD-1 expression on T cells during viral infection. In this study, we further analyzed the impact of PD-1 expression on T cell functional markers as well as its expression in the effector/memory subsets. Overall, our study indicates that analyzing polyfunctionality of T cells can provide additional insight into T cell effector functions. Analysis of T cell heterogeneity is important to highlight changes in the evolution of memory/effector functions during chronic viral infections. Our study also highlights the impact of METH on PD-1 expression and its consequences on T cell responses.

Meth-

Memory T cell

10.1371/journal.pone.0164966

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Citations (3)