Snapshot of Science for May 2020

Welcome to our Snapshot of Science for May 2020

Here's a quick look at some recent publications, press releases and stories about the Mass General Research Institute community.

In this issue we highlight:

21 new studies published in high impact journals, along with 14 summaries submitted by the research teams
14 new research-related press releases from the Mass General Public Affairs office
5 posts from the Mass General Research Institute blog

Publications

NEUTROPHILS RESTRICT FUNGAL GROWTH
Neutrophil Swarming Delays the Growth of Clusters of Pathogenic Fungi
Hopke A, Scherer A, Kreuzburg S, Abers MS, Zerbe CS [et al.], Irmia D.
Published in Nature Communications on April 27, 2020 | *Summary available

MAPPING AQUEOUS HUMOR IMPROVES UNDERSTANDING OF GLAUCOMA
Cell Atlas of Aqueous Humor Outflow Pathways in Eyes of Humans and Four Model Species Provides Insight Into Glaucoma Pathogenesis
van Zyl T, Yan W, McAdams A, Peng Y, Shekhar K [et al.], Sanes JR.
Published in PNAS on April 27, 2020

CORONAVIRUS IN A BOSTON HOMELESS SHELTER
Prevalence of SARS-CoV-2 Infection in Residents of a Large Homeless Shelter in Boston
Baggett TP, Keyes H, Sporn N, Gaeta JM.
Published in JAMA on April 27, 2020 | *Summary available

ASSESSING IMPORTANT PATHOGENIC DNA VARIANTS
Association of Rare Pathogenic DNA Variants for Familial Hypercholesterolemia, Hereditary Breast and Ovarian Cancer Syndrome, and Lynch Syndrome with Disease Risk in Adults According to Family History
Patel AP, Wang M, Fahed AC, Mason-Suares H, Brockman D [et al.], Khera AV.
Published in JAMA Open Network on April 29, 2020 | *Summary available

MITOCHONDRIAL CALCIUM LINKED TO NEURONAL DEATH IN ALZHEIMER'S
Increased Mitochondrial Calcium Levels Associated with Neuronal Death in a Mouse Model of Alzheimer's Disease
Calvo-Rodriguez M, Hou SS, Snyder AC, Kharitonova EK, Russ AN [et al.], Bacskai BJ.
Published in Nature Communications on May 1, 2020 | *Summary available | Press Release

ANGPTL7 GENE VARIANTS PROTECT AGAINST GLAUCOMA
Rare Protein-Altering Variants in ANGPTL7 Lower Intraocular Pressure and Protect Against Glaucoma
Tanigawa Y, Wainberg M, Karjalainen J, Kiiskinen T [et al.], Daly MJ, Rivas MA.
Published in PLoS Genetics on May 5, 2020

LEARNED NEURAL PATTERNS ARE REPLAYED DURING SLEEP
Replay of Learned Neural Firing Sequences During Rest in Human Motor Cortex
Eichenlaub J, Jarosiewicz B, Saab J, Franco B, Kelemen J [et al.], Cash SS.
Published in Cell Reports on May 5, 2020

MRI YIELDS GENETIC INSIGHTS INTO CARDIOMYOPATHY
Analysis of Cardiac Magnetic Resonance Imaging in 36,000 Individuals Yields Genetic Insights Into Dilated Cardiomyopathy
Pirruccello JP, Bick A, Wang M, Chaffin M, Friedman S [et al.], Aragam KG.
Published in Nature Communications on May 7, 2020 | *Summary available

NON-CODING RNA ON GENE EXPRESSION & CELL CYCLE
S-phase Enriched Non-coding RNAs Regulate Gene Expression and Cell Cycle Progression
Yildirim O, Izgu EC, Damle M, Chalei V, Sadreyev RI [et al.], Kingston RE.
Published in Cell Reports on May 12, 2020

RESIDUAL SHUNT FOLLOWING PFO CLOSURE INCREASES STROKE RISK
Residual Shunt After Patent Foramen Ovale Closure and Long-Term Stroke Recurrence
Deng W, Yin S, McMullin D, Inglessis-Azuaje I, Elmariah S [et al.], Ning MM.
Published in Annals of Internal Medicine on May 12, 2020

PATHWAYS OF CHEMOTAXING NEUTROPHILS
Chemotaxing Neutrophils Enter Alternate Branches at Capillary Bifurcations
Wang X, Hossain M, Bogoslowski A, Kubes P, Irimia D.
Published in Nature Communications on May 13, 2020 | *Summary available

PHASE III TRIAL OF IVOSIDENIB
Ivosidenib in IDH1-mutant, Chemotherapy-Refractory Cholangiocarcinoma (ClarIDHy): A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 3 Study
Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ [et al.], Zhu AX.
Published in Lancet Oncology on May 13, 2020

COST EFFECTIVENESS OF STATIN USE GUIDELINES IN AFRICAN AMERICANS
Cost-effectiveness of Contemporary Statin Use Guidelines with or without Coronary Artery Calcium Assessment in African American Individuals
Spahillari A, Zhu J, Ferket BS, Myriam Hunink MG, Carr JJ [et al.], Pandya A.
Published in JAMA Cardiology on May 13, 2020 | *Summary available

PERSONALIZED PROGENITOR CELLS FOR PARKINSON'S
Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease
Schweitzer JS, Song B, Herrington TM, Park T, Lee N [et al.], Kim K.
Published in The New England Journal of Medicine on May 14, 2020 | *Summary available | Press Release

CELLULAR DIVERSITY OF THE HUMAN HEART
Transcriptional and Cellular Diversity of the Human Heart
Tucker NR, Chaffin M, Fleming SJ, Hall AW, Parsons VA [et al.], Ellinor PT.
Published in Circulation on May 14, 2020 | *Summary available

ROLE OF DENDRITIC CELLS IN ZIKV
Immune-profiling of ZIKV-infected Patients Identifies a Distinct Function of Plasmacytoid Dendritic Cells for Immune Cross-Regulation
Sun X, Hua S, Gao C, Blackmer JE, Ouyang Z [et al.], Yu XG.
Published in Nature Communications on May 15, 2020 | *Summary available

DISTRACTED DRIVING LAWS & CRASHES
Distracted Driving Laws and Motor Vehicle Crash Fatalities
Flaherty MR, Kim AM, Salt MD, Lee LK.
Published in Pediatrics on May 15, 2020 | *Summary available

ADRENALECTOMY FOR SECONDARY MALIGNANCY
Adrenalectomy for Secondary Malignancy: Patients, Outcomes, and Indications
Wachtel H, Roses RE, Kuo LE, Lindeman BM, Nehs MA [et al.], Lubitz CC.
Published in Annals of Surgery on May 18, 2020

CITED4 GENE AND PHYSIOLOGICAL STRESS
CITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological Stress
Lerchenmueller C, Rabolli CP, Yeri AS, Kitchen R, Salvador AM [et al.], Rosenzweig A.
Published in Circulation Research on May 18, 2020 | *Summary available

ALLERGIC PATHOGENICITY AND IMMUNOGLOBULIN E
Sialylation of Immunoglobulin E is a Determinant of Allergic Pathogenicity
Shade KC, Conroy ME, Washburn N, Kitaoko M, Huynh DJ [et al.], Anthony RM.
Published in Nature on May 20, 2020 | *Summary available | Press Release

EXERCISE AND CARDIAC AGING IN PRESERVED EJECTION FRACTION
Exercise Training Reverses Cardiac Aging Phenotypes Associated with Heart Failure with Preserved Ejection Fraction in Male Mice
Roh JD, Houstis N, Yu A, Chang B, Yeri A [et al.], Rosenzweig A.
Published in Aging Cell on May 22, 2020 | *Summary available

Summaries

New evidence shows that neutrophils can cooperate as a “swarm” when attacking microbes. To probe this understudied process, we designed an assay in which swarms of neutrophils are pitched against large clusters of Candida albicans. We found that neutrophils employ lethal chemicals and physical traps against Candida to prevent the surviving fungi from escaping. We found that neutrophils from patients with chronic granulomatous disease form larger neutrophil swarms but are less efficient at killing and restricting Candida. External signals could enhance the efficacy of neutrophils during swarming, suggesting new avenues for antimicrobial interventions that leverage the body’s resources in more effective ways.

(Summary submitted by Alex Hopke, PhD, Department of Surgery and Center for Engineering in Medicine)

The crowded conditions of homeless shelters create the potential for rapid transmission of SARS-CoV-2. After identifying a cluster of COVID-19 cases arising from a single shelter in Boston, Boston Health Care for the Homeless Program conducted symptom assessments and universal testing for SARS-CoV-2 infection among all remaining residents over a 2-day period in early April. Of 408 individuals, 147 (36.0%) tested positive for SARS-CoV-2. Of these, 87.8% were asymptomatic and symptoms such as cough (7.5%), shortness of breath (1.4%), and fever (0.7%) were uncommon. These findings suggest that symptom screening alone will not adequately capture the extent of COVID-19 transmission in shelters and support the need for proactive mass testing in this vulnerable population.

(Summary submitted by Travis Baggett, MD, Division of General Internal Medicine, Department of Medicine)

Certain genetic changes, termed "pathogenic variants," substantially increase risk for cardiovascular disease and cancer—the leading causes of death. However, testing to identify individual carriers is not part of current clinical practice. We analyzed the gene sequencing data from about 50,000 people and found that 1% of individuals had important such pathogenic variants, and these individuals are at markedly increase risk of disease. What was really striking was that a family history of disease — the current standard within clinical practice — was present in only 40% of these high-risk individuals.

(Summary submitted by Aniruddh Patel, MD, Cardiology Division, Department of Medicine)

We shed light on the toxic effects of amyloid beta (Aß)– a primary component of Alzheimer’s disease senile plaques on mitochondrial calcium in the living brain. Mitochondrial calcium homeostasis is a tightly regulated process, because excessive calcium in mitochondria can lead to apoptosis mediated cell death. We observed elevated calcium levels in neuronal mitochondria in the brains of mice after pathology deposition. Our study implicates toxic soluble Aß oligomers and the mitochondrial calcium uniporter, which allows calcium entry to mitochondria. Importantly, elevated calcium in mitochondria preceded neuronal death and could be a target for neuroprotective therapies in Alzheimer’s disease.

(Summary submitted by Maria Calvo-Rodriguez, PhD, Department of Neurology)

Identifying the DNA changes that underlie heart failure has been challenging. We adopted a new approach, conducting a genetic analysis of cardiac MRI-derived measures of heart size and function in 36,000 participants of the UK Biobank. We identified 45 novel genetic signals associated with cardiac structure and function and established a link between these genetic signals and dilated cardiomyopathy (DCM), a condition that damages the organ’s muscle tone and is a leading cause of heart failure. In addition, we developed a genetic tool capable of prognosticating future risk of DCM in the general population.

(Summary submitted by Krishna Aragam, MD, Division of Cardiology, Department of Medicine)

We were recently surprised to discover that squads of neutrophils arriving at capillary bifurcations migrate to alternating branches rather than the random choices predicted by our current understanding of cell migration. We explained this unusual behavior by the change in hydraulic resistance induced by the first neutrophil in one branch, which biases the migration of the following neutrophil towards the other branch. These processes are relevant to the efficient movement of neutrophils through tissues and capillary networks towards wounds and infections when neutrophils avoid traffic jams despite a large number of neutrophils moving at once.

(Summary submitted by Daniel Irimia, MD, PhD, Department of Surgery and Center for Engineering in Medicine)

We compared costs, benefits and harms between two strategies of statin treatment based on ACC-AHA guidelines in African American individuals at intermediate cardiovascular disease risk. The main difference was that based on the 2018 guidelines, those who did not have coronary artery calcification were not treated with statins, whereas using the 2013 guidelines, all individuals at risk were prescribed statins. If patients did not mind taking a pill daily, then the 2013 guidelines (that resulted in widespread statin treatment eligibility) were optimal. However, for patients who had a strong preference to avoid statin treatment, the 2018 guidelines were optimal.

(Summary submitted by Aferdita Spahillari, MD, Division of Cardiology, Department of Medicine)

Parkinson’s disease is caused in part by the loss of brain cells called dopaminergic neurons. We took a sample of an individual patient’s skin cells, coaxed them to become dopamine neurons and transplanted them into the brain and showed that the transplants were recognized as “self” and not rejected. At two years, the cells were surviving and functioning. The patient reported improvement in symptoms and no adverse events. Conclusions about safety and efficacy are limited in a single-patient study, but the results will help design future clinical trials.

(Summary submitted by Jeffrey Schweitzer, MD, PhD, Department of Neurosurgery)

Ever wonder how many cell types are in the human heart? Our recent work in Circulation seeks to address this question. We performed single nucleus RNA sequencing in 280,000 cells from the four chambers of the normal human heart. This revealed nine major cell types and more than 20 cell subtypes, defined a unique population of fibroblasts, and uncovered unexpected chamber and laterality specificity for non-myocyte cells. This rich atlas of the transcriptional diversity in the heart will facilitate the prioritization of novel therapeutic targets and enable future studies of other cardiovascular diseases.

(Summary submitted by Patrick Ellinor, MD, PhD, Division of Cardiology, Department of Medicine)

Several vaccine candidates for ZIKA virus (ZIKV) are currently under development, although the precise correlates of effective ZIKV immune protection remain incompletely understood. In this study, we examined transcriptional signatures of peripheral blood immune cells from acutely ZIKV-infected individuals. We demonstrate that plasmacytoid dendritic cells (pDCs) are poorly susceptible to ZIKV infection but mount strong antiviral responses. Furthermore, we frequently observed collaborative interconnections between gene expression signatures from pDCs and alternative immune cell populations, particularly B cells. Together, our work points to a central role of pDCs in immune defense during acute ZIKV infection in humans.

(Summary submitted by Xiaoming Sun, PhD, Ragon Institute of MGH, MIT, and Harvard)

DISTRACTED DRIVING LAWS & CRASHES
Distracted Driving Laws and Motor Vehicle Crash Fatalities
Flaherty MR, Kim AM, Salt MD, Lee LK.
Published in Pediatrics on May 15, 2020

Our study investigated the effects of distracted driving laws in the United States on motor vehicle crash deaths involving 16-19-year-old drivers, those at the early stages of their driving career. As many states implement new legislation, it is important to learn which laws seem to work best at saving lives. We found that laws that apply universal handheld cellphone bans seem to have the greatest reduction in motor vehicle crash deaths when a teen is driving. Laws that ban text messaging also were associated with reduced deaths. Laws that applied only to specific age groups, such as handheld device bans only for novice drivers, had no association with MVC fatalities.

(Summary submitted by Michael Flaherty, DO, Mass General for Children)

CITED4 GENE AND PHYSIOLOGICAL STRESS
CITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological Stress
Lerchenmueller C, Rabolli CP, Yeri AS, Kitchen R, Salvador AM [et al.], Rosenzweig A.
Published in Circulation Research on May 18, 2020

Although the beneficial preventive and therapeutic effects of exercise are well established, the underlying molecular mechanisms are not well understood. We previously found CITED4 is induced in the heart by exercise and sufficient to induce many aspects seen in athlete’s hearts as well as preserving heart function after a heart attack. To understand the role of endogenous CITED4, we generated mice in which CITED4 was deleted from heart muscle cells (C4KO mice). These mice, while normal at baseline, manifested maladaptive responses to exercise and pathological pressure overload, showing impaired cardiac growth as well as increased cell death and fibrosis. These studies underscore the important role of CITED4 in beneficial, adaptive responses to both physiological and pathological stimuli.

(Summary submitted by Anthony Rosenzweig, MD, Division of Cardiology, Department of Medicine)

Nearly one third of the world’s population suffers from allergies, which are caused by IgE antibodies. When IgE antibodies bind to an allergen, it leads to mast cell activation and release of mediators that are responsible for allergic symptoms, and in extreme cases, anaphylaxis. We analyzed the glycans, or sugars, attached to IgE from peanut allergic and non-allergic individuals and found sialic acid was enriched on IgE for peanut allergic individuals. The addition of sialic acid enhanced IgE pathogenicity and removing sialic acid from IgE attenuated allergic disease. Thus, quantifying sialic acid on IgE may serve as a biomarker for more accurate diagnosis of allergic disease, and removal of sialic acid from IgE is a novel therapeutic strategy for allergic disease, including food allergy.

(Summary submitted by Robert Anthony, PhD, Department of Medicine and Center for Immunology & Inflammatory Diseases)

Heart failure with preserved ejection fraction (HFpEF) accounts for roughly half of heart failure overall and is the most common form of heart failure in the elderly. Although there are no proven medical treatments for HFpEF, exercise training has emerged as the most effective intervention in HFpEF patients. We found that aged mice recapitulate many of the hallmark features of human HFpEF. Similar to older humans, exercise training in old mice improved exercise capacity and reduced heart failure. Analyses of gene expression in hearts from elderly, exercised mice showed that exercise reversed multiple age-related pathways including the global downregulation of regenerative pathways seen in old mice. Taken together, these studies establish a valuable model for studying the role of aging biology in HFpEF and provide a molecular framework for how exercise potentially reverses cardiac aging phenotypes in HFpEF.

(Summary submitted by Anthony Rosenzweig, MD, Division of Cardiology, Department of Medicine)

Press Releases

Researchers Release COVID-19 Symptom Tracker App
Featuring Andrew Chan, MD, MPH

A consortium of scientists with expertise in big data research and epidemiology recently developed the COVID Symptom Tracker app aimed at rapidly collecting information to aid in the response to the ongoing COVID-19 pandemic.

Study Reveals the Risk of COVID-19 Infection Among Health Care Workers
Featuring Andrew Chan, MD, MPH

In an analysis of information from the U.K. and U.S., frontline health care workers had a nearly 12-times higher risk of testing positive for COVID-19 compared with individuals in the general community, and those workers with inadequate access to personal protective equipment had an even higher risk.

Mass General Advancing Novel Experimental Gene-based COVID-19 Vaccine, AAVCOVID
Featuring Mason Freeman, MD, and Luk H. Vandenberghe, PhD

Massachusetts Eye and Ear and Mass General, members of Mass General Brigham, announced progress towards the testing and development of an experimental vaccine called AAVCOVID, a novel gene-based vaccine candidate against SARS-CoV2, the virus that causes COVID-19.

Study Reveals Most Critically Ill Patients with COVID-19 Survive with Standard Treatment
Featuring Jehan Alladina, MD, and C. Corey Hardin, MD, PhD

Clinicians from two hospitals in Boston report that the majority of even the sickest patients with COVID-19—those who require ventilators in intensive care units—get better when they receive existing guideline-supported treatment for respiratory failure.

The COVID-19 Pandemic Reveals the Potential of Telehealth to Improve Care
Featuring Lee Schwamm, MD

Two new articles provide insights on the use of telehealth or virtual care in the age of COVID-19 and beyond, pointing to its value to not only prevent contagious diseases but also to provide access to effective and equitable care.

Mass General Researchers Link High Calcium Levels in Mitochondria to Neuronal Death in Alzheimer’s Disease
Featuring Brian J. Bacskai, PhD, and Maria Calvo-Rodriguez, PhD

For the first time, using a mouse model of Alzheimer’s disease, scientists have documented a link between raised levels of calcium in mitochondria and neuronal death in the living brain.

Novel Treatment Using Patient’s Own Cells Opens New Possibilities to Treat Parkinson’s Disease
Featuring Bob Carter, MD, PhD, Todd Herrington, MD, PhD, and Jeff Schweitzer, MD, PhD

Reprogramming a patient’s own skin cells to replace cells in the brain that are progressively lost during Parkinson’s disease has been shown to be technically feasible.

Mass General Researchers Find Potential Drug Treatment Targets for Alcohol-related Liver Disease
Featuring Jay Luther, MD, and Suraj J. Patel, MD, PhD

A Mass General research team has uncovered key molecular steps in ALD that may provide targets for drug therapy development.

New Insights on Allergies May Improve Diagnosis and Treatment
Featuring Robert Anthony, PhD

Results from a study led by investigators at Mass General may help to improve the diagnosis and treatment of allergies, pointing to a potential marker of these conditions and a new therapeutic strategy.

Electronic Consults Between Clinicians and Specialists Have Increased During the COVID-19 Pandemic
Featuring Jason Wasfy, MD, and Neelam A. Phadke, MD

New research from Mass General points to the usefulness of electronic consultations, or e-consults, during the COVID-19 pandemic.

Researchers Find New Evidence for a Blood-Based Biomarker for Alzheimer's Disease
Featuring Yakeel Quiroz, PhD

A team of Mass General researchers has found that neurofilament light chain has great potential as a biomarker for early detection of Alzheimer’s disease and could be also useful for monitoring treatment response for that condition.

New Study Reveals That an Imbalance of Electrons in the Liver Appears to Be a Risk Factor for Many Common Diseases
Featuring Vamsi Mootha, MD, and Russel Goodman, MD, DPhil

Researchers at Mass General have uncovered an unexpected connection between an imbalance of electrons in liver cells and many metabolic problems that increase the risk for conditions such as cardiovascular disease and fatty liver disease.

Study Finds Overwhelming Disparities in use of Medications for Opioid Use Disorder During Pregnancy
Featuring Davida Schiff, MD

Based on a population-level sample of women with OUD in the State of Massachusetts, the researchers found racial and ethnic disparities in the range of 60 to 75 percent.

Lymph Node Metastases Form Through a Wider Evolutionary Bottleneck than Distant Metastases
Featuring Kamila Naxerova, PhD

Lymph node metastasis formation is comparatively ‘easy’ and can be achieved my many cells. Dissemination to and outgrowth in distant organs, on the other hand, appears to be much more challenging and represents a major bottleneck in tumor progression.

Blog Posts

The Ventilator: Understanding One of Today’s Most Valuable Devices
Featuring George Alba, MD

Ventilators are typically used in modest numbers, but highly infectious COVID-19 and its potential to lead to severe respiratory issues has made them crucial in hospitals everywhere. The rapid spread of the disease has created a situation where these devices are in short supply across many healthcare systems.

A Nurse’s Perspective: COVID-19 and Homeless Populations
Featuring Kirsten Dickins, PhD, AM, MSN, FNP-C

Kirsten Dickins, PhD, AM, MSN, FNP-C, Connell postdoctoral fellow in Nursing Research at the Yvonne L. Munn Center for Nursing Research focuses on identifying and reducing the barriers that homeless individuals experience in accessing and optimally utilizing healthcare services.

How a Mass General Vaccine Accelerator Could Play a Crucial Role in the COVID-19 Response
Featuring Mark Poznansky, MD, PhD

Almost a decade before the current COVID-19 outbreak, Mark Poznansky, MD, PhD, received funding from DARPA to develop a platform for accelerated vaccine development in the event of a rapidly spreading EID. The funding resulted in the creation of the VaxCelerate Consortium, a platform capable of generating and clinically testing a new vaccine in less than 120 days.

Ragon Institute Researchers Discuss Progress on Serology Testing and Safe Return to Work
Featuring Bruce Walker, MD

Researchers at the Ragon Institute of MGH, MIT and Harvard have played a key role in the development of serological tests—blood-based tests for antibodies to the SARS-CoV-2 virus—to meet a crucial need in the COVID-19 response.

How Serology Testing Will Improve our Understanding of COVID-19
Featuring David Louis, MD

Researchers at Mass General, the Ragon Institute of MGH, Harvard and MIT and beyond are now looking to blood-based serology tests to get a better sense of how many people have been exposed to the virus and had mild or no symptoms.

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Snapshot of Science for May 2020