Snapshot of Science for November 2019

Welcome to our Snapshot of Science for November 2019

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:

37 new studies published in high impact journals, along with 25 summaries submitted by the research teams
10 new research-related press releases from the Mass General Public Affairs office
9 posts from the Mass General Research Institute blog

Publications

EFFECTS OF TESAMORELIN ON NAFLD IN HIV
Effects of Tesamorelin on Non-Alcoholic Fatty Liver Disease in HIV: a Randomised, Double-Blind, Multicentre Trial
Stanley TL, Fourman LT, Feldpausch MN, Purdy J, Zheng I [et al.], Grinspoon SK.
Published in Lancet HIV on October 11, 2019 | *Summary Available

TESTING HISTONE METHYLATION WITH INDUCED MUTATION
Inducible Histone K-to-M Mutations Are Dynamic Tools to Probe the Physiological Role of Site-Specific Histone Methylation in vitro and in vivo
Brumbaugh J, Kim IS, Ji F, Huebner AJ, Di Stefano B [et al.], Hochedlinger K.
Published in Nature Cell Biology on October 28, 2019

HISTORY OF DRUG-RESISTANT TB IN SOUTH AFRICA
Pre-Detection History of Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa
Brown TS, Challagundla L, Baugh EH, Omar SV, Mustaev A [et al.], Mathema B.
Published in PNAS on October 28, 2019 | *Summary available

CBT VS. ANTIDEPRESSANTS IN THE U.S.
The Cost-Effectiveness of Cognitive Behavioral Therapy Versus Second-Generation Antidepressants for Initial Treatment of Major Depressive Disorder in the United States: A Decision Analytic Model
Ross EL, Vijan S, Miller EM, Valenstein M, Zivin K.
Published in Annals of Internal Medicine on October 29, 2019

IMMUNITY TO PAPILLOMAVIRUSES PREVENTS SKIN CANCER
Immunity to Commensal Papillomaviruses Protects against Skin Cancer
Strickley JD, Messerschmidt JL, Awad ME, Li T, Hasegawa T [et al], Demehri S.
Published in Nature on October 30, 2019 | *Summary available

DRUG RESISTANT E. COLI TRANSMITTED BY FECAL TRANSPLANT
Drug-Resistant E. coli Bacteremia Transmitted by Fecal Microbiota Transplant
DeFilipp Z, Bloom PP, Torres Soto M [et al.], Hohmann EL.
Published in New England Journal of Medicine on October 30, 2019 | *Summary available

SEX DIFFERENCES IN PATIENTS WITH HFPEF
Sex Differences in Cardiometabolic Traits and Determinants of Exercise Capacity in Heart Failure with Preserved Ejection Fraction
Lau ES, Cunningham T, Hardin KM [et al.], Ho JE.
Published in JAMA Cardiology on October 30, 2019 | *Summary available

FLUID OSCILLATION DURING SLEEP
Coupled Electrophysiological, Hemodynamic, and Cerebrospinal Fluid Oscillations in Human Sleep
Fultze NE, Bonmassar G, Setsompop K [et al.], Lewis LD.
Published in Science on November 1, 2019

GENERATION OF THE HUMAN ALPHA RHYTHM
The Generation and Propagation of the Human Alpha Rhythm
Halgren M, Ulbert I, Bastuji H, Fabó D, Eross L [et al.], Cash SS.
Published in PNAS on November 4, 2019

COST-EFFECTIVENESS OF LUNG CANCER SCREENING
Cost-Effectiveness Analysis of Lung Cancer Screening in the United States: A Comparative Modeling Study
Criss SD, Cao P, Bastani M, Ten Haaf K, Chen Y [et al.], Kong CY.
Published in Annals of Internal Medicine on November 5, 2019 | *Summary available

CARDIOVASCULAR RISK IN PREGNANT WOMEN WITH HYPERTENSION
Long-Term Cardiovascular Risk in Women with Hypertension During Pregnancy
Honigberg MC, Zekavat SM, Aragam K, Klarin D, Bhatt DL [et al.], Natarajan P.
Published in Journal of the American College of Cardiology on November 6, 2019 | *Summary available

GENETIC CONTRIBUTORS OF ATRIAL FIBRILLATION RISK
Monogenic and Polygenic Contributions to Atrial Fibrillation Risk: Results from a National Biobank
Choi SH, Jurgens SJ, Weng LC [et al.], Ellinor PT.
Published in Circulation Research on November 6, 2019 | *Summary Available

EXERCISE REDUCES CARDIOVASCULAR INFLAMMATION
Exercise Reduces Inflammatory Cell Production and Cardiovascular Inflammation via Instruction of Hematopoietic Progenitor Cells
Frodermann V, Rohde D, Courties G [et al.], Nahrendorf M.
Published in Nature Medicine on November 7, 2019 | *Summary available

US TRENDS IN BRONCHIOLITIS HOSPITALIZATIONS (2000-2016)
Trends in Bronchiolitis Hospitalizations in the United States: 2000-2016
Fujiogi M, Goto T, Yasunaga H, Fujishiro J, Manbach JM, Camargo CA Jr, Hasegawa K.
Published in Pediatrics on November 7, 2019 | *Summary available

NON-ENZYMATIC REPLICATION PROVIDES A HINT AT THE ORIGINS OF RNA
Non-Enzymatic Primer Extension with Strand Displacement
Zhou L, Kim S, Ho KH, O'Flaherty DK, Giurgiu C, Wright TH, Szostak JW.
Published in eLife on November 8, 2019 | *Summary available

GENETIC SIGNALING IMPACTS CARDIAC RISK
Genetic IL-6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis
Bick AG, Pirruccello JP, Griffin GK, Gupta N, Gabriel S [et al.], Natarajan P.
Published in Circulation on November 11, 2019 | *Summary available

CRT AFFECTS EJECTION FRACTION IN CARDIOMYOPATHY PATIENTS
Association of Cardiac Resynchronization Therapy with Change in Left Ventricular Ejection Fraction in Patients with Chemotherapy-Induced Cardiomyopathy
Singh JP, Solomon SD, Fradley MG, Barac A, Kremer KA [et al.], Kutiya V.
Published in JAMA on November 12, 2019

NANOCHELATORS FOR IRON OVERLOAD THERAPY
Renal Clearable Nanochelators for Iron Overload Therapy
Kang H, Han M, Xue J, Baek Y, Chang J [et al.], Kim J.
Published in Nature Communications on November 13, 2019 | *Summary available

EOL CARE FOR IMPOVERISHED YOUNG ADULT CANCER PATIENTS
End-of-Life Care among Adolescent and Young Adult Patients with Cancer Living in Poverty
Roeland EJ, Lindley JC, Gilbertson-White S, Saeidzadeh S, Currie ER [et al.], Mack JW.
Published in Cancer on November 14, 2019

ORGANELLE BUFFERING REVEALED BY GENETIC MODIFIERS
A Compendium of Genetic Modifiers of Mitochondrial Dysfunction Reveals Intra-organelle Buffering
To TL, Cuadros AM, Shah H, Hung WHW, Li Y [et al.], Mootha VK.
Published in Cell on November 14, 2019 | *Summary available

GENETIC VARIANTS LINKED TO SUDDEN CARDIAC DEATH
Rare Genetic Variants Associated with Sudden Cardiac Death in Adults
Khera AV, Mason-Suares H, Brockman D, Wang M, VanDenburgh MJ [et al.], Kathiresan S.
Published in Journal of the American College of Cardiology on November 15, 2019

PREMATURE MENOPAUSE ASSOCIATED WITH INCIDENT CVD
Association of Premature Natural and Surgical Menopause with Incident Cardiovascular Disease
Honigberg MC, Zekavat SM, Aragam K, Finneran P, Klarin D [et al.], Natarajan P
Published in JAMA on November 18, 2019 | *Summary available

SCHIZOPHRENIA GENETIC COMPARISON: EUROPE AND EAST ASIA
Comparative Genetic Architectures of Schizophrenia in East Asian and European Populations
Lam M, Chen CY, Li Z, Martin AR, Bryois J [et al.], Huang H.
Published in Nature Genetics on November 18, 2019 | *Summary available

MACROPHAGE RESPONSES TO INJURY AFFECT IMMUNE CHALLENGE
Tissue-Specific Macrophage Responses to Remote Injury Impact the Outcome of Subsequent Local Immune Challenge
Hoyer FF, Naxerova K, Schloss MJ, Hulsmans M, Nair AV [et al.], Nahrendorf M.
Published in Immunity on November 19, 2019 | *Summary Available

CLUSTERS IN VISUAL CORTEX IMPACT GLOBAL PERCEPTION
Asymmetries in Global Perception Are Represented in Near- vs. Far-Preferring Clusters in Human Visual Cortex
Nasr S, Tootell RB.
Published in Journal of Neuroscience on November 19, 2019 | *Summary Available

CLONOTYPIC T-CELLS REVEALED BY TCR AND RNA SEQUENCING
TCR Sequencing Paired with Massively Parallel 3' RNA-seq Reveals Clonotypic T Cell Signatures
Tu AA, Gierahn TM, Monian B, Morgan DM, Mehta NK [et al.], Love JC.
Published in Nature Immunology on November 19, 2019 | *Summary available

MAPPING FMRI BY RECORDING CALCIUM IN NEURONS
Mapping Optogenetically-Driven Single-Vessel FMRI with Concurrent Neuronal Calcium Recordings in the Rat Hippocampus
Chen X, Sobczak F, Chen Y, Jiang Y, Qian C [et al.], Yu X.
Published in Nature Communications on November 20, 2019 | *Summary Available

PHASE 2 TRIAL OF BREAST CANCER TREATMENT
A Phase 2 Clinical Trial Assessing the Efficacy and Safety of Pembrolizumab and Radiotherapy in Patients with Metastatic Triple-Negative Breast Cancer
Ho AY, Barker CA, Arnold BB, Powell SN, Hu ZI [et al.], McArthur HL.
Published in Cancer on November 20, 2019 | *Summary available

PULMONARY HYPERTENSION LINKED TO TMVR
Association of Pulmonary Hypertension With Clinical Outcomes of Transcatheter Mitral Valve Repair
Al-Bawardy R, Vemulapalli S, Thourani VH, Mack M, Dai D [et al.], Elmariah S.
Published in JAMA Cardiology on November 20, 2019

BRAIN-TO-CLN PATHWAY LINKED TO SEVERITY OF STROKE
Brain-to-Cervical Lymph Node Signaling After Stroke
Esposito E, Ahn BJ, Shi J, Nakamura Y, Park JH [et al.], Hayakawa K.
Published in Nature Communications on November 22, 2019 | *Summary available

COMPLEMENTARY FEEDING TIMING IN RELATION TO ADIPOSITY
Timing of Complementary Feeding Introduction and Adiposity Throughout Childhood
Gingras V, Aris IM, Rifas-Shiman SL, Switkowski KM, Oken E, Hivert MF.
Published in Pediatrics on November 22, 2019 | *Summary available

EXOME SEQUENCING LINKS NEW GENE TO ALS
Exome Sequencing in Amyotrophic Lateral Sclerosis Implicates a Novel Gene, DNAJC7, Encoding a Heat-Shock Protein
Farhan SMK, Howrigan DP, Abbott LE, Klim JR, Topp SD [et al.], Neale BM.
Published in Nature Neuroscience on Date November 25, 2019 | *Summary available

ASD AND ADHD SHARE CERTAIN RARE GENES
Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder Have a Similar Burden of Rare Protein-Truncating Variants
Satterstrom FK, Walters RK, Singh T, Wigdor EM, Lescai F [et al.], Daly MJ.
Published in Nature Neuroscience on November 25, 2019 | *Summary available

HEMOGLOBIN FROM SICKLE CELL PATIENTS ANALYZED UNDER CONTROLLED OXYGEN TENSION
High-Throughput Assessment of Hemoglobin Polymer in Single Red Blood Cells From Sickle Cell Patients Under Controlled Oxygen Tension
Di Caprio G, Schonbrun E, Gonçalves BP, Valdez JM, Wood DK, Higgins JM.
Published in PNAS on November 25, 2019 | *Summary available

LOOKING AT BOTH GENOTYPE AND PHENOTYPE MAKES ANTIBIOTIC SUSCEPTIBILITY DETERMINATION MORE EFFICIENT
Simultaneous Detection of Genotype and Phenotype Enables Rapid and Accurate Antibiotic Susceptibility Determination
Bhattacharyya RP, Bandyopadhyay N, Ma P, Son SS, Liu J [et al.], Hung DT.
Published in Nature Medicine on November 25, 2019 | *Summary available

NOVEL METHOD MAY HELP TO INHIBIT CANCER-CAUSING GENE
Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition.
Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E [et al.], Corcoran RB.
Published in Clinical Cancer Research on November 27, 2019 | *Summary available

EARLY ANTIRETROVIRAL THERAPY MAY HELP BABIES WITH HIV-1 BUILD IMMUNITY
Early Antiretroviral Therapy in Neonates with HIV-1 Infection Restricts Viral Reservoir Size and Induces a Distinct Innate Immune Profile
Garcia-Broncano P, Maddali S, Einkauf KB, Jiang C, Gao C [et al.], Lichterfeld M.
Published in Science Translational Medicine on November 27, 2019 | *Summary available

Summaries

Nonalcoholic fatty liver disease (NAFLD) is a major comorbidity affecting over one-third of people living with HIV. Though NAFLD imposes a critical threat to public health, no treatment has been approved to treat NAFLD in either HIV or the general population. In a randomized, double-blind placebo-controlled trial, we demonstrated that the growth hormone-releasing hormone analogue tesamorelin significantly reduced liver fat and prevented fibrosis progression in individuals with HIV-associated NAFLD. Thus, tesamorelin is now the first therapeutic that has been shown to attenuate the course of NAFLD in HIV with potential benefits to reduce morbidity and mortality.

(Summary submitted by Steven K. Grinspoon, MD, Metabolism Unit)

Antibiotic-resistant pathogens are often detected years or decades after they evolve and only after they have dispersed into locations distant from their geographic origin. Late detection of newly-evolved antibiotic-resistant pathogens represents a lost opportunity for early containment of these critical threats to global public health. In our study, we use whole genome sequence data to reconstruct the joint evolutionary and epidemiological histories of an important highly drug-resistant strain of tuberculosis endemic to KwaZulu-Natal, South Africa. We localize the most likely geographic origin of this strain, show that transmission of this strain increased concurrent with the onset of the generalized HIV epidemic and delineate key mutations driving the dispersal and expansion of this highly drug-resistant infection.

(Summary submitted by Tyler S. Brown, MD, Division of Infectious Diseases and Department of Medicine)

We investigated the role of commensal human papillomaviruses (HPVs) in the development of skin cancer. Using a novel skin colonization model, we show that immune responses against papillomavirus infection can protect the host from skin cancer caused by ultraviolet radiation. This work reveals the significant and previously unrecognized beneficial contributions of skin-resident HPVs. Considering the increased risk of skin cancer among elderly and immunosuppressed patients, these findings create the foundation for novel therapeutic interventions to prevent the development of skin cancer in high-risk populations. Furthermore, these results establish a new field of investigation into the beneficial contributions of viruses that live in our skin and other organs.

(Summary submitted by Shawn Demehri, MD, PhD, Department of Dermatology, Cutaeneous Biology Research Center and Cancer Center)

Following the infection of two patients who received drug resistant Extended Spectrum Beta-Lactamase (ESBL) E. coli via capsulized fecal microbiota transplants (FMT), increased screening for drug resistant E. coli in FMT is recommended for all stool donors. Patients who are immunocompromised are at higher risk of complications of infection after FMT. Investigators recommend continued efforts to improve donor screening to limit transmission of drug resistant organisms. Ongoing research is needed to continue to assess the risks and benefits of FMT.

(Summary submitted by Elizabeth Hohmann, MD, Division of Infectious Diseases and Department of Medicine)

Heart failure with preserved ejection fraction (HFpEF), a rising public health concern, is more common in women than men. We explored differences in risk factors and exercise traits in men and women with HFpEF. Using data from the Mass General cardiopulmonary exercise testing (CPET) lab, we found numerous sex differences in cardiac and skeletal muscle responses to exercise in HFpEF. In particular, women with HFpEF have greater cardiac and extracardiac deficits including less efficient utilization of oxygen during exercise. These findings may shed light on the mechanisms that drive HFpEF.

(Summay submitted by Emily Lau, MD, Department of Cardiology)

Lung cancer screening with low-dose computed tomography is associated with a reduction in mortality among current and former smokers, but the optimal age at which to stop screening is unknown. Four decision analytic models were independently developed to evaluate the cost-effectiveness of alternative age cutoffs. The authors found that screening up until ages 74, 77 and 80 as per existing recommendations all represented cost-effective strategies. Screening an older population was estimated to save more lives but was associated with a higher overdiagnosis rate. This study helps to characterize the benefits and harms of different screening strategies and suggests that those with lower age cutoffs are more likely to be cost-effective.

(Summary submitted by Chung-Yin (Joey) Kong, PhD, Department of Radiology and Institute for Technology Assessment)

Women who experience hypertensive disorders of pregnancy (HDP), such as preeclampsia, face increased cardiovascular disease risk, but the long-term cardiovascular complications of HDP were previously unclear. In this study of 220,000 middle-aged women, women with prior HDP had higher rates of elevated blood pressure and were more likely to develop coronary artery disease, heart failure, narrowing of the aortic valve (aortic stenosis) and leakage of the mitral valve (mitral regurgitation). These findings imply blood pressure treatment may be especially important in women with HDP and suggest new avenues of research to better understand why women with HDP develop cardiovascular disease.

(Summary submitted by Michael C. Honigberg, MD, MPP, Department of Medicine and Division of Cardiology)

GENETIC CONTRIBUTORS TO RISK OF ATRIAL FIBRILLATION
Monogenic and Polygenic Contributions to Atrial Fibrillation Risk: Results from a National Biobank
Choi SH, Jurgens SJ, Weng LC [et al.], Ellinor PT.
Published in Circulation Research on November 6, 2019

Great progress has been made in defining the genetic basis of atrial fibrillation (AF), but the relative contribution of rare and common genetic variants to AF risk remains unclear. In an exome wide analysis, we found that LOF mutations in Transient Tachypnea of the Newborn (TTN) were strongly associated with AF risk and were highly penetrant. A polygenic risk score of common variants explains a great proportion of AF risk than mutations in TTN. Among TTN mutation carriers, it will be interesting in future work to determine if a subtle cardiomyopathy is present by cardiac imaging or to examine the progression to heart failure or other AF co-morbidities.

(Summary submitted by Patrick Ellinor, MD, PhD, Cardiovascular Research Center and Division of Cardiology)

Modern life comes with many dangers. This includes sedentary behavior, as we all spend increasing time sitting: on the office chair, in the car, on the sofa. This is risky and leads to cardiovascular disease. The Nahrendorf lab describes that mice with access to treadmills had lower blood stem cell proliferation in their bone marrow. Sedentary mice had higher leptin levels which triggered over-production of inflammatory leukocytes, resulting in more atherosclerosis and heart failure. The team also looked at clinical data from the CANTOS trial, observing similar relationships between physical activity, leptin and leukocytes.

(Summary submitted by Matthias Nahrendorf, MD, PhD, Center for Systems Biology)

US TRENDS IN BRONCHIOLITIS HOSPITALIZATIONS
Trends in Bronchiolitis Hospitalizations in the United States: 2000-2016
Fujiogi M, Goto T, Yasunaga H, Fujishiro J, Manbach JM, Camargo CA Jr, Hasegawa K.
Published in Pediatrics on November 7, 2019

Bronchiolitis is the most common lower respiratory tract infection among young children in the US. In the 2000s, the overall incidence of bronchiolitis hospitalization decreased, whereas the use of mechanical ventilation and hospital charges increased. In this study, we analyzed a database of nation-wide pediatric hospitalizations to investigate the changes in the incidence of bronchiolitis, their characteristics, inpatient resource use, and hospital cost from 2000 through 2016. We found that the incidence of hospitalization decreased from 17.9 to 13.5 per 1000 person-years (25% decrease). By contrast, there were significant increases in the proportion of patients with pediatric complex chronic conditions, hospitalization to children’s hospitals, mechanical ventilation use and cost.

(Summary submitted by Michimasa Fujiogi, MD, and Kohei Hasegawa, MD, Department of Emergency Medicine)

At the dawn of life, there were no evolved enzymes to propagate genes across generations. To accomplish a full cycle of enzyme-free RNA replication, RNA duplexes must be separated in order to initiate the next round of copying. Now, we illustrate a simple solution to copy one strand of RNA while the other is pried off by short RNA "invaders." This prebiotic approach is the first demonstration of non-enzymatic RNA copying on a template preoccupied by its complementary strand, hinting at a possible pathway for RNA replication under early earth conditions.

(Summary submitted by Lijun Zhou, PhD, Department of Molecular Biology)

More than one in 10 adults over the age of 70 have a blood disorder called clonal hematopoiesis of indeterminate potential (CHIP) in which some blood stem cells become too abundant because of acquired cancer-predisposing mutations. CHIP can lead to cancer, but the biggest health risk from the disorder may be a heart attack or stroke. We found that a genetic variant disrupting the IL-6R gene, which encodes an inflammatory molecule, leads to a greater reduction in cardiovascular disease risk in patients with CHIP. These findings suggest that therapeutically blocking this inflammatory pathway could be highly effective in preventing cardiovascular disease through a new precision medicine approach.

(Summary submitted by Alexander Bick, MD, PhD, Department of Medicine)

Iron is an essential nutrient metal, but excess iron is toxic due to increased oxidative stress produced by iron-catalyzed reactive oxygen species. Although several iron chelators are clinically used to reduce iron burden, the use of these chelators is limited due to significant adverse effects likely due to nonspecific distribution of chelators in off-target tissues. To overcome this challenge, we developed iron chelator-coated ultrasmall nanochelators that could capture iron from plasma, without distributing into nontarget tissues, and leave the body through urinary excretion. Our renal clearable nanochelators can decrease iron burden and reduce the risk of iron-mediated organ toxicity, with no overt chelator-related side effects.

(Summary submitted by Homan Kang, PhD, Department of Radiology)

Mitochondrial dysfunction accompanies a spectrum of conditions, ranging from rare metabolism errors to common diseases, such as type 2 diabetes, and the aging process. Understanding how genetic variations can alleviate or aggravate these diverse pathologies remains a major unsolved problem. To systematically identify the cellular pathways involved, we used genome-wide CRISPR screening to build a compendium to describe the genetic modifiers for different models of mitochondrial dysfunction. Among the results, we highlighted the unexpected finding that certain forms of mitochondrial dysfunction may best be alleviated by “second site” inhibition to the organelle.

(Summary submitted by Tsz-Leung To, PhD, Department of Molecular Biology)

Women who experience early menopause face increased risk of coronary artery disease, but the risk of other cardiovascular conditions was previously unclear. In this study of >144,000 middle-aged women, women with menopause before age 40 were more likely to develop coronary artery disease, heart failure, valvular heart disease, arrhythmia, stroke and venous blood clots, as well as high blood pressure, high cholesterol and type 2 diabetes. These findings reflect more diverse cardiovascular effects of premature menopause than previously appreciated and imply that early lifestyle modification (e.g., dietary changes, weight loss) to prevent cardiovascular disease may be especially important in affected women.

(Summary submitted by Michael C. Honigberg, MD, MPP, Department of Medicine and Division of Cardiology)

Using the largest to date psychiatric genetics samples of East Asia ancestry, an international team identifed 176 genetic loci (53 new) associated with schizophrenia. They also found that genetic variants that confer risk for schizophrenia have highly similar effects in those of East Asian and European ancestry, indicating for the first time that the genetic basis of schizophrenia and its biology are broadly shared across these world populations. A novel fine-mapping method enabled by the diversity in linkage disequilibrium across ancestries more precisely isolated schizophrenia causal alleles in 70% of genetic regions. Investigators also found genetic risk prediction has reduced performance when used across populations, highlighting the importance of including all major ancestral groups with sufficient sample size to ensure the findings have maximum relevance for all populations.

(Summary submitted by Hailiang Huang, PhD, Broad Institute)

Patients with acute illnesses frequently experience complications in remote organs that were initially unaffected. Tissue resident macrophages are cells of the innate immune system that populate all vital organs in steady-state. The authors found that these cells responded vigorously in lungs, hearts, kidneys, livers, and brains in mice with either myocardial infarction, stroke, or sepsis. Macrophages’ changes were either protective or harmful for the host. For instance, mice with prior myocardial infarction were protected against subsequent pneumonia. This study suggests that tissue resident macrophages are promising targets to modulate and alleviate remote complications.

(Summary submitted by Matthias Nahrendorf, MD, PhD, Center for Systems Biology)

In everyday life, we see different types of visual details when we view objects from different perspectives. Here we used an advanced technique of functional magnetic resonance imaging (‘fMRI’) to reveal very tiny ‘columns’ of brain activity, when different objects were shown to subjects, at either near or far locations. Different people have different numbers of these ‘columns’, and that difference in brain activity matched differences in perception. These findings reveal a fine-scaled brain organization which processes near and far stimuli, at a spatial scale that has not been seen previously.

(Summary submitted by Roger Tootell, PhD, Martinos Center)

Each T cell recognizes a specific target — whether a virus or a cancer cell — using variable sequences in the receptors on its surface called T-cell receptors (TCRs). We have developed a new approach, compatible with common high-throughput single-cell RNA sequencing (scRNA-seq) methods, that can determine a cell’s TCR sequences along with its corresponding full transcriptome. Using this approach, we identified T cells sharing enriched TCRs in mice and in patients with food allergy and showed that these cells were associated with distinct cellular states compared to those sharing different, unenriched TCR sequences.

(Summary submitted by Alex Shalek, PhD, Ragon Institute and Broad Institute)

The high-field fMRI (14.1Tesla) allows directly measuring the mesoscale hemodynamic responses of the rat hippocampal vasculature. In particular, the single-vessel fMRI method maps the large-scale hippocampal activity-coupled hemodynamic signals from individual arterioles and venules penetrating the hippocampus, which goes beyond the penetration depth of conventional optical imaging methods. Using implanted optical fibers, optogenetically-evoked neuronal Ca2+ and the spreading depression-like Ca2+ transients are recorded with the simultaneous single-vessel fMRI, demonstrating distinct spatiotemporal features of the vascular hemodynamic responses. Here, we develop a novel multi-modal fMRI platform to identify the varying neurovascular coupling (NVC) efficiency across multiple scales in the hippocampus.

(Summary submitted by Xin Yu, PhD, Martinos Center)

This was the first clinical trial to prospectively evaluate the combination of immune checkpoint inhibitor and radiotherapy, exclusively in women with metastatic triple negative breast cancer. Our primary goal was to assess the overall response rate outside of the irradiation field. The treatment was well-tolerated. The results of this signal-seeking study were modest but encouraging (18% response in entire cohort and 33% in those who were radiographically evaluable). They have led us to initiate other studies assessing innovative combinations of immunotherapy with radiation, which can be a practical yet powerful treatment to combine with select, targeted therapies for breast cancer.

(Summary submitted by Alice Ho, MD, Department of Radiation Oncology and Cancer Center)

After acute ischemic stroke, peripheral immune cells become activated and these systemic responses may amplify neuroinflammation and brain damage. But how the injured brain sends out signals to trigger systemic inflammation remains unclear. We found that a brain-to-cervical lymph node (CLN) pathway may underlie the ability of the injured brain to activate systemic inflammation. Importantly, surgical removal of CLNs in mice significantly reduced brain infarction after focal cerebral ischemia. This study may help us to understand the pathophysiology of brain-lymphatic crosstalk and lead us to novel mechanisms and targets for stroke.

(Summary submitted by Kazuhide Hayakawa, PhD, Department of Radiology)

Complementary feeding introduction represents the transition from exclusive breastfeeding or formula feeding to family or “solid” foods. Some studies suggested that the timing of introduction of complementary feeding could contribute to childhood obesity. In Project Viva, a large U.S. pre-birth cohort study, we found that introduction of complementary feeding before 4 months old was associated with higher adiposity measurements throughout childhood while introduction after 6 months old was associated with higher adiposity throughout childhood in children who were never breastfed or stopped breastfeeding before 4 months old only. Our findings support current recommendations not to introduce complementary feeding before 4 monthsof age.

(Summary submitted by Veronique Gingras, PhD, Department of Population Medicine at Harvard Medical)

To understand the genetic basis of amyotrophic lateral sclerosis (ALS), a fatal adult-onset neurodegenerative disease, we sequenced and combined data from over 5,000 cases. We identified a novel ALS gene, DNAJC7, which encodes a heat-shock protein (HSP). HSPs play an important role in cellular maintenance and clearance of degraded proteins, and when these processes are disrupted, it can lead to neurodegeneration. These discoveries have enhanced our understanding of the disease mechanism and how to properly develop therapeutic targets for ALS patients.

(Summary submitted by Sali Farhan, PhD, Analytical and Translational Genetics Unit)

ASD AND ADHD SHARE CERTAIN RARE GENES
Autism Apectrum Disorder and Attention Deficit Hyperactivity Disorder Have a Similar Burden of Rare Protein-Truncating Variants
Satterstrom FK, Walters RK, Singh T, Wigdor EM, Lescai F [et al.], Daly MJ.
Published in Nature Neuroscience on November 25, 2019

It has been known for a few years that children with autism have a higher rate of certain types of mutations in their DNA than “typically developing” children do. Using samples from a Danish national biobank, we found that children with ADHD have similarly elevated rates, and that their mutations occur in a similar set of genes. Although these mutations are rare, so that only a minority of children with autism or ADHD would have one, they help to shed light on the shared aspects of autism and ADHD genetics.

(Summary submitted by Kyle Satterstrom, PhD, Analytical and Translational Genetics Unit)

Hundreds of thousands of babies are born each year with sickle cell disease, and all morbidity and mortality are ultimately caused by hemoglobin polymers. Hemoglobin polymers make blood cells stiff and rigid, compromising blood flow, damaging blood vessels, and causing permanent damage to tissues. Our study describes a method to assess hemoglobin polymers at the single-cell level to infer the amount of polymer in each cell based on its reaction to oxygen. This method provides a precise way to improve management of sickle cell patients with existing treatments and to optimize the development and prioritization of candidate cures.

(Summary submitted by John M. Higgins, M.D., Center for Systems Biology)

Programs to prevent mother-to-child transmission of HIV-1 effectively protect newborns from HIV-1, but an estimated 300-500 infants are still infected in sub-Saharan Africa every day. This study describes a unique, first-of-its kind study to treat HIV-infected newborns in Botswana within hours after birth with a combination of three antiretroviral drugs. We reported results from the first 10 infants from this study, who were followed for two years after treatment initiation. Compared with 10 children who started treatment at approximately 4 months after birth, we show that early treatment translates into multiple benefits for the infants, such as a limited establishment of a long-lived viral reservoir cells and improved immune responses.

(Summary submitted by Pilar Garcia-Broncano, PhD, Ragon Institute)

Press Releases

Gene Variant May Help Protect Against Alzheimer's disease
Featuring Yakeel T. Quiroz, PhD

New study led by investigators at Massachusetts General Hospital, in collaboration with the University of Antioquia, Schepens Eye Research Institute of Mass. Eye and Ear and Banner Alzheimer’s Institute, provides insights on why some people may be more resistant to Alzheimer’s disease than others. The findings may lead to strategies to delay or prevent the condition.

Women with Hypertension During Pregnancy Remain at Greater Risk of Several Cardiovascular Conditions Later in Life
Featuring Michael C. Honigberg, MD, MPP

Research published online in Journal of the American College of Cardiology, confirms that women who have gestational hypertension or preeclampsia in at least one pregnancy will have higher cardiovascular risk than women without such a history, and that this elevated risk persists at least into their 60s.

Study Identifies New Genetic Links to Serious Blood Clot Condition
Featuring Derek Klarin, MD

22 new genetic variants are being linked to VTE, as published in a recent study from researchers working at Massachusetts General Hospital (MGH), the Broad Institute of MIT and Harvard, and the U.S. Department of Veterans Affairs (VA) Boston Healthcare System.

Physical Activity May Protect Against New Episodes of Depression Even in People Who Are Genetically Vulnerable
Featuring Karmel Choi, PhD, and Jordan Smoller, MD, ScD

In a paper published in the journal Depression and Anxiety, a team reported that individuals who engaged in at least several hours of exercise each week were less likely to be diagnosed with a new episode of depression, even in the face of high genetic risk for the disorder.

Pacemakers Can Improve Heart Function in Patients with Chemotherapy-induced Heart Disease
Featuring Jagmeet P. Singh, MD

Research published in JAMA has shown that treating chemotherapy-induced heart diseaseCHIC with commercially available cardiac resynchronization therapy delivered through a surgically implanted defibrillator or pacemaker can significantly improve patient outcomes.

Study Teases Out Factors Associated with Postpartum Overdose
Featuring Davida M. Schiff, MD, MSc

Massachusetts researchers have published a new study in the journal Addiction that uncovers several risk factors associated with postpartum opioid overdose.

Glowing Particles in the Blood May Help Diagnose and Monitor Brain Cancer
Featuring Pamela Jones, MD, MPH, and Leonora Balai

A chemical that has improved surgeries for brain cancer by making tumor cells fluorescent may also help doctors safely diagnose the disease and monitor its response to treatment.

Study Finds That Uninfected Young Adults Born to Mothers Living with HIV Are at Risk of Obesity and Asthma Later in Life
Featuring Lindsay Fourman, MD

In a study published in Journal of Acquired Immune Deficiency Syndromes, a team revealed for the first time that HIV-negative teens and young adults with a history of in utero HIV exposure showed more than fourfold increased odds of obesity and asthma-like symptoms compared to their unexposed peers.

Rare Genetic Variants Predispose to Sudden Cardiac Death
Featuring Amit Khera, MD

By identifying rare DNA variants that substantially increase risk of sudden cardiac death, researchers led by investigators at Massachusetts General Hospital and the Broad Institute of MIT and Harvard have laid the foundation for efforts to identify individuals who could benefit from prevention strategies prior to experiencing symptoms.

Blog Posts

2019 MGRI Image Contest: Meet the Winner and Finalists

The second annual Mass General Research Institute Image Contest produced 46 amazing images from researchers across 15 centers and departments at Mass General. After two weeks of deliberation, the judges have finally selected a winner and eight finalists.

DISCOVERY Study Seeks to Learn More About the Causes of Post-Stroke Cognitive Disability
Featuring Natalia Rost, MD, MPH

We are excited to announce that, last month, the National Institute of Neurological Disorders and Stroke awarded Massachusetts General Hospital 39 million ($62+ million in total direct and indirect costs) for the DISCOVERY (Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on RecoverY) Network.

Five Things to Do Improve Your Science Presentations

A member of our communications team recently sat on a panel at MIT for the Northeast Symposium on Biomedical Optics to discuss the importance of effective science communication along with five other local experts. Here are a few things the panelists suggested to improve your next presentation.

Research Roundup: Genetic Protection from Alzheimer’s Disease, Football Players and Heart Health, and More

Research Roundup is a monthly recap of recent news from investigators at the Massachusetts General Hospital Research Institute.

Researcher Studies Grandson’s Rare Genetic Mutation
Featuring Marian DiFiglia, PhD

For decades, researcher Marian DiFiglia, PhD, has investigated neurodegenerative diseases at Massachusetts General Hospital. Then, three years ago, her grandson Quinn was diagnosed with a genetic mutation so rare that, at the time, it had no name. Coming to grips with the genetic mutation involved was a life-changing experience for Dr. DiFiglia, her daughter, Liz Aronin, and son-in-law, Jamie Mills.

Mass General Celebrates the 25th Anniversary of the Ataxia Unit and Launching of the Ataxia Center
Featuring Jeremy Schmahmann, MD

Jeremy Schmahmann, MD, has been a pioneer in cerebellar ataxia clinical care and research for over 35 years. In 1994 he founded the Massachusetts General Hospital Ataxia Unit, the first clinic of its kind to focus exclusively on disorders of the cerebellum.

A Matter of Touch: Researchers Uncover A New Source of Symptoms in Autism Spectrum Disorder
Featuring Lauren Orefice, PhD

In studies of mouse models for autism spectrum disorder (ASD) at Harvard Medical School, Lauren Orefice, PhD (now an Assistant Investigator in the Mass General Department of Molecular Biology), David Ginty, PhD, and their team found that a similar process of peripheral nerve dysfunction occurs in some genetic forms of ASD, which could explain symptoms such as touch overreactivity, anxiety and social impairment.

Postdoc Profile: Hannah Twarkowski, PhD
Featuring Hannah Twarkowski, PhD

Hannah Twarkowski, PhD, is a postdoctoral fellow in the lab of Amar Sahay, PhD, MGH Research Scholar 2019-2024. His lab investigates ways to use hippocampal neurogenesis and hippocampal circuit mechanisms to improve memory in adulthood and aging.

Thankful for Friends, Family and Science

Thanksgiving is a holiday that was initially created to celebrate the harvest, and over the years it has evolved to become a holiday about friends, family, food and being thankful. With Thanksgiving right around the corner, we couldn’t wait to share one of the things we’re grateful for: science! Science has helped us learn more about the world we live in and its role in medicine and technology has helped us live longer and healthier lives.

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Snapshot of Science for November 2019