Welcome to our Snapshot of Science for January 2021

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:

  • 28 new studies published in high impact journals, along with 23 summaries submitted by the research teams
  • 14 new research-related press releases from the Mass General Public Affairs office
  • 6 posts from the Mass General Research Institute blog
Publications

THE RELATIONSHIP BETWEEN COVID-19 SEVERITY AND HUMORAL IMMUNE RESPONSE
COVID-19-Neutralizing Antibodies Predict Disease Severity and Survival
Garcia-Beltran WF, Lam EC, Astudillo MG, Yang D, Miller TE [et al.], Balazs AB
Published in Cell on December 15, 2020


DBT SCREENING YIELDS FEWER FALSE-POSITIVE RESULTS
Imaging Surveillance of Breast Cancer Survivors with Digital Mammography versus Digital Breast Tomosynthesis
Bahl M, Mercaldo S, McCarthy AM, Lehman CD
Published in Radiology on December 22, 2020 | *Summary available


TARGETING SIL-6R TO MODULATE INFLAMMATORY IMMUNE REACTIONS
The Persistence of Interleukin-6 Is Regulated by a Blood Buffer System Derived from Dendritic Cells
Yousif AS, Ronsard L, Shah P, Omatsu T, Sangesland M [et al.], Lingwood D
Published in Immunity on December 22, 2020 | *Summary available


PREDICTING IN-HOSPITAL MORTALITY OF EMERGENCY SURGERY PATIENTS
Validation of the AI-based Predictive OpTimal Trees in Emergency Surgery Risk (POTTER) Calculator in Patients 65 Years and Older
Maurer LR, Chetlur P, Zhuo D, El Hechi M, Velmahos GC [et al.], Kaafarani HMA
Published in Annals of Surgery on December 23, 2020 | *Summary available


LIMITED SARS-COV-19 ANTIBODY TRANSER THROUGH PLACENTA
Compromised SARS-CoV-2-specific Placental Antibody Transfer
Atyeo C, Pullen KM, Bordt EA, Fischinger S, Burke J [et al.], Alter G
Published in Cell on December 23, 2020


AIRWAY STEM CELLS MITIGATE HYPOXIA-INDUCED DAMAGE
Airway Stem Cells Sense Hypoxia and Differentiate into Protective Solitary Neuroendocrine Cells
Shivaraju M, Chitta UK, Grange RMH, Jain IH, Capen D [et al.], Rajagopal J
Published in Science on January 01, 2021 | *Summary available


QRICH1 GENE MANAGES CELL STRESS RESPONSES
QRICH1 Dictates the Outcome of ER Stress Through Transcriptional Control of Proteostasis
You K, Wang L, Chou CH, Liu K, Nakata T [et al.], Xavier RJ
Published in Science on January 01, 2021 | *Summary available


MEDICAID FEE DID NOT INCREASE PRIMARY CARE VISITS FOR DUAL-ELIGIBLE PATIENTS
Assessment of the Patient Protection and Affordable Care Act's Increase in Fees for Primary Care and Access to Care for Dual-Eligible Beneficiaries
Fung V, Price M, Hull P, Cook BL, Hsu J, Newhouse JP
Published in JAMA Network Open on January 04, 2021 | *Summary available


GASTROINTESTINAL INFECTION INCREASES MICROSCOPIC COLITIS RISK
Gastrointestinal Infection and Risk of Microscopic Colitis: A Nationwide Case-Control Study in Sweden
Khalili H, Axelrad JE, Roelstraete B, Olén O, D'Amato M, Ludvigsson JF
Published in Gastroenterology on January 06, 2021


THE ROLE OF CARM1 IN CHEMORESISTANCE
CARM1 Regulates Replication Fork Speed and Stress Response by Stimulating PARP1
Genois MM, Gagné JP, Yasuhara T, Jackson J, Saxena S [et al.], Zou L
Published in Molecular Cell on January 06, 2021 | *Summary available


REGULATING CAR T CELL THERAPY WITH LENALIDOMIDE
Reversible ON- and OFF-Switch Chimeric Antigen Receptors Controlled by Lenalidomide
Jan M, Scarfò I, Larson RC, Walker A, Schmidts A [et al.], Maus MV, Ebert BL
Published in Science Translational Medicine on January 06, 2021 | *Summary available


BLUE LIGHT AND CAVACROL TREATMENT FOR MULTIDRUG-RESISTANT BACTERIA
Bacteria-specific Phototoxic Reactions Triggered by Blue Light and Phytochemical Carvacrol
Lu M, Wang S, Wang T, Hu S, Bhayana B [et al.], Wu MX
Published in Science Translational Medicine on January 06, 2021 | *Summary available


GENE THERAPY TREATMENT FOR TUBEROUS SCLEROSIS COMPLEX
Gene Therapy for Tuberous Sclerosis Complex Type 2 in a Mouse Model by Delivery of AAV9 Encoding a Condensed Form of Tuberin
Cheah PS, Prabhakar S, Yellen D, Beauchamp RL, Zhang X [et al.], Breakefield XO
Published in Science Advances on January 08, 2021 | *Summary available | Press Release


LOW HUNTINGTIN MAY NOT BE FUNDAMENTAL CAUSE OF HUNTINGTON'S DISEASE
Mutations Causing Lopes-Maciel-Rodan Syndrome Are Huntingtin Hypomorphs
Jung R, Lee Y, Barker D, Correia K, Shin B [et al.], Seong IS
Published in Human Molecular Genetics on January 11, 2021 | *Summary available


TIMING OF INHIBITOR THERAPY MAY PLAY A ROLE IN AML CONTROL
Imaging Dynamic Mtorc1 Pathway Activity in Vivo Reveals Marked Shifts That Support Time-specific Inhibitor Therapy in AML
Oki T, Mercier F, Kato H, Jung Y, McDonald TO [et al.], Scadden DT
Published in Nature Communications on January 11, 2021 | *Summary available


BLOCKING PIGF ENHANCES EFFICACY OF CHEMOTHERAPY FOR AGGRESSIVE LIVER CANCER
Placental Growth Factor Promotes Tumour Desmoplasia and Treatment Resistance in Intrahepatic Cholangiocarcinoma
Aoki S, Inoue K, Klein S, Halvorsen S, Chen J [et al.], Duda DG
Published in Gut on January 11, 2021 | *Summary available | Press Release


LACK OF KCTD1 LEADS TO PROGRESSIVE METABOLIC BONE DISEASE
Magnesium and Calcium Homeostasis Depend on KCTD1 Function in the Distal Nephron
Marneros AG
Published in Cell Reports on January 12, 2021 | *Summary available | Press Release


MOCO SUPPLEMENT MAY BE THERAPY FOR LETHAL GENETIC DISORDER
Protein-bound Molybdenum Cofactor Is Bioavailable and Rescues Molybdenum Cofactor-deficient C. Elegans
Warnhoff K, Hercher TW, Mendel RR, Ruvkun G
Published in Genes & Development on January 14, 2021 | *Summary available | Press Release


SLEEP SPINDLES ARE A BIOMARKER OF COGNITIVE DYSFUNCTION IN EPILEPSY
Focal Sleep Spindle Deficits Reveal Focal Thalamocortical Dysfunction and Predict Cognitive Deficits in Childhood Epilepsy with Centrotemporal Spikes
Kramer MA, Stoyell SM, Chinappen D, Ostrowski LM, Spencer ER [et al.], Chu CJ
Published in Journal of Neuroscience on January 14, 2021 | *Summary available


TELOMERIC BREAK-INDUCED REPLICATION IS A SELF-PERPETUATING PROCESS
Alternative Lengthening of Telomeres Is a Self-perpetuating Process in ALT-associated PML Bodies
Zhang JM, Genois MM, Ouyang J, Lan L, Zou L
Published in Molecular Cell on January 15, 2021


TIMELY RESTORATION OF BLOOD FLOW CAN IMPROVE HEALING AFTER DVT
Time-Restricted Salutary Effects of Blood Flow Restoration on Venous Thrombosis and Vein Wall Injury in Mouse and Human Subjects
Li W, Kessinger CW, Orii M, Lee H, Wang L [et al.], Jaffer FA
Published in Circulation on January 15, 2021 | *Summary available


NEW SOFTWARE FACILITATES THE INCLUSION OF ADMIXED INDIVIDUALS IN GENETIC RESEARCH
Tractor Uses Local Ancestry to Enable the Inclusion of Admixed Individuals in GWAS and to Boost Power
Atkinson EG, Maihofer AX, Kanai M, Martin AR, Karczewski KJ [et al.], Neale BM
Published in Nature Genetics on January 18, 2021 | *Summary available


OVERLAPPING BRAIN STATE CHANGES IN SCHIZOPHRENIA AND IN AT-RISK YOUTH
Altered Temporal, but Intact Spatial, Features of Transient Network Dynamics in Psychosis
Wang D, Peng X, Pelletier-Baldelli A, Orlov N, Farabaugh A [et al.], Holt DJ
Published in Molecular Psychiatry on January 18, 2021 | *Summary available


MODEL TO OPTIMIZE COVID-19 RESPONSE AND TREATMENT
In Silico Dynamics of COVID-19 Phenotypes for Optimizing Clinical Management
Voutouri C, Nikmaneshi MR, Hardin CC, Patel AB, Verma A [et al.], Jain RK
Published in Proceedings of the National Academy of Sciences on January 19, 2021 | *Summary available | Press Release


MARKERS FOR SEVERITY OF MITOCHONDRIAL DISEASE
Circulating Markers of NADH-reductive Stress Correlate with Mitochondrial Disease Severity
Sharma R, Reinstadler B, Engelstad K, Skinner OS, Stackowitz E [et al.], Mootha VK
Published in Journal of Clinical Investigation on January 19, 2021 | *Summary available


PRECISE PET SCANS MAY PREDICT FUTURE ALZHEIMER'S DISEASE
The Cortical Origin and Initial Spread of Medial Temporal Tauopathy in Alzheimer's Disease Assessed with Positron Emission Tomography
Sanchez JS, Becker JA, Jacobs HIL, Hanseeuw BJ, Jiang S [et al.], Johnson KA
Published in Science Translational Medicine on January 20, 2021 | *Summary available


NEW INSIGHTS INTO HOW GENE SILENCING PROTEIN IDENTIFIES TARGETS
Motif-driven Interactions Between RNA and PRC2 Are Rheostats That Regulate Transcription Elongation
Rosenberg M, Blum R, Kesner B, Aeby E, Garant JM [et al.], Lee JT
Published in Nature Structural & Molecular Biology on January 24, 2021 | Press Release


MALIGNANT SYS CELLS EXPRESS NOVEL CELLULAR PROGRAM
Opposing Immune and Genetic Mechanisms Shape Oncogenic Programs in Synovial Sarcoma
Jerby-Arnon L, Neftel C, Shore ME, Weisman HR, Mathewson ND [et al.], Regev A
Published in Nature Medicine on January 25, 2021 | *Summary available


Publication Summaries

DBT SCREENING YIELDS FEWER FALSE-POSITIVE RESULTS
Imaging Surveillance of Breast Cancer Survivors with Digital Mammography versus Digital Breast Tomosynthesis
Bahl M, Mercaldo S, McCarthy AM, Lehman CD
Published in Radiology on December 22, 2020

Given that breast cancer survivors are at higher-than-average risk of developing breast cancer in the future (either a recurrent cancer or a second cancer in either breast), continued imaging surveillance in these patients is warranted. Digital breast tomosynthesis (DBT; also known as 3D mammography) is used for screening, but data on DBT for surveillance in this high-risk population are limited. We studied whether DBT leads to improved screening performance metrics when compared with conventional 2D digital mammography among breast cancer survivors. We found that screening with tomosynthesis leads to fewer false-positive results and higher specificity but did not affect cancer detection.

(Summary submitted by Manisha Bahl, MD, MPH, Division of Breast Imaging, Department of Radiology)


TARGETING SIL-6R TO MODULATE INFLAMMATORY IMMUNE REACTIONS
The Persistence of Interleukin-6 Is Regulated by a Blood Buffer System Derived from Dendritic Cells
Yousif AS, Ronsard L, Shah P, Omatsu T, Sangesland M [et al.], Lingwood D
Published in Immunity on December 22, 2020

IL-6 is a potent inflammatory cytokine released into the bloodstream after injury or infection. However, hyper-elevated levels of IL-6 underscore inflammatory disorders, including severe COVID-19 disease. In mouse studies, we show that a type of immune cell called dendritic cells produce a molecule called the soluble IL-6 receptor (sIL6R), which then circulates throughout the body and captures IL-6. We showed that this capture activity forms a biological buffer system that finely tunes the body-wide concentration of IL-6, highlighting a molecular "rheostat" that could inform therapeutic interventions for treating inflammatory diseases.

(Summary submitted by Daniel Lingwood, PhD, Ragon Institute of MGH, MIT and Harvard)


PREDICTING IN-HOSPITAL MORTALITY OF EMERGENCY SURGERY PATIENTS
Validation of the AI-based Predictive OpTimal Trees in Emergency Surgery Risk (POTTER) Calculator in Patients 65 Years and Older
Maurer LR, Chetlur P, Zhuo D, El Hechi M, Velmahos GC [et al.], Kaafarani HMA
Published in Annals of Surgery on December 23, 2020

Geriatric patients are particularly vulnerable to adverse outcomes after emergency surgery (ES). Our group previously developed the Predictive OpTimal Trees in Emergency Surgery Risk (POTTER) calculator for ES patients, using a novel, interpretable AI-based methodology. In this work, we specifically assess the performance of POTTER in ES patients 65 years and older and conclude that the POTTER tool is a highly accurate predictor of in-hospital mortality in the elderly ES patient up to age 85 years. POTTER could prove useful for bedside counseling of elderly patients and their families and for benchmarking of ES care.

(Summary submitted by Lydia R. Maurer, MD, Department of Surgery)


AIRWAY STEM CELLS MITIGATE HYPOXIA-INDUCED DAMAGE
Airway Stem Cells Sense Hypoxia and Differentiate into Protective Solitary Neuroendocrine Cells
Shivaraju M, Chitta UK, Grange RMH, Jain IH, Capen D [et al.], Rajagopal J
Published in Science on January 01, 2021

How does a tissue sense stress? We show that airway stem cells sense hypoxic stress and directly convert into specialized neuroendocrine (NE) cells that help mitigate hypoxia-induced damage. Interestingly, the increase in number of NE cells is observed in many respiratory diseases like asthma, cystic fibrosis and sudden infant death syndrome. This work suggests that the unexplained NE cell hyperplasia that accompanies many lung diseases could represent a compensatory physiologic response. More broadly, it raises the possibility that stem cells throughout the body sense hypoxia and differentiate into unique organ-specific NE cells.

(Summary submitted by Jayaraj Rajagopal, MD, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Center for Regenerative Medicine)


QRICH1 GENE MANAGES CELL STRESS RESPONSES
QRICH1 Dictates the Outcome of ER Stress Through Transcriptional Control of Proteostasis
You K, Wang L, Chou CH, Liu K, Nakata T [et al.], Xavier RJ
Published in Science on January 01, 2021

Tissue homeostasis is maintained through coordinated stress responses involving multiple cell types and signaling pathways. The unfolded protein response (UPR) is one such pathway that is activated by misfolded protein accumulation in the endoplasmic reticulum (ER) and results in either restoration of ER homeostasis or programmed cell death. We defined gene programs associated with these divergent outcomes and identified the QRICH1 as a transcriptional regulator of protein translation and secretion that determines ER stress-induced cell fate. Enrichment of the QRICH1 gene signature in diseased colon and liver biopsies supports a broader role for QRICH1 in managing cell stress responses across a range of human diseases.

(Summary submitted by Heather Kang, PhD, Broad Institute of MIT and Harvard)


MEDICAID FEE DID NOT INCREASE PRIMARY CARE VISITS FOR DUAL-ELIGIBLE PATIENTS
Assessment of the Patient Protection and Affordable Care Act's Increase in Fees for Primary Care and Access to Care for Dual-Eligible Beneficiaries
Fung V, Price M, Hull P, Cook BL, Hsu J, Newhouse JP
Published in JAMA Open Network on January 04, 2021

Fees paid to providers for treating dual-eligible Medicare-Medicaid beneficiaries are often lower compared with fees for Medicare-only beneficiaries because of state and federal financing policy. These policies could reduce access to care for vulnerable dual-eligible beneficiaries. The Affordable Care Act (ACA) required that states increase Medicaid payments for primary care practitioners (PCPs) to Medicare levels in 2013 and 2014, which also increased fees for PCPs treating dual-eligible patients in most states. We found that the ACA fee increase was not associated with increases in primary care visits for dual-eligible beneficiaries. These findings could be attributable to policy implementation challenges.

(Summary submitted by Vicki Fung, PhD, Department of Medicine, Mongan Institute for Health Policy)


THE ROLE OF CARM1 IN CHEMORESISTANCE
CARM1 Regulates Replication Fork Speed and Stress Response by Stimulating PARP1
Genois MM, Gagné JP, Yasuhara T, Jackson J, Saxena S [et al.], Zou L
Published in Molecular Cell on January 06, 2021

DNA replication stress is a common cancer vulnerability that is increasingly targeted in cancer therapy. We have identified the protein arginine methyltransferase CARM1 as a key regulator of the replication stress response. CARM1 regulates the replication stress response by stimulating PARP at replication forks. In the absence of CARM1, cancer cells switch to low-fidelity replication mechanisms to tolerate replication stress, leading to chemoresistance. This study helps explain and ultimately overcome the chemoresistance of cancer cells.

(Summary submitted by Lee Zou, PhD, Mass General Cancer Center)


REGULATING CAR T CELL THERAPY WITH LENALIDOMIDE
Reversible ON- and OFF-Switch Chimeric Antigen Receptors Controlled by Lenalidomide
Jan M, Scarfò I, Larson RC, Walker A, Schmidts A [et al.], Maus MV, Ebert BL
Published in Science Translational Medicine on January 06, 2021

CAR T cells are a breakthrough class of highly effective cancer therapies in which a patient's own immune cells are genetically modified to recognize and attack tumor cells. Once given, these "living drugs" autonomously proliferate and kill tumor cells over weeks to months. Sometimes CAR T cells can expand very rapidly and cause toxicity, and their long lives can make the development of new CAR T cells for other tumors more risky. Our team engineered switchable CAR T cells that can be turned on and off with lenalidomide, an approved cancer drug. In the future, such regulatable cell therapies might allow patients with their physicians to take a pill—or not—to tune the amount of CAR T cell activity from day to day and therefore improve tolerability and enable testing of new targets.

(Summary submitted by Marcela V. Maus, MD, PhD, Division of Hematology/Oncology, Mass General Cancer Center)


BLUE LIGHT AND CAVACROL TREATMENT FOR MULTIDRUG-RESISTANT BACTERIA
Bacteria-specific Phototoxic Reactions Triggered by Blue Light and Phytochemical Carvacrol
Lu M, Wang S, Wang T, Hu S, Bhayana B [et al.], Wu MX
Published in Science Translational Medicine on January 06, 2021

Multidrug-resistant (MDR) bacteria have become one of the biggest threats to the public healthcare of our time due to a lack of significant progress in development of new antibiotics in the past decades. We combine carvacrol, an ingredient of edible oils, with blue light to safely and quickly kill an array of MDR bacterial pathogens including their biofilms and persisters that are tough to treat with antibiotics. This bactericidal activity results from photo-catalytical oxidization of carvacrol into a series of photoreactive substrates occurring exclusively in bacteria. This highly selective modality may represent a unique strategy to disinfect body surface wounds if it can be successfully validated in a large animal in the future.

(Summary submitted by Meixiong Wu, MD, PhD, Department of Dermatology, Wellman Center for Photomedicine)


GENE THERAPY TREATMENT FOR TUBEROUS SCLEROSIS COMPLEX
Gene Therapy for Tuberous Sclerosis Complex Type 2 in a Mouse Model by Delivery of AAV9 Encoding a Condensed Form of Tuberin
Cheah PS, Prabhakar S, Yellen D, Beauchamp RL, Zhang X [et al.], Breakefield XO
Published in Science Advances on January 08, 2021 | Press Release

Patients with tuberous sclerosis complex, a genetic disorder characterized by the growth of noncancerous tumors in multiple organs of the body, and epilepsy, have limited treatment options. We show that gene replacement therapy can effectively treat mice that have lost one of the tumor suppressor genes responsible for this disease. The gene, called TSC2, codes for tuberin, a protein that regulates cell growth and proliferation. When loss of function of this gene occurs, cells enlarge and divide, leading to the formation of tumors. We developed a form of gene therapy using an adeno-associated virus vector carrying the DNA that codes for a condensed form of tuberin. A single injection of this vector into the blood of the Tsc2 mouse model reduced lesions in the brain and extended their lifespan.

(Summary submitted by Shilpa Prabhakar, MSc, Department of Neurology)


LOW HUNTINGTIN MAY NOT BE FUNDAMENTAL CAUSE OF HUNTINGTON'S DISEASE
Mutations Causing Lopes-Maciel-Rodan Syndrome Are Huntingtin Hypomorphs
Jung R, Lee Y, Barker D, Correia K, Shin B [et al.], Seong IS
Published in Human Molecular Genetics on January 11, 2021

Huntington's disease (HD) is a fatal, neurodegenerative disorder caused by trinucleotide repeat mutation in the huntingtin gene (HTT). Recently, a family with two siblings presenting a novel developmental disorder was found to contain extremely rare mutations in HTT. In tissue biopsies, we confirm the exact nature of the mutations and their molecular consequences, resulting in abnormally low amounts of huntingtin protein. This evidence supports the theory that the fundamental cause of HD is not low huntingtin and is encouraging for new huntingtin-lowering therapies.

(Summary submitted by Ihn Sik Seong, PhD, Department of Neurology, Center for Genomic Medicine)


TIMING OF INHIBITOR THERAPY MAY PLAY A ROLE IN AML CONTROL
Imaging Dynamic Mtorc1 Pathway Activity in Vivo Reveals Marked Shifts That Support Time-specific Inhibitor Therapy in AML
Oki T, Mercier F, Kato H, Jung Y, McDonald TO [et al.], Scadden DT
Published in Nature Communications on January 11, 2021

Acute myeloid leukemia responds to therapy at a rate of >80%, yet has a mortality rate of >70% often due to the failure of drugs targeting molecular pathways for cancer cell growth. We developed methods to track individual leukemic cell growth as well as fluorescence-based tools to monitor the activity of key growth (mTOR) and death pathways (Caspase3). Notably, the mTOR pathway shut off as leukemia progressed but reactivated in leukemic stem cells to enable relapse. When the mTOR pathway was inhibited immediately following chemotherapy, leukemia cells were efficiently killed. Our study points to how molecular dependencies in cancer cells shift in the body and that by changing the timing of inhibitors better cancer control may be possible.

(Summary submitted by David Scadden, MD, Division of Hematology/Oncology, Mass General Cancer Center, Center for Regenerative Medicine)


BLOCKING PIGF ENHANCES EFFICACY OF CHEMOTHERAPY FOR AGGRESSIVE LIVER CANCER
Placental Growth Factor Promotes Tumour Desmoplasia and Treatment Resistance in Intrahepatic Cholangiocarcinoma
Aoki S, Inoue K, Klein S, Halvorsen S, Chen J [et al.], Duda DG
Published in Gut on January 11, 2021 | Press Release

Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer of the liver with a five-year survival rate of 15% for patients with early-stage disease, and 6% for those with metastases to regional lymph nodes. The cancer is characterized by vascular abnormalities, abundant connective tissue (known as desmoplasia) produced by activated CAFs and has few therapeutic options. We found that blocking placental growth factor (PlGF), a member of the vascular endothelial growth factor family, inhibits desmoplasia and the progression of ICC, and enhances the efficacy of chemotherapy in mouse models. This novel approach to targeting the connective tissue microenvironment of ICC, a rare but notoriously treatment-resistant form of liver cancer, could pave the way for combination therapies, including chemotherapy and immune checkpoint blockade.

(Summary submitted by Dan G. Duda, DMD, PhD, Department of Radiation Oncology, Mass General Cancer Center)


LACK OF KCTD1 LEADS TO PROGRESSIVE METABOLIC BONE DISEASE
Magnesium and Calcium Homeostasis Depend on KCTD1 Function in the Distal Nephron
Marneros AG
Published in Cell Reports on January 12, 2021 | Press Release

The KCTD1 gene directs production of a protein that regulates the kidney's ability to reabsorb magnesium and calcium from urine and return it to the bloodstream. We found that lack of KCTD1 in mutant mice leads to progressive kidney abnormalities, in part resembling the findings in patients with chronic kidney disease. We observed that patients with KCTD1 mutations also developed chronic kidney disease with renal fibrosis (scarring of kidney tissue). These findings reveal that KCTD1 is a key regulator of distal nephrons' ability to not only reabsorb salt, but also magnesium and calcium from urine, thereby maintaining a healthy balance.

(Summary submitted by Alexander G. Marneros, MD, PhD, Department of Dermatology, Cutaneous Biology Research Center)


MOCO SUPPLEMENT MAY BE AN EFFECTIVE THERAPY FOR LETHAL GENETIC DISORDER
Protein-bound Molybdenum Cofactor Is Bioavailable and Rescues Molybdenum Cofactor-deficient C. Elegans
Warnhoff K, Hercher TW, Mendel RR, Ruvkun G
Published in Genes & Development on January 14, 2021 | Press Release

Essential biochemical reactions in cells are often catalyzed by enzymes that require cofactors synthesized within our bodies or acquired from our diet, microbiome or multivitamins (i.e., heme, B vitamins, etc.). The molybdenum cofactor (Moco) is an enigmatic cofactor that is synthesized in nearly all organisms and essential for human development. Yet, nothing is known about whether or not Moco is absorbed as a dietary nutrient. We show that Moco bound to protein is bioavailable and remarkably stable. Our work suggests that supplemental protein-bound Moco might be an effective therapy for Moco deficiency—a rare, lethal genetic disorder.

(Summary submitted by Kurt Warnhoff, PhD, Department of Molecular Biology)


SLEEP SPINDLES ARE A BIOMARKER OF COGNITIVE DYSFUNCTION IN EPILEPSY
Focal Sleep Spindle Deficits Reveal Focal Thalamocortical Dysfunction and Predict Cognitive Deficits in Childhood Epilepsy with Centrotemporal Spikes
Kramer MA, Stoyell SM, Chinappen D, Ostrowski LM, Spencer ER [et al.], Chu CJ
Published in Journal of Neuroscience on January 14, 2021

Although cognitive disabilities are a common feature of many childhood epilepsy syndromes, the cause of these symptoms is unknown. In this paper, we demonstrate that sleep spindles, brain rhythms necessary for memory consolidation during sleep, are disrupted and predict cognitive symptoms in a common sleep activated childhood epilepsy syndrome. To do so, we validate a reliable automated approach to find these signals in EEG recordings and show that the spindle disruptions are restricted to the same brain regions impacted by epilepsy. The discovery of disrupted sleep spindles introduces a mechanistic biomarker for cognitive symptoms in this developmental epilepsy and localizes the brain circuit disrupted in this disease and opens new avenues for treatment.

(Summary submitted by Catherine Chu, MD, MA, MMSC, Department of Neurology, MassGeneral Hospital for Children)


TIMELY RESTORATION OF BLOOD FLOW CAN IMPROVE HEALING AFTER DEEP VEIN THROMBOSIS
Time-Restricted Salutary Effects of Blood Flow Restoration on Venous Thrombosis and Vein Wall Injury in Mouse and Human Subjects
Li W, Kessinger CW, Orii M, Lee H, Wang L [et al.], Jaffer FA
Published in Circulation on January 15, 2021

Post-thrombotic syndrome (PTS) is debilitating disorder that occurs in up to 50% of deep vein thrombosis (DVT) patients, despite the use of blood thinners. Catheter-based therapies to restore blood flow have been inconclusive in improving PTS outcomes. However, the impact of the age of DVT and subsequent PTS has not been assessed. In this mouse and human study, we demonstrate that restoring blood flow within a restricted therapeutic window can improve PTS outcomes and reduce vein wall fibrosis, thrombus burden and DVT inflammation. We anticipate these findings will help optimize the use of catheter-based and new approaches to reduce PTS.

(Summary submitted by Wenzhu Li, MD, and Farouc A. Jaffer, MD, PhD, Division of Cardiology, Department of Medicine, Cardiovascular Research Center)


NEW SOFTWARE FACILITATES THE INCLUSION OF ADMIXED INDIVIDUALS IN GENETIC RESEARCH
Tractor Uses Local Ancestry to Enable the Inclusion of Admixed Individuals in GWAS and to Boost Power
Atkinson EG, Maihofer AX, Kanai M, Martin AR, Karczewski KJ [et al.], Neale BM
Published in Nature Genetics on January 18, 2021

Admixed individuals, whose ancestry reflects multiple populations, are routinely excluded from genomic studies due to statistical concerns. Such populations are more than one-third of the U.S. populace, and face disparities in research and treatment due to being underrepresented. In this manuscript, we present a statistical framework and scalable software package, Tractor, that facilitates the inclusion of admixed individuals in large-scale association studies by considering the local ancestry context of genetic variants across the genome. Tractor often boosts GWAS power and identifies ancestry-specific hits missed by standard GWAS.

(Summary submitted by Elizabeth G. Atkinson, PhD, Analytic and Translational Genomics Unit)


OVERLAPPING BRAIN STATE CHANGES IN SCHIZOPHRENIA AND IN AT-RISK YOUTH
Altered Temporal, but Intact Spatial, Features of Transient Network Dynamics in Psychosis
Wang D, Peng X, Pelletier-Baldelli A, Orlov N, Farabaugh A [et al.], Holt DJ
Published in Molecular Psychiatry on January 18, 2021

We used functional magnetic resonance imaging (fMRI) to measure the brain activity of people diagnosed with schizophrenia, those at risk for developing schizophrenia and healthy people. We used a new analysis technique that quantifies the simultaneous activity of networks of brain regions, called “brain states,” over short periods of time. We found that people with schizophrenia had abnormally low levels of three distinct brain states. One of these three brain states was also less active in the at-risk group, compared to the healthy individuals, which correlated with the severity of subclinical psychotic symptoms. These findings suggest that fMRI can be used to detect subtle changes in brain function that could be associated with risk for developing schizophrenia or other serious neuropsychiatric disorders.

(Summary submitted by Daphne Holt, MD, PhD, Department of Psychiatry)


MODEL TO OPTIMIZE COVID-19 RESPONSE AND TREATMENT
In Silico Dynamics of COVID-19 Phenotypes for Optimizing Clinical Management
Voutouri C, Nikmaneshi MR, Hardin CC, Patel AB, Verma A [et al.], Jain RK
Published in Proceedings of the National Academy of Sciences on January 19, 2021 | Press Release

A distinctive feature of COVID-19 is its extreme heterogeneity—illness ranges from minimally symptomatic to life threatening. To better understand clinical heterogeneity and design optimal treatment, we developed a comprehensive mathematical model incorporating elements of the innate and adaptive immune response, the renin-angiotensin system (which the virus exploits for cellular entry), rates of viral replication, inflammatory cytokines and the coagulation cascade for thrombus formation. Our model reveals divergent treatment responses and clinical outcomes as a function of comorbidities, age and details of the innate and adaptive immune response, which can provide a framework for understanding individual patients' trajectories.

(Summary submitted by Lance L. Munn, PhD, Department of Radiation Oncology, Mass General Cancer Center)


DISCOVERING MARKERS FOR SEVERITY OF MITOCHONDRIAL DISEASE
Circulating Markers of Nadh-reductive Stress Correlate with Mitochondrial Disease Severity
Sharma R, Reinstadler B, Engelstad K, Skinner OS, Stackowitz E [et al.], Mootha VK
Published in Journal of Clinical Investigation on January 19, 2021

Mitochondrial diseases are inherited, multisystemic conditions that are challenging to manage partly due to the lack of biomarkers of severity. Application of proteomics and metabolomics to cohorts with MELAS, a common form of mitochondrial DNA disease, led to the discovery and validation of 20 markers. Among these were classic markers (lactate), recently identified analytes (e.g. GDF-15), as well as novel metabolites (e.g. N-lactoyl-amino acids) never previously linked to mitochondrial disease. As many analytes strongly correlated with severity and nearly all are mechanistically linked to NADH-reductive stress, this panel may form the basis of new blood tests to quantify mitochondrial dysfunction.

(Summary submitted by Rohit Sharma, MD, PhD Department of Molecular Biology, Department of Medicine)


PRECISE PET SCANS MAY PREDICT FUTURE ALZHEIMERS DISEASE
The Cortical Origin and Initial Spread of Medial Temporal Tauopathy in Alzheimer's Disease Assessed with Positron Emission Tomography
Sanchez JS, Becker JA, Jacobs HIL, Hanseeuw BJ, Jiang S [et al.], Johnson KA
Published in Science Translational Medicine on January 20, 2021

Although PET has enabled us to image tau pathology in Alzheimer's disease, precisely identifying the early stages of tau accumulation has been challenging due to individual differences in brain anatomy. We developed an automated method to identify the brain region most vulnerable to initial cortical tau deposition on an individual basis and observed the emergence of cortical tau in cognitively normal people. Tau deposits in this small region were highly predictive of subsequent tau spread, suggesting that tau PET measurements focused on precisely individualized specific brain areas may predict an individual's risk of future tau accumulation and consequent Alzheimer's disease.

(Summary submitted by Justin Sanchez, Department of Radiology, Gordon Center for Medical Imaging)


MALIGNANT SYS CELLS EXPRESS NOVEL CELLULAR PROGRAM
Opposing Immune and Genetic Mechanisms Shape Oncogenic Programs in Synovial Sarcoma
Jerby-Arnon L, Neftel C, Shore ME, Weisman HR, Mathewson ND [et al.], Regev A
Published in Nature Medicine on January 25, 2021

Synovial sarcoma (SyS) is a rare but highly aggressive soft tissue malignancy that remains poorly understood. We, along with colleagues at the Broad Institute and Lausanne University Hospital, combined single-cell RNA-sequencing profiling of patient samples, spatial transcriptomics and functional approaches to demonstrate that SyS invariably includes a previously unknown subpopulation of malignant cells that express a novel cellular program, named the “core oncogenic program.” Our findings demonstrate a strong connection between SyS development and immune evasion, and strengthen the notion that de-differentiation, immune evasion and cell cycle are co-regulated, and that cellular immunity can be enhanced through modulation of cell cycle and epigenetic processes.

(Summary submitted by Mario L. Suvà, MD, PhD, Department of Pathology, Mass General Cancer Center)


Press Releases

Study Resolves Long-running Controversy Over Critical Step in Gene Silencing
Featuring Jeannie T. Lee, MD, MPH

A long-running debate over how an important gene-silencing protein identifies its targets has been resolved by researchers at Mass General.


Diet and Lifestyle Guidelines Can Greatly Reduce Gastroesophageal Reflux Disease Symptoms
Featuring Andrew T. Chan, MD, MPH

Findings from the Nurses' Health Study show that five diet and lifestyle factors can make a significant impact on heartburn symptoms.


COVID-19 Unmasked: Math Model Suggests Optimal Treatment Strategies
Featuring Rakesh K. Jain, PhD

Getting control of COVID-19 will take more than widespread vaccination; it will also require better understanding of why the disease causes no apparent symptoms in some people but leads to rapid multi-organ failure and death in others, as well as better insight into what treatments work best and for which patients.


Investigational Drug Pridopidine Enters HEALEY ALS Platform Trial
Featuring Merit Cudkowicz, MD, MSc, and Sabrina Paganoni, MD, PhD

Mass General investigators have now added a fourth promising drug, pridopidine, to the HEALEY ALS Platform trial.


Gene Therapy Strategy Found Effective in Mouse Model of Hereditary Disease TSC
Featuring Xandra O. Breakefield, PhD, and Shilpa Prabhakar, MSc

A team led by investigators at Mass General have shown that gene therapy can effectively treat mice that express one of the mutated genes that cause tuberous sclerosis complex.


Hospitals Have a Moral Obligation to Help Their Own COVID Long-haulers Recover, Experts Argue
Featuring Zeina N. El-Chemali, MD, MPH

Experts call for medical institutions to support and promote the safe return to work for all health care workers disabled from lingering symptoms of COVID.


Study Reveals Previously Unknown Mechanisms in the Kidney That Control Magnesium and Calcium Levels
Featuring Alexander G. Marneros, MD, PhD

A Mass General researcher discovered a previously unknown mechanism in the kidneys that is important for regulating levels of magnesium and calcium in the blood.


Inpatient Mammograms Can Reduce Disparities in Breast Cancer Screening Rates
Featuring Andrew S. Hwang, MD, MPH

A team at Mass General explored the possibility of addressing preventive care needs when patients are admitted to the hospital to attain more equitable health outcomes.


Scientists Uncover New Path Toward Treating a Rare but Deadly Neurologic Condition
Featuring Kurt Warnhoff, PhD

Studies with a popular laboratory model, the nematode Caenorhabditis elegans, have revealed a possible therapeutic avenue for a rare but deadly condition in which children are born without the ability to make molybdenum cofactor (Moco) on their own.


Medical Terms for Opioid Addiction Don't Always Reduce Stigma, Study Finds
Featuring John F. Kelly, PhD, ABPP

Mass General researchers found that there was not one single term that can reduce all potential stigma biases against opioid addiction.


New Study Connects Religiosity in U.S. South Asians to Cardiovascular Disease
Featuring Alexandra Shields, PhD

The Study on Stress, Spirituality and Health (SSSH), a cutting-edge proteomics analysis, suggests that religious beliefs modulate protein expression associated with cardiovascular disease in South Asians in the United States.


Researchers Discover a Promising Approach to Inhibiting a Less Frequent but Highly Treatment-refractory Liver Cancer
Featuring Dan G. Duda, DMD, PhD

Reprogramming the rich connective tissue microenvironment of a liver cancer known as intrahepatic cholangiocarcinoma (ICC) inhibits its progression and resistance to standard chemotherapy in animal models, researchers from Mass General have found.


Does Aspirin Lower Colorectal Cancer Risk in Older Adults? It Depends on When They Start.
Featuring Andrew T. Chan, MD, MPH

There is substantial evidence that a daily aspirin can reduce risk of colorectal cancer in adults up to age 70. But until now there was little evidence about whether older adults should start taking aspirin.


Neuroscientists Identify Individual Neurons Responsible for Complex Social Reasoning in Humans
Featuring Ziv Williams, MD

Mass General researchers revealed the basic cellular mechanism involved in a fundamental cognitive process vital to successful social interactions. Now researchers have a framework to investigate disorders in which social behavior is affected.


Blog Posts

A Mass General Researcher's Perspective: Science Out of Focus
Featuring Lisa Goers, PhD

A postdoctoral research fellow shares her perspective balancing her career as a scientist and her personal life over the last year.


Mass General and MIT Researchers Collaborate to Create the First "Beating" Biorobotic Hybrid Heart
Featuring Christopher Nguyen, PhD

The breakthrough design of the biorobotic heart could help to accelerate the development of new prosthetic valves and cardiac devices for patients with heart disease.


Humans of MGRI: Chih-Chung "Jerry" Lin, PhD

Profile of Chih-Chung "Jerry" Lin, PhD, a postdoctoral researcher in Dr. Rudolph Tanzi's group at the Genetics and Aging Research Unit within the Department of Neurology.


Mass General Research Wrapped for 2020
A round up of all the research at the Mass General Research Institute in 2020.


Zoom Dysmorphia: How Frequent Zoom Calls May Be Changing the Way We See Ourselves
Featuring Shadi Kourosh, MD, MPH

Dermatologists report a surge in patients citing their appearance on Zoom and other remote meeting platforms as the reason for seeking care—with a particular concern for acne and wrinkles.


Promoting Mental Health and Well-Being Throughout the Pandemic

The Women in Science group recently hosted a webinar called “Mental Health from PIs to Mentees” to discuss the importance of mental health and self-care during this challenging time and provide tools and resources to help us get through it.