Snapshot of Science is a monthly digest of publication summaries, press releases and blog posts featuring researchers from Massachusetts General Hospital.

Welcome to the June 2018 edition of Snapshot of Science. Here's a quick look at some recent publications, press releases and stories about the Mass General research community.

In this issue we highlight:

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

Publications

*Author-submitted summaries available when indicated

A REFINED DEFINITION OF RNA SPLICING REGIONS
Base-specific Mutational Intolerance Near Splice-sites Clarifies Role of Non-essential Splice Nucleotides
Zhang S, Samocha KE, Rivas MA, Karczewski KJ, Daly E, Schmandt B [et al.], Daly MJ
Published in Genome Research on June 1, 2018


ASSESSING SAFETY AND EFFECTIVENESS OF THERAPY FOR LIVER CANCER
Pembrolizumab in Patients with Advanced Hepatocellular Carcinoma Previously Treated with Sorafenib (KEYNOTE-224): A Non-randomised, Open-label Phase 2 Trial
Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D [et al.], Kudo M
Published in The Lancet Onocology on June 1, 2018


EFFECT OF INCREASED ATTENDING PHYSICIAN SUPERVISION ON RESIDENT INPATIENT TEAM
Effect of Increased Inpatient Attending Physician Supervision on Medical Errors, Patient Safety, and Resident Education
Finn KM, Metlay JP, Chang Y, Nagarur A, Yang S, Landrigan CP, Iyasere C
Published in JAMA Internal Medicine on June 4, 2018 | *Summary available


EXPANDING UNDERSTANDING OF NONCODING RNAS
A Network of Noncoding Regulatory RNAs Acts in the Mammalian Brain
Kleaveland B, Shi CY, Stefano J, Bartel DP
Published in Cell on June 4, 2018 | *Summary available


IMPACT OF ADVANCED CARE PLANNING TOOL ON TREATMENT FOR PATIENTS WITH DEMENTIA
An Advance Care Planning Video Decision Support Tool for Nursing Home Residents With Advanced Dementia: A Cluster Randomized Clinical Trial
Mitchell SL, Shaffer ML, Cohen S, Hanson LC, Habtemariam D, Volandes AE
Published in JAMA Internal Medicine on June 4, 2018 | *Summary available


NEW INSIGHT INTO INTERACTIONS BETWEEN SHIGELLA AND HOST CELLS
Synthetic Bottom-up Approach Reveals the Complex Interplay of Shigella Effectors in Regulation of Epithelial Cell Death
Mou X, Souter S, Du J, Reeves AZ, Lesser CF
Published in PNAS on June 4, 2018 | *Summary available


UNCOVERING HEALTH DISPARITIES IN RECURRENT RISK FOR INTRACEREBRAL HEMORRHAGE
Hypertension and Intracerebral Hemorrhage Recurrence Among White, Black, and Hispanic Individuals
Rodriguez-Torres A, Murphy M, Kourkoulis C, Schwab K, Ayres AM, Moomaw CJ [et al.], Biffi A
Published in Neurology on June 6, 2018 | *Summary available


IDENTIFYING A STRUCTURAL PROTEIN THAT IS ESSENTIAL TO X CHROMOSOME INACTIVATION
SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X
Wang CY, Jégu T, Chu HP, Oh HJ, Lee JT
Published in Cell on June 7, 2018 | *Summary available | See press release


UNDERSTANDING THE BIOLOGICAL PATHWAYS UNDERLYING ATRIAL FIBRILLATION
Multi-ethnic Genome-wide Association Study for Atrial Fibrillation
Roselli C, Chaffin MD, Weng LC, Aeschbacher S, Ahlberg G, Albert CM [et al.], Ellinor PT
Published in Nature Genetics on June 11, 2018 | *Summary available


IDENTIFYING A PROTEIN'S ROLE IN MEDIATING BRAIN'S RESPONSE TO STRESS
Targeting Kruppel-like Factor 9 in Excitatory Neurons Protects against Chronic Stress-Induced Impairments in Dendritic Spines and Fear Responses
Besnard A, Langberg T, Levinson S, Chu D, Vicidomini C, Scobie KN, Dwork AJ [et al.], Sahay A
Published in Cell Reports on June 12, 2018 | *Summary available | See press release


PROVIDING INSIGHTS INTO A RNA-BINDING COMPLEX
The RNA-binding Complex ESCRT-II in Xenopus Laevis Eggs Recognizes Purine-rich Sequences Through its Subunit Vps25
Emerman AB, Blower M
Published in Journal of Biological Chemistry on June 14, 2018 | *Summary available


CELL PLASTICITY AND TISSUE REGENERATION
Modulating Cell Fate as a Therapeutic Strategy
Lin B, Srikanth P, Castle AC, Nigwekar S, Malhotra R, Galloway JL, Sykes DB, Rajagopal J
Published in Cell Stem Cell on June 14, 2018 | *Summary available


AFFECT OF QUANTITY AND QUALITY OF SLEEP ON CARDIOVASCULAR RISK FACTORS IN ADOLESCENTS
Objective Sleep Characteristics and Cardiometabolic Health in Young Adolescents
Cespedes Feliciano EM, Quante M, Rifas-Shiman SL, Redline S, Oken E, Taveras EM
Published in Pediatrics on June 15, 2018 | *Summary available | See press release


ASSESSING HEALTH‐RELATED QUALITY OF LIFE IN CHILDREN WITH PROTON‐TREATED BRAIN TUMORS
Quality of Life in Patients with Proton-treated Pediatric Medulloblastoma: Results of a Prospective Assessment with 5-year Follow-up
Kamran SC, Goldberg SI, Kuhlthau KA, Lawell MP, Weyman EA, Gallotto SL [et al.], Yock TI
Published in Cancer on June 15, 2018 | *Summary available


EXPLORING RELATIONSHIPS BETWEEN PATIENTS WITH CANCER AND PTSD SYPMTOMS
Symptoms of Posttraumatic Stress Disorder Among Hospitalized Patients with Cancer
Nipp RD, El-Jawahri A, D'Arpino SM, Chan A, Fuh CX, Johnson PC [et al.], Greer JA
Published in Cancer on June 15, 2018 | *Summary available


ANALYZING THE MITOCHONDRIAL AND NUCLEAR GENOMES OF BENIGN KIDNEY TUMORS
Early Loss of Mitochondrial Complex I and Rewiring of Glutathione Metabolism in Renal Oncocytoma
Gopal RK, Calvo SE, Shih AR, Chaves FL, McGuone D, Mick E [et al.], Mootha VK
Published in PNAS on June 18, 2018 | *Summary available


A MACHINE-LEARNING MODEL FOR COMPARING FUNCTIONAL GENOMICS NETWORKS
GeNets: A Unified Web Platform for Network-based Genomic Analyses
Li T, Kim A, Rosenbluh J, Horn H, Greenfeld L, An D [et al.], Lage K
Published in Nature Methods on June 18, 2018 | *Summary available


ENHANCING OUR UNDERSTANDING OF HOW BACTERIA CAUSE DISEASE
High-Throughput Screening of Type III Secretion Determinants Reveals a Major Chaperone-Independent Pathway
Ernst NH, Reeves AZ, Ramseyer JE, Lesser CF
Published in mBio on June 19, 2018 | *Summary available


EFFECTS OF POLICE KILLINGS ON MENTAL HEALTH OF BLACK AMERICANS
Police Killings and Their Spillover Effects on the Mental Health of Black Americans: A Population-based, Quasi-experimental Study
Bor J, Venkataramani AS, Williams DR, Tsai AC
Published in The Lancet on June 21, 2018 | *Summary available


FINDING GENETIC LINKS BETWEEN PSYCHIATRIC ILLNESSES
Analysis of Shared Heritability in Common Disorders of the Brain
Anttila V, Bulik-Sullivan B, Finucane HK, Walters RK, Bras J, Duncan L [et al.], Neale BM
Published in Science on June 22, 2018


IDENTIFING GENETIC ROOTS AND TRANSFER OF CHOLERA
Defining Endemic Cholera at Three Levels of Spatiotemporal Resolution Within Bangladesh
Domman D, Chowdhury F, Khan AI, Dorman MJ, Mutreja A, Uddin MI [et al.], Ryan ET, Qadri F, Thomson NR
Published in Nature Genetics on June 25, 2018 | *Summary available| See press release


DEMONSTRATING APPLICATION OF A SENSOR THAT COULD ENABLE THE CHEMICAL REPLICATION OF RNA
A Fluorescent G-quadruplex Sensor for Chemical RNA Copying
Giurgiu C, Wright T, O'Flaherty D, Szostak J
Published in Angewandte Chemie International Edition on June 25, 2018 | *Summary available


ANALYZING GENETIC DIFFERENCES IN NEURODEVELOPMENTAL DISORDERS WITH EPILEPSY
De Novo Variants in Neurodevelopmental Disorders with Epilepsy
Heyne HO, Singh T, Stamberger H, Abou Jamra R, Caglayan H, Craiu D [et al.], Lemke JR
Published in Nature Genetics on June 25, 2018 | *Summary available


UNCOVERING GENE-DRIVEN MECHANISMS FOR PANCREATIC CANCER
Mutant GNAS Drives Pancreatic Tumourigenesis by Inducing PKA-mediated SIK Suppression and Reprogramming Lipid Metabolism
Patra KC, Kato Y, Mizukami Y, Widholz S, Boukhali M, Revenco I [et al.], Bardeesy N
Published in Nature Cell Biology on June 25, 2018 | *Summary available


DETECTING CONTAMINATION LEVEL IN TUMOR CELLS
DeTiN: Overcoming Tumor-in-normal Contamination
Taylor-Weiner A, Stewart C, Giordano T, Miller N, Rosenberg M, Macbeth A [et al.], Getz G
Published in Nature Methods on June 25, 2018


ASSOCIATIONS BETWEEN HIV ANTIVIRAL USE AND DEPRESSION AND SUICIDAL IDEATION AMONG PERSONS LIVING WITH HIV
Depression and Suicidal Ideation Among HIV-Infected Adults Receiving Efavirenz Versus Nevirapine in Uganda: A Prospective Cohort Study
Chang JL, Tsai AC, Musinguzi N, Haberer JE, Boum Y, Muzoora C [et al.], Siedner MJ
Published in Annals of Internal Medicine on June 26, 2018 | *Summary available


ASSOCIATIONS BETWEEN AMYLOID BETA AND AN ALZHEIMER’S-RELATED PROTEIN
A Flow Cytometry-based In Vitro Assay Reveals that Formation of Apolipoprotein E (ApoE)-amyloid Beta Complexes Depends on ApoE Isoform- and Cell Type
Kara E, Marks JD, Roe AD, Commins C, Fan Z, Calvo-Rodriguez M [et al.], Hyman BT
Published in Journal of Biological Chemistry on June 27, 2018


UNDERSTANDING THE EFFECTS OF BUNDLED PAYMENTS ON CARDIOVASCULAR CARE
Factors Associated With Participation in Cardiac Episode Payments Included in Medicare's Bundled Payments for Care Improvement Initiative
Oseran AS, Howard SE, Blumenthal DM
Published in JAMA Cardiology on June 27, 2018


MODELING NEURODEGENERATION AND NEUROINFLAMMATION IN ALZHEIMER’S DISEASE
A 3D Human Triculture System Modeling Neurodegeneration and Neuroinflammation in Alzheimer’s Disease
Park J, Wetzel I, Marriott I, Dréau D, D’Avanzo C, Yeon Kim D, Tanzi RE, Cho H
Published in Nature Neuroscience on June 27, 2018 | *Summary available


Publication Summaries

1. EFFECT OF INCREASED ATTENDING PHYSICIAN SUPERVISION ON RESIDENT INPATIENT TEAM
Effect of Increased Inpatient Attending Physician Supervision on Medical Errors, Patient Safety, and Resident Education
Finn KM, Metlay JP, Chang Y, Nagarur A, Yang S, Landrigan CP, Iyasere C
Published in JAMA Internal Medicine on June 4, 2018

Medical training utilizes the apprenticeship model, where residents work closely with senior physicians to acquire clinical skills to practice independently. The exact balance between adequate supervision and appropriate distance between supervisor and learner is unknown. To investigate this, we studied the impact of increased physician supervision on an inpatient resident medical team. We found no difference in patient safety outcomes between the increased verses usual care supervision models. However, trainees spoke less and felt their ability to make decisions was limited by the extra supervision. These results suggest that trainee supervision is a complex process and more supervision does not always improve patient safety and may hinder independent learning.

(Summary submitted by Kathleen Finn, MD, of the Department of Medicine)


2. EXPANDING UNDERSTANDING OF NONCODING RNAS
A Network of Noncoding Regulatory RNAs Acts in the Mammalian Brain
Kleaveland B, Shi CY, Stefano J, Bartel DP
Published in Cell on June 4, 2018

While RNA may be best known for acting as a template for making protein, most RNA molecules do not actually code for proteins. Some of these noncoding RNAs play important regulatory roles. We identify a unique regulatory network centered on four noncoding RNAs--a long noncoding RNA, a circular RNA, and two microRNAs--acting in the mammalian brain. This discovery expands our understanding of how several noncoding RNAs can interact to regulate each other.

(Summary submitted by Benjamin Kleaveland, MD, PhD, of the Department of Pathology)


3. IMPACT OF ADVANCED CARE PLANNING TOOL ON TREATMENT FOR PATIENTS WITH DEMENTIA
An Advance Care Planning Video Decision Support Tool for Nursing Home Residents With Advanced Dementia: A Cluster Randomized Clinical Trial
Mitchell SL, Shaffer ML, Cohen S, Hanson LC, Habtemariam D, Volandes AE
Published in JAMA Internal Medicine on June 4, 2018

Our team from Massachusetts General Hospital and Hebrew SeniorLife's Institute for Aging Research has discovered that nursing home residents with advanced dementia are more likely to have advance directives indicating that they wish to get feeding tubes after their proxies viewed a 12-minute video on advance care planning. In addition, when proxies stated comfort was the goal of care, residents were more likely to have advance directives aligned with that goal. However, the videos did not have an effect on level of care preferences, decisions around do-not-hospitalize status, or other burdensome treatments.

(Summary submitted by Angelo Volandes, MD, MPH, of the Department of Medicine)


4. NEW INSIGHT INTO INTERACTIONS BETWEEN SHIGELLA AND HOST CELLS
Synthetic Bottom-up Approach Reveals the Complex Interplay of Shigella Effectors in Regulation of Epithelial Cell Death
Mou X, Souter S, Du J, Reeves AZ, Lesser CF
Published in PNAS on June 4, 2018

Many bacterial pathogens use nanomachines to inject molecules into human cells. A key to understanding how these bacteria cause infections is to understand what these molecules do. However, how each one works can be difficult to decipher using traditional methods focused on figuring out what happens in their absence, as they often work in a redundant manner. To address this limitation, our team developed a way to study these molecules on their own by introducing them and a nanomachine into bacteria that do not cause disease. Using this method, we have uncovered new functions for several molecules, thus demonstrating the strength of this new approach.

(Summary submitted by Cammie Lesser, MD, PhD, and Xiangyu Mou, PhD, of the Department of Medicine)


5. UNCOVERING HEALTH DISPARITIES IN RECURRENT RISK FOR INTRACEREBRAL HEMORRHAGE
Hypertension and Intracerebral Hemorrhage Recurrence Among White, Black, and Hispanic Individuals
Rodriguez-Torres A, Murphy M, Kourkoulis C, Schwab K, Ayres AM, Moomaw CJ [et al.], Biffi A
Published in Neurology on June 6, 2018

We studied survivors of intracerebral hemorrhage, the most severe form of stroke. Black and Hispanic participants were found to be at higher risk for a recurrent (i.e. second) intracerebral hemorrhage when compared to white individuals. Because elevated blood pressure greatly increases risk for intracerebral hemorrhage, we also analyzed differences in its measurements across racial/ethnic groups. While black and Hispanic participants had higher blood pressure on average, these differences did not fully account for the disparity in risk for repeat intracerebral hemorrhage. Additional studies are required to identify novel strategies for intracerebral hemorrhage prevention among vulnerable minority populations.

(Summary submitted by Alessandro Biffi, MD, of the Department of Neurology)


6. IDENTIFYING A STRUCTURAL PROTEIN THAT IS ESSENTIAL TO X CHROMOSOME INACTIVATION
SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X
Wang CY, Jégu T, Chu HP, Oh HJ, Lee JT
Published in Cell on June 7, 2018

X-chromosome inactivation turns off gene expression from one of the two X chromosomes in females, which is critical for balancing the dosage of genes on the X chromosome between sexes. We show that a protein named SMCHD1 controls X-inactivation by folding the inactive X chromosome into a structure that prevents gene expression. As mutations of SMCHD1 are associated with several human diseases, our research implicates a role of abnormal chromatin folding in these disorders. Furthermore, the knowledge gained in this study would help develop a strategy to awaken genes on the inactive X chromosome to treat diseases such as Rett syndrome.

(Summary submitted by Chen-Yu Wang, MD, of the Department of Molecular Biology)


7. UNDERSTANDING THE BIOLOGICAL PATHWAYS UNDERLYING ATRIAL FIBRILLATION
Multi-ethnic Genome-wide Association Study for Atrial Fibrillation
Roselli C, Chaffin MD, Weng LC, Aeschbacher S, Ahlberg G, Albert CM [et al.], Ellinor PT
Published in Nature Genetics on June 11, 2018

Our team conducted a massive genomic analysis for atrial fibrillation (AF). Using data from over 50 studies throughout the world, we identified nearly 100 genetic regions associated with AF, including 70 of which were not previously linked to the arrhythmia. The detected genetic regions implicate genes underlying the development, electrophysiology, and contractile function of the heart. These results may facilitate the development of new therapeutic targets for AF.

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


8. IDENTIFYING A PROTEIN'S ROLE IN MEDIATING BRAIN'S RESPONSE TO STRESS
Targeting Kruppel-like Factor 9 in Excitatory Neurons Protects against Chronic Stress-Induced Impairments in Dendritic Spines and Fear Responses
Besnard A, Langberg T, Levinson S, Chu D, Vicidomini C, Scobie KN, Dwork AJ [et al.], Sahay A
Published in Cell Reports on June 12, 2018

We show that chronic stress induces a transient elevation in hippocampal Klf9 expression in mice and that Klf9 expression is upregulated in hippocampus of women with major depressive disorder and following stressful life experiences. Genetic silencing of Klf9 expression prevents chronic stress-induced enlargements of dendritic spines and maladaptive fear responses in male and female mice. Thus, Klf9 functions as a stress responsive transcription factor that mediates circuit and behavioral resilience in a sex-specific manner.

(Summary submitted by Amar Sahay, PhD, of the Department of Psychiatry)


9. PROVIDING INSIGHTS INTO A RNA-BINDING COMPLEX
The RNA-binding Complex ESCRT-II in Xenopus Laevis Eggs Recognizes Purine-rich Sequences Through its Subunit Vps25
Emerman AB, Blower M
Published in Journal of Biological Chemistry on June 14, 2018

During early development, cells receive external signals that bind to the receptors on the exterior of cells in order to promote growth and proliferation. An essential part of this process is the down-regulation and destruction of cellular growth receptors. Defects in destruction of growth receptors are a common feature of cancer cells. Destruction of cellular growth receptors is accomplished through sorting growth receptors into a structure called the lysosome. In our current work we discovered a novel function for a protein complex (ESCRT-II) involved in growth receptor destruction. We found that ESCRT-II also binds to and regulates expression of cellular mRNAs. This work discovers a novel link between control of growth factor receptors and control of gene expression.

(Summary submitted by Michael Blower, PhD, of the Department of Molecular Biology)


10. CELL PLASTICITY AND TISSUE REGENERATION
Modulating Cell Fate as a Therapeutic Strategy
Lin B, Srikanth P, Castle AC, Nigwekar S, Malhotra R, Galloway JL, Sykes DB, Rajagopal J
Published in Cell Stem Cell on June 14, 2018

Cells can convert into other kinds of cells to respond to injury and regenerate in a process known as “plasticity.” Unfortunately, cell plasticity can take an unwanted form in disease and normal cells can convert into harmful cells. For example, blood cells can refuse to mature into functional cells or blood vessels can turn on cartilage or bone programs. A very diverse group of scientists and physicians from nephrologists or orthopedic scientists came together and realized that we may be able to prevent bad plasticity from occurring. Indeed, this concept may form the basis for new drug therapies. The ideas generated were a result of a team effort to rethink our approaches to a variety of diseases across the hospital.

(Summary submitted by Jayaraj Rajagopal, MD, of the Department of Medicine)


11. AFFECT OF QUANTITY AND QUALITY OF SLEEP ON CARDIOVASCULAR RISK FACTORS IN ADOLESCENTS
Objective Sleep Characteristics and Cardiometabolic Health in Young Adolescents
Cespedes Feliciano EM, Quante M, Rifas-Shiman SL, Redline S, Oken E, Taveras EM
Published in Pediatrics on June 15, 2018

Earlier research has linked shorter sleep duration with increased obesity levels in children, but few studies have examined the effects of too little sleep on other risk factors – such as blood pressure, blood lipids and glucose metabolism – or examined associations of sleep quality with these outcomes. Our study found that both the amount of time spent sleeping and the percentage of sleep that is undisturbed in young adolescents have significant effects on aspects of cardiovascular health such as blood pressure, cholesterol levels and abdominal fat deposition. Our findings suggest a lack of good sleep could be setting kids up for serious health issues later in life, and emphasize the importance of establishing healthy sleep patterns.

(Summary submitted by Elsie Taveras, MD, MPH, of the Department of Pediatrics)


12. ASSESSING HEALTH‐RELATED QUALITY OF LIFE IN CHILDREN WITH PROTON‐TREATED BRAIN TUMORS
Quality of Life in Patients with Proton-treated Pediatric Medulloblastoma: Results of a Prospective Assessment with 5-year Follow-up
Kamran SC, Goldberg SI, Kuhlthau KA, Lawell MP, Weyman EA, Gallotto SL [et al.], Yock TI
Published in Cancer on June 15, 2018

Little is known about the long-term health-related quality of life (HRQOL) for children receiving proton radiation therapy for pediatric medulloblastoma, a type of brain tumor. We measured HRQOL of our patients in the years after they finished treatment using Pediatric Quality of Life Inventory surveys completed both by the patient and a parent. We found that HRQOL appears to increase over time following the end of treatment; however, their HRQOL remains lower compared with a sample of healthy children. We hope our findings will lead to more specialized research in long-term HRQOL of pediatric brain tumor survivors, and will ultimately help us learn how to improve HRQOL in this patient population.

(Summary submitted by Torunn Yock, MD, and Rachel Strauss, EdM, both of the Department of Radiation Oncology)


13. EXPLORING RELATIONSHIPS BETWEEN PATIENTS WITH CANCER AND PTSD SYPMTOMS
Symptoms of Posttraumatic Stress Disorder Among Hospitalized Patients with Cancer
Nipp RD, El-Jawahri A, D'Arpino SM, Chan A, Fuh CX, Johnson PC [et al.], Greer JA
Published in Cancer on June 15, 2018

Patients with cancer experience many stressors related to their diagnosis, which puts them at risk for symptoms of post-traumatic stress disorder (PTSD). However, little is known about factors associated with PTSD symptoms among patients with cancer. We sought to explore relationships among patients’ PTSD symptoms, physical and psychological symptom burden, and risk for hospital readmissions. We demonstrated that a substantial proportion of patients experience PTSD symptoms and identified characteristics associated with greater likelihood of experiencing these symptoms. Importantly, we also found that patients’ PTSD symptoms were significantly associated not only with their physical and psychological symptom burden but also with their healthcare utilization. Collectively, these findings provide important new evidence regarding the rates and correlates of PTSD symptoms, while also highlighting associations between these symptoms and other important patient outcomes.

(Summary submitted by Ryan Nipp, MD, MPH, of the Department of Hematology/Oncology)


14. ANALYZING THE MITOCHONDRIAL AND NUCLEAR GENOMES OF BENIGN KIDNEY TUMORS
Early Loss of Mitochondrial Complex I and Rewiring of Glutathione Metabolism in Renal Oncocytoma
Gopal RK, Calvo SE, Shih AR, Chaves FL, McGuone D, Mick E [et al.], Mootha VK
Published in PNAS on June 18, 2018

Renal oncocytomas are benign kidney tumors with a remarkable accumulation of mitochondria. Mitochondria play key roles in cell metabolism and are considered the energy powerhouses of the cell. An intriguing possibility is that the mitochondrial abundance contributes to the growth of renal oncocytomas. Although most cancers are connected to mutations in nuclear DNA, we found a high prevalence of mutations in the mitochondrial DNA of these tumors. This change in the mitochondrial DNA was accompanied by a marked increase in glutathione, an important antioxidant molecule. We believe the mitochondrial DNA mutations and glutathione accumulation are signature genetic and metabolic events helping renal oncocytoma tumors to grow.

(Summary submitted by Vamsi Mootha, MD, of the Department of Molecular Biology)


15. A MACHINE-LEARNING MODEL FOR COMPARING FUNCTIONAL GENOMICS NETWORKS
GeNets: A Unified Web Platform for Network-based Genomic Analyses
Li T, Kim A, Rosenbluh J, Horn H, Greenfeld L, An D [et al.], Lage K
Published in Nature Methods on June 18, 2018

Recent technological advances have made it possible to generate an unprecedented amount of tissue- and cell-type-specific functional genomics data. These data can be conveniently represented as gene networks, in which genes are connected if they interact or are functionally correlated. Network representations of complicated datasets can be combined with genetic analysis to identify molecular processes that are implicated in diseases and serve as the starting point for drug-target exploration. In this work, we have developed a new web platform where researchers can upload their datasets and make analyses of, for example cell-type-specific datasets relevant to autism spectrum disorders. Users can also visualize, interact with, and share their data using a custom graphical user interface.

(Summary submitted by Kasper Lage, PhD, of the Department of Surgery)


16. ENHANCING OUR UNDERSTANDING OF HOW BACTERIA CAUSE DISEASE
High-Throughput Screening of Type III Secretion Determinants Reveals a Major Chaperone-Independent Pathway
Ernst NH, Reeves AZ, Ramseyer JE, Lesser CF
Published in mBio on June 19, 2018

Numerous bacterial pathogens have syringe-like nanomachines that they use to directly inject virulence molecules into human cells. These molecules are essential for the development of an infection. For many years, it has been thought that all these molecules are delivered to the nanomachines via interactions with helper molecules. However, in contrast to this dogma, we have found a common alternative delivery pathway that functions independently of all known helper molecules. This discovery not only promotes our understanding regarding how bacteria cause disease, but also reveals a potential new target for the development of new treatment strategies for these potentially deadly pathogens.

(Summary submitted by Cammie Lesser, MD, PhD, and Nadja Heinz Ernst, of the Department of Medicine)


17. EFFECTS OF POLICE KILLINGS ON MENTAL HEALTH OF BLACK AMERICANS
Police Killings and Their Spillover Effects on the Mental Health of Black Americans: A Population-based, Quasi-experimental Study
Bor J, Venkataramani AS, Williams DR, Tsai AC
Published in The Lancet on June 21, 2018

This research study found that when the police kill an unarmed black American, there is significant collateral mental health fallout among black Americans in the general population who are not directly affected by the killings (i.e., friends/family). Only police killings of unarmed blacks (not armed, not white) resulted in mental health impacts, and only among blacks (not whites) -- suggesting that the social meaning of these killings explained the findings. At the population level, these killings result in more than 50 million additional days of poor mental health per year among black Americans, comparable to the population mental health burden due to diabetes.

(Summary submitted by Alexander Tsai, MD, PhD, of the Department of Psychiatry)


18. IDENTIFING GENETIC ROOTS AND TRANSFER OF CHOLERA
Defining Endemic Cholera at Three Levels of Spatiotemporal Resolution Within Bangladesh
Domman D, Chowdhury F, Khan AI, Dorman MJ, Mutreja A, Uddin MI [et al.], Ryan ET, Qadri F, Thomson NR
Published in Nature Genetics on June 25, 2018

Recent data show that new cholera epidemics like those in Haiti, Africa, and Yemen are imported from cholera’s ancestral home in South Asia. This means we need to understand cholera in South Asia to control cholera globally. In this study, we analyzed the organism that causes cholera in its ancestral home in Bangladesh. We found that multiple strains of cholera can circulate simultaneously, even within a single individual. This can lead to genetic transfers and formation of new strains. We also found that all currently circulating strains in Bangladesh descended from a common ancestor dating to massive regional floods in the 1980s, suggesting that a given strain can massively explode when optimal conditions come into existence, giving rise to new and evolving sub-strains in South Asia, and facilitating spin outs of new epidemics into other at-risk communities such as in Haiti or Yemen.

(Summary submitted by Edward Ryan, MD, of the Department of Medicine)


19. DEMONSTRATING APPLICATION OF A SENSOR THAT COULD ENABLE THE CHEMICAL REPLICATION OF RNA
A Fluorescent G-quadruplex Sensor for Chemical RNA Copying
Giurgiu C, Wright T, O'Flaherty D, Szostak J
Published in Angewandte Chemie International Edition on June 25, 2018

Explaining how life began is one of science’s greatest challenges. One theory is that life started with RNA strands that encoded genetic information within simple cells. If this theory is correct, RNA must have somehow been copied initially to make evolution possible. In this paper, we describe our new method for analyzing RNA copying reactions using a fluorescent reporter that is only generated when the RNA strand is successfully extended. This method is faster and easier to perform than previous methods, meaning we can now rapidly explore variables that may affect the copying process. We hope the simplicity of our method will encourage more scientists to explore the RNA copying chemistry that could have led to early life.

(Summary submitted by Thomas Wright, PhD, of the Department of Molecular Biology)


20. ANALYZING GENETIC DIFFERENCES IN NEURODEVELOPMENTAL DISORDERS WITH EPILEPSY
De Novo Variants in Neurodevelopmental Disorders with Epilepsy
Heyne HO, Singh T, Stamberger H, Abou Jamra R, Caglayan H, Craiu D [et al.], Lemke JR
Published in Nature Genetics on June 25, 2018

Epilepsy is a frequent feature of neurodevelopmental disorders such as autism spectrum disorder, but it’s not clear what genetic differences separate the cases that occur with epilepsy from those that do not. A team led by Henrike Heyne and Johannes Lemke (University of Leipzig) sought to answer this question by profiling 6,753 patients with different neurodevelopmental disorders, including nearly 2,000 individuals also diagnosed with epilepsy. We identified new disease genes, genetic differences between cases with and without epilepsy and showed how their results impact routine diagnostics as well as therapy.

(Summary submitted by Henrike Heyne, PhD, of the Department of Medicine)


21. UNCOVERING GENE-DRIVEN MECHANISMS FOR PANCREATIC CANCER
Mutant GNAS Drives Pancreatic Tumourigenesis by Inducing PKA-mediated SIK Suppression and Reprogramming Lipid Metabolism
Patra KC, Kato Y, Mizukami Y, Widholz S, Boukhali M, Revenco I [et al.], Bardeesy N
Published in Nature Cell Biology on June 25, 2018

Pancreatic ductal adenocarcinoma (PDA) is an aggressive tumor type that arises from different precancerous lesions. These include pancreatic cysts, which commonly exhibit mutations in the GNAS gene. We found that GNAS mutations cause tumor growth through a biochemical ‘cascade’ involving stimulation of the PKA protein, which in turn inactivates the related SIK1, 2 and 3 proteins, changing the way cells use various nutrients. This work highlights the biochemical underpinnings of distinct PDA subtypes and suggest the potential of more specific therapeutic approaches.

(Summary submitted by Nabeel El-Bardeesy, PhD, of the Department of Medicine)


22. ASSOCIATIONS BETWEEN HIV ANTIVIRAL USE AND DEPRESSION AND SUICIDAL IDEATION AMONG PERSONS LIVING WITH HIV
Depression and Suicidal Ideation Among HIV-Infected Adults Receiving Efavirenz Versus Nevirapine in Uganda: A Prospective Cohort Study
Chang JL, Tsai AC, Musinguzi N, Haberer JE, Boum Y, Muzoora C [et al.], Siedner MJ
Published in Annals of Internal Medicine on June 26, 2018

We found that efavirenz, the key component of the most commonly used HIV cocktail in the world, was not associated with increased risk for depression or suicide in patients living with HIV in Uganda. These findings conflict with previous reports from the United States and Europe linking efavirenz with adverse psychiatric side effects. These results contribute guidance around the safety of efavirenz in sub-Saharan Africa. Although additional data are needed comparing efavirenz to newer regimens, these preliminary data on the safety of efavirenz offer some degree of reassurance for its continued use among people receiving treatment for HIV in sub-Saharan Africa.

(Summary submitted by Jonathan Chang, MPH, of the Department of Medicine)


23. MODELING NEURODEGENERATION AND NEUROINFLAMMATION IN ALZHEIMER’S DISEASE
A 3D Human Triculture System Modeling Neurodegeneration and Neuroinflammation in Alzheimer’s Disease
Park J, Wetzel I, Marriott I, Dréau D, D’Avanzo C, Yeon Kim D, Tanzi RE, Cho H
Published in Nature Neuroscience on June 27, 2018

Accumulation of pathogenic beta-amyloid (amyloid plaques), hyperphosphorylated tau (neurofibrillary tangle) and inflammation (gliosis) are three major pathological hallmarks of Alzheimer’s disease (AD). In this study, we created a three-dimensional human neuron-astrocyte-microglia triculture model of AD using a microfluidic platform that enables microglial activation/recruitment (neuroinflammation) and cellular death (neurodegeneration) as well as robust accumulation of beta-amyloid and tau pathology. Our model will serve to facilitate the development of more precise human brain models for basic mechanistic studies in neural-glial interactions and drug discovery.

(Summary submitted by Doo Yeon Kim, PhD, of the Department of Neurology)

Press Releases

Maternal Fatty Acid Balance Affects Offspring Obesity Thorough Gut Microbial Population
Featuring Jing X. Kang, MD, PhD

A Massachusetts General Hospital study finds the balance between omega-6 and omega-3 fatty acids in the tissues of female mammals, which previous research has suggested can impact the incidence of obesity in their offspring, may do so through its effect on the microbial population of the infant’s gastrointestinal tract.


Structural Protein Found Essential to X Chromosome Inactivation
Featuring Chen-Yu Wang, MD, and Jeannie T. Lee, MD, PhD

A Massachusetts General Hospital research team has identified the essential role of a structural protein in the silencing of the inactive X chromosome, a process that prevents both copies of the same gene from being expressed in female mammals, which carry two copies of the X chromosome.


Study Identifies Protein's Role in Mediating Brain's Response to Stress
Featuring Amar Sahay, PhD

A study led by Massachusetts General Hospital investigators has identified a critical role for a protein called Kruppel-like factor 9 in the brain’s response to stress, which has implications for protecting against the effects of stress in conditions like major depression and post-traumatic stress disorder.


Mindfulness Meditation and Relaxation Response Have Different Effects on Brain Function
Featuring Sara Lazar, PhD, and Gunes Sevinc, PhD

A team led by Massachusetts General Hospital investigators has identified specific effects that relaxation response training and mindfulness meditation have within the brain.


Both Quantity and Quality of Sleep Affect Cardiovascular Risk Factors in Adolescents
Featuring Elsie Taveras, MD, MPH

A study from a research team led by a MassGeneral Hospital for Children physician finds that both the quantity and quality of sleep – the amount of time spent sleeping and the percentage of sleep that is undisturbed – in young adolescents have significant effects on cardiovascular health.


BCG Vaccine Leads to Long-term Improvement in Blood Sugar Levels in Type 1 Diabetes Patients
Featuring Denise Faustman, MD, PhD

Long-term follow-up of participants in Massachusetts General Hospital clinical trials of a generic vaccine to reverse advanced type 1 diabetes finds significant clinical benefits, including restoration of near-normal blood sugar levels.


Mass General Co-led Study Identifies the Genetic Roots and Transfer of Cholera in South Asia
Featuring Edward T. Ryan, MD

Study finds multiple strains of cholera exist simultaneously in Dhaka and frequently, one individual may have several at a given time which may lead to genetic transfers and the formation of new strains.


Patients Believed to be Allergic to Penicillin Have Significantly Increased Risks of MRSA and C. Difficile
Featuring Kimberly Blumenthal, MD, MSc

Analysis by Massachusetts General Hospital investigators of a large group of outpatient reveals that patients believed to be allergic to penicillin have significantly increased risks of contracting the dangerous infections MRSA and C. difficile.


Blog Posts

Celebrating Mass General’s Remarkable Research Staff
Featuring Harry Orf, PhD, Sue Slaugenhaupt, PhD, and Maurizio Fava, MD

Research Staff Appreciation Day lunch in May celebrated the 2,000+ research staff members who contribute so much to the Massachusetts General Hospital research community.


A Snapshot of Science
Featuring Aarno Palotie, PhD, MD, Padhraig James Gormley, PhD, Alicia Martin, PhD, Anne Marie McCarthy, PhD, Ziv Williams, MD, and Jack Szostak, PhD

What's new in research at Massachusetts General Hospital? From dissecting the RNA copying process to developing a better understanding of human language, here’s a snapshot of studies recently published in top-tier scientific journals.


Looking for Insights to A Rare Genetic Neurologic Disease
Featuring Amanda Furness, PhD

Amanda Furness, a postdoc in the Center for Genomic Medicine at Massachusetts General Hospital, is studying Mucolipidosis IV (MLIV), a rare genetic neurologic disease that affects children. Her team's ultimate goal is to discover several treatments which could be given to MLIV patients to attack the disease from different angles and recover cell function.


New Tool for Predicting C. Difficile Infections Shows Promising Results
Featuring Erica Shenoy, MD, PhD

A research team from Massachusetts General Hospital and University of Michigan has developed a new method for predicting a patient's risk of contracting C. difficile, a bacterium that can cause symptoms ranging from diarrhea to life-threatening inflammation of the colon. Their tool could help limit the severity and spread of outbreaks in healthcare settings.


Learning Not to Fear: Mindfulness-Based Stress Reduction Improves Fear Extinction
Featuring Gunes Sevinc, PhD

Recent research from Gunes Sevinc, a postdoc in the Department of Psychiatry at Massachusetts General Hospital, has found a mechanism in the brain that helps to explain how mindfulness meditation can regulate emotions and lessen stress.


Awards and Honors: June 2018
Featuring Ouri Cohen, PhD, Adam Feldman, MD, MPH, Farrah J. Mateen, MD, PhD, Marc Succi, MD, and Ingrid Bassett, MD, MPH

Congratulations to the Mass General researchers who recently received awards and honors.


On the Hunt for New Strategies to Defeat a Killer Fungus
Featuring Michael Mansour, MD, PhD

Michael Mansour, MD, PhD, an infectious diseases specialist at Mass General, discusses the mysterious rise of a new strain of fungus that is resistant to all known antifungal medications and how he is helping to lead the hospital's response.


Investigating the Relationship Between MRSA and the Lymphatic System
Featuring Dennis Jones, PhD

Fourteen million people develop bacterial infections in their skin and soft tissues each year, and many are due to a difficult to treat condition known as MRSA. Dennis Jones, a postdoctoral fellow in the Edwin L. Steele Labs at Massachusetts General Hospital, is studying how MRSA impacts the lymphatic system, a network of tissues and organs that help rid the body of toxins, waste and other unwanted materials.


Nursing Research Day Celebrates Advances in Clinical Research and Care
Featuring Susan O’Donnell, MSN, RN, OCN, BMTCN, Colleen McGauley, RN, BSN, and Debra M. Lundquist PhD(c), MSN, RN

Every year, Nursing Research Day – hosted by the Yvonne L. Munn Center for Nursing Research at Massachusetts General Hospital - provides an opportunity to showcase and celebrate the inspiring and impactful research being conducted by Mass General nurses. Learn more about this year's event and award-winning research.


Lab Day Provides Exclusive Look Behind the Scientific Curtain
Featuring Jay Rajagopal, MD, Caroline Burns, PhD, Mark Poznansky, MD, PhD, Lawrence Wald, PhD, David Fisher, MD, PhD, and Gary Tearney, MD, PhD

When you love music, you go to a concert. When you love art, you go to a gallery. But when you love science you can’t just go to a laboratory — or can you? Read about six scientists from Massachusetts General Hospital who recently opened their laboratory doors for a special tour.


Mass General Researchers Share Their Science On-screen
Featuring Harald C. Ott, MD, Joel Salinas, MD, MS, MBA, Edmarie Guzman-Velez, PhD, and Bernard Hanseeuw, PhD, MD

From the Wall Street Journal to local TedTalks, Massachusetts General Hospital researchers are finding new outlets for sharing their science with the public. Check out just a few recent videos highlighting investigators from Mass General.


Science Experiments for Kids
Featuring Nitya Jain, PhD

Check out these children's books about science and some experiments that kids can do after reading the books.