Snapshot of Science for August 2022

Welcome to our Snapshot of Science for August 2022.

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:

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

Publications

COVID-19 Infections Often Severe in Untreated HIV Patients
Unsuppressed HIV Infection Impairs T Cell Responses to SARS-CoV-2 Infection and Abrogates T Cell Cross-recognition
Nkosi T, Chasara C, Papadopoulos AO, Nguni TL, Karim F [et al.], Ndhlovu ZM
Published in eLife on July 26, 2022

mRNA Vaccines Are Safe and Effective in Children
SARS-CoV-2 mRNA Vaccination Elicits Robust Antibody Responses in Children
Bartsch YC, St Denis KJ, Kaplonek P, Kang J, Lam EC [et al.], Alter G
Published in Science Translational Medicine on July 26, 2022

Neurogenetic Topological Vulnerabilities in Distinctive Brain Circuits of Tau
Network Tau Spreading Is Vulnerable to the Expression Gradients of APOE and Glutamatergic-related Genes
Montal V, Diez I, Kim CM, Orwig W, Bueichekú E [et al.], Sepulcre J
Published in Science Translational Medicine on July 27, 2022

Subclasses of Antibodies Have Different Protections Against HIV Infection
Antibody-mediated Prevention of Vaginal HIV Transmission is Dictated by IgG Subclass in Humanized Mice
Brady JM, Phelps M, MacDonald SW, Lam EC, Nitido A [et al.], Balazs AB
Published in Science Translational Medicine on July 27, 2022 | *Summary available

Deeper Understanding of the Molecular Underpinnings of Pancreatic Cancer
Single-Nucleus and Spatial Transcriptome Profiling of Pancreatic Cancer Identifies Multicellular Dynamics Associated With Neoadjuvant Treatment
Hwang WL, Jagadeesh KA, Guo JA, Hoffman HI, Yadollahpour P [et al.], Regev A
Published in Nature Genetics on July 28, 2022 | *Summary available

RAG-dependent 'Domino Effect' That Impacts Stringency of Tolerance and B Cell Fate
Partial RAG Deficiency in Humans Induces Dysregulated Peripheral Lymphocyte Development and Humoral Tolerance Defect With Accumulation of T-bet + B Cells
Csomos K, Ujhazi B, Blazso P, Herrera JL, Tipton CM [et al.], Walter JE
Published in Nature Immunology on July 28, 2022

Small Molecules Could Inhibit or Enhance Antibody-Epitope Interactions
Epitope Alteration by Small Molecules and Applications in Drug Discovery
Zhu B, Yang J, Van R, Yang F, Yu Y [et al.], Ran C
Published in Chemical Science on July 28, 2022 | *Summary available

Cost-effectiveness of Four Chemotherapy Regimens in Kenya
Evaluation of Four Chemotherapy Regimens for Treatment of Advanced AIDS-associated Kaposi Sarcoma in Kenya: A Cost-effectiveness Analysis
Freeman EE, McCann NC, Semeere A, Reddy KP, Laker-Oketta M [et al.], Hyle EP
Published in Lancet Global Health on August 1, 2022 | *Summary available

Discovery of Process for Early Life Formation
Template-free Assembly of Functional RNAs by Loop-closing Ligation
Wu LF, Liu Z, Roberts SJ, Su M, Szostak JW, Sutherland JD
Published in Journal of the American Chemical Society on August 3, 2022 | *Summary available

Streptococcus Pneumoniae Vaccine With Broader, More Durable, Antibody Response
Polysaccharide and Conjugate Vaccines to Streptococcus Pneumoniae Generate Distinct Humoral Responses
Davies LRL, Cizmeci D, Guo W, Luedemann C, Alexander-Parrish R [et al.], Alter G
Published in Science Translational Medicine on August 3, 2022

The "Social Contagion" Hypothesis of Transgender and Gender Diverse Identities
Sex Assigned at Birth Ratio Among Transgender and Gender Diverse Adolescents in the United States
Turban JL, Dolotina B, King D, Keuroghlian AS
Published in Pediatrics on August 3, 2022 | *Summary available

New Map of Chronic Lymphocytic Leukemia
Molecular Map of Chronic Lymphocytic Leukemia and Its Impact on Outcome
Knisbacher BA, Lin Z, Hahn CK, Nadeu F, Duran-Ferrer M [et al.], Getz G
Published in Nature Genetics on August 4, 2022 | Press Release

Small-Group Virtual Intervention (STRIDE) to Help Manage Breast Cancer Treatment
A Telehealth Intervention for Symptom Management, Distress, and Adherence to Adjuvant Endocrine Therapy: A Randomized Controlled Trial
Jacobs JM, Post K, Massad K, Horick NK, Walsh EA [et al.], Greer JA
Published in Cancer on August 4, 2022 | *Summary available

Resources to Improve Interpretation of CNVs in Human Genetic Research and Diagnostic Screening
A Cross-Disorder Dosage Sensitivity Map of the Human Genome
Collins RL, Glessner JT, Porcu E, Lepamets M, Brandon R [et al.], Talkowski ME
Published in Cell on August 4, 2022 | *Summary available

Circulating Antibodies Determine Immune Response to Reinfection
Antibodies From Primary Humoral Responses Modulate the Recruitment of Naive B Cells During Secondary Responses
Tas JMJ, Koo JH, Lin YC, Xie Z, Steichen JM [et al.], Batista FD
Published in Immunity on August 4, 2022 | *Summary available

Researchers Use Microscopic Worms to Study Embryonic Development
Stereotyped Behavioral Maturation and Rhythmic Quiescence in C.elegans Embryos
Ardiel EL, Lauziere A, Xu S, Harvey BJ, Christensen RP [et al.], Shroff H
Published in Elife on August 5, 2022 | *Summary available

Wrist-worn Devices Cost-effective for Screening of Atrial Fibrillation
Cost-effectiveness of Screening for Atrial Fibrillation Using Wearable Devices
Chen W, Khurshid S, Singer DE, Atlas SJ, Ashburner JM [et al.], Chhatwal J
Published in JAMA Health Forum on August 5, 2022 | Press Release

Importance of Personalizing Approaches to Universal Influenza Vaccines
Allelic Polymorphism Controls Autoreactivity and Vaccine Elicitation of Human Broadly Neutralizing Antibodies Against Influenza Virus
Sangesland M, Torrents de la Peña A, Boyoglu-Barnum S, Ronsard L, Mohamed FAN [et al.], Lingwood D
Published in Immunity on August 6, 2022 | *Summary available

Underlying Mechanisms of Proteins That May Play Distinct and Critical Roles in Neurological Diseases
A Positron Emission Tomography Imaging Probe Selectively Targeting the BD1 Bromodomain and Extra-terminal Domain
Bai P, Yan L, Bagdasarian FA, Wilks MQ, Wey HY, Wang C
Published in Chemical Communications on August 9, 2022

Significant Rise in CV Risk Factors and CV Diseases Anticipated by 2060
Cardiovascular Disease Projections in the United States Based on the 2020 Census Estimates
Mohebi R, Chen C, Ibrahim NE, McCarthy CP, Gaggin HK [et al.], Januzzi JL Jr
Published in Journal of the American College of Cardiology on August 9, 2022 | *Summary available

Genetic Mutations Drive Crohn's Disease
Epigenetic Reader SP140 Loss of Function Drives Crohn's Disease Due to Uncontrolled Macrophage Topoisomerases
Amatullah H, Fraschilla I, Digumarthi S, Huang J, Adiliaghdam F [et al.], Jeffrey KL
Published in Cell on August 10, 2022 | *Summary available

Specific Cognitive Control Signals Implemented by Prefrontal Neurons
Neuronal Congruency Effects in Macaque Prefrontal Cortex
Yao T, Vanduffel W
Published in Nature Communications on August 10, 2022 | *Summary available

Precise Distribution of RB on Human Chromatin
Chromatin-bound RB Targets Promoters, Enhancers, and CTCF-bound Loci and Is Redistributed by Cell-cycle Progression
Sanidas I, Lee H, Rumde PH, Boulay G, Morris R [et al.], Lawrence MS
Published in Molecular Cell on August 12, 2022 | *Summary available

Need for Development of Better Tailored Colonoscopy Screening
Clinical and Genomic Characterization of Interval Colorectal Cancer in Three Prospective Cohorts
Yang K, Cao Y, Gurjao C, Liu Y, Guo CG [et al.], Chan AT
Published in Gastroenterology on August 12, 2022 | *Summary available

BCG Vaccine Protect Patients With Type 1 Diabetes From COVID-19
Multiple BCG Vaccinations for Prevention of COVID-19 and Other Infectious Diseases in Type 1 Diabetes
Faustman DL, Lee A, Hostetter ER, Aristarkhova A, Ng NC [et al.], Kühtreiber WM
Published in Cell Reports Medicine on August 15, 2022 | *Summary available | Press Release

Blood Pressure Medication May Have Role in Treatment for Sepsis
Angiotensin II Enhances Bacterial Clearance via Myeloid Signaling in a Murine Sepsis Model
Leisman DE, Privratsky JR, Lehman JR, Abraham MN, Yaipan OY [et al.], Taylor MD
Published in Proceedings of the National Academy of Sciences (PNAS) on August 15, 2022 | *Summary available

Gout More Prevalent Among Black Americans
Racial and Sex Disparities in Gout Prevalence Among U.S. Adults
McCormick N, Lu N, Yokose C, Joshi AD, Sheehy S [et al.], Choi HK
Published in JAMA Network Open on August 15, 2022 | *Summary available

IpaB as Boostable Target for Protection Against Shigellosis
Systems Approach to Define Humoral Correlates of Immunity to Shigella
Bernshtein B, Ndungo E, Cizmeci D, Xu P, Kováč P, Kelly M [et al.], Alter G
Published in Cell Reports on August 16, 2022 | *Summary available

Massive Study Redefines the Genetic Causes of Autism
Rare Coding Variation Provides Insight Into the Genetic Architecture and Phenotypic Context of Autism
Fu JM, Satterstrom FK, Peng M, Brand H, Collins RL [et al.], Talkowski ME
Published in Nature Genetics on August 18, 2022 | *Summary available

Surgical Procedures Still Below Prepandemic Volume
Institutional Surgical Response and Associated Volume Trends Throughout the COVID-19 Pandemic and Postvaccination Recovery Period
Ghoshal S, Rigney G, Cheng D, Brumit R, Gee MS [et al.], Succi MD
Published in JAMA Network Open on August 18, 2022 | *Summary available

Uncovering Stem Cells and Cells-of-Origins in Pediatric Muscle Cancer
Single-Cell Analysis and Functional Characterization Uncover the Stem Cell Hierarchies and Developmental Origins of Rhabdomyosarcoma
Wei Y, Qin Q, Yan C, Hayes MN, Garcia SP [et al.], Langenau DM
Published in Nature Cancer on August 18, 2022 | *Summary available

Nigeria Not on Track to Reduce Child Mortality by 2030
Infant Mortality and Risk Factors in Nigeria in 2013-2017: A Population-level Study
Shobiye DM, Omotola A, Zhao Y, Zhang J, Ekawati FM, Shobiye HO
Published in eClinicalMedicine - Part of THE LANCET Discovery Science on August 25, 2022 | *Summary available

Selective Manipulation of the Gut Microbiome In Vivo
Inhibition of Microbial Deconjugation of Micellar Bile Acids Protects Against Intestinal Permeability and Liver Injury
Li DK, Chaudhari SN, Lee Y, Sojoodi M, Adhikari AA [et al.], Devlin AS
Published in Science Advances on August 26, 2022 | *Summary available

Publication Summaries

HIV infection or vaccination results in the production of immunoglobulin G (IgG) antibodies composed of four classes, each encoding distinct elements that differentially mediate immune responses against HIV-infected cells. We used humanized mice to study the efficacy of individual IgG subclasses during the prevention of vaginal HIV transmission. We found that IgG2, which lacked innate immune functionality, exhibited substantially reduced protection relative to other subclasses. Highly functional IgG1 yielded substantial protection at low concentrations, suggesting that interventions capable of eliciting modest titers of more functional IgG subclasses may be better at preventing HIV infection.

(Summary submitted by Alejandro Balazs, PhD, Ragon Institute of MGH, MIT, and Harvard)

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer. Current molecular subtypes of the disease do not broadly predict response to therapy or inform clinical management. We performed single-nucleus RNA sequencing of 43 human PDAC tumors that were either untreated or treated with chemotherapy and radiotherapy. In doing so, we discovered a novel "neural-like progenitor" subtype of cancer cells that were markedly enriched after treatment and associated with poor outcomes. In addition, we performed spatial transcriptome profiling of 21 tumor specimens, which revealed that cancer cell, fibroblast, and immune cell subtypes organize into distinct multicellular communities. This high-resolution examination of PDAC deepens our understanding of its molecular underpinnings and provides clues for targeting residual disease that is resistant to current treatment paradigms.

(Summary submitted by William L. Hwang, MD, PhD, Department of Radiation Oncology)

Small molecules and antibodies are normally considered separately in drug discovery, except covalent conjugates. This study discovered that small molecules could inhibit or enhance antibody-epitope interactions, which opens new possibilities in drug discovery and therapeutic modulation of auto-antibodies. Also, this study reported a label-free screening platform based on epitope alteration for drug discovery (SPEED), and successfully identified obatoclax and GNF-5837 as new leads for amyloid-beta protein. SPEED reveals the sensitivity of antibody-epitope interactions to perturbation by small molecules and will have multiple applications in biotechnology and drug discovery.

(Summary submitted by Biyue Zhu, PhD, Department of Radiology)

Advanced Kaposi sarcoma (KS) substantially contributes to mortality in low- and middle-income countries. We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) model to project long-term clinical outcomes, cost-effectiveness, and budget impact of four different chemotherapy regimens for treatment of advanced KS in Kenya. The chemotherapy paclitaxel would be cost-effective and increase life expectancy compared with current standard of care. Liposomal doxorubicin (PLD) would also improve life expectancy but would only be cost-effective with a 44% price reduction. Paclitaxel should become the standard of care for people with HIV in Kenya; advocacy is needed to reduce the price of PLD.

(Summary submitted by Maya Hajny Fernandez, Medical Practice Evaluation Center, Department of Medicine)

The emergence of RNA functions in the onset of life is a central topic in the origins of life studies. Most functional RNAs have stem-loop hairpin structures. In this work, we demonstrated that full-length, functional RNAs can be assembled from their constituent, short fragments by loop-closing ligation without external templates. The loop-closing ligation strategy use the inherent RNA hairpin structures to place the ligation sites, contrasting the conventional templated ligation. In light of this work, a plausible pathway whereby structurally complex functional RNAs could have emerged at an early stage of evolution when protocell genomes might have consisted only of collections of short replicating oligonucleotides.

(Summary submitted by Longfei Wu, PhD, Department of Molecular Biology)

Representatives of some pediatric gender clinics have reported an increase in transgender youth assigned female at birth relative to those assigned male at birth. Such data have been used in some legislative and political arenas to suggest a theory of "social contagion" leading to transgender and gender diverse identities, with the presumption that adolescents assigned female at birth are more susceptible to such social contagion. Using data of nearly 100,000 adolescents from the CDC's Youth Risk Behavior Survey, researchers found that there were more adolescents assigned male at birth relative to adolescents assigned female at birth, arguing against this hypothesis.

(Summary submitted by Jack Turban, MD, MHS, University of California, San Francisco)

Women taking adjuvant endocrine therapy (AET) after breast cancer experience stress from side effects (e.g., pain, hot flashes, mood fluctuations) and emotional distress. These challenges may negatively affect how they take their AET every day. Our team developed a brief, small-group virtual intervention (STRIDE) to help women manage their side effects, cope with mood changes, and take their medication as prescribed. In a randomized controlled trial, STRIDE was well-received and led to improvements in how upset women were due to side effects, how confident they were in managing side effects, and how well they could cope with stress.

(Summary submitted by Jamie M. Jacobs, PhD, Center for Psychiatric Oncology & Behavioral Sciences, Department of Psychiatry)

Large copy number variants (CNVs)—deletions or duplications of more than 100,000 DNA nucleotides—are collectively one of the strongest risk factors for abnormal neurodevelopment. However, interpreting CNVs in clinical genetic practice is challenging due to the lack of standardized resources for predicting the impact of CNVs on individual genes. By harmonizing and jointly analyzing genetic data from nearly one-million individuals, we produced a genome-wide catalog of associations between CNVs and 54 different diseases. We also used a machine learning approach to predict the effects of CNVs on all genes in the human genome, yielding a prediction of 2,987 genes intolerant to loss of one copy (haploinsufficient) and 1,559 genes intolerant to gain of a copy (triplosensitive). These resources will greatly improve interpretation of CNVs in human genetic research and diagnostic screening.

(Summary submitted by Ryan Collins, PhD, Center for Genomic Medicine)

The human immune system contains a record of past exposures, from infection to vaccination: our circulating antibodies. This study took advantage of cutting-edge, preclinical SARS-CoV and HIV mouse models to show that antibodies elicited by an initial immunization could either help or inhibit the development of new antibodies after a later, identical immunization. Strong, specific first-round antibodies competed with B cells, which produce antibodies and limited new antibody generation, while broader and weaker initial antibodies encouraged better second-round responses. Our circulating antibodies may be important determinants of when vaccines are administered and when they require redesign to avoid diminishing returns.

(Summary submitted by Stephanie Weldon, PhD, Ragon Institute of MGH, MIT and Harvard)

Researchers Use Microscopic Worms to Study Embryonic Development
Stereotyped Behavioral Maturation and Rhythmic Quiescence in C.elegans Embryos
Ardiel EL, Lauziere A, Xu S, Harvey BJ, Christensen RP [et al.], Shroff H
Published in Elife on August 5, 2022

What are the first embryonic behaviors and how do they evolve as the brain develops? A new study addresses these questions by documenting every twitch and turn of microscopic worm embryos. By watching embryos engineered to glow green, researchers comprehensively describe embryo behaviors in the final five hours before birth (equivalent to the third trimester of a human pregnancy). Behavioral maturation was highly stereotyped. Just before birth, embryos exhibit a rhythmic pattern of brief rest periods, which are generated by the same circuitry that controls sleep postnatally. Embryonic sleep-like states could play an important role in promoting normal brain development.

(Summary submitted by Evan Ardiel, PhD, Department of Molecular Biology)

We demonstrate that the human antibody gene IGHV1-69 encodes for human B cell receptors that naturally engage a conserved site of vulnerability on influenza virus and that these B cells can be triggered by a candidate "universal" nanoparticle vaccine to elicit broadly neutralizing antibody (bnAb) responses within a humanized mouse model. However, IGHV1-69 comes in two allelic flavors: F54-IGHV1-69 and L54-IGHV1-69; and we show that bnAbs are elicited via the former and not the latter. L54-IGHV1-69 is an ethnically skewed polymorphism, and its deterministic control over influenza bnAb output points to the importance of personalizing approaches to universal influenza vaccines.

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

In this study, using National Health and Nutrition Examination Survey and 2020 U.S. Census estimates, we projected the prevalence of cardiovascular (CV) risk factors (diabetes mellitus, hypertension, dyslipidemia) and CV disease (ischemic heart disease, heart failure, stroke) for the U.S. adult population in the next four decades. By 2060, a significant rise in CV risk factors and CV diseases is anticipated, with a pattern of increase for CV risk factors and CV diseases that excessively affect Asian, Black, and Hispanic populations. We are optimistic that the provided statistics would guide our health policymakers to build better strategies to tackle CV health issues and inequalities and ultimately help our next generations.

(Summary submitted by Reza Mohebi, MD, Cardiovascular Research Center, Department of Medicine)

Mutations within epigenetic reader SP140 associate with Crohn's disease, a type of inflammatory bowel disease, but the relevance of these mutations and mechanisms underlying how SP140 contributes to Crohn's were unknown. We solved the proteome of SP140 and found it normally suppresses topoisomerases, enzymes that unravel DNA for transcription. In Crohn's patients lacking SP140, topoisomerases were uncontrolled rendering macrophages, a type of immune cell, unable to control bacteria in the gut. Topoisomerase inhibitors are approved for use in cancer, and we repurposed them to rescue SP140 loss. The work highlights the power of examining human disease associated genetic mutations to advance mechanistic understanding of disease and uncovers a potentially new therapeutic strategy for Crohn's disease.

(Summary submitted by Kate Jeffrey, PhD, Moderna)

When the word blue is printed in a color, which differs from its semantic meaning (e.g., "blue" printed in red), naming the color requires longer time and results in more errors than when its meaning is congruent with its ink color. The underlying neuronal mechanisms of this interference effect are poorly understood. By recording neuronal responses in prefrontal cortex when monkeys were performing a variant of this "Stroop" task, we found that in difficult (incongruent), compared to easy (congruent) trials, neurons coding for correct and wrong answers became less and more responsive, respectively. Our study suggests how specific cognitive control signals can be easily implemented by prefrontal neurons.

(Summary submitted by Wim J. Vanduffel, PhD, Martinos Center for Biomedical Imaging, Department of Radiology)

The retinoblastoma tumor suppressor (RB) is a key cell cycle regulator that binds to E2F-promoters and inhibits the expression of genes essential for cell proliferation. However, this simple model cannot explain why RB's tumor suppressor activity is cell type- and context-specific. We unraveled the precise distribution of RB on human chromatin, suggesting new aspects of RB's mechanism of action. Rather than exclusively targeting E2F-promoters, RB is recruited by distinct transcription factors to specific groups of promoters, enhancers, and insulators to target different sets of genes. Cell cycle progression redistributes RB from E2F-promoters toward cell type-specific enhancers.

(Summary submitted by Ioannis Sanidas, PhD, Mass General Cancer Center)

Although screening endoscopies are very effective in preventing colorectal cancers (CRCs), CRCs diagnosed despite a recent screening endoscopy (interval CRCs) reflect an unprecedented challenge in CRC detection/prevention. Using three cohorts, we found interval CRCs had significantly increased risk of CRC-specific and overall mortality compared to screen detected CRCs that were not explained by established clinical prognostic factors. Intriguingly, the survival disadvantage of interval cancer did not appear to be explained by differences in the genomic landscape of tumors characterized by whole exome sequencing. The survival disadvantage associated with interval cancers supports the development of better tailored colonoscopy screening/surveillance strategies and more studies to characterize the mechanisms by which interval cancers may exhibit a more aggressive biological profile.

(Summary submitted by Keming Yang, PhD, Clinical and Translational Epidemiology Unit, Department of Medicine)

We published results of a Phase II/III double blinded placebo-controlled trial of the potential of the Bacillus Calmette-Guerin (BCG) vaccine to protect type 1 diabetics against COVID-19 and other infectious diseases. We found that multi-dose BCG vaccines yielded a COVID-19 effectiveness of 92% similar to the effectiveness of the Moderna and Pfizer vaccines in this highly vulnerable population. The BCG-vaccinated group also displayed protective effects against other infectious diseases. We are hoping the results will spur a larger scale study of the effects of the safe and affordable BCG vaccine in type 1 against COVID-19 and future pandemic infections.

(Summary submitted by Denise Faustman, MD, PhD, Diabetes Unit, Department of Medicine)

Sepsis, a dysregulated immune response to infection and the leading cause of death in U.S. hospitals, often causes life-threateningly low blood pressure that requires treatment with norepinephrine. However, norepinephrine is immunosuppressive and may impair bacterial defense. Angiotensin-II, a cardiovascular hormone, is an alternative approved treatment for low blood pressure but whether angiotensin-II impacts immune function in sepsis had not been explored. This study found angiotensin-II acted directly on immune cells to enhance bacterial killing functions, increase bacterial clearance, and modulate systemic inflammatory responses without increasing inflammatory injury. These immune supporting effects suggest angiotensin-II may have a role in sepsis treatment not just to increase blood pressure, but also as an immunomodulator.

(Summary submitted by Daniel Leisman, MD, Department of Medicine)

Gout is a type of inflammatory arthritis characterized by painful joint flares and increased cardiovascular disease. We found gout has become more common among Black adults in the U.S. general population than white adults, with this racial disparity explained entirely by differences in social determinants of health and clinical factors. Interestingly, higher BMI levels and poverty explained much of the racial difference among women but not among men. Chronic kidney disease and diet quality were contributing factors for both genders. Culturally sensitive interventions for addressing these social and clinical factors, at health system and societal levels, could reduce these disparities.

(Summary submitted by Natalie McCormick, PhD, Division of Rheumatology, Allergy and Immunology, Department of Medicine)

Researchers from Mass General Brigham, Ragon Institute and University of Maryland collaborated to study antibody mediated protection against Shigellosis, a disease that kills 50,000 kids under the age of five every year. We deeply analyzed serum samples from a Shigella human challenge study and correlated humoral features with severity of disease. We found that antibodies that are specific to IpaB, a type 3 secretion system protein, are protective against severe shigellosis. However, it's not just binding to IpaB that protects. IpaB specific antibodies bind to Fc receptors and activate neutrophils and monocytes to perform protective phagocytosis. To mimic what happens in endemic areas, where kids are repeatedly exposed to Shigella infection, study participants were rechallenged with Shigella three months after the first challenge. All participants were protected from shigellosis at the second challenge. Importantly, Fc-recpetor binding of IpaB-specific antibodies was induced by the first challenge, remained robustly high until the second challenge, and boosted after the rechallenge. Altogether, our study points to IpaB as a boost-able target for protection against shigellosis.

(Summary submitted by Biana Bernshtein, PhD, Ragon Institute of MGH, MIT and Harvard )

A new study brings together genetic data from more than 150,000 people across multiple international consortia to shed new light on the genetic landscape of autism. This study uncovered 72 genes strongly associated with autism and almost 400 genes linked to related neurodevelopmental conditions. The work reveals the diverse genetic changes that influence the function of genes associated with autism, and surveys their expression patterns to explore when and how these genes exert influence on brain development and contribute to neurodiversity.

(Summary submitted by Michael Talkowski, PhD, Center for Genomic Medicine)

Tracking how surgical procedures fluctuated after the initial shock of COVID-19 and through mass vaccination provides insights for public health, deferred care, and hospital operations. We tracked surgical procedure volume from pre-pandemic to the end of 2021. We found a 72% drop during the pandemic peak, and while we saw a large recovery, by the end of 2021 our institution remained below their pre-pandemic projected volumes, reaching 89% of expected volumes, with some subspecialties such as cancer surgeries achieving only 80% of expected procedures. This is important because delaying specific surgeries can have adverse impacts for patient outcomes. This study informs ours and other institutions of which surgical specialties may need increased attention to achieve full surgical recovery.

(Summary submitted by Marc D. Succi, MD, Department of Radiology)

Uncovering Stem Cells and Cells-of-Origins in Pediatric Muscle Cancer
Single-cell Analysis and Functional Characterization Uncover the Stem Cell Hierarchies and Developmental Origins of Rhabdomyosarcoma
Wei Y, Qin Q, Yan C, Hayes MN, Garcia SP [et al.], Langenau DM
Published in Nature Cancer on August 18, 2022

Rhabdomyosarcoma (RMS) is a common pediatric cancer of muscle and is prone to relapse that is driven by only a small fraction of tumor cells. Here, we identified a wide diversity of functional cell states in RMS and identified a novel cancer stem cell that expresses epithelial-to-mesenchymal markers and shares similarity to a bipotent, muscle mesenchyme progenitor that can make both muscle and osteogenic cells. We also discovered that fusion-positive RMS express a highly specific gene program found in muscle cells transiting from embryonic to fetal development at 7 to 7.75 weeks of age, suggesting an early transformation event in the genesis of this aggressive disease subtype.

(Summary submitted by David M. Langenau, PhD, Department of Pathology)

Over the past two decades, many countries have significantly reduced the rate of infant mortality, globally. Yet, in Africa, Nigeria remains one of the countries with the highest infant mortality rate. Findings from this retrospective study imply that Nigeria is not on track to achieving the SDG target of reducing child mortality by 2030. Sustainable interventions are urgently needed to address the challenges for women of reproductive age, particularly those that are living in the rural areas and Northern regions, having limited/no access to health care/skilled providers, and are delivering their first child.

(Summary submitted by Damilola M. Shobiye, MPH, Department of Obstetrics and Gynecology)

Selective Manipulation of the Gut Microbiome In Vivo
Inhibition of Microbial Deconjugation of Micellar Bile Acids Protects Against Intestinal Permeability and Liver Injury
Li DK, Chaudhari SN, Lee Y, Sojoodi M, Adhikari AA [et al.], Devlin AS
Published in Science Advances on August 26, 2022

There is growing interest in targeting the gut microbiome for the improvement of health. However, there are very few examples of selective manipulation of the microbiome in vivo. Here, we use a selective small molecule tool that specifically targets one class of enzymes in gut bacteria, bile salt hydrolases (BSH). Inhibition of these enzymes increases the abundance of conjugated bile acids metabolites, which benefit the host by protecting gut barrier integrity. BSH inhibition results in successful treatment of an animal model of liver disease. This work has implications for treatment of a range of human diseases, including diabetes and depression.

(Summary submitted by Yongtao Wang, PhD, Division of Surgical Oncology, Department of Surgery)

Press Releases

Molecular Map Reveals Insights into the Genetic Drivers of Chronic Lymphocytic Leukemia
Featuring Gad Getz, PhD

Tool may guide researchers who are striving to improve cancer diagnostic and treatment strategies.

Wrist-worn Devices are Shown by Mass General Researchers to Be Cost-effective for Screening of Atrial Fibrillation
Featuring Jagpreet Chhatwal, PhD

A study simulating a population of 30 million people, aged 65 and older, found that wrist-wearable devices are more cost-effective than traditional electrocardiograms and pulse palpation for atrial fibrillation screening, and that they are associated with a reduction in stroke incidence.

Multiple Shots of the Bacillus Calmette-Guerin (BCG) Vaccine Protect Patients With Type 1 Diabetes from COVID-19
Featuring Denise Faustman, MD, PhD

Researchers at Mass General demonstrated the protective potential of multiple doses of the Bacillus Calmette-Guerin vaccine against COVID-19 and other infectious diseases.

Blog Posts

Mass General Research Awards and Honors: July 2022

The talented and dedicated researchers working at the Mass General Research Institute are pushing the boundaries of science and medicine every day. In this Research Awards and Honors series, we highlight some of the individuals who have recently received awards or honors for their research achievements.

Summer Safety Awareness Campaign: Heat Exposure
Featuring Michael Flaherty, DO

The Summer Safety Awareness Campaign is geared toward sharing science-based strategies to reduce the risk of preventable injuries to children this summer.

Conversations on Mental Health: What A Troubling Rise in Gun Ownership and Depression Rates Means for the Risks of Gun-Related Suicide
Featuring Roy Perlis, MD, MSc

Mass General researchers explore how firearm purchases were impacted by the pandemic, and what it might mean for suicide in the United States.

Campaña de Concientización Sobre la Seguridad Durante el Verano: Exposición al Calor
Featuring Michael Flaherty, DO

La campaña de concientización sobre la seguridad durante el verano del Mass General Research Institute está orientada a compartir estrategias basadas en la ciencia para reducir el riesgo de lesiones prevenibles en los niños este verano.

Summer Safety Awareness Campaign: Mosquito and Tick Prevention
Featuring Michael Flaherty, DO

The Summer Safety Awareness Campaign is geared toward sharing science-based strategies to reduce the risk of preventable injuries to children this summer.

Five Things to Know: Researchers Identify New Ways to Differentiate Between Helpful and Harmful inflammatory Responses
Featuring John Higgins, MD

The study suggests there are common features of recovery that could be applied to a surprisingly large range of diseases.

Summer Research Programs for Students Help to Educate, Mentor and Inspire the Next Generation of Scientists

This summer approximately 1,200 undergraduate and graduate students came to Mass General to participate in summer research training programs.

Humans of MGRI: Leidys Gutiérrez-Martínez, MD, MSc

Leidys Gutierrez, MD, is working on research projects geared towards brain care, aiming to shift the focus of brain care from reactive to preventive.

Introducing the 2022 Mass General Research Institute Image Awards

Check out the new categories and contest rules for the 2021 MGRI Image Awards!

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Snapshot of Science for August 2022