Snapshot of Science for December 2023

Welcome to our Snapshot of Science for December 2023.

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: 

36 new studies published in high-impact journals, along with 30 summaries submitted by the research teams
7 new research-related press releases
3 research spotlights
6 posts from the Mass General Research Institute blog

Publications

Insight into Causes of Heart Failure with Preserved Ejection Fraction
Eicosanoid and Eicosanoid-related Inflammatory Mediators and Exercise Intolerance in Heart Failure with Preserved Ejection Fraction
Lau ES, Roshandelpoor A, Zarbafian S, Wang D, Guseh JS [et al.], Ho JE
Published in Nature Communications on 11/20/2023 | *Summary available

Rapid Diagnostic Screener for PTSD after Traumatic Childbirth Experience
Establishing the Validity of a Diagnostic Questionnaire for Childbirth-related Posttraumatic Stress Disorder
Arora IH, Woscoboinik GG, Mokhtar S, Quagliarini B, Bartal A [et al.], Dekel S
Published in American Journal of Obstetrics and Gynecology on 11/21/2023 | *Summary available

Increasing Utilization of Recommended Screening Strategies Could Reduce the Burden of Cancer in the US
Estimated US Cancer Deaths Prevented With Increased Use of Lung, Colorectal, Breast, and Cervical Cancer Screening
Knudsen AB, Trentham-Dietz A, Kim JJ, Mandelblatt JS, Meza R [et al.], Feuer EJ
Published in JAMA Network Open on 11/22/2023

New, Efficient Method to Detect DNA Sample Contamination
CHARR Efficiently Estimates Contamination from DNA Sequencing Data
Lu W, Gauthier LD, Poterba T, Giacopuzzi E, Goodrich JK [et al.], Karczewski KJ
Published in American Journal of Human Genetics on 11/23/2023 | *Summary available

STMN2 a Potential Target for ALS Therapy Development
Stathmin-2 Loss Leads to Neurofilament-dependent Axonal Collapse Driving Motor and Sensory Denervation
López-Erauskin J, Bravo-Hernandez M, Presa M, Baughn MW, Melamed Z [et al.], Lagier-Tourenne C
Published in Nature Neuroscience on 11/23/2023 | *Summary available

Mental Illness and Suicidal Ideation Widespread among the US Academic Surgeons
Unspoken Truths: Mental Health Among Academic Surgeons
Collins RA, Herman T, Snyder RA, Haines KL, Stey A [et al.], Cunningham C
Published in Annals of Surgery on 11/23/2023 | *Summary available

Simple Modification of Mitochondria Improves Success of Therapeutic Mitochondrial Transplantation
O-GlcNAcylation is Essential for Therapeutic Mitochondrial Transplantation
Park JH, Tanaka M, Nakano T, Licastro E, Nakamura Y, Li W, Esposito E, Mandeville ET, Chou SH, Ning M, Lo EH, Hayakawa K
Published in Communications Medicine on 11/25/2023 | *Summary available

Prioritizing Equity-centered Goals Critical to Reduce Inequities in Life Expectancy among Black and White MSM with HIV
Projected Life Expectancy Gains From Improvements in HIV Care in Black and White Men Who Have Sex With Men
Rich KM, Pandya A, Chiosi JJ, Reddy KP, Shebl FM [et al.], Hyle EP
Published in JAMA Network Open on 11/28/2023 | *Summary available | Research Spotlight

Potential Low Cost COVID Booster
Beta-spike-containing Boosters Induce Robust and Functional Antibody Responses to SARS-CoV-2 in Macaques Primed with Distinct Vaccines
Deng Y, Atyeo C, Yuan D, Chicz TM, Tibbitts T [et al.], McNamara RP
Published in Cell Reports on 11/28/2023 | *Summary available

Pediatric Care Management May Provide High-quality Care Coordination
Cost, Utilization, and Patient and Family Experience With ACO-Based Pediatric Care Management
Schiavoni KH, Flom M, Blumenthal KJ, Orav EJ, Hefferon M [et al.], Vogeli C
Published in Pediatrics on 11/28/2023 | *Summary available

Protective Role for SARS-CoV-2–specific T Cells
T Cell Responses to SARS-CoV-2 Infection and Vaccination are Elevated in B cell Deficiency and Reduce Risk of Severe COVID-19
Zonozi R, Walters LC, Shulkin A, Naranbhai V, Nithagon P [et al.], Gaiha GD
Published in Science Translational Medicine on 11/29/2023

Accuracy of Identifying Sparse Causal Variants Improved When Additional Infinitesimal Genetic Effects Included
Improving Fine-mapping by Modeling Infinitesimal Effects
Cui R, Elzur RA, Kanai M, Ulirsch JC, Weissbrod O [et al.], Finucane HK
Published in Nature Genetics on 11/30/2023 | *Summary available

New Potential Alzheimer's Treatment Uses Light to Activate Brain Cells
Sleep Restoration by Optogenetic Targeting of GABAergic Neurons Reprograms Microglia and Ameliorates Pathological Phenotypes in an Alzheimer's Disease Model
Zhao Q, Maci M, Miller MR, Zhou H, Zhang F [et al.], Kastanenka KV
Published in Molecular Neurodegeneration on 12/1/2023 | *Summary available

Brain Care Score Can Assess Current Health Habits and Risk to Future Brain Health
The Predictive Validity of a Brain Care Score for Dementia and Stroke: Data from the UK Biobank Cohort
Singh SD, Oreskovic T, Carr S, Papier K, Conroy M [et al.], Rosand, J
Published in Frontiers in Neurology on 12/1/2023 | *Summary available | Press Release

Call for Changes in Genetic Test Reporting Practices
The Landscape of Reported VUS in Multi-gene Panel and Genomic Testing: Time for a Change
Rehm HL, Alaimo JT, Aradhya S, Bayrak-Toydemir P [et al.], Zouk H; Medical Genome Initiative Steering Committee
Published in Genetics in Medicine on 12/1/2023 | *Summary available

Emerging Role of Innate Immune Pathways in Natural, Drug-free Control of HIV-1
IL-15-dependent Immune Crosstalk between Natural Killer Cells and Dendritic Cells in HIV-1 Elite Controllers
Hartana CA, Lancien M, Gao C, Rassadkina Y, Lichterfeld M, Yu XG
Published in Cell Reports on 12/2/2023

Genetics Study Sheds Light on Coronary Calcification
Whole-genome Sequencing Uncovers Two Loci for Coronary Artery Calcification and Identifies ARSE as a Regulator of Vascular Calcification
de Vries PS, Conomos MP, Singh K, Nicholson CJ, Jain D [et al.], Malhotra R
Published in Nature Cardiovascular Research on 12/4/2023 | *Summary available

Single Dose HPV Vaccination Significantly Reduces Risk of Cervical Cancer
Durability of Single-dose HPV Vaccination in Young Kenyan Women: Randomized Controlled Trial 3-year Results
Barnabas RV, Brown ER, Onono MA, Bukusi EA [et al.], Mugo NR; KEN SHE Study Team
Published in Nature Medicine on 12/4/2023 | *Summary available

New Method for 3D Brain Imaging
In Vivo Three-dimensional Brain Imaging with Chemiluminescence Probes in Alzheimer's Disease Models
Zhang J, Wickizer C, Ding W, Van R, Yang L [et al.], Ran C
Published in PNAS on 12/4/2023 | *Summary available

Large-scale DNA Sequence Resource Reveals New Regions of the Human Genome under Natural Selection
A Genomic Mutational Constraint Map Using Variation in 76,156 Human Genomes
Chen S, Francioli LC, Goodrich JK, Collins RL, Kanai M [et al.], Karczewski KJ
Published in Nature on 12/6/2023 | *Summary available |  Press Release

Approach to Study Rare Gene Variant Pairs that Contribute to Disease
Inferring Compound Heterozygosity from Large-scale Exome Sequencing Data
Guo MH, Francioli LC, Stenton SL, Goodrich JK, Watts NA [et al.], Samocha KE
Published in Nature Genetics on 12/6/2023 | *Summary available | Press Release

Promising Gene-Editing Strategy for Spinal Muscular Atrophy
Optimization of Base Editors for the Functional Correction of SMN2 as a Treatment for Spinal Muscular Atrophy
Alves CRR, Ha LL, Yaworski R, Sutton ER, Lazzarotto CR [et al.], Kleinstiver BP
Published in Nature Biomedical Engineering on 12/6/2023 | *Summary available |  Press Release

Smoking May Lead to Increased Susceptibility to TB
Tobacco Smoke Exposure Recruits Inflammatory Airspace Monocytes That Establish Permissive Lung Niches for Mycobacterium Tuberculosi
Corleis B, Tzouanas CN, Wadsworth MH 2nd, Cho JL, Linder AH [et al.], Kwon DS
Published in Science Translational Medicine on 12/6/2023 | *Summary available

Immune Dictionary, A Compendium of Single-cell Transcriptomic Profiles
Dictionary of Immune Responses to Cytokines at Single-cell Resolution
Cui A, Huang T, Li S, Ma A, Pérez JL [et al.], Hacohen N
Published in Nature on 12/6/2023

New Tool to Screen for Childbirth Related PTSD
Screening for Post-traumatic Stress Disorder Following Childbirth Using the Peritraumatic Distress Inventory
Jagodnik KM, Ein-Dor T, Chan SJ, Ashkenazy AT, Bartal A, Barry RL, Dekel S
Published in Journal of Affective Disorders on 12/7/2023 | *Summary available

Increased Intestinal Permeability as Precursor of Celiac Disease in Pediatric Study; Antibiotic Use Effects Zonulin Levels
Zonulin as a Biomarker for the Development of Celiac Disease
DaFonte TM, Valitutti F, Kenyon V, Locascio JJ [et al.], Leonard MM; CD-GEMM Study Group
Published in Pediatrics on 12/8/2023 | *Summary available | Press Release

Neoadjuvant Treatment with Sacituzumab Govitecan for Localized Triple Negative Breast Cancer Safe and Feasible
Response-guided Neoadjuvant Sacituzumab Govitecan for Localized Triple Negative Breast Cancer: Results from the NeoSTAR Trial
Spring LM, Tolaney SM, Fell G, Bossuyt V, Abelman RO [et al.], Bardia A
Published in Annals of Oncology on 12/11/2023

New Guidelines for Variant Classification
ClinGen Guidance for Use of the PP1/BS4 Co-segregation and PP4 Phenotype Specificity Criteria for Sequence Variant Pathogenicity Classification
Biesecker LG, Byrne AB, Harrison SM, Pesaran T [et al.], Rehm HL; ClinGen Sequence Variant Interpretation Working Group
Published in American Journal of Human Genetics on 12/12/2023 | *Summary available

First Comprehensive Atlas of Cell Types in a Mammalian Brain
The Molecular Cytoarchitecture of the Adult Mouse Brain
Langlieb J, Sachdev NS, Balderrama KS, Nadaf NM, Raj M [et al.], Macosko EZ
Published in Nature on 12/13/2023 | *Summary available

Potential Target for Reversing Poor Metabolic Traits
ChREBP is Activated by Reductive Stress and Mediates GCKR-associated Metabolic Traits
Singh C, Jin B, Shrestha N, Markhard AL, Panda A [et al.], Goodman RP
Published in Cell Metabolism on 12/14/2023 | *Summary available | Press Release

Socioeconomic and Environmental Risk Score Can Determine Which Non-smokers Develop COPD
Prediction and Stratification of Longitudinal Risk for Chronic Obstructive Pulmonary Disease across Smoking Behaviors
He Y, Qian DC, Diao JA, Cho MH, Silverman EK [et al.], Patel CJ
Published in Nature Communications on 12/14/2023 | *Summary available

Structural Analysis and Inhibition of Human LINE-1 ORF2 Protein Reveals Novel Adaptations and Functions
Structures, Functions, and Adaptations of the Human LINE-1 ORF2 Protein
Baldwin ET, van Eeuwen T, Hoyos D, Zalevsky A, Tchesnokov EP [et al.], Taylor MS
Published in Nature on 12/14/2023 | *Summary available | Research Spotlight

Blocking PPM1D Increases Activity of Clinically Used Therapies Against Leukemia
PPM1D Modulates Hematopoietic Cell Fitness and Response to DNA Damage and is a Therapeutic Target in Myeloid Malignancy
Miller PG, Sperling AS, Mayerhofer C, McConkey ME, Ellegast JM [et al.], Ebert BL
Published in Blood on 12/14/2023 | *Summary available

Early Promise in Elucidating Novel Biomarkers to Guide Precision Oncology
Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer
Kamran SC, Zhou Y, Otani K, Drumm M, Otani Y [et al.], Miyamoto DT
Published in Clinical Cancer Research on 12/15/2023 | *Summary available | Research Spotlight

Therapy for PTSD Following Childbirth is Effective
Preventing Post-Traumatic Stress Disorder following Childbirth: A Systematic Review and Meta-Analysis
Dekel S, Papadakis JE, Quagliarini B, Pham CT, Pacheco-barrios K [et al.], Nandru R
Published in American Journal of Obstetrics and Gynecology on 12/17/2023 | *Summary available

Reason for Placement of Congenital Skin Defect of the Midline Scalp
KCTD1/KCTD15 Complexes Control Ectodermal and Neural Crest Cell Functions and their Impairment Causes Aplasia Cutis
Raymundo JR, Zhang H, Smaldone G, Zhu W, Daly KE, Glennon BJ, Pecoraro G, Salvatore M, Devine WA, Lo CW, Vitagliano L, Marneros AG
Published in Journal of Clinical Investigation on 12/19/2023 | *Summary available

Publication Summaries

Heart failure with preserved ejection fraction (HFpEF) is a major public health concern today, but little is understood about the disease. Inflammation is thought to cause HFpEF. We studied eicosanoids, small lipid molecules that regulate inflammation in humans, in 510 patients who underwent a specialized stress test called a cardiopulmonary exercise test at Massachusetts General Hospital. Of 890 eicosanoids that we measured, 70 of them were linked with HFpEF. We also found that some of these molecules may explain the relationship between risk factors like obesity, diabetes, and high blood pressure with HFpEF. Our findings may help to uncover the causes of HFpEF and help us find new treatments.

(Summary submitted by Emily S. Lau, MD, MPH, Cardiology Division, Department of Medicine)

Rapid Diagnostic Screener for PTSD after Traumatic Childbirth Experience
Establishing the Validity of a Diagnostic Questionnaire for Childbirth-related Posttraumatic Stress Disorder
Arora IH, Woscoboinik GG, Mokhtar S, Quagliarini B, Bartal A [et al.], Dekel S
Published in  American Journal of Obstetrics and Gynecology  on 11/21/2023

Although childbirth is a happy event, a significant portion of American women have complicated and even traumatic deliveries. These experiences can result in developing posttraumatic stress disorder, a mental disorder which is different from postpartum depression. Routine perinatal care screening for maternal mental conditions is to identify women with postpartum depression using the Edinburgh Postnatal Depression Scale (EPDS). There is no recommended or routine screening for postpartum PTSD. We show that a simple patient-report questionnaire that measures symptoms of PTSD can accurately identify women who suffer from PTSD related to a traumatic childbirth when compared against the gold standard clinician diagnostic interview for PTSD. The questionnaire known as the PTSD Checklist for DSM-5 has been traditionally used to provide an initial diagnosis of PTSD in war veterans and we show that may be used as a rapid diagnostic screener for PTSD after a traumatic childbirth experience.

(Summary submitted by Sharon Dekel, PhD, MS, MPhil, Department of Psychiatry)

New, Efficient Method to Detect DNA Sample Contamination
CHARR Efficiently Estimates Contamination from DNA Sequencing Data
Lu W, Gauthier LD, Poterba T, Giacopuzzi E, Goodrich JK [et al.], Karczewski KJ
Published in  American Journal of Human Genetics  on 11/23/2023

Detecting DNA sample contamination is critical in genomics research and clinical applications, where even modest contamination levels can substantially affect the quality of genomic data. Our method, CHARR (Contamination from Homozygous Alternate Reference Reads), estimates contamination levels by assessing reference reads in homozygous alternate variant calls. CHARR is extremely efficient, significantly reducing computational costs operating only on variant calls instead of large short read data, yet maintaining accuracy, empowering analysis of genomic datasets as data sizes grow into the millions of individuals.

(Summary submitted by Konrad Karczewski, PhD, Analytic and Translational Genetics Unit, Center for Genomic Medicine)

Loss of nuclear TDP-43, a pathological hallmark in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), results in misplicing and severe reduction of the RNA encoding Stathmin-2 (STMN2). Using different strategies to deplete STMN2 in the mouse nervous system, we established its role in the maintenance of axonal architecture and innervation of the muscles. Indeed, sustained STMN2 loss in adult mice leads to nerve fiber collapse, denervation of the neuromuscular junctions, and motor impairments, which closely mirror ALS pathology. Collapse of the axons and disrupted neurofilament organization following STMN2 depletion are shown to be analogous to defects observed in postmortem ALS samples. These findings indicate a critical role for STMN2 in ALS, highlighting its potential as a target for therapy development.

(Summary submitted by Clotilde Lagier-Tourenne MD, PhD, Department of Neurology)

Mental illness and suicide are growing concerns worldwide in the medical community; however, the current state of the problem is largely unknown. To understand it better, we conducted a survey of over 600 academic surgeons in the United States. Of 622 participants, 16% screened positive for current depression, 18% for anxiety, 17% for post-traumatic stress disorder, 11% for hazardous alcohol consumption and nearly 1 in 7 respondents reported thoughts of suicide in the past year. The results suggest that mental illness and suicidal ideation are widespread in US academic surgery.

(Summary submitted by Reagan Collins, Department of Surgery)

Mitochondria are the part of a cell that generate most of its energy to perform its functions. In injury or disease, mitochondrial function can become disrupted. Transplantation of healthy mitochondria is being explored as a potential therapy to replace damaged mitochondria and restore normal cellular function. However, this approach is difficult to perform because mitochondria are not able to maintain their healthy state outside of cells due to advanced glycation end product modification in the pathophysiological extracellular environment. We show that simple modification of mitochondria with O-GlcNAc prevents this process and helps to improve the success of therapeutic mitochondrial transplantation.

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

Prioritizing Equity-centered Goals Critical to Reduce Inequities in Life Expectancy among Black and White MSM with HIV
Projected Life Expectancy Gains From Improvements in HIV Care in Black and White Men Who Have Sex With Men
Rich KM, Pandya A, Chiosi JJ, Reddy KP, Shebl FM [et al.], Hyle EP
Published in  JAMA Network Open  on 11/28/2023 | Research Spotlight

Substantial racial inequities in HIV care outcomes exist between Black and White MSM in the US. A new modeling study projects that the mean age at death for Black MSM with HIV would be 68.8 years compared with 75.6 years for White MSM, if current rates of HIV testing and treatment continued. Achieving equity-centered goals (i.e., annual HIV testing, 95% engaged in care, 95% virologic suppression for all, regardless of race/ethnicity) would result in 3.5 years of life gained for Black MSM compared with 2.1 years of life gained for White MSM. Prioritizing equity-centered goals is critical to reduce inequities in life expectancy among Black and White MSM with HIV.

(Summary submitted by Katherine Rich, MD, MPH, Department of Medicine)

Several different vaccine platforms for COVID-19 have been globally deployed including mRNA, subunit/component, and adenovirus-based immunizations. How vaccine boosters enhance protection from these distinct primary immunization platforms is unclear. In this study, we identified that a subunit-based booster consisting of the Beta variant Spike elicited strong antibody responses, particularly the mucosal guardian IgA, to all Spike variants independent of the primary immunization platform in primates. Since the virus’s target is the airway mucosa, boosting strategies that stimulate IgA may be ideal for protection. A boosting strategy such as this can be done at low cost as subunit-based vaccines do not require ultracold storage, allowing for equitable distribution.

(Summary submitted by Ryan McNamara, PhD, Ragon Institute of MGH, MIT and Harvard)

Mass General Brigham's Pediatric integrated Care Management Program (iCMP) was evaluated using claims data, patient and family surveys, and interviews. The program was found to reduce unnecessary hospitalizations, Emergency Department visits and cost of health care, while improving quality of care coordination and having high satisfaction from participating patients and families. Children and youth in the program have special medical, behavioral health, and/or social health care needs and receive longitudinal services from a care manager embedded in their primary care practice. Pediatric care management programs like iCMP can be an effective way to improve value-based care in Accountable Care Organizations (ACOs).

(Summary submitted by Katherine H. Schiavoni, MD, Department of Pediatrics)

Bayesian fine-mapping algorithms are widely used to identify causal genetic variants for phenotypes, but calibrating them can be challenging. We propose methods that control for infinitesimal effects while fine-mapping sparse causal effects. Our analysis showed that common statistical models may be miscalibrated in real data applications and that polygenic architecture of genetic effects may contribute to miscalibration. The work demonstrates that the accuracy of identifying sparse causal variants is improved when additional infinitesimal genetic effects are included.

(Summary submitted by Ran Cui, PhD, Analytic and Translational Genetics Unit, Center for Genomic Medicine)

Patients with Alzheimer’s disease (AD), the most common form of dementia, experience significant problems with memory and sleep quality. Deep sleep, specifically, is important for storing and maintaining memories. In this study, we used a mouse model of Alzheimer’s disease to see how deep sleep patterns look early in the disease progression, the ideal time to treat AD patients. We used light to activate brain cells that increased the amount of deep sleep in mice, prevented harmful protein accumulations, and improved memory. Further work can now develop similar therapies to treat patients and limit the number of Alzheimer’s disease diagnoses.

(Summary submitted by Stephen Perle, Department of Neurology)

Brain Care Score Can Assess Current Health Habits and Risk to Future Brain Health
The Predictive Validity of a Brain Care Score for Dementia and Stroke: Data from the UK Biobank Cohort
Singh SD, Oreskovic T, Carr S, Papier K, Conroy M [et al.], Rosand, J
Published in  Frontiers in Neurology  on 12/1/2023 | Press Release

In order to answer the question, “what can I do to take good care of my brain?” researchers in partnership with patients developed a Brain Care Score (BCS) to based on 12 easily actionable steps, covering modifiable physical, lifestyle and social-emotional components of health. Now, the tool has been scientifically backed in this article where the researchers followed 398,990 adults aged 40-69 and found that those with a higher BCS had a lower risk of developing dementia or stroke as they aged.

(Summary submitted by Jonathan M. Rosand, MD, MSC, McCance Center for Brain Health, Department of Neurology )

This study examined the rate of variants of uncertain significance (VUS) reported in over 1.5 million tests performed on individuals with a suspected genetic disorder and found an alarmingly high rate of VUS, though interestingly it was statistically significantly lower in exome and genome sequencing tests compared to multi-gene panels. These data speak to common practices employed when performing panel tests (reporting all Pathogenic, Likely Pathogenic and VUS variants) compared to ES/GS where only those variants with a high likelihood of causality are reported. These findings call for changes in genetic test reporting practices that will enable patients and physicians to focus on results of known or high potential medical relevance and eliminate unnecessary distraction and medical costs from variants unlikely to be causal. A working group of the American College of Medical Genetics and Genomics has now been convened to develop new guidance for clinical laboratories around reporting VUS.

(Summary submitted by Heidi Rehm, PhD, Center for Genomic Medicine)

Coronary artery calcification is a strong independent predictor of adverse cardiovascular events. In this study, we performed a multi-ethnic genome-wide association study of coronary artery calcification which included a total of 22,400 participants. In addition to previously known loci, we identified two novel genetic loci (Arylsulfatase E and MMP16) to be associated with coronary calcification. Functional studies in human cell lines identified Arylsulfatase E as a potent inducer of both calcification as well as a bone-like phenotype transition of vascular smooth muscle cells, which occurs in atherosclerotic heart disease. Thus, this study discovered novel genetic underpinnings and biologic mechanisms for vascular calcification and has identified Arylsulfatase E as a potential therapeutic target to treat vascular calcification.

(Summary submitted by Rajeev Malhotra, MD, Cardiovascular Research Center, Department of Medicine)

Cervical cancer is a leading cause of cancer-related deaths, which could be prevented with HPV vaccination. A single-dose HPV vaccine approach could increase access to vaccination. This study reported that single-dose of HPV vaccination is >95% effective in preventing HPV infections among young women in Kenya over three years. As a result of this work, the World Health Organization recommended single-dose HPV vaccination. To-date, thirty-two countries have made the switch to single-dose including Australia, Mexico, Mozambique Tanzania, and the United Kingdom. This evidence supports that HPV vaccination significantly reduces the risk of cervical cancer and could reduce barriers to delivery.

(Summary submitted by Ruanne Barnabas, MBChB, MSc, DPhil, Division of Infectious Diseases, Department of Medicine)

MRI, PET, CT, and SPECT have been routinely used for 3D brain imaging; however, optical 3D molecular brain imaging is rare and highly challenging because several hurdles, including strong light scattering and attenuation by the skull and dispersal of the target, need to be overcome. Our group designed chemiluminescence probes ADLumin-Xs with advantages in quantum yields, emission wavelengths, and signal-to-noise ratios to fulfill the requirements for 3D brain imaging. The signal of the mouse brain can reach 0.5 cm depth. This method could have significant potential for widespread applications in preclinical brain disorder research at a low cost.

(Summary submitted by Chongzhao Ran, PhD, Martinos Center for Biomedical Imaging)

Every human genome has millions of genetic variants, but most have little to no effect - finding the “needle in the haystack” is a challenge in genetic diagnosis. Using patterns of variation from 76,156 individuals with whole-genome sequence data, we identify important regions of the genome that are depleted of variation, due to the effects of natural selection. While our previous work evaluated 2% of the genome that encodes genes, our new metrics extend our analysis to the entire genome, greatly expanding our knowledge about how natural selection shapes patterns of human genetic variation and which functional genomic elements likely harbor variation with potential clinical significance.

(Summary submitted by Konrad Karczewski, PhD, Analytic and Translational Genetics Unit, Center for Genomic Medicine)

Approach to Study Rare Gene Variant Pairs that Contribute to Disease
Inferring Compound Heterozygosity from Large-scale Exome Sequencing Data
Guo MH, Francioli LC, Stenton SL, Goodrich JK, Watts NA [et al.], Samocha KE
Published in  Nature Genetics  on 12/6/2023 | Press Release

Recessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. Our work focuses on the challenging, yet common, scenario of determining whether two rare variants identified in the exome sequencing of patients with rare diseases are impacting the same copy of the gene (are “in cis”) or both copies of the gene (“in trans”). Using exome sequencing data from 125,748 individuals, we developed a highly accurate approach to predict phase of rare variant pairs, and demonstrate that very few genes harbor rare, damaging variants in trans in the general population.

(Summary submitted by Kaitlin E Samocha, PhD, Center for Genomic Medicine)

Promising Gene-Editing Strategy for Spinal Muscular Atrophy
Optimization of Base Editors for the Functional Correction of SMN2 as a Treatment for Spinal Muscular Atrophy
Alves CRR, Ha LL, Yaworski R, Sutton ER, Lazzarotto CR [et al.], Kleinstiver BP
Published in  Nature Biomedical Engineering  on 12/6/2023 | Press Release

Spinal muscular atrophy (SMA) is still the leading genetic cause of infantile death worldwide. In our study, we sought to develop a genome editing-based approach to treat all SMA patients by editing and altering the SMN2 gene. We undertook an extensive engineering campaign to optimize highly efficient and safe CRISPR base editors capable of installing a single genetic edit in SMN2, demonstrating efficacy in patient-derived cells and a mouse model of SMA. Correction of the SMN2 sequence re-activates SMN expression to normal levels. Our approach should provide durable benefits for SMA patients, with potential advantages compared to current therapies.

(Summary submitted by Christiano R. R. Alves, PhD & Benjamin P. Kleinstiver, PhD, Center for Genomic Medicine)

Tuberculosis (TB) affects over 20 percent of the global population, and is responsible for 1.3 million deaths every year. Tobacco smoking doubles the risk of active TB but how smoking promotes TB infection remains incompletely understood. We demonstrated enrichment of immature inflammatory immune cells in the lungs of smokers compared to non-smokers. These cells allowed efficient growth of Mycobacterium tuberculosis (Mtb), the bacterial cause of TB, but this growth could be inhibited with certain anti-inflammatory drugs. This work defines how smoking may lead to increased susceptibility to TB and potential new therapies to reduce this increased susceptibility.

(Summary submitted by Douglas S Kwon, MD, PhD, Ragon Institute of MGH, MIT and Harvard)

Screening tools for PTSD following childbirth are lacking. Although women with complicated deliveries are at risk for PTSD, how the event is appraised and perceived is important in understand the chances of developing a mental illness. A large sample of women were asked about the subjective emotional reactions that they have experienced during and/or immediately after childbirth and negative appraisals (“I thought I might die) using a measure called the Peritraumatic Distress Inventory (PDI). They also completed an assessment of PTSD symptoms related to childbirth. The vast majority of women who had PTSD and those who did not have PTSD were accurately classified based on their scores on the PDI. Hence, a women's subjective emotional reactions to childbirth could offer valuable information about her mental health and chances of probable suffering from PTSD.

(Summary submitted by Sharon Dekel, PhD, MS, MPhil, Department of Psychiatry)

Increased intestinal permeability seems to be a key factor in the pathogenesis of celiac disease (CeD). Here, we examined whether intestinal permeability changes before CeD onset by measuring serum zonulin - a widely used marker of intestinal permeability. We evaluated 51 cases diagnosed with CeD autoimmunity and 51 controls from the CDGEMM birth cohort study and measured serial zonulin levels. We found that zonulin levels significantly rise in the 18 months that precede CeD diagnosis and this increase was influenced by exposure to a greater number of antibiotic courses. This suggests zonulin may be used as a biomarker CeD screening in at-risk children.

(Summary submitted by Maureen Leonard, MD, MMSc, Mucosal Immunology and Biology Research Center, Mass General Hospital for Children)

New Guidelines for Variant Classification
ClinGen Guidance for Use of the PP1/BS4 Co-segregation and PP4 Phenotype Specificity Criteria for Sequence Variant Pathogenicity Classification
Biesecker LG, Byrne AB, Harrison SM, Pesaran T [et al.], Rehm HL; ClinGen Sequence Variant Interpretation Working Group
Published in  American Journal of Human Genetics  on 12/12/2023

Current 2015 professional guidelines for variant classification include both pathogenic (PP1) and benign (BS4) criteria for evaluating phenotype-genotype co-segregation data for variants, but details of how to apply those criteria at appropriate evidence levels were sparse. In these new guidelines, we have developed a practical heuristic for genetic co-segregation evidence and have also determined that the specific phenotype criterion (PP4) is inseparably coupled to the co-segregation criterion. We have also determined that negative evidence at one locus constitutes positive evidence for other loci for disorders with locus heterogeneity. Finally, we provide a points-based system for evaluating phenotype and co-segregation as evidence types to support or refute a locus and show how that can be integrated into the Bayesian framework now used for variant classification and consistent with the 2015 guidelines.

(Summary submitted by Heidi Rehm, PhD, Center for Genomic Medicine)

In this work, we present the first comprehensive atlas of cell types in a mammalian brain. Leveraging new methods our lab developed in single cell and spatial genomics, we sampled millions of single-cell gene expression profiles from across the mouse brain, and localized them to specific brain regions. We found nearly 5,000 different kinds of cells, most of which were neurons. Primarily, these cell types were in more evolutionarily ancient brain areas in the hypothalamus, midbrain, and hindbrain. We used these profiles to establish principles of neurotransmission in the brain, and identify cell types with particularly enriched expression for disease-associated genes.

(Summary submitted by Evan Macosko, MD, PhD, Department of Psychiatry)

Potential Target for Reversing Poor Metabolic Traits
ChREBP is Activated by Reductive Stress and Mediates GCKR-associated Metabolic Traits
Singh C, Jin B, Shrestha N, Markhard AL, Panda A [et al.], Goodman RP
Published in  Cell Metabolism  on 12/14/2023 | Press Release

Reductive stress refers to when you have too many electrons in metabolism. We studied what happens when you have reductive stress in the liver. We found it changes how the liver makes proteins, resulting in negative health traits. We think this helps explain why some people who are obese or have fatty liver or who have mutations in a gene have these negative metabolic traits. Trying to get rid of reductive stress in these people might make them healthier.

(Summary submitted by Russell P Goodman, MD, DPHIL, Gastroenterology Division, Department of Medicine)

Smoking is the leading risk factor for chronic obstructive pulmonary disease (COPD) worldwide, yet many people who never smoke develop COPD. We used data from over 300,000 individuals in the UK to develop the Socioeconomic and Environmental Risk Score (SERS) which captures environmental, behavioral, and socioeconomic exposure risks beyond tobacco smoking. Individuals with high SERS have higher risk for developing COPD. Never smokers with extremely high SERS are more likely to develop COPD than previous and current smokers with low SERS. Our finding highlights the importance of other non-smoking environmental and socioeconomic variables.

(Summary submitted by Yixuan He, PhD, Analytic and Translational Genetics Unit, Department of Medicine)

A third of the human genome is hundreds of thousands of the same sequences, written by a virus-like element called LINE-1. While transposons such as LINE-1 were dismissed as ‘junk DNA’, they are increasingly recognized to contribute to the pathologies of diseases including cancer, autoimmunity, and neurodegeneration. However, how much LINE-1 contributes and the underlying mechanisms are unknown. Here, we determine the first structures of the LINE-1 reverse transcriptase and use them to understand how drugs designed for HIV-1 do and do not inhibit it. We also discover that LINE-1 can synthesize inflammatory RNA:DNA hybrids in the cytosol, which trigger inflammation through cGAS/STING and provide a critical mechanistic basis for contributions of LINE-1 to disease.

(Summary submitted by Martin Taylor, MD, PhD, Department of Pathology)

In our recent paper, we showed how a gene, called PPM1D, influences blood cell development and the resistance of cancer cells to chemotherapy and radiation. PPM1D is activated in a variety of cancers including myelodysplastic syndrome and acute myeloid leukemia. Using a combination of mouse models and human cell lines, we found that PPM1D activity increases the ability of blood stem cells and leukemia cells to escape the effects of DNA damage. We subsequently found that blocking PPM1D increases the activity of clinically used therapies against leukemia and are now working on better understanding PPM1D as a drug target.

(Summary submitted by Peter G Miller, MD, PhD, Krantz Family Center for Cancer Research, Mass General Cancer Center)

Early Promise in Elucidating Novel Biomarkers to Guide Precision Oncology
Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer
Kamran SC, Zhou Y, Otani K, Drumm M, Otani Y [et al.], Miyamoto DT
Published in Clinical Cancer Research  on 12/15/2023 | Research Spotlight

Although trimodality therapy (TMT) is an effective organ sparing alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), not all patients have favorable long-term outcomes after TMT. A better understanding of molecular determinants of response to chemoradiation can provide biomarkers for the optimal selection of appropriate patients for TMT. We identified that mutations in the gene ERCC2 were significantly associated with improved long-term outcomes after TMT, particularly in patients who received concurrent cisplatin- based chemotherapy.

(Summary submitted by Sophia C. Kamran, MD, Department of Radiation Oncology)

Therapy for PTSD Following Childbirth is Effective
Preventing Post-Traumatic Stress Disorder following Childbirth: A Systematic Review and Meta-Analysis
Dekel S, Papadakis JE, Quagliarini B, Pham CT, Pacheco-barrios K [et al.], Nandru R
Published in  American Journal of Obstetrics and Gynecology  on 12/17/2023

PTSD after childbirth occurs in 6% of women and can impair mothers health and also her ability to provide care of their infant. Recommended treatments for postpartum PTSD are unclear. We reviewed all studies that tested a therapy for postpartum PTSD with a focus on prevention published until recently We find that brief psychological therapies administered often in the first postpartum days to women who had a traumatic childbirth experience can be helpful and even if they involve single session. Based on the existing studies available, the most promising early therapies are intervention that are conventional "trauma-focused" and also midwife led dialogue based counseling at bed side. Educational material alone do not seem to help.

(Summary submitted by Sharon Dekel, PhD, MS, MPhil, Department of Psychiatry)

Reason for Placement of Congenital Skin Defect of the Midline Scalp
KCTD1/KCTD15 Complexes Control Ectodermal and Neural Crest Cell Functions and their Impairment Causes Aplasia Cutis
Raymundo JR, Zhang H, Smaldone G, Zhu W, Daly KE, Glennon BJ, Pecoraro G, Salvatore M, Devine WA, Lo CW, Vitagliano L, Marneros AG
Published in  Journal of Clinical Investigation  on 12/19/2023

Aplasia cutis congenita (ACC) is a congenital skin defect of the midline scalp. Why it forms mainly at this anatomic site has remained a longstanding enigma. We found that combined inactivation of KCTD1/KCTD15, which are mutated in patients with ACC, in cells of the epidermis results in abnormal skin appendages (hairs, sweat glands, sebaceous glands), but not in ACC. Instead, KCTD1/KCTD15 inactivation in a cell population that gives rise to cells of the midline cranial sutures results in midline skull defects, and as a secondary consequence to ACC due to loss of expression of growth factors that promote skin formation.

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

Press Releases

Mass General-Developed Brain Care Score (BCS) is a Scientifically Validated Way to Assess Current Health Habits and Risk to Future Brain Health
Featuring Jonathan Rosand MD, MSc

Investigators have developed a Brain Care Score composed of physical, lifestyle, and social-emotional components, with a higher score indicating better brain care. In a recent study, adults with a higher Brain Care Score had a lower risk of developing dementia and stroke as they aged.

Researchers Develop a Promising Gene-Editing Strategy for Spinal Muscular Atrophy
Featuring Christiano Alves, PhD, and Benjamin Kleinstiver, PhD

Spinal muscular atrophy is a leading genetic cause of infant death worldwide, and is typically caused by loss-of-function mutations in the SMN1 gene, which produces the SMN protein. Gene therapy and small molecule treatments for spinal muscular atrophy (SMA) have led to extraordinary improvements for patients, but there is no definitive genetic cure. In lab models, the Mass General-led research team used a CRISPR-based approach to edit a comparable gene (SMN2) to produce the SMN protein, a strategy that may overcome limitations of current treatments.

Large-scale DNA Sequence Resource Reveals New Regions of the Human Genome under Natural Selection
Featuring Konrad Karczewski, PhD

Investigators have developed a map that identifies non-coding regions of the human genome that lack typical variation, indicating that they are important sequences conserved during evolution and natural selection. The work will help scientists study genomic regions that, when mutated, may cause disease.

Researchers Develop Approach to Study Rare Gene Variant Pairs that Contribute to Disease
Featuring Kaitlin E. Samocha, PhD

When two mutations arise within a particular gene in a patient’s genome, both may be present in the same copy of the gene (“in cis”) or each may be on a different copy (“in trans”). Researchers have developed a strategy for inferring which of these phases is present for rare variant pairs within genes. The work could help improve genetic diagnoses, especially for recessive diseases, which arise when both copies of a gene are mutated.

MGfC Researchers Find Increased Intestinal Permeability as Precursor of Celiac Disease in Pediatric Study; Antibiotic Use Effects Zonulin Levels
Featuring Alessio Fasano, MD and Maureen Leonard, MD

Researchers from Mass General for Children and Italy have identified a potential biomarker preceding the development of celiac disease autoimmunity in children.

Spike in Dermatology Visits for Skin Problems Seen During Summer of Wildfires
Featuring Shadi Kourosh, MD, MPH

Levels of carbon monoxide, a byproduct of wildfires, peaked during the summer of 2023 in Boston. There was also a striking rise in dermatology clinic visits for eczema and related skin conditions, suggesting a connection between air pollution and skin inflammation. Air pollution disproportionately affects vulnerable groups, including low-income communities, older individuals, and children.

Researchers Identify a Potential Target for Reversing Poor Metabolic Traits
Featuring Russell Goodman, MD, DPhil

A common genetic variant promotes reductive stress in the liver, leading to activation of a transcription factor. This transcription factor in turn alters gene expression to cause undesirable metabolic traits. Targeting this pathway is likely to have numerous beneficial metabolic effects.

Research Spotlights

Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer

Sophia C. Kamran, MD, a physician investigator in the Mass General Cancer Center and an assistant professor of Radiation Oncology at Harvard Medical School, is the first author of a recently published paper in Clinical Cancer Research, “Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer”. David Miyamoto, MD, PhD, a physician investigator in the Department of Radiation Oncology and an Assistant Professor of Radiation Oncology at Harvard Medical School and Jason Efstathiou, MD, DPhil, a physician investigator in the Department of Radiation Oncology and a Professor of Radiation Oncology at Harvard Medical School and Kent W. Mouw, MD, PhD, a physician investigator in the Department of Radiation Oncology at Dana-Farber Cancer Institute and an Assistant Professor of Radiation Oncology at Harvard Medical School are co-senior authors of the paper.

Structural Analysis and Inhibition of Human LINE-1 ORF2 Protein Reveals Novel Adaptations and Functions

Martin Taylor, MD, PhD, a physician investigator in the Department of Pathology at Massachusetts General Hospital and an instructor in Pathology at Harvard Medical School, is the lead corresponding author of a new study in Nature, “Structural Analysis and Inhibition of Human LINE-1 ORF2 Protein Reveals Novel Adaptations and Functions”.

Improvements in HIV Care in Black and White Men Who Have Sex with Men

Katherine Rich, MD MPH, resident in the MGH Department of Medicine, is the first author of a recently published paper in JAMA Network Open, “Projected Life Expectancy Gains from Improvements in HIV Care in Black and White Men Who Have Sex With Men.” Aima Ahonkhai, MD MPH and Emily Hyle, MD MSc, physician investigators in the Division of Infectious Diseases at Massachusetts General Hospital, are co-senior authors.

Blog Posts

Snapshot of Science: Mass General’s High Impact Research Publications for November 2023

COVID rebound on Paxlovid, mental and behavioral consequences of firearms injuries in children and much more and much more

Through the Magnifying Glass: The Meditation Research Program at Massachusetts General Hospital
Featuring Matthew Sacchet, PhD

The Meditation Research Program at Mass General uses advanced brain imaging techniques to study how meditation affects the human brain.

Mass General Scientists Predict Big ‘Breakthroughs’ In Medicine For 2024

Researchers and clinicians from Massachusetts General Hospital share their predictions for science and medicine in 2024.

Mass General Research Wrapped for 2023

Looking back at another remarkable year for research at Massachusetts General Hospital, including facts and figures, top stories and more.

A Holiday History Story: Mass General, Halifax and the Christmas Tree that Comes to Boston Every Year
A care team from Massachusetts General Hospital was among the first to arrive in Halifax in 1917 to help after a deadly blast.

Check out the Latest MGH Research Scholars Notebook
Florez to lead the Department of Medicine with compassion and collaboration, plus new insights on aging, mental health and lots more.

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Snapshot of Science for December 2023