6,666 results match your criteria: "Massachusetts 02142; email: joelh@broadinstitute.org.[Affiliation]"
J Org Chem
January 2025
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, United States.
A scalable, seven step synthesis is reported for a trifluoromethyl toluene protected sulfonated phenylalanine building block whose utility was demonstrated in the synthesis of four CXCR4-derived sulfonopeptides. When compared to a conventional trichloroethyl protected building block, overall yield was improved by up to 4-fold. We believe this building block will prove to be of significant value for the synthesis of a variety of peptide targets containing phenylalanine sulfonate, a bioisostere of tyrosine sulfate, enabling orthogonal protection strategies and improving synthetic efficiency and yield.
View Article and Find Full Text PDFJ Am Chem Soc
January 2025
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
Ni-catalyzed asymmetric reductive cross-coupling reactions provide rapid and modular access to enantioenriched building blocks from simple electrophile precursors. Reductive coupling reactions that can diverge through a common organometallic intermediate to two distinct families of enantioenriched products are particularly versatile but underdeveloped. Here, we describe the development of a bis(oxazoline) ligand that enables the desymmetrization of -anhydrides.
View Article and Find Full Text PDFGenome Res
January 2025
Whitehead Institute, Cambridge, Massachusetts 02142, USA;
The Y-linked gene and its X-linked homolog survived the evolution of the human sex chromosomes from ordinary autosomes. encodes a multifunctional RNA helicase, with mutations causing developmental disorders and cancers. We find that, among X-linked genes with surviving Y homologs, is extraordinarily dosage sensitive.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Malignant gliomas are heterogeneous tumors, mostly incurable, arising in the central nervous system (CNS) driven by genetic, epigenetic, and metabolic aberrations. Mutations in isocitrate dehydrogenase (IDH1/2) enzymes are predominantly found in low-grade gliomas and secondary high-grade gliomas, with IDH1 mutations being more prevalent. Mutant-IDH1/2 confers a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), resulting in an aberrant hypermethylation phenotype.
View Article and Find Full Text PDFACS Mater Lett
January 2025
Air Force Research Laboratory, Materials and Manufacturing Directorate, Wright-Patterson AFB, Ohio 45433, United States.
Photocurable self-healing elastomers are promising candidates for producing complex soft devices that can mend damage. However, the practicality of these materials is limited by reliance on external stimuli, custom synthesis, manual realignment, and multihour healing cycles. This paper introduces a tough 3D-printable hybrid acrylate/thiol-ene elastomer (prepared with commercially available precursors) that exhibits nearly instantaneous damage repair in the absence of external stimuli.
View Article and Find Full Text PDFNPJ Biofilms Microbiomes
January 2025
Department of Biomedical Engineering, University of Massachusetts Lowell, Lowell, 01854, MA, USA.
The human body houses many distinct and interconnecting microbial populations with long-lasting systemic effects, where the oral cavity serves as a pathogens' reservoir. The correlation of different disease states strongly supports the need to understand the interplay between the oral tissue niche and microbiome. Despite efforts, the recapitulation of gingival architecture and physiological characteristics of the periodontal niche has yet to be accomplished by traditional cultural strategies.
View Article and Find Full Text PDFACS Chem Biol
January 2025
Harvard University, Department of Chemistry and Chemical Biology, Cambridge, Massachusetts 02138, United States.
Hyperammonemia is characterized by the accumulation of ammonia within the bloodstream upon liver injury. Left untreated, hyperammonemia contributes to conditions such as hepatic encephalopathy that have high rates of patient morbidity and mortality. Previous studies have identified gut bacterial urease, an enzyme that converts urea into ammonia, as a major contributor to systemic ammonia levels.
View Article and Find Full Text PDFmedRxiv
December 2024
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA USA.
Background: Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is often not specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants.
Methods: Using dedicated pipelines to address the technical challenges posed by the mtDNA - circular genome, variant heteroplasmy, and nuclear misalignment - single nucleotide variants, small indels, and large mtDNA deletions were called from exome and genome sequencing data, in addition to RNA-sequencing when available.
Cell Chem Biol
December 2024
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address:
Chemical inducers of proximity (CIPs) are molecules that recruit one protein to another and introduce new functionalities toward modulating protein states and activities. While CIP-mediated recruitment of E3 ligases is widely exploited for the development of degraders, other therapeutic modalities remain underexplored. We describe a non-degrader CIP-DNA-encoded library (CIP-DEL) that recruits FKBP12 to target proteins using non-traditional acyclic structures, with an emphasis on introducing stereochemically diverse and rigid connectors to attach the combinatorial library.
View Article and Find Full Text PDFNat Commun
January 2025
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Genome editing using CRISPR-Cas systems is a promising avenue for the treatment of genetic diseases. However, cellular and humoral immunogenicity of genome editing tools, which originate from bacteria, complicates their clinical use. Here we report reduced immunogenicity (Red)(i)-variants of two clinically relevant nucleases, SaCas9 and AsCas12a.
View Article and Find Full Text PDFNat Commun
January 2025
Division of Gastroenterology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cell types and their heterogeneity within the human liver, but the spatial organization at single-cell resolution has not yet been described. Here we apply multiplexed error robust fluorescent in situ hybridization (MERFISH) to map the zonal distribution of hepatocytes, spatially resolve subsets of macrophage and mesenchymal populations, and investigate the relationship between hepatocyte ploidy and gene expression within the healthy human liver. Integrating spatial information from MERFISH with the more complete transcriptome produced by single-nucleus RNA sequencing (snRNA-seq), also reveals zonally enriched receptor-ligand interactions.
View Article and Find Full Text PDFNat Commun
January 2025
Center for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
Circulating Tumor Cells (CTCs) in blood encompass DNA, RNA, and protein biomarkers, but clinical utility is limited by their rarity. To enable tumor epitope-agnostic interrogation of large blood volumes, we developed a high-throughput microfluidic device, depleting hematopoietic cells through high-flow channels and force-amplifying magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.
View Article and Find Full Text PDFDNA Repair (Amst)
December 2024
Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Tandem duplications (TD) are among the most frequent type of structural variant (SV) in the cancer genome. They are characterized by a single breakpoint junction that defines the boundaries and the size of the duplicated segment. Cancer-associated TDs often increase oncogene copy number or disrupt tumor suppressor gene function, and thus have important roles in tumor evolution.
View Article and Find Full Text PDFACS Synth Biol
December 2024
Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States.
Nat Commun
December 2024
Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA.
Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), nearly 20% of hospitalized patients are at risk for thromboembolic events. This prothrombotic state is considered a key factor in the increased risk of stroke, which is observed clinically during both acute infection and long after symptoms clear. Here, we develop a model of SARS-CoV-2 infection using human-induced pluripotent stem cell-derived endothelial cells (ECs), pericytes (PCs), and smooth muscle cells (SMCs) to recapitulate the vascular pathology associated with SARS-CoV-2 exposure.
View Article and Find Full Text PDFCell Chem Biol
December 2024
Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:
The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa, a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging.
View Article and Find Full Text PDFDev Cell
December 2024
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address:
Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the gene transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing.
View Article and Find Full Text PDFStem Cell Reports
December 2024
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA; Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research at MIT, 500 Main St, Cambridge, MA 02142, USA. Electronic address:
Heparan sulfate (HS) is an anionic polysaccharide generated by all animal cells, but our understanding of its roles in human pluripotent stem cell (hPSC) self-renewal and differentiation is limited. We derived HS-deficient hPSCs by disrupting the EXT1 glycosyltransferase. These EXT1 hPSCs maintain self-renewal and pluripotency under standard culture conditions that contain high levels of basic fibroblast growth factor(bFGF), a requirement for sufficient bFGF signaling in the engineered cells.
View Article and Find Full Text PDFJ Cardiovasc Dev Dis
November 2024
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
Ischemic stroke is a major cause of mortality and disability and has become a significant public health concern among women. Overall, women have more ischemic stroke events than men, in part due to their longer life span, and also suffer from more severe stroke-related disabilities compared to men. Women are also more likely than men to present with atypical non-focal neurological symptoms, potentially leading to delayed diagnosis and treatment.
View Article and Find Full Text PDFAdv Mater
December 2024
David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Immune reactions to medical implants often lead to encapsulation by fibrotic tissue and impaired device function. This process is thought to initiate by protein adsorption, which enables immune cells to attach and mount an inflammatory response. Previously, several antifibrotic materials have been either designed to reduce protein adsorption or discovered via high-throughput screens (HTS) to favorably regulate inflammation.
View Article and Find Full Text PDFLaser Photon Rev
October 2024
Harvard Medical School, Boston, MA 02114, USA; Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Cardiology, Erasmus Medical Center, Rotterdam GD3015, The Netherlands; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Photoacoustic microscopy (PAM) is a high-resolution and non-invasive imaging modality that provides optical absorption contrast. By employing dual- or multiple-wavelength excitation, PAM extends its capabilities to offer valuable spectroscopic information. To achieve efficient multispectral PAM imaging, an essential requirement is a light source characterized by a high repetition rate and switching rate, a ≈microjoule pulse energy, and a ≈nanosecond pulse duration.
View Article and Find Full Text PDFBioinformatics
December 2024
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
Motivation: The Variant Call Format (VCF) is widely used in genome sequencing but scales poorly. For instance, we estimate a 150,000 genome VCF would occupy 900 TiB, making it costly and complicated to produce, analyze, and store. The issue stems from VCF's requirement to densely represent both reference-genotypes and allele-indexed arrays.
View Article and Find Full Text PDFbioRxiv
December 2024
Dept. of Integrative Structural and Computational Biology, The Scripps Research Institute; La Jolla, CA, 92037, USA.
Current COVID-19 vaccines are largely limited in their ability to induce broad, durable immunity against emerging viral variants. Design and development of improved vaccines utilizing existing platforms requires an in-depth understanding of the antigenic and immunogenic properties of available vaccines. Here we examined the antigenicity of two of the original COVID-19 vaccines, mRNA-1273 and NVX-CoV2373, by electron microscopy-based polyclonal epitope mapping (EMPEM) of serum from immunized non-human primates (NHPs) and clinical trial donors.
View Article and Find Full Text PDFmedRxiv
December 2024
Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Variably protease-sensitive prionopathy (VPSPr) is a rare, atypical subtype of prion disease in which many patients exhibit a family history of dementia. Rare protein-coding variants in , which are causal for all known forms of genetic prion disease, have been ruled out in all VPSPr cases to date, leading to suspicion that VPSPr could be caused by variants in other genes or by non-coding variation in or near . We performed exome sequencing and targeted sequencing of non-coding regions on genomic DNA from autopsy-confirmed VPSPr patients (N=67) in order to search for a possible genetic cause.
View Article and Find Full Text PDFCell Rep
December 2024
Precision Cardiology Laboratory, The Broad Institute, Cambridge, MA 02142, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address:
We sought to characterize cellular composition across the cardiovascular system of the healthy Wistar rat, an important model in preclinical cardiovascular research. We performed single-nucleus RNA sequencing (snRNA-seq) in 78 samples in 10 distinct regions, including the four chambers of the heart, ventricular septum, sinoatrial node, atrioventricular node, aorta, pulmonary artery, and pulmonary veins, which produced 505,835 nuclei. We identified 26 distinct cell types and additional subtypes, with different cellular composition across cardiac regions and tissue-specific transcription for each cell type.
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