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Frederick W. Alt
Harvard University
GeneMolecular biologyB cellGeneticsBiology
609Publications
157H-index
78.5kCitations
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#1Huan Chen (Harvard University)H-Index: 1
#2Yuxiang Zhang (Harvard University)H-Index: 13
Last. Donna Neuberg (Harvard University)H-Index: 115
view all 12 authors...
The antigen-binding variable regions of the B cell receptor (BCR) and of antibodies are encoded by exons that are assembled in developing B cells by V(D)J recombination1. The BCR repertoires of primary B cells are vast owing to mechanisms that create diversity at the junctions of V(D)J gene segments that contribute to complementarity-determining region 3 (CDR3), the region that binds antigen1. Primary B cells undergo antigen-driven BCR affinity maturation through somatic hypermutation and cellul...
1 CitationsSource
#1A. Tena (Harvard University)H-Index: 8
#2Yuxiang Zhang (Harvard University)H-Index: 13
Last. Frederick W. Alt (Harvard University)H-Index: 157
view all 7 authors...
Mild replication stress enhances appearance of dozens of robust recurrent genomic break clusters, termed RDCs, in cultured primary mouse neural stem and progenitor cells (NSPCs). Robust RDCs occur within genes (“RDC-genes”) that are long and have roles in neural cell communications and/or have been implicated in neuropsychiatric diseases or cancer. We sought to develop an in vitro approach to determine whether specific RDC formation is associated with neural development. For this purpose, we ada...
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#1Ming Tian (Harvard University)H-Index: 17
#2Kelly McGovern (Harvard University)
Last. Nicole Manfredonia (Harvard University)
view all 15 authors...
HIV-1 vaccine development aims to elicit broadly neutralizing antibodies (bnAbs) against diverse viral strains. In some HIV-1–infected individuals, bnAbs evolved from precursor antibodies through affinity maturation. To induce bnAbs, a vaccine must mediate a similar antibody maturation process. One way to test a vaccine is to immunize mouse models that express human bnAb precursors and assess whether the vaccine can convert precursor antibodies into bnAbs. A major problem with such mouse models ...
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#1Todd BradleyH-Index: 13
Last. Robert Parks (Duke University)H-Index: 36
view all 30 authors...
Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX4...
1 CitationsSource
#1Meiyan Wang (UCSD: University of California, San Diego)H-Index: 3
#2Pei-Chi Wei (DKFZ: German Cancer Research Center)H-Index: 4
Last. Fred H. Gage (UCSD: University of California, San Diego)H-Index: 195
view all 8 authors...
Summary The association between macrocephaly and autism spectrum disorder (ASD) suggests that the mechanisms underlying excessive neural growth could contribute to ASD pathogenesis. Consistently, neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSCs) of ASD individuals with early developmental brain enlargement are inherently more proliferative than control NPCs. Here, we show that hiPSC-derived NPCs from ASD individuals with macrocephaly display an altered DNA...
3 CitationsSource
#1Ming Tian (Boston Children's Hospital)H-Index: 17
#2Kelly McGovern (Boston Children's Hospital)
Last. Frederick W. Alt (Boston Children's Hospital)H-Index: 157
view all 15 authors...
HIV-1 vaccine development aims to elicit broadly neutralizing antibodies (bnAbs) against diverse viral strains. In some HIV-1 infected individuals, bnAbs evolve from precursor antibodies through affinity maturation. To induce bnAbs, a vaccine must mediate a similar process of antibody maturation. One way to test vaccination strategies is to immunize mouse models that express human bnAb precursors. Such immunization experiments can assess whether the vaccine can convert precursor antibody into bn...
Source
#1Zhaoqing Ba (HHMI: Howard Hughes Medical Institute)H-Index: 4
#2Jiangman Lou (HHMI: Howard Hughes Medical Institute)
Last. Frederick W. Alt (HHMI: Howard Hughes Medical Institute)H-Index: 157
view all 9 authors...
RAG endonuclease initiates V(D)J recombination in progenitor (pro)-B cells1. Upon binding a recombination center (RC)-based JH, RAG scans upstream chromatin via loop extrusion, potentially mediated by cohesin2-10, to locate Ds and assemble a DJH-based RC11. CTCF looping factor-bound elements (CBEs) within IGCR1 upstream of Ds impede RAG-scanning12-15; but their inactivation allows scanning to proximal VHs where additional CBEs activate rearrangement and impede scanning any further upstream15,16....
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#1A. Tena (Boston Children's Hospital)H-Index: 8
#1Aseda Tena (Boston Children's Hospital)
Last. Frederick W. Alt (Boston Children's Hospital)H-Index: 157
view all 7 authors...
Mild replication stress enhances appearance of dozens of robust recurrent genomic break clusters, termed RDCs, in cultured primary mouse neural stem and progenitor cells (NSPCs). Robust RDCs occur within genes ("RDC-genes") that are long and have roles in neural cell communications and/or have been implicated in neuropsychiatric diseases or cancer. We sought to develop an in vitro approach to determine whether specific RDC formation is associated with neural development. For this purpose, we ada...
Source
#1Kevin O. Saunders (Duke University)H-Index: 19
#2Kevin Wiehe (Duke University)H-Index: 20
Last. Barton F. Haynes (Duke University)H-Index: 121
view all 35 authors...
INTRODUCTION A major goal of HIV-1 vaccine development is the design of immunogens that induce broadly neutralizing antibodies (bnAbs). However, vaccination of humans has not resulted in the induction of affinity-matured and potent HIV-1 bnAbs. To devise effective vaccine strategies, we previously determined the maturation pathway of select HIV-1 bnAbs from acute infection through neutralizing antibody development. During their evolution, bnAbs acquire an abundance of improbable amino acid subst...
10 CitationsSource
#1Xuefei Zhang (Harvard University)H-Index: 2
#2Yu ZhangH-Index: 12
Last. Frederick W. Alt (Harvard University)H-Index: 157
view all 6 authors...
Antibody class switch recombination (CSR) in B lymphocytes replaces immunoglobulin heavy chain locus (Igh) Cμ constant region exons (CHs) with one of six CHs lying 100–200 kb downstream1. Each CH is flanked upstream by an I promoter and long repetitive switch (S) region1. Cytokines and activators induce activation-induced cytidine deaminase (AID)2 and I-promoter transcription, with 3′ IgH regulatory region (3′ IgHRR) enhancers controlling the latter via I-promoter competition for long-range 3′ I...
4 CitationsSource
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