Cold Spring Harbor Laboratory

About: Cold Spring Harbor Laboratory is a nonprofit organization based out in Cold Spring Harbor, New York, United States. It is known for research contribution in the topics: Gene & Genome. The organization has 3772 authors who have published 6603 publications receiving 1010873 citations. The organization is also known as: CSHL.

Principles and concepts of DNA replication in bacteria, archaea, and eukarya

Abstract: The accurate copying of genetic information in the double helix of DNA is essential for inheritance of traits that define the phenotype of cells and the organism. The core machineries that copy DNA are conserved in all three domains of life: bacteria, archaea, and eukaryotes. This article outlines the general nature of the DNA replication machinery, but also points out important and key differences. The most complex organisms, eukaryotes, have to coordinate the initiation of DNA replication from many origins in each genome and impose regulation that maintains genomic integrity, not only for the sake of each cell, but for the organism as a whole. In addition, DNA replication in eukaryotes needs to be coordinated with inheritance of chromatin, developmental patterning of tissues, and cell division to ensure that the genome replicates once per cell division cycle.

Design, synthesis, and application of a Protein A mimetic

Abstract: Low-molecular-weight synthetic molecules that mimic the activity of native biological macromolecules have therapeutic potential, utility in large-scale production of biopharmaceuticals, and the capacity to act as probes to study molecular recognition events. We have developed a nonpeptidyl mimic for Staphylococcus aureus Protein A (SpA). The specific recognition and complexation elements between the B domain (Fb) of SpA and the Fc fragment of IgG were identified from the x-ray crystallographic structure. Computer-aided molecular modeling was used to design a series of biomimetic molecules around the Phe132-Tyr133 dipeptide involved in its binding to IgG. One of the ligands binds IgG competitively with SpA in solution and when immobilized on agarose beads, with an affinity constant of 10(5)-10(6) M-1. The immobilized artificial Protein A was used to purify IgG from human plasma and murine IgG from ascites fluid, and to remove bovine IgG from fetal calf serum.

Large-scale human promoter mapping using CpG islands.

Abstract: Vertebrate genomic DNA is generally CpG depleted(1,2), possibly because methylation of cytosines at 80% of CpG dinucleotides results in their frequent mutation to thymine. and thus CpG to TpG dinucleotides(3). There are, however, genomic regions of high G+C content (CpG islands), where the occurrence of CpGs is significantly higher, close to the expected frequency, whereas the methylation concentration is significantly lower than the overall genome(4). CpG islands(5) are longer than 200 bp and have over 50% of G+C content and CpG frequency, at least 0.6 of that statistically expected. Approximately 50% of mammalian gene promoters are associated with one or more CpG islands(6). Although biologists often intuitively use CpG islands for 5' gene identification(7,8). this has not been rigorously quantified(9). We have determined the features that discriminate the promoter-associated and non-associated CpG islands. This led to an effective algorithm for large-scale promoter mapping (with 2kb resolution) with a concentration of false-positive predictions of promoters much lower than previously obtained. Using this algorithm, we correctly discriminated approximately 85% of the CpG islands within an interval (-500 to +1500) around a transcriptional start site (TSS) from those that lie further away from TSSs. We also correctly mapped approximately 93% of the promoters containing CpG islands.

Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution

Abstract: Pancreatic adenocarcinoma presents as a spectrum of a highly aggressive disease in patients. The basis of this disease heterogeneity has proved difficult to resolve due to poor tumor cellularity and extensive genomic instability. To address this, a dataset of whole genomes and transcriptomes was generated from purified epithelium of primary and metastatic tumors. Transcriptome analysis demonstrated that molecular subtypes are a product of a gene expression continuum driven by a mixture of intratumoral subpopulations, which was confirmed by single-cell analysis. Integrated whole-genome analysis uncovered that molecular subtypes are linked to specific copy number aberrations in genes such as mutant KRAS and GATA6. By mapping tumor genetic histories, tetraploidization emerged as a key mutational process behind these events. Taken together, these data support the premise that the constellation of genomic aberrations in the tumor gives rise to the molecular subtype, and that disease heterogeneity is due to ongoing genomic instability during progression.