The hallmarks of cancer.

The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

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Initial sequencing and analysis of the human genome.

The emergence of order in natural systems is a constant source of inspiration for both physical and biological sciences. While the spatial order characterizing for example the crystals has been the basis of many advances in contemporary physics, most complex systems in nature do not offer such high degree of order. Many of these systems form complex networks whose nodes are the elements of the system and edges represent the interactions between them. 
Traditionally complex networks have been described by the random graph theory founded in 1959 by Paul Erdohs and Alfred Renyi. One of the defining features of random graphs is that they are statistically homogeneous, and their degree distribution (characterizing the spread in the number of edges starting from a node) is a Poisson distribution. In contrast, recent empirical studies, including the work of our group, indicate that the topology of real networks is much richer than that of random graphs. In particular, the degree distribution of real networks is a power-law, indicating a heterogeneous topology in which the majority of the nodes have a small degree, but there is a significant fraction of highly connected nodes that play an important role in the connectivity of the network. 
The scale-free topology of real networks has very important consequences on their functioning. For example, we have discovered that scale-free networks are extremely resilient to the random disruption of their nodes. On the other hand, the selective removal of the nodes with highest degree induces a rapid breakdown of the network to isolated subparts that cannot communicate with each other. 
The non-trivial scaling of the degree distribution of real networks is also an indication of their assembly and evolution. Indeed, our modeling studies have shown us that there are general principles governing the evolution of networks. Most networks start from a small seed and grow by the addition of new nodes which attach to the nodes already in the system. This process obeys preferential attachment: the new nodes are more likely to connect to nodes with already high degree. We have proposed a simple model based on these two principles wich was able to reproduce the power-law degree distribution of real networks. Perhaps even more importantly, this model paved the way to a new paradigm of network modeling, trying to capture the evolution of networks, not just their static topology.

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Statistical mechanics of complex networks

A genetic model for colorectal tumorigenesis

http://www.maths.qmul.ac.uk/%7Elatora/report_06.pdf

Complex networks: Structure and dynamics

The adenoviruses were discovered in 1953–54 by two independent groups studying respiratory diseases (1, 2). W. Rowe and his collegues at the National Institute of Health in Bethesda, MD, USA, developed an experimental method for culturing adenoids that were removed from children. Cells derived from such cultured tissues subsequently liberated a viral agent which then destroyed these cells. The agent was called “the adenoid degenerating agent” or AD agent (1). At about the same time M. Hilleman and his research group at Merck Sharp and Dohme isolated a virus from the throat washings of military recruits (2). This virus replicated in and killed human HeLa cells in culture and was called “the respiratory illness agent” or RI agent (2). The RI agent and the AD agent were rapidly shown to be related to each other and the name adenoviruses was adopted to describe this group of viruses. Employing immunological reagents to classify viral antigens a large number of related adenoviruses, with a common group specific antigen, were detected in humans (3), monkies (4), dogs (5), mice (6), cattle (7), and birds (8). The adenovirus group now has over 90 members (9) with more than 40 distinct isolates of human origin (3). These viruses all share a common group specific antigen which is the exon virion subunit or virion surface capsid. Individual viruses are identified by a type specific antigen on the virion fiber protein which is responsible for absorption of viruses to cells.

The Molecular Biology of Adenoviruses

r(ts107)202 was isolated in HeLa cells as a temperature-independent revertant of H5ts107, an adenovirus mutant that maps in the structural gene of the viral DNA-binding protein. r(ts107)202 is a host-range temperature-conditional mutant: it is temperature independent for growth in HeLa cells but temperature sensitive for growth in 293 cells, a type 5 adenovirus-transformed human cell line. Marker rescue experiments using H5ts107 DNA and restriction enzyme fragments from r(ts107)202 DNA demonstrated that the mutations causing the r(ts107)202 phenotype were localized in HindIII fragment A containing the entire DNA-binding protein gene. To obtain a fine structure map of the r(ts107)202 mutations, overlap recombination between EcoRI fragment A (0-75.9 map units) from either Ad5wt or r(ts107)202 and BamHI fragment B (59.5-100 map units) from either Ad5wt or r(ts107)202 was performed. Segregation of the H5ts107 primary-site mutation away from the accompanying reversion mutation could be demonstrated in 5 of 200 plaques when r(ts107)202 EcoRI fragment A was crossed with the Ad5wt BamHI fragment. In the reciprocal cross, none of 200 plaques contained the H5ts107 mutant. These results permitted a determination of the order of the primary-site mutation (H5ts107) and secondary-site mutation in r(ts107)202, and the frequency of recombination predicted a distance of 50-340 base pairs between these two mutations. This experimental result agrees with the nucleotide sequence of the r(ts107)202 mutant which shows that 182 base pairs separate the primary-site and secondary-site mutations in r(ts107)202.

Detection, rescue, and mapping of mutations in the adenovirus DNA binding protein gene

A cell culture assay has been developed that detects and validates single-nucleotide polymorphisms (SNPs) in genes that populate the p53 pathway. One hundred thirteen EBV-transformed human B-lymphocyte cell lines obtained from a diverse population were employed to measure the apoptotic response to gamma radiation. Each cell line undergoes a reproducible, characteristic frequency of apoptosis, and the response of the population forms a normal distribution around a median of 35.5% apoptosis with a range from 12% to 58% apoptosis. Polymorphisms in the AKT1 and Perp genes significantly affect the frequency of apoptosis. The assay can detect both racial and sexual dimorphisms in these genes and has the ability to demonstrate epistatic relationships within the p53 pathway. The cell lines used in this assay provide biological materials to explore the molecular basis of the polymorphisms.

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Single-nucleotide polymorphisms in the p53 pathway.

Suppression of the temperature-sensitive character of adenovirus 12 early mutants in monkey cells transformed by an adenovirus 7-simian virus 40 hybrid.

Arnold J. Levine

Papers

The Molecular Biology of Adenoviruses

Detection, rescue, and mapping of mutations in the adenovirus DNA binding protein gene

Single-nucleotide polymorphisms in the p53 pathway.

Suppression of the temperature-sensitive character of adenovirus 12 early mutants in monkey cells transformed by an adenovirus 7-simian virus 40 hybrid.

The replication of papovavirus DNA.