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Celebrating the Nobel Prize at Barbetta Restaurant
No full textCelebrating the Nobel Prize at Barbetta Restauranthttps://digitalcommons.rockefeller.edu/blobel-molecular-biology/1039/thumbnail.jp
The Frauenkirche and the Dresden Synagogue
No full textGünter Blobel with posters of the Frauenkirche and the Dresden Synagogue, 2000. Photo by I. Hargittaihttps://digitalcommons.rockefeller.edu/blobel-molecular-biology/1057/thumbnail.jp
Marjorie McCarty Oral History. Part 5: New career
No full textInterview recorded on September 14th, 2017. Part of the Rita and Frits Markus Library Oral History project.https://digitalcommons.rockefeller.edu/marjorie-mccarty/1004/thumbnail.jp
Biological Consequences of Atypical Phage Conversion in Gram-Positive Pathogens
Get PDFTemperate bacteriophage have a complex, dynamic relationship with bacteria: parasitizing in the lytic cycle, but often increasing bacteria\u27s fitness as lysogens. The phage-bacteria relationship is vast and has evolved over more than an estimated three billion years, and there are likely many uncharacterized, intricate events between host and phage with important impacts on bacterial pathogenesis. This Thesis explores some of these lesser-studied phage-bacteria interactions, describing atypical mechanisms ( conversion events ) by which phage shape the populations of Bacillus anthracis and Staphylococcus aureus, driving their increased diversity and likely impacting their natural behaviors. In B. anthracis, phage contributions to virulence are largely unknown. The first part of this Thesis describes how an induced phage from a highly virulent, B. anthracis-like isolate affects the well-characterized strain Sterne and selects for a phage-resistant variant with a markedly altered phenotype, but with no apparent difference in virulence potential. In this work, we characterize this variant strain by a variety of techniques, including whole-genome DNA and RNA-sequencing. In addition, we connect the Sterne variant phenotype to that of the phage\u27s parent strain, B. cereus Biovar anthracis CA, uncovering lytic phage-bacteria interactions (i.e., selection by lysis) that may act to promote phenotypic diversity and shape populations of B. anthracis and B. anthracis-like pathogenic species in the wild. Unlike B. anthracis, S. aureus has well-characterized bacteriophage contributions to its virulence potential, with known lysogens carrying virulence factors stably integrated into the host chromosome. The second part of this Thesis describes an extra-chromosomal DNA sequencing screening that uncovers the presence of episomal prophages in a number of S. aureus clinical isolates. QPCR characterization of one of these strains, MSSA476, reveals that the episomal nature of one of its prophages, ɸSa4ms, would have been missed if sequencing whole genomic and not specifically extra-chromosomal DNA. In addition, we find that ɸSa4ms excision into the cytoplasm is a temporal event, and that the prophage does not appear to undergo lytic cycle replication after excision—suggesting that its excision is part of a lysogenic switch. Follow-up experiments show that ɸSa4ms excision can alter expression of htrA2 and promote increased heat-stress tolerance. This work suggests that for S. aureus, in addition to carrying important virulence determinants, phage may also play a rather widespread role as DNA-level switches to control virulence factor expression and/or generate distinct subpopulations. While this Thesis discusses atypical phage conversion events, it also illustrates perhaps the most important, universal role of phage in bacterial pathogens: tools to create diversity and allow for bacteria\u27s increased infection and success under different evolutionary selections and environmental conditions
The Role of Neuronal Pentraxin 1 in Promoting Pancreatic Cancer Progression
Get PDFPancreatic cancer is a deadly malignancy because it is usually diagnosed at an advanced stage and does not respond to the majority of treatments. More than 80% of patients present with advanced stage disease at the time of diagnosis and metastatic pancreatic cancer has a median survival of eight to eleven months under current standard of care. In the United States, pancreatic cancer is the fourth leading cause of cancer death. Efforts in using targeted agents to treat pancreatic cancer have mostly been fruitless. The dismal survival outcome of this disease and lack of success in clinical trials indicate the necessity for new models and improved approaches toward therapies. Understanding the cellular and physiological basis of metastatic pancreatic cancer is therefore of great interest to the medical and scientific community with regard to developing new targeted therapies and diagnostic biomarkers. The first part of this thesis describes the establishment of two complementary pancreatic cancer metastasis mouse models using in vivo selection of livermetastatic pancreatic cancer cells from their poorly metastatic parental population. The first mouse model utilized a xenograft system, and the second model used a syngeneic system. Transcriptomic profiling was used to identify genes that were differentially expressed between the in vivo selected, highly metastatic cells and their poorly metastatic parental population in both mouse models. This approach identified Neuronal Pentraxin 1 (NPTX1) as a potential metastasis promoter because it was highly expressed in the in vivo selected, highly metastatic cancer cells compared to the poorly metastatic parental cells. Through in vivo functional assays, NPTX1 was found to promote pancreatic cancer progression. NPTX1 was necessary to promote progression of established liver macro-metastases, a rate limiting step in the metastasis cascade. The second part of this thesis presents mechanistic studies that describe NPTX1\u27s role in promoting cancer cell proliferating under a hypoxic tumor microenvironment. This proliferation advantage allows cancer cells to survive both in the primary tumor and promotes distal organ metastatic colonization. The final part of this study reveals NPTX1 to be clinically relevant in patient samples. NPTX1 was found to be expressed in pancreatic tumor samples, but not in healthy pancreatic tissues. In addition, NPTX1 could be detected in the plasma of the xenograft mouse model, demonstrating the diagnostic and therapeutic potential of this secreted protein in pancreatic cancer
In Search of Generic Properties of Evolved Systems: From Elasticity of Proteins to Structure of Metabolic Networks
No full textIn many proteins - especially allosteric proteins that couple regulatory state at allosteric sites to function at active sites - structural deformations are functionally important. To understand these deformations, dynamical experiments are ideal but challenging. Structural displacements can be difficult to analyze and interpret. Static structural information, although more limited than dynamical analysis, is much more experimentally accessible. The large quantity of available static protein structural data makes more effective analysis and interpretation of such data a valuable tool to supplement experimental study of protein mechanics. Although underused for protein analysis, strain is the natural quantity for studying local deformations. I calculated strain tensor fields in proteins deformed by ligand binding or thermal fluctuations using X-ray crystallography, NMR, and electron microscopy structure ensembles. Strains - primarily shears - show deformations around binding sites. These deformations can be induced solely by ligand binding at distant allosteric sites. Shears reveal quasi-2D paths of mechanical coupling between allosteric and active sites that may constitute a widespread mechanism of allostery. Moreover, other transformations of displacements yield additional insights. I studied divergence and curl of deformations of the transmembrane channel KcsA. In addition, I introduced quantities analogous to bend, splay, and twist deformation energies of nematic liquid crystals. These transformations enable decomposition of displacements into distinct modes of deformation, helping characterize the types of deformation a protein undergoes. I applied these calculations to study the filter and gating regions of KcsA. I identified a continuous path of rotational deformations that physically couples these two regions and, I propose, underlies the allosteric interaction between these regions. Bend, splay, and twist distinguish KcsA gate opening, filter opening, and filter-gate coupling, respectively. I argue that strain - particularly shear - is the most appropriate quantity for analysis of local protein deformations. More generally, physically meaningful representations of deformations such as strain, curl, bend, splay, and twist can make testable predictions and provide insights into protein mechanics, augmenting experimental methods and more fully exploiting available structural data. Separately, I worked to better understand the consequences of environmental fluctuations on evolved systems. Previous work by several groups in addition to my own preliminary investigations, has shown that a variety of interesting effects - including evolution of noise-robust phenotypes and increased speed of evolutionary adaptation in fluctuating environments - can occur as a result of environmental changes. However, these results are model-dependent, resulting in need for a biologically plausible model system. Previous work has employed flux balance analysis to predict the metabolic phenotypes of synthetic genotypes sampled from a genotype space determined by empirical metabolic databases. That work identified intriguing properties of the set of viable genotypes: the viable fraction of genotypes is very small, yet the set is connected and spans the genotype space. Seeking to better understand the organization of the viable set in that model, I investigated the geometry of the viable set. I found that the viable set has a very small effective dimension (approximately 3, in an 8000-dimensional genotype space) and exhibits significant spatial correlations. In contrast, the embedding dimension of the viable set is large (at least 1000-dimensions in cases studied here). While further work to better understand the relationship between the small effective dimension and large embedding dimension is ongoing, I studied random walk dynamics on the viable set to test how its geometry could affect evolutionary dynamics. The drift speed of biased random walks increases monotonically with the bias, suggesting a lack of trapping. Consequently and in contrast to some model systems, evolutionary dynamics in alternating environmental conditions are not faster than dynamics in fixed environments in this metabolic model. Better understanding of the geometry of the viable set in the metabolic genotype space could yield insight into the degree to which these properties were evolutionarily selected or were generic properties of high-dimensional fitness landscapes
Leyla Vural, Franklin Hoke, Matthew Covey
No full text(left to right): Leyla Vural, Franklin Hoke, Matthew Covey
Photo by Lubosh Stepanekhttps://digitalcommons.rockefeller.edu/open-house-2018/1010/thumbnail.jp
Reception. Guests
No full textMarkus Library Open House, reception
Photo by Lubosh Stepanekhttps://digitalcommons.rockefeller.edu/open-house-2018/1022/thumbnail.jp
The history and present state of discoveries relating to vision, light, and colours
No full textPriestley, Joseph. The history and present state of discoveries relating to vision, light, and colours. London, 1772
Photo by Lubosh Stepanekhttps://digitalcommons.rockefeller.edu/alfred-cohn-collection/1038/thumbnail.jp
Waltersdorf
No full textWaltersdorf, Germany; circa 1935
Günter Blobel was born on May 21st, 1936 in Waltersdorf in the Prussian Province of Lower Silesia, then located in eastern Germany (now part of Poland).https://digitalcommons.rockefeller.edu/blobel-molecular-biology/1001/thumbnail.jp