Recursos de colección

DSpace at MIT (104.280 recursos)

This site is a university repository providing access to the publication output of the institution. Registered users can set up email alerts to notify them of newly added relevant content. A certain level of encryption and security is embedded in the site which may cause some users accessibility problems.

Computational and Systems Biology - Ph.D. / Sc.D.

Mostrando recursos 1 - 20 de 48

  1. Biochemical and functional characterization of human RNA binding proteins

    Freese, Peter (Peter Dale)
    RNA not only shuttles information between DNA and proteins but also carries out many other essential cellular functions. Nearly all steps of an RNA's life cycle are controlled by approximately one thousand RNA binding proteins (RBPs) that direct RNA splicing, cleavage and polyadenylation, localization, translation, and degradation. Despite the central role of RBPs in RNA processing and gene expression, they have been less well studied than DNA binding proteins, in part due to the historical dearth of technologies to probe RBP binding and activity in a high-throughput, comprehensive manner. In this thesis, I describe the affinity landscapes of the largest...

  2. Linking sequence to function in microbial genomics

    Spencer, Sarah Jean
    Microbial genomes show high plasticity due to horizontal transfer, large community sizes, and rapid growth paired with adaptive mutations. Despite this mutability of gene content, most studies of microbial communities still rely on bulk, single-gene amplicon sequencing. In this thesis, I present methods that interrogate the gene content of single cells derived from complex natural communities. In the first project, I present a novel molecular biology method to link a bacterial functional gene to its host species with single-cell resolution. This high-throughput protocol is applied to assess the distribution of anaerobic respiration genes in a lake ecosystem. In the second...

  3. A C. elegans histone methyltransferase promotes spermatocyte gene expression, spermatid production and fertility

    Engert, Christoph G
    To better understand the tissue-specific regulation of chromatin state in cell-fate determination and development, we defined the tissue-specific expression of all 36 lysine methyltransferase (KMT) genes by endogenous mRNA detection in C. elegans. We found that most KMTs are expressed in only one or two tissues and that the germline is the tissue with the most general KMT expression. We discovered that the germline-expressed C. elegans ortholog of mammalian PRDM9, SET-1 7, promotes fertility through gene regulation in primary spermatocytes. SET-17 drives transcription of spermatocyte-specific genes from four genomic clusters to promote spermatid production. SET-1 7 is concentrated in stable,...

  4. Enabling high-throughput single-cell growth measurements with parallel microchannel resonators

    Cermak, Nathan
    Single cells constitute a fundamental unit of biological organization, yet most laboratory techniques are unable to characterize single cell behavior and instead measure average properties of many thousands of cells. Among cellular behaviors, one of the most fundamental is growth, in which a cell turns inanimate material into biomass, which is then used to further create more biomass. However, there are few tools available to study the process of single cells growing. In this thesis, I demonstrate a new method for observing and quantifying the growth of single cells in high-throughput. This method is applicable to any cell that can...

  5. Enabling high-throughput single-cell growth measurements with parallel microchannel resonators

    Cermak, Nathan
    Single cells constitute a fundamental unit of biological organization, yet most laboratory techniques are unable to characterize single cell behavior and instead measure average properties of many thousands of cells. Among cellular behaviors, one of the most fundamental is growth, in which a cell turns inanimate material into biomass, which is then used to further create more biomass. However, there are few tools available to study the process of single cells growing. In this thesis, I demonstrate a new method for observing and quantifying the growth of single cells in high-throughput. This method is applicable to any cell that can...

  6. Deciphering the mitotic and meiotic phases of spermatogenesis in the mouse

    Romer, Katherine A
    Mammalian spermatogenesis includes two types of cell divisions. First, germ cells undergo transit-amplifying mitotic divisions, which enable prodigious output of mature spermatozoa. Second, they undergo reductive meiotic divisions to produce haploid gametes. In this thesis, I examine gene expression and regulation during the mitotic and meiotic phases of spermatogenesis. Chapter 2 describes how RA-STRA8 signaling regulates two key transitions: spermatogonial differentiation, which begins the transit-amplifying mitotic divisions, and meiotic initiation, which ends them. First, in mice lacking the RA (retinoic acid) target gene Stra8, undifferentiated spermatogonia accumulated; thus, Stra8 promotes spermatogonial differentiation as well as meiotic initiation. Second, injection of...

  7. Deciphering the mitotic and meiotic phases of spermatogenesis in the mouse

    Romer, Katherine A
    Mammalian spermatogenesis includes two types of cell divisions. First, germ cells undergo transit-amplifying mitotic divisions, which enable prodigious output of mature spermatozoa. Second, they undergo reductive meiotic divisions to produce haploid gametes. In this thesis, I examine gene expression and regulation during the mitotic and meiotic phases of spermatogenesis. Chapter 2 describes how RA-STRA8 signaling regulates two key transitions: spermatogonial differentiation, which begins the transit-amplifying mitotic divisions, and meiotic initiation, which ends them. First, in mice lacking the RA (retinoic acid) target gene Stra8, undifferentiated spermatogonia accumulated; thus, Stra8 promotes spermatogonial differentiation as well as meiotic initiation. Second, injection of...

  8. Measurement of rapid protein diffusion in the cytoplasm by photoconverted intensity profile expansion

    Gura Sadovsky, Rotem
    Whether at the level of a single protein, or in the cytoplasm as a whole, the diffusive mobility of proteins plays a key role in biological function. To measure protein diffusion in cells, researchers have developed multiple fluorescence microscopy methods, and have tested them rigorously. However, using these methods for precise measurement of diffusion coefficients requires expertise that can be a barrier to broad utilization of these methods. Here, we report on a new method we have developed, which we name Photo-converted Intensity Profile Expansion (PIPE). It is a simple and intuitive technique that works on commercial imaging systems and...

  9. Protein structure and interaction under environmental stress : from quality control recognition to evolution of collective behavior

    Brock, Kelly Paige
    A protein's function in the cell depends on its structure, which in turn depends on the intracellular environment. Stress like heat shock or nutrient starvation can alter intracellular conditions, leading to protein misfolding - i.e. the inability of a protein to reach or maintain its native conformation. Since many proteins interact with each other, protein misfolding and cellular stress response must be examined both on the scale of individual protein conformational changes and on a more global level, where interaction patterns can reveal larger-scale protein responses to cellular stress. On the individual scale, one example of a protein particularly susceptible...

  10. Uncovering the variability, regulatory roles and mutation rates of short tandem repeats

    Willems, Thomas F. (Thomas Frederick)
    Over the past decade, the advent of next-generation DNA sequencing technologies has ushered in an exciting era of biological research. Through large-scale sequencing projects, scientists have begun to unveil the variability and function of millions of DNA mutations called single nucleotide polymorphisms. Despite this rapid growth in understanding, short tandem repeats (STRs), genomic elements consisting of a repeating pattern of 2-6 bases, have remained poorly understood. Mutating orders of magnitude more rapidly than most of the human genome, STRs have been identified as the causal variants in diseases such as Fragile X syndrome and Huntington's disease. However, in spite of...

  11. Microbial community structure and dynamics on patchy landscapes

    Datta, Manoshi Sen
    Microbes are tiny metabolic engines with large-scale effects on industry, the environment, and human health. Understanding how the micron-scale actions (and interactions) of individual microbes give rise to macro-scale consequences remains a major challenge in microbial ecology. However, for the most part, studies employ coarsegrained sampling schemes, which average over the heterogeneous microscopic structure of microbial communities. This has limited our ability to establish mechanistic links between dynamics occurring across these disparate spatial scales. However, such links are critical for (a) making sense of the tremendous extant microbial diversity on Earth, and (b) predicting how perturbations (e.g., global climate change)...

  12. Computational insights into the ecology of the human microbiota

    Smillie, Christopher Scott
    The vast community of microbes that inhabit the human body, the human microbiota, is important to human health and disease. These microbes contribute to human metabolism, the development of the immune system and pathogen resistance, while imbalances among them have been associated with several diseases. In this work, I develop computational methods to gain key insights into the ecological principles that shape these communities. In the first chapter, I develop an evolutionary rate heuristic that leads to the discovery of a massive network of recently exchanged genes, connecting diverse bacteria throughout the human microbiota. Using this network, I examine the...

  13. Coordination of cellular force-generation during Drosophila ventral furrow formation

    Xie, Shicong, Ph. D. Massachusetts Institute of Technology
    Spatiotemporally coordinated cell behavior is observed during morphogenesis, in both embryonic development as well as tissue regeneration. An open question is how individual cells collectively generate force to achieve the correct tissue architecture. This thesis examines how the apical forces generated by Drosophila ventral furrow cells undergoing collective apical constriction are coordinated to fold the tissue. In Chapter 2, I investigate how discrete actomyosin contraction events are coordinated in time and between neighboring cells to yield tissue contraction and folding. I developed a computational pipeline to identify and classify contraction events from live images of ventral furrow formation. Using this...

  14. Rational drug combinations design against intratumoral heterogeneity and clonal evolution

    Zhao, Boyang
    Cancer is a clonal evolutionary process. This results in complex clonal architecture and intratumoral heterogeneity in each patient. This also presents challenges for effective therapeutic intervention - with constant selective pressure to induce or select pre-existing resistant subclones toward drug resistance. Mathematical/computational modeling from population genetics, evolutionary dynamics, and engineering are being utilized to a greater extent in recent times to study tumor progression, intratumoral heterogeneity, drug resistance, and rational drug scheduling/combinations design. In this thesis we present several joint quantitative and experimental approaches for the rational design of drug combinations to tackle the issue of intratumoral heterogeneity and clonal...

  15. MicroRNAs : principles of target recognition and developmental roles

    Agarwal, Vikram
    MicroRNAs (miRNAs) are ~21-24 nt non-coding RNAs that mediate the degradation and translational repression of target mRNAs. The genomes of vertebrate organisms encode hundreds of miRNAs, each of which may regulate hundreds of mRNA targets. Thus, miRNAs are crucial post-transcriptional regulators engaged in vast regulatory networks. To date, the characteristics of these networks remain mysterious due to the difficulty of identifying miRNA targets through either experimental or computational means. To understand the physiological roles of miRNAs in animal species, it is of fundamental importance to elucidate the structure of the targeting networks in which they participate. The recognition of a...

  16. Transcriptional and structural control of cell identity genes

    Fan, Zi Peng
    Mammals contain a wide array of cell types with distinct functions, yet nearly all cell types have the same genomic DNA. How the genetic instructions in DNA are selectively interpreted by cells to specify various cellular functions is a fundamental question in biology. This thesis work describes two genome-wide studies designed to study how transcriptional control of gene expression programs defines cell identity. Recent studies suggest that a small number of transcription factors, called "master" transcription factors, dominate the control of gene expression programs. These master transcription factors and the transcriptional regulatory circuitry they produce, however, are not known for...

  17. The dynamics of invariant object and action recognition in the human visual system

    Isik, Leyla
    Humans can quickly and effortlessly recognize objects, and people and their actions from complex visual inputs. Despite the ease with which the human brain solves this problem, the underlying computational steps have remained enigmatic. What makes object and action recognition challenging are identity-preserving transformations that alter the visual appearance of objects and actions, such as changes in scale, position, and viewpoint. The majority of visual neuroscience studies examining visual recognition either use physiology recordings, which provide high spatiotemporal resolution data with limited brain coverage, or functional MRI, which provides high spatial resolution data from across the brain with limited temporal...

  18. Order, disorder, and protein aggregation

    Gurry, Thomas
    Protein aggregation underlies a number of human diseases. Most notably, it occurs widely in neurodegenerative diseases, including Alzheimer's and Parkinson's. At the molecular level, neurotoxicity is thought to originate from toxic gains of function in multimeric aggregates of proteins that are otherwise predominantly monomeric and disordered, fluctuating between a very large number of structurally dissimilar states on nano- and microsecond timescales. These proteins, termed Intrinsically Disordered Proteins (IDPs), are notoriously difficult to probe using traditional biophysical techniques. In order to obtain structural information pertaining to the aggregation of IDPs, it is often necessary to develop computational and modeling tools, both...

  19. Computational design of orthogonal antiparallel homodimeric coiled coils

    Negron, Christopher
    Living cells integrate a vast array of protein-protein interactions (PPIs) to govern cellular functions. For instance, PPIs are critical to biosynthesis, nanostructural assembly, and in processing environmental stimuli through cell-signaling pathways. As fields such as synthetic biology and protein engineering mature they seek to mimic and expand the functions found in living systems that integrate PPIs. A critical feature to many PPIs that are integrated together to perform a complex function is orthogonality, i.e. PPIs that do not cross interact with each other. The engineering of orthogonal PPIs is thus an alluring problem. Since it not only tests our understanding...

  20. The mechanism and function of pervasive noncoding transcription in the mammalian genome

    Wu, Xuebing, Ph. D. Massachusetts Institute of Technology
    The vast majority of the mammalian genome does not encode proteins. Only 2% of the genome is exonic, yet recent deep survey of human transcripitome suggested that 75% of the genome is transcribed, including half of the intergenic regions. Such pervasive transcription typically leads to short-lived, low-copy number noncoding RNAs (ncRNAs). We are starting to understand the biogenesis and mechanisms regulating the noncoding transcription. However, it is still unclear what's the functional impact of pervasive transcription and the ncRNAs at the level of the'genome, the cell, and the organism. A large fraction of ncRNAs in cells is generated by divergent...

Aviso de cookies: Usamos cookies propias y de terceros para mejorar nuestros servicios, para análisis estadístico y para mostrarle publicidad. Si continua navegando consideramos que acepta su uso en los términos establecidos en la Política de cookies.