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MIT Open Access Articles
Mostrando recursos 41 - 60 de 11,271
Identifying Recent Adaptations in Large-Scale Genomic Data - Andersen, Kristian G.; Shlyakhter, Ilya; Tabrizi, Shervin; Winnicki, Sarah; Yen, Angela; Park, Daniel J.; Griesemer, Dustin; Karlsson, Elinor K.; Wong, Sunny H.; Cabili, Moran; Adegbola, Richard A.; Bamezai, Rameshwar N.K.; Hill, Adrian V.S.; Vannberg, Fredrik O.; Rinn, John L.; Lander, Eric S.; Schaffner, Stephen F.; Sabeti, Pardis C.; Grossman, Sharon Rachel; Lander, Eric S.
Although several hundred regions of the human genome harbor signals of positive natural selection, few of the relevant adaptive traits and variants have been elucidated. Using full-genome sequence variation from the 1000 Genomes (1000G) Project and the composite of multiple signals (CMS) test, we investigated 412 candidate signals and leveraged functional annotation, protein structure modeling, epigenetics, and association studies to identify and extensively annotate candidate causal variants. The resulting catalog provides a tractable list for experimental follow-up; it includes 35 high-scoring nonsynonymous variants, 59 variants associated with expression levels of a nearby coding gene or lincRNA, and numerous variants associated...
An Sp1 transcription factor coordinates caspase-dependent and -independent apoptotic pathways - Hirose, Takashi; Horvitz, H. Robert
During animal development, the proper regulation of apoptosis requires the precise spatial and temporal execution of cell-death programs, which can include both caspase-dependent and caspase-independent pathways. Although the mechanisms of caspase-dependent and -independent cell killing have been examined extensively, how these pathways are coordinated within a single cell that is fated to die is unknown. Here we show that the Caenorhabditis elegans Sp1 transcription factor SPTF-3 specifies the programmed cell deaths of at least two cells—the sisters of the pharyngeal M4 motor neuron and the AQR sensory neuron—by transcriptionally activating both caspase-dependent and -independent apoptotic pathways. SPTF-3 directly drives the...
A mm-Scale Aeroelastic Oscillation-Based Anemometer - McKay, Ian
By combining the aeroelastic and vortex-forced flutter modes of a thin plastic strip, its oscillation frequency can be confined to scale monotonically with fluid velocity. This principle has been used to produce a low-cost, mm-scale anemometer that measures air speed to ±(5% + 0.5m/s) from 1–18m/s. The device uses a 2mm slot-type photointerrupt detector to monitor the fundamental frequency of a 7μm thick Kapton strip suspended parallel to air flow. This paper describes the prototype and three of the experiments that informed its design. These investigated the effect of a bluff body on flutter onset velocity, the effect of filament...
Lattice ellipsoidal statistical BGK model for thermal non-equilibrium flows - Meng, Jianping; Zhang, Yonghao; Radtke, Gregg A.; Shan, Xiaowen; Hadjiconstantinou, Nicolas
A thermal lattice Boltzmann model is constructed on the basis of the ellipsoidal statistical Bhatnagar–Gross–Krook (ES-BGK) collision operator via the Hermite moment representation. The resulting lattice ES-BGK model uses a single distribution function and features an adjustable Prandtl number. Numerical simulations show that using a moderate discrete velocity set, this model can accurately recover steady and transient solutions of the ES-BGK equation in the slip-flow and early transition regimes in the small-Mach-number limit that is typical of microscale problems of practical interest. In the transition regime in particular, comparisons with numerical solutions of the ES-BGK model, direct and low-variance deviational...
ZFHX4 Interacts with the NuRD Core Member CHD4 and Regulates the Glioblastoma Tumor-Initiating Cell State - Chudnovsky, Yakov; Kim, Dohoon; Zheng, Siyuan; Whyte, Warren A.; Bansal, Mukesh; Bray, Mark-Anthony; Gopal, Shuba; Theisen, Matthew A.; Bilodeau, Steve; Thiru, Prathapan; Muffat, Julien; Yilmaz, Omer; Mitalipova, Maya; Woolard, Kevin; Lee, Jeongwu; Nishimura, Riko; Sakata, Nobuo; Fine, Howard A.; Carpenter, Anne E.; Silver, Serena J.; Verhaak, Roel G.W.; Califano, Andrea; Young, Richard A.; Ligon, Keith L.; Mellinghoff, Ingo K.; Root, David E.; Sabatini, David M.; Hahn, William C.; Chheda, Milan G.; Whyte, Warren A.
Glioblastoma (GBM) harbors subpopulations of therapy-resistant tumor-initiating cells (TICs) that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397 kDa transcription factor. ZFHX4 is required to maintain TIC-associated and normal human neural precursor cell phenotypes in vitro, suggesting that ZFHX4 regulates differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the nucleosome remodeling and deacetylase (NuRD) complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression...
Heterogeneity of tumor-induced gene expression changes in the human metabolic network - Hu, Jie; Locasale, Jason W; Bielas, Jason H; O'Sullivan, Jacintha; Sheahan, Kieran; Cantley, Lewis C; Vander Heiden, Matthew G.; Vitkup, Dennis
Reprogramming of cellular metabolism is an emerging hallmark of neoplastic transformation. However, it is not known how the expression of metabolic genes in tumors differs from that in normal tissues, or whether different tumor types exhibit similar metabolic changes. Here we compare expression patterns of metabolic genes across 22 diverse types of human tumors. Overall, the metabolic gene expression program in tumors is similar to that in the corresponding normal tissues. Although expression changes of some metabolic pathways (e.g., upregulation of nucleotide biosynthesis and glycolysis) are frequently observed across tumors, expression changes of other pathways (e.g., oxidative phosphorylation) are very...
Detection of 2-Hydroxyglutarate in IDH-Mutated Glioma Patients by In Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy - Andronesi, Ovidiu C.; Kim, Grace S.; Gerstner, Elizabeth; Batchelor, Tracy; Tzika, Aria A.; Fantin, Valeria R.; Vander Heiden, Matthew G.; Sorensen, A. Gregory
Mutations in the gene isocitrate dehydrogenase 1 (IDH1) are present in up to 86% of grade II and III gliomas and secondary glioblastoma. Arginine 132 (R132) mutations in the enzyme IDH1 result in excess production of the metabolite 2-hydroxyglutarate (2HG), which could be used as a biomarker for this subset of gliomas. Here, we use optimized in vivo spectral-editing and two-dimensional (2D) correlation magnetic resonance spectroscopy (MRS) methods to unambiguously detect 2HG noninvasively in glioma patients with IDH1 mutations. By comparison, fitting of conventional 1D MR spectra can provide false-positive readouts owing to spectral overlap of 2HG and chemically similar...
Promoter directionality is controlled by U1 snRNP and polyadenylation signals - Almada, Albert Ernesto; Wu, Xuebing; Kriz, Andrea J.; Burge, Christopher B.; Sharp, Phillip A.
Transcription of the mammalian genome is pervasive, but productive transcription outside of protein-coding genes is limited by unknown mechanisms1. In particular, although RNA polymerase II (RNAPII) initiates divergently from most active gene promoters, productive elongation occurs primarily in the sense-coding direction2, 3, 4. Here we show in mouse embryonic stem cells that asymmetric sequence determinants flanking gene transcription start sites control promoter directionality by regulating promoter-proximal cleavage and polyadenylation. We find that upstream antisense RNAs are cleaved and polyadenylated at poly(A) sites (PASs) shortly after initiation. De novo motif analysis shows PAS signals and U1 small nuclear ribonucleoprotein (snRNP) recognition...
Identification of the Cdc48•20S Proteasome as an Ancient AAA+ Proteolytic Machine - Barthelme, Dominik; Sauer, Robert T.
Proteasomes are the major energy-dependent proteolytic machines in the eukaryotic and archaeal domains of life. To execute protein degradation, the 20S core peptidase combines with the AAA+ ring of the 19S regulatory particle in eukarya or with the AAA+ proteasome-activating nucleotidase ring in some archaea. Here, we find that Cdc48 and 20S from the archaeon Thermoplasma acidophilum interact to form a functional proteasome. Cdc48 is an abundant and essential double-ring AAA+ molecular machine ubiquitously present in archaea, where its function has been uncertain, and in eukarya where Cdc48 participates by largely unknown mechanisms in diverse cellular processes, including multiple proteolytic...
Signal integration by DegS and RseB governs the E-mediated envelope stress response in Escherichia coli - Chaba, Rachna; Alba, Benjamin M.; Guo, Monica S.; Sohn, Jungsan; Ahuja, Nidhi; Sauer, Robert T.; Gross, Carol A.
In Escherichia coli, the σ[superscript E] transcription factor monitors and maintains outer membrane (OM) integrity by activating genes required for assembly of its two key components, outer membrane proteins (OMPs) and lipopolysaccharide (LPS) and by transcribing small RNAs to down-regulate excess unassembled OMPs. σ[superscript E] activity is governed by the rate of degradation of its membrane-spanning anti-σ factor, RseA. Importantly, the DegS protease can initiate RseA cleavage only when activated by binding to unassembled OMPs. The prevalent paradigm has been that the σE response is controlled by the amount of activated DegS. Here we demonstrate that inactivation of a second...
Oxygen-Dependent Morphogenesis of Modern Clumped Photosynthetic Mats and Implications for the Archean Stromatolite Record - Sim, Min Sub; Liang, Biqing; Petroff, Alexander P.; Evans, Alexander; Klepac-Ceraj, Vanja; Flannery, David T.; Walter, Malcolm R.; Bosak, Tanja
Some modern filamentous oxygenic photosynthetic bacteria (cyanobacteria) form macroscopic tufts, laminated cones and ridges that are very similar to some Archean and Proterozoic stromatolites. However, it remains unclear whether microbes that constructed Archean clumps, tufts, cones and ridges also produced oxygen. Here, we address this question by examining the physiology of cyanobacterial clumps, aggregates ~0.5 mm in diameter that initiate the growth of modern mm- and cm-scale cones. Clumps contain more particulate organic carbon in the form of denser, bowed and bent cyanobacterial filaments, abandoned sheaths and non-cyanobacterial cells relative to the surrounding areas. Increasing concentrations of oxygen in the...
Biofilm Growth and Fossil Form - Petroff, Alexander P.; Beukes, N. J.; Rothman, Daniel H.; Bosak, Tanja
Stromatolites can grow under the influence of microbial processes, but it is often unclear whether and how the macroscopic morphology of these rocks records biological processes. Conical stromatolites, which formed in the absence of sedimentation, provide a comparatively simple record of the interplay between microbial growth and lithification. Here, we show that the dynamics shaping conical stromatolites result from diffusive gradients within the overlying microbial mat. These gradients cause minerals to precipitate faster in regions of high curvature, resulting in measurable properties of the shapes of stromatolite laminas. This model allows us to estimate the thickness of ancient stromatolite-forming mats...
Spectral and spin measurement of two small and fast-rotating near-Earth asteroids - Polishook, David; Binzel, Richard P.; Lockhart, Matthew; DeMeo, Francesca E.; Golisch, W.; Bus, S.J.; Gulbis, Amanda A. S.
In May 2012 two asteroids made near-miss “grazing” passes at distances of a few Earth-radii: 2012 KP24 passed at 9 Earth-radii and 2012 KT42 at only 3 Earth-radii. The latter passed inside the orbital distance of geosynchronous satellites. From spectral and imaging measurements using NASA’s 3-m Infrared Telescope Facility (IRTF), we deduce taxonomic, rotational, and physical properties. Their spectral characteristics are somewhat atypical among near-Earth asteroids: C-complex for 2012 KP24 and B-type for 2012 KT42, from which we interpret the albedos of both asteroids to be between 0.10 and 0.15 and maximum effective diameters of 20 ± 6 and 6...
Dynamical parameter determinations in Pluto’s system - Beauvalet, L.; Lainey, V.; Arlot, J.-E.; Binzel, Richard P.
Pluto is the multiple system that has been observed the longest. Yet, the masses of its smallest satellites, Nix and Hydra, which were discovered in 2005, are still imprecisely known, because of the short time span and number of available observations. We present a numerical model that takes into account the second order gravity fields and Pluto’s orbital motion in the solar system. We investigated the dynamical parameters that may be reliably determined today. We also assessed the possible improvements on the parameter uncertainties with the future increase of observations, including the New Horizons mission. Fitting our model to simulated...
Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation - Shi, Junwei; Whyte, Warren A.; Zepeda-Mendoza, Cinthya J.; Milazzo, Joseph P.; Shen, Chen; Roe, Jae-Seok; Minder, Jessica L.; Mercan, Fatih; Wang, Eric; Eckersley-Maslin, Melanie A.; Campbell, Amy E.; Kawaoka, Shinpei; Shareef, Sarah; Zhu, Zhu; Kendall, Jude; Muhar, Matthias; Haslinger, Christian; Yu, Ming; Roeder, Robert G.; Wigler, Michael H.; Blobel, Gerd A.; Zuber, Johannes; Spector, David L.; Young, Richard A.; Vakoc, Christopher R.
Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cell types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 Mb downstream from Myc that are occupied by SWI/SNF as well...
SnapShot: DNA Polymerases II Mammals - Foti, James J.; Walker, Graham C.
DNA polymerases ensure the faithful duplication of genetic information inside the nuclease and mitochondria of eukaryotic cells and the nucleoid of prokaryotic cells. These remarkable enzymes synthesize polynucleotide chains based on the complementarity of an incoming nucleotide to an existing DNA template. DNA polymerases are grouped into six families (A, B, C, D, X, and Y). The previous SnapShot (DNA Polymerases I Prokaryotes) described the structural and functional characteristics conserved across the families, using the DNA polymerases from the bacterium Escherichia coli as an example. In this SnapShot, we now highlight DNA polymerases from humans (Homo sapiens) and their relationship...
SnapShot: DNA Polymerases I Prokaryotes - Foti, James J.; Walker, Graham C.
The nucleus and mitochondria of eukaryote cells and the nucleoid of prokaryote cells contain remarkable enzymes, called DNA polymerases, which ensure the faithful duplication of genetic material. These enzymatic machines incorporate the building blocks of DNA, deoxyribonucleotide triphosphates (dNTPs), into growing polynucleotide chains. The error rate of these enzymes is astonishingly low with only ~1 error for every 10 [superscript 9]–10[superscript 10] bases replicated. The first safeguard contributing to this low error rate is the ability of the DNA polymerase to discriminate among incoming dNTPs based on their complementarity to a parental DNA template. However, in the event of misincorporation,...
Hydroxyurea Induces Hydroxyl Radical-Mediated Cell Death in Escherichia coli - Davies, Bryan W.; Kohanski, Michael A.; Simmons, Lyle A.; Winkler, Jonathan A.; Collins, James J.; Walker, Graham C.
Hydroxyurea (HU) specifically inhibits class I ribonucleotide reductase (RNR), depleting dNTP pools and leading to replication fork arrest. Although HU inhibition of RNR is well recognized, the mechanism by which it leads to cell death remains unknown. To investigate the mechanism of HU-induced cell death, we used a systems-level approach to determine the genomic and physiological responses of E. coli to HU treatment. Our results suggest a model by which HU treatment rapidly induces a set of protective responses to manage genomic instability. Continued HU stress activates iron uptake and toxins MazF and RelE, whose activity causes the synthesis of...
Understanding Metabolic Regulation and Its Influence on Cell Physiology - Metallo, Christian M.; Vander Heiden, Matthew G.; Vander Heiden, Matthew G.
Metabolism impacts all cellular functions and plays a fundamental role in biology. In the last century, our knowledge of metabolic pathway architecture and the genomic landscape of disease has increased expo- nentially. Combined with these insights, advances in analytical methods for quantifying metabolites and systems approaches to analyze these data now provide powerful tools to study metabolic regulation. Here we review the diverse mechanisms cells use to adapt metabolism to specific physiological states and discuss how metabolic flux analyses can be applied to identify important regulatory nodes to understand normal and pathological cell physiology.
Development of schemas revealed by prior experience and NMDA receptor knock-out - Dragoi, George; Tonegawa, Susumu
Prior experience accelerates acquisition of novel, related information through processes like assimilation into mental schemas, but the underlying neuronal mechanisms are poorly understood. We investigated the roles that prior experience and hippocampal CA3 N-Methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity play in CA1 place cell sequence encoding and learning during novel spatial experiences. We found that specific representations of de novo experiences on linear environments were formed on a framework of pre configured network activity expressed in the preceding sleep and were rapidly, flexibly adjusted via NMDAR-dependent activity. This prior experience accelerated encoding of subsequent experiences on contiguous or isolated novel tracks,...