Klevers, Denis; Taylor IV, Washington
We give an explicit construction of a class of F-theory models with matter in the three-index symmetric (4) representation of SU(2). This matter is realized at codimen-sion two loci in the F-theory base where the divisor carrying the gauge group is singular; the associated Weierstrass model does not have the form associated with a generic SU(2) Tate model. For 6D theories, the matter is localized at a triple point singularity of arithmetic genus g = 3 in the curve supporting the SU(2) group. This is the first explicit realization of matter in F-theory in a representation corresponding to a genus...
Bates, Richard B; Altantzis, Christos; Ghoniem, Ahmed F
Char conversion is one of the most pivotal factors governing the effectiveness of fluidized bed gasification systems. Gasification-assisted attrition is a phenomenon whereby heterogeneous reactions progressively weaken a char’s structure throughout its lifetime leading to enhanced attrition and the production of a significant fraction of fines that exit the reactor unconverted. While this effect has been observed and measured experimentally, few models have been developed to quantitatively account for it, particularly for biomass chars. In this study, a transient gasification and combustion particle model is presented to describe primary fragmentation, attrition, and heterogeneous reactions of a single batch of particles....
Jonas, Oliver H.; Cheah, Jaime H; Cima, Michael J; Langer, Robert S
Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRISPR-Cas9 and RNAi loss-of-function screens and a small-molecule screen focused on druggable cancer targets. Integrating these three complementary and orthogonal methods, we identify CDK4 and XPO1 as potential
Makarova, Kira S.; van der Oost, John; Koonin, Eugene V.; Zetsche, Bernd; Gootenberg, Jonathan S; Abudayyeh, Omar Osama; Slaymaker, Ian; Essletzbichler, Patrick; Volz, Sara E.; Joung, Julia; Regev, Aviv; Zhang, Feng
The microbial adaptive immune system CRISPR mediates defense against foreign genetic elements through two classes of RNA-guided nuclease effectors. Class 1 effectors utilize multiprotein complexes, whereas Class 2 effectors rely on single-component effector proteins such as the well-characterized Cas9. Here we report characterization of Cpf1, a putative Class 2 CRISPR effector. We demonstrate that Cpf1 mediates robust DNA interference with features distinct from Cas9. Cpf1 is a single RNA-guided endonuclease lacking tracrRNA, and it utilizes a T-rich protospacer adjacent motif. Moreover, Cpf1 cleaves DNA via a staggered DNA double stranded break. Out of 16 Cpf1-family proteins, we identified two candidate...
Mehta, Arnav; Zhao, Jimmy L.; Sinha, Nikita; Marinov, Georgi K.; Mann, Mati; Kowalczyk, Monika S.; Galimidi, Rachel P.; Du, Xiaomi; Erikci, Erdem; Chowdhury, Kamal; Baltimore, David; Regev, Aviv
MicroRNAs are critical post-transcriptional regulators of hematopoietic cell-fate decisions, though little remains known about their role in aging hematopoietic stem cells (HSCs). We found that the regulated during aging. Both over-expression and deletion of microRNAs in this cluster leads to inappropriate hematopoiesis with age. Enforced expression of miR-132 in the bone marrow of mice led to rapid HSC cycling and depletion. A genetic deletion of Mirc19 in mice resulted in HSCs that had altered cycling, function, and survival in response to growth factor starvation. We found that miR-132 exerted its effect on aging HSCs by targeting the transcription factor FOXO3,...
Satija, Rahul; Farrell, Jeffrey A; Gennert, David; Schier, Alexander F; Regev, Aviv
Spatial localization is a key determinant of cellular fate and behavior, but methods for spatially resolved, transcriptome-wide gene expression profiling across complex tissues are lacking. RNA staining methods assay only a small number of transcripts, whereas single-cell RNA-seq, which measures global gene expression, separates cells from their native spatial context. Here we present Seurat, a computational strategy to infer cellular localization by integrating single-cell RNA-seq data with in situ RNA patterns. We applied Seurat to spatially map 851 single cells from dissociated zebrafish (Danio rerio) embryos and generated a transcriptome-wide map of spatial patterning. We confirmed Seurat's accuracy using several...
Raychowdhury, Raktima; Jovanovic, Marko; Stumpo, Deborah J.; Pauli, Andrea; Hacohen, Nir; Schier, Alexander F.; Blackshear, Perry J.; Friedman, Nir; Amit, Ido; Rabani, Michal; Rooney, Michael Steven; Regev, Aviv
Cells control dynamic transitions in transcript levels by regulating transcription, processing, and/or degradation through an integrated regulatory strategy. Here, we combine RNA metabolic labeling, rRNA-depleted RNA-seq, and DRiLL, a novel computational framework, to quantify the level; editing sites; and transcription, processing, and degradation rates of each transcript at a splice junction resolution during the LPS response of mouse dendritic cells. Four key regulatory strategies, dominated by RNA transcription changes, generate most temporal gene expression patterns. Noncanonical strategies that also employ dynamic posttranscriptional regulation control only a minority of genes, but provide unique signal processing features. We validate Tristetraprolin (TTP) as...
van Wolfswinkel, Josien C.; Wagner, Daniel Elger; Reddien, Peter
Planarians are flatworms capable of regenerating any missing body region. This capacity is mediated by neoblasts, a proliferative cell population that contains pluripotent stem cells. Although population-based studies have revealed many neoblast characteristics, whether functionally distinct classes exist within this population is unclear. Here, we used high-dimensional single-cell transcriptional profiling from over a thousand individual neoblasts to directly compare gene expression fingerprints during homeostasis and regeneration. We identified two prominent neoblast classes that we named ζ (zeta) and σ (sigma). Zeta-neoblasts encompass
specified cells that give rise to an abundant postmitotic lineage including epidermal cells, and are
not required for regeneration. By...
Mansuripur, Tobias S.; Vernet, Camille; Chevalier, Paul; Aoust, Guillaume; Schwarz, Benedikt; Xie, Feng; Caneau, Catherine; Lascola, Kevin; Zah, Chung-en; Caffey, David P.; Day, Timothy; Belyanin, Alexey; Capasso, Federico; Missaggia, Leo J.; Connors, Michael K.; Wang, Christine A.
We report the observation of a clear single-mode instability threshold in continuous-wave Fabry-Perot quantum cascade lasers (QCLs). The instability is characterized by the appearance of sidebands separated by tens of free spectral ranges (FSR) from the first lasing mode, at a pump current not much higher than the lasing threshold. As the current is increased, higher-order sidebands appear that preserve the initial spacing, and the spectra are suggestive of harmonically phase-locked waveforms. We present a theory of the instability that applies to all homogeneously broadened standing-wave lasers. The low instability threshold and the large sideband spacing can be explained by...
Hummelt, Jason Samuel; Lu, X.; Xu, H.; Mastovsky, Ivan; Shapiro, Michael; Temkin, Richard J
An electron beam passing through a metamaterial structure is predicted to generate reversed Cherenkov radiation, an unusual and potentially very useful property. We present an experimental test of this phenomenon using an intense electron beam passing through a metamaterial loaded waveguide. Power levels of up to 5 MW are observed in backward wave modes at a frequency of 2.40 GHz using a one microsecond pulsed electron beam of 490 keV, 84 A in a 400 G magnetic field. Contrary to expectations, the output power is not generated in the Cherenkov mode. Instead, the presence of the magnetic field, which is required to transport the electron...
Zhang, Xue-Qing; Farokhzad, Omid C.; Xu, Xiaoyang; Xue, Yuan; Langer, Robert S
The incidence of obesity, which is recognized by the American Medical Association as a disease, has nearly doubled since 1980, and obesity-related comorbidities have become a major threat to human health. Given that adipose tissue expansion and transformation require active growth of new blood vasculature, angiogenesis offers a potential target for the treatment of obesity-associated disorders. Here we construct two peptide-functionalized nanoparticle (NP) platforms to deliver either Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) activator rosiglitazone (Rosi) or prostaglandin E2 analog (16,16-dimethyl PGE2) to adipose tissue vasculature. These NPs were engineered through self-assembly of a biodegradable triblock polymer composed of end-to-end linkages...
Yurtsev, Eugene; Conwill, Arolyn Macdonald; Gore, Jeff
Cooperation between microbes can enable microbial communities to survive in harsh environments. Enzymatic deactivation of antibiotics, a common mechanism of antibiotic resistance in bacteria, is a cooperative behavior that can allow resistant cells to protect sensitive cells from antibiotics. Understanding how bacterial populations survive antibiotic exposure is important both clinically and ecologically, yet the implications of cooperative antibiotic deactivation on the population and evolutionary dynamics remain poorly understood, particularly in the presence of more than one antibiotic. Here, we show that two Escherichia coli strains can form an effective crossprotection mutualism, protecting each other in the presence of two antibiotics...
Apyan, Aram; Bauer, Gerry P; Busza, Wit; Butz, Erik M.; Cali, Ivan Amos; Chan, Matthew Hans; Dutta, Valentina; Gomez-Ceballos, Guillelmo; Goncharov, Maxim; Kim, Yongsun; Klute, Markus; Levin, Andrew Michael; Luckey Jr, P David; Ma, Teng; Nahn, Steven; Paus, Christoph M. E.; Ralph, Duncan Kelley; Roland, Christof E; Roland, Gunther M; Stephans, George S. F.; Stoeckli, Fabian; Sumorok, Konstanty C; Sung, Kevin Kai Hong; Velicanu, Dragos Alexandru; Wolf, Roger; Wyslouch, Boleslaw; Yang, Mingming; Yilmaz, Yetkin; Yoon, A. S.; Zanetti, Marco; Wyslouch, Victoria
A search for a standard-model-like Higgs boson in the H → WW and H → ZZ decay channels is reported, for Higgs boson masses in the range 145 < mH < 1000 GeV. The search is based upon proton–proton collision
data samples corresponding to an integrated luminosity of up to 5.1 fb[superscript −1] at √s = 7 TeV and up to 5.3 fb[superscript −1] at √s = 8 TeV, recorded by the CMS experiment at the LHC. The combined upper limits at 95 % confidence level on products of the cross section and branching fractions exclude a standard-model-like Higgs boson in...
Taylor, Frank E
A study of W[superscript ±]Z production in proton-proton collisions at √s = 7 TeV is presented using data corresponding to an integrated luminosity of 4.6 fb[superscript −1] collected with the ATLAS detector at the Large Hadron Collider in 2011. In total, 317 candidates, with a background expectation of 68 ± 10 events, are observed in double-leptonic decay final states with electrons, muons and missing transverse momentum. The total cross-section is determined to be σ[superscript tot][subscript WZ] = 19.0[superscript +1.4][subscript −1.3](stat.) ± 0.9(syst.) ± 0.4(lumi.) pb, consistent with the Standard Model expectation of 17.6[superscript +1.1]
[subscript−1.0] pb. Limits on anomalous triple gauge...
Alver, Burak Han; Bauer, Gerry P; Bendavid, Joshua L.; Busza, Wit; Cali, Ivan Amos; Chan, Matthew Hans; Dutta, Valentina; Gomez-Ceballos, Guillelmo; Goncharov, Maxim; Hahn, Kristian Allan; Kim, Yongsun; Klute, Markus; Lee, Yen-Jie; Li, W.; Luckey Jr, P David; Ma, Teng; Nahn, Steven; Paus, Christoph M. E.; Ralph, Duncan Kelley; Roland, Christof E; Roland, Gunther M; Rudolph, Matthew Scott; Stephans, George S. F.; Stoeckli, Fabian; Sumorok, Konstanty C; Sung, Kevin Kai Hong; Velicanu, Dragos Alexandru; Wenger, Edward Allen; Wolf, Roger; Wyslouch, Boleslaw; Xie, Si; Yang, Mingming; Yilmaz, Yetkin; Yoon, A. S.; Zanetti, Marco
A measurement of the underlying event (UE) activity in proton–proton collisions at a center-of-mass energy of 7 TeV is performed using Drell–Yan events in a data sample corresponding to an integrated luminosity of 2.2 fb[superscript −1], collected by the CMS experiment at the LHC. The activity measured in the muonic final state (qq → μ[superscript +]μ[superscript −]) is corrected to the particle level and compared with the predictions of various Monte Carlo generators and hadronization models. The dependence of the UE activity on the dimuon invariant mass is well described by PYTHIA and HERWIG++ tunes derived from the leading jet/track...
Dann, Christoph; Dabney, William; Geramifard, Alborz; Klein, Robert Henry; How, Jonathan P.
RLPy is an object-oriented reinforcement learning software package with a focus on valuefunction-based methods using linear function approximation and discrete actions. The framework was designed for both educational and research purposes. It provides a rich library of fine-grained, easily exchangeable components for learning agents (e.g., policies or representations of value functions), facilitating recently increased specialization in reinforcement learning. RLPy is written in Python to allow fast prototyping, but is also suitable for large-scale experiments through its built-in support for optimized numerical libraries and parallelization. Code profiling, domain visualizations, and data analysis are integrated in a self-contained package available under the...
Agarwal, Vikram; Bell, George W; Nam, Jin-Wu; Bartel, David
MicroRNA targets are often recognized through pairing between the miRNA seed region and complementary sites within target mRNAs, but not all of these canonical sites are equally effective, and both computational and in vivo UV-crosslinking approaches suggest that many mRNAs are targeted through non-canonical interactions. Here, we show that recently reported non-canonical sites do not mediate repression despite binding the miRNA, which indicates that the vast majority of functional sites are canonical. Accordingly, we developed an improved quantitative model of canonical targeting, using a compendium of experimental datasets that we pre-processed to minimize confounding biases. This model, which considers site...
Fields, Alexander P.; Rodriguez, Edwin H.; Jovanovic, Marko; Stern-Ginossar, Noam; Haas, Brian J.; Mertins, Philipp; Raychowdhury, Raktima; Hacohen, Nir; Carr, Steven A.; Ingolia, Nicholas T.; Weissman, Jonathan S.; Regev, Aviv
A fundamental goal of genomics is to identify the complete set of expressed proteins. Automated annotation strategies rely on assumptions about protein-coding sequences (CDSs), e.g., they are conserved, do not overlap, and exceed a minimum length. However, an increasing number of newly discovered proteins violate these rules. Here we present an experimental and analytical framework, based on ribosome profiling and linear regression, for systematic identification and quantification of translation. Application of this approach to lipopolysaccharide-stimulated mouse dendritic cells and HCMV-infected human fibroblasts identifies thousands of novel CDSs, including micropeptides and variants of known proteins, that bear the hallmarks of canonical...
Qu, Kun; Garamszegi, Sara; Wu, Felix; Thorvaldsdottir, Helga; Liefeld, Ted; Ocana, Marco; Pochet, Nathalie; Robinson, James T; Demchak, Barry; Hull, Tim; Ben-Artzi, Gil; Blankenberg, Daniel; Barber, Galt P; Lee, Brian T; Kuhn, Robert M; Nekrutenko, Anton; Segal, Eran; Ideker, Trey; Reich, Michael; Chang, Howard Y; Mesirov, Jill P; Borges-Rivera, Diego Ramon; Regev, Aviv
Complex biomedical analyses require the use of multiple software tools in concert and remain challenging for much of the biomedical research community. We introduce GenomeSpace (http://www.genomespace.org), a cloud-based, cooperative community resource that currently supports the streamlined interaction of 20 bioinformatics tools and data resources. To facilitate integrative analysis by non-programmers, it offers a growing set of 'recipes', short workflows to guide investigators through high-utility analysis tasks.
Jovanovic, M.; Mertins, P.; Przybylski, D.; Chevrier, N.; Satija, R.; Rodriguez, E. H.; Fields, A. P.; Schwartz, S.; Raychowdhury, R.; Mumbach, M. R.; Eisenhaure, T.; Rabani, M.; Gennert, D.; Lu, D.; Delorey, T.; Weissman, J. S.; Carr, S. A.; Hacohen, N.; Regev, Aviv; Rooney, Michael Steven
Protein expression is regulated by production and degradation of mRNAs and proteins, but their specific relationships remain unknown. We combine measurements of protein production and degradation and mRNA dynamics to build a quantitative genomic model of the differential regulation of gene expression in LPS-stimulated mouse dendritic cells. Changes in mRNA
abundance play a dominant role in determining most dynamic fold changes in protein levels. Conversely, the preexisting proteome of proteins performing basic cellular functions is remodeled primarily through changes in protein production or degradation, accounting for over half of the
absolute change in protein molecules in the cell. Thus, the proteome is...