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Fraser J.S.,University of California at San Francisco | Fraser J.S.,California Institute for Quantitative Biosciences QB3 | Gross J.D.,University of California at San Francisco | Gross J.D.,California Institute for Quantitative Biosciences QB3 | And 3 more authors.
Molecular Cell | Year: 2013

There is a wide gap between the generation of large-scale biological data sets and more-detailed, structural and mechanistic studies. However, recent studies that explicitly combine data from systems and structural biological approaches are having a profound effect on our ability to predict how mutations and small molecules affect atomic-level mechanisms, disrupt systems-level networks, and ultimately lead to changes in organismal fitness. In fact, we argue that a shared framework for analysis of nonadditive genetic and thermodynamic responses to perturbations will accelerate the integration of reductionist and global approaches. A stronger bridge between these two areas will allow for a deeper and more-complete understanding of complex biological phenomenon and ultimately provide needed breakthroughs in biomedical research. © 2013 Elsevier Inc.


Bouchard J.,University of California at San Francisco | Bouchard J.,Center for Regeneration Medicine and Stem Cell Research | Villeda S.A.,University of California at San Francisco | Villeda S.A.,Center for Regeneration Medicine and Stem Cell Research | Villeda S.A.,California Institute for Quantitative Biosciences QB3
Journal of Neurochemistry | Year: 2015

The effects of aging were traditionally thought to be immutable, particularly evident in the loss of plasticity and cognitive abilities occurring in the aged central nervous system (CNS). However, it is becoming increasingly apparent that extrinsic systemic manipulations such as exercise, caloric restriction, and changing blood composition by heterochronic parabiosis or young plasma administration can partially counteract this age-related loss of plasticity in the aged brain. In this review, we discuss the process of aging and rejuvenation as systemic events. We summarize genetic studies that demonstrate a surprising level of malleability in organismal lifespan, and highlight the potential for systemic manipulations to functionally reverse the effects of aging in the CNS. Based on mounting evidence, we propose that rejuvenating effects of systemic manipulations are mediated, in part, by blood-borne 'pro-youthful' factors. Thus, systemic manipulations promoting a younger blood composition provide effective strategies to rejuvenate the aged brain. As a consequence, we can now consider reactivating latent plasticity dormant in the aged CNS as a means to rejuvenate regenerative, synaptic, and cognitive functions late in life, with potential implications even for extending lifespan. © 2014 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of the International Society for Neurochemistry.


Qi L.,University of California at Berkeley | Qi L.,University of California at San Francisco | Qi L.,Caribou Biosciences, Inc. | Haurwitz R.E.,University of California at Berkeley | And 8 more authors.
Nature Biotechnology | Year: 2012

Complex interactions among genetic components often result in variable systemic performance in designed multigene systems. Using the bacterial clustered regularly interspaced short palindromic repeat (CRISPR) pathway we develop a synthetic RNA-processing platform, and show that efficient and specific cleavage of precursor mRNA enables reliable and predictable regulation of multigene operons. Physical separation of linked genetic elements by CRISPR-mediated cleavage is an effective strategy to achieve assembly of promoters, ribosome binding sites, cis-regulatory elements, and riboregulators into single- and multigene operons with predictable functions in bacteria. We also demonstrate that CRISPR-based RNA cleavage is effective for regulation in bacteria, archaea and eukaryotes. Programmable RNA processing using CRISPR offers a general approach for creating context-free genetic elements and can be readily used in the bottom-up construction of increasingly complex biological systems in a plug-and-play manner. © 2012 Nature America, Inc. All rights reserved.


Swaney D.L.,University of Washington | Beltrao P.,European Bioinformatics Institute | Starita L.,University of Washington | Starita L.,Howard Hughes Medical Institute | And 7 more authors.
Nature Methods | Year: 2013

Cross-talk between different types of post-translational modifications on the same protein molecule adds specificity and combinatorial logic to signal processing, but it has not been characterized on a large-scale basis. We developed two methods to identify protein isoforms that are both phosphorylated and ubiquitylated in the yeast Saccharomyces cerevisiae, identifying 466 proteins with 2,100 phosphorylation sites co-occurring with 2,189 ubiquitylation sites. We applied these methods quantitatively to identify phosphorylation sites that regulate protein degradation via the ubiquitin-proteasome system. Our results demonstrate that distinct phosphorylation sites are often used in conjunction with ubiquitylation and that these sites are more highly conserved than the entire set of phosphorylation sites. Finally, we investigated how the phosphorylation machinery can be regulated by ubiquitylation. We found evidence for novel regulatory mechanisms of kinases and 14-3-3 scaffold proteins via proteasome-independent ubiquitylation. © 2013 Nature America, Inc. All rights reserved.


Pang Y.,University of California at San Francisco | Zhang X.,University of California at San Francisco | Zhang X.,California Institute for Quantitative Biosciences QB3
PLoS ONE | Year: 2013

Sparse MRI has been introduced to reduce the acquisition time and raw data size by undersampling the k-space data. However, the image quality, particularly the contrast to noise ratio (CNR), decreases with the undersampling rate. In this work, we proposed an interpolated Compressed Sensing (iCS) method to further enhance the imaging speed or reduce data size without significant sacrifice of image quality and CNR for multi-slice two-dimensional sparse MR imaging in humans. This method utilizes the k-space data of the neighboring slice in the multi-slice acquisition. The missing k-space data of a highly undersampled slice are estimated by using the raw data of its neighboring slice multiplied by a weighting function generated from low resolution full k-space reference images. In-vivo MR imaging in human feet has been used to investigate the feasibility and the performance of the proposed iCS method. The results show that by using the proposed iCS reconstruction method, the average image error can be reduced and the average CNR can be improved, compared with the conventional sparse MRI reconstruction at the same undersampling rate. © 2013 Pang, Zhang.


Lasker K.,California Institute for Quantitative Biosciences QB3 | Lasker K.,Tel Aviv University | Phillips J.L.,California Institute for Quantitative Biosciences QB3 | Phillips J.L.,University of California at San Francisco | And 8 more authors.
Molecular and Cellular Proteomics | Year: 2010

Proteomics techniques have been used to generate comprehensive lists of protein interactions in a number of species. However, relatively little is known about how these interactions result in functional multiprotein complexes. This gap can be bridged by combining data from proteomics experiments with data from established structure determination techniques. Correspondingly, integrative computational methods are being developed to provide descriptions of protein complexes at varying levels of accuracy and resolution, ranging from complex compositions to detailed atomic structures. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Wu B.,University of California at San Francisco | Wang C.,University of California at San Francisco | Lu J.,University of California at San Francisco | Pang Y.,University of California at San Francisco | And 4 more authors.
IEEE Transactions on Medical Imaging | Year: 2012

Radio-frequency (RF) transceiver array design using primary and higher order harmonics for in vivo parallel magnetic resonance imaging imaging (MRI) and spectroscopic imaging is proposed. The improved electromagnetic decoupling performance, unique magnetic field distributions and high-frequency operation capabilities of higher-order harmonics of resonators would benefit transceiver arrays for parallel MRI, especially for ultrahigh field parallel MRI. To demonstrate this technique, microstrip transceiver arrays using first and second harmonic resonators were developed for human head parallel imaging at 7T. Phantom and human head images were acquired and evaluated using the GRAPPA reconstruction algorithm. The higher-order harmonic transceiver array design technique was also assessed numerically using FDTD simulation. Compared with regular primary-resonance transceiver designs, the proposed higher-order harmonic technique provided an improved g-factor and increased decoupling among resonant elements without using dedicated decoupling circuits, which would potentially lead to a better parallel imaging performance and ultimately faster and higher quality imaging. The proposed technique is particularly suitable for densely spaced transceiver array design where the increased mutual inductance among the elements becomes problematic. In addition, it also provides a simple approach to readily upgrade the channels of a conventional primary resonator microstrip array to a larger number for faster imaging. © 2011 IEEE.


Harrison K.D.,California Institute for Quantitative Biosciences QB3 | Kadaba N.S.,California Institute for Quantitative Biosciences QB3 | Kelly R.B.,California Institute for Quantitative Biosciences QB3 | Crawford D.,California Institute for Quantitative Biosciences QB3
Science Translational Medicine | Year: 2012

Universities should support research with commercial potential, provide a supportive environment for start-ups, and partner enthusiastically with the private sector.


Harper N.,University of California at Berkeley | Harper N.,Howard Hughes Medical Institute | Rillo R.,University of California at Berkeley | Rillo R.,Howard Hughes Medical Institute | And 9 more authors.
Developmental Cell | Year: 2011

Faithful segregation of homologous chromosomes during meiosis requires pairing, synapsis, and crossing-over. In C. elegans, homolog pairing and synapsis depend on pairing centers (PCs), special regions near one end of each chromosome that interact with the nuclear envelope (NE) and cytoplasmic microtubules. Here, we report that PCs are required for nuclear reorganization at the onset of meiosis. We demonstrate that PCs recruit the Polo-like kinase PLK-2 to induce NE remodeling, chromosome pairing, and synapsis. Recruitment of PLK-2 is also required to mediate a cell cycle delay and selective apoptosis of nuclei containing unsynapsed chromosomes, establishing a molecular link between these two quality control mechanisms. This work reveals unexpected functions for the conserved family of Polo-like kinases, and advances our understanding of how meiotic processes are properly coordinated to ensure transmission of genetic information from parents to progeny. © 2011 Elsevier Inc.


Kelly R.B.,California Institute for Quantitative Biosciences QB3
IFMBE Proceedings | Year: 2010

Biologists seek an accurate description of the biological world. Engineers do not describe things. Instead they design devices that they then build and test. Bioengineers bring these disparate disciplines together in two ways that are conceptually very different. In the past, bioengineering has meant designing, building and testing mechanical devices that operate on biological tissue. A rapidly growing branch of bioengineering, however, applies biological principles to design, build and test novel forms of cells that execute reliably a desired function. We offer a brief review of recent developments in both forms of bioengineering and examine their potential value for Vietnamese bioengineers. © Springer-Verlag 2010.

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