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31.
Meirav Noach-Hirsh Hadas Nevenzal Yair Glick Evelin Chorni Dorit Avrahami Efrat Barbiro-Michaely Doron Gerber Amit Tzur 《Molecular & cellular proteomics : MCP》2015,14(10):2824-2832
Protein post-translational modifications mediate dynamic cellular processes with broad implications in human disease pathogenesis. There is a large demand for high-throughput technologies supporting post-translational modifications research, and both mass spectrometry and protein arrays have been successfully utilized for this purpose. Protein arrays override the major limitation of target protein abundance inherently associated with MS analysis. This technology, however, is typically restricted to pre-purified proteins spotted in a fixed composition on chips with limited life-time and functionality. In addition, the chips are expensive and designed for a single use, making complex experiments cost-prohibitive. Combining microfluidics with in situ protein expression from a cDNA microarray addressed these limitations. Based on this approach, we introduce a modular integrated microfluidic platform for multiple post-translational modifications analysis of freshly synthesized protein arrays (IMPA). The system''s potency, specificity and flexibility are demonstrated for tyrosine phosphorylation and ubiquitination in quasicellular environments. Unlimited by design and protein composition, and relying on minute amounts of biological material and cost-effective technology, this unique approach is applicable for a broad range of basic, biomedical and biomarker research.Protein post-translational modifications (PTMs)1 vastly diversify eukaryotic proteomes and are integrated in essentially all cellular processes (1). Proteomic approaches, such as mass spectrometry (MS), have been instrumental in monitoring global molecular dynamics for research and clinical applications (2–5). However, even in this modern era, large-scale analyses of PTMs by MS is challenging because of the limited number of modified peptides derived from proteins that, by themselves, may not be abundant. Moreover, comprehensive PTM analysis by MS often requires significant amounts of biological material that may not be available. PTM analysis using protein arrays can overcome these limitations because of the equimolar amount of the arrayed proteins (6, 7). Large-scale protein arrays have been successfully integrated into PTM research (8, 9). However, this technology relies on pre-purified proteins that are arrayed on a surface and thus, incompatible with biochemically challenging proteins, let alone insoluble proteins. Moreover, the production of recombinant protein arrays is impractical in-house. Therefore, such arrays cannot be used fresh, and they are inherently limited to certain designs, protein compositions, and model organisms of high commercial value. To overcome the abovementioned limitations, we designed a modular integrated microfluidic platform for PTM analysis (IMPA). 相似文献
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Yanqin Ren Szu Han Huang Amanda B. Macedo Adam R. Ward Winiffer D. Conce Alberto Thais Klevorn Louise Leyre Dennis C. Copertino Talia M. Mota Dora Chan Ronald Truong Thomas Rohwetter Paul Zumbo Friederike Dündar Doron Betel Colin Kovacs Erika Benko Alberto Bosque R. Brad Jones 《Journal of virology》2021,95(15)
34.
Yael Ben Shabat Avraham Shitzer Dusan Fiala 《International journal of biometeorology》2014,58(6):1007-1015
Wind chill equivalent temperatures (WCETs) were estimated by a modified Fiala’s whole body thermoregulation model of a clothed person. Facial convective heat exchange coefficients applied in the computations concurrently with environmental radiation effects were taken from a recently derived human-based correlation. Apart from these, the analysis followed the methodology used in the derivation of the currently used wind chill charts. WCET values are summarized by the following equation: $$ \mathrm{WCET}=12.87+0.5334\ast {T}_o-\left(12.66-0.4414\ast {T}_o\right)\ast {U}_{reported}{}^{0.1228} $$ Results indicate consistently lower estimated facial skin temperatures and consequently higher WCETs than those listed in the literature and used by the North American weather services. Calculated dynamic facial skin temperatures were additionally applied in the estimation of probabilities for the occurrence of risks of frostbite. Predicted weather combinations for probabilities of “Practically no risk of frostbite for most people,” for less than 5 % risk at wind speeds above 40 km h?1, were shown to occur at air temperatures above ?10 °C compared to the currently published air temperature of ?15 °C. At air temperatures below ?35 °C, the presently calculated weather combination of 40 km h?1/?35 °C, at which the transition for risks to incur a frostbite in less than 2 min, is less conservative than that published: 60 km h?1/?40 °C. The present results introduce a fundamentally improved scientific basis for estimating facial skin temperatures, wind chill temperatures and risk probabilities for frostbites over those currently practiced. 相似文献
35.
Doron Shultziner Thomas Stevens Martin Stevens Brian A. Stewart Rebecca J. Hannagan Giulia Saltini-Semerari 《Biology & philosophy》2010,25(3):319-346
This paper reviews and synthesizes emerging multi-disciplinary evidence toward understanding the development of social and
political organization in the Last Glacial. Evidence for the prevalence and scope of political egalitarianism is reviewed
and the biological, social, and environmental influences on this mode of human organization are further explored. Viewing
social and political organization in the Last Glacial in a much wider, multi-disciplinary context provides the footing for
coherent theory building and hypothesis testing by which to further explore human political systems. We aim to overcome the
claim that our ancestors’ form of social organization is untestable, as well as counter a degree of exaggeration regarding
possibilities for sedentism, population densities, and hierarchical structures prior to the Holocene with crucial advances
from disparate disciplines. 相似文献
36.
Edry E Koralov SB Rajewsky K Melamed D 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(10):6555-6560
Mature B cells replace the mu constant region of the H chain with a downstream isotype in a process of class switch recombination (CSR). Studies suggest that CSR induction is limited to activated mature B cells in the periphery. Recently, we have shown that CSR spontaneously occur in B lymphopoiesis. However, the mechanism and regulation of it have not been defined. In this study, we show that spontaneous CSR occurs at all stages of B cell development and generates aberrant joining of the switch junctions as revealed by: 1) increased load of somatic mutations around the CSR break points, 2) reduced sequence overlaps at the junctions, and 3) excessive switch region deletion. In addition, we found that incidence of spontaneous CSR is increased in cells carrying VDJ rearrangements. Our results reveal major differences between spontaneous CSR in developing B cells and CSR induced in mature B cells upon activation. These differences can be explained by deregulated expression or function of activation-induced cytidine deaminase early in B cell development. 相似文献
37.
We develop a mathematical framework for modeling regulatory mechanisms in the immune system. The model describes dynamics of key components of the immune network within two compartments: lymph node and tissue. We demonstrate using numerical simulations that our system can eliminate virus-infected cells, which are characterized by a tendency to increase without control (in absence of an immune response), while tolerating normal cells, which are characterized by a tendency to approach a stable equilibrium population. We experiment with different combinations of T cell reactivities that lead to effective systems and conclude that slightly self-reactive T cells can exist within the immune system and are controlled by regulatory cells. We observe that CD8+ T cell dynamics has two phases. In the first phase, CD8+ cells remain sequestered within the lymph node during a period of proliferation. In the second phase, the CD8+ population emigrates to the tissue and destroys its target population. We also conclude that a self-tolerant system must have a mechanism of central tolerance to ensure that self-reactive T cells are not too self-reactive. Furthermore, the effectiveness of a system depends on a balance between the reactivities of the effector and regulatory T cell populations, where the effectors are slightly more reactive than the regulatory cells. 相似文献
38.
Synchronization of cell death in a dinoflagellate population is mediated by an excreted thiol protease 总被引:3,自引:0,他引:3
Vardi A Eisenstadt D Murik O Berman-Frank I Zohary T Levine A Kaplan A 《Environmental microbiology》2007,9(2):360-369
Regulated programmed cell death (PCD) processes have been documented in several phytoplankton species and are hypothesized to play a role in population dynamics. However, the mechanisms leading to the coordinated collapse of phytoplankton blooms are poorly understood. We showed that the collapse of the annual bloom of Peridinium gatunense, an abundant dinoflagellate in Lake Kinneret, Israel, is initiated by CO2 limitation followed by oxidative stress that triggers a PCD-like cascade. We provide evidences that a protease excreted by senescing P. gatunense cells sensitizes younger cells to oxidative stress and may consequently trigger synchronized cell death of the population. Ageing of the P. gatunense cultures was characterized by a remarkable rise in DNA fragmentation and enhanced sensitivity to H2O2. Exposure of logarithmic phase (young) cultures to conditioning media from stationary phase (old) cells sensitized them to H2O2 and led to premature massive cell death. We detected the induction of specific extracellular protease activity, leupeptin-sensitive, in ageing cultures and in lake waters during the succession of the P. gatunense bloom. Partial purification of the conditioned media revealed that this protease activity is responsible for the higher susceptibility of young cells to oxidative stress. Inhibition of the protease activity lowered the sensitivity to oxidative stress, whereas application of papain to logarithmic phase P. gatunense cultures mimicked the effect of the spent media and enhanced cell death. We propose a novel mechanistic framework by which a population of unicellular phytoplankton orchestrates a coordinated response to stress, thereby determine the fate of its individuals. 相似文献
39.
Julia Sauerwald Tobias Jores Michal Eisenberg-Bord Silvia Gabriela Chuartzman Maya Schuldiner Doron Rapaport 《Molecular and cellular biology》2015,35(18):3200-3211
A special group of mitochondrial outer membrane (MOM) proteins spans the membrane several times via multiple helical segments. Such multispan proteins are synthesized on cytosolic ribosomes before their targeting to mitochondria and insertion into the MOM. Previous work recognized the import receptor Tom70 and the mitochondrial import (MIM) complex, both residents of the MOM, as required for optimal biogenesis of these proteins. However, their involvement is not sufficient to explain either the entire import pathway or its regulation. To identify additional factors that are involved in the biogenesis of MOM multispan proteins, we performed complementary high-throughput visual and growth screens in Saccharomyces cerevisiae. Cardiolipin (CL) synthase (Crd1) appeared as a candidate in both screens. Our results indeed demonstrate lower steady-state levels of the multispan proteins Ugo1, Scm4, and Om14 in mitochondria from crd1Δ cells. Importantly, MOM single-span proteins were not affected by this mutation. Furthermore, organelles lacking Crd1 had a lower in vitro capacity to import newly synthesized Ugo1 and Scm4 molecules. Crd1, which is located in the mitochondrial inner membrane, condenses phosphatidylglycerol together with CDP-diacylglycerol to obtain de novo synthesized CL molecules. Hence, our findings suggest that CL is an important component in the biogenesis of MOM multispan proteins. 相似文献
40.