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Kei Nakajima Pamela D. Arora Ajay Plaha Christopher A. McCulloch 《Journal of cellular physiology》2021,236(2):1270-1280
Many adult connective tissues undergo continuous remodeling to maintain matrix homeostasis. Physiological remodeling involves the degradation of collagen fibers by the intracellular cathepsin‐dependent phagocytic pathway. We considered that a multidomain, small GTPase activating protein, IQGAP1, which is involved in the generation of cell extensions, is required for collagen phagocytosis, possibly arising from its interactions with cdc42 and the actin‐binding protein Flightless I (FliI). We examined the role of IQGAP1 in collagen phagocytosis by human gingival fibroblasts (HGFs) and by IQGAP1+/+ and IQGAP1?/? mouse embryonic fibroblasts. IQGAP1 was strongly expressed by HGFs, localized to vinculin‐stained cell adhesions and sites where cell extensions are initiated, and colocalized with FliI. Immunoprecipitation showed that IQGAP1 associated with FliI. HGFs showed 10‐fold increases of collagen binding, 6‐fold higher internalization, and 3‐fold higher β1 integrin activation between 30 and 180 min after incubation with collagen. Compared with IQGAP1+/+ fibroblasts, deletion of IQGAP1 reduced collagen binding (1.4‐fold), collagen internalization (3‐fold), β1 integrin activation (2‐fold), and collagen degradation (1.8‐fold). We conclude that IQGAP1 affects collagen remodeling through its regulation of phagocytic degradation pathways, which may involve the interaction of IQGAP1 with FliI. 相似文献
174.
Leslie A Mitchell Laura H McCulloch Sudarshan Pinglay Henri Berger Nazario Bosco Ran Brosh Milica Bulaji Emily Huang Megan S Hogan James A Martin Esteban O Mazzoni Teresa Davoli Matthew T Maurano Jef D Boeke 《Genetics》2021,218(1)
Design and large-scale synthesis of DNA has been applied to the functional study of viral and microbial genomes. New and expanded technology development is required to unlock the transformative potential of such bottom-up approaches to the study of larger mammalian genomes. Two major challenges include assembling and delivering long DNA sequences. Here, we describe a workflow for de novo DNA assembly and delivery that enables functional evaluation of mammalian genes on the length scale of 100 kilobase pairs (kb). The DNA assembly step is supported by an integrated robotic workcell. We demonstrate assembly of the 101 kb human HPRT1 gene in yeast from 3 kb building blocks, precision delivery of the resulting construct to mouse embryonic stem cells, and subsequent expression of the human protein from its full-length human gene in mouse cells. This workflow provides a framework for mammalian genome writing. We envision utility in producing designer variants of human genes linked to disease and their delivery and functional analysis in cell culture or animal models. 相似文献
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Gillum LA Gouveia C Dorsey ER Pletcher M Mathers CD McCulloch CE Johnston SC 《PloS one》2011,6(2):e16837
Background
An analysis of NIH funding in 1996 found that the strongest predictor of funding, disability-adjusted life-years (DALYs), explained only 39% of the variance in funding. In 1998, Congress requested that the Institute of Medicine (IOM) evaluate priority-setting criteria for NIH funding; the IOM recommended greater consideration of disease burden. We examined whether the association between current burden and funding has changed since that time.Methods
We analyzed public data on 2006 NIH funding for 29 common conditions. Measures of US disease burden in 2004 were obtained from the World Health Organization''s Global Burden of Disease study and national databases. We assessed the relationship between disease burden and NIH funding dollars in univariate and multivariable log-linear models that evaluated all measures of disease burden. Sensitivity analyses examined associations with future US burden, current and future measures of world disease burden, and a newly standardized NIH accounting method.Results
In univariate and multivariable analyses, disease-specific NIH funding levels increased with burden of disease measured in DALYs (p = 0.001), which accounted for 33% of funding level variation. No other factor predicted funding in multivariable models. Conditions receiving the most funding greater than expected based on disease burden were AIDS ($2474 M), diabetes mellitus ($390 M), and perinatal conditions ($297 M). Depression ($719 M), injuries ($691 M), and chronic obstructive pulmonary disease ($613 M) were the most underfunded. Results were similar using estimates of future US burden, current and future world disease burden, and alternate NIH accounting methods.Conclusions
Current levels of NIH disease-specific research funding correlate modestly with US disease burden, and correlation has not improved in the last decade. 相似文献177.
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Calcification rates are reported for 41 long-lived Porites corals from 7 reefs, in an inshore to offshore transect across the central Great Barrier Reef (GBR). Over multi-decadal timescales, corals in the mid-shelf (1947–2008) and outer reef (1952–2004) regions of the GBR exhibit a significant increase in calcification of 10.9 ± 1.1 % (1.4 ± 0.2 % per decade; ±1 SE) and 11.1 ± 3.9 % (2.1 ± 0.8 % per decade), respectively, while inner-shelf (1930–2008), reefs show a decline of 4.6 ± 1.3 % (0.6 ± 0.2 % per decade). This long-term decline in calcification for the inner GBR is attributed to the persistent ongoing effects of high sediment/nutrients loads from wet season river discharges, compounded by the effects of thermal stress, especially during the 1998 bleaching event. For the recent period (1990–2008), our data show recovery from the 1998 bleaching event, with no significant trend in the rates of calcification (1.1 ± 2.0 %) for the inner reefs, while corals from the mid-shelf central GBR show a decline of 3.3 ± 0.9 %. These results are in marked contrast to the extreme reef-wide declines of 14.2 % reported by De’ath et al. (2009) for the period of 1990–2005. The De’ath et al. (2009) results are, however, found to be compromised by the inclusion of incomplete final years, duplicated records, together with a bias toward inshore reefs strongly affected by the 1998 bleaching. Our new findings nevertheless continue to raise concerns, with the inner-shelf reefs continuing to show long-term declines in calcification consistent with increased disturbance from land-based effects. In contrast, the more ‘pristine’ mid- and outer-shelf reefs appear to be undergoing a transition from increasing to decreasing rates of calcification, possibly reflecting the effects of CO2-driven climate change. Our study highlights the importance of properly undertaken, regular assessments of coral calcification that are representative of the distinctive cross-shelf environments and discriminate between local disturbances and the global impacts of climate change and ocean acidification. 相似文献
179.
Travis G. Gerwing Elmar Plate Jess Kidd Jesse Sinclair Christopher W. Burns Shane Johnson Steven Roias Cameron McCulloch Robert C. Bocking 《Restoration Ecology》2020,28(3):623-631
The Kaouk River estuary is located on the northwest coast of Vancouver Island, British Columbia, Canada, in the Treaty Settlement Lands of the Ka:'yu:'k't'h'/Che:k'tles7et'h First Nations. Stretching across the widest point of this estuary is a causeway providing road access to Fair Harbour. This causeway was observed to decrease habitat connectivity throughout the estuary, specifically limiting juvenile salmon access to high‐quality rearing habitat in the tidal marsh. As such, the causeway was breached in 2019 and a bridge was installed. Juvenile salmon were observed using the new connection and were captured both up and downstream of the causeway immediately following breaching. Postbreach water chemistry (dissolved oxygen, pH, salinity, and temperature) near the causeway was recorded within the range of values observed throughout the estuary. Use of the breach by juvenile salmon and homogenized water chemistry indicate the project succeeded in improving habitat connectivity within the Kaouk River estuary and has enhanced juvenile salmon access to 2.7 km2 of wetland rearing habitat. 相似文献
180.
Nasrine Bendjilali Helen Kim Shantel Weinsheimer Diana E. Guo Pui-Yan Kwok Jonathan G. Zaroff Stephen Sidney Michael T. Lawton Charles E. McCulloch Bobby P. C. Koeleman Catharina J. M. Klijn William L. Young Ludmila Pawlikowska 《PloS one》2013,8(10)