Mice Expressing Low Levels of CalDAG-GEFI Exhibit Markedly Impaired Platelet Activation With Minor Impact on HemostasisHighlights

OBJECTIVE: The tight regulation of platelet adhesiveness, mediated by the αIIbβ3 integrin, is critical for hemostasis and prevention of thrombosis. We recently demonstrated that integrin affinity in platelets is controlled by the guanine nucleotide exchange factor, CalDAG-GEFI (CD-GEFI), and its target, RAP1. In this study, we investigated whether low-level expression of CD-GEFI leads to protection from thrombosis without pathological bleeding in mice. APPROACH AND RESULTS: Cdg1(low) mice were generated by knockin of human CD-GEFI cDNA into the mouse Cdg1 locus. CD-GEFI expression in platelets from Cdg1(low) mice was reduced by ≈90% when compared with controls. Activation of RAP1 and αIIbβ3 was abolished at low agonist concentrations and partially inhibited at high agonist concentrations in Cdg1(low) platelets. Consistently, the aggregation response of Cdg1(low) platelets was weaker than that of wild-type platelets, but more efficient than that observed in Cdg1(-/-) platelets. Importantly, Cdg1(low) mice were strongly protected from arterial and immune complex-mediated thrombosis, with only minimal impact on primary hemostasis. CONCLUSIONS: Together, our studies suggest the partial inhibition of CD-GEFI function as a powerful new approach to safely prevent thrombotic complications

Progress in Interferometry for LISA at JPL

Recent advances at JPL in experimentation and design for LISA interferometry include the demonstration of Time Delay Interferometry using electronically separated end stations, a new arm-locking design with improved gain and stability, and progress in flight readiness of digital and analog electronics for phase measurements.Comment: 11 pages, 9 figures, LISA 8 Symposium, Stanford University, 201

Utilizing "Omic" technologies to identify and prioritize novel sources of resistance to the oomycete pathogen <i>Phytophthora infestans</i> in potato germplasm collections

The biggest threat to potato production world-wide is late blight, caused by the oomycete pathogen Phytophthora infestans. A screen of 126 wild diploid Solanum accessions from the Commonwealth Potato Collection (CPC) with P. infestans isolates belonging to the genotype 13-A2 identified resistances in the species S. bulbocastanum, S. capsicibaccatum, S. microdontum, S. mochiquense, S. okadae, S. pinnatisectum, S. polyadenium, S. tarijense and S. verrucosum. Effector-omics, allele mining and diagnostic RenSeq (dRenSeq) were utilized to investigate the nature of resistances in S. okadae accessions. dRenSeq in resistant S. okadae accessions 7129, 7625, 3762 and a bulk of 20 resistant progeny confirmed the presence of full-length Rpi-vnt1.1 under stringent mapping conditions and corroborated allele mining results in the accessions 7129 and 7625 as well as Avr-vnt1 recognition in transient expression assays. In contrast, susceptible S. okadae accession 3761 and a bulk of 20 susceptible progeny lacked sequence homology in the 5’ end compared to the functional Rpi-vnt1.1 gene. Further evaluation of S. okadae accessions with late blight isolates that have a broad spectrum of virulence demonstrated that, although S. okadae accessions 7129, 7625 and 7629 contain functional Rpi-vnt1.1, they also carry a novel resistance gene. We provide evidence that existing germplasm collection are important sources of novel resistances and that ‘omic’ technologies such as dRenSeq-based genomics and effector-omics are efficacious tools to rapidly explore the diversity within these collections

Olivine friction at the base of oceanic seismogenic zones

Author Posting. © American Geophysical Union, 2007. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 112 (2007): B01205, doi:10.1029/2006JB004301.We investigate the strength and frictional behavior of olivine aggregates at temperatures and effective confining pressures similar to those at the base of the seismogenic zone on a typical ridge transform fault. Triaxial compression tests were conducted on dry olivine powder (grain size ≤ 60 μm) at effective confining pressures between 50 and 300 MPa (using Argon as a pore fluid), temperatures between 600°C and 1000°C, and axial displacement rates from 0.06 to 60 μm/s (axial strain rates from 3 × 10−6 to 3 × 10−3 s−1). Yielding shows a negative pressure dependence, consistent with predictions for shear enhanced compaction and with the observation that samples exhibit compaction during the initial stages of the experiments. A combination of mechanical data and microstructural observations demonstrate that deformation was accommodated by frictional processes. Sample strengths were pressure-dependent and nearly independent of temperature. Localized shear zones formed in initially homogeneous aggregates early in the experiments. The frictional response to changes in loading rate is well described by rate and state constitutive laws, with a transition from velocity-weakening to velocitystrengthening at 1000°C. Microstructural observations and physical models indicate that plastic yielding of asperities at high temperatures and low axial strain rates stabilizes frictional sliding. Extrapolation of our experimental data to geologic strain rates indicates that a transition from velocity weakening to velocity strengthening occurs at approximately 600°C, consistent with the focal depths of earthquakes in the oceanic lithosphere.This research was supported by the Deep Ocean Exploration Institute at WHOI and NSF grants to Greg Hirth and Brian Evans

Head & neck optical diagnostics: vision of the future of surgery

Review paper and Proceedings of the Inaugural Meeting of the Head and Neck Optical Diagnostics Society (HNODS) on March 14th 2009 at University College London

Fundamentals of impulsive energy release in the corona

It is essential that there be coordinated and co-optimized observations in X-rays, gamma-rays, and EUV during the peak of solar cycle 26 (~2036) to significantly advance our understanding of impulsive energy release in the corona. The open questions include: What are the physical origins of space-weather events? How are particles accelerated at the Sun? How is impulsively released energy transported throughout the solar atmosphere? How is the solar corona heated? Many of the processes involved in triggering, driving, and sustaining solar eruptive events -- including magnetic reconnection, particle acceleration, plasma heating, and energy transport in magnetized plasmas -- also play important roles in phenomena throughout the Universe. This set of observations can be achieved through a single flagship mission or, with foreplanning, through a combination of major missions (e.g., the previously proposed FIERCE mission concept).Comment: White paper submitted to the Decadal Survey for Solar and Space Physics (Heliophysics) 2024-2033; 5 pages, 1 figur

Tissue-Specific Increases in 11β-Hydroxysteroid Dehydrogenase Type 1 in Normal Weight Postmenopausal Women

With age and menopause there is a shift in adipose distribution from gluteo-femoral to abdominal depots in women. Associated with this redistribution of fat are increased risks of type 2 diabetes and cardiovascular disease. Glucocorticoids influence body composition, and 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) which converts inert cortisone to active cortisol is a putative key mediator of metabolic complications in obesity. Increased 11βHSD1 in adipose tissue may contribute to postmenopausal central obesity. We hypothesized that tissue-specific 11βHSD1 gene expression and activity are up-regulated in the older, postmenopausal women compared to young, premenopausal women. Twenty-three pre- and 23 postmenopausal, healthy, normal weight women were recruited. The participants underwent a urine collection, a subcutaneous adipose tissue biopsy and the hepatic 11βHSD1 activity was estimated by the serum cortisol response after an oral dose of cortisone. Urinary (5α-tetrahydrocortisol+5β-tetrahydrocortisol)/tetrahydrocortisone ratios were higher in postmenopausal women versus premenopausal women in luteal phase (P<0.05), indicating an increased whole-body 11βHSD1 activity. Postmenopausal women had higher 11βHSD1 gene expression in subcutaneous fat (P<0.05). Hepatic first pass conversion of oral cortisone to cortisol was also increased in postmenopausal women versus premenopausal women in follicular phase of the menstrual cycle (P<0.01, at 30 min post cortisone ingestion), suggesting higher hepatic 11βHSD1 activity. In conclusion, our results indicate that postmenopausal normal weight women have increased 11βHSD1 activity in adipose tissue and liver. This may contribute to metabolic dysfunctions with menopause and ageing in women

The future of medical diagnostics: Review paper

While histopathology of excised tissue remains the gold standard for diagnosis, several new, non-invasive diagnostic techniques are being developed. They rely on physical and biochemical changes that precede and mirror malignant change within tissue. The basic principle involves simple optical techniques of tissue interrogation. Their accuracy, expressed as sensitivity and specificity, are reported in a number of studies suggests that they have a potential for cost effective, real-time, in situ diagnosis. We review the Third Scientific Meeting of the Head and Neck Optical Diagnostics Society held in Congress Innsbruck, Innsbruck, Austria on the 11th May 2011. For the first time the HNODS Annual Scientific Meeting was held in association with the International Photodynamic Association (IPA) and the European Platform for Photodynamic Medicine (EPPM). The aim was to enhance the interdisciplinary aspects of optical diagnostics and other photodynamic applications. The meeting included 2 sections: oral communication sessions running in parallel to the IPA programme and poster presentation sessions combined with the IPA and EPPM posters sessions. © 2011 Jerjes et al; licensee BioMed Central Ltd