The aberrant activity of Ras homologous (Rho) family small GTPases (20 human members) has been implicated in cancer and other human diseases. However, in contrast to the direct mutational activation ...of Ras found in cancer and developmental disorders, Rho GTPases are activated most commonly in disease by indirect mechanisms. One prevalent mechanism involves aberrant Rho activation via the deregulated expression and/or activity of Rho family guanine nucleotide exchange factors (RhoGEFs). RhoGEFs promote formation of the active GTP-bound state of Rho GTPases. The largest family of RhoGEFs is comprised of the Dbl family RhoGEFs with 70 human members. The multitude of RhoGEFs that activate a single Rho GTPase reflects the very specific role of each RhoGEF in controlling distinct signaling mechanisms involved in Rho activation. In this review, we summarize the role of Dbl RhoGEFs in development and disease, with a focus on Ect2 (epithelial cell transforming squence 2), Tiam1 (T-cell lymphoma invasion and metastasis 1), Vav and P-Rex1/2 (PtdIns(3,4,5)P3 (phosphatidylinositol (3,4,5)-triphosphate)-dependent Rac exchanger).
Glassy carbon is a technologically important material with isotropic properties that is nongraphitizing up to ∼3000 °C and displays complete or "superelastic" recovery from large compression. The ...pressure limit of these properties is not yet known. Here we use experiments and modeling to show permanent densification, and preferred orientation occurs in glassy carbon loaded to 45 GPa and above, where 45 GPa represents the limit to the superelastic and nongraphitizing properties of the material. The changes are explained by a transformation from its sp^{2} rich starting structure to a sp^{3} rich phase that reverts to fully sp^{2} bonded oriented graphite during pressure release.
Several state‐of‐the‐art general circulation models (GCMs) predict that large volcanic eruptions should result in anomalous dry conditions throughout much of monsoon Asia. Here, we use long and ...well‐validated proxy reconstructions of Asian droughts and pluvials to detect the influence of volcanic radiative forcing on the hydroclimate of the region since the late Medieval period. Superposed epoch analysis reveals significantly wetter conditions over mainland southeast Asia in the year of an eruption, with drier conditions in central Asia. Our proxy and model comparison suggests that GCMs may not yet capture all of the important ocean‐atmosphere dynamics responsible for the influence of explosive volcanism on the climate of Asia.
Hyperglycemia is associated with increased mortality in critically ill patients. Randomized trials of intensive insulin therapy have reported inconsistent effects on mortality and increased rates of ...severe hypoglycemia. We conducted a meta-analysis to update the totality of evidence regarding the influence of intensive insulin therapy compared with conventional insulin therapy on mortality and severe hypoglycemia in the intensive care unit (ICU).
We conducted searches of electronic databases, abstracts from scientific conferences and bibliographies of relevant articles. We included published randomized controlled trials conducted in the ICU that directly compared intensive insulin therapy with conventional glucose management and that documented mortality. We included in our meta-analysis the data from the recent NICE-SUGAR (Normoglycemia in Intensive Care Evaluation - Survival Using Glucose Algorithm Regulation) study.
We included 26 trials involving a total of 13 567 patients in our meta-analysis. Among the 26 trials that reported mortality, the pooled relative risk (RR) of death with intensive insulin therapy compared with conventional therapy was 0.93 (95% confidence interval CI 0.83-1.04). Among the 14 trials that reported hypoglycemia, the pooled RR with intensive insulin therapy was 6.0 (95% CI 4.5-8.0). The ICU setting was a contributing factor, with patients in surgical ICUs appearing to benefit from intensive insulin therapy (RR 0.63, 95% CI 0.44-0.91); patients in the other ICU settings did not (medical ICU: RR 1.0, 95% CI 0.78-1.28; mixed ICU: RR 0.99, 95% CI 0.86-1.12). The different targets of intensive insulin therapy (glucose level < or = 6.1 mmol/L v. < or = 8.3 mmol/L) did not influence either mortality or risk of hypoglycemia.
Intensive insulin therapy significantly increased the risk of hypoglycemia and conferred no overall mortality benefit among critically ill patients. However, this therapy may be beneficial to patients admitted to a surgical ICU.
In this study, microarrays of stromal-cell RNA showed one signature that correlated with extracellular-matrix deposition and monocytic infiltration and another that reflected tumor blood-vessel ...density. Immune cells, fibrosis, and angiogenesis in the microenvironment strongly influence the behavior of these lymphomas.
In this study, microarrays of stromal-cell RNA showed one signature that correlated with extracellular-matrix deposition and monocytic infiltration and another that reflected tumor blood-vessel density.
Although diffuse large-B-cell lymphoma is curable with anthracycline-based chemotherapy regimens such as a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP),
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the addition of rituximab immunotherapy (R-CHOP) has improved overall survival among patients with diffuse large-B-cell lymphoma by 10 to 15%.
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Diffuse large-B-cell lymphoma is a molecularly heterogeneous disease,
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and it is unclear whether rituximab preferentially improves the outcome in certain subgroups of patients.
Gene-expression profiling has identified two biologically and clinically distinct molecular subtypes of diffuse large-B-cell lymphoma.
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,
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The germinal-center B-cell–like diffuse large-B-cell lymphoma subtype probably arises from normal germinal-center B cells, whereas the activated B-cell–like subtype may . . .
Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct ...a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10
) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.
Volcanic eruptions have global climate impacts, but their effect on the hydrologic cycle is poorly understood. We use a modified version of superposed epoch analysis, an eruption year list collated ...from multiple data sets, and seasonal paleoclimate reconstructions (soil moisture, precipitation, geopotential heights, and temperature) to investigate volcanic forcing of spring and summer hydroclimate over Europe and the Mediterranean over the last millennium. In the western Mediterranean, wet conditions occur in the eruption year and the following 3 years. Conversely, northwestern Europe and the British Isles experience dry conditions in response to volcanic eruptions, with the largest moisture deficits in posteruption years 2 and 3. The precipitation response occurs primarily in late spring and early summer (April–July), a pattern that strongly resembles the negative phase of the East Atlantic Pattern. Modulated by this mode of climate variability, eruptions force significant, widespread, and heterogeneous hydroclimate responses across Europe and the Mediterranean.
Key Points
We investigate volcanic forcing of spring‐summer European hydroclimate over the last millennium using three paleoclimatic reconstructions
We find significant wetting over the western Mediterranean and drying over northwestern Europe up to 3 years posteruption
Post eruption hydroclimate anomalies strongly resemble a negative phase of the East Atlantic Pattern
Bt technologies have played a major role in the control of bollworm, Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae), in cotton.Variation in expression levels among varieties and plant parts, along ...with selection pressure on bollworm populations, has led to the development of resistance to some Bt proteins. Trials were conducted to evaluate how cotton varieties expressing different Bt proteins affect bollworm larval behavior and their damage in flowering cotton. Differences in larval recovery were observed among cotton varieties at 3 d with 3-gene Bt cotton having the lowest recovery and non-Bt cotton having the greatest recovery. Loss of bloom tags and abscission of small bolls at the site of infestation affected bollworm larval recovery among varieties. Day after infestation was the main factor that affected bollworm movement across all varieties. Number of total damaged fruiting forms by an individual bollworm larva was different among all varieties. Overall, flower bud (square) and fruit (boll) damage by an individual larva was lower on 3-gene cotton than 2-gene cotton and non-Bt cotton. An individual larva damaged fewer squares on 2-gene cotton than non-Bt cotton, but boll damage from bollworm was similar among 2-gene cotton and non-Bt cotton. The level of square and boll damage in 2-gene cotton has increased compared to previous research further supporting the occurrence of bollworm resistance to Cry proteins. The 3-gene cotton containing the Vip3A gene experienced low levels of damage and survival. These results will be important for improving management recommendations of bollworm in Bt cotton technologies.
Abstract
We present an analysis of photometric observations of the eclipsing novalike variable DW UMa made by the CBA consortium between 1999 and 2015. Analysis of 372 new and 260 previously ...published eclipse timings reveals a 13.6 yr period or quasi-period in the times of minimum light. The seasonal light curves show a complex spectrum of periodic signals: both positive and negative ‘superhumps’, likely arising from a prograde apsidal precession and a retrograde nodal precession of the accretion disc. These signals appear most prominently and famously as sidebands of the orbital frequency; but the precession frequencies themselves, at 0.40 and 0.22 cycles per day, are also seen directly in the power spectrum. The superhumps are sometimes seen together, and sometimes separately. The depth, width and skew of eclipses are all modulated in phase with both nodal and apsidal precession of the tilted and eccentric accretion disc. The superhumps, or more correctly the precessional motions that produce them, may be essential to understanding the mysterious ‘SW Sextantis’ syndrome. Disc wobble and eccentricity can both produce Doppler signatures inconsistent with the true dynamical motions in the binary, and disc wobble might boost the mass-transfer rate by enabling the hot white dwarf to directly irradiate the secondary star.
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