ALBERT

Beschreibung: Direct application of histone-deacetylase-inhibitors (HDACis) to dental pulp cells (DPCs) induces chromatin changes, promoting gene expression and cellular-reparative events. We have previously demonstrated that HDACis (Valproic acid, Trichostatin A) increase mineralization in dental papillae-derived cell-lines and primary DPCs by stimulation of dentinogenic gene expression. Here, we investigated novel genes regulated by the HDACi, suberoylanilide hydroxamic acid (SAHA), to identify new pathways contributing to DPC differentiation. SAHA significantly compromised DPC viability only at relatively high concentrations (5 μM); while low concentrations (1 μM) SAHA did not increase apoptosis. HDACi-exposure for 24 h induced mineralization-per-cell dose-dependently after 2 weeks; however, constant 14d SAHA-exposure inhibited mineralization. Microarray analysis (24 h and 14d) of SAHA exposed cultures highlighted that 764 transcripts showed a significant 〉2.0-fold change at 24 h, which reduced to 36 genes at 14d. 59% of genes were down-regulated at 24 h and 36% at 14d, respectively. Pathway analysis indicated SAHA increased expression of members of the matrix metalloproteinase (MMP) family. Furthermore, SAHA-supplementation increased MMP-13 protein expression (7d, 14 d) and enzyme activity (48 h, 14d). Selective MMP-13-inhibition (MMP-13i) dose-dependently accelerated mineralization in both SAHA-treated and non-treated cultures. MMP-13i-supplementation promoted expression of several mineralization-associated markers, however, HDACi-induced cell migration and wound healing were impaired. Data demonstrate that short-term low-dose SAHA-exposure promotes mineralization in DPCs by modulating gene pathways and tissue proteases. MMP-13i further increased mineralization-associated events, but decreased HDACi cell migration indicating a specific role for MMP-13 in pulpal repair processes. Pharmacological inhibition of HDAC and MMP may provide novel insights into pulpal repair processes with significant translational benefit. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT The present study investigates the characteristics of active and break cycles associated with the Indian summer monsoon (ISM) during developing and decaying phase of El Niño and in the years in which Indian Ocean Dipole (IOD) co-occurred with El Niño (co-occurred years). Observations show that break days are more in number (∼2–3 times) and long lasting (∼15–20 days) than active days in El Niño developing summers and vice versa for decay years. During El Niño developing years, northward propagation is well organized with significant anomalies in both active and break phases. The increased convection associated with active phase persists longer over Indian Ocean, than over the monsoon region, while the reduced convection in break phase propagates faster from ocean to land and persists there for a longer time. Compared to break events, active events have slower (faster) propagation over the monsoon (oceanic) region during El Nino decay years. The present study put forward the argument that the contrasting persistent circulations over Indo-western Pacific regions favour particular phase of intra-seasonal oscillation (ISO) in developing and decay phase of El Nino. These long-lasting circulations advect anomalous dry (moist) air to ISM region for longer period, resulting in long-lasting break (active) events in El Niño developing (decay) years. During co-occurrence years, the number of break (active) days is reduced by two to three times compared to the developing (decaying) phase of El Niño. It is found that 30- to 60-day scale ISO is strongly modulated, than 10 - to 20-day scale, by the changes in seasonal mean state associated with El Nino. Thus, this study demonstrates that the ISO characteristics such as its variance, northward propagation, spatial distribution and duration of active and break days are strongly modulated by seasonal background anomalies over the Indo-Pacific region.

Beschreibung: ABSTRACT The World Meteorological Organization (WMO) Lead Centre for Long-Range Forecast Multi-Model Ensemble (WMO LC-LRFMME) has been established to collect and share long-range forecasts from the WMO designated Global Producing Centres (GPC). In this study, the seasonal skill of the deterministic multi-model prediction of GPCs in WMO LC-LRFMME is investigated. The GPC models included in the analysis cover 30 years of common hindcast period from 1981 to 2010 and real-time forecast for the period from DJF2011/2012 to SON2014. The equal-weighted multi-model ensemble (MME) method is used to produce the MME forecast. We show that the GPC models generally capture the observed climatological patterns and seasonal variations in temperature and precipitation. However, some systematic biases/errors in simulation of the climatological mean patterns and zonal mean profiles are also found, most of which are located in mid-latitudes or high latitudes. The temporal correlation coefficients both of 2 m temperature and precipitation in the tropical region (especially over the ocean) exceed 95%, but drop gradually towards high latitudes and are even negative in the polar region for precipitation. The prediction skills of individual models and the MME over 13 regional climate outlook forum (RCOF) regions for four calendar seasons are also assessed. The prediction skills vary with season and region, with the highest skill being demonstrated by the MME forecasts for the regions of the tropical RCOFs. These predictions are strongly affected by the ENSO over Pacific Islands, Southeast Asia and Central America. Additionally, Southeast of South America and North Eurasian regions show relatively low skills for all seasons when compared to other regions.

Beschreibung: Deficiency in the retinoblastoma protein (Rb) favors leanness and a healthy metabolic profile in mice largely attributed to activation of oxidative metabolism in white and brown adipose tissues. Less is known about Rb modulation of skeletal muscle metabolism. This was studied here by transiently knocking down Rb expression in differentiated C2C12 myotubes using small interfering RNAs. Compared with control cells transfected with non-targeting RNAs, myotubes silenced for Rb (by 80–90%) had increased expression of genes related to fatty acid uptake and oxidation such as Cd36 and Cpt1b (by 61% and 42%, respectively), increased Mitofusin 2 protein content (∼2.5-fold increase), increased mitochondrial to nuclear DNA ratio (by 48%), increased oxygen consumption (by 65%) and decreased intracellular lipid accumulation. Rb silenced myotubes also displayed up-regulated levels of glucose transporter type 4 expression (∼5-fold increase), increased basal glucose uptake, and enhanced insulin-induced Akt phosphorylation. Interestingly, exercise in mice led to increased Rb phosphorylation (inactivation) in skeletal muscle as evidenced by immunohistochemistry analysis. In conclusion, the silencing of Rb enhances mitochondrial oxidative metabolism and fatty acid and glucose disposal in skeletal myotubes, and changes in Rb status may contribute to muscle physiological adaptation to exercise. This article is protected by copyright. All rights reserved

Beschreibung: MDA-9/Syntenin is a small PDZ domain containing scaffolding protein with diverse array of function regulating membrane trafficking, cell adhesion, neural and synaptic development, ubiquitination and exosome biogenesis. An appreciable number of studies also established a pivotal role of MDA-9/Syntenin in cancer development and progression. In this review, we will discuss the dynamic role of MDA-9/Syntenin in regulating normal and abnormal fate of various cellular processes. This article is protected by copyright. All rights reserved

Beschreibung: Because early-stage hepatocellular carcinoma (HCC) is difficult to diagnose using the existing techniques, identifying better biomarkers would likely improve the patients' prognoses. We performed a systematic review and meta-analysis of published studies to appraise the utility of microRNAs (miRNAs) for the early diagnosis of HCC. Pertinent literature was collected from the Medline, Embase, and Chinese National Knowledge Infrastructure databases. We analyzed 50 studies that included 3423 cases of HCC, 2403 chronic hepatic disease (CH) patients, and 1887 healthy controls in 16 articles. Summary receiver operating characteristic analyses of all miRNAs showed an area under the curve (AUC) of 0.82, with 75.8% sensitivity and 75.0% specificity in discriminating patients with HCC from healthy controls. miR-21 and miR-122 individually distinguished patients with HCC from healthy controls, with an AUC of 0.88 for miR-21 and 0.77 for miR-122. The sensitivity and specificity for miR-21 were 86.6% and 79.5%, respectively; those for miR-122 were 68.0% and 73.3%. We conclude that circulating miRNAs, particularly miR-21 and miR-122, are promising biomarkers for the early diagnosis of HCC. This article is protected by copyright. All rights reserved

Beschreibung: We have synthesized a novel derivative of Digitoxin, termed “MonoD”, which demonstrates cytotoxic effects in lung cancer cells with much higher potency as compared to Digitoxin. Our data show that within one hour of MonoD treatment, H460 cells showed increased oxidative stress, increased formation of autophagic vacuoles and increased expression of pro-autophagic markers Beclin-1 and LC3-II. Cells pretreated with MnTBAP, a superoxide scavenger not only lowered superoxide production, but also had lower levels of LC3-II and Beclin-1. Prolonged treatment with MonoD induced apoptosis in lung cancer cells. We investigated MonoD-dependent regulation of Akt and Bcl2, proteins that are known regulators of both autophagy and apoptosis. Molecular and pharmacologic inhibitors of Bcl2 and Akt, when combined with MonoD, led to higher expression of LC3-II and Beclin-1 as compared to MonoD alone, suggesting a repressive effect for these proteins in MonoD-dependent autophagy. Pretreatment of cells with an autophagy inhibitor repressed the apoptotic potential of MonoD, confirming that early autophagic flux is important to drive apoptosis. Therapeutic entities such as MonoD that target multiple pathways such as autophagy and apoptosis may prove advantageous over current therapies that have unimodal basis for action and may drive sustained tumor regression, which is highly desirable. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT This study examines the trends in reference evapotranspiration (ET o ) in Turkey by analysing data from 77 weather stations for a 32-year period (1975–2006). ET o values were calculated using the Penman–Monteith method using air temperature, wind speed, relative humidity, and sunshine hours data. Trends in annual and monthly ET o were determined using the Mann–Kendall trend test with the trend-free prewhitening procedure. The magnitude of trends was estimated by calculating the Sen's slope. The collective or field significance of the trends was evaluated using Walker test. The possible causes of changes in ET o were discussed by analysing the trends in air temperature, wind speed, relative humidity, and solar radiation data collected at the same stations. The implications of ET o trends for crop water requirements were evaluated. The analyses showed that the majority of stations (88%) in Turkey had annual ET o between 750 and 1200 mm during the 32-year period and ET o decreased gradually from south to north. From 1975 to 2006, 58% of stations had upward trends in annual ET o . Upward trends were statistically significant at the 0.05 level for 32% of stations. The rates of changes in annual ET o were on average 1.20 mm year −2 . The trends detected in monthly ET o were mostly upward with an average magnitude between −0.01 and 0.14 mm month year −1 . Trends detected at the annual timescale and for the majority of the months provided the field significance at the 0.05 level. Analysis of other climatic data showed that upward trends in air temperatures, downward trends in wind speeds, and downward trends in relative humidity were widespread over Turkey for the same time period. Changes in these three parameters could explain the majority of the changes in ET o rates. The ET o changes affect crop water requirements and increase the demand for irrigation.

Beschreibung: ABSTRACT We explore the occurrence of intraseasonal summer heat waves in southeastern Patagonia (SEPG, 46°–52°S; 65°–70°W) since the late 19th century by means of the Twentieth Century Reanalysis version 2 (20CRv2). In total, we identify 201 cases for 1872–2010 using criteria of intensity and persistence. In SEPG, the corresponding intraseasonal temperature signals are centred around the first day of each cluster of days fulfilling those conditions (named day 0). The mean warm deviation lasts for approximately 2 weeks and exhibits a mean temperature peak of 4.3 °C on day 0 (the warmest day in the mean signal). In a regional context, the mean temperature perturbation associated with these heat waves affects a broad area on both sides of the Andes. The warming in SEPG is caused by temperature advection and enhanced radiative heating, following a high pressure system over southern South America (SSA). This atmospheric perturbation is embedded in a wave-train-like pattern along the South Pacific. As part of this pattern, a cyclonic anomaly progresses eastward over the Tasman Sea in Oceania, moving from southeastern Australia (day −6, causing a dry anomaly there) over New Zealand (day −3, inducing a wet anomaly on its Southern Island). The anomalous circulation triggered by the wave train leads thus to a teleconnection between SSA and Oceania, documented in a previous work for the interannual scale. Two thirds of the heat wave events are linked to enhanced ascent in the South Atlantic Convergence Zone (SACZ) and around one third of the events within 1957–2010 are associated with extreme absolute maximum temperatures observed at a station-based record from SEPG. Finally, possible spatial modulations of the wave train pattern at the interannual and interdecadal timescales are discussed.

Beschreibung: ABSTRACT The Pacific-Japan (PJ) pattern affects interannual variability in the East Asian and western North Pacific (WNP) summer monsoons. This teleconnection pattern is characterized by a meridional dipole of anomalous circulation and precipitation between the tropical WNP and the midlatitudes. This study develops a long index of the PJ pattern using station-based atmospheric pressure data to track the PJ variability from 1897 to 2013. This index is correlated with a wide array of climate variables including air temperature, precipitation, Yangtze River flow, Japanese rice yield and the occurrence of tropical cyclones over the WNP (especially those that make landfall on the Chinese and Korean coast). For the recent three decades, the PJ index reproduces well-known correlations with El Niño-Southern Oscillation (ENSO) in the preceding boreal winter and Indian Ocean temperature in the concurrent summer. For the 117-year period, this ENSO-PJ relationship varies on interdecadal time scales, with low correlations in the 1920s and from the 1940s to 1970s, and recurrences of significant correlations at the beginning of the 20th century and the 1930s. In accordance with the modulation, the magnitude and regional climate effect of the PJ variability have changed. These results highlight the importance of interdecadal modulations of climate anomalies in the summer WNP and the need of long-term observations to study such modulations.

Beschreibung: To overcome the drug resistance phenomenon induced by Imatibib (IM), in clinical practice, are often used second generation of tyrosine kinase inhibitors as Nilotinib (NIL) a such potent inhibitor of the BCR/ABL kinase and Dasatinib (DAS) a inhibitor of BCR/ABL kinase and inhibitor SrC family kinase. In this study we evaluated the in vivo effect of DAS, NIL and IM on intracellular calcium concentration, oxidative stress and apoptosis in peripheral blood leukocytes of 45 newly diagnosed patients with chronic myeloid leukaemia (CML-PBM). Our data demonstrated that treatment with DAS and NIL showed an higher modulating potential than IM on intracellular calcium concentration by inhibiting the thapsigargin, a sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor and Lithium (Li) an inositol 1,4,5-triphosphate (InsP3) receptor inhibitor activities. Moreover our data demonstrated that NIL and DAS have significantly increased apoptosis more than IM by involving both intracellular calcium signaling as well as oxidative stress. The acquisition of the oxidative stress and calcium channels receptors values data could help the hematologist to modulate and improve the treatment of chronic myeloid leukaemia (CML) pathology. This article is protected by copyright. All rights reserved

Beschreibung: Fucoidan, a natural component of seaweeds, is reported to have immunomodulatory and anti-tumor effects. The mechanisms underpinning these activities remain poorly understood. In this study, the cytotoxicity and anti-tumor activities of fucoidan were investigated in acute myeloid leukemia (AML) cells. The human AML cell lines NB4, KG1a, HL60 and K562 were treated with fucoidan and cell cycle, cell proliferation and expression of apoptotic pathways molecules were analyzed. Fucoidan suppressed the proliferation and induced apoptosis through the intrinsic and extrinsic pathways in the acute promyelocytic leukemia (APL) cell lines NB4 and HL60, but not in KG1a and K562 cells. In NB4 cells, apoptosis was caspase-dependent as it was significantly attenuated by pre-treatment with a pan-caspase inhibitor. P21/WAF1/CIP1 was significantly up-regulated leading to cell cycle arrest. Fucoidan decreased the activation of ERK1/2 and down-regulated the activation of AKT through hypo-phosphorylation of Thr(308) residue but not Ser(473). In vivo , a xenograft model using the NB4 cells was employed. Mice were fed with fucoidan and tumor growth was measured following inoculation with NB4 cells. Subsequently, splenic natural killer (NK) cell cytotoxic activity was also examined. Oral doses of fucoidan significantly delayed tumor growth in the xenograft model and increased cytolytic activity of NK cells. Taken together, these data suggest that the selective inhibitory effect of fucoidan on APL cells and its protective effect against APL development in mice warrant further investigation of fucoidan as a useful agent in treatment of certain types of leukemia. This article is protected by copyright. All rights reserved

Beschreibung: Virtual Reality (VR), a computer-generated virtual environment, has been increasingly used in the entertainment world becoming a very new evolving field, but VR technology has also found a variety of applications in the biomedical field. VR can offer to subjects a safe environment within which to carry on different interventions ranging from the rehabilitation of discharged patients directly at home, to the support of hospitalized patients during different procedures and also of oncological inpatient subjects. VR appears as a promising tool for support and monitoring treatments in cancer patients influencing psychological and physiological functions. The aim of this systematic review is to provide an overview of all the studies that used VR intervention on cancer patients and analyze their main findings. Nineteen studies across nearly a thousand articles were identified that explored effects of VR interventions on cancer patients. Although these studies varied greatly in setting and design, this review identified some overarching themes. Results found that VR improved patients' emotional well-being, and diminished cancer related psychological symptoms. The studies explored various relevant variables including different types of settings (i.e. during chemotherapy, during pain procedures, during hospitalization). Here, we point to the need of a global and multi-disciplinary approach aimed at analyzing the effects of VR taking advantage of the new technology systems like bio sensors as well as electroencephalogram monitoring pre-during and after intervention. Devoting more attention to bio physiological variables, standardized procedures, extending duration to longitudinal studies and adjusting for motion sickness related to VR treatment need to become standard of this research field. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT The aim of this article is to present a methodology that describes the relationship between two time series according to their oscillatory modes. Cross-wavelet analysis is used to analyse the connection between the outputs of the empirical mode decomposition (EMD). The combined EMD and cross-wavelet methodology is used for the description of the connection between the annual mean streamflow of Quebec rivers and the North Atlantic Oscillation index (NAO). The relationship between the two time series is analysed by cross-wavelet analysis at the level of the mode of oscillation extracted from the EMD algorithm. The resulting cross-spectra are obtained individually for 18 stations and show intermittent intensity in these relationships between 1970 and 1990 for different oscillation modes. To highlight its particularity, the present methodology is compared with the results of a similar combination of multiresolution analysis (MRA) and cross-wavelet analysis. It shows that EMD isolates clearer bands of frequencies than MRA. Finally, a multi-site analysis is proposed, which performs a principal component analysis of the cross-spectra. This analysis illustrates the evolution of the relationships according to the geographic location. Finally, the advantages and limitations of the proposed methodology are discussed.

Beschreibung: ABSTRACT Hot summer days may lead to reduced thermal discomfort, labour productivity, and higher morbidity and mortality for vulnerable groups. The projected climate change may raise this thermal discomfort in the future. To implement measures to prevent adverse health conditions, robust estimates of the future human thermal comfort (HTC) are required. This study analyses the future HTC for both coastal and inland Dutch cities and countryside. The future conditions are based on the KNMI-06 climate scenarios. Using these scenarios, observed weather data from 1976 to 2005 are transformed to future weather design data representative for 2050. Subsequently, HTC expressed in the physiological equivalent temperature (PET) is estimated for these future scenarios. A substantial increase of heat stress abundance is foreseen in all climate scenarios, for both urban and rural areas, particularly, under the most intense warming. In these scenarios, the frequency of hours with heat stress will more than double, and the increase will develop faster in an urban canyon than in rural areas. In urban areas, PET shows a maximum as function of sky-view factor (SVF), i.e. for a smaller SVF a wind speed reduction increases the PET on one hand and shading reduces the PET on the other hand.

Beschreibung: ABSTRACT El Niño phenomenon is the leading mode of sea surface temperature interannual variability. It can affect weather patterns worldwide and therefore crop production. Crop models are useful tools for impact and predictability applications, allowing to obtain long time series of potential and attainable crop yield, unlike to available time series of observed crop yield for many countries. Using this tool, crop yield variability in a location of Iberia Peninsula (IP) has been previously studied, finding predictability from Pacific El Niño conditions. Nevertheless, the work has not been done for an extended area. The present work carries out an analysis of maize yield variability in IP for the whole 20th century, using a calibrated crop model at five contrasting Spanish locations and reanalyses climate datasets to obtain long time series of potential yield. The study tests the use of reanalysis data for obtaining only climate-dependent time series of crop yield for the whole region, and to use these yield to analyse the influences of oceanic and atmospheric patterns. The results show a good reliability of reanalysis data. The spatial distribution of the leading principal component of yield variability shows a similar behaviour over all the studied locations in the IP. The strong linear correlation between El Niño index and yield is remarkable, being this relation non-stationary on time, although the air temperature–yield relationship remains on time, being the highest influences during grain filling period. Regarding atmospheric patterns, the summer Scandinavian pattern has significant influence on yield in IP. The potential usefulness of this study is to apply the relationships found to improving crop forecasting in IP.

Beschreibung: ABSTRACT There is growing evidence of significant changes in components of the Antarctic climate system, an important issue given the influence Antarctica has on global climate. It is important to infer to what extent these regional changes could be attributed to human-induced processes and to what extent to natural variability. Standard methods such as linear trend estimates or piecewise linear trends can be inadequate because they may result in erratic, non-systematic results, particularly if different scales of variability are present in each record and various records are to be compared. The Orcadas Antarctic Station (Argentina), with daily surface meteorological observations since April 1903, provides Antarctica's longest observational record. This study analyses the Orcadas seasonal surface temperature variability. Multidecadal variability and short-term trends are studied to provide an improved assessment of climate evolution and necessary information for the determination of mechanisms driving regional/local change. A combined method using wavelet transform (WT), non-linear statistical model approaches and derivative of fits is developed. This methodology is also applied for validation and comparison to the Gomez ice core oxygen isotope record for the 1857–2006 and 1903–2006 time intervals. Significant quasi 50-year and quasi 20-year variability bands were obtained, both for the quarterly and seasonal Orcadas temperature records, with warming (cooling) periods detected between 1903–1912, 1927–1961 and 1972–2004 (1912–1927 and 1962–1972). If seasons are considered, the only one with a fairly sustained warming is summer, where actual cooling is observed only at the beginning, prior to the early 1930s. Quasi 50-year variability was also detected in the Gomez record. Long periods are obtained in the model fits, longer than the time series, which varied with window length. Although not representing variability cycles, they could represent the best fit of the non-linear, non oscillating asymptotic stationary component of the series, i.e. a non-linear trend.

Beschreibung: Fabry disease (FD) is a hereditary X-linked metabolic lysosomal storage disorder due to insufficient amounts or a complete lack of the lysosomal enzyme α -galactosidase A ( α  − GalA). The loss of α -GalA activity leads to an abnormal accumulation of globotriaosylceramide (Gb3) in lysosomes and other cellular components of different tissues and cell types, affecting the cell function. However, whether these biochemical alterations also modify functional processes associated to the cell mitotic ability is still unknown. The goal of the present study was to characterize lineages of human dermal fibroblasts (HDFs) of FD patients and healthy controls focusing on Gb3 accumulation, expression of chloride channels that regulate proliferation, and proliferative activity. The biochemical and functional analyses indicate the existence of quantitative differences in some but not all the parameters of cytoskeletal organization, proliferation and differentiation processes. This article is protected by copyright. All rights reserved

Beschreibung: Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disease caused by alpha-L-iduronidase deficiency in which heparan and dermatan sulfate degradation is compromised. Besides primary lysosomal glycosaminoglycan accumulation, further changes in cellular functions have also been described in several murine MPS models. Herein, we evaluated alterations in hematopoiesis and its implications on the production of mature progeny in a MPS I murine model. Despite the significant increase in hematopoietic stem cells, a reduction in common myeloid progenitors and granulocyte-macrophage progenitor cells was observed in Idua -/- mice bone marrow. Furthermore, no alterations in number, viability nor activation of cell death mechanisms were observed in Idua -/- mice mature macrophages but they presented higher sensitivity to apoptotic induction after staurosporine treatment. In addition, changes in Ca 2+ signaling and a reduction in phagocytosis ability were also found. In summary, our results revealed significant intracellular changes in mature Idua -/- macrophages related to alterations in Idua -/- mice hematopoiesis, revealing a disruption in cell homeostasis. These results provide new insights into physiopathology of MPS I. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT This article presents a climatology of total cloud cover (TCC) in the area of the three inland Eurasian seas (Black, Caspian, and Aral Sea). Analyses are performed on the basis of 20 years of data (1991–2010), collected from almost 200 ground stations. Average TCC is 49%, with broad spatial and seasonal variability: minimum TCC values are found in summer and to the southeast, whereas maximum values correspond to winter and to the northwest. For the whole area, linear trend analyses show that TCC did not vary during the study period. We only detected a statistically significant positive trend (+1.2% decade −1 ) in autumn. We obtained different results for the regions delimited by means of a principal component analysis: a clear decrease, both for the annual, spring, and summer series, was detected for the south of Black Sea, while increasing TCC was found for the annual, autumn, and winter series in the north Caucasus and the west and north of Black Sea. We also analysed the TCC data from global gridded products, including satellite projects [International Satellite Cloud Climatology Project (ISCCP), Pathfinder Atmospheres Extended (PATMOS-x), cLoud, Albedo & Radiation (CLARA)], reanalyses [ERA-interim, National Centers for Environmental Prediction/Department of Energy (NCEP/DOE), Modern-Era Retrospective Analysis for Research and Applications (MERRA)], and surface observations [Climatic Research Unit (CRU)]. Although all these products capture the seasonal evolution over the study area, they differ substantially both among them and in relation to the ground observations: reanalyses produce much lower values of TCC, while ISCCP and CLARA provide a summer minimum that is too high. Trend analyses applied to these data generally showed a decrease in TCC; only CRU and NCEP/DOE tally with the ground data as regards the absence of overall trends. These results are discussed in relation to previous studies presenting trends of other variables such as sunshine duration, diurnal temperature range, or precipitation; we also discuss the connections with changes in synoptic patterns and environmental changes, in particular in the Aral Sea region.

Beschreibung: ABSTRACT The Southern Annular Mode (SAM) is a natural climate mode of variability whose discovery can be traced back at least as far as the beginning of the 20th century, before human activities produced enough gases to noticeably change the climate. However, recent observed changes in the SAM are linked to increases of greenhouse gases and stratospheric ozone depletion, hence assigning SAM's alterations, in large part, to human activities. In this study, the 20th century reanalysis data were used to establish the SAM's prominent shifts during the years 1917, 1961 and 1997. The first shift coincides with abrupt greenhouse gas increases and the latter shifts are attributed to stratospheric ozone level changes. The East Africa ‘Short Rains’ (EASR) index derived from the Global Precipitation Climatology Center (GPCC) dating back to the beginning of the 20th century, demonstrates coinciding shifts with the SAM index. However, the SAM's influence on EASR appears to be achieved through a meridional dipole that is formed in the sea-level pressure of the Indian Ocean basin, with one pole over the Tropics and the other over the extratropics. When this dipole pattern is weakly developed as the period between 1961 and 1997, the SAM is decoupled from the EASR and the Indian Ocean Dipole (IOD) demonstrates a dominant role in modulating the EASR. The SAM is also linked to the IOD through its control of the Mascarene High variability, hence connecting the SAM to the dominant circulation variability in the Indian Ocean. Although the El Nino Southern Oscillation is strongly correlated to EASR, it is not related to the epochal variability in the rainfall. Therefore, the slow modulation in EASR is linked to the SAM whose shifts are triggered by gases emanating from human influences.

Beschreibung: ABSTRACT The Hawaiian Islands have one of the most spatially diverse rainfall patterns on earth. Knowledge of these patterns is critical for a variety of resource management issues and, until now, only long-term mean monthly and annual rainfall maps have been available for Hawai‘i. In this study, month-year rainfall maps from January 1920 to December 2012 were developed for the major Hawaiian Islands. The maps were produced using climatologically aided interpolation (CAI), where the station anomalies were interpolated first, and then combined with the mean maps. A geostatistical method comparison was performed to choose the best interpolation method. The comparison focuses on three kriging algorithms: ordinary kriging (OK), ordinary cokriging (OCK), and kriging with an external drift (KED). Two covariates, elevation and mean rainfall, were tested with OCK and KED. The combinations of methods and covariates were compared using cross-validation statistics, where OK produced the lowest error statistics. Station anomalies for each month were interpolated using OK and combined with the mean monthly maps to produce the final month-year rainfall maps.

Beschreibung: ABSTRACT E-OBS(European Observations) is a gridded climate data set which contains maximum temperature, minimum temperature, and precipitation on a daily time step. The data can be as fine as 0.25° in resolution and extends over the entire European continent and parts of Africa and Asia. However, for studying regional or local climatic effects, a finer resolution would be more appropriate. A continental data set with resolution would allow research that is large in scale and still locally relevant. Until now, a climate data set with high spatial and temporal resolution has not existed for Europe. To fulfil this need, we produced a downscaled version of E-OBS, applying the delta method, which uses WorldClim climate surfaces to obtain a 0.008 ° (about 1 × 1 km) resolution climate data set on a daily time step covering the European Union. The new downscaled data set includes minimum and maximum temperature and precipitation for the years 1951–2012. It is analysed against weather station data from six countries: Norway, Germany, France, Italy, Austria, and Spain. Our analysis of the downscaled data set shows a reduction in the mean bias error of 3 °C for mean daily minimum temperature and of 4 °C for mean daily maximum temperature. Daily precipitation improved by 0.15 mm on average for all weather stations in the validation. The entire data set is freely and publically available at ftp://palantir.boku.ac.at/Public/ClimateData .

Beschreibung: ABSTRACT In this study, we investigated changes in the precipitation characteristics for China from 1960 to 2012 based on a recent daily precipitation dataset of 666 climate stations and robust non-parametric trend detection techniques. We divided all precipitation events into four non-overlapping categories: light, moderate, heavy and very heavy based on percentile thresholds. We then established the trends for annual total and precipitation of different intensity categories, and examined their regional and seasonal variations. The results show that there was little change in annual total precipitation for entire China, but distinctive regional patterns existed. In general, precipitation increased in the west and decreased in east. Precipitation of different intensities, in general, changed in the same direction as the mean, but heavy and very heavy precipitation events had higher rates of change than mean precipitation. The exception was the southeast region, where despite the slight decrease in mean precipitation, heavy and very heavy precipitation still increased significantly. In addition, we used multiple regression models to explore the contribution of changes of frequency and intensity to total precipitation change, and the contributions of changes of precipitation at different intensities to total precipitation change. For western China, total precipitation change was associated more with frequency change, whereas in eastern China intensity contributed more. For precipitation amount, moderate, heavy and very heavy precipitations contributed to the total change, with little contribution from light precipitation change. For frequency, changes in light and moderate precipitation frequencies dominated the total change, with very little contributions from heavy and very heavy precipitation frequency changes. In addition, we examined the linkage between summer precipitation in eastern China and the East-Asian Summer Monsoon (EASM), found that the northern decrease and southern increase in summer precipitation was likely caused by the weakening of EASM over the study period.

Beschreibung: ABSTRACT Southeastern South America (SESA) rainfall is influenced by the tropical Pacific, Atlantic and Indian Oceans. At the same time, these tropical oceans interact with each other inducing sea surface temperature anomalies in remote basins through atmospheric and oceanic teleconnections. In this study, we employ a tool from complex networks to analyse the collective influence of the three tropical oceans on austral spring rainfall variability over SESA during the 20th century. To do so we construct a climate network considering as nodes the observed Niño3.4, Tropical North Atlantic (TNA), and Indian Ocean Dipole (IOD) indices, together with an observed and simulated precipitation (PCP) index over SESA. The mean network distance is considered as a measure of synchronization among all these phenomena during the 20th century. The approach allowed to uncover two main synchronization periods characterized by different interactions among the oceanic and precipitation nodes. Whereas in the 1930s El Niño and the TNA were the main tropical oceanic phenomena that influenced SESA precipitation variability, during the 1970s they were El Niño and the IOD. The influence of El Niño on SESA precipitation variability might be understood through an increase of the northerly transport of moisture in lower-levels and advection of cyclonic vorticity in upper-levels. On the other hand, the interaction between the IOD and PCP can be interpreted in two possible ways. One possibility is that both nodes (IOD and PCP) are forced by El Niño. Another possibility is that the Indian Ocean warming influences rainfall over SESA through the eastward propagation of Rossby waves as suggested previously. Finally, the influence of TNA on SESA precipitation persists even when the El Niño signal is removed, suggesting that SST anomalies in the TNA can directly influence SESA precipitation and further studies are needed to elucidate this connection.

Beschreibung: ABSTRACT How boreal summer intraseasonal oscillation (BSISO) modulates the probability and spatial distributions of extreme rainfall occurrence over populous southern China was examined, using the newly proposed BSISO indices and two high-resolution rain-gauge-based rainfall datasets in China. The probability density function of May–August rainfall in southern China is skewed towards large values in phases 2–4 of the first component and in phases 5–7 of the second component of BSISO life cycle, during which the probability of extreme rainfall events at the 75th (90th) percentile increases by 30–50% (over 60%) relative to the non-BSISO period. The devastating floods with prolonged extreme rainfall in southern China over the three past decades occurred coincidently with these BSISO phases. The first component of BSISO, associated with 30–60-day eastward/northeastward-propagating ISO, is more favourable for the rainfall extreme over in-land China. In contrast, the second component of BSISO, related to the 10–30-day northwestward propagating ISO, tends to link with the rainfall extreme along the southeast coast of South China. Moisture budget indicates that the favourable environment for rainfall extreme is associated with southwesterly moisture convergence over southern China, while the moisture advection contributes insignificantly. This study suggests a potential for monitoring and probabilistic prediction of extreme rainfall events in southern China based on the real-time BSISO indices.

Beschreibung: ABSTRACT The sea surface temperature (SST) in the Bay of Bengal (BoB) during the period 1960–1995 showed a decadal cycle, riding over a warming trend. The disruption of the decadal cycle was noticed post-1995 and was followed by a slowdown in the sea surface warming. The cause for the disruption of the SST decadal cycle was the weakening of the link between SST and sunspot number. The rising trend in the SST is due to the increasing atmospheric CO 2 concentration. The post-1995 SST slowdown was due to the increasing influence of the number of depressions, cyclones and severe cyclones in the BoB, the occurrence of which showed an upward trend. Using Price–Weller–Pinkel model we show that cyclonic systems deepen the mixed-layer through enhanced mechanical-mixing with cooler sub-surface waters, thereby reducing the mixed-layer temperature and consequently the SST. This process opposes the SST rise due to increasing atmospheric CO 2 concentration. The net effect of the wind-mixing caused by the increased number of depressions, cyclones and severe cyclones and the increased CO 2 concentration is a SST slowdown in the BoB. This mechanism differs from the SST slowdown mechanisms suggested for the Atlantic and the Pacific.

Beschreibung: ABSTRACT In the last few years, there has been an increasing application of gridded precipitation data sets for studies analysing seasonal and interannual precipitation variability as well as for performing validation analysis of climate and regional models. Consequently, the purpose of the present study is to analyse the representation of temporal variability and spatial patterns of precipitation in South America for the period 1971–2010, derived by three data sets based exclusively on rain gauge information (Climate Research Unit – CRU, Global Precipitation Climatology Centre – GPCC and University of Delaware – UDel), in order to identify discrepancies and/or agreements among them. Further analysis is performed for three particular sub-regions within the continent (southern sector of southeastern South America – SSESA, central South America – CSA and southeastern Brazil – SEBR). Results show that the three products represent key spatial features of precipitation analogously. Significant coherence in capturing the temporal variability, associated with the dominant modes of variability, is found in all sub-regions, though they differ largely in some areas, especially in CSA. Overall, depending on the region, the gridded products behave differently, without one particular data set standing out as an outlier in all the analysed cases.

Beschreibung: ABSTRACT Land and water management in semi-arid regions requires detailed information on precipitation distribution, including extremes, and changes therein. Such information is often lacking. This paper describes statistics of mean and extreme precipitation in a unique data set from the Mount Kenya region, encompassing around 50 stations with at least 30 years of data. We describe the data set, including quality control procedures and statistical break detection. Trends in mean precipitation and extreme indices calculated from these data for individual rainy seasons are compared with corresponding trends in reanalysis products. From 1979 to 2011, mean precipitation decreased at 75% of the stations during the ‘long rains’ (March to May) and increased at 70% of the stations during the ‘short rains’ (October to December). Corresponding trends are found in the number of heavy precipitation days, and maximum of consecutive 5-day precipitation. Conversely, an increase in consecutive dry days within both main rainy seasons is found. However, trends are only statistically significant in very few cases. Reanalysis data sets agree with observations with respect to interannual variability, while correlations are considerably lower for monthly deviations (ratios) from the mean annual cycle. While some products well reproduce the rainfall climatology and some the spatial trend pattern, no product reproduces both.

Beschreibung: ABSTRACT Precipitation variability at inter- and intra-annual scales may influence land-use management decisions in semi-arid savannas worldwide, and in particular, over the Kavango-Zambezi Transfrontier Conservation Area (KAZA) in southern Africa. Over KAZA, spatiotemporal precipitation variability forced by the El Niño Southern Oscillation (ENSO) and the Indian Ocean Dipole (IOD) is important to local and regional-scale decisions for planting, livestock grazing, and wildlife migration patterns. We investigate the annual water year (October–September) and early rainy season [October–November–December (OND)] precipitation patterns during 60 years before and after a 1970s shift in the global ocean–atmosphere system for this region in southern Africa. The coincidence of the number of wet (upper tercile) and dry (lower tercile) years and OND seasons during the various phases of ENSO and IOD are compared prior to (1950–1975) and after (1980–2008) the 1970s climate shift over KAZA. Since the 1970s climate shift, KAZA has been significantly drier and observed fewer wet years and OND seasons. ENSO is the dominant forcing of precipitation differences over southern Africa before and after the 1970s climate shift, with IOD playing a secondary role. However, when ENSO and IOD phases are analysed simultaneously, El Niño and positive IOD events are significantly related to dry periods. The forcing of atmospheric circulation over southern Africa before and after the 1970s climate shift during El Niño and La Niña events is significantly different. Prior to the 1970s climate shift, atmospheric circulation during El Niño (La Niña) favoured strong (weak) precipitation increases (decreases). Afterward the 1970s climate shift, atmospheric circulation during La Niña (El Niño) favoured strong (weak) precipitation decreases (increases). The shifting nature of climate modes, especially ENSO, and respective influence on rainfall variability for southern Africa is important to understand to better inform seasonal climate forecasts to improve operational decision-making for land-use and water management decisions in semi-arid savanna regions.

Beschreibung: ABSTRACT A unique approach for downscaling daily precipitation extremes from historical analogues is presented. While various analogue methods have been developed for the purpose of downscaling local climate data, few have placed an emphasis on downscaling daily extremes. Unlike previous approaches, the new method utilizes a two-step procedure in which the occurrence of extreme precipitation on a given target day is first determined based on the observed probability of extreme precipitation on that day's closest historical analogue days. Then, if extreme precipitation occurred on the selected analogue day, the historical precipitation observations associated with the analogue day are used to ascribe precipitation amounts on the corresponding target day. The method is developed and tested for a very strict definition of extreme precipitation (partial duration series events), as well as a more lenient definition of extreme precipitation (95th percentile of non-zero precipitation events). The analogue approach is more skillful than climatology at identifying the occurrence of both partial duration series (PDS) and 95th percentile events. In both cases, the analogue method slightly underestimates the observed occurrence of extreme precipitation. Return period precipitation amounts estimated from the downscaled PDS are similar to, but generally lower than those calculated from observed PDS. Over the entire study domain (157 stations in New York State and surrounding regions of adjacent states and Canada), the median difference between downscaled and observed 5-year (100-year) return period precipitation amounts is less than 5% (10%). These median differences are smaller than those obtained from historical dynamically downscaled climate model simulations.

Beschreibung: ABSTRACT The summer time cloud diurnal cycle over western Iberia is analysed here using a satellite climate data record of fractional cloud cover based on 9 years of Meteosat Second Generation observations which is distributed by the EUMETSAT's Climate Monitoring Satellite Applications Facility. These observations were complemented with a corresponding mean cloud diurnal cycle using SYNOP reports on six locations over the studied domain. It is shown that the main coastal mountain range separates regions that are characterized by two very different cloud regimes: stratocumulus-topped boundary layer convection dominates the region towards the coast and continental cumulus convection dominates the region to the east of these mountains. To explain the observed variability, a long-term regional climate model [Weather Research and Forecasting model (WRF)] simulation over Iberia was used. A comparison of the observations against model output for the common period between observations and simulation shows that although the model generally underestimates cloudiness, it is able to represent the diurnal cycle in a realistic manner. It is shown that the observed cloud diurnal evolution is linked to the thermal circulations generated by the land-sea contrast and orography. The extent to which the cloud deck penetrates inland is closely related to the coastal orography: although smaller hills tend to enhance cloudiness, larger mountains block the progression of the marine boundary layer further inland, as it behaves as a density current. Larger mountains also produce katabatic flow and a rather strong subsidence aloft during the night. The warming due to this subsidence helps the blocking of the cloud deck as it is partially responsible for evaporating clouds, as shown by a potential temperature budget analysis.

Beschreibung: ABSTRACT High-quality temperature estimates with good spatio-temporal coverage are necessary for completely understanding the influences of warming climate on cryosphere and hydrological systems in High Mountain Asia (HMA). In this study, we compare reanalysis temperature data from ERA-Interim and National Centers for Environmental Prediction/National Center for Atmospheric Research (NCEP/NCAR) with station observations in HMA during 1979–2011. The results indicate that although reanalysis temperature data can capture the warming trends in HMA, the trend magnitudes are clearly underestimated by reanalysis data. In particular, the increase in summer temperature cannot be identified from the NCEP/NCAR reanalysis. For ERA-Interim, temperature increases are underestimated in the north and northwest of HMA; for NCEP/NCAR, the warming magnitudes show evident biases in the Pamir, Himalayas, and southeastern Tibetan Plateau. Considering that high-frequency signals and periodical fluctuations among the three datasets are in good agreement, and based on the wavelet transform method, the low-frequency component decomposed from the temperature time series of ERA-Interim and NCEP/NCAR reanalyses is adjusted by that derived from station observations. The resulting homogenized reanalysis temperature data show much better spatio-temporal consistency with station data. The differences in monthly and annual temperature anomalies between station and homogenized ERA-Interim and NCEP/NCAR reanalysis data become more convergent. The homogenized temperature time series are better correlated with station data at annual and seasonal timescales.

Beschreibung: Chondrogenesis subtends the development of most skeletal elements and involves mesenchymal cell condensations differentiating into growth plate chondrocytes that proliferate, undergo hypertrophy and are replaced by bone. In the pediatric disorder Hereditary Multiple Exostoses, however, chondrogenesis occurs also at ectopic sites and causes formation of benign cartilaginous tumors –exostoses- near the growth plates. No treatment is currently available to prevent or reverse exostosis formation. Here, we asked whether chondrogenesis could be stopped by targeting the hedgehog pathway, one of its major regulators. Micromass cultures of limb mesenchymal cells were treated with increasing amounts of the hedgehog inhibitor HhAntag or vehicle. The drug effectively blocked chondrogenesis and did so in a dose-dependent manner as monitored by: alcian blue-positive cartilage nodule formation; gene expression of cartilage marker genes; and reporter activity in Gli1-LacZ cell cultures. HhAntag blocked chondrogenesis even when the cultures were co-treated with bone morphogenetic protein 2 (rhBMP-2), a strong pro-chondrogenic factor. Immunoblots showed that HhAntag action included modulation of canonical (pSmad1/5/8) and non-canonical (pp38) BMP signaling. In cultures co-treated with HhAntag plus rhBMP-2, there was a surprising strong up-regulation of pp38 levels. Implantation of rhBMP-2-coated beads near metacarpal elements in cultured forelimb explants induced formation of ectopic cartilage that however, was counteracted by HhAntag co-treatment. Collectively, our data indicate that HhAntag inhibits not only hedgehog signaling, but also modulates canonical and non-canonical BMP signaling and blocks basal and rhBMP2-stimulated chondrogenesis, thus representing a potentially powerful drug-based strategy to counter ectopic cartilage growth or induce its involution. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT Cholangiocarcinoma (CCAs) may be defined as tumors that derived from the biliary tree with the differentiation in the biliary epithelial cells. This tumor is malignant, extremely aggressive with a poor prognosis. It can be treated surgically and its pathogenesis is poorly understood. The tumor microenvironment (TME) is a very important factor in the regulation of tumor angiogenesis, invasion, and metastasis. Besides cancer stem cells (CSCs) can modulate tumor growth, stroma formation and migratory capability. The initial stage of tumorigenesis is characterized by genetic mutations and epigenetic alterations due to intrinsic factors which lead to the generation of oncogenes thus inducing tumorigenesis. CSCs may result from precancerous stem cells, cell de-differentiation, normal stem cells or an epithelial-mesenchymal transition (EMT). CSCs have been found in the cancer niche, and EMT may occur early within the tumor microenvironment. Previous studies have demonstrated evidence of cholangiocarcinoma stem cells (CD133, CD24, EpCAM, CD44, and others) and the presence of these markers has been associated with malignant potential. The interaction between TME and cholangiocarcinoma stem cells via signaling mediators may create an environment that accommodates tumor growth, yielding resistance to cytotoxic insults (chemotherarapeutic). While progress has been made in the understanding of the mechanisms, the interactions in the tumorigenic process still remain a major challenge. Our review, addresses recent concepts of TME-CSCs interaction and will emphasize the importance of early detection with the use of novel diagnostic mechanisms such as CCA-CSC biomarkers and the importance of tumor stroma to define new treatments. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT The mean climatology, seasonal and interannual variability and trend of wind speeds at the hub height (80 m) of modern wind turbines over China and its surrounding regions are revisited using 33-year (1979–2011) wind data from the Climate Forecast System Reanalysis (CFSR) that has many improvements including higher spatial resolution over previous global reanalysis products. Mean 80-m wind speeds are consistently higher over China Seas and the ocean areas than over land, and inside China high winds are found in areas of Inner Mongolia and the Tibetan Plateau. There is a considerable seasonal variability that reflects primarily the influence of East and Southeast Asia Monsoon with generally higher speeds in winter followed by summer, and weaker winds in autumn, followed by spring. There is also a strong interannual variability, and regions of larger amplitude of variability coincide with regions of higher mean winds. A decreasing trend, dominated by a sharp decline beginning in 2005, is seen across China and the surrounding seas in summer and autumn, and the summer trends over land and over ocean appear to be related respectively to the Pacific Decadal Oscillation (PDO) and the East Asian summer monsoon. Trends are not consistent across the region in spring and winter, however, with positive trends over some areas in northeastern and northwestern China, Mongolia and tropical oceans whereas negative trends in other regions. Nearly all areas of China experience mean annual 80-m wind speed less than 6.9 m s −1 (wind power classes of 1–2) except for some areas of Inner Mongolia where mean annual 80-m wind speeds exceed 6.9 m s −1 (Classes 3 or higher, suitable for wind energy development). China Seas and ocean areas generally fall in Class 3 or above, with the Taiwan and Luzon Straights reaching the highest Class 7.

Beschreibung: ABSTRACT Capturing the intensity and return period of extreme rainfall events in the historic record and projecting them into the future are essential to managing, planning, and designing infrastructure. In this study, we assess the performance of the combination of four General Circulation Models (GCMs) and six Regional Climate Models (RCMs) that comprise the North American Regional Climate Change Assessment Program (NARCCAP) and evaluate their performance in simulating rainfall extremes in the continental United States. We adopt a regionalization method to objectively delineate 12 regions in the continental United States with relatively homogenous annual maximum 24-h rainfall patterns from the North American Regional Reanalysis (NARR) data set. We then compare the Intensity–Duration–Frequency (IDF) curves generated from control simulations of NARCCAP models with those from NARR in each of these regions. We find significant spatial variability of model performance. The models perform reasonably well in many parts of the country, but poorly in the southeastern United States. The GCM providing boundary conditions strongly influences results – output from those RCMs driven by the Community Climate System Model (CCSM) and Canadian Global Climate Model version 3 (CGCM3) matched the NARR data best. Performance of individual RCMs also varied, often in response to nudging, wherein the regional model is constrained by the GCM fields. We also measure changes in bias-corrected IDF curves generated from NARCCAP projections of the future. In most regions, most models project intensified 24-h rainfall events in the future (exceptions include some model-projected decreases in southern California, the extreme north-central US, Florida, and the Texas Plains). This study provides a valuable means of assessing NARCCAP models' performance in simulating rainfall extremes at the regional scale and understanding how the GCMs, RCMs, and spatial variability affect model performance.

Beschreibung: ABSTRACT Climate data from the southwest coast of the Caspian Sea (CS) were statistically analysed to find connections with large-scale atmospheric variabilities and regional impacts. The study area is characterized by a subtropical humid climate. This enclave of high precipitation is extremely important for Iranian food production and is recognized for its high biodiversity. The data sets were investigated for inconsistencies before carrying out the main investigations, and several problems have been identified. The results show three distinct climatic periods in the temperature time series since 1956: 1956 to 1975 with values near to the overall mean, 1977 to 1995 with values lower by 0.5 °C and from 1996 to 2010 with values higher by 0.5 °C. These periods can be positively correlated with rapid sea level changes of the CS. Moreover, an agreement exists between the three climatic periods and the North Atlantic Oscillation (NAO) variability. The sea surface temperature of the southern CS is shown to be the driving force of the 2 m temperatures in the study area. While temperature changes are in accordance with NAO variability, the precipitation variations show connections with ENSO and less with NAO. The trends of precipitation during the period are diverse but display mostly a weak decrease, while the trends of temperature display a clear increase, larger than that for global mean temperatures, overlaid with inter-decadal variations.

Beschreibung: ABSTRACT This paper studies how the anthropogenic-induced global warming affects the East Asian winter monsoon (EAWM) by using 26 Coupled Model Intercomparison Project phase 5 (CMIP5) models. The simulated present-day EAWM is evaluated and future projections under RCP4.5 and RCP8.5 scenarios are presented in terms of the climatology and interannual variability. All 26 models can well reproduce the spatial pattern of EAWM climatology and 16 out of the 26 models can reasonably capture major features of interannual variability. The projection made by 26-model ensemble mean indicate that winter surface air temperature averaged over 20°–60°N, 100°–140°E will increase by 3 °C in RCP4.5 and 5.5 °C in RCP8.5 towards the end of the 21st century. The corresponding regional mean precipitation will increase by 12.3% in RCP4.5 and 21.8% in RCP8.5. The strong warming over high-latitude North Pacific due to melting sea ice in the Bering Sea and Okhotsk Sea leads to significant intensification and a northward shift of the Aleutian Low, resulting in prominent increase in the low-level northerly along the coastal regions of northeastern Asia. At 500 hPa the characteristic East Asian Trough is projected to weaken slightly and tilt more eastward with latitude. The selected 16-model ensemble mean projects future enhanced interannual variability of surface air temperature and sea-level pressure over mid-latitude North Pacific and high-latitude East Asia (EA) and reduced variability over eastern China, suggesting that the EAWM will be more variable in the high-latitude EA and mid-latitude North Pacific but less variable in East China. Accordingly, the year-to-year precipitation variability will be significantly enhanced over high-latitude EA. Majority of the 26 models project that the leading mode of EAWM interannual variation (the ‘northern mode’) will become more dominant in the warmer climate.

Beschreibung: ABSTRACT Crop loss due to drought is a complex issue, because it changes according to the drought intensity and duration, and the developmental stage of the plants when drought occurs. In order to assess the drought-induced decline in crop harvest, drought variability and the yield sensitivity of winter wheat, maize, sugar beet, and sunflower to drought during their growing seasons is investigated in the Republic of Moldova. This is then used as an example of the response of non-irrigated crops to increasing drought tendency in south-eastern Europe. The quantification of drought was done by using the standardized precipitation evapotranspiration index (SPEI) at 1- to 12-month lags during the period from 1951 to 2012. The relationship between drought at various time scales and the standardized yield residuals series (SYRS) for individual crops over the country and the Balti chernozem steppe of Moldova (represented by Balti experimental site) for the 1962–2012 farming years were investigated. In order to detect the trends and the shifts in the SPEI time series over 62 years, the non-parametric, Mann–Kendall and Pettitt tests were used for each month of the year to cover the main life cycle of the crops. The trend analysis of agricultural drought emphasizes an increasing trend from June to October, and becomes significant in the southern region at the 95% level during July to September. The SPEI highlights the main periods of dry/wet persistence and the regional characteristics of drought which are present in the Southern region, and make this region more prone to severe drought persistence, mostly during the last decade. Drought during the plant reproductive stages may significantly reduce grain yield potential, the relation between the SYRS and the SPEI explaining up to 62% of the low-yield variability.

Beschreibung: ABSTRACT In the face of limited or no precipitation data, global precipitation data sets (GPDs) may provide a viable alternative to gauge or ground radar data. This study aims to provide guidance to the choice of GPDs targeting scales relevant to water resources management in data poor regions. Specifically, the 34 000 km 2 Kilombero Valley in central Tanzania, where water resource management is seen as integral to poverty reduction and food security, is used as a case study for performance evaluation of seven GPDs and their ensemble mean against the Tropical Rainfall Measuring Mission (TRMM) multi-satellite precipitation analysis research-grade product v7 (TRMMv7). The GPDs include one satellite rainfall product [Climate Prediction Center morphing technique v1.0 CRT (CMORPH)], three reanalysis products [Climate Forecasting System Reanalysis (CFSR), European reanalysis interim (ERA-i) and Modern Era Retrospective-Analysis for Research and Applications (MERRA)] and three interpolated data sets [Climate Research Unit Time Series 3.21 (CRU), Global Precipitation and Climatology Center v6 data set (GPCC) and University of Delaware Air Temperature and Precipitation v3.01 data set (UDEL)]. Standard statistical performance measures and spatial patterns were evaluated for the common overlap time period 1998–2010. For this region, the principal seasonality of the climatology was well represented in all GPDs; however, the intraseasonal variability and the spatial precipitation patterns were less well represented. The ensemble mean and GPCC had the best performance with regard to the analysis of the time series while CMORPH and GPCC had the best performance with regard to the spatial pattern analysis. These results indicate that the spatial scale intended for application is a major factor impacting the suitability of a given GPD for hydrometrological studies that form a basis for development of water management strategies.

Beschreibung: ABSTRACT This study investigates the effect of varying the vertical level of a synoptic circulation classification on its predictive skill with respect to surface temperature, rainfall, solar radiation and wind in Trentino, a mountainous region in the South-Eastern Alps. A synoptic climatology based on the same data set and classification method presented in part I of the present article, in fact, showed that seasonal anomalies of mean daily temperature, daily rainfall, daily solar irradiation and mean daily wind intensity vary not only among weather types and seasons but also within the same type and season for different vertical levels. This analysis quantifies the ability of the method to classify synoptic circulation in classes associated with distributions of atmospheric variables different from climatology and to identify the occurrence of extreme events. The statistical metrics presented in the article demonstrate that the differences in predictive skill between classifications applied to distinct levels are comparable in magnitude to those between different atmospheric variables and seasons for the same level. The level of 500 hPa generally provides the largest predictive skill with respect to total daily rainfall, daily solar irradiation and daily temperature range in all seasons. On the other hand, the largest skill with respect to wind intensity is found for sea level pressure and 850 hPa circulation types. Large seasonal variations are also evident, with the colder seasons providing the largest predictive skill. Combinations of circulation types derived at two vertical levels increase the skill, although an optimal combination of levels could not be found even for the same atmospheric variable and season.

Beschreibung: ABSTRACT In this paper, we analyse observed changes in characteristics of sub-daily heavy summer precipitation and erosive precipitation events for the Czech Republic, taking into consideration 51 years of data (1961–2011) for 17 stations. The sub-daily data were checked for consistency with the daily control records, and unreliable data were removed from the data set. Subsequently, four statistical tests were applied to assess the homogeneity of the data set. The trend magnitude was estimated using the Theil–Sen slope estimator, and two tests were applied to evaluate its significance. For most of the indices, the tests did not indicate inhomogeneity, with the exception of characteristics related to rainfall intensity. The trends are positive for most of the stations and most precipitation characteristics, and significant positive trends are much more frequent than negative trends. The analysis revealed a significant increase in the contribution of heavy precipitation to the precipitation total in half of the stations at short aggregation levels.

Beschreibung: ABSTRACT This study evaluates the simulation of the spring Arctic Oscillation (AO)-western North Pacific linkage based on the 16 state-of-the-art climate models from the Coupled Model Intercomparison Project Phase 5. The validation focuses on the predominant process connecting the spring AO with the East Asian summer monsoon: the formation and persistence of the spring AO-associated cyclonic anomaly over western North Pacific (WPCA) from spring to summer. The results indicate that 8 of 16 models can reproduce both the formation and persistence of the WPCA. Because the formation of the WPCA is directly related to the existence of the spring upper-level North Pacific atmospheric dipole (NPAD), the analyses suggest that a given model can reproduce the spring AO-associated NPAD if the model is capable of simulating the spring AO-associated deceleration of the subtropical westerly jet and the transient eddy activities around the westerly jet exit. Furthermore, the westerly jet anomalies are closely related to the simulated mean state of the westerly jet and the AO Pacific component, which could be further attributed to the simulated sea surface temperature biases over the equatorial Western Pacific.

Beschreibung: ABSTRACT Climate variability has major impacts on crop yields and food production in South Asia. The spatial differences of the impact are not, however, well understood. In this study, we thus aim to analyse the spatio-temporal relationship between precipitation and rice yields in the Ganges–Brahmaputra–Meghna region. The effects of rainfall variation on yields were analysed with regression models using the Standardized Precipitation Index (SPI) as an explanatory variable. Our results indicate that in large part of the study region, a strong relationship between precipitation and rice yields exists and the SPI at various lags chosen as the predictor variable performed well in describing the inter-annual yield variability. However, the study demonstrated large spatial variations in the strength of this relationship or optionally in the suitability of the chosen methodology for investigating it. In the mid-plains of the Ganges, which represent very important agricultural areas, precipitation variability has a strong impact on rice yields, while in downstream Ganges as well as in Brahmaputra, where precipitation is more abundant, the relationship was less pronounced. Where the performance of the regression models was weaker, it is likely that yield variation depended on other factors such as management practices or on other climate factors such as temperature. The results further showed that the SPI at 1, 3, 6 and 12 month lags calculated for the monsoon time (June–October) are most commonly the best at explaining the rice yield variability. The SPI can thus be considered a very useful predictor of rice yield variability in some parts of the study region, demonstrating that they could be used for agricultural applications and policy decisions to improve the region's food security.

Beschreibung: ABSTRACT Features and interdecadal variability of droughts were assessed over the East Asian monsoon region (20°–50°N, 103°–149°E) using the standardized precipitation index (SPI) and the gridded rainfall data set (1978–2007) at 0.5° resolution. To assess the spatial and temporal patterns of droughts, seven homogeneous rainfall zones that exhibit unique rainfall regimes and long-term variability over the region were used. The statistical analysis method known as the theory of runs was used to identify and characterize drought events. A run was defined as a portion of SPI drought series in which all values were below the selected threshold level. Run-length and run-sum were used to define the drought duration and drought severity, respectively. The study revealed unique drying and wetting patterns for different zones in the region. Interdecadal analysis of droughts over the past three decades revealed a significant increase in drought duration and severity in the low rainfall zones, whereas a significant decrease appeared in the high rainfall zones. In particular, the duration and severity dwindled to zero with no major drought event over the eastern and the East Sea coastal region of Japan during the last decade (1998–2007). These patterns pose serious threats of increasing droughts in the low rainfall zones and flooding in the high rainfall zones. The spectral analysis, using the Fast Fourier Transform, was performed to identify the cyclic patterns of SPI time series in each zone, which revealed dominant cycles of 15, 7.5, and 3.4 years in the different zones. These results suggest the possible influence of interdecadal Pacific Oscillations and North Atlantic Oscillations on droughts in the region, although these relations remain a challenging task.

Beschreibung: ABSTRACT Heavy rainfall months of more than 450 mm occur in all 56 meteorological stations in eight climatic zones of Vietnam during the rainy season from April to September in the north (〉20°N), from August to December in the centre and from May to November in the south (〈12°N). The severity of an El Niño Southern Oscillation (ENSO) episode, expressed as the integral of sea surface temperature anomaly (SSTA) in the central tropical Pacific over the duration, shows a 4.6-fold (2.3-fold) increase in number of heavy rainfall months during La Niña (El Niño) per unit change in severity during the 1960–2009 period, suggesting a twin peak occurrence with both ENSO extremes. A heavy rainfall index (HRI) links heavy rainfall months to the rainy season duration, and allows evaluation of the rainfall severity per station, climatic zone and ENSO cycle. For the deltas and central climatic zones, seasonal rainfall and number of heavy rainfall months are significantly higher at the p  〈 0.05 level during La Niña than during El Niño episodes. Interpolated seasonal rainfall shows distinct differences between regions, with location having a larger effect than ENSO cycles on monthly rainfall amounts. Twenty-year return monthly rainfall derived from generalized Pareto distributions for peak over thresholds range from 475 mm in the central highlands to 2185 mm in the central coast. The spatial and temporal patterns of heavy monthly rainfall help explain flooding and paddy inundation which occur at least twice as frequent during La Niña as compared to El Niño conditions, particularly in Central Vietnam. The relation of HRI with both 20-year return levels and ENSO cycles offers opportunities for fast screening of impacts in a wider region of Southeast Asia. Because ENSO cycles have an impact on flooding and paddy inundation, it provides prospects for early warning, differentiated for different zones and rainfall regimes.

Beschreibung: ABSTRACT Early detection of colorectal cancer (CRC) remains a challenge. It has been highlighted that the pathological alterations within an organ and tissues might be reflected in serum or plasma proteomic/peptidic patterns. The aim of the study was to follow the changes in the plasma peptides associated to colorectal cancer progression by mass spectrometry. This study included 27 adenoma, 67 CRC (n = 33 I-II stage and n = 34 III-IV stage), 23 liver metastasis from CRC patients and 34 subjects disease-free as controls. For plasma peptides analysis, samples purification was performed on the Nanoporous Silica Chips technology followed by matrix-assisted laser desorption/ionisation-time of flight analysis. Since the high complexity of the obtained dataset, multivariate statistical analysis and discriminant pattern recognition were performed for study groups classification. Forty-four of 88 ionic species were successfully identified as fragments of peptides and proteins physiologically circulating in the blood and belonging to immune and coagulation systems and inflammatory mediators. Many peptides clustered into sets of overlapping sequences with ladder-like truncation clearly associated to proteolytic processes of both endo- and exoproteases activity. Comparing to controls, a different median ion intensity of the group-type fragments distribution was observed. Moreover, the degradation pattern obtained by proteolytic cleavage was different into study groups. This pattern was specific and characteristic of each group: controls, colon tumour disease (including adenoma and CRC) and liver metastasis, revealing a role as biomarker in early diagnosis and prognosis. Our findings highlighted peculiar changes in protease activity characteristic of CRC progression from pre-cancer lesion to metastatic disease. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT The aim of this study was to verify the effects of running overtraining protocols performed in downhill, uphill and without inclination on the proteins related to hypertrophy signaling pathway in extensor digitorum longus (EDL) and soleus of C57BL/6 mice. We also performed histological and stereological analyses. Rodents were divided into control (CT; sedentary mice), overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up) and overtrained by running without inclination (OTR). The incremental load, exhaustive and grip force tests were used as performance evaluation parameters. 36h after the grip force test, EDL and soleus were removed and immediately used for immunoblotting analysis or stored at -80 ° C for histological and stereological analyses. For EDL, OTR/down decreased the protein kinase B (Akt) and tuberous sclerosis protein 2 (TSC2) phosphorylation (p), and increased myostatin, receptor-activated Smads (pSMAD2-3) and insulin receptor substrate-1 (pIRS-1; Ser307/636). OTR/down also presented low and high relative proportions of cytoplasm and connective tissue, respectively. OTR/up increased the mammalian target of rapamycin (pmTOR), 70-kDa ribosomal protein S6 kinase 1 (pS6K1) and pSMAD2-3, and decreased pTSC2. OTR decreased pTSC2 and increased pIRS-1 (Ser636). For soleus, OTR/down increased S6 ribosomal protein (pS6RP) and pSMAD2-3, and decreased pIRS-1 (Ser639). OTR/up decreased pS6K1, pS6RP and pIRS-1 (Ser639), and increased pTSC2 (Ser939) and pSMAD2-3. OTR increased pS6RP, 4E-binding protein-1 (p4E-BP1), pTSC2 (Ser939), and pSMAD2-3, and decreased pIRS-1 (Ser639). In summary, OTR/down inhibited the skeletal muscle hypertrophy with concomitant signs of atrophy in EDL. The effects of OTR/up and OTR depended on the analyzed skeletal muscle type. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT Recent studies have pointed out the statistical occurrence of dual-season droughts detected in tree-ring chronologies over the southwestern US region that is not well described by instrumental observed records of the 20th century. In this study, a multi-statistical approach that evaluates persistent dual-season drought using a mode-of-variability oriented approach is proposed, considering a new network of tree-ring earlywood (EW)- and latewood-adjusted (LW adj ) chronologies from throughout southwestern North America. To determine dominant patterns of spatiotemporal variability, empirical, orthogonal functions, canonical correlation analysis, and multi-taper-method singular value decomposition analyses were applied, with focus on variability from inter-annual to centennial periods and highlighting the multi-decadal signals inherent to proxy record network. During the instrumental period, we demonstrate that EW and LW adj networks of tree-ring chronologies are able to capture the associated precipitation responses of cool and warm season atmospheric teleconnections. Considering the four-century period of the complete tree-ring network, we explore the possibility of a dual summer–winter variability signal in the low-frequency climate regime. EW and LW adj seem to be coherent in-phase at the very low-frequency scale (50–100 years spectral band). This provocative result is supported by major historic documented multi-year droughts of the region since 1650. Thus, the temporal variation of these chronologies time series and its associated spatial pattern strongly suggest that this low-frequency mode might represents an important spatiotemporal variation of droughts in the Southwest; however, the source of this signal is still an open question and of great interest for drought planning and resource management in the region.

Beschreibung: ABSTRACT Spatiotemporal patterns of precipitation regimes in terms of precipitation amount and number of precipitation days at different time scales are investigated using the entropy-based methodologies in the Huai River basin, China. Trends of precipitation variability are quantitatively evaluated using the modified Mann–Kendall trend test method. Correlations between the largest 7-day precipitation amount (R × 7day) and precipitation variability within 1 year are also analysed. Results indicate the following: (1) there is increasing nonuniformity of annual precipitation amount and annual precipitation days from south to north in the Huai River basin, indicating larger precipitation variability in the northern parts. Transition of precipitation changes is evident in the basin which is reflected by decreasing precipitation variability in the north and increasing precipitation variability in the south. (2) The disorder indices (DIs) exhibit variations at different time scales. In general, precipitation variability is larger at shorter time scales, such as daily, and is smaller at longer time scales, such as annual. (3) Significant relations are identified between the DI and extreme precipitation events, i.e. significant relations between apportionment DI and the largest 7-day precipitation amount and it is particularly the case in the central and southwestern parts. Thus, it can be said that higher precipitation variability is due to higher frequency of extreme precipitation regimes. Results of this study are of practical significance for planning and management of water resources and agricultural irrigation and agricultural activities during climate change and particularly for enhancement of measures for mitigation of consequences of climate change.

Beschreibung: ABSTRACT The aim of this study was to provide a better understanding of how vegetation and building geometry influence the spatial distribution of air temperature and nocturnal cooling rates (CR) in a high-latitude city. Intra-urban thermal variations were analysed in two seasons (May–September and November–March) and in different weather conditions (clear, calm and cloudy, windy) in Gothenburg, Sweden. Simultaneous air temperature measurements were conducted for 2 years (2012–2013) at ten fixed park and street sites characterized by varying type and amount of vegetation, building geometry, openness and surface cover. Several spatial characteristics, including sky view factor (SVF) as well as the cover and volume of buildings and trees, were calculated within circular areas of radii ranging from 10 to 150 m. Spatial characteristics were found to explain air temperature distribution in the studied area to a large extent throughout the day and year, in both clear, calm as well as cloudy, windy conditions. The highest correlations were found for weighted calculation areas accounting for the influence of both nearest (10 m) and wider (25–150 m) surroundings. Park sites remained cooler than built-up areas, with the most pronounced cooling effect (0.8 °C) on clear, calm days of the warm season. The most important factor governing CR around sunset was SVF. However, on clear, calm nights of the warm season, they were also enhanced by vegetation, indicating the influence of evapotranspiration. Minimum night-time air temperature was governed mostly by the presence of buildings. Within the street canyon, a daytime cooling and night-time warming effect of a street tree was observed, particularly in the warm season. The study shows the importance of various spatial characteristics describing openness, amount of vegetation and building geometry in analysing intra-urban variations in daytime and night-time air temperature.

Beschreibung: ABSTRACT This paper examines the skill of seasonal precipitation forecasts over Iran using one two-tiered model, three National Multi-Model Ensemble (NMME) models, and two coupled ocean–atmosphere or one-tiered models. These models are, respectively, the ECHAM4.5 atmospheric model that is forced with sea surface temperature (SST) anomalies forecasted using constructed analogue SSTs (ECHAM4.5-SSTCA); the IRI-ECHAM4.5-DirectCoupled, the NASA-GMAO-062012 and the NCEP-CFSv2; and the ECHAM4.5 Modular Ocean Model version 3 (ECHAM4.5-MOM3-DC2) and the ECHAM4.5-GML-NCEP Coupled Forecast System (CFSSST). The precipitation and 850 hPa geopotential height fields of the forecast models are statistically downscaling to the 0.5° × 0.5° spatial resolution of the Global Precipitation Climatology Centre (GPCC) Version 6 gridded precipitation data, using model output statistics (MOS) developed through the canonical correlation analysis (CCA) option of the Climate Predictability Tool (CPT). Retroactive validations for lead times of up to 3 months are performed using the relative operating characteristic (ROC) and reliability diagrams, which are evaluated for above- and below-normal categories and defined by the upper and lower 75th and 25th percentiles of the data record over the 15-year test period of 1995/1996 to 2009/2010. The forecast models' skills are also compared with skills obtained by (a) downscaling simulations produced by forcing the ECHAM4.5 with simultaneously observed SST, and (b) the 850 hPa geopotential height NCEP-NCAR (National Centers for Environmental Prediction-National Center for Atmospheric Research) reanalysis data. Downscaling forecasts from most models generally produce the highest skill forecast at lead times of up to 3 months for autumn precipitation – the October-November-December (OND) season. For most seasons, a high skill is obtained from ECHAM4.5-MOM3-DC2 forecasts at a 1-month lead time when the models' 850 hPa geopotential height fields are used as the predictor fields. For this model and lead time, the Pearson correlation between the area-averaged of the observed and forecasts over the study area for the OND, November-December-January (NDJ), December-January-February (DJF) and January-February-March (JFM) seasons were 0.68, 0.62, 0.42 and 0.43, respectively.

Beschreibung: ABSTRACT The complexity, predictability and predictive instability of the Western Mediterranean Oscillation index (WeMOi) at monthly scale, years 1856–2000, are analysed from the viewpoint of monofractal and multifractal theories. The complex physical mechanism is quantified by: (1) the Hurst exponent, H , of the rescaled range analysis; (2) correlation and embedding dimensions, μ * and d E , together with Kolmogorov entropy, κ , derived from the reconstruction theorem; and (3) the critical Hölder exponent, α o , the spectral width, W , and the asymmetry of the multifractal spectrum, f ( α ). The predictive instability is described by the Lyapunov exponents, λ , and the Kaplan–Yorke dimension, D KY , while the self-affine character is characterized by the Hausdorff exponent, H a . Relationships between the exponent β , which describes the dependence of the power spectrum S ( f ) on frequency f , and the Hurst and Hausdorff exponents suggest fractional Gaussian noise (fGn) as a right simulation of empiric WeMOi. Comparisons are made with monthly North-Atlantic Oscillation and Atlantic Multidecadal Oscillation indices. The analysis is complemented with an ARIMA(p,1,0) autoregressive process, which yields a more accurate prediction of WeMOi than that derived from fGn simulations.

Beschreibung: Pain can vary over the estrous cycle as a result of changes in estradiol concentration but the mechanism causing this variation is unclear. Because the thalamus is important in pain control, gene expression in the lateral thalamus (ventral posteromedial, ventral posterolateral, reticular thalamic nuclei) was screened at different phases of the estrous cycle. Gene expression changes in Sprague-Dawley rats were further analyzed by real-time PCR and ELISA and plasma estradiol levels were measured by RIAs at different phases of the estrous cycle. Our results indicated that both the RNA and protein expression of glutamate decarboxylase 1 and 2 (GAD1, GAD2), GABA(A) receptor-associated protein like 1 (GABARAPL1) and vesicular GABA transporter (VGAT) significantly increased in the lateral thalamus when plasma estradiol levels were elevated. Estradiol levels were elevated during the proestrus and estrus phases of the estrous cycle. Estrogen receptor α (ERα) was observed to be co-localized in thalamic cells and thalamic infusion of an ERα antagonist significantly reduced GAD1 and VGAT transcript. GAD1, GAD2 GABARAPL1 and VGAT have been shown to effect neuronal responses suggesting that modulation of pain during the estrous cycle can be dependent, in part, through estradiol induced changes in thalamic gene expression. This article is protected by copyright. All rights reserved

Beschreibung: Generation of fully functional hematopoietic multipotent progenitor (MPP) cells from human pluripotent stem cells (hPSCs) has a great therapeutic potential to provide an unlimited cell source for treatment of hematological disorders. We previously demonstrated that CD34 + CD31 + CD144 + population derived from hPSCs contain hemato-endothelial progenitors (HEPs) that give rise to hematopoietic and endothelial cells. Here, we report a differentiation system to generate definitive hematopoietic MPP cells from HEPs via endothelial monolayer. In the presence of angiogenic factors, HEPs formed an endothelial monolayer, from which hematopoietic clusters emerged through the process of endothelial-to-hematopoietic transition (EHT). EHT was significantly enhanced by hematopoietic growth factors. The definitive MPP cells generated from endothelial monolayer were capable of forming multilineage hematopoietic colonies, giving rise to T lymphoid cells, and differentiating into enucleated erythrocytes. Emergence of hematopoietic cells from endothelial monolayer occurred transiently. Hematopoietic potential was lost during prolonged culture of HEPs in endothelial growth conditions. Our study demonstrated that CD34 + CD31 + CD144 + HEPs gave rise to hematopoietic MPP cells via hemogenic endothelial cells that exist transiently. The established differentiation system provides a platform for future investigation of regulatory factors involved in de novo generation of hematopoietic MPP cells and their applications in transplantation. This article is protected by copyright. All rights reserved

Beschreibung: Epididymal sperm binding protein 1 (ELSPBP1) is secreted by the epididymal epithelium via epididymosomes and is specifically transferred to dead spermatozoa during epididymal transit. We identified biliverdin reductase A (BLVRA) as a partner of ELSPBP1 by immunoprecipitation followed by tandem mass spectrometry. Pull down assays showed that these two proteins interact in the presence of zinc ions. The BLVRA enzyme is known to convert biliverdin to bilirubin, both of which possess antioxidant activity. Assessment by real-time RT-PCR showed that BLVRA is highly expressed in the caput and the corpus epididymis, but is expressed at lower levels in the testis and the cauda epididymis. It is primarily found in the soluble fraction of the caput epididymal fluid, is barely detectable in the cauda fluid, and is detectable to a lesser extent in the epididymosome fraction of both caput and cauda fluids. Immunocytometry on epididymal sperm showed that BLVRA is found on all sperm recovered from the caput region, whereas it is undetectable on cauda sperm. biliverdin and bilirubin are found in higher concentrations in the caput epididymal fluid, as measured by mass spectrometry. Lipid peroxidation was limited by 1 μM of biliverdin, but not bilirubin when caput spermatozoa were challenged with 500 μM H 2 O 2 . Since immature spermatozoa are a source of reactive oxygen species, BLVRA may be involved in the protection of maturing spermatozoa. It is also plausible that BLVRA is implicated in haemic protein catabolism in the epididymal luminal environment. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT The complexity of impacts resulting from extreme precipitation events varies with the spatial extent of precipitation extremes. Characteristics of precipitation extremes, defined by the top 5% of 3-day accumulated precipitation, including their spatial coherence and relationships to two contrasting synoptic phenomena, were examined at stations across the Northwestern United States. The spatial coherence of precipitation extremes generally decayed with distance between stations. However, distinct geographic variability in region-wide coherence of precipitation extremes was present with overall higher coherence west of the Cascades, and lower coherence in the lee of the Cascades and Northern Rocky Mountains. Illustrative patterns of coherence were also seen with respect to atmospheric circulation regimes; atmospheric rivers favoured broadly coherent extremes occurring primarily west of the Cascades during fall and winter, while closed lows favoured more isolated precipitation extremes in the lee of the Northern Rocky Mountains and Cascades, occurring primarily during spring. Geographic variability in spatial coherence, direction of maximum coherence and seasonality of extremes suggest that extreme precipitation events result from the interaction of atmospheric circulation and complex topography.

Beschreibung: Situated along the coast of southern China and facing the South China Sea, Hong Kong has been experiencing a significant rise in sea level by about 2.9 mm year −1 since the 1950s. For a densely populated coastal city prone to storm surge impacts during the passages of tropical cyclones, accentuated by the threat of sea-level rise as a result of global warming and local vertical land displacement, projection of the sea-level change for Hong Kong is essential for local risk assessment and long-term planning of adaptation measures. This study presented the projection of sea-level change in Hong Kong and its adjacent waters under the Representative Concentration Pathway 4.5 and 8.5 (RCP4.5 and RCP8.5) scenarios in the 21st century based on climate projections by models in phase 5 of Coupled Model Intercomparison Project, in combination with contributions from land ice and land water storage determined from published literatures, and local vertical land displacement as estimated by using continuous high-precision GPS observations in Hong Kong. The results show that the sea level in Hong Kong and its adjacent waters is projected to rise by 0.67 (0.50–0.84) m and 0.84 (0.63–1.07) m in 2081–2100 relative to 1986–2005 under RCP4.5 and RCP8.5, respectively, about 0.2 m higher than the global mean values projected by the Fifth Assessment Report of Intergovernmental Panel on Climate Change. The higher projected sea-level rise in Hong Kong and its adjacent waters as compared with the global mean values is primarily due to local vertical land displacement which contributes around 28% and 23% of the projected sea-level rise in 2081–2100 relative to 1986–2005 in the two respective RCP scenarios.

Beschreibung: Oxygen levels range from 2-9% in vivo . Atmospheric O 2 levels (21%) are known to induce cell proliferation defects and cellular senescence in primary cell cultures. However, the mechanistic basis of the deleterious effects of higher O 2 levels is not fully understood. On the other hand, immortalized cells including cancer cell lines, which evade cellular senescence are normally cultured at 21% O 2 and the effects of higher O 2 on these cells are understudied. Here we addressed this problem by culturing immortalized human bronchial epithelial (BEAS-2B) cells at ambient atmospheric, 21% O 2 and lower, 10% O 2 . Our results show increased inflammatory response at 21% O 2 but not at 10% O 2 . We found higher RelA binding at the NF-κB1/RelA target gene promoters as well as upregulation of several pro-inflammatory cytokines in cells cultured at 21% O 2 . RelA knockdown prevented the upregulation of the pro-inflammatory cytokines at 21% O 2 , suggesting NF-κB1/RelA as a major mediator of inflammatory response in cells cultured at 21% O 2 . Interestingly, unlike the 21% O 2 cultured cells, exposure of 10% O 2 cultured cells to H 2 O 2 did not elicit inflammatory response, suggesting increased ability to tolerate oxidative stress in cells cultured at lower O 2 levels. This article is protected by copyright. All rights reserved

Beschreibung: Acute inflammation is accompanied from its outset by the release of specialized pro-resolving mediators (SPMs), including resolvins, that orchestrate the resolution of local inflammation. We showed earlier that, in rats with subcutaneous inflammation of the back induced by carrageenan, stretching for 10 minutes twice daily reduced inflammation and improved pain, two weeks after carrageenan injection. In this study, we hypothesized that stretching of connective tissue activates local pro-resolving mechanisms within the tissue in the acute phase of inflammation. In rats injected with carrageenan and randomized to stretch vs. no stretch for 48 hours, stretching reduced inflammatory lesion thickness and neutrophil count, and increased resolvin (RvD1) concentrations within lesions. Furthermore, subcutaneous resolvin injection mimicked the effect of stretching. In ex vivo experiments, stretching of connective tissue reduced the migration of neutrophils and increased tissue RvD1 concentration. These results demonstrate a direct mechanical impact of stretching on inflammation-regulation mechanisms within connective tissue. This article is protected by copyright. All rights reserved

Beschreibung: Bone morphogenetic proteins 2 and 4 (BMP2/4) are essential for osteoblast differentiation and osteogenesis. Generation of a BMP2/4 dual knock out ( ko/ko ) osteoblastic cell line is a valuable asset for studying effects of BMP2/4 on skeletal development. In this study, our goal was to create immortalized mouse deleted BMP2/4 osteoblasts by infecting adenoviruses with Cre recombinase and green fluorescent protein genes into immortalized murine floxed BMP2/4 osteoblasts. Transduced BMP2/4 ko/ko cells were verified by green immunofluorescence and PCR. BMP2/4 ko/ko osteoblasts exhibited small size, slow cell proliferation rate and cell growth was arrested in G1 and G2 phases. Expression of bone-relate genes was reduced in the BMP2/4 ko/ko cells, resulting in delay of cell differentiation and mineralization. Importantly, extracellular matrix remodeling was impaired in the BMP2/4 ko/ko osteoblasts as reflected by decreased Mmp-2 and Mmp-9 expressions. Cell differentiation and mineralization were rescued by exogenous BMP2 and/or BMP4. Therefore, we for the first time described establishment of an immortalized deleted BMP2/4 osteoblast line useful for study of mechanisms in regulating osteoblast lineages. This article is protected by copyright. All rights reserved

Beschreibung: Voltage-gated potassium Kv1.2 channels play pivotal role in maintaining of resting membrane potential and, consequently, regulation of cellular excitability of neurons. Endogenously generated electric field (EF) have been proven as an important regulator for cell migration and tissue repair. The mechanisms of ion channel involvement in EF-induced cell responses are extensively studied but largely are poorly understood. In this study we generated three COS-7 clones with different expression levels of Kv1.2 channel, and confirmed their functional variations with patch clamp analysis. Time-lapse imaging analysis showed that EF-induced cell migration response was Kv1.2 channel expression level depended. Inhibition of Kv1.2 channels with charybdotoxin (ChTX) constrained the sensitivity of COS-7 cells to EF stimulation more than their motility. Immunocytochemistry and pull-down analyses demonstrated association of Kv1.2 channels with actin-binding protein cortactin and its re-localization to the cathode-facing membrane at EF stimulation, which confirms the mechanism of EF-induced directional migration. This study displays that Kv1.2 channels represent an important physiological link in EF-induced cell migration. The described mechanism suggests a potential application of EF which may improve therapeutic performance in curing injuries of neuronal and/or cardiac tissue repair, post operational therapy and various degenerative syndromes. This article is protected by copyright. All rights reserved

Beschreibung: Dentin matrix protein 1 (DMP1) is found abundantly in the extracellular matrices of bone and dentin. Secretory DMP1 begins with a tripeptide of leucine-proline-valine (LPV) after the endoplasmic reticulum (ER)-entry signal peptide is cleaved. The goal of this study was to determine the role of the LPV motif in the secretion of DMP1. A series of DNA constructs was generated to express various forms of DMP1 with or without the LPV motif. These constructs were transfected into a preosteoblast cell line, the MC3T3-E1 cells, and the subcellular localization and secretion of various forms of DMP1 were examined by immunofluorescent staining and Western-blotting analyses. Immunofluorescent staining showed that the LPV-containing DMP1 variants were primarily localized in the Golgi complex, whereas the LPV-lacking DMP1 variants were found abundantly within the ER. Western-blotting analyses demonstrated that the LPV-containing DMP1 variants were rapidly secreted from the transfected cells, as they did not accumulate within the cells, and the amounts increased in the conditioned media over time. In contrast, the LPV-lacking DMP1 variants were predominantly retained within the cells, and only small amounts were secreted out of the cells over time. These results suggest that the LPV motif is essential for the efficient export of secretory DMP1 from the ER to the Golgi complex. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT In this study, the detrended fluctuation analysis (DFA) method is used to analyse the drought and flood index (DFI) of the past 531 years in 20 stations over east central China. It is found that the variation of the DFI exhibits long-range correlation. The long-range correlation gradually decreases from northwest to southeast over the studied region. Moreover, the recurrence times of droughts or floods also show long-range correlation. The long-range correlation in the DFI data will disappear if the DFI data are randomly shuffled, which was also found in the recurrence time of the randomly shuffled DFI series for each station. The results show that long-range correlation is an intrinsic property of drought or flood events, which could result in the long-range correlation of the corresponding recurrence times. At present, the prediction skill of droughts/floods in Asian-Australian monsoon region is relatively low, particularly in most of China. The long-range correlation of the DFI provides a theoretical basis for climate predictions of droughts/floods and may help improve model performance by amending the model configuration, in terms of addressing parameterization problems and improving atmosphere–ocean coupling.

Beschreibung: ABSTRACT This work analysed the changes in air temperature in 25 meteorological stations in the Altiplano and the surrounding Andean slopes of Bolivia and Peru, and their relationship with El Niño-Southern Oscillation (SO) and the Pacific Decadal Oscillation (PDO). The analysis focused on annual, warm season (DJF) and cold season (JJA) maximum and minimum temperatures. All analyses were undertaken during 1965–2012, but some analyses were also from 1945 and 1955 when data were available. Principal component analysis was applied to the annual and seasonal series to identify spatial differences of changes in maximum and minimum air temperature. There was an overall increase of temperatures since the mid-20th century. The most intense and spatially coherent warming was observed for annual and warm season maximum temperature, with warming rates from 0.15 to 0.25 °C decade −1 . Changes in the cold season maximum temperature were more heterogeneous, and statistically significant trends were mostly in the Bolivian Altiplano. Minimum temperatures increased, but there was higher spatial variability and lower rates of warming. Maximum temperature was negatively correlated with the Southern Oscillation index (SO) in the warm season, and positively correlated with the SO in the cold season; there were less statistically significant correlations with the PDO, that exhibited inverse sign than those for SO. The strongest correlations were in the region near Lake Titicaca. The negative correlation of minimum temperatures with SO and the positive correlation of minimum temperatures with PDO were lower than the observed for maximum temperature. The changes in temperature and correlations with SO and PDO were highly dependent on the selected period, with stronger trends in the last 30–40 years. This suggests reinforcement of warming rates that cannot be only explained by SO and PDO variability.

Beschreibung: Although 〉90 of the human genome is transcribed, only 〈2% is transcribed into protein-coding RNA (messenger RNA, mRNA). Many thousands of noncoding RNAs are transcribed and recognized as functional RNAs with diverse sizes, structures and biological functions. Based on size, noncoding RNA can be generally divided into two subgroups: short noncoding RNA (〈 200 nucleotides including microRNA or miRNA) and long noncoding RNA (lncRNA, 〉 200 nucleotides). It is now clear that these RNAs fulfil critical roles as transcriptional and post-transcriptional regulators and as guides of chromatin-modifying complexes. Although not translated into protein, noncoding RNAs can regulate cardiac function through diverse mechanisms and their dysregulation is increasingly linked with cardiovascular pathophysiology. Furthermore, a series of recent studies have discovered that noncoding RNAs can be found in the bloodstream and some species are remarkably stable. This has raised the possibility that such noncoding RNAs may be measured in body fluids and serve as novel diagnostic biomarkers. Here, we summarize the current knowledge of noncoding RNAs' function and biomarker potential in cardiac diseases, concentrating mainly on circulating miRNAs and lncRNAs. This article is protected by copyright. All rights reserved

Beschreibung: Increasing evidence indicates that long noncoding RNAs (lncRNAs) are involved in diverse biological process. Mouse maternal expressed gene 3 (Meg3), is an imprinted gene and essential for development. Here, we explored the relationship between Meg3 and the function of mouse beta cells in vitro and vivo . Real-time PCR analyses revealed Meg3 was more abundantly expressed in Balb/c mouse islets than exocrine glands. Moreover, the expression of Meg3 in islets was decreased in T1DM (NOD female mice) and T2DM (db/db mice) models. Meg3 expression was modulated dynamically by glucose in Min6 cells and isolated mouse islets. The function role of Meg3 was investigated in Min6 cells and normal mouse by knockdown of Meg3 using small interfering RNA. After suppression of Meg3 expression in vitro , insulin synthesis and secretion were impaired and the rate of beta cells apoptosis was increased. Moreover, knockdown of Meg3 in vivo led to the impaired glucose tolerance and decreased insulin secretion, consisted with the reduction of insulin positive cells areas by immunochemistry assays. Notably, islets from Meg3 interference groups showed significant decrease of Pdx-1 and MafA expression in mRNA and protein levels. These results indicate that Meg3 may function as a new regulator of maintaining beta cells identity via affecting insulin production and cell apoptosis. This article is protected by copyright. All rights reserved

Beschreibung: Interleukin-24 (IL-24) is a unique IL-10 family cytokine that could selectively induce apoptosis in cancer cells without harming normal cells. Previous research demonstrated that intracellular IL-24 protein induces an endoplasmic reticulum (ER) stress response only in cancer cells, culminating in apoptosis. In this study, we developed a novel recombinant fusion protein to penetrate into cancer cells and locate on ER. It is composed of three distinct functional domains, IL-24, and the targeting domain of transactivator of transcription (TAT) and an ER retention four-peptide sequence KDEL (Lys-Asp-Glu-Leu) that link at its NH 2 and COOH terminal, respectively. The in vitro results indicated that TAT-IL-24-KDEL inhibited growth in bladder cancer cells, as well as in non-small cell lung cancer cell line and breast cancer cell line, but the normal human lung fibroblast cell line was not affected, indicating the cancer specificity of TAT-IL-24-KDEL. Western blot analysis showed that apoptosis activation was induced by TAT-IL-24-KDEL through the ER stress-mediated cell death pathway. Treatment with TAT-IL-24-KDEL significantly inhibited the growth of human H460 xenografts in nude mice, and the tumor growth inhibition was correlated with increased hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. These findings suggest that the artificially designed recombinant fusion protein TAT-IL-24-KDEL may be highly effective in cancer therapy and worthy of further evaluation and development. This article is protected by copyright. All rights reserved

Beschreibung: MicroRNAs (miRNAs) are a group of small non-coding RNAs that are involved in regulating a range of developmental and physiological processes; their dysregulation has been associated with development of diseases including cancer. Circulating miRNAs and exosomal miRNAs have also been proposed as being useful in diagnostics as biomarkers for diseases and different types of cancer. In this review, miRNAs are discussed as biomarkers for cancer and other diseases, including viral infections, nervous system disorders, cardiovascular disorders, and diabetes. We summarize some of the clinical evidence for the use of miRNAs as biomarkers in diagnostics and provide some general perspectives on their use in clinical situations. The analytical challenges in using miRNAs in cancer and disease diagnostics are evaluated and discussed. Validation of specific miRNA signatures as biomarkers is a critical milestone in diagnostics. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT Bacterial lipopolysaccharide (LPS)-stimulated hepatic stellate cells (HSCs) produce many cytokines including IFNβ, TNFα and IL6, strongly inhibit DNA synthesis, but induce apoptosis of a small number of hepatocytes. In vivo administration of LPS (up to 10 mg/ml) causes modest inflammation and weight loss in rats but not mortality. We determined whether LPS-stimulated HSCs instigate mechanisms of hepatocyte survival. Rats received 10 mg/kg LPS (i.p.) and determinations were made at 6h. In vitro , HSCs were treated with 100 ng/ml LPS till 24h. The medium was transferred to hepatocytes, and determinations were made at 0-12h. Controls were HSC-conditioned medium or medium-containing LPS. LPS treatment of rats caused autophagy in hepatocytes, a physiological process for clearance of undesirable material including injured or damaged organelles. This was accompanied by activation of c-Jun NH2 terminal kinase (JNK) and apoptosis of ∼4-5% of hepatocytes. In vitro , LPS-conditioned HSC medium (LPS/HSC) induced autophagy in hepatocytes but apoptosis of only ∼10% of hepatocytes. While LPS/HSC stimulated activation of JNK (associated with cell death), it also activated NFkB and ERK1/2 (associated with cell survival). LPS-stimulated HSCs produced IFNβ, and LPS/HSC-induced autophagy in hepatocytes and their apoptosis were significantly inhibited by anti-IFNβ antibody. Blockade of autophagy, on the other hand, strongly augmented hepatocyte apoptosis. While LPS-stimulated HSCs cause apoptosis of a subpopulation of hepatocytes by producing IFNβ, they also induce cell survival mechanisms, which may be of critical importance in resistance to liver injury during endotoxemia. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT In cancer therapy, it is imperative to increase the efficacy and reduce side effects of chemotherapeutic drugs. Nanotechnology offers the unique opportunity to overcome these barriers. In particular, in the last few years DNA nanostructures have gained attention for their biocompatibility, easy customized synthesis and ability to deliver drugs to cancer cells. Here, an open-caged pyramidal DNA@Doxorubicin ( Py-Doxo ) nanostructure was constructed with 10 DNA sequences of 26–28 nucleotides for drug delivery to cancer cells. The synthesized DNA nanostructures are sufficiently stable in biological medium. Py-Doxo exhibited significantly enhanced cytotoxicity of the delivered doxorubicin to breast and liver cancer cells up to two fold compared to free doxorubicin. This study demonstrates the importance of the shape and structure of the designed transporter DNA nanostructures for biomedical applications. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT Preserving the integrity of the DNA double helix is crucial for the maintenance of genomic stability. Therefore, DNA double-strand breaks represent a serious threat to cells. In this review, we describe the two major strategies used to repair double strand breaks: non-homologous end joining and homologous recombination, emphasizing the mutagenic aspects of each. We focus on emerging evidence that homologous recombination, long thought to be an error-free repair process, can in fact be highly mutagenic, particularly in contexts requiring large amounts of DNA synthesis. Recent investigations have begun to illuminate the molecular mechanisms by which error-prone double-strand break repair can create major genomic changes, such as translocations and complex chromosome rearrangements. We highlight these studies and discuss proposed models that may explain some of the more extreme genetic changes observed in human cancers and congenital disorders. This article is protected by copyright. All rights reserved

Beschreibung: As regulators in gene expression, microRNAs take part in most biological processes including cell differentiation, apoptosis, cell cycle and epithelial-to-mesenchymal transition (EMT). In order to evaluate their roles in EMT process, microRNA expression profile changes induced by EGF or TGF-β treatment on nasopharyngeal carcinoma cell HK-1 were analyzed, and miR-21, miR-148a, miR-505 and miR-1207-5p were found to be upregulated in growth factors-induced EMT process. miR-21 is already known as an oncogenic miRNA to promote metastasis, however, the exact functions of other three miRNAs in EMT are unclear. To our surprise, we found that miR-148a, miR-505 and miR-1207-5p can suppress EMT and metastasis phenotypes in HK-1 cells both in vitro and in vivo , which may relate to their inhibition on EMT and Wnt signaling molecules. MiRNAs confer robustness to biological processes by posttranscriptional repression of key transcriptional programs that are related to previous developmental stages or to alternative cell fates. Our findings indicate that miRNA feedback circuit is tuned to respond to growth factors-induced EMT, and we suggested a new negative feedback loop which may be an important element of the EMT process and confer biological robustness. This article is protected by copyright. All rights reserved

Beschreibung: Regulation is at the heart of biology. What bioregulatory mechanisms finely tune and coordinate our cell's numerous complicated biochemical processes, maintaining constancy of the cell internal environment when external conditions change and it differentiates during development? Knowledge of the biochemistry of small molecules in normal cells progressed greatly in the early 1900s. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT Previous work has shown that acidosis prevents bone nodule formation by osteoblasts in vitro by inhibiting mineralisation of the collagenous matrix. The ratio of phosphate (P i ) to pyrophosphate (PP i ) in the bone microenvironment is a fundamental regulator of bone mineralisation. Both P i and PP i , a potent inhibitor of mineralisation, are generated from extracellular nucleotides by the actions of ecto-nucleotidases. This study investigated the expression and activity of ecto-nucleotidases by osteoblasts under normal and acid conditions. We found that osteoblasts express mRNA for a number of ecto-nucleotidases including NTPdase 1-6 (ecto-nucleoside triphosphate diphosphohydrolase) and NPP1-3 (ecto-nucleotide pyrophosphatase/phosphodiesterase). The rank order of mRNA expression in differentiating rat osteoblasts (day 7) was Enpp1  〉  NTPdase 4  〉  NTPdase 6  〉  NTPdase 5  〉 alkaline phosphatase 〉 ecto-5-nucleotidase 〉  Enpp3  〉  NTPdase 1  〉  NTPdase 3  〉  Enpp2  〉  NTPdase 2 . Acidosis (pH 6.9) upregulated NPP1 mRNA (2.8-fold) and protein expression at all stages of osteoblast differentiation compared to physiological pH (pH 7.4); expression of other ecto-nucleotidases was unaffected. Furthermore, total NPP activity was increased up to 53% in osteoblasts cultured in acid conditions (p 〈 0.001). Release of ATP, one of the key substrates for NPP1, from osteoblasts, was unaffected by acidosis. Further studies showed that mineralised bone formation by osteoblasts cultured from NPP1 knockout mice was increased compared with wildtypes (2.5-fold, p 〈 0.001) and was partially resistant to the inhibitory effect of acidosis. These results indicate that increased NPP1 expression and activity might contribute to the decreased mineralisation observed when osteoblasts are exposed to acid conditions. This article is protected by copyright. All rights reserved

Beschreibung: Connexin43 (Cx43) has been shown to regulate cell proliferation and its down-regulation is correlated with poor prognosis and survival in several types of human cancer. Cx43 expression levels are frequently down-regulated in human ovarian cancer, suggesting a potential role for Cx43 in regulating the progression of this disease. Epidermal growth factor (EGF) is a well-characterized hormone that stimulates ovarian cancer cell proliferation. Although EGF is able to regulate Cx43 expression in other cell types, it is unclear whether EGF can regulate Cx43 expression in ovarian cancer cells. Additionally, it remains unknown whether Cx43 is involved in EGF-stimulated ovarian cancer cell proliferation. In the present study, we demonstrate that treatment with EGF up-regulates Cx43 expression in two ovarian cancer cell lines, SKOV3 and OVCAR4. Although treatment with EGF activates both ERK1/2 and Akt signaling pathways, pharmacological inhibition and siRNA-mediated knockdown suggest that only the activation of Akt1 is required for EGF-induced Cx43 up-regulation. Functionally, Cx43 knockdown enhanced basal and EGF-induced cell proliferation, whereas the proliferative effects of EGF were reduced by Cx43 overexpression. Co-treatment with the gap junction inhibitor carbenoxolone did not alter the suppressive effects of Cx43 overexpression on EGF-induced cell proliferation, suggesting a gap junction-independent mechanism. This study reveals an important role for Cx43 as a negative regulator of EGF-induced human ovarian cancer cell proliferation. This article is protected by copyright. All rights reserved

Beschreibung: p53 and Notch-1 play important roles in breast cancer biology. Notch-1 inhibits p53 activity in cervical and breast cancer cells. Conversely, p53 inhibits Notch activity in T-cells but stimulates it in human keratinocytes. Notch co-activator MAML1 binds p53 and functions as a p53 co-activator. We studied the regulation of Notch signaling by p53 in MCF-7 cells and normal human mammary epithelial cells (HMEC). Results show that overexpression of p53 or activation of endogenous p53 with Nutlin-3 inhibits Notch-dependent transcriptional activity and Notch target expression in a dose-dependent manner. This effect could be partially rescued by transfection of MAML1 but not p300. Standard and quantitative co-immunoprecipitation experiments readily detected a complex containing p53 and Notch-1 in MCF-7 cells. Formation of this complex was inhibited by dominant negative MAML1 (DN-MAML1) and stimulated by wild-type MAML1. Standard and quantitative far-Western experiments showed a complex including p53, Notch-1 and MAML1. Chromatin immunoprecipitation (ChIP) experiments showed that p53 can associate with Notch-dependent HEY1 promoter and this association is inhibited by DN-MAML1 and stimulated by wild-type MAML1. Our data support a model in which p53 associates with the Notch transcriptional complex (NTC) in a MAML1-dependent fashion, most likely through a p53-MAML1 interaction. In our cellular models, the effect of this association is to inhibit Notch-dependent transcription. Our data suggest that p53-null breast cancers may lack this Notch-modulatory mechanism, and that therapeutic strategies that activate wild-type p53 can indirectly cause inhibition of Notch transcriptional activity. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT In this study, we investigate the influence of global climate oscillations on the local temperature and precipitation over the United Arab Emirates (UAE), which is one of the driest regions in the world with very high temperatures and low precipitation. The identification and assessment of remote interactions (teleconnections) are carried out by using ground station and gridded data sets. Monthly rainfall data from six ground stations over the UAE for the period of 1982–2010 is used in this study along with the long-term gridded precipitation and temperature data from the Global Precipitation Climatology Center and Global Historic Climatic Network. Linear correlations, wavelet analysis, and cross-wavelet analysis have been applied to identify the relation between climate indices and precipitation (temperature). The analysis reveals that the strong variability in precipitation is closely associated with the Southern Oscillation Index (SOI) and the Indian Ocean Dipole Index (IOD) during the months of August–March, September–January, respectively. In case of temperature, the strong variability is associated with the North Atlantic Oscillation Index (NAO) and the East Atlantic Oscillation Index (EAO) during the months of April–October, July–December. Spatial analysis of cross-wavelet reveals that the winter precipitation is significantly influenced by SOI and temperature during summer by the NAO. This research concludes that the negative phases of SOI (NAO) play a significant role in the increase of precipitation (decrease in summer temperatures) over the UAE region.

Beschreibung: ABSTRACT Interannual variability and long-term changes of summer temperature extremes and hot spells in Moscow during 1949–2012 are investigated using air temperature station data, the National Centres for Environmental Prediction/the National Centre for Atmospheric Research (NCEP/NCAR) reanalysis and the Climatic Research Unit (CRU) data sets. Significant interdecadal changes in different characteristics of the temperature extremes are revealed. It is shown that summertime warming detected in the Moscow region in recent decades is not solely due to an increase in the number of hot days, but also due to a decrease in the number of cold days. Statistically significant positive (negative) trends in the number of anomalously hot (cold) days since the mid 1970s are detected. Respective trend values are 5%/decade –1 for the positive trends and −6%/decade –1 for the negative trends. We find that in 1981–2012 the number of summer seasons with extremely hot days has doubled with respect to earlier period (1949–1980). However, we do not find statistically significant trend-like changes in the duration of the hot events in Moscow. A chronology of temperature extremes in Moscow has been constructed. This can be used as a diagnostic tool allowing the detection of extremes. Typical regional sea level pressure patterns associated with air temperature extremes in Moscow are defined and briefly described.

Beschreibung: ABSTRACT This study evaluates the capability of regional climate models (RCMs) in simulating extreme rainfall events over Southern Africa, and in reproducing the characteristics of widespread extreme rainfall events (WERE) in the Western Cape (South Africa). We obtained simulation datasets of nine RCMs from the Co-ordinated Regional Downscaling Experiment (CORDEX) and compared them with observation datasets from the Global Precipitation Climatology Project (GPCP) and Tropical Rainfall Measuring Mission (TRMM) as well as with the reanalysis dataset (ERAINT) that forced the simulations. A self-organising map was used to classify the WEREs into 12 nodes. The contribution of each RCM to each node was compared with the contributions of GPCP, TRMM and ERAINT. Using ERAINT dataset, we analysed the synoptic-scale atmospheric condition associated with each node. The results show that, in simulating the spatial distribution of the extreme rainfall event over Southern Africa, only four RCMs perform better than the forcing reanalysis (ERAINT) while two RCMs perform worse than the reanalysis. All the RCMs underestimate the threshold of extreme rainfall over Western Cape, poorly simulate the inter-annual variability of the WEREs ( r ≤ 0.3), but correctly reproduce the maximum frequency of the WEREs in Autumn (March–May). The WEREs in the Western Cape may be broadly grouped into four synoptic rainfall patterns. The first pattern links WEREs with tropical rainfall activities (tropical-temperate troughs); the second pattern shows isolated WEREs; the third and fourth patterns link WEREs with rainfall activities in the mid-latitudes (frontal systems) and over the Agulhas Current, respectively. While most RCMs overestimate the frequency of the first pattern, they all underestimate the frequency of the second pattern but simulate the frequencies of the third and fourth patterns well. The results of this study should help in improving the RCM simulations over Southern Africa and in downscaling impacts of climate change on extreme rainfall events over the region.

Beschreibung: ABSTRACT The research objectives were to describe heat waves (HWs) in Central Europe and define the synoptic situations that cause their occurrence. In this article, a hot day was defined as a day when the maximum temperature was above the 95th annual percentile and an HW was considered a sequence of at least five hot days. In the analysed multi-year period and study area, 11 HWs were observed in the north and 51 HWs were observed in the south. The occurrence of HWs was mainly connected with positive anomalies of sea level pressure and with the 500 hPa level, which shows the presence of high-pressure systems. HWs were also accompanied by positive T850 and precipitable water (PW) anomalies.

Beschreibung: ABSTRACT A statistical-dynamical downscaling method is used to estimate future changes of wind energy output ( Eout ) of a benchmark wind turbine across Europe at the regional scale. With this aim, 22 global climate models (GCMs) of the Coupled Model Intercomparison Project Phase 5 (CMIP5) ensemble are considered. The downscaling method uses circulation weather types and regional climate modelling with the COSMO-CLM model. Future projections are computed for two time periods (2021–2060 and 2061–2100) following two scenarios (RCP4.5 and RCP8.5). The CMIP5 ensemble mean response reveals a more likely than not increase of mean annual Eout over Northern and Central Europe and a likely decrease over Southern Europe. There is some uncertainty with respect to the magnitude and the sign of the changes. Higher robustness in future changes is observed for specific seasons. Except from the Mediterranean area, an ensemble mean increase of Eout is simulated for winter and a decreasing for the summer season, resulting in a strong increase of the intra-annual variability for most of Europe. The latter is, in particular, probable during the second half of the 21st century under the RCP8.5 scenario. In general, signals are stronger for 2061–2100 compared to 2021–2060 and for RCP8.5 compared to RCP4.5. Regarding changes of the inter-annual variability of Eout for Central Europe, the future projections strongly vary between individual models and also between future periods and scenarios within single models. This study showed for an ensemble of 22 CMIP5 models that changes in the wind energy potentials over Europe may take place in future decades. However, due to the uncertainties detected in this research, further investigations with multi-model ensembles are needed to provide a better quantification and understanding of the future changes.

Beschreibung: ABSTRACT Atmospheric teleconnections have an important influence on the variability of the Mediterranean climate. This region has a unique and sensitive climate due to its complex topography and atmospheric circulation, thus making it challenging in climate simulations. This article focuses on the representation of five teleconnections in and around the Mediterranean region and how they affect one another and the region. The Regional Climate Model, RegCM4, has been used to simulate the climate from 1969 to 1999 for a domain covering the Mediterranean and the surrounding region. A generalized method for calculating the indices for these patterns was identified and the corresponding indices were constructed from the modelled data and compared with reanalysis data. The modelled data was found to be highly correlated with the 20th Century Reanalysis data and the probability density functions (PDFs) were very similar to the reanalysis data, showing that the teleconnections were successfully represented within the model. Maps of the influence of these teleconnections on temperature, precipitation and wind were also comparable to the reanalysis data, thereby suggesting that model data can be used for future projections of teleconnections and their effects on these parameters. With the use of this high-resolution data, inter-pattern relationships suggested in previous studies (such as that between the Mediterranean Oscillation and North sea-Caspian Pattern) became more evident. This article also shows how the influence of teleconnections on winds affects the circulation and hence the temperature and precipitation of the region.

Beschreibung: ABSTRACT The Mediterranean coast of Spain often experiences intense rainfall, sometimes reaching remarkable amounts of more than 400 mm in one day. The aim of this work is to study possible changes of extreme precipitation in Spain for this century, simulated from several Coupled Model Intercomparison Project Phase 5 (CMIP5) climate models. Eighteen climate projections (nine models under RCP4.5 and nine RCP8.5 scenarios) were downscaled using a two-step analogue/regression statistical method. We have selected 144 rain gauges as the rainiest of a network by using a threshold of 250 mm in one day for a return period of 100 years. Observed time-series have been extended using the ERA40 reanalysis and have subsequently been used to correct the climate projections according to a parametric quantile–quantile method. Five theoretical distributions (Gamma, Weibull, Classical Gumbel, Reversed Gumbel and Log-logistic) have been used to fit the empirical cumulative functions (entire curves, not only the upper tail) and to estimate the expected precipitation according to several return periods: 10, 20, 50 and 100 years. Results in the projected changes for 2051–2100 compared to 1951–2000 are similar (in terms of sign and value) for the four return periods. The analysed climate projections show that changes in extreme rainfall patterns will be generally less than the natural variability. However, possible changes are detected in some regions: decreases are expected in a few kilometres inland, but with a possible increase in the coastline of southern Valencia and northern Alicante, where the most extreme rainfall was recorded. These results should be interpreted with caution because of the limited number of climate projections; anyway, this work shows that the developed methodology is useful for studying extreme rainfall under several climate scenarios.

Beschreibung: ABSTRACT Air temperatures have increased globally over the past decades, while rainfall changes have been more variable, but are taking place. In South Africa, substantial climate-related impacts are predicted, and protected area management agencies will need to respond actively to impacts. It is critical for management agencies to understand the way in which climate is changing locally to predict impacts and respond appropriately. Here, for the first time, we quantify observable changes in temperature and rainfall in South African national parks over the past five to ten decades. Our results show significant increases in temperatures in most parks, with increases being most rapid in the arid regions of the country. Increases in the frequency of extreme high temperature events were also most pronounced in these regions. These results are consistent with other climate studies conducted in these areas. Similar increases were identified for both minimum and maximum temperatures, though absolute minimum temperatures increased at greater rates than absolute maxima. Overall, rainfall trends were less obvious, but a decrease in rainfall was observed for the southern Cape (in three parks), and an increase was detected in one park. The observed temperature changes over the last 20–50 years have in several instances already reached those predicted for near future scenarios (2035), indicating that change scenarios are conservative. These results provide individual parks with evidence-based direction for managing impacts under current and projected changes in local climate. They also provide the management agency with sub-regional information to tailor policy and impact monitoring. Importantly, our results highlight the critical role that individual weather stations play in informing local land management and the concerns for parks that have no local information on changes in climate.

Beschreibung: ABSTRACT Aims Type 1 diabetes mellitus is associated with a high risk for bone fractures. Although bone mass is reduced, bone quality is also dramatically altered in this disorder. However, recent evidences suggest a beneficial effect of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) pathways on bone quality. The aims of the present study were to conduct a comprehensive investigation of bone strength at the organ and tissue level; and to ascertain whether enzyme resistant GIP or GLP-1 mimetic could be beneficial in preventing bone fragility in type 1 diabetes mellitus. Materials and methods Streptozotocin-treated mice were used as a model of type 1 diabetes mellitus. Control and streptozotocin-diabetic animals were treated for 21 days with an enzymatic-resistant GIP peptide ([D-Ala 2 ]GIP) or with liraglutide (each at 25 nmol/kg bw, ip). Bone quality was assessed at the organ and tissue level by microCT, qXRI, 3-point bending, qBEI, nanoindentation and Fourier-transform infrared microspectroscopy. Results [D-Ala 2 ]GIP and liraglutide treatment did prevent loss of whole bone strength and cortical microstructure in the STZ-injected mice. However, tissue material properties were significantly improved in STZ-injected animals following treatment with [D-Ala 2 ]GIP or liraglutide. Conclusions Treatment of STZ-diabetic mice with [D-Ala 2 ]GIP or liraglutide was capable of significantly preventing deterioration of the quality of the bone matrix. Further studies are required to further elucidate the molecular mechanisms involved and to validate whether these findings can be translated to human patients. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT Desertification is an international environmental challenge which poses a risk to portions of over 100 countries. Research into desertification and climate change has the potential to contribute to natural resources management and adaptation to climatic and other changes in Earth systems. An Earth system model of intermediate complexity (EMIC), the McGill Paleoclimate Model-2 (MPM-2) was used to explore the climatic biogeophysical effects of desertification in different latitude bands from 1700 to 2000 AD. It was found that latitudinal-band desertification attributable to forest and grass removal caused global cooling, land surface albedo increasing and precipitation reduction in the Northern Hemisphere as well as heat transport increasing in global ocean. These results highlighted global climate reaction to local desertification and demonstrated that the location of the desertification projected a potentially differential impact on local and global climate. That was, desertification in 0°–15°N gave a somewhat minor effect on global and local climate; desertification in 45°–60°N caused a significant reduction in global temperature while desertification in 15°–30°N induced a prominent reduction in local temperature. In response to desertification, surface albedo change as a forcing was the dominant biogeophysical driver of climate over the Northern Hemisphere while precipitation change as a response was probably the primary driver of climate over the Southern Hemisphere. Overall, the regional desertification may cause a global climatic effect, especially concerning desert expansion along the 15°–30°N and 45°–60°N latitude bands, which led to a more prominent effect on the Earth's climate and even oceanic circulation. The results of this study provide useful information when comparing the effects of desertification in different latitude bands on climate.

Beschreibung: ABSTRACT The spatial structure and temporal evolution of the intraseasonal variability (ISV) of the subsurface ocean temperature (STA) in the equatorial Pacific associated with the two flavours of El Niño [i.e. the canonical or eastern Pacific (EP) El Niño and the central Pacific (CP) El Niño] are investigated using observations and 1.5-layer linear reduced gravity model. Results suggest that the ISV characteristics show some differences in the two types of El Niño, although both oscillate along the thermocline in the form of the intraseasonal equatorial Kelvin wave (IEKW), which is excited in the western tropical Pacific by the zonal wind stress associated with the Madden–Julian oscillation (MJO). First, the period of dominant mode of the STA ISV during CP El Niño broadly distributes in 50–80 days with the spectra peaking in 60–65 days. By contrast, the spectrum of STA ISV during EP El Niño shows a peak in 75–80-day period. This indicates that the wave speed is faster in the CP El Niño than in EP El Niño. Second, the ISV activity peaks in previous spring during the developing phase of EP El Niño, whereas during CP El Niño it becomes the most active during the mature phase. Third, the strongest IEKW occurs in the CP around the dateline during CP El Niño and attenuates quickly east of 130°W due to strong eddy viscosity dissipation, while the IEKW during the EP El Niño propagates efficiently from the western to the eastern Pacific with a relative weak diffusion.

Beschreibung: ABSTRACT Mount Kenya is an equatorial mountain whose climatic setting is fairly simple (two rainy seasons in March–May, the Long Rains, and October–December, the Short Rains) though concealing significant spatial variations related to elevation and aspect (part I, Camberlin et al. , 2014). This part II is dedicated to the sensitivity of sorghum yields to climate variability in space and time, with a focus on the intra-seasonal characteristics of the rainy seasons. To that aim we use the crop model SARRA-H calibrated for the region and fed with rainfall, temperature, wind speed, humidity and solar radiation data over the period 1973–2001 at three stations located on the eastern slopes of Mount Kenya. The crop model is run independently for the two rainy seasons. Four groups of simulations are conducted by varying the initialization date of the simulation, the sowing dates and the type of soil, in order to test sorghum sensitivity to water availability. Evidence is found that potential sorghum yields are dominantly controlled by variations in seasonal rainfall amounts: mean yields are higher at higher and wetter locations, and are higher during the wettest rainy season and years. However, beyond this apparent simplicity, more complex aspects emerge of the crop–climate relationships. First, the yield–elevation relationship is altered at high elevation due to lower temperature. Second, despite a strong link with the seasonal rainfall amounts, we evidence an underlying role of some intra-seasonal rainfall characteristics such as the number of rainy days (itself mainly determined by the rainy season duration) or the occurrence of long dry spells. Third, unseasonal rains occurring after the end of the rainy season, especially after the Short Rains, play a role in final crop yield. Fourth, variations of climate variables such as solar radiation by modulating the potential evapotranspiration concur to yield variations at the wettest locations.

Beschreibung: ABSTRACT Climate variability modulates spatio-temporal variability of dry spells (DSs) and wet spells (WSs) within a river basin and will affect water resources management practices leading to various impacts on the socio-economic development in river basins. In this study, we evaluated spatio-temporal variability of DS and WS in Huai River basin (HRB), China, by developing copula-based severity-duration-frequency (SDF) curves. The result shows that the upper reach and the southern part of middle reach of HRB are prone to both DS and WS; however, the duration and severity of WS are comparatively higher in comparison to DS. It was observed that DS is more frequent in spring and summer, whereas WS in summer and autumn. The choice of copula plays an important role in deriving the SDF curves, and an inappropriately chosen copula function may result in a large bias of SDF estimation. The arch12 copula was found to be the best choice in the majority of stations for deriving the SDF curves. The constructed SDF curves primarily shows two major patterns for DS and WS, i.e. concave down pattern and convex up pattern. The frequency of extreme DS decreases from 1960s to 1990s, and increases after 2000s, while the frequency of extreme WS increases from 1970s to 1990s and then decreases from 1990s to 2000s. The results in this study can provide useful information for designing conservation structures and to develop water allocation strategies at different temporal scales.

Beschreibung: ABSTRACT Careful planning of the use of water resources is critical in the semi-arid eastern Mediterranean region. The relevant areas are characterized by complex terrain and coastlines, and exhibit large spatial variability in seasonal precipitation. Global seasonal forecasts provide only partial information of the precipitation as a result of their coarse spatial resolution. We present two statistical downscaling methods of global forecasts, both identifying past-analogue synoptic-weather patterns and their connection to precipitation at specific stations. The first method utilizes a classification of the large-scale weather patterns into regimes, and the other identifies the closest past analogues directly without grouping the weather events. The validation of the algorithms using NCEP/NCAR reanalyses and past precipitation observations at 18 stations shows that both methods provide good skill in predicting mean precipitation amounts and quantiles of the precipitation distribution, and in reproducing the observed inter-annual and spatial variability. Both methods show good correlations between predicted and observed precipitation amounts (∼0.8), and the downscaled precipitation reproduces the observed differences between the stations, which are not available in the coarse global models. Based on these results, we downscaled the operational global-seasonal forecasts issued by the NCEP CFS1.0 ensemble. This approach could also have utility in climate change scenario downscaling.

Beschreibung: ABSTRACT Small Island Developing States in the tropical western Pacific are among the most vulnerable to climate change. While a great deal of information on the observed climate change trends and their cause is available for many other regions and for the globe as a whole, much less information has been available specifically for the Pacific. Here, we show that warming over the past 50 years in the western Pacific is evident in recently homogenized tropical station data, and in gridded surface temperature data sets for the region. The warming has already emerged from the background climate variability. The observational data and Coupled Model Intercomparison Project Phase 5 climate model output are used to show that the observed warming was primarily caused by human-forced changes to the earth's radiative balance. Further warming is projected to occur in the same models under all three Representative Concentration Pathways (RCPs) considered (RCP2.6, RCP4.5 and RCP8.5), with the magnitude far exceeding the warming to date under the two scenarios with higher emissions (RCP4.5 and RCP8.5).

Beschreibung: ABSTRACT The contribution by tropical cyclones (TCs) to extreme rainfall in Australia is examined using daily rainfall measurements from over 2000 rain gauges. Analyses focus on the period beginning with regular satellite monitoring of TCs (1969/1970) through the year 2012/2013 and consider daily and multi-daily annual maximum rainfall series. Our results indicate that TCs play a prominent role in extreme rainfall over much Australia, with more than half of the highest annual rainfall events associated with these storms over the coastal regions and in particular over Western Australia. Moreover, the TC fractional contribution to extreme rainfall increases as we focus on the largest rainfall events, with approximately 66–100% of annual maxima in excess of 100 mm (∼4 inches) over Western Australia associated with TCs at over one third of the locations. Given the well-established controls on Australian TC activity by the El Niño–Southern Oscillation (ENSO), we also examined the relationship between extreme rainfall associated with TCs and ENSO using logistic regression. A larger probability of having an annual rainfall maximum related to TCs occurs during La Niña years, consistent with enhanced Australian cyclogenesis during these phases of ENSO. We also highlighted regional differences in the link between ENSO and extreme rainfall events, highlighting the stronger connection along the coastal areas and in particular over Western Australia.

Beschreibung: ABSTRACT In the study, the clear-sky aerosol radiative effects have been quantified at 52 European sites using empirical and radiative transfer modelling approaches. Furthermore, the trends of the aerosol radiative effects are also determined for the period of 2001–2012. The aerosol radiative effects are simulated using the Mesoscale Atmospheric Global Irradiance Code radiation code with aerosol and water vapour climatology. The annual mean of the surface aerosol radiative effects in clear-sky situations over Europe is −7.1 ± 2.9 W m −2 . The trends of the aerosol radiative effects are derived assigning radiative effects to monthly Moderate Resolution Imaging Spectroradiometer aerosol optical depth time series applying linear fitting. In the indirect approach, the clear-sky situations are selected from daily surface solar radiation observations from the Word Radiation Data Centre, and the trends of the aerosol radiative effects are delimitated in these clear-sky radiation time series. The two approaches give good fit, based on the direct approach the annual trend of the aerosol radiative effects on clear-sky solar surface radiation is −4.41 W m −2 per decade for the period of 2001–2013, while in the case of the indirect approach, this trend is found to be −4.46 W m −2 per decade. The seasonal trends of the aerosol radiative effects vary between −7.57 and −0.17 W m −2 per decade indicating stronger decreases in summertime. The results are presented for four sub-regions of Europe detecting negative changes in all cases with a stronger decrease in the central, north-eastern and southern part of the continent. The trends of the aerosol radiative effect have the same magnitude as the trends detected in clear-sky solar surface radiation, and are an order of magnitude higher than the radiative effects of water vapour (0.20 W m −2 per decade).

Beschreibung: Testicular germ cell tumors (TGCTs) are frequent solid malignant tumors and cause of death in men between 20–40 years of age. Genetic and environmental factors play an important role in the origin and development of TGCTs. Although the majority of TGCTs are responsive to chemotherapy, about 20% of patient presents incomplete response or tumors relapse. In addition, the current treatments cause acute toxicity and several chronic collateral effects, including sterility. The present mini-review collectively summarize the most recent findings on the new discovered molecular biomarkers such as tyrosine kinases, HMGAs, Aurora B kinase, and GPR30 receptor predictive of TGCTs and as emerging new possible molecular targets for therapeutic strategies. This article is protected by copyright. All rights reserved

Beschreibung: ABSTRACT Atrogin-1, an E3 ligase present in skeletal, cardiac and smooth muscle, down-regulates myocardin protein during skeletal muscle differentiation. Myocardin, the master regulator of smooth muscle cell (SMC) differentiation, induces expression of smooth muscle marker genes through its association with serum response factor (SRF), which binds to the CArG box in the promoter. Myocardin undergoes ubiquitylation and proteasomal degradation. Evidence suggests that proteasomal degradation of myocardin is critical for myocardin to exert its transcriptional activity, but there is no report about the E3 ligase responsible for myocardin ubiquitylation and subsequent transactivation. Here, we showed that overexpression of atrogin-1 increased contractility of cultured SMCs and mouse aortic tissues in organ culture. Overexpression of dominant-negative myocardin attenuated the increase in SMC contractility induced by atrogin-1. Atrogin-1 overexpression increased expression of the SM contractile markers while downregulated expression of myocardin protein but not mRNA. Atrogin-1 also ubiquitylated myocardin for proteasomal degradation in vascular SMCs. Deletion studies showed that atrogin-1 directly interacted with myocardin through its amino acids 284-345. Immunostaining studies showed nuclear localization of atrogin-1, myocardin and the Rpt6 subunit of the 26S proteasome. Atrogin-1 overexpression not only resulted in degradation of myocardin but also increased recruitment of RNA Polymerase II onto the promoters of myocardin target genes. In summary, our results have revealed the roles for atrogin-1 in the regulation of smooth muscle contractility through enhancement of myocardin ubiquitylation/degradation and its transcriptional activity. This article is protected by copyright. All rights reserved