Quantitative determination of estrone by liquid chromatography-tandem mass spectrometry in subcutaneous adipose tissue from the breast in postmenopausal women

Estrone is the most abundant estrogen after the menopause. We developed a liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for determination of estrone in adipose tissue. Subcutaneous adipose tissue from the breast was collected during elective surgery in postmenopausal women undergoing mastectomy for treatment of breast cancer (n = 13) or reduction mammoplasty (controls, n = 11). Homogenized adipose tissue was extracted with organic solvents and the estrone fraction was purified by LH-20 column chromatography from the excess of lipids. The concentration of estrone was analyzed by LC-MS/MS. The method was accurate with an intra-assay variation of 8% and an interassay variation of 10%. The median concentration of estrone in subcutaneous adipose tissue from the breast did not differ between breast cancer and control women, 920 pmol/kg and 890 pmol/kg, respectively. In breast cancer patients but not in the controls, breast adipose tissue estrone levels correlated positively with the serum estrone concentration. In conclusion, the new method provides a reliable means to measure estrone concentrations in adipose tissue in postmenopausal women. (C) 2015 Elsevier Ltd. All rights reserved.Peer reviewe

Estrogen biosynthesis in breast adipose tissue during menstrual cycle in women with and without breast cancer

Circulating estrogens fluctuate during the menstrual cycle but it is not known whether this fluctuation is related to local hormone levels in adipose tissue. We analyzed estrogen concentrations and gene expression of estrogen-regulating enzymes in breast subcutaneous adipose tissue in premenopausal women with (n = 11) and without (n = 17) estrogen receptor-positive breast cancer. Estrone (E-1) was the predominant estrogen in premenopausal breast adipose tissue, and E-1 and mRNA expression of CYP19A1 in adipose tissue correlated positively with BMI. Adipose tissue estradiol (E-2) concentrations fluctuated during the menstrual cycle, similarly to the serum concentrations. In women with breast cancer median adipose tissue E-1 (1519 vs. 3244, p <.05) and E-2 (404 vs. 889 pmol/kg, p <.05) levels were lower in the follicular than in the luteal phase whereas in control women no significant differences were observed. In the follicular phase, mRNA expressions of HSD17B1 (median 0.06; interquartile range 0.05-0.07 vs. 0.17; 0.03-0.2, p = .010) and CYP19A1 (0.08; 0.07-0.14 vs. 0.22; 0.09-0.54, p = .025) were lower in women with breast cancer than in controls. In conclusion, the changes in adipose tissue E-1 and E-2 concentrations and the estrogen-regulating CYP19A1 and HSD17B1 during the menstrual cycle may be related to dysfunctional local estrogen metabolism in women with breast cancer.Peer reviewe

Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington's Disease

Huntington's disease (HD) is an inherited neurodegenerative disorder with onset of characteristic motor symptoms at midlife, preceded by subtle cognitive and behavioral disturbances. Transcriptional dysregulation emerges early in the disease course and is considered central to HD pathogenesis. Using wild-type (wt) and HD knock-in mouse striatal cell lines we observed a HD genotype-dependent reduction in the protein levels of transcription factor 4 (TCF4), a member of the basic helix-loop-helix (bHLH) family with critical roles in brain development and function. We characterized mouse Tcf4 gene structure and expression of alternative mRNAs and protein isoforms in cell-based models of HD, and in four different brain regions of male transgenic HD mice (R6/1) from young to mature adulthood. The largest decrease in the levels of TCF4 at mRNA and specific protein isoforms were detected in the R6/1 mouse hippocampus. Translating this finding to human disease, we found reduced expression of long TCF4 isoforms in the postmortem hippocampal CA1 area and in the cerebral cortex of HD patients. Additionally, TCF4 protein isoforms showed differential synergism with the proneural transcription factor ASCL1 in activating reporter gene transcription in hippocampal and cortical cultured neurons. Induction of neuronal activity increased these synergistic effects in hippocampal but not in cortical neurons, suggesting brain region-dependent differences in TCF4 functions. Collectively, this study demonstrates isoform-specific changes in TCF4 expression in HD that could contribute to the progressive impairment of transcriptional regulation and neuronal function in this disease

Ruokajärjestelmämalli lähiruoan kestävyyden monitieteiseen tutkimukseen

Paikallinen ruokajärjestelmä, lähiruoka, on erityisesti globaalistuvan ruokajärjestelmän vastakohtanakiinnostava tutkimuskohde. Ruokajärjestelmän paikallistamisella tavoitellaan ruoan tasaveroista jayhteisöllisesti omatoimista saavutettavuutta, taloudellista ruokaturvaa sekä vastuullisuutta ruoan tuotannonluonnonvaroista ja tuotantoympäristöstä. Nämä tavoitteet liittyvät läheisesti väestö-, talous-, ympäristö- jakulttuurisiin kysymyksiin analyysin mittakaavasta riippumatta.Olemme tutkineet ruokajärjestelmän paikallistamisen vaikutuksia ja siihen liittyviäoppimishaasteita kunta- ja maakuntatasolla Etelä-Savossa. Tämänkaltainen kansallista mittakaavaapaikallisempi lähiruoka-ajattelu ilmaantui etenkin maaseudun toimijoiden hankkeisiin 1990-luvunloppupuolella reaktiona maaseudun elinolojen ja -keinojen taantumiseen. Hankkeessa kehitimmemonitieteiseen kommunikointiin ja tieteiden-väliseen yhdistämiseen tähtäävän käsitteellisen LOFOjärjestelmämallin. Mallissa ruokajärjestelmän ajatellaan muodostuvan kolmesta osajärjestelmästä, jotkaolivat yhteiskunnallis-taloudellinen, biofysikaalinen sekä toiminnan osajärjestelmä.Yhteiskunnallis-taloudellinen osajärjestelmä sisältää normatiivisen ja taloudellisen 'ympäristön',samaan tapaan kuin biofysikaalinen osajärjestelmä sisältää fyysisen ja biologisen ympäristön. Näidenehdoilla, niihin sopeutuen ja niitä muuntaen kaikki toiminnan osajärjestelmän osakkaat tuottajasta ruoankuluttajaan toimivat ja tekevät ruokajärjestelmää koskevia päätöksiä. Teimme jokaista osajärjestelmääkoskien menetelmällisiä rajauksia ja valintoja, ja toteutimme osajärjestelmäkohtaiset osatutkimuksetmenetelmällisesti erillisinä tieteenalakohtaisina harjoitelmina. Näin ollen tuloksemme ovat ikäänkuinnäytteitä tai palasia systeemimallin tarjoamaan kokonaisvaltaisempaan palapeliin.Toiminnan osajärjestelmään sisältyy keskeisen tärkeänä ruokajärjestelmään osallisten 'voimaannuttaminen'sekä lisäksi prosessi, jossa paikalliset yhteisöt neovottelevat yhteisestä tulevaisuudestaan jatunnistavat sen mahdollisuuksia. Lisäksi tuloksemme tukevat ruoan 'valuma-alue' (foodshed) -ajattelua: onvälttämätöntä sisällyttää sekä maatilojen ja maaseudun ruoan 'lähde'- (source) että taajamien ja kaupunkienruoan 'kohde'- (sink) alueet paikallisen järjestelmän rajauksen sisään

The melting arctic and midlatitude weather patterns: are they connected?

The potential of recent Arctic changes to influence hemispheric weather is a complex and controversial topic with considerable uncertainty, as time series of potential linkages are short (<10 yr) and understanding involves the relative contribution of direct forcing by Arctic changes on a chaotic climatic system. A way forward is through further investigation of atmospheric dynamic mechanisms. During several exceptionally warm Arctic winters since 2007, sea ice loss in the Barents and Kara Seas initiated eastward-propagating wave trains of high and low pressure. Anomalous high pressure east of the Ural Mountains advected Arctic air over central and eastern Asia, resulting in persistent cold spells. Blocking near Greenland related to low-level temperature anomalies led to northerly flow into eastern North America, inducing persistent cold periods. Potential Arctic connections in Europe are less clear. Variability in the North Pacific can reinforce downstream Arctic changes, and Arctic amplification can accentuate the impact of Pacific variability. The authors emphasize multiple linkage mechanisms that are regional, episodic, and based on amplification of existing jet stream wave patterns, which are the result of a combination of internal variability, lower-tropospheric temperature anomalies, and midlatitude teleconnections. The quantitative impact of Arctic change on midlatitude weather may not be resolved within the foreseeable future, yet new studies of the changing Arctic and subarctic low-frequency dynamics, together with additional Arctic observations, can contribute to improved skill in extended-range forecasts, as planned by the WMO Polar Prediction Project (PPP). © 2015 American Meteorological Society

Towards an advanced observation system for the marine Arctic in the framework of the Pan-Eurasian Experiment (PEEX)

The Arctic marine climate system is changing rapidly, which is seen in the warming of the ocean and atmosphere, decline of sea ice cover, increase in river discharge, acidification of the ocean, and changes in marine ecosystems. Socio-economic activities in the coastal and marine Arctic are simultaneously changing. This calls for the establishment of a marine Arctic component of the Pan-Eurasian Experiment (MA-PEEX). There is a need for more in situ observations on the marine atmosphere, sea ice, and ocean, but increasing the amount of such observations is a pronounced technological and logistical challenge. The SMEAR (Station for Measuring Ecosystem-Atmosphere Relations) concept can be applied in coastal and archipelago stations, but in the Arctic Ocean it will probably be more cost-effective to further develop a strongly distributed marine observation network based on autonomous buoys, moorings, autonomous underwater vehicles (AUVs), and unmanned aerial vehicles (UAVs). These have to be supported by research vessel and aircraft campaigns, as well as various coastal observations, including community-based ones. Major manned drift-ing stations may occasionally be comparable to terrestrial SMEAR flagship stations. To best utilize the observations, atmosphere-ocean reanalyses need to be further developed. To well integrate MA-PEEX with the existing terrestrialatmospheric PEEX, focus is needed on the river discharge and associated fluxes, coastal processes, and atmospheric transports in and out of the marine Arctic. More observations and research are also needed on the specific socioeconomic challenges and opportunities in the marine and coastal Arctic, and on their interaction with changes in the climate and environmental system. MA-PEEX will promote international collaboration; sustainable marine meteorological, sea ice, and oceanographic observations; advanced data management; and multidisciplinary research on the marine Arctic and its interaction with the Eurasian continent.Peer reviewe

Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by monoallelic mutation or deletion in the transcription factor 4 (TCF4) gene. Individuals with PTHS typically present in the first year of life with developmental delay and exhibit intellectual disability, lack of speech, and motor incoordination. There are no effective treatments available for PTHS, but the root cause of the disorder, TCF4 haploinsufficiency, suggests that it could be treated by normalizing TCF4 gene expression. Here, we performed proof-of-concept viral gene therapy experiments using a conditional Tcf4 mouse model of PTHS and found that postnatally reinstating Tcf4 expression in neurons improved anxiety-like behavior, activity levels, innate behaviors, and memory. Postnatal reinstatement also partially corrected EEG abnormalities, which we characterized here for the first time, and the expression of key TCF4-regulated genes. Our results support a genetic normalization approach as a treatment strategy for PTHS, and possibly other TCF4-linked disorders

Conceptual design of a measurement network of the global change

The global environment is changing rapidly due to anthropogenic emissions and actions. Such activities modify aerosol and greenhouse gas concentrations in the atmosphere, leading to regional and global climate change and affecting, e.g., food and fresh-water security, sustainable use of natural resources and even demography. Here we present a conceptual design of a global, hierarchical observation network that can provide tools and increased understanding to tackle the inter-connected environmental and societal challenges that we will face in the coming decades. The philosophy behind the conceptual design relies on physical conservation laws of mass, energy and momentum, as well as on concentration gradients that act as driving forces for the atmosphere-biosphere exchange. The network is composed of standard, flux and/or advanced and flagship stations, each of which having specific and identified tasks. Each ecosystem type on the globe has its own characteristic features that have to be taken into consideration. The hierarchical network as a whole is able to tackle problems related to large spatial scales, heterogeneity of ecosystems and their complexity. The most comprehensive observations are envisioned to occur in flagship stations, with which the process-level understanding can be expanded to continental and global scales together with advanced data analysis, Earth system modelling and satellite remote sensing. The denser network of the flux and standard stations allows application and up-scaling of the results obtained from flagship stations to the global level.Peer reviewe

Arctic Amplification metrics

One of the defining features of both recent and historical cases of global climate change is Arctic Amplification (AA). This is the more rapid change in the surface air temperature (SAT) in the Arctic compared to some wider reference region, such as the Northern Hemisphere (NH) mean. Many different metrics have been developed to quantify the degree of AA based on SAT anomalies, trends and variability. The use of different metrics, as well as the choice of dataset to use can affect conclusions about the magnitude and temporal variability of AA. Here we review the established metrics of AA to see how well they agree upon the temporal signature of AA, such as the multi-decadal variability, and 16 assess the consistency in these metrics across different commonly-used datasets which cover both the early and late 20th century warming in the Arctic. We find the NOAA 20th Century Reanalysis most closely matches the observations when using metrics based upon SAT trends (A2), variability (A3) and regression (A4) of the SAT anomalies, and the ERA 20th 19 Century Reanalysis is closest to the observations in the SAT anomalies (A1) and variability of SAT anomalies (A3). However, there are large seasonal differences in the consistency between datasets. Moreover, the largest differences between the century-long reanalysis products and observations are during the early warming period, likely due to the sparseness of the observations in the Arctic at that time. In the modern warming period, the high density of observations strongly constrains all the reanalysis products, whether they include satellite observations or only surface observations. Thus, all the reanalysis and observation products produce very similar magnitudes and temporal variability in the degree of AA during the recent warming period

Pan-Eurasian Experiment (PEEX) Program : An Overview of the First 5 Years in Operation and Future Prospects

The Pan-Eurasian Experiment (PEEX) program was initiated as a bottom-up approach by the researchers coming from Finland and Russia in October 2012. The PEEX China kick off meeting was held in November 2013. During its five years in operation, the program has established a governance structure and delivered a science plan for the Northern Eurasian region. PEEX has also introduced a concept design for a modelling platform and ground-based in situ observation systems for detecting land-atmosphere and ocean-atmosphere interactions. Today, PEEX has an extensive researcher’s network representing research communities coming from the Nordic countries, Russia and China. PEEX is currently carrying out its research activities on a project basis, but is looking for more coordinated funding bases, especially in Russia and in China. The near-future challenge in implementing the PEEX research agenda is to achieve a successful integration and identification of the methodological approaches of the socio-economic research to environmental sciences. Here we give insight into these issues and provide an overview on the main tasks for the upcoming years.The Pan-Eurasian Experiment (PEEX) program was initiated as a bottom-up approach by the researchers coming from Finland and Russia in October 2012. The PEEX China kick off meeting was held in November 2013. During its five years in operation, the program has established a governance structure and delivered a science plan for the Northern Eurasian region. PEEX has also introduced a concept design for a modelling platform and ground-based in situ observation systems for detecting land-atmosphere and ocean-atmosphere interactions. Today, PEEX has an extensive researcher’s network representing research communities coming from the Nordic countries, Russia and China. PEEX is currently carrying out its research activities on a project basis, but is looking for more coordinated funding bases, especially in Russia and in China. The near-future challenge in implementing the PEEX research agenda is to achieve a successful integration and identification of the methodological approaches of the socio-economic research to environmental sciences. Here we give insight into these issues and provide an overview on the main tasks for the upcoming years.The Pan-Eurasian Experiment (PEEX) program was initiated as a bottom-up approach by the researchers coming from Finland and Russia in October 2012. The PEEX China kick off meeting was held in November 2013. During its five years in operation, the program has established a governance structure and delivered a science plan for the Northern Eurasian region. PEEX has also introduced a concept design for a modelling platform and ground-based in situ observation systems for detecting land-atmosphere and ocean-atmosphere interactions. Today, PEEX has an extensive researcher’s network representing research communities coming from the Nordic countries, Russia and China. PEEX is currently carrying out its research activities on a project basis, but is looking for more coordinated funding bases, especially in Russia and in China. The near-future challenge in implementing the PEEX research agenda is to achieve a successful integration and identification of the methodological approaches of the socio-economic research to environmental sciences. Here we give insight into these issues and provide an overview on the main tasks for the upcoming years.Peer reviewe