450 research outputs found
p190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation
The mechanisms regulating hematopoietic stem and progenitor cell (HSPC) fate choices remain ill-defined. Here, we show that a signalling network of p190-B RhoGAP-ROS-TGF-β-p38MAPK balances HSPC self-renewal and differentiation. Upon transplantation, HSPCs express high amounts of bioactive TGF-β1 protein, which is associated with high levels of p38MAPK activity and loss of HSC self-renewal in vivo. Elevated levels of bioactive TGF-β1 are associated with asymmetric fate choice in vitro in single HSPCs via p38MAPK activity and this is correlated with the asymmetric distribution of activated p38MAPK. In contrast, loss of p190-B, a RhoGTPase inhibitor, normalizes TGF-β levels and p38MAPK activity in HSPCs and is correlated with increased HSC self-renewal in vivo. Loss of p190-B also promotes symmetric retention of multi-lineage capacity in single HSPC myeloid cell cultures, further suggesting a link between p190-B-RhoGAP and non-canonical TGF-β signalling in HSPC differentiation. Thus, intracellular cytokine signalling may serve as 'fate determinants' used by HSPCs to modulate their activity
Placental transfer of the polybrominated diphenyl ethers BDE-47, BDE-99 and BDE-209 in a human placenta perfusion system: an experimental study
<p>Abstract</p> <p>Background</p> <p>Polybrominated diphenyl ethers (PBDEs) have been widely used as flame retardants in consumer products. PBDEs may affect thyroid hormone homeostasis, which can result in irreversible damage of cognitive performance, motor skills and altered behaviour. Thus, in utero exposure is of very high concern due to critical windows in fetal development.</p> <p>Methods</p> <p>A human ex vivo placenta perfusion system was used to study the kinetics and extent of the placental transfer of BDE-47, BDE-99 and BDE-209 during four-hour perfusions. The PBDEs were added to the maternal circulation and monitored in the maternal and fetal compartments. In addition, the perfused cotyledon, the surrounding placental tissue as well as pre-perfusion placental tissue and umbilical cord plasma were also analysed. The PBDE analysis included Soxhlet extraction, clean-up by adsorption chromatography and GC-MS analysis.</p> <p>Results and Discussion</p> <p>Placental transfer of BDE-47 was faster and more extensive than for BDE-99. The fetal-maternal ratios (FM-ratio) after four hours of perfusion were 0.47 and 0.25 for BDE-47 and BDE-99, respectively, while the indicative permeability coefficient (IPC) measured after 60 minutes of perfusion was 0.26 h<sup>-1 </sup>and 0.10 h<sup>-1</sup>, respectively. The transport of BDE-209 seemed to be limited. These differences between the congeners may be related to the degree of bromination. Significant accumulation was observed for all congeners in the perfused cotyledon as well as in the surrounding placental tissue.</p> <p>Conclusion</p> <p>The transport of BDE-47 and BDE-99 indicates in utero exposure to these congeners. Although the transport of BDE-209 was limited, however, possible metabolic debromination may lead to products which are both more toxic and transportable. Our study demonstrates fetal exposure to PBDEs, which should be included in risk assessment of PBDE exposure of women of child-bearing age.</p
Antioxidant treatment attenuates lactate production in diabetic nephropathy
The early progression of diabetic nephropathy is notoriously difficult to detect and quantify before the occurrence of substantial histological damage. Recently, hyperpolarized [1-13C]pyruvate has demonstrated increased lactate production in the kidney early after the onset of diabetes, implying increased lactate dehydrogenase activity as a consequence of increased nicotinamide adenine dinucleotide substrate availability due to upregulation of the polyol pathway, i.e., pseudohypoxia. In this study, we investigated the role of oxidative stress in mediating these metabolic alterations using state-of-the-art hyperpolarized magnetic resonance (MR) imaging. Ten-week-old female Wistar rats were randomly divided into three groups: healthy controls, untreated diabetic (streptozotocin treatment to induce insulinopenic diabetes), and diabetic, receiving chronic antioxidant treatment with TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) via the drinking water. Examinations were performed 2, 3, and 4 wk after the induction of diabetes by using a 3T Clinical MR system equipped with a dual tuned 13C/1H-volume rat coil. The rats received intravenous hyperpolarized [1-13C]pyruvate and were imaged using a slice-selective 13C-IDEAL spiral sequence. Untreated diabetic rats showed increased renal lactate production compared with that shown by the controls. However, chronic TEMPOL treatment significantly attenuated diabetes-induced lactate production. No significant effects of diabetes or TEMPOL were observed on [13C]alanine levels, indicating an intact glucose-alanine cycle, or [13C]bicarbonate, indicating normal flux through the Krebs cycle. In conclusion, this study demonstrates that diabetes-induced pseudohypoxia, as indicated by an increased lactate-to-pyruvate ratio, is significantly attenuated by antioxidant treatment. This demonstrates a pivotal role of oxidative stress in renal metabolic alterations occurring in early diabetes. </jats:p
Impacts of agricultural mechanization: Evidence from four African countries
Agricultural mechanization is on the rise in Africa. A widespread replacement of manual labor will change the face of African agriculture. Despite this potentially transformative role, only few studies have looked at the potential effects of mechanization empirically, mostly focusing on yields and labor alone. This is the first paper that explores agronomic, environmental and socioeconomic effects together, thereby revealing linkages and trade- offs, some of which have been hitherto unknown. Data were collected using a novel data collection method called “Participatory Impact Diagrams” in four countries: Benin, Kenya, Nigeria and Mali. In 130 gendered focus group discussions, 1,330 respondents from 87 villages shared positive and negative effects experienced due to agricultural mechanization and were able to develop their own theory of change. This is the first study that gives a voice to the rural population on mechanization and allows them to identify causal impact chains. Regarding agronomic and environmental aspects, respondents perceived mechanization as a way to reduce labor shortages, improve timeliness and enhance land preparation, leading to higher yields. However, it is also associated with the cutting of farm trees as well as farmland expansion, and, subsequently, deforestation and a decline in firewood availability. Respondents also experienced that (plough-based) mechanization can have detrimental effects on soil fertility and cause erosion, which was associated with yield drops and risks in the long-term. Regarding socioeconomic effects, mechanization was reported to increase incomes, reduce drudgery and free up time for other farm and off- farm activities. However, mechanization was also linked with social tensions and conflicts, for example, related to land issues, which can pitch farmers against pastoralists. Tensions and conflicts also play out across gender. Some effects remain ambiguous. For example, depending on local factors, mechanization reportedly increases or decreases employment. Further research and policy efforts are needed to ensure that mechanization contributes to an African agricultural transformation that is sustainable from a social, economic and environmental perspective
Social Value of Marine and Coastal Protected Areas in England and Wales.
The U.K. government is committed to establishing a coherent network of marine protected
areas by 2012 and the recentMarine and Coastal Access Act, 2009 will designate
marine conservation zones and provide wider access rights to the coast. To fulfill these
goals, this article argues the need for a clearer, shared understanding of the social
value of protected areas in creating new designations and managing existing ones. Although
marine and coastal environments attract many people and are vitally important
in terms of realized and potential social value, the majority of the public in the United
Kingdom lacks understanding and awareness regarding them. Combined with this, the
social value of marine and coastal protected areas (MCPAs) have been largely ignored
relative to conservation and economics, with the latter invariably taking precedence
in environmental policymaking. Social value reflects the complex, individual responses
that people experience in a given place. Many reasons determine why one area is valued
above another, and this research investigates the social value of MCPAs from a
practitioner’s perspective through a series of interviews. Understanding why we “socially”
value MCPAs will ultimately equip managers with an informed understanding
of these spaces, influence management decisions, and, potentially, policymaking. This
article defines social value in the context of MCPAs in England and Wales from a
practitioner perspective, explores key concepts, and suggests possible improvements in
decision-making
Increased tartrate-resistant acid phosphatase (TRAP) expression in malignant breast, ovarian and melanoma tissue: an investigational study
BACKGROUND: Tartrate-resistant acid phosphatase (TRAP) is a metalloprotein enzyme that belongs to the acid phosphatases and is known to be expressed by osteoclasts. It has already been investigated as a marker of bone metastases in cancer patients. In this study, which examined the value of serum TRAP concentrations as a marker of bone disease in breast cancer patients, we observed high concentrations of TRAP even in patients without bone metastases. To elucidate this phenomenon, we examined the expression of TRAP in breast cancer cells and the cells of several other malignancies. METHODS: TRAP concentrations in the serum of tumor patients were determined by ELISA. The expression of TRAP in breast, ovarian, and cervical cancer and malignant melanoma was analyzed by immunohistochemistry. RT-PCR and immunocytology were used to evaluate TRAP expression in cultured tumor cells. RESULTS: A marked increase in serum TRAP concentrations was observed in patients with breast and ovarian cancer, regardless of the presence or absence of bone disease. TRAP expression was found in breast and ovarian cancers and malignant melanoma, while cervical cancer showed only minimal expression of TRAP. Expression of TRAP was absent in benign tissue or was much less marked than in the corresponding malignant tissue. TRAP expression was also demonstrated in cultured primary cancer cells and in commercially available cell lines. CONCLUSION: Overexpression of TRAP was detected in the cells of various different tumors. TRAP might be useful as a marker of progression of malignant disease. It could also be a potential target for future cancer therapies
Effect of Vitamin D Supplementation on Markers of Vascular Function: A Systematic Review and Individual Participant Meta- Analysis
Background-—Low 25-hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of
vitamin D supplementation on markers of vascular function associated with major adverse cardiovascular events is unclear.
Methods and Results-—We conducted a systematic review and individual participant meta-analysis to examine the effect of vitamin D
supplementation on flow-mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure,
microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and
http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo-controlled randomized trials
of at least4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial-level metaanalysis
was performed using random-effects models; individual participant meta-analyses used a 2-stage analytic strategy, examining
effects in prespecified subgroups. 31trials (2751 participants) were included; 29 trials (2641participants) contributed data to trial-level
meta-analysis, and24trials (2051 participants) contributed to individual-participant analyses. VitaminD3daily dose equivalents ranged
from 900 to 5000 IU; duration was 4 weeks to12 months. Trial-level meta-analysis showed no significant effect of supplementation on
macrovascularmeasures(flow-mediateddilatation,0.37%[95%confidenceinterval, 0.23to0.97]; carotid-femoralpulsewavevelocity,
0.00 m/s [95% confidence interval, 0.36 to 0.37]); similar results were obtained from individual participant data. Microvascular
function showed a modest improvement in trial-level data only. No consistent benefit was observed in subgroup analyses or between
different vitamin D analogues.
Conclusions-—Vitamin D supplementation had no significant effect on most markers of vascular function in this analysis
Observation of Hadronic W Decays in t-tbar Events with the Collider Detector at Fermilab
We observe hadronic W decays in t-tbar -> W (-> l nu) + >= 4 jet events using
a 109 pb-1 data sample of p-pbar collisions at sqrt{s} = 1.8 TeV collected with
the Collider Detector at Fermilab (CDF). A peak in the dijet invariant mass
distribution is obtained that is consistent with W decay and inconsistent with
the background prediction by 3.3 standard deviations. From this peak we measure
the W mass to be 77.2 +- 4.6 (stat+syst) GeV/c^2. This result demonstrates the
presence of two W bosons in t-tbar candidates in the W (-> l nu) + >= 4 jet
channel.Comment: 20 pages, 4 figures, submitted to PR
Search for charged Higgs decays of the top quark using hadronic tau decays
We present the result of a search for charged Higgs decays of the top quark,
produced in collisions at 1.8 TeV. When the charged
Higgs is heavy and decays to a tau lepton, which subsequently decays
hadronically, the resulting events have a unique signature: large missing
transverse energy and the low-charged-multiplicity tau. Data collected in the
period 1992-1993 at the Collider Detector at Fermilab, corresponding to
18.70.7~pb, exclude new regions of combined top quark and charged
Higgs mass, in extensions to the standard model with two Higgs doublets.Comment: uuencoded, gzipped tar file of LaTeX and 6 Postscript figures; 11 pp;
submitted to Phys. Rev.
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