Studying the genetic basis of drought tolerance in sorghum by managed stress trials and adjustments for phenological and plant height differences

Managed environments in the form of well watered and water stressed trials were performed to study the genetic basis of grain yield and stay green in sorghum with the objective of validating previously detected QTL. As variations in phenology and plant height may influence QTL detection for the target traits, QTL for flowering time and plant height were introduced as cofactors in QTL analyses for yield and stay green. All but one of the flowering time QTL were detected near yield and stay green QTL. Similar co-localization was observed for two plant height QTL. QTL analysis for yield, using flowering time/plant height cofactors, led to yield QTL on chromosomes 2, 3, 6, 8 and 10. For stay green, QTL on chromosomes 3, 4, 8 and 10 were not related to differences in flowering time/plant height. The physical positions for markers in QTL regions projected on the sorghum genome suggest that the previously detected plant height QTL, Sb-HT9-1, and Dw2, in addition to the maturity gene, Ma5, had a major confounding impact on the expression of yield and stay green QTL. Co-localization between an apparently novel stay green QTL and a yield QTL on chromosome 3 suggests there is potential for indirect selection based on stay green to improve drought tolerance in sorghum. Our QTL study was carried out with a moderately sized population and spanned a limited geographic range, but still the results strongly emphasize the necessity of corrections for phenology in QTL mapping for drought tolerance traits in sorghum.

Omega-3 improves glucose tolerance but increases lipid peroxidation and DNA damage in hepatocytes of fructose-fed rats

The high consumption of fructose is linked to the increase in various characteristics of the metabolic syndrome. Fish oil is beneficial for the treatment of these comorbidities, such as insulin resistance, dyslipidemia, and hepatic steatosis. The objective of this study was to evaluate the consequences of the administration of fish oil concomitant to fructose ingestion during the experiment (45 days) and during the final 15 days in high-fructose-fed rats. Male Wistar rats were divided into 5 groups: control; those receiving 10% fish oil (FO); those receiving 60% fructose (Fr); those receiving 60% fructose and 10% fish oil for 45 days (FrFO); and those receiving fructose plus soybean oil for 30 days and fish oil for the final 15 days of the study (FrFO15). There was an increase in triacylglycerol, serum total cholesterol, and hepatic volume in the Fr group. The FO and FrFO groups experienced an increase in lipid peroxidation and a decrease in serum reduced glutathione. The FrFO group suffered greater hepatic injury, with increased alanine aminotransferase levels and DNA damage. Marked n-3 incorporation occurred in the groups receiving fish oil, favoring a better response to the oral glucose tolerance test. Fructose induced comorbidities of the metabolic syndrome, and the use of fish oil promoted a better glucose tolerance, although it was accompanied by more hepatocyte damage.

Caffeic acid phenethyl ester reduces the activation of the nuclear factor kappa B pathway by high-fat diet-induced obesity in mice

Objective. The aim of this study was to investigate the effect of CAPE on the insulin signaling and inflammatory pathway in the liver of mice with high fat diet induced obesity. Material/Methods. Swiss mice were fed with standard chow or high-fat diet for 12-week. After the eighth week, animals in the HFD group with serum glucose levels higher than 200 mg/dL were divided into two groups, HFD and HFD receiving 30 mg/kg of CAPE for 4 weeks. After 12 weeks, the blood samples could be collected and liver tissue extracted for hormonal and biochemical measurements, and insulin signaling and inflammatory pathway analyzes. Results. The high-fat diet group exhibited more weight gain, glucose intolerance, and hepatic steatosis compared with standard diet group. The CAPE treatment showed improvement in glucose sensitivity characterized by an area under glucose curve similar to the control group in an oral glucose tolerance test Furthermore, CAPE treatment promoted amelioration in hepatic steatosis compared with the high-fat diet group. The increase in glucose sensitivity was associated with the improvement in insulin-stimulated phosphorylation of the insulin receptor substrate-2, followed by an increase in Akt phosphorylation. In addition, it was observed that CAPE reduced the induction of the inflammatory pathway, c-jun-N- terminal kinase, the nuclear factor kappa B, and cyclooxygenase-2 expression, respectively. Conclusions. Overall, these findings indicate that CAPE exhibited anti-inflammatory activity that partly restores normal metabolism, reduces the molecular changes observed in obesity and insulin resistance, and therefore has a potential as a therapeutic agent in obesity. (C) 2012 Elsevier Inc. All rights reserved.

Increasing Intensity of TENS Prevents Analgesic Tolerance in Rats

Transcutaneous electrical nerve stimulation (TENS) reduces hyperalgesia and pain. Both low-frequency (LF) and high-frequency (HF) TENS, delivered at the same intensity (90% motor threshold [MT]) daily, result in analgesic tolerance with repeated use by the fifth day of treatment. The current study tested 1) whether increasing intensity by 10% per day prevents the development of tolerance to repeated TENS; and 2) whether lower intensity TENS (50% MT) produces an equivalent reduction in hyperalgesia when compared to 90% MT TENS. Sprague-Dawley rats with unilateral knee joint inflammation (3% carrageenan) were separated according to the intensity of TENS used: sham, 50% LF, 50% HF, 90% LF, 90% HF, and increased intensity by 10% per day (IF and HF). The reduced mechanical withdrawal threshold following the induction of inflammation was reversed by application of TENS applied at 90% MT intensity and increasing intensity for the first 4 days. On the fifth day, the groups that received 90% MT intensity showed tolerance. Nevertheless, the group that received an increased intensity on each day still showed a reversal of the mechanical withdrawal threshold with TENS. These results show that the development of tolerance can be delayed by increasing intensity of TENS. Perspective: Our results showed that increasing intensity in both frequencies of TENS was able to prevent analgesic tolerance. Results from this study suggest that increasing intensities could be a clinical method to prevent analgesic tolerance and contribute to the effective use of TENS in reducing inflammatory pain and future clinical trials. (c) 2012 by the American Pain Society

Rootstocks for high fruit yield and quality of 'Tahiti' lime under rain-fed conditions

Despite considerable research conducted on 'Tahiti' lime [Citrus latifolia (Yu Tanaka) Tanaka] in several countries, few long-term studies have focused on rootstock effects on fruit production and quality under non-irrigated conditions. As for many other fruit crops, rootstock studies for 'Tahiti' lime are often based on the evaluation of several horticultural responses simultaneously, instead of considering multivariate statistical approaches which may provide with more comprehensive information. Consequently, a trial was installed to evaluate the horticultural performance of non-irrigated 'Tahiti' lime trees budded onto the following 12 rootstocks: 'HRS 801' and 'HRS 827' hybrids; 'Rubidoux', 'FCAV' and 'Flying Dragon' trifoliates; 'Sun Chu Sha Kat' and 'Sunki' mandarins; 'Cravo Limeira' and 'Cravo FCAV' 'Rangpur' limes; 'Carrizo' citrange, 'Swingle' citrumelo, and 'Orlando' tangelo. The trial was installed in 2001, in an 8 m x 5 m spacing with no supplementary irrigation. Measurements of yield, fruit quality oriented to different consuming markets, canopy volume and tree tolerance to drought, were performed. A multivariate cluster analysis identified both 'Rangpur' lime rootstocks as those inducing larger cumulative yield and higher percentage of fruits for the domestic market, with highest drought tolerance to the trees. Despite of their high susceptibility to drought stress under non-irrigated conditions, the 'Flying Dragon' and 'FCAV' trifoliate rootstocks performed outstandingly for 'Tahiti' lime, inducing higher yield efficiency, early bearing and larger percentage of high-quality fruits for foreign markets, with smaller trees more suitable for high-density plantings. (c) 2012 Elsevier B.V. All rights reserved.

A behavioral intervention in a cohort of Japanese-Brazilians at high cardiometabolic risk

OBJECTIVE: To assess the effect of a health promotion program on cardiometabolic risk profile in Japanese-Brazilians. METHODS: A total of 466 subjects from a study on diabetes prevalence conducted in the city of Bauru, southeastern Brazil, in 2000 completed a 1-year intervention program (2005-2006) based on healthy diet counseling and physical activity. Changes in blood pressure and metabolic parameters in the 2005-2006 period were compared with annual changes in these same variables in the 2000-2005 period. RESULTS: During the intervention, there were greater annual reductions in mean (SD) waist circumference [-0.5(3.8) vs. 1.2(1.2) cm per year, p<0.001], systolic blood pressure [-4.6(17.9) vs. 1.8(4.3) mmHg per year, p<0.001], 2-hour plasma glucose [-1.2(2.1) vs. -0.2(0.6) mmol/L per year, p<0.001], LDL-cholesterol [-0.3(0.9) vs. -0.1(0.2) mmol/L per year, p<0.001] and Framingham coronary heart disease risk score [-0.25(3.03) vs. 0.11(0.66) per year, p=0.02] but not in triglycerides [0.2(1.6) vs. 0.1(0.42) mmol/L per year, p<0.001], and fasting insulin level [1.2(5.8) vs. -0.7(2.2) IU/mL per year, p<0.001] compared with the pre-intervention period. Significant reductions in the prevalence of impaired fasting glucose/impaired glucose tolerance and diabetes were seen during the intervention (from 58.4% to 35.4%, p<0.001; and from 30.1% to 21.7%, p= 0.004, respectively). CONCLUSIONS: A one-year community-based health promotion program brings cardiometabolic benefits in a high-risk population of Japanese-Brazilians.

Tolerance and immunity to human tumor-associated antigens

Tumor-assoziierte Antigene (TAA) repräsentieren wichtige Zielstrukturen in zytotoxischen T-Zell (ZTL)-basierten Immuntherapien zur Behandlung maligner Erkrankungen. Die Tatsache, dass TAA nicht spezifisch nur in Tumoren sondern auch in nicht-transformierten Zellen vorhanden sind, kann infolge verschiedener Toleranz-Mechanismen zur Eliminierung von ZTL führen, deren T-Zell-Rezeptoren eine hohe Affinität für TAA besitzen. Entsprechend erfordert die Entwicklung effektiver Immuntherapeutika die genaue Analyse des verfügbaren T-Zell-Repertoires mit Spezifität für ein gegebenes TAA.Die Arbeit fokusierte das Tyrosinase (369-377) ZTL-Epitop, das im Komplex mit HLA-A*0201 (A2.1) auf der Zell-Oberfläche von malignen Melanomen und verschiedenen nicht-transformierten Zellen präsentiert wird. Es wurde gefunden, dass sowohl das humane als auch das murine Tyrosinase (369-377)-spezifische ZTL-Repertoire durch Selbst-Toleranz kompromittiert ist und dass diese Toleranz weder durch Verwendung einer bestimmten Peptid-Variante noch durch Interferenz mit CD4+CD25+ regulatorischen T-Zellen oder CTLA-4 umgangen werden kann. Diese Ergebnisse wurden anschließend auf ein anderes Krankheitsmodell, das Multiple Myelom (MM), adaptiert. Unter Umgehung von Selbst-Toleranz in A2.1-transgenen Mäusen wurde gezeigt, dass Transkriptionsfaktoren, die die terminale Differenzierung von B-Zellen in maligne und nicht-maligne Plasmazellen diktieren, als MM-assoziierte ZTL-Epitope dienen können.Diese Arbeit bietet einen bedeutenden und innovativen Beitrag zur Gestaltung von Tyrosinase-basierten Melanom- und MM-reaktiven Immuntherapien.

In vitro characterisation and expansion of human regulatory T cells for their in vivo application in the induction of tolerance in haematopoietic stem cell and solid organ transplantation

Solid organ transplantation (SOT) is considered the treatment of choice for many end-stage organ diseases. Thus far, short term results are excellent, with patient survival rates greater than 90% one year post-surgery, but there are several problems with the long term acceptance and use of immunosuppressive drugs. Hematopoietic Stem Cells Transplantation (HSCT) concerns the infusion of haematopoietic stem cells to re-establish acquired and congenital disorders of the hematopoietic system. The main side effect is the Graft versus Host Disease (GvHD) where donor T cells can cause pathology involving the damage of host tissues. Patients undergoing acute or chronic GvHD receive immunosuppressive regimen that is responsible for several side effects. The use of immunosuppressive drugs in the setting of SOT and GvHD has markedly reduced the incidence of acute rejection and the tissue damage in GvHD however, the numerous adverse side effects observed boost the development of alternative strategies to improve the long-term outcome. To this effect, the use of CD4+CD25+FOXP3+ regulatory T cells (Treg) as a cellular therapy is an attractive approach for autoimmunity disease, GvHD and limiting immune responses to allograft after transplantation. Treg have a pivotal role in maintaining peripheral immunological tolerance, by preventing autoimmunity and chronic inflammation. Results of my thesis provide the characterization and cell processing of Tregs from healthy controls and patients in waiting list for liver transplantation, followed by the development of an efficient expansion-protocol and the investigation of the impact of the main immunosuppressive drugs on viability, proliferative capacity and function of expanded cells after expansion. The conclusion is that ex vivo expansion is necessary to infuse a high Treg dose and although many other factors in vivo can contribute to the success of Treg therapy, the infusion of Tregs during the administration of the highest dose of immunosuppressants should be carefully considered.

Dynamic distance analysis : new geometric data structures and algorithms for the real-time calculation of tolerance violating regions in the digital mockup process

In vielen Industriezweigen, zum Beispiel in der Automobilindustrie, werden Digitale Versuchsmodelle (Digital MockUps) eingesetzt, um die Konstruktion und die Funktion eines Produkts am virtuellen Prototypen zu überprüfen. Ein Anwendungsfall ist dabei die Überprüfung von Sicherheitsabständen einzelner Bauteile, die sogenannte Abstandsanalyse. Ingenieure ermitteln dabei für bestimmte Bauteile, ob diese in ihrer Ruhelage sowie während einer Bewegung einen vorgegeben Sicherheitsabstand zu den umgebenden Bauteilen einhalten. Unterschreiten Bauteile den Sicherheitsabstand, so muss deren Form oder Lage verändert werden. Dazu ist es wichtig, die Bereiche der Bauteile, welche den Sicherhabstand verletzen, genau zu kennen. rnrnIn dieser Arbeit präsentieren wir eine Lösung zur Echtzeitberechnung aller den Sicherheitsabstand unterschreitenden Bereiche zwischen zwei geometrischen Objekten. Die Objekte sind dabei jeweils als Menge von Primitiven (z.B. Dreiecken) gegeben. Für jeden Zeitpunkt, in dem eine Transformation auf eines der Objekte angewendet wird, berechnen wir die Menge aller den Sicherheitsabstand unterschreitenden Primitive und bezeichnen diese als die Menge aller toleranzverletzenden Primitive. Wir präsentieren in dieser Arbeit eine ganzheitliche Lösung, welche sich in die folgenden drei großen Themengebiete unterteilen lässt.rnrnIm ersten Teil dieser Arbeit untersuchen wir Algorithmen, die für zwei Dreiecke überprüfen, ob diese toleranzverletzend sind. Hierfür präsentieren wir verschiedene Ansätze für Dreiecks-Dreiecks Toleranztests und zeigen, dass spezielle Toleranztests deutlich performanter sind als bisher verwendete Abstandsberechnungen. Im Fokus unserer Arbeit steht dabei die Entwicklung eines neuartigen Toleranztests, welcher im Dualraum arbeitet. In all unseren Benchmarks zur Berechnung aller toleranzverletzenden Primitive beweist sich unser Ansatz im dualen Raum immer als der Performanteste.rnrnDer zweite Teil dieser Arbeit befasst sich mit Datenstrukturen und Algorithmen zur Echtzeitberechnung aller toleranzverletzenden Primitive zwischen zwei geometrischen Objekten. Wir entwickeln eine kombinierte Datenstruktur, die sich aus einer flachen hierarchischen Datenstruktur und mehreren Uniform Grids zusammensetzt. Um effiziente Laufzeiten zu gewährleisten ist es vor allem wichtig, den geforderten Sicherheitsabstand sinnvoll im Design der Datenstrukturen und der Anfragealgorithmen zu beachten. Wir präsentieren hierzu Lösungen, die die Menge der zu testenden Paare von Primitiven schnell bestimmen. Darüber hinaus entwickeln wir Strategien, wie Primitive als toleranzverletzend erkannt werden können, ohne einen aufwändigen Primitiv-Primitiv Toleranztest zu berechnen. In unseren Benchmarks zeigen wir, dass wir mit unseren Lösungen in der Lage sind, in Echtzeit alle toleranzverletzenden Primitive zwischen zwei komplexen geometrischen Objekten, bestehend aus jeweils vielen hunderttausend Primitiven, zu berechnen. rnrnIm dritten Teil präsentieren wir eine neuartige, speicheroptimierte Datenstruktur zur Verwaltung der Zellinhalte der zuvor verwendeten Uniform Grids. Wir bezeichnen diese Datenstruktur als Shrubs. Bisherige Ansätze zur Speicheroptimierung von Uniform Grids beziehen sich vor allem auf Hashing Methoden. Diese reduzieren aber nicht den Speicherverbrauch der Zellinhalte. In unserem Anwendungsfall haben benachbarte Zellen oft ähnliche Inhalte. Unser Ansatz ist in der Lage, den Speicherbedarf der Zellinhalte eines Uniform Grids, basierend auf den redundanten Zellinhalten, verlustlos auf ein fünftel der bisherigen Größe zu komprimieren und zur Laufzeit zu dekomprimieren.rnrnAbschießend zeigen wir, wie unsere Lösung zur Berechnung aller toleranzverletzenden Primitive Anwendung in der Praxis finden kann. Neben der reinen Abstandsanalyse zeigen wir Anwendungen für verschiedene Problemstellungen der Pfadplanung.

The effect of temperature on pressure tolerance of the shallow-water shrimp Palaemon serratus

Tolerance to low temperature and high pressure may allow shallow-water species to extend bathymetric range in response to changing climate, but adaptation to contrasting shallow-water environments may affect tolerance to these factors. The brackish shallow-water shrimp Palaemon varians demonstrates remarkable tolerance to elevated hydrostatic pressure and low temperature, but inhabits a highly variable environment: environmental adaptation may therefore make P. varians tolerances unrepresentative of other shallow-water species. Critical thermal maximum (CTmax), critical hydrostatic pressure maximum (CPmax), and acute respiratory response to hydrostatic pressure were assessed in the shallow-water shrimp Palaemon serratus, which inhabits a more stable intertidal habitat. P. serratus’ CTmax was 22.3°C when acclimated at 10°C, and CPmax was 5.9, 10.1, and 14.1 MPa when acclimated at 5, 10, and 15°C respectively: these critical tolerances were consistently lower than P. varians. Respiratory responses to acute hyperbaric exposures similarly indicated lower tolerance to hydrostatic pressure in P. serratus than in P. varians. Contrasting tolerances likely reflect physiological adaptation to differing environments and reveal that the capacity for depth-range extension may vary among species from different habitats.

Intravenous iron treatment in pregnancy: comparison of high-dose ferric carboxymaltose vs. iron sucrose

Oral iron substitution has shown to be insufficient for treatment of severe iron deficiency anemia in pregnancy. Ferric carboxymaltose is a new intravenous (i.v.) iron formulation promising to be more effective and as safe as iron sucrose. We aimed to assess side effects and tolerance of ferric carboxymaltose compared to i.v. iron sucrose in pregnant women.

The contribution of intra- and interspecific tolerance variability to biodiversity changes along toxicity gradients

The worldwide distribution of toxicants is an important yet understudied driver of biodiversity, and the mechanisms relating toxicity to diversity have not been adequately explored. Here, we present a community model integrating demography, dispersal and toxicant-induced effects on reproduction driven by intraspecific and interspecific variability in toxicity tolerance. We compare model predictions to 458 species abundance distribu- tions (SADs) observed along concentration gradients of toxicants to show that the best predictions occur when intraspecific variability is five and ten times higher than interspecific variability. At high concentrations, lower settings of intraspecific variability resulted in predictions of community extinction that were not supported by the observed SADs. Subtle but significant species losses at low concentrations were predicted only when intraspecific variability dominated over interspecific variability. Our results propose intraspecific variability as a key driver for biodiversity sustenance in ecosystems challenged by environmental change.

Disentangling human tolerance and resistance against HIV.

In ecology, "disease tolerance" is defined as an evolutionary strategy of hosts against pathogens, characterized by reduced or absent pathogenesis despite high pathogen load. To our knowledge, tolerance has to date not been quantified and disentangled from host resistance to disease in any clinically relevant human infection. Using data from the Swiss HIV Cohort Study, we investigated if there is variation in tolerance to HIV in humans and if this variation is associated with polymorphisms in the human genome. In particular, we tested for associations between tolerance and alleles of the Human Leukocyte Antigen (HLA) genes, the CC chemokine receptor 5 (CCR5), the age at which individuals were infected, and their sex. We found that HLA-B alleles associated with better HIV control do not confer tolerance. The slower disease progression associated with these alleles can be fully attributed to the extent of viral load reduction in carriers. However, we observed that tolerance significantly varies across HLA-B genotypes with a relative standard deviation of 34%. Furthermore, we found that HLA-B homozygotes are less tolerant than heterozygotes. Lastly, tolerance was observed to decrease with age, resulting in a 1.7-fold difference in disease progression between 20 and 60-y-old individuals with the same viral load. Thus, disease tolerance is a feature of infection with HIV, and the identification of the mechanisms involved may pave the way to a better understanding of pathogenesis.

Cisplatin-resistant cells in malignant pleural mesothelioma cell lines show ALDH(high)CD44(+) phenotype and sphere-forming capacity

BACKGROUND Conventional chemotherapy in malignant pleural mesothelioma (MPM) has minimal impact on patient survival due to the supposed chemoresistance of cancer stem cells (CSCs). We sought to identify a sub-population of chemoresistant cells by using putative CSC markers, aldehyde dehydrogenase (ALDH) and CD44 in three MPM cell lines; H28, H2052 and Meso4. METHODS The Aldefluor assay was used to measure ALDH activity and sort ALDH(high) and ALDH(low) cells. Drug-resistance was evaluated by cell viability, anchorage-independent sphere formation, flow-cytometry and qRT-PCR analyses. RESULTS The ALDH(high) - and ALDH(low) -sorted fractions were able to demonstrate phenotypic heterogeneity and generate spheres, the latter being less efficient, and both showed an association with CD44. Cis- diamminedichloroplatinum (II) (cisplatin) treatment failed to reduce ALDH activity and conferred only a short-term inhibition of sphere generation in both ALDH(high) and ALDH(low) fractions of the three MPM cell lines. Induction of drug sensitivity by an ALDH inhibitor, diethylaminobenzaldehyde (DEAB) resulted in significant reductions in cell viability but not a complete elimination of the sphere-forming cells, suggestive of the presence of a drug-resistant subpopulation. At the transcript level, the cisplatin + DEAB-resistant cells showed upregulated mRNA expression levels for ALDH1A2, ALDH1A3 isozymes and CD44 indicating the involvement of these markers in conferring chemoresistance in both ALDH(high) and ALDH(low) fractions of the three MPM cell lines. CONCLUSIONS Our study shows that ALDH(high) CD44(+) cells are implicated in conveying tolerance to cisplatin in the three MPM cell lines. The combined use of CD44 and ALDH widens the window for identification and targeting of a drug-resistant population which may improve the current treatment modalities in mesothelioma.

Life style habits such as alcohol consumption and physical activity in relation to serum apoB / apoA-I ratio amongst 64-year-old women with varying degrees of glucose tolerance.

OBJECTIVES To investigate how life style factors such as alcohol consumption and physical activity relate to the serum apoB / apoA-I ratio in a cohort of middle-aged women with varying degrees of glucose tolerance. DESIGN Observational, cross-sectional cohort study. SETTING Research laboratory at a University Hospital. SUBJECTS A screened cohort of 64-year-old postmenopausal women with varying degrees of glucose tolerance, ranging from diabetes (n = 232), impaired (n = 212) and normal (n = 191) glucose tolerance. MAIN OUTCOME MEASURE ApoB / apoA-I ratio in relation to alcohol consumption and physical activity as assessed by questionnaires. RESULTS Alcohol consumption and regular physical activity at high levels were inversely associated with the serum apoB / apoA-I ratio independently of confounding factors such as obesity, lipid-lowering treatment, degree of glucose tolerance and hormone replacement therapy. Alcohol seemed related to the apoB / apoA-I ratio mainly through increasing apoA-I, whereas physical activity seemed mainly related to lowering of apoB. Alcohol consumption above a daily intake of 8.9 g, i.e. less than a glass of wine was accompanied by a decrease in apoB / apoA-I ratio. CONCLUSIONS Amongst these 64-year-old women with varying degrees of glucose tolerance, a moderate alcohol intake and regular physical exercise leading to sweating were associated with lower apoB / apoA-I ratio and these effects seem to be additive.