| 1. |
|
|
| 2. |
- Kranendijk, Martijn, et al.
(författare)
-
IDH2 Mutations in Patients with D-2-Hydroxyglutaric Aciduria.
- 2010
-
Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 330:6002
-
Tidskriftsartikel (refereegranskat)abstract
- Heterozygous somatic mutations in the genes encoding isocitrate dehydrogenase- 1 and -2 (IDH1 and IDH2) were recently discovered in human neoplastic disorders. These mutations disable the enzymes' normal ability to convert isocitrate to 2-ketoglutarate (2-KG) and confer on the enzymes a new function: the ability to convert 2-KG to d-2-hydroxyglutarate (D-2-HG). We have detected heterozygous germline mutations in IDH2 that alter enzyme residue R140 in 15 unrelated patients with d-2-hydroxyglutaric aciduria (D-2-HGA), a rare neurometabolic disorder characterized by supraphysiological levels of D-2-HG. These findings provide additional impetus for investigating the role of D-2-HG in the pathophysiology of metabolic disease and cancer.
|
|
| 3. |
- Yi, Chuixiang, et al.
(författare)
-
Climate control of terrestrial carbon exchange across biomes and continents
- 2010
-
Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 5:3
-
Tidskriftsartikel (refereegranskat)abstract
- Understanding the relationships between climate and carbon exchange by terrestrial ecosystems is critical to predict future levels of atmospheric carbon dioxide because of the potential accelerating effects of positive climate-carbon cycle feedbacks. However, directly observed relationships between climate and terrestrial CO2 exchange with the atmosphere across biomes and continents are lacking. Here we present data describing the relationships between net ecosystem exchange of carbon (NEE) and climate factors as measured using the eddy covariance method at 125 unique sites in various ecosystems over six continents with a total of 559 site-years. We find that NEE observed at eddy covariance sites is (1) a strong function of mean annual temperature at mid-and high-latitudes, (2) a strong function of dryness at mid-and low-latitudes, and (3) a function of both temperature and dryness around the mid-latitudinal belt (45 degrees N). The sensitivity of NEE to mean annual temperature breaks down at similar to 16 degrees C (a threshold value of mean annual temperature), above which no further increase of CO2 uptake with temperature was observed and dryness influence overrules temperature influence.
|
|
| 4. |
|
|
| 5. |
- Anderson, Beverley H., et al.
(författare)
-
Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus
- 2012
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:3, s. 338-342
-
Tidskriftsartikel (refereegranskat)abstract
- Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous gamma H2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the alpha-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-alpha primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.
|
|
| 6. |
- Upadhayaya, Ram Shankar, et al.
(författare)
-
Novel quinoline and naphthalene derivatives as potent antimycobacterial agents
- 2010
-
Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 45:5, s. 1854-1867
-
Tidskriftsartikel (refereegranskat)abstract
- We have designed and synthesized both the quinoline and naphthalene based molecules influenced by the unique structural make-up of mefloquine and TMC207, respectively. These compounds were evaluated for their anti-mycobacterial activity against drug sensitive Mycobacterium tuberculosis H37Rv in vitro at single-dose concentration (6.25 mu g/mL). The compounds 22,23, 26 and 27 inhibited the growth of M. tuberculosis H37Rv 99%, 90%, 98% and 91% respectively. Minimum inhibitory concentration of compounds 22, 23, 26 and 27 was found to be 6.25 mu g/mL.. Our molecular modeling and docking studies of designed compounds showed hydrogen bonding with Glu-61, Tyr-64 and Asn-190 amino acid residues at the putative binding site of ATP synthase, these interactions were coherent as shown by Mefloquine and TMC207, where hydrogen bonding was found with Tyr-64 and Glu-61 respectively. SAR analysis indicates importance of hydroxyl group and nature of substituents on piperazinyl-phenyl ring was critical in dictating the biological activity of newly synthesized compounds. (C) 2010 Elsevier Masson SAS. All rights reserved.
|
|
| 7. |
- Calfapietra, Carlo, et al.
(författare)
-
Challenges in elevated CO2 experiments on forests
- 2010
-
Ingår i: Trends in Plant Science. - : Elsevier BV. - 1360-1385. ; 15:1, s. 5-10
-
Forskningsöversikt (refereegranskat)abstract
- Current forest Free Air CO2 Enrichment (FACE) experiments are reaching completion. Therefore, it is time to define the scientific goals and priorities of future experimental facilities. In this opinion article, we discuss the following three overarching issues (i) What are the most urgent scientific questions and how can they be addressed? (ii) What forest ecosystems should be investigated? (iii) Which other climate change factors should be coupled with elevated CO2 concentrations in future experiments to better predict the effects of climate change? Plantations and natural forests can have conflicting purposes for high productivity and environmental protection. However, in both cases the assessment of carbon balance and how this will be affected by elevated CO2 concentrations and the interacting climate change factors is the most pressing priority for future experiments.
|
|
| 8. |
- De Kauwe, Martin G., et al.
(författare)
-
Forest water use and water use efficiency at elevated CO2: a model-data intercomparison at two contrasting temperate forest FACE sites
- 2013
-
Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 19:6, s. 1759-1779
-
Tidskriftsartikel (refereegranskat)abstract
- Predicted responses of transpiration to elevated atmospheric CO2 concentration (eCO2) are highly variable amongst process-based models. To better understand and constrain this variability amongst models, we conducted an intercomparison of 11 ecosystem models applied to data from two forest free-air CO2 enrichment (FACE) experiments at Duke University and Oak Ridge National Laboratory. We analysed model structures to identify the key underlying assumptions causing differences in model predictions of transpiration and canopy water use efficiency. We then compared the models against data to identify model assumptions that are incorrect or are large sources of uncertainty. We found that model-to-model and model-to-observations differences resulted from four key sets of assumptions, namely (i) the nature of the stomatal response to elevated CO2 (coupling between photosynthesis and stomata was supported by the data); (ii) the roles of the leaf and atmospheric boundary layer (models which assumed multiple conductance terms in series predicted more decoupled fluxes than observed at the broadleaf site); (iii) the treatment of canopy interception (large intermodel variability, 215%); and (iv) the impact of soil moisture stress (process uncertainty in how models limit carbon and water fluxes during moisture stress). Overall, model predictions of the CO2 effect on WUE were reasonable (intermodel =approximately 28%+/- 10%) compared to the observations (=approximately 30%+/- 13%) at the well-coupled coniferous site (Duke), but poor (intermodel =approximately 24%+/- 6%; observations =approximately 38%+/- 7%) at the broadleaf site (Oak Ridge). The study yields a framework for analysing and interpreting model predictions of transpiration responses to eCO2, and highlights key improvements to these types of models.
|
|
| 9. |
- Dixit, Shailesh S., et al.
(författare)
-
New parasite inhibitors encompassing novel conformationally-locked 5 '-acyl sulfamoyl adenosines
- 2012
-
Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 10:30, s. 6121-6129
-
Tidskriftsartikel (refereegranskat)abstract
- We describe the design, synthesis and biological evaluation of conformationally-locked 5'-acyl sulfamoyl adenosine derivatives as new parasitic inhibitors against Trypanosoma and Leishmania. The conformationally-locked (3'-endo, North-type) nucleosides have been synthesized by covalently attaching a 4'-CH2-O-2' bridge (Fig. 2) across C2'-C4' of adenosine in order to reduce the conformational flexibility of the pentose ring. This is designed to decrease the entropic penalty for complex formation with the target protein, which may improve free-energy of stabilization of the complex leading to improved potency. Conformationally-locked 5'-acyl sulfamoyl adenosine derivatives (16-22) were tested against parasitic protozoans for the first time in this work, and showed potent inhibition of Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma rhodesiense and Leishmania infantum with IC50 = 0.25-0.51 mu M. In particular, the potent 5'-pentanyl acyl sulfamoyl adenosine derivative 17 (IC50 = 0.25 mu M) against intracellular L. infantum amastigotes and Trypanosoma subspecies is interesting in view of its almost insignificant cytotoxicity in murine macrophage host cells (CC50 >4 mu M) and in diploid human fibroblasts MRC-5 cell lines (CC50 4 mu M). This work also suggests that variable alkyl chain length of the acyl group on the acylsulfamoyl side chain at 5' can modulate the toxicity of 5'-O-sulfamoylnucleoside analogues. This conformationally-locked sulfamoyl adenosine scaffold presents some interesting possibilities for further drug design and lead optimization.
|
|
| 10. |
- Patrinos, George P., et al.
(författare)
-
Human variome project country nodes: Documenting genetic information within a country
- 2012
-
Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 33:11, s. 1513-1519
-
Tidskriftsartikel (refereegranskat)abstract
- The Human Variome Project (http://www.humanvariomeproject.org) is an international effort aiming to systematically collect and share information on all human genetic variation. The two main pillars of this effort are gene/disease-specific databases and a network of Human Variome Project Country Nodes. The latter are nationwide efforts to document the genomic variation reported within a specific population. The development and successful operation of the Human Variome Project Country Nodes are of utmost importance to the success of Human Variome Project's aims and goals because they not only allow the genetic burden of disease to be quantified in different countries, but also provide diagnosticians and researchers access to an up-to-date resource that will assist them in their daily clinical practice and biomedical research, respectively. Here, we report the discussions and recommendations that resulted from the inaugural meeting of the International Confederation of Countries Advisory Council, held on 12th December 2011, during the 2011 Human Variome Project Beijing Meeting. We discuss the steps necessary to maximize the impact of the Country Node effort for developing regional and country-specific clinical genetics resources and summarize a few well-coordinated genetic data collection initiatives that would serve as paradigms for similar projects. Hum Mutat 33:15131519, 2012. (c) 2012 Wiley Periodicals, Inc.
|
|
| 11. |
- Roy, Rupak, et al.
(författare)
-
SN 2007uy-metamorphosis of an aspheric Type Ib explosion
- 2013
-
Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 434:3, s. 2032-2050
-
Tidskriftsartikel (refereegranskat)abstract
- The supernovae (SNe) of Type Ibc are rare and the detailed characteristics of these explosions have been studied only for a few events. Unlike Type II SNe, the progenitors of Type Ibc have never been detected in pre-explosion images. So, to understand the nature of their progenitors and the characteristics of the explosions, investigation of proximate events is necessary. Here we present the results of multiwavelength observations of Type Ib SN 2007uy in the nearby (similar to 29.5 Mpc) galaxy NGC 2770. Analysis of the photometric observations revealed this explosion as an energetic event with peak absolute R-band magnitude -18.5 +/- 0.16, which is about 1 mag brighter than the mean value (-17.6 +/- 0.6) derived for well observed Type Ibc events. The SN is highly extinguished, E(B - V) = 0.63 +/- 0.15 mag, mainly due to foreground material present in the host galaxy. From optical light curve modelling we determine that about 0.3 M-circle dot radioactive Ni-56 is produced and roughly 4.4 M-circle dot material is ejected during this explosion with liberated energy similar to 15 x 10(51) erg, indicating the event to be an energetic one. Through optical spectroscopy, we have noticed a clear aspheric evolution of several line-forming regions, but no dependency of asymmetry is seen on the distribution of Ni-56 inside the ejecta. The SN shock interaction with the circumstellar material is clearly noticeable in radio follow-up, presenting a synchrotron self-absorption dominated light curve with a contribution of free-free absorption during the early phases. Assuming a Wolf-Rayet (WR) star, with wind velocity greater than or similar to 10(3) km s(- 1), as a progenitor, we derive a lower limit to the mass-loss rate inferred from the radio data as M 2.4 10(-5) M-circle dot yr(-1), which is consistent with the results obtained for other Type Ibc SNe bright at radio frequencies.
|
|
| 12. |
- Srivastava, Tarak, et al.
(författare)
-
Fluid flow shear stress over podocytes is increased in the solitary kidney
- 2014
-
Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 29:1, s. 65-72
-
Tidskriftsartikel (refereegranskat)abstract
- Glomerular hyperfiltration is emerging as the key risk factor for progression of chronic kidney disease (CKD). Podocytes are exposed to fluid flow shear stress (FFSS) caused by the flow of ultrafiltrate within Bowmans space. The mechanism of hyperfiltration-induced podocyte injury is not clear. We postulated that glomerular hyperfiltration in solitary kidney increases FFSS over podocytes. Infant SpragueDawley rats at 5 days of age and C57BL/6J 14-week-old adult mice underwent unilateral nephrectomy. Micropuncture and morphological studies were then performed on 20- and 60-day-old rats. FFSS over podocytes in uninephrectomized rats and mice was calculated using the recently published equation by Friedrich et al. which includes the variablesusingle nephron glomerular filtration rate (SNGFR), filtration fraction (f), glomerular tuft diameter (2R(T)) and width of Bowmans space (s). Glomerular hypertrophy was observed in uninephrectomized rats and mice. Uninephrectomized rats on Day 20 showed a 2.0-fold increase in SNGFR, 1.0-fold increase in 2R(T) and 2.1-fold increase in FFSS, and on Day 60 showed a 1.9-fold increase in SNGFR, 1.3-fold increase in 2R(T) and 1.5-fold increase in FFSS, at all values of modeled s. Similarly, uninephrectomized mice showed a 2- to 3-fold increase in FFSS at all values of modeled SNGFR. FFSS over podocytes is increased in solitary kidneys in both infant rats and adult mice. This increase is a consequence of increased SNGFR. We speculate that increased FFSS caused by reduced nephron number contributes to podocyte injury and promotes the progression of CKD.
|
|
| 13. |
- Ulak, Manjeswori, et al.
(författare)
-
Infant feeding practices in Bhaktapur, Nepal: A cross-sectional, health facility based survey.
- 2012
-
Ingår i: International breastfeeding journal. - : Springer Science and Business Media LLC. - 1746-4358. ; 7:1, s. 1-8
-
Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Promotion of proper breastfeeding practices for the first six months of life is the most cost-effective intervention for reducing childhood morbidity and mortality. However, the adherence to breastfeeding recommendations in many developing countries is not satisfactory. The aims of the study were to determine breastfeeding and infant feeding patterns at nine months of age and to assess factors influencing exclusive breastfeeding practices. METHODS: In Bhaktapur, Nepal, we carried out a cross-sectional survey of 325 infants who came for measles vaccination at the age of nine months. Mothers were interviewed on details regarding feeding of their child and health since birth. RESULTS: Three quarters of all mothers reported that they did not receive any information on breastfeeding during the antenatal visit. Two hundred and ninety five (91%) mothers gave colostrum and 185 (57%) initiated breastfeeding within one hour of delivery. The prevalence of exclusively breastfeeding at 1, 3 and 6 months were 240 (74%), 78 (24%) and 29 (9%), and partial feeding was initiated in 49 (15%), 124 (38%) and 257 (79%) babies, respectively. The main reason, according to the mother, for introducing other foods before six months of age was insufficient breast milk. In logistic regression analyses, mother's knowledge on how long child should be given only breast milk and not living in joint families were associated positively with exclusive or predominant breastfeeding for four months or beyond. CONCLUSIONS: Despite the high proportion of mothers who initiated breastfeeding immediately after birth, continuation of exclusive breastfeeding for up to six months was not common. Very few mothers received any information on breastfeeding during the antenatal visit, indicating a need for counseling on exclusive breastfeeding. Possible options for this counseling could be during antenatal visits and at regular clinic visits for vaccination.
|
|
| 14. |
- Upadhayaya, Ram Shankar, et al.
(författare)
-
Conformationally-constrained indeno[2,1-c]quinolines : a new class of anti-mycobacterial agents
- 2010
-
Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 8:9, s. 2180-2197
-
Tidskriftsartikel (refereegranskat)abstract
- The design, synthesis and anti-mycobacterial activities of 23 conformationally-constrained indeno[2,1-c]quinolines against Mycobacterium tuberculosis H37Rv is reported. Based on a structural comparison with the anti-TB TMC207 we have devised a synthetic methodology for making new conformationally-constrained indeno[2,1-c] quinoline analogs (Fig. 1), by retaining the biologically significant quinoline and the phenyl rings in the SW and NW hemispheres, respectively. This new class of conformationally-constrained compounds has been designed such that their conformational flexibility across C4-C2' is diminished to nil by covalently locking the C4 center of the quinoline moiety in the SW hemisphere with the C2' center of the phenyl ring in the NW hemisphere, thereby decreasing the entropic penalty for their complex formation within the target protein, which will in turn give improved free-energy of stabilization of the complex. The efficacies of these anti-TB compounds were evaluated in vitro for 8/9 consecutive days using the BACTEC radiometric assay upon administration of a single-dose on day one. Compounds 11, 13, 16, 24, 30, 32 and 34 showed 85-99% growth inhibition of Mycobacterium tuberculosis. Compounds 13 and 34 however have inhibited the mycobacterial growth more effectively than others in the series, with minimum inhibitory concentrations (MIC) of 0.39 mu g mL(-1) (1 mu M) and 0.78 mu g mL(-1) (2 mu M) respectively.
|
|
| 15. |
- Upadhayaya, Ram Shankar, et al.
(författare)
-
New antiprotozoal agents : Their synthesis and biological evaluations
- 2013
-
Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 23:9, s. 2750-2758
-
Tidskriftsartikel (refereegranskat)abstract
- Here we report identification of new lead compounds based on quinoline and indenoquinolines with variable side chains as antiprotozoal agents. Quinolines 32, 36 and 37 (Table 1) and indenoquinoline derivatives 14 and 23 (Table 2) inhibit the in vitro growth of the Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma brucei rhodesiense subspecies and Leishmania infantum with IC50 = 0.25 mu M. These five compounds have superior activity to that of the front-line drugs such as benznidazole, nifurtimox and comparable to amphotericin B. Thus these compounds constitute new 'leads' for further structure-activity studies as potential active antiprotozoal agents.
|
|
| 16. |
- Upadhayaya, Ram Shankar, et al.
(författare)
-
Synthesis and antimycobacterial activity of prodrugs of indeno[2,1-c]quinoline derivatives
- 2011
-
Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 46:4, s. 1306-1324
-
Tidskriftsartikel (refereegranskat)abstract
- Recently we have reported anti-TB properties of a new class of conformationally-constrained indeno[2,1-c]quinolines, which are although considerably active (MIC 0.39-0.78 mu g/mL) suffered from intense solubility problems. We thought of improving their bioavailability by prodrugs approach. Accordingly esters of the "Lead" indeno[2,1-c]quinolines 1,15 and 27 derivatives were synthesized and their prodrug nature at the physiological pH were confirmed. Prodrugs were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv by MABA assay to show that they have 2- to 4-fold improved anti-TB activities, increased aqueous solubility and superior selectivity index over their respective parent compounds. MIC of these prodrugs was in the range of <0.20-6.0 mu g/mL and in general, no cytotoxicity was observed in VERO cells.
|
|
| 17. |
|
|
| 18. |
|
|
