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71.
Small molecule inhibitors of type 1 receptor serine threonine kinases (ALKs1-7), the mediators of TGFß and BMP signals, have been employed extensively to assess their physiological roles in cells and organisms. While all of these inhibitors have been reported as “selective” inhibitors of specific ALKs, extensive specificity tests against a wide array of protein kinases have not been performed. In this study, we examine the specificities and potencies of the most frequently used small molecule inhibitors of the TGFß pathway (SB-431542, SB-505124, LY-364947 and A-83-01) and the BMP pathway (Dorsomorphin and LDN-193189) against a panel of up to 123 protein kinases covering a broad spectrum of the human kinome. We demonstrate that the inhibitors of the TGFß pathway are relatively more selective than the inhibitors of the BMP pathway. Based on our specificity and potency profile and published data, we recommend SB-505124 as the most suitable molecule for use as an inhibitor of ALKs 4, 5 and 7 and the TGFß pathway. We do not recommend Dorsomorphin, also called Compound C, for use as an inhibitor of the BMP pathway. Although LDN-193189, a Dorsomorphin derivative, is a very potent inhibitor of ALK2/3 and the BMP-pathway, we found that it potently inhibited a number of other protein kinases at concentrations sufficient to inhibit ALK2/3 and its use as a selective BMP-pathway inhibitor has to be considered cautiously. Our observations have highlighted the need for caution when using these small molecule inhibitors to assess the physiological roles of BMP and TGFß pathways. 相似文献
72.
Fluge Ø Bruland O Risa K Storstein A Kristoffersen EK Sapkota D Næss H Dahl O Nyland H Mella O 《PloS one》2011,6(10):e26358
Background
Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.Methods and Findings
In this double-blind, placebo-controlled phase II study (), 30 CFS patients were randomised to either Rituximab 500 mg/m2 or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients.The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8–44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6–10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening. NCT00848692Conclusion
The delayed responses starting from 2–7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS.Trial registration
ClinicalTrials.gov NCT00848692相似文献73.
Purification and characterization of fibrinolytic enzyme from cultured mycelia of Armillaria mellea 总被引:9,自引:0,他引:9
Lee SY Kim JS Kim JE Sapkota K Shen MH Kim S Chun HS Yoo JC Choi HS Kim MK Kim SJ 《Protein expression and purification》2005,43(1):10-17
A fibrinolytic enzyme was purified from the cultured mycelia of Armillaria mellea by ion-exchange chromatography followed by gel filtration, and was designated A. mellea metalloprotease (AMMP). The purification protocol resulted in a 627-fold purification of the enzyme, with a final yield of 6.05%. The apparent molecular mass of the purified enzyme was estimated to be 21kDa by SDS-PAGE, fibrin-zymography and gel filtration chromatography, which revealed a monomeric form of the enzyme. The optimal reaction pH value and temperature were, pH 6.0, and 33 degrees C, respectively. This protease effectively hydrolyzed fibrinogen, preferentially digesting the Aalpha-chain over the Bbeta- and r-chains. Enzyme activity was inhibited by Cu(2+) and Co(2+), but enhanced by the addition of Ca(2+) and Mg(2+) ions. Furthermore, AMMP activity was potently inhibited by EDTA, and was found to exhibit a higher specificity for the substrate S-2586 for chymotrypsin, indicating that the enzyme is a chymotrypsin-like metalloprotease. The first 24 amino acid residues of the N-terminal sequence were MFSLSSRFFLYTLCL SAVAVSAAP, which is extremely similar to the 24 amino acid residues of the N-terminal sequence of the fruiting body of A. mellea. These data suggest that the fibrinolytic enzyme AMMP, obtained from the A. mellea exhibits a profound fibrinolytic activity. The mycelia of A. mellea may thus represent a potential source of new therapeutic agents to treat thrombosis. 相似文献
74.
Urmila Dyola Chitra Bahadur Baniya Pushpa Raj Acharya Pradip Subedi Anjeela Pandey Kumar Sapkota 《Ecology and evolution》2022,12(3)
Insect pollinators are important means for a stable ecosystem. The habitat types play a crucial role in the community composition, abundance, diversity, and species richness of the pollinators. The present study in Shivapuri‐Nagarjun National Park explored the species richness and abundances of insect pollinators in four different habitats and different environmental variables in determining the community composition of the pollinators. Data were collected from 1,500 m to 2,700 m using color pan traps and hand sweeping methods. Non‐Metric Multidimensional Scaling (NMDS) and Redundancy Analysis (RDA) were conducted to show the association between insect pollinators and environmental variables. The results firmly demonstrated that species richness and abundances were higher (158) in Open trail compared to other habitats. The distribution of the pollinator species was more uniform in the Open trail followed by the Grassland. Similarly, a strong positive correlation between flower resources and pollinators'' abundance (R2 = .63, P < .001) was found. In conclusion, the Open trail harbors rich insect pollinators in lower elevation. The community structure of the pollinators was strongly influenced by the presence of flowers in the trails. 相似文献
75.
Penaeid and carid communities were assessed in St Lucia over a wide range of saline conditions, water level conditions and mouth states, including a six-month marine connection and various connections to the Mfolozi Estuary. Samples were collected biannually in spring and autumn from November 2004 to May 2012 using seine nets. Seven penaeid and seven carid species were recorded, of which Palaemon pacificus, P. peringueyi, Penaeus indicus and Metapenaeus monoceros were the most abundant. The decline from 2004 to 2007 in both species recorded and densities of freshwater, estuarine and marine species during the initial closed period was linked to increased salinity, lack of recruitment and reduced estuarine surface area. Increased wave action and high seas following Cyclone Gamede opened the mouth in March 2007 after a 57-month closed period, resulting in recruitment of marine species, predominantly P. indicus, followed by a decline in densities after reclosure in August 2007. Increases in marine and freshwater species were evident after Mfolozi flood connections during 2008, 2009 and 2010. Highest densities were recorded after breaching in 2007 and after flood connections, highlighting the importance of a marine link to maintain the recruitment of penaeid species. 相似文献
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77.
Crystal Romeo Upperman Jennifer Parker Chengsheng Jiang Xin He Raghuram Murtugudde Amir Sapkota 《PloS one》2015,10(12)
Epidemiological investigation of the impact of climate change on human health, particularly chronic diseases, is hindered by the lack of exposure metrics that can be used as a marker of climate change that are compatible with health data. Here, we present a surrogate exposure metric created using a 30-year baseline (1960–1989) that allows users to quantify long-term changes in exposure to frequency of extreme heat events with near unabridged spatial coverage in a scale that is compatible with national/state health outcome data. We evaluate the exposure metric by decade, seasonality, area of the country, and its ability to capture long-term changes in weather (climate), including natural climate modes. Our findings show that this generic exposure metric is potentially useful to monitor trends in the frequency of extreme heat events across varying regions because it captures long-term changes; is sensitive to the natural climate modes (ENSO events); responds well to spatial variability, and; is amenable to spatial/temporal aggregation, making it useful for epidemiological studies. 相似文献
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79.
Brienna L. Anderson-Coughlin Shani Craighead Alyssa Kelly Samantha Gartley Adam Vanore Gordon Johnson Chengsheng Jiang Joseph Haymaker Chanelle White Derek Foust Rico Duncan Cheryl East Eric T. Handy Rhodel Bradshaw Rianna Murray Prachi Kulkarni Mary Theresa Callahan Sultana Solaiman Walter Betancourt Charles Gerba Sarah Allard Salina Parveen Fawzy Hashem Shirley A. Micallef Amir Sapkota Amy R. Sapkota Manan Sharma Kalmia E. Kniel 《Applied and environmental microbiology》2021,87(13)
80.
Joann Conner Sirjan Sapkota Stéphane Deschamps Kevin Fengler Mark Cigan Peggy Ozias-Akins 《Molecular breeding : new strategies in plant improvement》2016,36(5):60
Apospory is a form of gametophytic apomixis in which embryos develop from unreduced embryo sacs derived from aposporous initials formed from nucellar cells of ovules to produce offspring genetically identical to the female plant. Apospory in Pennisetum squamulatum (8X) and Cenchrus ciliaris (4X) is a dominant trait controlled by a physically large, hemizygous, heterochromatic chromosomal block called the apospory-specific genomic region (ASGR). Both apomictic species are polyploid, with genome sizes estimated at 2600 to 3000 Mbp for C. ciliaris and 9400 to 10,300 Mbp for P. squamulatum. A study was conducted to determine whether duplex-specific nuclease (DSN) normalization of DNA from apomictic and sexual genotypes would reduce repetitive sequences and allow bioinformatic analysis to predict sequence contigs derived from the ASGR. DSN libraries from four genotypes were sequenced using Illumina® HiSeq 2000 technology. 39 out of 44 tested sequence characterized amplified region (SCAR) markers from in silico predicted ASGR-specific contigs were mapped to the ASGR in a Pennisetum F1 mapping population. Eighteen SCARs showed apomict-specific amplification in C. ciliaris. The successful mapping of ~90 % of the SCAR markers to the ASGR in the Pennisetum F1 mapping population shows that DSN normalization and Illumina sequencing can be used as an effective strategy for targeted mapping of a physically large locus rich in repetitive sequences, like that of the ASGR. 相似文献