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991.
Zhang M Bailey DL Bastian JA Briggs SL Chirgadze NY Clawson DK Denney ML Gifford-Moore DS Harper RW Johnson LM Klimkowski VJ Kohn TJ Lin HS McCowan JR Richett ME Sall DJ Smith AJ Smith GF Snyder DW Takeuchi K Utterback BG Yan SC 《Bioorganic & medicinal chemistry letters》1999,9(5):775-780
Potent, subnanomolar thrombin inhibitors 4, 5, and 6 are developed through side chain optimization of novel, benzo[b]thiophene-based small organic entities 2 and 3 and through SAR additivity studies of the new structural elements identified. X-ray crystallographic studies of 4b-thrombin complex revealed a hydrophobic and an electrostatic interaction of these new elements with thrombin at the S2 and S3 binding sites. In vitro and in vivo pharmacological studies showed that 4, 5, and 6 are potent anticoagulants in human plasma with demonstrated antithrombotic efficacy in a rat model of thrombosis. 相似文献
992.
S. M. Mijan Uddin Nicholas R. R. Daniel Richard J. Harper David J. Henry 《Biogeochemistry》2017,134(1-2):147-161
Biogenic volatile organic compounds (BVOCs) are continually emitted from plants and are also a component of smoke during vegetation fire. Although vegetation fire events have been shown to have implications for the dynamics of soil water repellency (SWR) and there have been anecdotal reports that forest smoke can induce water repellency, the role of BVOCs in this process has not been explored. Accordingly, we investigated a selection of major BVOCs (cis-3-hexen-1-ol; levoglucosenone; 2-methyl-3-buten-2-ol; cineole; α-phellandrene; α-terpinene) that are emitted from the dominant native vegetation of Australia during fire. The potential of each compound to induce SWR was investigated by applying different loadings on acid washed sand (AWS) (300–350 µm diameter) and then assessing water repellency with the molarity of ethanol drop test. A long-chain amphiphilic molecule (palmitic acid) was also applied to AWS for comparison. Although palmitic acid was effective at inducing water repellency, the BVOCs were not, even at high loadings (5 × 10?4 mol g?1). Fully atomistic molecular dynamics simulations complemented the experimental measurements. These studies suggested that poor expression of water repellency by the BVOCs could be explained by their tendency to exhibit weak interactions towards the quartz surface but strong molecule–molecule attractions. In comparison, the long-chain amphiphilic molecules exhibited a balance between molecule–molecule and molecule–surface interactions that favored surface adhesion, which in turn led to the formation of a hydrophobic layer. 相似文献
993.
Documentation of use patterns of plants across national boundaries is of relevance in understanding the importance of plant resources to livelihood strategies of different ethnic groups. Plant resources have gained prominence as a natural asset through which families derive food, firewood, income, medicines and timber, enabling particularly poor communities to achieve self-sufficiency. The objective of this study was to investigate the trends in plant usage in South Africa and Zimbabwe. An ethnobotanical investigation was conducted between January 2012 and January 2013 in the Limpopo Province, South Africa and the Midlands Province, Zimbabwe. The study used questionnaire surveys and interviews with a total of 143 participants to explore plant use patterns in South Africa and Zimbabwe. A total of 98 plant species were identified, with Zimbabwe contributing 70 species and 47 species from South Africa. The uses were classified into 15 categories, major use categories were firewood, food plants, medicine and timber. Food plant was a major plant use category in Zimbabwe, contributing 55.1%, followed by medicinal plants (36.8%), firewood (35.7%) and timber (31.6%). In contrast, firewood was the major plant use category in South Africa, contributing 18.4%, followed by food plants (17.3%), medicinal (14.3%) and timber (1.0%). Comparison of the two countries demonstrated remarkable differences in plant use patterns. The results showed that rural households in Zimbabwe were more reliant on plant resources than their counterparts in South Africa. Such a trend could be attributed to a close relationship between the local people, and their natural and agricultural environment leading to a rich knowledge base on plants, plant use and related practices. This comparative analysis strengthens the firm belief that utilization of plant resources represents an important shared heritage, preserved over the centuries, which must be exploited in order to provide further new and useful body of ethnobotanical knowledge. 相似文献
994.
995.
Bart H. Harper Liping Wang Cheng Zhu Nam F. Kar Bing Li Christopher R. Moyes Stephen D. Goble Melissa Costa Karen Dingley Jerry Di Salvo Sookhee N. Ha Amanda Hurley Xiaofang Li Randy R. Miller Hiroshi Nagabukuro Gino M. Salituro Sean Smith Mary Struthers Richard Berger 《Bioorganic & medicinal chemistry letters》2017,27(4):1094-1098
The synthesis of a novel class of piperazine benzamide (reverse amides) targeting the human β3-adrenergic receptor for the treatment of overactive bladder (OAB) is described. The SAR studies directed towards maintaining well established β3 potency and selectivities while improving the overall pharmacokinetic profile in the reverse amide class will be evaluated. The results and consequences associated with functional activity at the norepinephrine transporter (NET) will also be discussed. 相似文献
996.
Aim: To determine the stability and variability in concentration of spore suspensions of Bacillus anthracis (BA) spore suspensions by comparing different methods of enumeration and to detect changes, if any, under different storage conditions. Methods and Results: Plate and microscope counts were compared to measuring the genomic equivalents based on DNA content BA spore suspensions. We developed chemical methods to extract spore DNA and extra-spore (ES) DNA. DNA mass was determined by gel electrophoresis and QPCR assays were developed using the markers on the chromosome (rpoB) and the pXO1 plasmid (pag). The plate counts and microscope counts were very stable (for up to 900 days). The effect of freezing and the presence of additives in samples were tested for up to 300 days, and the results indicated that the additives tested and freezing did not decrease the viability or microscope counts. Conclusions: Bacillus anthracis spore suspensions can be stored for long periods of time without significant loss of viability or clumping. The content of ES DNA was variable and changed with time. Significant and Impact of the Study: The study shows that BA spore suspensions can be developed for reference materials providing a uniform basis for comparing detection equipment and results from different laboratories. 相似文献
997.
Sheedy D Garrick T Dedova I Hunt C Miller R Sundqvist N Harper C 《Cell and tissue banking》2008,9(3):205-216
Research into neuropsychiatric disorders, including alcohol-related problems, is limited in part by the lack of appropriate animal models. However, the development of new technologies in pathology and molecular biology means that many more questions can be addressed using appropriately stored human brain tissues. The New South Wales Tissue Resource Centre (TRC) in the University of Sydney (Australia) is a human brain bank that can provide tissues to the neuroscience research community studying alcohol-related brain disorders, schizophrenia, depression and bipolar disorders. Carefully standardised operational protocols and integrated information systems means that the TRC can provide high quality, accurately characterised, tissues for research. A recent initiative, the pre-mortem donor program called "Using our Brains", encourages individuals without neuropsychiatric illness to register as control donors, a critical group for all research. Community support for this program is strong with over 2,000 people registering their interest. Discussed herein are the protocols pertaining to this multifaceted facility and the benefits of investment, both scientific and financial, to neuroscience researchers and the community at large. 相似文献
998.
Harper KN Ocampo PS Steiner BM George RW Silverman MS Bolotin S Pillay A Saunders NJ Armelagos GJ 《PLoS neglected tropical diseases》2008,2(1):e148
Background
Since the first recorded epidemic of syphilis in 1495, controversy has surrounded the origins of the bacterium Treponema pallidum subsp. pallidum and its relationship to the pathogens responsible for the other treponemal diseases: yaws, endemic syphilis, and pinta. Some researchers have argued that the syphilis-causing bacterium, or its progenitor, was brought from the New World to Europe by Christopher Columbus and his men, while others maintain that the treponematoses, including syphilis, have a much longer history on the European continent.Methodology/Principal Findings
We applied phylogenetics to this problem, using data from 21 genetic regions examined in 26 geographically disparate strains of pathogenic Treponema. Of all the strains examined, the venereal syphilis-causing strains originated most recently and were more closely related to yaws-causing strains from South America than to other non-venereal strains. Old World yaws-causing strains occupied a basal position on the tree, indicating that they arose first in human history, and a simian strain of T. pallidum was found to be indistinguishable from them.Conclusions/Significance
Our results lend support to the Columbian theory of syphilis''s origin while suggesting that the non-sexually transmitted subspecies arose earlier in the Old World. This study represents the first attempt to address the problem of the origin of syphilis using molecular genetics, as well as the first source of information regarding the genetic make-up of non-venereal strains from the Western hemisphere. 相似文献999.
Wither J Cai YC Lim S McKenzie T Roslin N Claudio JO Cooper GS Hudson TJ Paterson AD Greenwood CM Gladman D Pope J Pineau CA Smith CD Hanly JG Peschken C Boire G;CaNIOS Investigators Fortin PR 《Arthritis research & therapy》2008,10(5):R108-13
Introduction
Systemic lupus erythematosus is a genetically complex disease. Currently, the precise allelic polymorphisms associated with this condition remain largely unidentified. In part this reflects the fact that multiple genes, each having a relatively minor effect, act in concert to produce disease. Given this complexity, analysis of subclinical phenotypes may aid in the identification of susceptibility alleles. Here, we used flow cytometry to investigate whether some of the immune abnormalities that are seen in the peripheral blood lymphocyte population of lupus patients are seen in their first-degree relatives.Methods
Peripheral blood mononuclear cells were isolated from the subjects, stained with fluorochrome-conjugated monoclonal antibodies to identify various cellular subsets, and analyzed by flow cytometry.Results
We found reduced proportions of natural killer (NK)T cells among 367 first-degree relatives of lupus patients as compared with 102 control individuals. There were also slightly increased proportions of memory B and T cells, suggesting increased chronic low-grade activation of the immune system in first-degree relatives. However, only the deficiency of NKT cells was associated with a positive anti-nuclear antibody test and clinical autoimmune disease in family members. There was a significant association between mean parental, sibling, and proband values for the proportion of NKT cells, suggesting that this is a heritable trait.Conclusions
The findings suggest that analysis of cellular phenotypes may enhance the ability to detect subclinical lupus and that genetically determined altered immunoregulation by NKT cells predisposes first-degree relatives of lupus patients to the development of autoimmunity. 相似文献1000.
Maria Pino Susan Pereira Ribeiro Amlie Pagliuzza Khader Ghneim Anum Khan Emily Ryan Justin L. Harper Colin T. King Sarah Welbourn Luca Micci Sol Aldrete Keith A. Delman Theron Stuart Michael Lowe Jason M. Brenchley Cynthia A. Derdeyn Kirk Easley Rafick P. Sekaly Nicolas Chomont Mirko Paiardini Vincent C. Marconi 《PLoS pathogens》2021,17(8)
Clinical outcomes are inferior for individuals with HIV having suboptimal CD4 T-cell recovery during antiretroviral therapy (ART). We investigated if the levels of infection and the response to homeostatic cytokines of CD4 T-cell subsets contributed to divergent CD4 T-cell recovery and HIV reservoir during ART by studying virologically-suppressed immunologic responders (IR, achieving a CD4 cell count >500 cells/μL on or before two years after ART initiation), and virologically-suppressed suboptimal responders (ISR, did not achieve a CD4 cell count >500 cells/μL in the first two years after ART initiation). Compared to IR, ISR demonstrated higher levels of HIV-DNA in naïve, central (CM), transitional (TM), and effector (EM) memory CD4 T-cells in blood, both pre- and on-ART, and specifically in CM CD4 T-cells in LN on-ART. Furthermore, ISR had higher pre-ART plasma levels of IL-7 and IL-15, cytokines regulating T-cell homeostasis. Notably, pre-ART PD-1 and TIGIT expression levels were higher in blood CM and TM CD4 T-cells for ISR; this was associated with a significantly lower fold-changes in HIV-DNA levels between pre- and on-ART time points exclusively on CM and TM T-cell subsets, but not naïve or EM T-cells. Finally, the frequency of CM CD4 T-cells expressing PD-1 or TIGIT pre-ART as well as plasma levels of IL-7 and IL-15 predicted HIV-DNA content on-ART. Our results establish the association between infection, T-cell homeostasis, and expression of PD-1 and TIGIT in long-lived CD4 T-cell subsets prior to ART with CD4 T-cell recovery and HIV persistence on-ART. 相似文献