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821.
Denise M. Kenski Abby J. Cooper Jenny J. Li Aarron T. Willingham Henry J. Haringsma Tracy A. Young Nelly A. Kuklin Jeffrey J. Jones Mark T. Cancilla Daniel R. McMasters Melina Mathur Alan B. Sachs W. Michael Flanagan 《Nucleic acids research》2010,38(2):660-671
Small interfering RNAs (siRNAs) are short, double-stranded RNAs that use the endogenous RNAi pathway to mediate gene silencing. Phosphorylation facilitates loading of a siRNA into the Ago2 complex and subsequent cleavage of the target mRNA. In this study, 2′, 3′ seco nucleoside modifications, which contain an acylic ribose ring and are commonly called unlocked nucleic acids (UNAs), were evaluated at all positions along the guide strand of a siRNA targeting apolipoprotein B (ApoB). UNA modifications at positions 1, 2 and 3 were detrimental to siRNA activity. UNAs at positions 1 and 2 prevented phosphorylation by Clp1 kinase, abrogated binding to Ago2, and impaired Ago2-mediated cleavage of the mRNA target. The addition of a 5′-terminal phosphate to siRNA containing a position 1 UNA restored ApoB mRNA silencing, Ago2 binding, and Ago2 mediated cleavage activity. Position 1 UNA modified siRNA containing a 5′-terminal phosphate exhibited a partial restoration of siRNA silencing activity in vivo. These data reveal the complexity of interpreting the effects of chemical modification on siRNA activity, and exemplify the importance of using multiple biochemical, cell-based and in vivo assays to rationally design chemically modified siRNA destined for therapeutic use. 相似文献
822.
Contrasting population structure from nuclear intron sequences and mtDNA of humpback whales 总被引:21,自引:4,他引:21
Powerful analyses of population structure require information from multiple
genetic loci. To help develop a molecular toolbox for obtaining this
information, we have designed universal oligonucleotide primers that span
conserved intron-exon junctions in a wide variety of animal phyla. We test
the utility of exon-primed, intron-crossing amplifications by analyzing the
variability of actin intron sequences from humpback, blue, and bowhead
whales and comparing the results with mitochondrial DNA (mtDNA) haplotype
data. Humpback actin introns fall into two major clades that exist in
different frequencies in different oceanic populations. It is surprising
that Hawaii and California populations, which are very distinct in mtDNAs,
are similar in actin intron alleles. This discrepancy between mtDNA and
nuclear DNA results may be due either to differences in genetic drift in
mitochondrial and nuclear genes or to preferential movement of males, which
do not transmit mtDNA to offspring, between separate breeding grounds.
Opposing mtDNA and nuclear DNA results can help clarify otherwise hidden
patterns of structure in natural populations.
相似文献
823.
Sam Hodgson Qin Qin Huang Neneh Sallah Genes Health Research Team Chris J. Griffiths William G. Newman Richard C. Trembath John Wright R. Thomas Lumbers Karoline Kuchenbaecker David A. van Heel Rohini Mathur Hilary C. Martin Sarah Finer 《PLoS medicine》2022,19(5)
BackgroundType 2 diabetes (T2D) is highly prevalent in British South Asians, yet they are underrepresented in research. Genes & Health (G&H) is a large, population study of British Pakistanis and Bangladeshis (BPB) comprising genomic and routine health data. We assessed the extent to which genetic risk for T2D is shared between BPB and European populations (EUR). We then investigated whether the integration of a polygenic risk score (PRS) for T2D with an existing risk tool (QDiabetes) could improve prediction of incident disease and the characterisation of disease subtypes.Methods and findingsIn this observational cohort study, we assessed whether common genetic loci associated with T2D in EUR individuals were replicated in 22,490 BPB individuals in G&H. We replicated fewer loci in G&H (n = 76/338, 22%) than would be expected given power if all EUR-ascertained loci were transferable (n = 101, 30%; p = 0.001). Of the 27 transferable loci that were powered to interrogate this, only 9 showed evidence of shared causal variants. We constructed a T2D PRS and combined it with a clinical risk instrument (QDiabetes) in a novel, integrated risk tool (IRT) to assess risk of incident diabetes. To assess model performance, we compared categorical net reclassification index (NRI) versus QDiabetes alone. In 13,648 patients free from T2D followed up for 10 years, NRI was 3.2% for IRT versus QDiabetes (95% confidence interval (CI): 2.0% to 4.4%). IRT performed best in reclassification of individuals aged less than 40 years deemed low risk by QDiabetes alone (NRI 5.6%, 95% CI 3.6% to 7.6%), who tended to be free from comorbidities and slim. After adjustment for QDiabetes score, PRS was independently associated with progression to T2D after gestational diabetes (hazard ratio (HR) per SD of PRS 1.23, 95% CI 1.05 to 1.42, p = 0.028). Using cluster analysis of clinical features at diabetes diagnosis, we replicated previously reported disease subgroups, including Mild Age-Related, Mild Obesity-related, and Insulin-Resistant Diabetes, and showed that PRS distribution differs between subgroups (p = 0.002). Integrating PRS in this cluster analysis revealed a Probable Severe Insulin Deficient Diabetes (pSIDD) subgroup, despite the absence of clinical measures of insulin secretion or resistance. We also observed differences in rates of progression to micro- and macrovascular complications between subgroups after adjustment for confounders. Study limitations include the absence of an external replication cohort and the potential biases arising from missing or incorrect routine health data.ConclusionsOur analysis of the transferability of T2D loci between EUR and BPB indicates the need for larger, multiancestry studies to better characterise the genetic contribution to disease and its varied aetiology. We show that a T2D PRS optimised for this high-risk BPB population has potential clinical application in BPB, improving the identification of T2D risk (especially in the young) on top of an established clinical risk algorithm and aiding identification of subgroups at diagnosis, which may help future efforts to stratify care and treatment of the disease.Sam Hodgson and colleagues investigate whether the common genetic differences associated with type 2 diabetes in people of European ancestry can be transferred to people of British Pakistani and Bangladeshi ancestry, integrating a novel polygenic risk score with an established clinical risk score. 相似文献
824.
Shruti Mathur Prashant Deshmukh Shailesh Tripathi Palaniappan Marimuthu 《Journal of biomolecular structure & dynamics》2018,36(9):2342-2360
Bromodomain and extra-terminal family proteins recognize the acetylated histone code on chromatin and participate in downstream processes like DNA replication, modification, and repair. As part of epigenetic approaches, BRD2 and BRD4 were identified as putative targets, for the management of chronic diseases. We have recently reported the discovery of a new scaffold of the phenanthridinone-based inhibitor (L10) of the second bromodomain of BRD2 (BRD2-BD2). Here, we present the crystal structure of the BRD2-BD2, refined to 1.4 Å resolution, in complex with β-mercaptoethanol (a component of the protein buffer). The β-mercaptoethanol covalently links to C425 of BD2 in the acetyl-lysine binding pocket, to form a modified cysteine mercaptoethanol (CME). The CME modification significantly hinders the entry of ligands into the BD2 binding pocket, suggesting that β-mercaptoethanol should be removed during protein production process. Next, to confirm whether phenanthridionone scaffold is a new inhibitor family of BRD2-BD2, we have determined the crystal structure of BD2 in complex with 6(5H)-Phenanthridinone (a core moiety of L10), refined to 1.28 Å resolution. It confirmed that the phenanthridinone molecule, unambiguously, binds to BD2. Moreover, we performed molecular docking and molecular dynamic studies on selected phenanthridinone analogs. The predicted L10 analogs are stable with essential hydrophobic and hydrophilic interactions with BD2 during molecular dynamic simulations. We propose that the predicted phenanthridinone analogs may be potential molecules for inhibiting the BD2 function of acetylated histone recognition. 相似文献
825.
Nathan A. Gillespie Amanda Elswick Gentry Robert M. Kirkpatrick Chandra A. Reynolds Ravi Mathur Kenneth S. Kendler Hermine H. Maes Bradley T. Webb Roseann E. Peterson 《PLoS genetics》2022,18(8)
Genome-wide association studies (GWAS) have successfully identified common variants associated with BMI. However, the stability of aggregate genetic variation influencing BMI from midlife and beyond is unknown. By analysing 165,717 men and 193,073 women from the UKBiobank, we performed BMI GWAS on six independent five-year age intervals between 40 and 72 years. We then applied genomic structural equation modeling to test competing hypotheses regarding the stability of genetic effects for BMI. LDSR genetic correlations between BMI assessed between ages 40 to 73 were all very high and ranged 0.89 to 1.00. Genomic structural equation modeling revealed that molecular genetic variance in BMI at each age interval could not be explained by the accumulation of any age-specific genetic influences or autoregressive processes. Instead, a common set of stable genetic influences appears to underpin genome-wide variation in BMI from middle to early old age in men and women alike. 相似文献
826.
Jaideep Mathur 《Plant physiology》2021,185(3):593
The life strategy of plants includes their ability to respond quickly at the cellular level to changes in their environment. The use of targeted fluorescent protein probes and imaging of living cells has revealed several rapidly induced organelle responses that create the efficient sub-cellular machinery for maintaining homeostasis in the plant cell. Several organelles, including plastids, mitochondria, and peroxisomes, extend and retract thin tubules that have been named stromules, matrixules, and peroxules, respectively. Here, I combine all these thin tubular forms under the common head of organelle extensions. All extensions change shape continuously and in their elongated form considerably increase organelle outreach into the surrounding cytoplasm. Their pleomorphy reflects their interactions with the dynamic endoplasmic reticulum and cytoskeletal elements. Here, using foundational images and time-lapse movies, and providing salient information on some molecular and biochemically characterized mutants with increased organelle extensions, I draw attention to their common role in maintaining homeostasis in plant cells.Dynamic tubules extended from different organelles are integral components of the rapid subcellular response machinery involved in maintaining optimal working conditions within plant cells. 相似文献
827.
Undernutrition during suckling was induced in newborn rats by increasing the litter size to sixteen pups to be fed by one mother. Animals reared in litters of eight served as controls. Undernourished animals showed retarded body and testicular growth during a suckling period of 22 days. Sequential morphogenesis of the testis was not altered up to 15 days of age. However, certain morphological alterations in Sertoli cells and Leydig cells were observed from 15 days onwards. Cell generation cycle of spermatogonial germ cells and supporting cells (future Sertoli cells) on day 9 showed marked prolongation of DNA synthetic phase (S), unaltered post-DNA synthetic phase (G2) and total cycle (Tc) and shortening of the pre-DNA synthetic phase (G1) indicating a depression in DNA synthesis in undernutrition. 相似文献
828.
829.
830.
R Raghubir G K Patnaik B J Dhotre K B Mathur M M Dhar B N Dhawan 《Indian journal of experimental biology》1989,27(9):826-828
Opioid activity of a homologous series of met-enkephalin alkylamides was analysed. In guinea pig ileum test, the hexylamide derivative was most active, whereas the isopropylamide derivative was most potent in analgesia test. The results suggest that structural changes of this type at the C-terminus of the pentapeptide improve the opioid activity. 相似文献