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1.
mtDNA diversity in rhesus monkeys reveals overestimates of divergence time and paraphyly with neighboring species 总被引:4,自引:0,他引:4
Reconstructions of the human-African great ape phylogeny by using
mitochondrial DNA (mtDNA) have been subject to considerable debate. One
confounding factor may be the lack of data on intraspecific variation. To
test this hypothesis, we examined the effect of intraspecific mtDNA
diversity on the phylogenetic reconstruction of another Plio- Pleistocene
radiation of higher primates, the fascicularis group of macaque (Macaca)
monkey species. Fifteen endonucleases were used to identify 10 haplotypes
of 40-47 restriction sites in M. mulatta, which were compared with similar
data for the other members of this species group. Interpopulational,
intraspecific mtDNA diversity was large (0.5%- 4.5%), and estimates of
divergence time and branching order incorporating this variation were
substantially different from those based on single representatives of each
species. We conclude that intraspecific mtDNA diversity is substantial in
at least some primate species. Consequently, without prior information on
the extent of genetic diversity within a particular species, intraspecific
variation must be assessed and accounted for when reconstructing primate
phylogenies. Further, we question the reliability of hominoid mtDNA
phylogenies, based as they are on one or a few representatives of each
species, in an already depauperate superfamily of primates.
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2.
Mulji A Haslam C Brown F Randle R Karamshi B Smith J Eagle R Munoz-Muriedas J Taylor J Sheikh A Bridges A Gill K Jepras R Smee P Barker M Woodrow M Liddle J Thomas P Jones E Gordon L Tanner R Leveridge M Hutchinson S Martin M Brown M Kruidenier L Katso R 《Journal of biomolecular screening》2012,17(1):108-120
The biological complexity associated with the regulation of histone demethylases makes it desirable to configure a cellular mechanistic assay format that simultaneously encompasses as many of the relevant cellular processes as possible. In this report, the authors describe the configuration of a JMJD3 high-content cellular mechanistic imaging assay that uses single-cell multiparameter measurements to accurately assess cellular viability and the enzyme-dependent demethylation of the H3K27(Me)3 mark by exogenously expressed JMJD3. This approach couples robust statistical analyses with the spatial resolving power of cellular imaging. This enables segregation of expressing and nonexpressing cells into discrete subpopulations and consequently pharmacological quantification of compounds of interest in the expressing population at varying JMJD3 expression levels. Moreover, the authors demonstrate the utility of this hit identification strategy through the successful prosecution of a medium-throughput focused campaign of an 87 500-compound file, which has enabled the identification of JMJD3 cellular-active chemotypes. This study represents the first report of a demethylase high-content imaging assay with the ability to capture a repertoire of pharmacological tools, which are likely both to inform our mechanistic understanding of how JMJD3 is modulated and, more important, to contribute to the identification of novel therapeutic modalities for this demethylase enzyme. 相似文献
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Jane L Wagstaff Jonathan N Pruneda Stefan MV Freund David Komander 《The EMBO journal》2017,36(24):3555-3572
The Ser/Thr protein kinase PINK1 phosphorylates the well‐folded, globular protein ubiquitin (Ub) at a relatively protected site, Ser65. We previously showed that Ser65 phosphorylation results in a conformational change in which Ub adopts a dynamic equilibrium between the known, common Ub conformation and a distinct, second conformation wherein the last β‐strand is retracted to extend the Ser65 loop and shorten the C‐terminal tail. We show using chemical exchange saturation transfer (CEST) nuclear magnetic resonance experiments that a similar, C‐terminally retracted (Ub‐CR) conformation also exists at low population in wild‐type Ub. Point mutations in the moving β5 and neighbouring β‐strands shift the Ub/Ub‐CR equilibrium. This enabled functional studies of the two states, and we show that while the Ub‐CR conformation is defective for conjugation, it demonstrates improved binding to PINK1 through its extended Ser65 loop, and is a superior PINK1 substrate. Together our data suggest that PINK1 utilises a lowly populated yet more suitable Ub‐CR conformation of Ub for efficient phosphorylation. Our findings could be relevant for many kinases that phosphorylate residues in folded protein domains. 相似文献
5.
Background
The Evidence-Based Practice (EBP) Project has been investigating the implementation of evidence-based mental health practices (Assertive Community Treatment, Family Psychoeducation, Integrated Dual Diagnosis Treatment, Illness Management and Recovery, and Supported Employment) in state public mental health systems in the United States since 2001. To date, Project findings have yielded valuable insights into implementation strategy characteristics and effectiveness. This paper reports results of an effort to identify and classify state-level implementation activities and strategies employed across the eight states participating in the Project.Methods
Content analysis and Greenhalgh et al's (2004) definition of innovation were used to identify and classify state-level activities employed during three phases of EBP implementation: Pre-Implementation, Initial Implementation and Sustainability Planning. Activities were coded from site visit reports created from documents and notes from key informant interviews conducted during two periods, Fall 2002 – Spring 2003, and Spring 2004. Frequency counts and rank-order analyses were used to examine patterns of implementation activities and strategies employed across the three phases of implementation.Results
One hundred and six discreet implementation activities and strategies were identified as innovative and were classified into five categories: 1) state infrastructure building and commitment, 2) stakeholder relationship building and communications, 3) financing, 4) continuous quality management, and 5) service delivery practices and training. Implementation activities from different categories were employed at different phases of implementation.Conclusion
Insights into effective strategies for implementing EBPs in mental health and other health sectors require qualitative and quantitative research that seeks to: a) empirically test the effects of tools and methods used to implement EBPs, and b) establish a stronger evidence-base from which to plan, implement and sustain such efforts. This paper offers a classification scheme and list of innovative implementation activities and strategies. The classification scheme offers potential value for future studies that seek to assess the effects of various implementation processes, and helps establish widely accepted standards and criteria that can be used to assess the value of innovative activities and strategies. 相似文献6.
Tal Burt Savita Dhillon Pooja Sharma Danish Khan Deepa MV Sazid Alam Sarika Jain Bhavana Alapati Sanjay Mittal Padam Singh 《PloS one》2013,8(7)
Background
A public that is an informed partner in clinical research is important for ethical, methodological, and operational reasons. There are indications that the public is unaware or misinformed, and not sufficiently engaged in clinical research but studies on the topic are lacking. PARTAKE – Public Awareness of Research for Therapeutic Advancements through Knowledge and Empowerment is a program aimed at increasing public awareness and partnership in clinical research. The PARTAKE Survey is a component of the program.Objective
To study public knowledge and perceptions of clinical research.Methods
A 40-item questionnaire combining multiple-choice and open-ended questions was administered to 175 English- or Hindi-speaking individuals in 8 public locations representing various socioeconomic strata in New Delhi, India.Results
Interviewees were 18–84 old (mean: 39.6, SD±16.6), 23.6% female, 68.6% employed, 7.3% illiterate, 26.3% had heard of research, 2.9% had participated and 58.9% expressed willingness to participate in clinical research. The following perceptions were reported (% true/% false/% not aware): ‘research benefits society’ (94.1%/3.5%/2.3%), ‘the government protects against unethical clinical research’ (56.7%/26.3%/16.9%), ‘research hospitals provide better care’ (67.2%/8.7%/23.9%), ‘confidentiality is adequately protected’ (54.1%/12.3%/33.5%), ‘participation in research is voluntary’ (85.3%/5.8%/8.7%); ‘participants treated like ‘guinea pigs’’ (20.7%/53.2%/26.0%), and ‘compensation for participation is adequate’ (24.7%/12.9%/62.3%).Conclusions
Results suggest the Indian public is aware of some key features of clinical research (e.g., purpose, value, voluntary nature of participation), and supports clinical research in general but is unaware of other key features (e.g., compensation, confidentiality, protection of human participants) and exhibits some distrust in the conduct and reporting of clinical trials. Larger, cross-cultural surveys are required to inform educational programs addressing these issues. 相似文献7.
Michael J Leveridge 《Reviews in urology》2014,16(3):110-117
Social media have become so integrated into modern communications as to be universal in our personal and, increasingly, professional lives. Recent examples of social media uptake in urology, and the emergence of data to quantify it, reveal the expansion of conventional communication routes beyond the in-person forum. In every domain of urologic practice, from patient interaction through research to continuing professional development, the move online has unlocked another layer of conversation, dissemination, and, indeed, caveats. Social media have a democratizing effect, placing patients, trainees, practitioners, and thought leaders in the same arena and on equal footing. If uptake of social media in medicine even remotely parallels its rise to ubiquity in other areas, it will only expand and evolve in the coming years. For these reasons, this article presents an overview of the most recent data on the impact and potential complications of social media usage in the urologic community.Key words: Social media, Urologic practice, Education, Continuing professional development, Research publication and impactInterprofessional communication and continuing professional development of and by physicians have typically involved face-to face and in-person interaction, in meeting rooms or lecture halls. Dissemination of research findings has occurred through publication in print (and, more recently, online) journals, sifting through the editorial process and with limited potential for interaction; replies and queries regarding a study typically appear months after its initial publication. Citation in subsequent research papers is the foundation of measurement of a journal’s impact.Social media may be broadly defined as those Internet-based sites and services that are primarily conversational in nature. Users post information or opinion, and other users, either through curated access lists or public profiles, are able to comment on or share the original post. The standard bearers in the last several years have been services such as Facebook, boasting over 1 billion active users, and Twitter, with well over 200 million active users.1,2 Despite having, in large part, existed for less than a decade, these and many other services have become ubiquitous in personal and public life. In professional settings, however, uptake has been relatively guarded.3,4 Recent examples of social media uptake in urology, and the emergence of data to support it, reveal the expansion of conventional communication routes beyond the in-person forum. Journal clubs have emerged with international participation, and the use of Twitter at medical meetings has added a conversational element and dissemination potential that had not previously existed. Publication of research and measurement of its impact are also in evolution, with potential for rapid propagation of research findings and impact metrics at the article level. Concerns have emerged in step with these innovations, such as consternation about patient (and physician) privacy and boundaries, as well as risks of posting words or images that may be, or are perceived to be, unprofessional. 相似文献
8.
Richards GR Smith AJ Cuddon P Ma QP Leveridge M Kerby J Roderick HL Bootman MD Simpson PB 《Journal of neurochemistry》2006,97(1):201-210
The prospect of manipulating endogenous neural stem cells to replace damaged tissue and correct functional deficits offers a novel mechanism for treating a variety of CNS disorders. The aim of this study was to investigate pathways controlling neurite outgrowth in human neural precursor cells, in particular in response to platelet-derived growth factor (PDGF). PDGF-AA, -AB and -BB were found to initiate calcium signalling and produce robust increases in neurite outgrowth. PDGF-induced outgrowth of Tuj1-positive precursors was abolished by the addition of EGTA, suggesting that calcium entry is a critical part of the signalling pathway. Wortmannin and PD098059 failed to inhibit PDGF-induced outgrowth. Clostridium Toxin B increased the amount of PDGF-induced neurite branching but had no effect on basal levels. In contrast, WHI-P154, an inhibitor of Janus protein tyrosine kinase (JAK3), Hck and Syk, prevented PDGF-induced neurite outgrowth. PDGF activates multiple signalling pathways with considerable potential for cross-talk. This study has highlighted the complexity of the pathways leading to neurite outgrowth in human neural precursors, and provided initial evidence to suggest that calcium entry is critical in producing the morphological changes observed. 相似文献
9.
Howley Eimear Bestwick Michael Fradley Rosa Harrison Helen Leveridge Mathew Okada Kengo Fieldhouse Charlotte Farnaby Will Canning Hannah Sykes Andy P. Merchant Kevin Hazel Katherine Kerr Catrina Kinsella Natasha Walsh Louise Livermore David G. Hoffman Isaac Ellery Jonathan Mitchell Phillip Patel Toshal Carlton Mark Barnes Matt Miller David J. 《Neurochemical research》2017,42(11):3279-3288
Neurochemical Research - Irregular N-methyl-d-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of... 相似文献
10.
L Alonso EC Souza MV Oliveira LFE do Nascimento PMS Dantas 《Biology of sport / Institute of Sport》2014,31(4):267-270
The objective of this study was to evaluate the genetic and environmental contribution to variation in aerobic power in monozygotic (MZ) and dizygotic (DZ) twins. The sample consisted of 20 MZ individuals (12 females and 8 males) and 16 DZ individuals (12 females and 4 males), aged from 8 to 26 years, residents in Natal, Rio Grande do Norte. The twins were assessed by a multistage fitness test. The rate of heritability found for aerobic power was 77%. Based on the results, the estimated heritability was largely responsible for the differences in aerobic power. This implies that such measures are under strong genetic influence. 相似文献