scholarly journals Germline transmission of donor, maternal and paternal mtDNA in primates

2020 ◽  
Author(s):  
Hong Ma ◽  
Crystal Van Dyken ◽  
Hayley Darby ◽  
Aleksei Mikhalchenko ◽  
Nuria Marti-Gutierrez ◽  
...  
Keyword(s):  
General Health ◽  
Large Scale ◽  
Rhesus Macaques ◽  
Mitochondrial Gene ◽  
Reproductive Fitness ◽  
Diverse Range ◽  
Male And Female ◽  
Mtdna Mutations ◽  
Mtdna Haplotypes ◽  
Mitochondrial Replacement Therapy

Abstract STUDY QUESTION What are the long-term developmental, reproductive and genetic consequences of mitochondrial replacement therapy (MRT) in primates? SUMMARY ANSWER Longitudinal investigation of MRT rhesus macaques (Macaca mulatta) generated with donor mtDNA that is exceedingly distant from the original maternal counterpart suggest that their growth, general health and fertility is unremarkable and similar to controls. WHAT IS KNOWN ALREADY Mitochondrial gene mutations contribute to a diverse range of incurable human disorders. MRT via spindle transfer in oocytes was developed and proposed to prevent transmission of pathogenic mtDNA mutations from mothers to children. STUDY DESIGN, SIZE, DURATION The study provides longitudinal studies on general health, fertility as well as transmission and segregation of parental mtDNA haplotypes to various tissues and organs in five adult MRT rhesus macaques and their offspring. PARTICIPANTS/MATERIALS, SETTING, METHODS MRT was achieved by spindle transfer between metaphase II oocytes from genetically divergent rhesus macaque populations. After fertilization of oocytes with sperm, heteroplasmic zygotes contained an unequal mixture of three parental genomes, i.e. donor (≥97%), maternal (≤3%), and paternal (≤0.1%) mitochondrial (mt)DNA. MRT monkeys were grown to adulthood and their development and general health was regularly monitored. Reproductive fitness of male and female MRT macaques was evaluated by time-mated breeding and production of live offspring. The relative contribution of donor, maternal, and paternal mtDNA was measured by whole mitochondrial genome sequencing in all organs and tissues of MRT animals and their offspring. MAIN RESULTS AND THE ROLE OF CHANCE Both male and female MRT rhesus macaques containing unequal mixture of three parental genomes, i.e. donor (≥97%), maternal (≤3%), and paternal (≤0.1%) mtDNA reached healthy adulthood, were fertile and most animals stably maintained the initial ratio of parental mtDNA heteroplasmy and donor mtDNA was transmitted from females to offspring. However, in one monkey out of four analyzed, initially negligible maternal mtDNA heteroplasmy levels increased substantially up to 17% in selected internal tissues and organs. In addition, two monkeys showed paternal mtDNA contribution up to 33% in selected internal tissues and organs. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Conclusions in this study were made on a relatively low number of MRT monkeys, and on only one F1 (first generation) female. In addition, monkey MRT involved two wildtype mtDNA haplotypes, but not disease-relevant variants. Clinical trials on children born after MRT will be required to fully determine safety and efficacy of MRT for humans. WIDER IMPLICATIONS OF THE FINDINGS Our data show that MRT is compatible with normal postnatal development including overall health and reproductive fitness in nonhuman primates without any detected adverse effects. ‘Mismatched’ donor mtDNA in MRT animals even from the genetically distant mtDNA haplotypes did not cause secondary mitochondrial dysfunction. However, carry-over maternal or paternal mtDNA contributions increased substantially in selected internal tissues / organs of some MRT animals implying the possibility of mtDNA mutation recurrence. STUDY FUNDING/COMPETING INTEREST(S) This work has been funded by the grants from the Burroughs Wellcome Fund, the National Institutes of Health (RO1AG062459 and P51 OD011092), National Research Foundation of Korea (2018R1D1A1B07043216) and Oregon Health & Science University institutional funds. The authors declare no competing interests.

scholarly journals Evaluation of animal model congruence to human depression based on large-scale gene expression patterns of the CNS

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Stephen C. Gammie
Keyword(s):  
Gene Expression ◽  
Machine Learning ◽  
Animal Models ◽  
Large Scale ◽  
Mitochondrial Gene ◽  
Expression Patterns ◽  
Conditional Knockout ◽  
Gene Expression Patterns ◽  
Male And Female ◽  
Wide Range

AbstractDepression is a complex mental health disorder that is difficult to study. A wide range of animal models exist and for many of these data on large-scale gene expression patterns in the CNS are available. The goal of this study was to evaluate how well animal models match human depression by evaluating congruence and discordance of large-scale gene expression patterns in the CNS between almost 300 animal models and a portrait of human depression created from male and female datasets. Multiple approaches were used, including a hypergeometric based scoring system that rewards common gene expression patterns (e.g., up-up or down-down in both model and human depression), but penalizes opposing gene expression patterns. RRHO heat maps, Uniform Manifold Approximation Plot (UMAP), and machine learning were used to evaluate matching of models to depression. The top ranked model was a histone deacetylase (HDAC2) conditional knockout in forebrain neurons. Also highly ranked were various models for Alzheimer’s, including APPsa knock-in (2nd overall), APP knockout, and an APP/PS1 humanized double mutant. Other top models were the mitochondrial gene HTRA2 knockout (that is lethal in adulthood), a modified acetylcholinesterase, a Huntington’s disease model, and the CRTC1 knockout. Over 30 stress related models were evaluated and while some matched highly with depression, others did not. In most of the top models, a consistent dysregulation of MAP kinase pathway was identified and the genes NR4A1, BDNF, ARC, EGR2, and PDE7B were consistently downregulated as in humans with depression. Separate male and female portraits of depression were also evaluated to identify potential sex specific depression matches with models. Individual human depression datasets were also evaluated to allow for comparisons across the same brain regions. Heatmap, UMAP, and machine learning results supported the hypergeometric ranking findings. Together, this study provides new insights into how large-scale gene expression patterns may be similarly dysregulated in some animals models and humans with depression that may provide new avenues for understanding and treating depression.

Building a Culture of Ethical, Comparable, Authentic Assessment

2019 ◽  
pp. 463-481
Author(s):  
Andrew Reid ◽  
Julie Ballantyne
Keyword(s):  
Teaching And Learning ◽  
Large Scale ◽  
Authentic Assessment ◽  
Subject Area ◽  
Music Educators ◽  
System Level ◽  
Diverse Range ◽  
Effective Learning ◽  
School Based ◽  
The Subject

In an ideal world, assessment should be synonymous with effective learning and reflect the intricacies of the subject area. It should also be aligned with the ideals of education: to provide equitable opportunities for all students to achieve and to allow both appropriate differentiation for varied contexts and students and comparability across various contexts and students. This challenge is made more difficult in circumstances in which the contexts are highly heterogeneous, for example in the state of Queensland, Australia. Assessment in music challenges schooling systems in unique ways because teaching and learning in music are often naturally differentiated and diverse, yet assessment often calls for standardization. While each student and teacher has individual, evolving musical pathways in life, the syllabus and the system require consistency and uniformity. The challenge, then, is to provide diverse, equitable, and quality opportunities for all children to learn and achieve to the best of their abilities. This chapter discusses the designing and implementation of large-scale curriculum as experienced in secondary schools in Queensland, Australia. The experiences detailed explore the possibilities offered through externally moderated school-based assessment. Also discussed is the centrality of system-level clarity of purpose, principles and processes, and the provision of supportive networks and mechanisms to foster autonomy for a diverse range of music educators and contexts. Implications for education systems that desire diversity, equity, and quality are discussed, and the conclusion provokes further conceptualization and action on behalf of students, teachers, and the subject area of music.

A widespread pathway for substitution of adenine by diaminopurine in phage genomes

Science ◽  
2021 ◽  
Vol 372 (6541) ◽  
pp. 512-516
Author(s):  
Yan Zhou ◽  
Xuexia Xu ◽  
Yifeng Wei ◽  
Yu Cheng ◽  
Yu Guo ◽  
...  
Keyword(s):  
Large Scale ◽  
Restriction Enzymes ◽  
Diverse Range ◽  
Host Restriction ◽  
Form And Function ◽  
Multienzyme System ◽  
Dna Modifications ◽  
Dna Production ◽  
And Function

DNA modifications vary in form and function but generally do not alter Watson-Crick base pairing. Diaminopurine (Z) is an exception because it completely replaces adenine and forms three hydrogen bonds with thymine in cyanophage S-2L genomic DNA. However, the biosynthesis, prevalence, and importance of Z genomes remain unexplored. Here, we report a multienzyme system that supports Z-genome synthesis. We identified dozens of globally widespread phages harboring such enzymes, and we further verified the Z genome in one of these phages, Acinetobacter phage SH-Ab 15497, by using liquid chromatography with ultraviolet and mass spectrometry. The Z genome endows phages with evolutionary advantages for evading the attack of host restriction enzymes, and the characterization of its biosynthetic pathway enables Z-DNA production on a large scale for a diverse range of applications.

scholarly journals Genome size correlates with reproductive fitness in seed beetles

2015 ◽  
Vol 282 (1815) ◽  
pp. 20151421 ◽  
Author(s):  
Göran Arnqvist ◽  
Ahmed Sayadi ◽  
Elina Immonen ◽  
Cosima Hotzy ◽  
Daniel Rankin ◽  
...  
Keyword(s):  
Life History ◽  
Natural Selection ◽  
Genome Size ◽  
Evolutionary Biology ◽  
Large Scale ◽  
Life History Traits ◽  
Single Species ◽  
Reproductive Fitness ◽  
Correlated Evolution ◽  
Seed Beetles

The ultimate cause of genome size (GS) evolution in eukaryotes remains a major and unresolved puzzle in evolutionary biology. Large-scale comparative studies have failed to find consistent correlations between GS and organismal properties, resulting in the ‘ C -value paradox’. Current hypotheses for the evolution of GS are based either on the balance between mutational events and drift or on natural selection acting upon standing genetic variation in GS. It is, however, currently very difficult to evaluate the role of selection because within-species studies that relate variation in life-history traits to variation in GS are very rare. Here, we report phylogenetic comparative analyses of GS evolution in seed beetles at two distinct taxonomic scales, which combines replicated estimation of GS with experimental assays of life-history traits and reproductive fitness. GS showed rapid and bidirectional evolution across species, but did not show correlated evolution with any of several indices of the relative importance of genetic drift. Within a single species, GS varied by 4–5% across populations and showed positive correlated evolution with independent estimates of male and female reproductive fitness. Collectively, the phylogenetic pattern of GS diversification across and within species in conjunction with the pattern of correlated evolution between GS and fitness provide novel support for the tenet that natural selection plays a key role in shaping GS evolution.

Situating and Abandoning Geoengineering: A Typology of Five Responses to Dangerous Climate Change

2013 ◽  
Vol 46 (01) ◽  
pp. 23-27 ◽  
Author(s):  
Clare Heyward
Keyword(s):  
Climate Change ◽  
Large Scale ◽  
Solar Radiation Management ◽  
Diverse Range ◽  
Political Issues ◽  
Government Organizations ◽  
Mitigation And Adaptation ◽  
Potential Strategy ◽  
Dangerous Climate Change ◽  
Radiation Management

Geoengineering, the “deliberate, large-scale manipulation of the planetary environment in order to counteract anthropogenic climate change” (Shepherd et al. 2009, 1), is attracting increasing interest. As well as the Royal Society, various scientific and government organizations have produced reports on the potential and challenge of geoengineering as a potential strategy, alongside mitigation and adaptation, to avoid the vast human and environmental costs that climate change is thought to bring (Blackstock et al. 2009; GAO 2010; Long et al. 2011; Rickels et al. 2011). “Geoengineering” covers a diverse range of proposals conventionally divided into carbon dioxide removal (CDR) proposals and solar radiation management (SRM) proposals. This article argues that “geoengineering” should not be regarded as a third category of response to climate change, but should be disaggregated. Technically, CDR and SRM are quite different and discussing them together under the rubric of geoengineering can give the impression that all the technologies in the two categories of response always raise similar challenges and political issues when this is not necessarily the case. However, CDR and SRM should not be completely subsumed into the preexisting categories of mitigation and adaptation. Instead, they can be regarded as two parts of a five-part continuum of responses to climate change. To make this case, the first section of this article discusses whether geoengineering is distinctive, and the second situates CDR and SRM in relation to other responses to climate change.

scholarly journals Sexual Transmission of XMRV: A Potential Infection Route

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Prachi Sharma ◽  
Kenneth A. Rogers ◽  
Suganthi Suppiah ◽  
Ross J. Molinaro ◽  
Nattawat Onlamoon ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Chronic Infection ◽  
Protein Production ◽  
Reproductive Tract ◽  
Rhesus Macaques ◽  
Sexual Transmission ◽  
Seminal Vesicles ◽  
Male And Female ◽  
Route Of Transmission ◽  
Intravenous Inoculation

Although XMRV dissemination in humans is a matter of debate, the prostate of select patients seem to harbor XMRV, which raises questions about its potential route of transmission. We established a model of infection in rhesus macaques inoculated with XMRV. In spite of the intravenous inoculation, all infected macaques exhibited readily detectable XMRV signal in the reproductive tract of all 4 males and 1 female during both acute and chronic infection stages. XMRV showed explosive growth in the acini of prostate during acute but not chronic infection. In seminal vesicles, epididymis, and testes, XMRV protein production was detected throughout infection in interstitial or epithelial cells. In the female monkey, epithelial cells in the cervix and vagina were also positive for XMRV gag. The ready detection of XMRV in the reproductive tract of male and female macaques infected intravenously suggests the potential for sexual transmission for XMRV.

Harnessing Collective Intelligence Through Pattern Mining in Social Computational Systems

2018 ◽  
pp. 91-110
Author(s):  
Gaganmeet Kaur Awal ◽  
K. K. Bharadwaj
Keyword(s):  
Large Scale ◽  
Social Dynamics ◽  
Pattern Mining ◽  
Collective Intelligence ◽  
Social Systems ◽  
Big Data Analytics ◽  
Diverse Range ◽  
Business Applications ◽  
Computational Systems ◽  
The Web

Due to the digital nature of the web, the social web mimics the real-world social dynamics that manifest themselves as data and can be easily mined as patterns, making the web a fertile ground for business and research-oriented analytical applications. Collective intelligence (CI) is a multifaceted field with roots in sociology, biology, and many other disciplines. Various manifestations of CI support the successful existence of large-scale social systems. This chapter gives an overview of the principles of CI and the concept of “wisdom of crowds” and highlights how to maximize the potential of big data analytics for CI. Also, various techniques and approaches have been described that leverage these CI concepts across a diverse range of ever-evolving social systems for commercial business applications like influence mining, expertise discovery, etc.

Virtual Forensic Anthropology Applications of Advanced Computer Graphics Technology to the Identification of Human Remains

2011 ◽  
pp. 217-235 ◽  
Author(s):  
Stephanie L. Davy-Jow ◽  
Summer J. Decker ◽  
Damian Schofield
Keyword(s):  
Virtual Reality ◽  
Human Evolution ◽  
Forensic Anthropology ◽  
Large Scale ◽  
Physical Anthropology ◽  
Biological Anthropology ◽  
Diverse Range ◽  
Research And Teaching ◽  
Case Work ◽  
Advanced Computer

Anthropology is the “study of man” and encompasses a diverse range of topics, including socio-cultural studies, linguistics, archaeology, and physical anthropology. Physical anthropology, or “biological” anthropology, the study of humans both living and deceased, can be further subcategorized into osteology, primatology, human evolution, and forensic anthropology. Forensic anthropology is the application of physical anthropology techniques to medico-legal settings. Virtual Reality (VR) is being applied to forensic anthropology in a multitude of ways to benefit research and teaching. Several large-scale projects have been launched to digitize, reconstruct, and disseminate specimens (for example, http://www.virtual-anthropology.com). This chapter will begin with an overview of the discipline of forensic anthropology and discuss a number of representative applications of VR technology in this field that are changing the way in which case work may be handled in the future.

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