Identification of baboon microRNAs expressed in liver and lymphocytes

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are small noncoding RNAs (~22 nucleotides) that regulate gene expression by cleaving mRNAs or inhibiting translation. The baboon is a well-characterized cardiovascular disease model; however, no baboon miRNAs have been identified. Evidence indicates that the baboon and human genomes are highly conserved; based on this conservation, we hypothesized that comparative genomic methods could be used to identify baboon miRNAs.</p> <p>Methods</p> <p>We employed an <it>in silico </it>comparative genomics approach and human miRNA arrays to identify baboon expressed miRNAs in liver (n = 6) and lymphocytes (n = 6). Expression profiles for selected miRNAs in multiple tissues were validated by RT-PCR.</p> <p>Results</p> <p>We identified <it>in silico </it>555 putative baboon pre-miRNAs, of which 41% exhibited 100% identity and an additional 58% shared more than 90% sequence identity with human pre-miRNAs. Some of these miRNAs are primate-specific and are clustered in the baboon genome like human miRNA clusters. We detected expression of 494 miRNAs on the microarray and validated expression of selected miRNAs in baboon liver and lymphocytes by RT-PCR. We also observed miRNA expression in additional tissues relevant to dyslipidemia and atherosclerosis. Approximately half of the miRNAs expressed on the array were not predicted <it>in silico </it>suggesting that we have identified novel baboon miRNAs, which could not be predicted using the current draft of the baboon genome.</p> <p>Conclusion</p> <p>We identified a subset of baboon miRNAs using a comparative genomic approach, identified additional baboon miRNAs using a human array and showed tissue-specific expression of baboon miRNAs. Our discovery of baboon miRNAs in liver and lymphocytes will provide resources for studies on the roles of miRNAs in dyslipidemia and atherosclerosis, and for translational studies.</p

Potential miRNA biomarkers and therapeutic targets for early atherosclerotic lesions

Identification of potential therapeutic targets and biomarkers indicative of burden of early atherosclerosis that occur prior to advancement to life-threatening unstable plaques is the key to eradication of CAD prevalence and incidences. We challenged 16 baboons with a high cholesterol, high fat diet for 2 years and evaluated early-stage atherosclerotic lesions (fatty streaks, FS, and fibrous plaques, FP) in formalin-fixed common iliac arteries (CIA). We used small RNA sequencing to identify expressed miRNAs in CIA and in baseline blood samples of the same animals. We found 412 expressed miRNAs in CIA and 356 in blood samples. Eight miRNAs (miR-7975, -486-5p, -451a, -191-5p, -148a-3p, -17-5p, -378c, and -144-3p) were differentially expressed between paired fatty streak lesion and no-lesion sites of the tissue, and 27 miRNAs (e.g., miR-92a-3p, -5001, -342-3p, miR-28-3p, -21-5p, -221-3p, 146a-5p, and -16-5p) in fibrous plaques. The expression of 14 blood miRNAs significantly correlated with extent of lesions and the number of plaques. We identified coordinately regulated miRNA-gene networks in which miR-17-5p and miR-146a-5p are central hubs and miR-5001 and miR-7975 are potentially novel miRNAs associated with early atherosclerosis. In summary, we have identified miRNAs expressed in lesions and in blood that correlate with lesion burden and are potential therapeutic targets and biomarkers. These findings are a first step in elucidating miRNA regulated molecular mechanisms that underlie early atherosclerosis in a baboon model, enabling translation of our findings to humans

Identification of coordinately regulated microRNA-gene networks that differ in baboons discordant for LDL-cholesterol

Rationale Plasma low-density lipoprotein cholesterol (plasma LDL-C), vascular endothelial cells and peripheral blood mononuclear cells (PBMCs), particularly monocytes, play key roles in initiating atherosclerosis, the primary cause of cardiovascular disease (CVD). Although the mechanisms underlying development of atherosclerosis are not well understood, LDL-C is known to influence expression of endothelial microRNAs (miRNAs) and gene-targets of miRNAs to promote cell senescence. However, the impact of LDL-C on expression of PBMC miRNAs and miRNA targeted genes in response to an atherogenic diet is not known. In this study, we used unbiased methods to identify coordinately responsive PBMC miRNA- gene networks that differ between low and high LDL-C baboons when fed a high-cholesterol, high-fat (HCHF) diet. Methods and results Using RNA Seq, we quantified PBMC mRNAs and miRNAs from half-sib baboons discordant for LDL-C plasma concentrations (low LDL-C, n = 3; high LDL-C, n = 3) before and after a 7-week HCHF diet challenge. For low LDL-C baboons, 626 genes exhibited significant change in expression (255 down-regulated, 371 up-regulated) in response to the HCHF diet, and for high LDL-C baboons 379 genes exhibited significant change in expression (162 down-regulated, 217 up-regulated) in response to the HCHF diet. We identified 494 miRNAs identical to human miRNAs and 47 novel miRNAs. Fifty miRNAs were differentially expressed in low LDL-C baboons (21 up- and 29 down-regulated) and 20 in high LDL-C baboons (11 up- and 9 down-regulated) in response to the HCHF diet. Among the differentially expressed miRNAs were miR-221/222 and miR-34a-3p, which were down-regulated, and miR-148a/b-5p, which was up-regulated. In addition, gene-targets of these miRNAs, VEGFA, MAML3, SPARC, and DMGDH, were inversely expressed and are central hub genes in networks and signaling pathways that differ between low and high LDL-C baboon HCHF diet response. Conclusions We have identified coordinately regulated HCHF diet-responsive PBMC miRNA-gene networks that differ between baboons discordant for LDL-C concentrations. Our findings provide potential insights into molecular mechanisms underlying initiation of atherosclerosis where LDL-C concentrations influence expression of specific miRNAs, which in turn regulate expression of genes that play roles in initiation of lesions

Mechanistic Target of Rapamycin Complex 1 Promotes the Expression of Genes Encoding Electron Transport Chain Proteins and Stimulates Oxidative Phosphorylation in Primary Human Trophoblast Cells by Regulating Mitochondrial Biogenesis.

Trophoblast oxidative phosphorylation provides energy for active transport and protein synthesis, which are critical placental functions influencing fetal growth and long-term health. The molecular mechanisms regulating trophoblast mitochondrial oxidative phosphorylation are largely unknown. We hypothesized that mechanistic Target of Rapamycin Complex 1 (mTORC1) is a positive regulator of key genes encoding Electron Transport Chain (ETC) proteins and stimulates oxidative phosphorylation in trophoblast and that ETC protein expression is down-regulated in placentas of infants with intrauterine growth restriction (IUGR). We silenced raptor (mTORC1 inhibition), rictor (mTORC2 inhibition) or DEPTOR (mTORC1/2 activation) in cultured term primary human trophoblast (PHT) cells. mTORC1 inhibition caused a coordinated down-regulation of 18 genes encoding ETC proteins representing all ETC complexes. Inhibition of mTORC1, but not mTORC2, decreased protein expression of ETC complexes I-IV, mitochondrial basal, ATP coupled and maximal respiration, reserve capacity and proton leak, whereas activation of mTORC1 had the opposite effects. Moreover, placental protein expression of ETC complexes was decreased and positively correlated to mTOR signaling activity in IUGR. By controlling trophoblast ATP production, mTORC1 links nutrient and

The Impact of Demographic Factors and News Exposure of Child Sexual Abuse in the Mass Media Toward Communication Quality of Parents in Providing Sex Education for Children

Many cases of child sexual abuse become media spotlight, such as print media, TV, and online. However, not all the audience watch the news. They are motivated by differences in demographic factors, such as gender, age, education level, and income level. The cases spread in the mass media should be concern of many parents to pay more attention to the patterns of communication as a way of parents to control the safety of their children. Sex education is considered to be an appropriate way to provide sexual knownledge to children who are vulnerable from the damage of sexual crimes. However, not all parents are willing to deliver sex education to their children.This study employed the theory of social categories explain the difference between social categories can affect the audience\u27s response when receiving message from mass media (Rakhmat, 2011) and media functionalist theory that explain how media exposure can affect their communication activities that occur between the audience (Mc Quail, 1972). The population of this study were the parents of SD Negeri Padangsari 02 Semarang, who have child 10-12 years old. Sampling was done by simple random technique with a number of 63 respondents.The first hypothesis test indicate that the demographic factors of the three variables, those are gender, age, and educational level when calculated simultaneously using regression analysis techniques, do not affect the news exposure of child sexual abuse in the mass media. While the variable of income level has an impact to the news exposure of child sexual abuse in mass media with significance value of 0,011. The second hypothesis test prove that the news exposure of child sexual abuse in the mass media affects the communication quality of parents in providing sex education with a significance value of 0,001.Advice can be given from this study is that parents should pay more attention to their way to communicate with children, especially regarding sex education. Sex education can be good when it is given according to the child\u27s age and their understanding level considering the number of cases of sexual abuse is increase as in the media

Investigating the psychometric properties of the Suicide Stroop task

Behavioral measures are increasingly used to assess suicidal thoughts and behaviors. Some measures, such as the Suicide Stroop Task, have yielded mixed findings in the literature. An understudied feature of these behavioral measures has been their psychometric properties, which may affect the probability of detecting significant effects and reproducibility. In the largest investigation of its kind, we tested the internal consistency and concurrent validity of the Suicide Stroop Task in its current form, drawing from seven separate studies (N = 875 participants, 64% female, aged 12 to 81 years). Results indicated that the most common Suicide Stroop scoring approach, interference scores, yielded unacceptably low internal consistency (rs = -.09-.13) and failed to demonstrate concurrent validity. Internal consistency coefficients for mean reaction times (RTs) to each stimulus type ranged from rs = .93-.94. All scoring approaches for suicide-related interference demonstrated poor classification accuracy (AUCs = .52-.56) indicating that scores performed near chance in their ability to classify suicide attempters from nonattempters. In the case of mean RTs, we did not find evidence for concurrent validity despite our excellent reliability findings, highlighting that reliability does not guarantee a measure is clinically useful. These results are discussed in the context of the wider implications for testing and reporting psychometric properties of behavioral measures in mental health research

Advancing the Scientific Frontier with Increasingly Autonomous Systems

A close partnership between people and partially autonomous machines has enabled decades of space exploration. But to further expand our horizons, our systems must become more capable. Increasing the nature and degree of autonomy - allowing our systems to make and act on their own decisions as directed by mission teams - enables new science capabilities and enhances science return. The 2011 Planetary Science Decadal Survey (PSDS) and on-going pre-Decadal mission studies have identified increased autonomy as a core technology required for future missions. However, even as scientific discovery has necessitated the development of autonomous systems and past flight demonstrations have been successful, institutional barriers have limited its maturation and infusion on existing planetary missions. Consequently, the authors and endorsers of this paper recommend that new programmatic pathways be developed to infuse autonomy, infrastructure for support autonomous systems be invested in, new practices be adopted, and the cost-saving value of autonomy for operations be studied.Comment: 10 pages (compared to 8 submitted to PSADS), 2 figures, submitted to National Academy of Sciences Planetary Science and Astrobiology Decadal Survey 2023-203

Drug Discovery for Kinetoplastid Diseases : Future Directions

International audienceKinetoplastid parasites have caused human disease for millennia. Significant achievements have been made toward developing new treatments for leishmaniasis (particularly on the Indian subcontinent) and for human African trypanosomiasis (HAT). Moreover, the sustained decrease in the incidence of HAT has made the prospect of elimination a tantalizing reality. Despite the gains, no new chemical or biological entities to treat kinetoplastid diseases have been registered in more than three decades, and more work is needed to discover safe and effective therapies for patients with Chagas disease and leishmaniasis. Advances in tools for drug discovery and novel insights into the biology of the host-parasite interaction may provide opportunities for accelerated progress. Here, we summarize the output from a gathering of scientists and physicians who met to discuss the current status and future directions in drug discovery for kinetoplastid diseases