Testes Proteases Expression and Hybrid Male Sterility Between Subspecies of Drosophila pseudoobscura

Hybrid male sterility (HMS) is a form of postmating postzygotic isolation among closely related species that can act as an effective barrier to gene flow. The Dobzhansky-Muller model provides a framework to explain how gene interactions can cause HMS between species. Genomics highlights the preponderance of non-coding DNA targets that could be involved in gene interactions resulting in gene expression changes and the establishment of isolating barriers. However, we have limited knowledge of changes in gene expression associated with HMS, gene interacting partners linked to HMS, and whether substitutions in DNA regulatory regions (cis) causes misexpression (i.e. expression of genes beyond levels found in parental species) of HMS genes in sterile hybrids. A previous transcriptome survey in a pair of D. pseudoobscura species found male reproductive tract (MRT) proteases as the largest class of genes misregulated in sterile hybrids. Here we assay gene expression in backcross (BC) and introgression (IG) progeny, along with site of expression within the MRT, to identify misexpression of proteases that might directly contribute to HMS. We find limited evidence of an accumulation of cis-regulatory changes upstream of such candidate HMS genes. The expression of four genes was differentially modulated by alleles of the previously characterized HMS gene Ovd.

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Evidence for an Integrated Gene Repression Mechanism Based on mRNA Isoform Toggling in Human Cells

We recently described an unconventional mode of gene regulation in budding yeast by which transcriptional and translational interference collaborate to down-regulate protein expression. Developmentally timed transcriptional interference inhibited production of a well translated mRNA isoform and resulted in the production of an mRNA isoform containing inhibitory upstream open reading frames (uORFs) that prevented translation of the main ORF. Transcriptional interference and uORF-based translational repression are established mechanisms outside of yeast, but whether this type of integrated regulation was conserved was unknown. Here we find that, indeed, a similar type of regulation occurs at the locus for the human oncogene MDM2. We observe evidence of transcriptional interference between the two MDM2 promoters, which produce a poorly translated distal promoter-derived uORF-containing mRNA isoform and a well-translated proximal promoter-derived transcript. Down-regulation of distal promoter activity markedly up-regulates proximal promoter-driven expression and results in local reduction of histone H3K36 trimethylation. Moreover, we observe that this transcript toggling between the two MDM2 isoforms naturally occurs during human embryonic stem cell differentiation programs.

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Tibiofemoral Joint Forces in Female Recreational Runners Vary with Step Frequency

Purpose Elevated tibiofemoral joint (TFJ) contact forces have been linked to the development and progression of knee osteoarthritis. The primary objective of this study was to determine the association between peak TFJ shear and compression forces during running at different self-selected step frequencies (SF) in female recreational runners. Methods Fifty-five healthy female recreational runners ran at 2.98 m/s on an instrumented treadmill. Peak TFJ anterior shear force, peak axial TFJ compression force and peak medial compartment TFJ compression force were estimated using a musculoskeletal model with inputs from 3D joint kinematics and inverse dynamics calculations. Three SF groups were generated using tertiles and differences between the groups were compared using one-way analyses of variance (α=0.05). Results Runners with a SF of ≥178 steps per minute demonstrated the lowest peak TFJ anterior shear (p=0.049), peak axial TFJ compression force (p=0.001) and peak TFJ medial compartment compression forces (p=0.001) compared with runners using lower SF. Conclusion Female recreational runners with low SF of ≤166 steps per minute experience greater TFJ contact forces. This study provides evidence of an association between SF and both shear and axial peak TFJ contact forces during running. Corresponding author: Bhushan Thakkar, 1200 East Broad Street, Basement, Box 980224, Richmond, VA 23298. E-mail: thakkarbs2@vcu.edu. Phone: (804) 300-5578. Fax: (804) 828-8111 There was no funding received for this project. Conflict of Interest The authors have no conflicts of interests to disclose. The results of the present study do not constitute endorsement by ACSM. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Accepted for publication: 2 January 2019. © 2019 American College of Sports Medicine

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Combined Exercise Training Positively Affects Muscle Wasting in Tumor-bearing Mice

Introduction Cancer cachexia is characterized by loss of muscle mass and function. Increased protein catabolism, inflammation, impaired anabolism and mitochondrial function markedly contribute to the pathogenesis of this syndrome. Physical activity has been suggested as a useful tool to prevent or at least delay the onset and progression of cancer-induced muscle wasting. Two main types of exercise can be adopted, namely resistance and endurance training. The present study is aimed to investigate the effectiveness of a combined (resistance + endurance) exercise protocol in preventing/reverting cancer-induced muscle wasting. Methods Mice bearing the C26 colon carcinoma have been used as a model of cancer cachexia. They have been exposed to combined exercise training during 6 weeks (4 before tumor implantation, 2 during tumor growth). Climbing a 1-m ladder inclined at 85° has been used for resistance training, while aerobic (endurance) exercise has been carried out on the same day using a motorized wheel. Results In C26-bearing mice, both muscle mass and strength are improved by combined training, while just the latter increased in exercised healthy animals. Such a pattern is associated with modulations of two markers of autophagy, namely LC3B I/II ratio, increased in sedentary tumor hosts and reduced in exercised C26-bearing mice, and p62, steadily increased in both sedentary and trained tumor-bearing animals. Finally, combined training is not able to modify PGC-1α protein levels, while it improves succinate dehydrogenase activity, both reduced in the muscle of the C26 hosts. Conclusion The data reported in the present study show that combined training improves muscle mass and function in the C26 hosts, likely modulating autophagy and improving mitochondrial function; these observations suggest that combined exercise might become part of a multimodal approach to treat cancer cachexia. Corresponding author: Paola Costelli, Department of Clinical and Biological Sciences, University of Turin. Corso Raffaello, 30. 10125 Turin, Italy. E-mail: paola.costelli@unito.it These authors equally contributed to the work (Kia Ranjbar and Riccardo Ballarò) Work supported by University of Turin. K. Ranjbar was recipient of a scholarship funded by the Ministry of Science, Research and Technology, Islamic Republic of Iran. Conflict of interest: The authors declare no conflict interests. Authors declare that the results of the present study do not constitute endorsement by ACSM and that the data are presented clearly without inappropriate manipulation. Accepted for publication: 25 January 2019. © 2019 American College of Sports Medicine

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No further evidence for paternal leakage of mitochondrial DNA in humans yet [Biological Sciences]

Recently in PNAS, Luo et al. (1) report the observation of heteroplasmic mixtures of mitochondrial DNA (mtDNA) in the blood of three unrelated patients suffering from different mitochondrial disorders. The affected mixed positions coincide with signature mutations of established haplogroups (2), suggesting that each mixture consists of a different pair...

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A bipartite boundary element restricts UBE3A imprinting to mature neurons [Genetics]

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function from the maternal allele of UBE3A, a gene encoding an E3 ubiquitin ligase. UBE3A is only expressed from the maternally inherited allele in mature human neurons due to tissue-specific genomic imprinting. Imprinted expression of UBE3A is...

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Reply to Lutz-Bonengel et al.: Biparental mtDNA transmission is unlikely to be the result of nuclear mitochondrial DNA segments [Biological Sciences]

In Luo et al. (1), we report the transmission of paternal mtDNA in 17 individuals across three unrelated families. In their letter responding to this paper, Lutz-Bonengel et al. (2) argue that these results do not provide sufficient evidence for paternal inheritance of mtDNA. Instead, they propose that these biparental...

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