The miR199 and miR214 genes occupy an intronic cluster located on the opposite strand of the Dynamin3 gene. These miRNAs play major roles in a broad variety of developmental processes and diseases, including skeletal development and several types of cancer. In the work reported here, we first deciphered the origin of the miR199 and miR214 families by following evolution of miR paralogs and their host Dynamin paralogs. We then examined the expression patterns of miR199 and miR214 in developing zebrafish embryos and demonstrated their regulation through a common primary transcript. Results suggest an evolutionarily conserved regulation across vertebrate lineages. Our expression study showed predominant expression patterns for both miR in tissues surrounding developing craniofacial skeletal elements consistent with expression data in mouse and human, thus indicating a conserved role of miR199 and miR214 in vertebrate skeletogenesis.
The integration of circadian and metabolic signals is essential for maintaining robust circadian rhythms and ensuring efficient metabolism and energy use. Using Drosophila as an animal model, we show that cellular protein O-GlcNAcylation exhibits robust 24-hour rhythm and represents a key post-translational mechanism that regulates circadian physiology. We observe strong correlation between protein O-GlcNAcylation rhythms and clock-controlled feeding-fasting cycles, suggesting that O-GlcNAcylation rhythms are primarily driven by nutrient input. Interestingly, daily O-GlcNAcylation rhythms are severely dampened when we subject flies to time-restricted feeding at unnatural feeding time. This suggests the presence of clock-regulated buffering mechanisms that prevent excessive O-GlcNAcylation at non-optimal times of the day-night cycle. We show that this buffering mechanism is mediated by the expression and activity of GFAT, OGT, and OGA, which are regulated through integration of circadian and metabolic signals. Finally, we generate a mathematical model to describe the key factors that regulate daily O-GlcNAcylation rhythm.
The stress of water-borne hormone collection process was examined in sailfin mollies Poecilia latipinna. Baseline release rates of the stress hormone cortisol were measured and minimum confinement time for water sampling was evaluated for a standard 60 min v. a 30 min protocol. A 30 min hormone collection period reflects release rates over 60 min. Potential stress response to confinement in the beaker for the water-borne collection process was tested over 4 days. There was no evidence of stress due to the collection methods, as cortisol release rates did not differ significantly across four sequential days of handling for P. latipinna. Males and females did not differ significantly in baseline cortisol release rates. Baseline cortisol release rates from fish immediately after being collected in the field were also not significantly different than those in the 4 day confinement experiment. After exposure to a novel environment, however, P. latipinna mounted a stress response. Stress may also affect sex steroids and behaviour but cortisol release rates were not significantly correlated with sex steroids [11-ketotestosterone (KT), testosterone, or oestradiol], or mating attempts. The correlation between water-borne release rates and plasma steroid levels was validated for both cortisol and KT. Finally, normalizing cortisol release rates using standard length in lieu of mass is viable and accurate. Water-borne hormone assays are a valuable tool for investigating questions concerning the role of hormones in mediating stress responses and reproductive behaviours in P. latipinna and other livebearing fishes.
Intracellular signaling dynamics play fundamental roles in cell biology. Precise modulation of the amplitude, duration, and frequency of signaling activation will be a powerful approach to investigate molecular mechanisms as well as to engineer signaling to control cell behaviors. Here, we showed a practical approach to achieve precise amplitude modulation (AM), frequency modulation (FM), and duration modulation (DM) of MAP kinase activation. Alternating current (AC) electrical stimulation induced synchronized ERK activation. Amplitude and duration of ERK activation were controlled by varying stimulation strength and duration. ERK activation frequencies were arbitrarily modulated with trains of short AC applications with accurately defined intervals. Significantly, ERK dynamics coded by well-designed AC can rewire PC12 cell fate independent of growth factors. This technique can be used to synchronize and modulate ERK activation dynamics, thus would offer a practical way to control cell behaviors in vivo without the use of biochemical agents or genetic manipulation.
Background Gamma sensory stimulation may reduce AD-specific pathology. Yet, the efficacy of alternating electrical current stimulation in animal models of AD is unknown, and prior research has not addressed intensity-dependent effects. Methods The intensity-dependent effect of gamma electrical stimulation (GES) with a sinusoidal alternating current at 40 Hz on Aβ clearance and microglia modulation were assessed in 5xFAD mouse hippocampus and cortex, as well as the behavioral performance of the animals with the Morris Water Maze. Results One hour of epidural GES delivered over a month significantly (1) reduced Aβ load in the AD brain, (2) increased microglia cell counts, decreased cell body size, increased length of cellular processes of the Iba1 + cells, and (3) improved behavioral performance (learning & memory). All these effects were most pronounced when a higher stimulation current was applied. Conclusion The efficacy of GES on the reduction of AD pathology and the intensity-dependent feature provide guidance for the development of this promising therapeutic approach.
Xiphophorus fishes are comprised of 26 known species. Interspecies hybridization between select species has been utilized to produce experimental models to study melanoma development. Xiphophorus melanoma induction protocols utilize ultraviolet light (UVB) to induce DNA damage and associated downstream tumorigenesis. However, the impact of induced stress caused by the UVB treatment of the experimental animals undergoing tumor induction protocols has not been assessed. Stress is an adaptive physiological response to excessive or unpredictable environmental stimuli. The stress response in fishes may be measured by assay of cortisol released into the water. Here, we present results from investigations of stress response during experimental treatment and UVB exposure in X. maculatus Jp 163 B, X. couchianus, and F1 interspecies hybrids produced from the mating X. maculatus Jp 163 B x X. couchianus. Overall, cortisol release rates for males and females after UVB exposure showed no statistical differences. At lower UVB doses (8 and 16 kJ/m2), X. couchianus exhibited 2 fold higher levels of DNA damage then either X. maculatus or the F1 hybrid. However, based on cortisol release rates, none of the fish types tested induced a primary stress response at the UVB lower doses (8 and 16 kJ/m2). In contrast, at a very high UVB dose (32 kJ/m2) both X. maculatus and the F1 hybrid showed a 5 fold increase in cortisol release rate. To determine the effect of pigmentation on UVB induced stress, wild type and albino X. hellerii were exposed to UVB (32 kJ/m2). Albino X. hellerii exhibited 3.7 fold increase in cortisol release while wild type X. hellerii did not exhibit a significant cortisol response to UVB. Overall, the data suggest the rather low UVB doses often employed in tumour induction protocols do not induce a primary stress response in Xiphophorus fishes.
Bioelectricity is an endogenous biological electric field (EF) that can be measured in vivo. A biological direct current (DC) EF is produced by ion fluctuations, and is a common response to wounds in various tissues. Our lab previously illustrated DC EF responses in corneal wounds in rodent models in vivo and in human corneal epithelial cell (hCEC) culture. We have observed that both endogenous DC EF and applied exogenous DC EF are capable of guiding cell migration in the process of electrotaxis. However, we have yet to examine exogenous DC EF responses in epithelial monolayers, which are more representative of a wound edge. Our aim was to characterize collective migration of epithelial monolayers to model electrotaxis of a wound edge. We hypothesized that exogenous DC EF can improve collective migration in hCEC monolayers, and therefore DC EF might be applicable for medical treatments of corneal wounds. To test the first part of this hypothesis, we applied exogenous DC EF to hCEC monolayers. We used a standard method of cell tracking combined with an advanced method of particle image velocimetry (PIV) analysis to extrapolate collective migration data. We observed that applications of DC EF to hCEC monolayers induced collective migration and directionality ‐ the directional precision of migration parallel to the EF. Increasing DC EF voltages of 0, 50, and 200 mV/mm2 positively correlated with increasing migration rates. In controls (0 mV/mm2), we observed no directionality, but at DC EF voltages of 50 and 200 mV/mm2 we observed a comparable directionality response, guiding cell migration parallel (0 degrees) to the DC EF. Further, directionality was promptly reversed following DC EF reversals (180 degrees). We concluded that DC EF provides a precise guidance signal for hCEC monolayers that might be applicable for corneal wound healing therapies. Future investigations will aim to dissect cellular mechanisms of the collective migration response to DC EF and to examine the feasibility of DC EF applications to corneal wounds in vivo.Support or Funding InformationNIH, NEI ‐ 2R01EY019101‐05A1 to MZ; DOD, MURI ‐ FA9550‐16‐1‐0052 to WL and MZThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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