Shortly after birth, the eyes of most animals (including humans) are hyperopic because the short axial length places the retina in front of the focal plane. During postnatal development, an emmetropization mechanism uses cues related to refractive error to modulate the growth of the eye, moving the retina toward the focal plane. One possible cue may be longitudinal chromatic aberration (LCA), to signal if eyes are getting too long (long [red] wavelengths in better focus than short [blue]) or too short (short wavelengths in better focus). It could be difficult for the short-wavelength sensitive (SWS, “blue”) cones, which are scarce and widely spaced across the retina, to detect and signal defocus of short wavelengths. We hypothesized that the SWS cone retinal pathway could instead utilize temporal (flicker) information. We thus tested if exposure solely to long-wavelength light would cause developing eyes to slow their axial growth and remain refractively hyperopic, and if flickering short-wavelength light would cause eyes to accelerate their axial growth and become myopic. Four groups of infant northern tree shrews (Tupaia glis belangeri, dichromatic mammals closely related to primates) began 13 days of wavelength treatment starting at 11 days of visual experience (DVE). Ambient lighting was provided by an array of either long-wavelength (red, 626±10 nm) or short-wavelength (blue, 464±10 nm) light-emitting diodes placed atop the cage. The lights were either steady, or flickering in a pseudo-random step pattern. The approximate mean illuminance (in human lux) on the cage floor was red (steady, 527 lux; flickering, 329 lux), and blue (steady, 601 lux; flickering, 252 lux). Refractive state and ocular component dimensions were measured and compared with a group of age-matched normal animals (n=15 for refraction (first and last days); 7 for ocular components) raised in broad spectrum white fluorescent colony lighting (100-300 lux). During the 13 day period, the refraction of the normal animals decreased from (mean±SEM) 5.8±0.7 diopters (D) to 1.5±0.2 D as their vitreous chamber depth increased from 2.77±0.01mm to 2.80±0.03 mm. Animals exposed to red light (both steady and flickering) remained hyperopic throughout the treatment period so that the eyes at the end of wavelength treatment were significantly hyperopic (7.0±0.7 D, steady; 4.7±0.8 D, flickering) compared with the normal animals (p<0.01). The vitreous chamber of the steady red group (2.65±0.03 mm) was significantly shorter than normal (p<0.01). On average, steady blue light had little effect; the refractions paralleled the normal refractive decrease. In contrast, animals housed in flickering blue light increased the rate of refractive decrease so that the eyes became significantly myopic (−2.9±1.3 D) compared with the normal eyes and had longer vitreous chambers (2.93±0.04 mm). Upon return to colony lighting, refractions in all groups gradually returned toward emmetropia. These data are consistent both with the hypothesis that LCA can be an important visual...

In infant tree shrews, exposure to narrow-band long-wavelength (red) light, that stimulates long-wavelength sensitive cones almost exclusively, slows axial elongation and produces hyperopia. We asked if red light produces hyperopia in juvenile and adolescent animals, ages when plus lenses are ineffective. Animals were raised in fluorescent colony lighting (100–300 lux) until they began 13 days of red-light treatment at 11 (n=5, “infant”), 35 (n=5, “juvenile”) or 95 (n=5, “adolescent”) days of visual experience (DVE). LEDs provided 527–749 lux on the cage floor. To control for the higher red illuminance, a fluorescent control group (n=5) of juvenile (35 DVE) animals was exposed to ~ 975 lux. Refractions were measured daily; ocular component dimensions at the start and end of treatment and end of recovery in colony lighting. These groups were compared with normals (n=7). In red light, the refractive state of both juvenile and adolescent animals became significantly (P<0.05) hyperopic: juvenile 3.9±1.0 diopters (D, mean±SEM) vs. normal 0.8±0.1 D; adolescent 1.6±0.2 D vs. normal 0.4±0.1 D. The fluorescent control group refractions (0.6±0.3 D) were normal. In red-treated juveniles the vitreous chamber was significantly smaller than normal (P<0.05): juvenile 2.67±0.03 mm vs. normal 2.75±0.02 mm. The choroid was also significantly thicker: juvenile 77±4 μm vs. normal 57±3 μm (P<0.05). Although plus lenses do not restrain eye growth in juvenile tree shrews, the red light-induced slowed growth and hyperopia in juvenile and adolescent tree shrews demonstrates that the emmetropization mechanism is still capable of restraining eye growth at these ages.

Inherited genetic modifiers and pharmacologic agents that enhance fetal hemoglobin (HbF) expression reverse the clinical severity of sickle cell disease (SCD). Recent efforts to develop novel strategies of HbF induction include discovery of molecular targets that regulate γ-globin gene transcription and translation. The purpose of this study was to perform genome-wide microRNA (miRNA) analysis to identify genes associated with HbF expression in patients with SCD. We isolated RNA from purified reticulocytes for microarray-based miRNA expression profiling. Using samples from patients with contrasting HbF levels, we observed an eightfold upregulation of miR-144–3p (miR-144) and miR-144–5p in the low-HbF group compared with those with high HbF. Additional analysis by reverse transcription quantitative polymerase chain reaction confirmed individual miR-144 expression levels of subjects in the two groups. Subsequent functional studies in normal and sickle erythroid progenitors showed NRF2 gene silencing by miR-144 and concomitant repression of γ-globin transcription; by contrast, treatment with miR-144 antagomir reversed its silencing effects in a dose-dependent manner. Because NRF2 regulates reactive oxygen species levels, additional studies investigated mechanisms of HbF regulation using a hemin-induced oxidative stress model. Treatment of KU812 cells with hemin produced an increase in NRF2 expression and HbF induction that reversed with miR-144 pretreatment. Chromatin immunoprecipitation assay confirmed NRF2 binding to the γ-globin antioxidant response element, which was inhibited by miR-144 mimic treatment. The genome-wide miRNA microarray and primary erythroid progenitor data support a miR-144/NRF2-mediated mechanism of γ-globin gene regulation in SCD.

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During postnatal refractive development, an emmetropization mechanism uses refractive error to modulate the growth rate of the eye. Hyperopia (image focused behind the retina) produces what has been described as "GO" signaling that increases growth. Myopia (image focused in front of the retina) produces "STOP" signaling that slows growth. The interaction between GO and STOP conditions is non-linear; brief daily exposure to STOP counteracts long periods of GO. In young tree shrews, long-wavelength (red) light, presented 14 h per day, also appears to produce STOP signals. We asked if red light also shows temporal non-linearity; does brief exposure slow the normal decrease in hyperopia in infant animals? At 11 days after eye opening (DVE), infant tree shrews (n = 5/group) began 13 days of daily treatment (red LEDs, 624 ± 10 or 636 ± 10 nm half peak intensity bandwidth) at durations of 0 h (normal animals, n = 7) or 1, 2, 4, or 7 h. Following each daily red period, colony lighting resumed. A 14 h red group had no colony lights. Refractive state was measured daily; ocular component dimensions at the end of the 13-day red-light period. Even 1 h of red light exposure produced some hyperopia. The average hyperopic shift from normal rose exponentially with duration (time constant 2.5 h). Vitreous chamber depth decreased non-linearly with duration (time constant, 3.3 h). After red treatment was discontinued, refractions in colony lighting recovered toward normal; the initial rate was linearly related to the amount of hyperopia. The red light may produce STOP signaling similar to myopic refractive error.