Increase In Aberrations Research Articles

Study of the InnovEyes Sightmap Platform in Comparing Ray-Tracing-Guided LASIK and Topography-Guided LASIK.

To evaluate the performance of the InnovEyes Sightmap platform (Alcon Laboratories, Inc) in refractive surgery by comparing the visual acuity and higher order aberrations (HOAs) between ray-tracing-guided laser in situ keratomileusis (LASIK) and topography-guided LASIK. This prospective study enrolled participants who underwent either ray-tracing-guided LASIK or topography-guided LASIK. Comprehensive ophthalmic evaluations were performed preoperatively, as well as at 1 day, 2 weeks, 1 month, and 3 months postoperatively. Patients in the ray-tracing-guided LASIK group underwent wavefront, tomography, and biometry assessment using the InnovEyes Sightmap diagnostic device. Assessments included visual acuity, manifest refraction, and whole-eye HOAs. A total of 42 eyes treated with ray-tracing-guided LASIK and 42 eyes treated with topography-guided LASIK were analyzed. Both strategies demonstrated comparable good refraction accuracy and refractive stability (P > .05). The ray-tracing-guided LASIK group exhibited significantly better postoperative uncorrected distance visual acuity (UDVA) compared to the topography-guided LASIK group (-0.12 ± 0.05 vs -0.07 ± 0.04 logarithm of the minimum angle of resolution, respectively; P < .05), with 48% of eyes achieving a UDVA of 20/12.5 or better. Ray-tracing-guided LASIK induced a small but statistically significant increase in HOAs and vertical coma aberration, along with a significant reduction in spherical aberration (P < .05). In contrast, topography-guided LASIK resulted in a significant increase in vertical coma (P < .05) without significant changes in overall HOAs or spherical aberration (P > .05). At 3 months postoperatively, spherical aberration was significantly different between the two groups (-0.021 ± 0.031 vs 0.054 ± 0.122 µm, respectively; P < .05). The InnovEyes Sightmap platform's ray-tracing-guided LASIK demonstrated potential advantages in visual acuity outcomes compared to topography-guided LASIK. The observed negative shift in spherical aberration, characterized by a lower absolute value, may have contributed to the enhanced visual acuity results. [J Refract Surg. 2024;40(12):e994-e1002.].

Epigenetic Drift Is Involved in the Efficacy of HBV Vaccination

Background/Objectives: HBV infections can lead to serious liver complications that can have fatal consequences. In 2022, around 1.1 million individuals died from HBV-related cirrhosis and hepatocellular carcinoma. Vaccines allow us to save more than 2.5 million lives each year; however, up to 10% of vaccinated individuals may not develop sufficient protective antibody levels. The aim of this study was to investigate the epigenetic drift in the response to HBV vaccine in isolated B cells. Methods: Epigenetic drift was measured by counting rare DNA methylation variants. These epivariants were detected in epigenome-wide data collected from isolated B cell samples from 41 responders and 30 non-responders (age range 22–62 years) to vaccination against HBV. Results: We found an accumulation of epivariants in the NR group, with a significant increase in hyper-methylated aberrations. We identified the chromosomes (1, 3, 11, 12, and 14) and genes (e.g., RUSC1_AS1 or TROVE2) particularly enriched in epivariants in NRs. The literature search and pathway analysis indicate that such genes are involved in the correct functioning of the immune system. Moreover, we observed a correlation between epigenetic drift and DNA methylation entropy in the male population of the cohort. Finally, we confirmed the correlation between epivariant loads and age-related epigenetic clocks. Conclusions: Our findings support the idea that an age-related derangement of the epigenetic architecture is involved in unresponsiveness to the HBV vaccine. Furthermore, the overall results highlight the interconnection between various epigenetic dynamics (such as drift, clocks, and entropy), although these interconnections seem not to be involved in the altered immunological activity.

Suffruticosol B from Paeonia lactiflora Ameliorates Alzheimer's Disease Pathology by Inhibiting MAO-B Activity.

Monoamine oxidase B (MAO-B) has emerged as a therapeutic target for Alzheimer's disease (AD) due to its involvement in the synthesis of γ-aminobutyric acid (GABA) in reactive astrocytes, which inhibits neuronal activity. Suffruticosol B (Suf-B), isolated from Paeonia lactiflora, is one of the resveratrol oligomers. Although resveratrol oligomers have demonstrated neuroprotective effects, it remains unexplored whether Suf-B exerts therapeutic effects on AD by targeting MAO-B. In this study, we investigated whether Suf-B alleviates AD pathology by mitigating reactive astrogliosis and inhibiting the overproduction of astrocytic GABA. After confirming the MAO-B inhibitory effect of Suf-B through MAO-B enzyme assay, we administered Suf-B to APP/PS1 AD model mice. To test the potential therapeutic action of Suf-B in AD, a series of experiments were conducted, including behavioral tests such as the open field test, novel object recognition test, Barnes maze test, passive avoidance test, as well as immunohistochemistry and whole-cell patch-clamp recordings. We found that Suf-B markedly inhibited MAO-B activity without causing cytotoxicity. Immunohistochemistry and electrophysiology experiments demonstrated that Suf-B significantly reduced astrocyte reactivity, as well as an aberrant increase in GABA production and tonic GABA release from astrocytes in AD. Behavior test results indicated that Suf-B treatment restored cognitive function in APP/PS1 mice. In conclusion, Suf-B effectively reduces excessive GABA production in reactive astrocytes by inhibiting MAO-B, normalizing aberrant inhibition in hippocampal neurons in an AD mouse model. These results suggest that Suf-B has potential as a treatment for AD and may be applicable to other brain diseases associated with reactive astrogliosis.

Assessing Cell Viability and Genotoxicity in Trigonella foenum-graecum L. Exposed to 2100 MHz and 2300 MHz Electromagnetic Field Radiations

The escalating utilization of wireless electronic devices, notably cellular phones, has led to a substantial augmentation in the levels of electromagnetic field radiation (EMF-r) within the environment. Consequently, an imperative arises to investigate the impact of these radiations on biological systems, specifically on plants. In this study, we examined the genotoxic and cytotoxic effects of 2100 MHz and 2300 MHz EMF-r on the Trigonella foenum-graecum L. test system, evaluating parameters such as percentage germination, growth characteristics, biochemical activities, cell viability and chromosomal aberrations. The roots and shoots of T. foenum-graecum L. were exposed to 2100 MHz and 2300 MHz EMF-r for varied exposure durations (0.5 h, 1 h, 2 h, 4 h and 8 h/day) (at a power density of 10.0 dBm). Substantial reductions in root and shoot lengths were observed after a exposure period of 4 h and 8 h at a frequency of 2100 MHz and 2300 MHz. Genotoxic studies revealed both physiological and clastogenic effects of EMF-r, as evidenced by an increase in chromosomal aberrations (CAs). Biochemical analyses demonstrated elevated malondialdehyde levels and activities of various antioxidative enzymes following 2 h and 4 h per day exposure to 2100 MHz and 2300 MHz EMF-r. Chromosomal aberrations increased by 2.88% to 14.86% and 2.84% to 18.49% (0.5 h to 8 h per day) exposure to 2100 MHz and 2300 MHz, respectively when compared to that of the control group. Exposure to electromagnetic fields (EMF-r) at both 2100 MHz and 2300 MHz resulted in reduced cell viability. This study examines the impact of electromagnetic fields (EMF-r) at 2100 MHz and 2300 MHz on plant root meristems. The results reveal more pronounced genotoxic effects at 2100 MHz, highlighting the frequency-dependent nature of EMF-r impacts. By providing insights into these frequency-specific effects, this research addresses a critical gap in understanding how EMF-r influences plant cellular health and offers guidance for mitigating potential environmental risks from mobile communication technologies.

High dose of liraglutide impairs renal function in female hypertensive rats.

Glucagon-like peptide-1 (GLP-1) receptor agonists exhibit beneficial cardiovascular effects. However, the renal effects of different doses of liraglutide in an essential hypertension model have not yet been investigated. SHR female rats were treated for 30 days, twice a day, with saline (control) or liraglutide at low (0.06 mg/kg, LL) and high (0.6 mg/kg, LH) doses. Volume intake and excretion were monitored for a period of 24h. In renal tissue, nitrite-NO2-, nitrate-NO3-, advanced protein oxidation products-AOPP, collagen deposition, creatinine (Cr), urea (U), sodium, and potassium were analyzed. liraglutide reduced body weight gain in both groups. However, in the high dose, it increased urinary volume excretion and sodium/potassium ratio. Both doses reduced the urinary U/Cr ratio and LH increased the serum U/Cr ratio. AOPP was reduced only in LL. LH augmented collagen and early markers of kidney injury (blood urea nitrogen-BUN, BUN/Cr). LH increased NO3-, reduced NO2-, and caused an aberrant increase in GFR. Both doses' effects were independent of blood pressure and glycemic control. liraglutide appears to have distinct effects on the hypertensive female kidney depending on the dose, with higher doses impairing kidney function.

ISWI chromatin remodeler SMARCA5 is essential for meiotic gene expression and male fertility in mammals.

Regulation of the transcriptome to promote meiosis is important for sperm development and fertility. However, how chromatin remodeling directs the transcriptome during meiosis in male germ cells is largely unknown. Here, we demonstrate that the ISWI family ATP-dependent chromatin remodeling factor SMARCA5 (SNF2H) plays a critical role in regulating meiotic prophase progression during spermatogenesis. Males with germ cell-specific depletion of SMARCA5 are infertile and unable to form sperm. Loss of Smarca5 results in failure of meiotic progression with abnormal spermatocytes beginning at the pachytene stage and an aberrant global increase in chromatin accessibility, especially at genes important for meiotic prophase.

Exaggerated postnatal surge of orexin neurons and the effects of elimination of excess orexin on blood pressure and exaggerated chemoreflex in spontaneously hypertensive rats.

An overactive orexin (OX) system is associated with neurogenic hypertension and an exaggerated chemoreflex in spontaneously hypertensive rats (SHRs). However, the chronology and mechanism of this association is unclear. We hypothesized that increased postnatal neurogenesis of OX neurons in SHRs precedes and contributes to the aberrant increase in mean arterial blood pressure (MAP) and the exaggerated response to hypercapnia during postnatal development. Using immunohistochemical methods and bromodeoxyuridine, we mapped the timeline of orexin neuron neurogenesis and maturation during early postnatal development. We then used whole-body plethysmography with EEG and EMG to map the development of mean arterial pressure (MAP) and state regulation. Finally, we used OX-targeted saporin toxin to determine the effects of eliminating excess OX neurons on the elevated MAP and exaggerated chemoreflex in adult SHRs. We found that both SHRs and Wistar-Kyoto (WKY) rats experienced postnatal increases in OX neurons. However, SHRs experienced a greater increase than WKY rats before P15, which led to significantly more OX neurons in SHRs than age-matched WKY controls by P15-16 (3,720 ± 780 vs. 2,406 ± 363, p = 0.005). We found that neurogenesis, as evidenced by BrdU staining in OX-positive neurons, was the primary contributor to the excess OX neurons in SHRs during early postnatal development. While SHRs develop more OX neurons by P15-16, SHRs and normotensive WKY control rats have similar MAP during postnatal development until P25 in wakefulness (81.6 ± 6.6 vs. 67.5 ± 6.8mmHg, p = 0.006) and sleep (79.3 ± 6.1 vs. 66.6 ± 6.5, p = 0.009), about 10 days after the surge of OX neurons. By selectively eliminating excess (∼30%) OX neurons in SHRs, we saw a significantly lowered MAP and hypercapnic ventilatory chemoreflex compared to non-lesioned SHRs at P40. Additionally, we found unique signatures in state indicative of the attention defecit phenotype commonly associated with this model. We suggest that the postnatal increase of OX neurons, primarily attributed to exaggerated postnatal OX neurogenesis, may be necessary for the development of higher MAP and exaggerated chemoreflex in SHRs, and modulation of the overactive OX system may have a potential therapeutic effect during the pre-hypertensive period.

A 6-Month Follow-Up Comparative Study of Single-Step Transepithelial Photorefractive Keratectomy (Trans-PRK) Using the StreamLight Software with and without Epithelial Thickness Customization.

To compare corneal aberrometry, densitometry, and refractive outcomes of single-step Transepithelial Photorefractive Keratectomy (Trans-PRK) with and without epithelial thickness customization. This was a prospective, interventional, randomized controlled study. Patients undergoing Trans-PRK using the WaveLight EX500 laser with StreamLight software (Alcon Laboratories, Forth Worth, TX, USA) were randomly assigned to control (55µm standard epithelial thickness) or customized (thinnest point of epithelial thickness for each patient) groups. MS-39 (CSO, Italy) anterior segment optical coherence tomography was used to measure the epithelial thickness. Inclusion criteria were spherical equivalent <6 diopters (D), astigmatism <4D, and CDVA 20/25 or better. The assessments were at baseline and 6 months post-op: visual acuity, refraction, aberrometry, and corneal densitometry. 108 eyes were enrolled, [control group (n=56) and customized group (n=52)]. Mean epithelial ablation thickness in the customized group was 54.81±3.56µm (p=0.470 vs control group). Both groups experienced significant postoperative increases in higher-order aberrations (HOA) and spherical aberrations, with no significant intergroup differences. Mean HOA RMS (µm) of the frontal cornea and total cornea increased by 0.27, and 0.29, respectively, in the control group, and 0.26 and 0.28, respectively, in the customized group (p<0.001 for all). Mean change in spherical aberrations in the frontal cornea and total cornea was 0.23µm (p<0.001) and 0.25µm (p<0.001), in the control group, and 0.19µm (p<0.001) and 0.20µm (p<0.001), in the customized group. Mean corneal densitometry in anterior cornea decreased by 0.63GSU (p=0.021) and 1.18GSU (p<0.001) in the control and customized groups. In the posterior cornea, it increased by 1.67GSU (p=0.004) and 0.38GSU (p=0.006). No significant differences in refractive and aberrometry outcomes between control and customized Trans-PRK groups, with corneal densitometry changes not affecting visual acuity.

Analysis of third and fourth corneal high-order aberrations before and after small incision lenticule extraction (SMILE) in myopic and myopic astigmatic eyes using ray tracing aberrometry

BackgroundAim is to analyze alterations in third and fourth corneal higher-order aberrations using a ray tracing aberrometer (iTrace) induced by SMILE (small incision lenticule extraction) refractive surgery on Algerian patients; and also to investigate how corneal aberrations vary with spherical equivalent (SE), corneal central thickness (CCT), and age. Design Prospective, non-randomized case series that were carried out at the Chiali Smile Center, Algiers, Algeria.ParticipantsA total of 219 eyes from 110 myopic patients, with and without astigmatism, successfully concluded the ultimate follow-up. Participants exhibited an average age of 32.48 years, with preoperative mean corneal high-order aberrations (CHOA) measuring 0.005 ± 0.036 μm.MethodsA tracking trend analysis of high-order aberrations (HOAs) was conducted on the three groups of patients, assessing total corneal high-order aberrations after SMILE over periods of two, six, and twelve months.ResultsA substantial increase in total corneal high-order aberrations following SMILE, with a P value < 0.05. Conversely, there was a noteworthy and significant decrease in vertical trefoil for all groups (P value = 0.000). Interestingly, the corneal higher-order aberrations were more pronounced after two months compared to the six and twelve-month intervals. Spherical aberration demonstrated a significant increase with the extent of preoperative myopia and preoperative spherical equivalent both before and after SMILE surgery (P < 0.05), particularly in cases of high myopia. Moreover, there were significant reductions in preoperative and postoperative vertical coma (P = 0.047, P = 0.004, respectively) corresponding to the degree of preoperative myopia, with a more substantial decrease in vertical coma observed in cases of low myopia.ConclusionIn the post-SMILE period, a notable increase in vertical coma and spherical aberrations was observed, accompanied by a significant decrease in vertical trefoil across all eyes. These aberration changes were identified to be closely associated with the spherical equivalent.

Comparison of objective visual quality between SMILE and FS-LASIK in moderate-to-high myopia.

This study aims to compare the changes in the corneal wavefront aberrations and the objective visual quality resulting from two types of eye surgery-small incision lenticule extraction (SMILE) and femtosecond laser-assisted in situ keratomileusis (FS-LASIK)-in patients with moderate-to-high myopia. A prospective analysis was performed on 98 eyes of 51 patients who underwent SMILE. Additionally, 88 eyes of 45 patients who underwent FS-LASIK were analyzed. All patients underwent ocular examination preoperatively and at 1 day, 1 week, 1 month, and 3 months postoperatively. Corneal aberrations and objective visual quality were measured using the Optical Quality Analysis System II (OQAS II) and Optical Path Difference Scan III (OPD-Scan III). At postoperative 1 day and 1 week, there was a statistically significant difference in uncorrected distance visual acuity (UDVA) between SMILE and FS-LASIK (P < 0.05). Postoperative spherical (S), cylinder (C) and spherical equivalent refraction (SE) were similar between the two groups (P > 0.05). In both groups, the absolute magnitude of total higher-aberrations (tHOA), piston, vertical tilt, vertical coma, and spherical aberration (SA) increased after surgery compared to preoperative values (P < 0.05). There was no significant difference in Δhorizontal tHOA, Δhorizontal tilt, Δhorizontal coma, and Δhorizontal trefoil between the two groups (P > 0.05), and the FS-LASIK had higher Δvertical trefoil and ΔSA (P < 0.05) but lower Δpiston, Δvertical tilt, and Δvertical coma than the SMILE group (P < 0.05). There was a rise in objective scattering index (OSI) and a decline in both modulation transfer function (MTF) cutoff and Strehl ratio (SR) after surgery compared to preoperative values in both groups (P < 0.05). There was a statistically significant difference in the OSI at 1 day and 3 months between the two groups (P < 0.05). Postoperative MTF cutoff and SR were similar between the two groups (P > 0.05). Postoperative OSI was positively correlated with corneal tHOA (0.261 ≤ R ≤ 0.483, P < 0.05) and was negatively correlated with vertical tilt and vertical coma (-0.315 ≤ R ≤ -0.209, P < 0.05) in both groups. While both SMILE and FS-LASIK can effectively correct moderate-to-high myopia, there is an increase in corneal aberrations and a postoperative delay in objective visual quality. The cornea may require a longer recovery period in the SMILE. OPD-Scan III combined with OQAS II is a useful supplementary inspection for assessing the optical quality following refractive surgery.

Abstract P383: Increased renal afferent nerve activity and peak response to pro-inflammatory cytokine interleukin 6 in isolated dorsal root ganglion neurons from hypertensive rats

Renal afferent nerves are reported to mediate the progression of hypertension in preclinical models, putatively via an aberrant increase in activation. The underlying source of this nerve activation is unknown but we hypothesized renal inflammatory cytokines are a primary driver. We previously reported interleukin 6 (IL-6) is increased in the kidneys of hypertensive rats, and intrarenal administration of IL-6 can activate renal afferent nerves. Though these data are promising, the direct effects of IL-6 on afferent renal nerves remain unclear. We hypothesized that isolated renal afferent neurons from hypertensive rats will have increased activity and responsiveness to inflammatory cytokine IL-6 compared to normotensive controls. To test our hypothesis, we tested the direct effects of interleukin-6 (IL-6) on renal afferent nerve action potentials (AP) generated in freshly isolated dorsal root ganglion (DRG) neurons. To model salt-sensitive hypertension, uninephrectomized rats (n=6) were administered deoxycorticosterone acetate (DOCA; 100mg, sc) and 0.9% saline for drinking water for 21 days. Control rats (n=6) were uninephrectomized. To label renal afferent nerves, neuronal tracer DiI was introduced by intrarenal injection 6 days prior to DRG collection. DRGs from T10-L1 were isolated, enzymatically digested and dissociated, and cultured overnight for whole-cell patch-clamp the following day. DiI-positive neurons from both control and DOCA rats generated AP during the delivery of 100, 200, and 300 pA current steps. Data were analyzed by two-way, repeat-measures ANOVA (α=.05). At baseline, DOCA neurons had a higher (p&lt;0.05) mean AP frequency compared to controls (no difference in AP mean peak amplitude or AP duration). In both groups, increasing concentrations of IL-6 (0. 4, 4, and 40 ng/ml) elicited a dose-dependent increase in AP peak amplitude compared to baseline. No difference was detected in IL-6 responses between DOCA and controls. Overall, these data supported our original hypothesis that pro-inflammatory cytokine IL-6 would increase renal afferent nerve activity, and that said activity is increased in hypertensive DOCA-salt rats. IL-6 accumulation triggered by end organ damage due to hypertension might lead to increased afferent renal nerve activity, which exacerbates the hypertensive phenotype through a sympatho-excitatory response. Additional measurements of isolated DRG responses to pro-inflammatory mediators are underway for direct comparison.

Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle.

Nemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in the NEB gene (NEB-NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super-relaxed state was significantly impaired in NEB-NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. Because the small-molecule Mavacamten is known to promote the myosin super-relaxed state and reduce the ATP demand, we tested its potency in the context of NEB-NM. We first conducted in vitro experiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP overconsumption. Following this, we assessed its short-term in vivo effects using the conditional nebulin knockout (cNeb KO) mouse model and subsequently performing global proteomics profiling in dissected soleus myofibres. After a 4week treatment period, we observed a remodelling of a large number of proteins in both cNeb KO mice and their wild-type siblings. Nevertheless, these changes were not related to the energy proteome, indicating that short-term Mavacamten treatment is not sufficient to properly counterbalance the metabolically dysregulated proteome of cNeb KO mice. Taken together, our findings emphasize Mavacamten potency in vitro but challenge its short-term efficacy in vivo. KEY POINTS: No cure exists for nemaline myopathy, a type of genetic skeletal muscle disease mainly derived from mutations in genes encoding myofilament proteins. Applying Mavacamten, a small molecule directly targeting the myofilaments, to isolated membrane-permeabilized muscle fibres from human patients restored myosin energetic disturbances. Treating a mouse model of nemaline myopathy in vivo with Mavacamten for 4weeks, remodelled the skeletal muscle fibre proteome without any noticeable effects on energetic proteins. Short-term Mavacamten treatment may not be sufficient to reverse the muscle phenotype in nemaline myopathy.

Physiological, genetical changes and cdc2 gene expression for osmotic stressed Vicia faba reveal the alleviation effect of gamma radiation and putrescine

Climate change caused increasing in soil salinity worldwide. Therefore, it is critical to enhance the capability of plant to tolerate salinity stress. For this goal, putrescine and irradiation by gamma radiation were used to improve the salt tolerance of Vicia faba (the most important human crop). The results indicated depression in mitotic division and all growth parameters associated with the induction of micronucleus (MN) when salinity increased to 100mM, while there was increase in mitotic aberrations. NaCl decreased total soluble sugar, while total N%, total free amino acid, proline and protein contents showed slight increase with increasing salinity stress. Putrescine and gamma radiation mitigated the effect of salinity on cell division and growth parameters. Salt stress decreased the expression of gene encoding cyclin-dependent kinase 2 (cdc2). Both putrescine and gamma radiation increased cdc2 expression. The genetic diversity has been detected among control and treated V. faba using ISSR and SCoT markers. Ten primers had successfully generated 129 reproducible polymorphic amplicons that were suitable for studying the genetic diversity between studied genotypes. ISSR markers provided more discriminating data and were more informative than SCoT markers. Besides, cluster analysis using UPGMA and PAC successfully explained the genetic diversity within studied genotypes. These findings emphasize the efficiency of putrescine and gamma radiation for alleviating the negative impact of salt stress. Moreover, prove the importance of assessing mitotic activity, chromosomes behavior, physiological parameters, the expression level of cdc2 and molecular diversity in V. faba under stress to improve the salt tolerance of it.

Effect of hydroxy-α-sanshool on lipid metabolism in liver and hepatocytes based on AMPK signaling pathway

BackgroundWith the increasing awareness of the safety of traditional Chinese medicine and food, as well as in-depth studies on the pharmacological activity and toxicity of Zanthoxylum armatum DC. (ZADC), it has been found that ZADC is hepatotoxic. However, the toxic substance basis and mechanism of action have not been fully elucidated. Hydroxy-α-sanshool (HAS) belongs to an amide compound in the fruits of ZADC, which may be hepatotoxic. However, the specific effects of HAS, including liver toxicity, are unclear. PurposeThe objectives of this research was to determine how HAS affects hepatic lipid metabolism, identify the mechanism underlying the accumulation of liver lipids by HAS, and offer assurances on the safe administration of HAS. MethodsAn in vivo experiment was performed by gavaging C57 BL/6 J mice with various dosages of HAS (5, 10, and 20 mg/kg). Biochemical indexes were measured, and histological analysis was performed to evaluate HAS hepatotoxicity. Hepatic lipid levels were determined using lipid indices and oil red O (ORO) staining. Intracellular lipid content were determined by biochemical analyses and ORO staining after treating HepG2 cells with different concentrations of HAS in vitro. Mitochondrial membrane potential, respiratory chain complex enzymes, and ATP levels were assessed by fluorescence labeling of mitochondria. The levels of proteins involved in lipogenesis and catabolism were determined using Western blotting. ResultsMice in the HAS group had elevated alanine and aspartate aminotransferase blood levels as well as increased liver index compared with the controls. The pathological findings showed hepatocellular necrosis. Serum and liver levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were increased, whereas high-density lipoprotein cholesterol levels decreased. The ORO staining findings demonstrated elevated liver lipid levels. In vitro experiments demonstrated a notable elevation in triglyceride and total cholesterol levels in the HAS group. ATP, respiratory chain complex enzyme gene expression, mitochondrial membrane potential, and mitochondrial number were reduced in the HAS group. The levels of lipid synthesis-associated proteins (ACC, FASN, and SREBP-1c) were increased, and lipid catabolism-associated protein levels (PPARα and CPT1) and the p-AMPK/AMPK ratio were decreased in vivo and in vitro. ConclusionHAS has hepatotoxic effects, which can induce fatty acid synthesis and mitochondrial function damage by inhibiting the AMPK signaling pathway, resulting in aberrant lipid increases.

Loss of protein tyrosine phosphatase receptor delta PTPRD increases the number of cortical neurons, impairs synaptic function and induces autistic-like behaviors in adult mice

BackgroundThe brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and are associated with the etiology of brain disorders. We previously found that the protein tyrosine phosphatase receptor delta Ptprd, which is genetically associated with several human neurodevelopmental disorders, is essential to cortical brain development. Loss of Ptprd expression induced an aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRβ in neural precursor cells. However, whether these alterations have long-lasting consequences in adulthood remains unknown.ResultsHere, we found that in Ptprd+/- or Ptprd-/- mice, the developmental increase of excitatory neurons persists through adulthood, affecting excitatory synaptic function in the medial prefrontal cortex. Likewise, heterozygosity or homozygosity for Ptprd also induced an increase of inhibitory cortical GABAergic neurons and impaired inhibitory synaptic transmission. Lastly, Ptprd+/- or Ptprd-/- mice displayed autistic-like behaviors and no learning and memory impairments or anxiety.ConclusionsThese results indicate that loss of Ptprd has long-lasting effects on cortical neuron number and synaptic function that may aberrantly impact ASD-like behaviors.

Acute exposure to dihydroxyacetone promotes genotoxicity and chromosomal instability in lung, cardiac, and liver cell models.

Inhalation exposures to dihydroxyacetone (DHA) occur through spray tanning and e-cigarette aerosols. Several studies in skin models have demonstrated that millimolar doses of DHA are cytotoxic, yet the genotoxicity was unclear. We examined the genotoxicity of DHA in cell models relevant to inhalation exposures. Human bronchial epithelial cells BEAS-2B, lung carcinoma cells A549, cardiomyocyte Ac16, and hepatocellular carcinoma HepG3 were exposed to DHA, and low millimolar doses of DHA were cytotoxic. IC90 DHA doses induced cell cycle arrest in all cells except the Ac16. We examined DHA's genotoxicity using strand break markers, DNA adduct detection by Repair Assisted Damage Detection (RADD), metaphase spreads, and a forward mutation assay for mutagenesis. Similar to results for skin, DHA did not induce significant levels of strand breaks. However, RADD revealed DNA adducts were induced 24 h after DHA exposure, with BEAS-2B and Ac16 showing oxidative lesions and A549 and HepG3 showing crosslink-type lesions. Yet, only low levels of reactive oxygen species or advanced glycation end products were detected after DHA exposure. Metaphase spreads revealed significant increases in chromosomal aberrations in the BEAS-2B and HepG3 with corresponding changes in ploidy. Finally, we confirmed the mutagenesis observed using the supF reporter plasmid. DHA increased the mutation frequency, consistent with methylmethane sulfonate, a mutagen and clastogen. These data demonstrate DHA is a clastogen, inducing cell-specific genotoxicity and chromosomal instability. The specific genotoxicity measured in the BEAS-2B in this study suggests that inhalation exposures pose health risks to vapers, requiring further investigation.

Arachidonic Acid Mobilization and Peroxidation Promote Microglial Dysfunction in Aβ Pathology.

Aberrant increase of arachidonic acid (ARA) has long been implicated in the pathology of Alzheimer's disease (AD), while the underlying causal mechanism remains unclear. In this study, we revealed a link between ARA mobilization and microglial dysfunction in Aβ pathology. Lipidomic analysis of primary microglia from AppNL-GF mice showed a marked increase in free ARA and lysophospholipids (LPLs) along with a decrease in ARA-containing phospholipids, suggesting increased ARA release from phospholipids (PLs). To manipulate ARA-containing PLs in microglia, we genetically deleted lysophosphatidylcholine acyltransferase 3 (Lpcat3), the main enzyme catalyzing the incorporation of ARA into PLs. Loss of microglial Lpcat3 reduced the levels of ARA-containing PLs, free ARA and LPLs, leading to a compensatory increase in monounsaturated fatty acid (MUFA)-containing PLs in both male and female App NL-GF mice. Notably, the reduction of ARA in microglia significantly ameliorated oxidative stress and inflammatory responses while enhancing the phagocytosis of Aβ plaques and promoting the compaction of Aβ deposits. Mechanistically, scRNA seq suggested that LPCAT3 deficiency facilitates phagocytosis by facilitating de novo lipid synthesis while protecting microglia from oxidative damage. Collectively, our study reveals a novel mechanistic link between ARA mobilization and microglial dysfunction in AD. Lowering brain ARA levels through pharmacological or dietary interventions may be a potential therapeutic strategy to slow down AD progression.

Patient-Reported Outcomes and Higher Order Aberrations Following Topography-Guided Femtosecond Laser-Assisted In Situ Keratomileusis.

To examine patient-reported outcomes and higher order aberrations following topography-guided laser-assisted in situ keratomileusis (LASIK). This was a prospective, nonrandomized observational study at a single academic center. Sixty eyes from 30 patients underwent bilateral topography-guided femtosecond LASIK for correction of myopia using the VisuMax 500 femtosecond laser (Zeiss; Oberkochen, Germany) and Allegretto Wave Eye-Q 400 Hz Excimer Laser (Alcon/Wavelight; Erlangen, Germany) with the Contoura topography system (Alcon; Geneva, Switzerland) for topography-modified refraction. The main outcomes of this study were higher order aberrations (HOAs) and results from the Patient-Reported Outcomes with LASIK questionnaire. There was a small, significant increase in HOA root mean square, spherical aberration, and coma at 1, 3, 6, and 12 months following topography-guided LASIK (all P < 0.05), but no change in trefoil. In addition, self-reported worry related to vision (P < 0.001) and ability to perform activities (P < 0.001) significantly improved after surgery. The prevalence of double images, glare, halos, or starbursts decreased from 73% preoperatively to 56%, and no participants reported "very" or "extremely" bothersome visual symptoms after 12 months. Dry eye symptoms per Ocular Surface Disease Index score decreased significantly at 6 (P = 0.01) and 12 (P = 0.002) months after surgery. There was a 100% satisfaction rate with visual outcomes and duration of time to improvement in vision following the procedure. Although there was an increase in HOAs following topography-guided LASIK, there were significant improvements in the presence of double images, glare, halos, and starbursts and vision-related quality-of-life metrics. Overall satisfaction rates in this study were high.

Genetic alteration profiling in middle-aged women acutely exposed during the mechanical processing of dental nanocomposites

Nanoparticles (NPs) have become an important part of everyday life, including their application in dentistry. Aside from their undoubted benefits, questions regarding their risk to human health, and/or genome have arisen. However, studies concerning cytogenetic effects are completely absent. A group of women acutely exposed to an aerosol released during dental nanocomposite grinding was sampled before and after the work. Exposure monitoring including nano (PM0.1) and respirable (PM4) fractions was performed. Whole-chromosome painting for autosomes #1, #4, and gonosome X was applied to estimate the pattern of cytogenetic damage including structural and numerical alterations. The results show stable genomic frequency of translocations (FG/100), in contrast to a significant 37.8% (p<0.05) increase of numerical aberrations caused by monosomies (p<0.05), but not trisomies. Monosomies were mostly observed for chromosome X. In conclusion, exposure to nanocomposites in stomatology may lead to an increase in numerical aberrations which can be dangerous for dividing cells.

Ovarian PERK/NRF2/CX43/StAR/progesterone pathway activation mediates female reproductive dysfunction induced by cold exposure

Ambient air temperature is a key factor affecting human health. Female reproductive disorders are representative health risk events under low temperature. However, the mechanism involving in cold-induced female reproductive disorders remains largely unknown. Female mice were intermittently exposed to cold conditions (4 °C) to address the health risk of low temperature on female reproductive system. Primary granulosa cells (GCs) were prepared and cultured under low temperature (35 °C) or exposed to β3-adrenoreceptor agonist, isoproterenol, to mimic the condition of cold exposure. Western-blot, RT-PCR, co-IP, ELISA, pharmacological inhibition or siRNA-mediated knockdown of target gene were performed to investigate the possible role of hormones, gap conjunction proteins, and ER stress sensor protein in regulating female reproductive disorders under cold exposure. Cold exposure induced estrous cycle disorder and follicular dysplasia in female mice, accompanying with abnormal upregulation of progesterone and its synthetic rate-limiting enzyme, StAR, in the ovarian granulosa cells. Under the same conditions, an increase in connexin 43 (CX43) expressions in the GCs was also observed, which contributed to elevated progesterone levels in the ovary. Moreover, ER stress sensor protein, PERK, was activated in the ovarian GCs after cold exposure, leading to the upregulation of downstream NRF2-dependent CX43 transcription and aberrant increase in progesterone synthesis. Most importantly, blocking PERK expression in vivo significantly inhibited NRF2/CX43/StAR/progesterone pathway activation in the ovary and efficiently rescued the prolongation of estrous cycle and the increase in follicular atresia of the female mice induced by cold stress. We have elucidated the mechanism of ovarian PERK/NRF2/CX43/StAR/progesterone pathway activation in mediating female reproductive disorder under cold exposure. Targeting PERK might be helpful for maintaining female reproductive health under cold conditions.