Mechanistic perspectives on anti-aminoacyl-tRNA synthetase syndrome.

Antisynthetase syndrome (ASSD) is an autoimmune disease characterized by circulating autoantibodies against one of eight aminoacyl-tRNA synthetases (aaRSs). Although these autoantibodies are believed to play critical roles in ASSD pathogenesis, the nature of their roles remains unclear. Here we describe ASSD pathogenesis and discuss ASSD-linked aaRSs - from the WHEP domain that may impart immunogenicity to the role of tRNA in eliciting the innate immune response and the secretion of aaRSs from cells. Through these explorations, we propose that ASSD pathogenesis involves the tissue-specific secretion of aaRSs and that extracellular tRNAs or tRNA fragments and their ability to engage Toll-like receptor signaling may be important disease factors.

Prediction of DNA i-motifs via machine learning.

i-Motifs (iMs), are secondary structures formed in cytosine-rich DNA sequences and are involved in multiple functions in the genome. Although putative iM forming sequences are widely distributed in the human genome, the folding status and strength of putative iMs vary dramatically. Much previous research on iM has focused on assessing the iM folding properties using biophysical experiments. However, there are no dedicated computational tools for predicting the folding status and strength of iM structures. Here, we introduce a machine learning pipeline, iM-Seeker, to predict both folding status and structural stability of DNA iMs. The programme iM-Seeker incorporates a Balanced Random Forest classifier trained on genome-wide iMab antibody-based CUT&Tag sequencing data to predict the folding status and an Extreme Gradient Boosting regressor to estimate the folding strength according to both literature biophysical data and our in-house biophysical experiments. iM-Seeker predicts DNA iM folding status with a classification accuracy of 81% and estimates the folding strength with coefficient of determination (R2) of 0.642 on the test set. Model interpretation confirms that the nucleotide composition of the C-rich sequence significantly affects iM stability, with a positive correlation with sequences containing cytosine and thymine and a negative correlation with guanine and adenine.

iM-Seeker: a webserver for DNA i-motifs prediction and scoring via automated machine learning.

DNA, beyond its canonical B-form double helix, adopts various alternative conformations, among which the i-motif, emerging in cytosine-rich sequences under acidic conditions, holds significant biological implications in transcription modulation and telomere biology. Despite recognizing the crucial role of i-motifs, predictive software for i-motif forming sequences has been limited. Addressing this gap, we introduce 'iM-Seeker', an innovative computational platform designed for the prediction and evaluation of i-motifs. iM-Seeker exhibits the capability to identify potential i-motifs within DNA segments or entire genomes, calculating stability scores for each predicted i-motif based on parameters such as the cytosine tracts number, loop lengths, and sequence composition. Furthermore, the webserver leverages automated machine learning (AutoML) to effortlessly fine-tune the optimal i-motif scoring model, incorporating user-supplied experimental data and customised features. As an advanced, versatile approach, 'iM-Seeker' promises to advance genomic research, highlighting the potential of i-motifs in cell biology and therapeutic applications. The webserver is freely available at https://im-seeker.org.

Potential roles of the interactions between gut microbiota and metabolites in LPS-induced intrauterine inflammation (IUI) and associated preterm birth (PTB).

BACKGROUND: Prenatal exposure to intrauterine inflammation (IUI) is a crucial event in preterm birth (PTB) pathophysiology, increasing the incidence of neurodevelopmental disorders. Gut microbiota and metabolite profile alterations have been reported to be involved in PTB pathophysiology. METHOD AND RESULTS: In this study, IUI-exposed PTB mouse model was established and verified by PTB rate and other perinatal adverse reactions; LPS-indued IUI significantly increased the rates of PTB, apoptosis and inflammation in placenta tissue samples. LPS-induced IUI caused no significant differences in species richness and evenness but significantly altered the species abundance distribution. Non-targeted metabolomics analysis indicated that the metabolite profile of the preterm mice was altered, and differential metabolites were associated with signaling pathways including pyruvate metabolism. Furthermore, a significant positive correlation between Parasutterella excrementihominis and S4572761 (Nb-p-coumaroyltryptamine) and Mreference-1264 (pyruvic acid), respectively, was observed. Lastly, pyruvic acid treatment partially improved LPS-induced IUI phenotypes and decreased PTB rates and decreased the apoptosis and inflammation in placenta tissue samples. CONCLUSION: This study revealed an association among gut microbiota dysbiosis, metabolite profile alterations, and LPS-induced IUI and PTB in mice models. Our investigation revealed the possible involvement of gut microbiota in the pathophysiology of LPS-induced IUI and PTB, which might be mediated by metabolites such as pyruvic acid. Future studies should be conducted to verify the findings through larger sample-sized animal studies and clinical investigations.

Carbon Nanotubes as Controllable Electric-Field-Induced Bipolar Electrodes for Efficient Water Purification.

Advanced oxidation processes (AOPs) are the most efficient water cleaning technologies, but their applications face critical challenges in terms of mass/electron transfer limitations and catalyst loss/deactivation. Bipolar electrochemistry (BPE) is a wireless technique that is promising for energy and environmental applications. However, the synergy between AOPs and BPE has not been explored. In this study, by combining BPE with AOPs, we develop a general approach of using carbon nanotubes (CNTs) as electric-field-induced bipolar electrodes to control electron transfer for efficient water purification. This approach can be used for permanganate and peroxide activation, with superior performances in the degradation of refractory organic pollutants and excellent durability in recycling and scale-up experiments. Theoretical calculations, in situ measurements, and physical experiments showed that an electric field could substantially reduce the energy barrier of electron transfer over CNTs and induce them to produce bipolar electrodes via electrochemical polarization or to form monopolar electrodes through a single particle collision effect with feeding electrodes. This approach can continuously provide activated electrons from one pole of bipolar electrodes and simultaneously achieve "self-cleaning" of catalysts through CNT-mediated direct oxidation from another pole of bipolar electrodes. This study provides a fundamental scientific understanding of BPE, expands its scope in the environmental field, and offers a general methodology for water purification.

Auxin guides germ-cell specification in Arabidopsis anthers.

Germ cells (GCs) are the key carriers delivering genetic information from one generation to the next. In a majority of animals, GCs segregate from somatic cells during embryogenesis by forming germlines. In land plants, GCs segregate from somatic cells during postembryonic development. In a majority of angiosperms, male GCs (archesporial cells) initiate at the four corners of the anther primordia. Little is known about the mechanism underlying this initiation. Here, we discovered that the dynamic auxin distribution in developing anthers coincided with GC initiation. A centripetal auxin gradient gradually formed toward the four corners where GCs will initiate. Local auxin biosynthesis was necessary for this patterning and for GC specification. The GC determinant protein SPOROCYTELESS/NOZZLE (SPL/NZZ) mediated the effect of auxin on GC specification and modified auxin biosynthesis to maintain a centripetal auxin distribution. Our work reveals that auxin is a key factor guiding GC specification in Arabidopsis anthers. Moreover, we demonstrate that the GC segregation from somatic cells is not a simple switch on/off event but rather a complicated process that involves a dynamic feedback circuit among local auxin biosynthesis, transcription of SPL/NZZ, and a progressive GC specification. This finding sheds light on the mystery of how zygote-derived somatic cells diverge into GCs in plants.

Male Germ Cell Specification in Plants.

Germ cells (GCs) serve as indispensable carriers in both animals and plants, ensuring genetic continuity across generations. While it is generally acknowledged that the timing of germline segregation differs significantly between animals and plants, ongoing debates persist as new evidence continues to emerge. In this review, we delve into studies focusing on male germ cell specifications in plants, and we summarize the core gene regulatory circuits in germ cell specification, which show remarkable parallels to those governing meristem homeostasis. The similarity in germline establishment between animals and plants is also discussed.

Small extracellular vesicles-transported lncRNA TDRKH-AS1 derived from AOPPs-treated trophoblasts initiates endothelial cells pyroptosis through PDIA4/DDIT4 axis in preeclampsia.

BACKGROUND: Substantial studies have demonstrated that oxidative stress placenta and endothelial injury are considered to inextricably critical events in the pathogenesis of preeclampsia (PE). Systemic inflammatory response and endothelial dysfunction are induced by the circulating factors released from oxidative stress placentae. As a novel biomarker of oxidative stress, advanced oxidation protein products (AOPPs) levels are strongly correlated with PE characteristics. Nevertheless, the molecular mechanism underlying the effect of factors is still largely unknown. METHODS: With the exponential knowledge on the importance of placenta-derived extracellular vesicles (pEVs), we carried out lncRNA transcriptome profiling on small EVs (sEVs) secreted from AOPPs-treated trophoblast cells and identified upregulated lncRNA TDRKH-AS1 as a potentially causative factor for PE. We isolated and characterized sEVs from plasma and trophoblast cells by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting. The expression and correlation of lncRNA TDRKH-AS1 were evaluated using qRT-PCR in plasmatic sEVs and placentae from patients. Pregnant mice injected with TDRKH-AS1-riched trophoblast sEVs was performed to detect the TDRKH-AS1 function in vivo. To investigate the potential effect of sEVs-derived TDRKH-AS1 on endothelial function in vitro, transcriptome sequencing, scanning electron Microscopy (SEM), immunofluorescence, ELISA and western blotting were conducted in HUVECs. RNA pulldown, mass spectrometry, RNA immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP) and coimmunoprecipitation (Co-IP) were used to reveal the latent mechanism of TDRKH-AS1 on endothelial injury. RESULTS: The expression level of TDRKH-AS1 was significantly increased in plasmatic sEVs and placentae from patients, and elevated TDRKH-AS1 in plasmatic sEVs was positively correlated with clinical severity of the patients. Moreover, pregnant mice injected with TDRKH-AS1-riched trophoblast sEVs exhibited a hallmark feature of PE with increased blood pressure and systemic inflammatory responses. Pyroptosis, an inflammatory form of programmed cell death, is involved in the development of PE. Indeed, our in vitro study indicated that sEVs-derived TDRKH-AS1 secreted from AOPPs-induced trophoblast elevated DDIT4 expression levels to trigger inflammatory response of pyroptosis in endothelial cells through interacting with PDIA4. CONCLUSIONS: Herein, results in the present study supported that TDRKH-AS1 in sEVs isolated from oxidative stress trophoblast may be implicated in the pathogenesis of PE via inducing pyroptosis and aggravating endothelial dysfunction.

Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease.

FARS2 encodes the mitochondrial phenylalanyl-tRNA synthetase (mtPheRS), which is essential for charging mitochondrial (mt-) tRNAPhe with phenylalanine for use in intramitochondrial translation. Many biallelic, pathogenic FARS2 variants have been described previously, which are mostly associated with two distinct clinical phenotypes; an early onset epileptic mitochondrial encephalomyopathy or a later onset spastic paraplegia. In this study, we report on a patient who presented at 3 weeks of age with tachypnoea and poor feeding, which progressed to severe metabolic decompensation with lactic acidosis and seizure activity followed by death at 9 weeks of age. Rapid trio whole exome sequencing identified compound heterozygous FARS2 variants including a pathogenic exon 2 deletion on one allele and a rare missense variant (c.593G > T, p.(Arg198Leu)) on the other allele, necessitating further work to aid variant classification. Assessment of patient fibroblasts demonstrated severely decreased steady-state levels of mtPheRS, but no obvious defect in any components of the oxidative phosphorylation system. To investigate the potential pathogenicity of the missense variant, we determined its high-resolution crystal structure, demonstrating a local structural destabilization in the catalytic domain. Moreover, the R198L mutation reduced the thermal stability and impaired the enzymatic activity of mtPheRS due to a lower binding affinity for tRNAPhe and a slower turnover rate. Together these data confirm the pathogenicity of this FARS2 variant in causing early-onset mitochondrial epilepsy.

Identification of circular RNAs as regulators and noninvasive biomarkers for placenta accreta spectrum.

In brief: Placenta accreta spectrum (PAS) has an urgent need for reliable prenatal biomarkers. This study profiled the circular RNAs (circRNAs) in PAS placenta and maternal blood and identified two circRNAs can regulate trophoblast cells invasion and serve as noninvasive prenatal biomarkers for PAS prediction. Abstract: PAS is one of the most alarming obstetric diseases with high mortality rates. The regulating mechanism underlying PAS remains to be investigated, and reliable blood biomarkers for PAS have not emerged. Circular RNAs (circRNAs) have become important regulators and biomarkers for disparate human diseases. However, the circRNA profiles of PAS were not reported, and the regulatory role and predictive value of circRNAs in PAS were unknown. Here, we comprehensively profiled the circRNAs in the placenta of PAS by transcriptome sequencing and analysis and uncovered 217 abnormally expressed circRNAs. Through competing endogenous RNA network analysis, we found that the target genes of upregulated circRNAs in PAS were enriched in placenta development-related pathways and further uncovered two circRNAs, circPHACTR4 and circZMYM4, that could regulate trophoblast cells invasion and migration in vitro. Finally, we verified that circPHACTR4 and circZMYM4 were also upregulated in the maternal peripheral blood of PAS women before delivery using transcriptome sequencing and RT-qPCR and evaluated their predictive value by ROC curves. We found that circPHACTR4 and circZMYM4 could serve as effective predicting biomarkers for PAS (area under the curve (AUC): 0.86 and 0.85) and propose an improved model for PAS prenatal prediction by combining the conventional ultrasound diagnosis with the new circRNA predictive factors (AUC: 0.91, specificity: 0.89, sensitivity: 0.82).Altogether, this work provides new resources for deciphering the biological roles of circRNAs in PAS, identified two circRNAs that could regulate trophoblast cells invasion during placentation, and revealed two noninvasive diagnostic markers for PAS.

Impact of statin treatment and exposure on the risk of chronic allograft dysfunction in Chinese lung transplant recipients.

PURPOSE: Chronic lung allograft dysfunction (CLAD) was a common complication following lung transplantation that contributed to long-term morbidity and mortality. Statin therapy had been suggested to attenuate recipient inflammation and immune response, potentially reducing the risk and severity of CLAD. This study aimed to evaluate the impact of statin use and in vivo exposure on the incidence of CLAD in lung transplant recipients (LTRs), as well as their effects on immune cells and inflammatory factors. METHODS: A retrospective cohort study was conducted on patients who underwent lung transplantation between January 2017 and December 2020. The incidence of CLAD, as per the 2019 ISHLT criteria, was assessed as the clinical outcome. The plasma concentrations of statin were measured using a validated UPLC-MS/MS method, while inflammation marker levels were determined using ELISA kits. RESULTS: The statin group exhibited a significantly lower rate of CLAD (P = 0.002). Patients receiving statin therapy showed lower CD4+ T-cell counts, total T-lymphocyte counts, and IL-6 levels (P = 0.017, P = 0.048, and P = 0.038, respectively). Among the CLAD groups, the atorvastatin level (2.51 ± 1.31 ng/ml) was significantly lower than that in the non-CLAD group (OR = 1.438, 95%CI (1.007-2.053), P = 0.046). CONCLUSION: Statin therapy significantly reduced the incidence of CLAD, as well as immune cell counts and inflammatory cytokine levels in LTRs. Although the statin exposure was significantly lower in CLAD patients, it was not associated with the incidence of CLAD.

Pseudogene CLEC4GP1 modulates trophoblast cell apoptosis and invasion via IL-15 inhibition.

Preeclampsia (PE) is a pregnancy-associated complication accompanied by gestational hypertension and proteinuria, affecting 2-8% of pregnancies globally. The placental trophoblast cell invasion of decidua and myometrium during early gestation is crucial for healthy placentation. Thus, trophoblast dysfunction might contribute to PE onset. Therefore, further investigations are needed to elucidate the underlying mechanism of trophoblast cell functions. In the present study, we identified a novel pseudogene named C-Type Lectin Domain Family 4 Member G Pseudogene 1 (CLEC4GP1), which was aberrantly expressed in PE placental tissues. In vitro analyses showed that CLEC4GP1 overexpression significantly increased the cell viability and invasiveness and decreased the apoptosis rate of HTR-8/SVneo and JEG-3 cells, while CLEC4GP1 knockdown exerted opposite effects, suggesting the beneficial role of CLEC4GP1 in trophoblast cells. Next, co-expression analysis found that CLEC4GP1 was negatively correlated with Interleukin 15 (IL-15). The expression of IL-15 dramatically increased in PE placental tissues. In HTR-8/SVneo and JEG-3 cells, IL-15 exhibited detrimental effects, opposite to CLEC4GP1, and they were negatively correlated. In addition, CLEC4GP1 attenuates the mRNA stability of IL-16 by inhibiting the binding between human antigen R (HuR) protein and IL-15 RNA. Finally, the obverse effects of CLEC4GP1 and IL-15 were investigated, and results showed that IL-15 reverted CLEC4GP1 induced cellular functions. In brief, these data suggest that CLEC4GP1/IL-15 axis might modulate the occurrence and progression of PE via influencing the trophoblast cell viability, apoptosis, and invasive capability. This study provided cognizance of targeting the CLEC4GP1/IL-15 axis as a novel therapeutic approach to mitigate PE progression.

Sensitive, Highly Stable, and Anti-Fouling Electrode with Hexanethiol and Poly-A Modification for Exosomal microRNA Detection.

It remains a huge challenge to integrate the sensitivity, stability, reproducibility, and anti-fouling ability of electrochemical biosensors for practical applications. Herein, we propose a self-assembled electrode combining hexanethiol (HT), poly-adenine (poly-A), and cholesteryl-modified DNA to meet this challenge. HT can tightly pack at the electrode interface to form a hydrophobic self-assembled monolayer (SAM), effectively improving the stability and signal-to-noise ratio (SNR) of electrochemical detection. Cholesteryl-modified DNA was immobilized at the electrode through the hydrophobic interaction with HT to avoid the competition between the SAM and the DNA probe on the gold site. Thus, the assembly efficiency and uniformity of the DNA probe as well as the detection reproducibility were increased remarkedly. Poly-A was added on the HT assembled electrode to occupy the unreacted sites of gold to further enhance the anti-fouling ability. The combination of HT and poly-A allows the electrode to ensure favorable anti-fouling ability without sacrificing the detection performance. On this basis, we proposed a dual-signal amplification electrochemical biosensor for the detection of exosomal microRNAs, which showed excellent sensitivity with a detection limit down to 1.46 aM. Importantly, this method has been successfully applied to detect exosomal microRNA-21 in cells and human serum samples, proving its potential utility in cancer diagnosis.

The population pharmacokinetics and dose optimization of polymyxin B in critically ill patients with or without extracorporeal membrane oxygenation.

WHAT IS KNOWN AND OBJECTIVE: The presence of extracorporeal membrane oxygenation (ECMO) is suggested to further exacerbate the pharmacokinetics (PK) alterations that occur during critical illness. The objectives of this study were to determine the population PK model of polymyxin B in critically ill patients with or without ECMO support investigated the influence of ECMO on PK variability and to identify an optimal dosing strategy. METHODS: Forty-four critically ill patients were enrolled, including eight patients with ECMO support. Eight serial serum samples were collected from each patient at steady state. The population PK was determined using NONMEM and Monte Carlo simulation was performed to evaluate the exposures of different dosing regimens. RESULTS: The PK analyses included 342 steady-state concentrations and a two-compartment model was optimal for polymyxin B PK data modelling. In the final model, creatinine clearance (CLCR ) was the significant covariate on CL (typical value 1.27 L/h; between-subject variability 15.1%) and ECMO did not show a significant impact on the polymyxin B PK. Additionally, we found that the PK parameter estimates of patients with and without ECMO support were mostly similar. Based on Monte Carlo simulations, the dose escalation of polymyxin B in patients with increased CLCR improved the probability of achieving required exposure. For patients with CLCR ≤ 120 ml/min, a dosage regimen of 100 mg every 12 h may represent the optimal regimen at an MIC of 1 mg/L. WHAT IS NEW AND CONCLUSION: The impact of ECMO on the polymyxin B PK is likely to be minimal. Our study showed a potential relationship between CLCR and polymyxin B CL, and the dose of polymyxin B should be adjusted in patients with increased CLCR .

Effect of ABCB1 gene variants on rivaroxaban pharmacokinetic and hemorrhage events occurring in patients with non-valvular atrial fibrillation.

Hemorrhage events occur most frequently in anticoagulant therapy for non-valvular atrial fibrillation (NVAF). Rivaroxaban is used widely for routine anticoagulation care. Genetic polymorphisms are thought to contribute to the wide intraindividual variability seen in rivaroxaban metabolism and the anticoagulant response. The aim of this study was to evaluate the effect of drug transport related single-nucleotide polymorphisms (SNPs) on rivaroxaban metabolism and on the risk of a hemorrhage event. A total of 216 Chinese patients with NVAF were enrolled in the study. Rivaroxaban was used for anticoagulation therapy. Rivaroxaban plasma concentrations were detected using a validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Seven SNPs in four genes were genotyped using the Sanger dideoxy DNA sequencing method. Associations between genotype variants, the incidence of hemorrhage events, and the time of bleeding were analyzed. ABCB1 2677G (rs2032582) variation was highly associated with the dose-adjusted rivaroxaban peak concentration in plasma (Cmax /D) (p = 0.025, FDR = 0.042). The ABCB1 G allele carriers had a higher rivaroxaban Cmax /D than non-carriers. Logistic regression showed that rivaroxaban Cmax /D and ABCB1 genotype variants were associated with a higher incidence of hemorrhage events. No statistically significant difference was found between ABCB1 genotypes and the time of bleeding after anticoagulant therapy in 30 days. These results indicated that ABCB1 2677G (rs2032582) genetic variant affects the rivaroxaban Cmax /Dose and the incidence of hemorrhage events significantly.

A structural equation modeling approach to determine the correlation between the vertical and sagittal skeletal patterns and posterior basal bones mismatching in patients with skeletal Class III malocclusion.

INTRODUCTION: Matching the maxillomandibular basal bone width is essential to the stability of orthodontic treatment. We aimed to determine the relationship between basal bone width mismatching and the vertical and sagittal skeletal pattern in patients with skeletal Class III malocclusion through shape analysis and structural equation modeling (SEM). METHODS: Cone-beam computed tomography images were collected from 45 men and 51 women. Width mismatching of the basal bone was determined using generalized Procrustes analysis. Twenty-two parameters from the synthesized cephalogram were measured, followed by factor analysis and SEM. RESULTS: Mismatch occurred at the second molar (men, -4.29 ± 4.32 mm; women, -5.55 ± 4.43 mm) and retromolar regions (men, -8.49 ± 5.11 mm; women: -8.93 ± 5.25 mm). The sum of angles had the largest loading for vertical-1 (extracted from 18 vertical cephalometric measurements) (men, 0.9477; women, 0.9489), followed by MP-SN angle (0.9408) in men and N-Me/S-Go (0.9342) in women. Wits appraisal and anteroposterior dysplasia indicator were largest for Sagittal-1. SEM showed a positive effect of male vertical-1 and 2 on width difference in the retromolar region (P <0.001; B >0). Female vertical-1 had a significant positive effect on DW7 (P <0.001; B = 5.535) and DWR (P = 0.016; B = 3.427) as vertical-2. Sagittal-1 showed a negative correlation with DW7 in both genders (P <0.05; B <0) and with DWR in men. CONCLUSIONS: Basal bone width mismatching occurred at the second molar and retromolar regions, especially in low-angle and patients with severe skeletal Class III malocclusion.

Comparing the accuracy of new intraocular lens power calculation formulae in short eyes after cataract surgery: a systematic review and meta-analysis.

PURPOSE: Calculating the intraocular lens (IOL) power in short eyes for cataract surgery has been a challenge. A meta-analysis was conducted to identify, among several classic and new IOL power calculation formulae, which obtains the best accuracy. METHODS: All studies aiming at comparing the accuracy of IOL power calculation formulae in short eyes were searched up in the databases of PubMed, EMBASE, Web of Science and the Cochrane library from Jan. 2011 to Mar. 2021. Primary outcomes were the percentages of eyes with a refractive prediction error in ± 0.25D, ± 0.5D and ± 1.0D. RESULTS: Totally 1,476 eyes from 14 studies were enrolled in comparison of 13 formulae (Barrett Universal II, Castrop, Haigis, Hoffer Q, Holladay1, Holladay2, Kane, Ladas Super Formula, Okulix, Olsen, Pearl-DGS, SRK/T and T2). Pearl-DGS had the highest percentage within ± 0.25D. In the ± 0.5D range, Pearl-DGS obtained the highest percentage again, and it was significantly higher than Barrett Universal II, Haigis, Hoffer Q, Holladay1, Holladay2 and Olsen (P = 0.001, P = 0.02, P = 0.0003, P = 0.01, P = 0.007, P = 0.05, respectively). In the ± 1.0D range, Okulix possessed the highest percentage, and it was significantly higher than Barrett Universal II, Castrop, Hoffer Q and Holladay2 (P = 0.0005, P = 0.03, P = 0.003, P = 0.02, respectively). CONCLUSION: The new generation formulae, based on artificial intelligence or ray-tracing principle, are more accurate than the convergence formulae. Pearl-DGS and Okulix are the two most accurate formulae in short eyes.

Noninvasive high-frequency oscillatory ventilation versus bi-level positive pressure ventilation in premature infants with respiratory failure: A retrospective study.

Objectives: Noninvasive high-frequency oscillatory ventilation (nHFOV) is a novel respiratory support mode for premature infants. This retrospective study aimed to compare the effect of nHFOV and bi-level nasal continuous positive airway pressure (BiPAP) in premature infants with neonatal respiratory failure (NRF) as initial noninvasive ventilation (NIV) support mode. Methods: We retrospectively analyzed medical records of preterm infants admitted to the tertiary neonatal intensive care units (NICUs) of Fujian Maternal and Child Health Hospital from January 2019 to December 2020. Preterm infants with the gestational age of 25-34 weeks, diagnosed with NRF, used nHFOV or BiPAP as the initial respiratory support mode were analyzed. The rates of invasive mechanical ventilation (IMV) within the first seven days after birth and adverse outcomes were compared between the two groups. Results: Two hundred fifty-five preterm infants were analyzed (128 in nHFOV group,127 in BiPAP group). There was no significant difference in baseline characteristics between the two groups. Compared with the BiPAP group, the nHFOV group had significantly lower need for IMV within the first seven days after birth (18/128 vs. 33/127, p = 0.01) and PCO2 at 12 and 24 hours post-treatment (46.34±5.24mmHg vs. 51.18±4.83mmHg, P<0.01; 40.72±4.02mmHg vs. 42.50±3.86mmHg, P<0.01). The incidence of BPD, ROP, air leak syndromes, IVH≥ grade 3, PVL, NEC≥II stage, abdominal distension, and nasal trauma were similar between the two groups. Conclusion: nHFOV significantly reduced the need for IMV and improved the elimination of CO2 compared with BiPAP in preterm infants with NRF without increasing the incidence of adverse effects.

The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy.

Epilepsy, deafness, onychodystrophy, osteodystrophy and intellectual disability are associated with a spectrum of mutations of human TBC1D24. The mechanisms underlying TBC1D24-associated disorders and the functions of TBC1D24 are not well understood. Using CRISPR-Cas9 genome editing, we engineered a mouse with a premature translation stop codon equivalent to human S324Tfs*3, a recessive mutation of TBC1D24 associated with early infantile epileptic encephalopathy (EIEE). Homozygous S324Tfs*3 mice have normal auditory and vestibular functions but show an abrupt onset of spontaneous seizures at postnatal day 15 recapitulating human EIEE. The S324Tfs*3 variant is located in an alternatively spliced micro-exon encoding six perfectly conserved amino acids incorporated postnatally into TBC1D24 protein due to a micro-exon utilization switch. During embryonic and early postnatal development, S324Tfs*3 homozygotes produce predominantly the shorter wild-type TBC1D24 protein isoform that omits the micro-exon. S324Tfs*3 homozygotes show an abrupt onset of seizures at P15 that correlates with a developmental switch to utilization of the micro-exon. A mouse deficient for alternative splice factor SRRM3 impairs incorporation of the Tbc1d24 micro-exon. Wild-type Tbc1d24 mRNA is abundantly expressed in the hippocampus using RNAscope in situ hybridization. Immunogold electron microscopy using a TBC1D24-specific antibody revealed that TBC1D24 is associated with clathrin-coated vesicles and synapses of hippocampal neurons, suggesting a crucial role of TBC1D24 in vesicle trafficking important for neuronal signal transmission. This is the first characterization of a mouse model of human TBC1D24-associated EIEE that can now be used to screen for antiepileptogenic drugs ameliorating TBCID24 seizure disorders.

Cataract formation in transgenic HO-1 G143H mutant mice: Involvement of oxidative stress and endoplasmic reticulum stress.

Oxidative stress and endoplasmic reticulum (ER) stress are the key contributing factors for cataract progression. In our previous studies, we demonstrated that the nuclear factor erythroid 2-like-2 (Nrf-2)/heme oxygenase-1 (HO-1)/carbon monoxide (CO) axis protects lens epithelial cells (LECs) against oxidants and ER stress. In the present study, transgenic FVB/N mice overexpressing the negative dominant mutant HO-1 G143H (TgHO-1 G143H) were generated to evaluate the crosstalk among HO-1, oxidative stress and ER stress in maintaining lens transparency. Slit-lamp examination revealed that nuclear cataracts occurred at 4 months in the TgHO-1 G143H mice, which was 5 months earlier than that of the control mice. The lenses of the transgenic mice showed an accumulation of malondialdehyde and protein carbonyl with a decrease in glutathione and protein sulfhydryl levels. Elevated concentrations of ER stress biomarkers (Bip, PERK, ATF6, IRE1, CHOP, caspase-12 and caspase-3) in the lenses of the TgHO-1 G143H mice were identified by western blotting. Furthermore, we confirmed that overexpressed HO-1 G143H in LECs resulted in oxidative insult and apoptosis in vitro. All of these data suggested that HO-1 enzymatic activity loss induces early-onset nuclear cataracts by activating oxidative stress and ER stress.