Optogenetically engineered Ca2+ oscillation-mediated DRP1 activation promotes mitochondrial fission and cell death.

Mitochondrial dynamics regulate the quality and morphology of mitochondria. Calcium (Ca2+) plays an important role in regulating mitochondrial function. Here, we investigated the effects of optogenetically engineered Ca2+ signaling on mitochondrial dynamics. More specifically, customized illumination conditions could trigger unique Ca2+ oscillation waves to trigger specific signaling pathways. In this study, we found that modulating Ca2+ oscillations by increasing the light frequency, intensity and exposure time could drive mitochondria toward the fission state, mitochondrial dysfunction, autophagy and cell death. Moreover, illumination triggered phosphorylation at the Ser616 residue but not the Ser637 residue of the mitochondrial fission protein, dynamin-related protein 1 (DRP1, encoded by DNM1L), via the activation of Ca2+-dependent kinases CaMKII, ERK and CDK1. However, optogenetically engineered Ca2+ signaling did not activate calcineurin phosphatase to dephosphorylate DRP1 at Ser637. In addition, light illumination had no effect on the expression levels of the mitochondrial fusion proteins mitofusin 1 (MFN1) and 2 (MFN2). Overall, this study provides an effective and innovative approach to altering Ca2+ signaling for controlling mitochondrial fission with a more precise resolution than pharmacological approaches in the temporal dimension.

Integrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte Hypertrophy.

BACKGROUND: Signaling by cAMP is organized in multiple distinct subcellular nanodomains regulated by cAMP-hydrolyzing PDEs (phosphodiesterases). Cardiac ß-adrenergic signaling has served as the prototypical system to elucidate cAMP compartmentalization. Although studies in cardiac myocytes have provided an understanding of the location and properties of a handful of cAMP subcellular compartments, an overall view of the cellular landscape of cAMP nanodomains is missing. METHODS: Here, we combined an integrated phosphoproteomics approach that takes advantage of the unique role that individual PDEs play in the control of local cAMP, with network analysis to identify previously unrecognized cAMP nanodomains associated with ß-adrenergic stimulation. We then validated the composition and function of one of these nanodomains using biochemical, pharmacological, and genetic approaches and cardiac myocytes from both rodents and humans. RESULTS: We demonstrate the validity of the integrated phosphoproteomic strategy to pinpoint the location and provide critical cues to determine the function of previously unknown cAMP nanodomains. We characterize in detail one such compartment and demonstrate that the PDE3A2 isoform operates in a nuclear nanodomain that involves SMAD4 (SMAD family member 4) and HDAC-1 (histone deacetylase 1). Inhibition of PDE3 results in increased HDAC-1 phosphorylation, leading to inhibition of its deacetylase activity, derepression of gene transcription, and cardiac myocyte hypertrophic growth. CONCLUSIONS: We developed a strategy for detailed mapping of subcellular PDE-specific cAMP nanodomains. Our findings reveal a mechanism that explains the negative long-term clinical outcome observed in patients with heart failure treated with PDE3 inhibitors.

Molecularly imprinted dispersive micro solid-phase extraction and tandem derivatization for the determination of histamine in fermented wines.

Histamine causes allergic reactions and can serve as an indicator for assessing food quality. This study designed and developed a dispersive micro solid-phase extraction (D-µSPE) method that combined the advantages of dispersive liquid-liquid extraction and solid-phase extraction (SPE). Molecularly imprinted polymers (MIPs) were employed as the solid phase in the D-µSPE method to extract histamine in wine samples. We used microwave energy to significantly reduce the synthesis time, achieving an 11.1-fold shorter synthesis time compared to the conventional MIP synthetic method. Under optimized D-µSPE conditions, our results showed that the dispersive solvent could effectively increase the adsorption performance of MIPs in wine samples by 97.7%. To improve the sensitivity of histamine detection in gas chromatography-mass spectrometry, we employed the microwave-assisted tandem derivatization method to reuse excess derivatization reagents and reduce energy consumption and reaction time. Calibration curves were constructed for wine samples spiked with 0-400 nmol histamine using the standard addition method, resulting in good linearity with a coefficient of determination of 0.999. The intra- and inter-batch relative standard deviations of the slope and intercept were < 0.7% and < 5.3%, respectively. The limits of quantitation and detection were 0.4 nmol and 0.1 nmol, respectively. The developed method was successfully applied to analyze the histamine concentration in 10 commercial wine samples. In addition, the AGREEprep tool was used to evaluate the greenness performance of the developed method, which obtained a higher score than the other reported methods.

Visual vertigo and motion sickness is different between persistent postural-perceptual dizziness and vestibular migraine.

INTRODUCTION: Persistent postural-perceptual dizziness (PPPD) and vestibular migraine (VM) share symptoms of visual vertigo and motion sickness that can be confusing for clinicians to distinguish. We compare the severity of these symptoms and dynamic subjective visual vertical (dSVV) in these two common vestibular conditions. METHOD: Twenty-nine patients with PPPD, 37 with VM, and 29 controls were surveyed for subjective symptoms using the visual vertigo analogue scale (VVAS) and motion sickness susceptibility questionnaire during childhood (MSA) and the past 10 years (MSB). dSVV is a measure of visual dependence measures perception of verticality against a rotating background (5 deg./s). RESULTS: VVAS revealed contextual differences for dizziness between those with PPPD and VM. Ratings of visual vertigo were most severe in PPPD, less in VM, and mild in controls (VVAS PPPD 27.1, VM 11.2, control 4.6, p < 0.001). MSA was more severe in VM than in PPPD or control (12.8 vs 7.6 vs 8.5, p = 0.01). MSB was more severe in VM than controls (MSB score 12.9 VS 8.1 p = 0.009) but was not different than PPPD (MSB score 10.0, p = 0.10). dSVV alignment was similar among the three groups (p = 0.83). Both VM and PPPD groups had greater simulator sickness than controls after completing the dSVV. CONCLUSIONS: Patients with PPPD report more visual vertigo than those with VM, but a history of motion sickness as a child is more common in VM. Additionally, the environmental context that induces visual vertigo is different between PPPD and VM.

Hsa-miR-379 down-regulates Rac1/MLK3/JNK/AP-1/Collagen I cascade reaction by targeting connective tissue growth factor in human alveolar basal epithelial A549 cells.

OBJECTIVE: This study was aimed to screen and identify miRNAs that could regulate human CTGF gene and downstream cascade reaction Rac1/MLK3/JNK/AP-1/Collagen I by bioinformatics and experimental means. METHODS: TargetScan and Tarbase were used to predict miRNAs that may have regulatory effects on human CTGF gene. The dual-luciferase reporter gene assay was employed to verify the results obtained in bioinformatics. Human alveolar basal epithelial A549 cells were exposed to silica (SiO2) culture medium for 24 h to establish an in vitro model of pulmonary fibrosis, and bleomycin (BLM) of 100 ng/mL was used as a positive control. The miRNA and mRNA expression levels were determined by RT-qPCR, and the protein levels were measured by western blot in hsa-miR-379-3p overexpression group or not. RESULTS: A total of 9 differentially expressed miRNAs that might regulate the human CTGF gene were predicted. Hsa-miR-379-3p and hsa-miR-411-3p were selected for the subsequent experiments. The results of the dual-luciferase reporter assay showed that hsa-miR-379-3p could bind to CTGF, but hsa-miR-411-3p could not. Compared with the control group, SiO2 exposure (25 and 50 µg/mL) could significantly reduce the expression level of hsa-miR-379-3p in A549 cells. SiO2 exposure (50 µg/mL) could significantly increase the mRNA expression levels of CTGF, Collagen I, Rac1, MLK3, JNK, AP1, and VIM in A549 cells, while CDH1 level was significantly decreased. Compared with SiO2 + NC group, the mRNA expression levels of CTGF, Collagen I, Rac1, MLK3, JNK, AP1, and VIM were significantly decreased, and CDH1 level was significantly higher when hsa-miR-379-3p was overexpressed. At the same time, overexpression of hsa-miR-379-3p improved the protein levels of CTGF, Collagen I, c-Jun and phospho-c-Jun, JNK1 and phospho-JNK1 significantly compared with SiO2 + NC group. CONCLUSION: Hsa-miR-379-3p was demonstrated for the first time that could directly target and down-regulate human CTGF gene, and further affect the expression levels of key genes and proteins in Rac1/MLK3/JNK/AP-1/Collagen I cascade reaction.

{[In2S7]8-}∞ Chain and Isolated HgS4 Planar Unit Constructed One-Dimensional Pentanary Sulfide K2Ba7HgIn4S16 Exhibiting Nonlinear-Optical Activity.

Hg-based chalcogenides possess diverse structures, large nonlinear-optical (NLO) responses, and suitable birefringences, making them potentially suitable for numerous crucial criteria of practical application as infrared (IR) NLO crystals. Here, a new pentanary Hg-based sulfide K2Ba7HgIn4S16 has been discovered by a high-temperature solid-state method. It crystallizes in the orthorhombic P21212 space group, and its one-dimensional structure is constructed by {[In2S7]8-}∞ chains and isolated [HgS4]6- planar quadrilateral units located bewteeen the chains, representing a novel type of chalcogenide. K2Ba7HgIn4S16 exhibits a moderate NLO effect of 0.5 × AGS at 2.1 µm and a high laser-induced damage threshold of ∼5.8 × AGS, as well as a band gap of 2.98 eV, demonstrating that K2Ba7HgIn4S16 is a potential IR NLO material. This work enriches the structural chemistry of chalcogenides and the family of Hg-based IR NLO chalcogenides.

A 24-year longitudinal study of Klebsiella pneumoniae isolated from patients with bacteraemia and urinary tract infections reveals the association between capsular serotypes, antibiotic resistance, and virulence gene distribution.

Longitudinal studies on the variations of phenotypic and genotypic characteristics of K. pneumoniae across two decades are rare. We aimed to determine the antimicrobial susceptibility and virulence factors for K. pneumoniae isolated from patients with bacteraemia or urinary tract infection (UTI) from 1999 to 2022. A total of 699 and 1,267 K. pneumoniae isolates were isolated from bacteraemia and UTI patients, respectively, and their susceptibility to twenty antibiotics was determined; PCR was used to identify capsular serotypes and virulence-associated genes. K64 and K1 serotypes were most frequently observed in UTI and bacteraemia, respectively, with an increasing frequency of K20, K47, and K64 observed in recent years. entB and wabG predominated across all isolates and serotypes; the least frequent virulence gene was htrA. Most isolates were susceptible to carbapenems, amikacin, tigecycline, and colistin, with the exception of K20, K47, and K64 where resistance was widespread. The highest average number of virulence genes was observed in K1, followed by K2, K20, and K5 isolates, which suggest their contribution to the high virulence of K1. In conclusion, we found that the distribution of antimicrobial susceptibility, virulence gene profiles, and capsular types of K. pneumoniae over two decades were associated with their clinical source.

PREDICTING VISUAL OUTCOME AFTER SURGERY IN PATIENTS WITH IDIOPATHIC EPIRETINAL MEMBRANE USING A NOVEL CONVOLUTIONAL NEURAL NETWORK.

PURPOSE: To develop a deep convolutional neural network that enables the prediction of postoperative visual outcomes after epiretinal membrane surgery based on preoperative optical coherence tomography images and clinical parameters to refine surgical decision making. METHODS: A total of 529 patients with idiopathic epiretinal membrane who underwent standard vitrectomy with epiretinal membrane peeling surgery by two surgeons between January 1, 2014, and June 1, 2020, were enrolled. The newly developed Heterogeneous Data Fusion Net was introduced to predict postoperative visual acuity outcomes (improvement ≥2 lines in Snellen chart) 12 months after surgery based on preoperative cross-sectional optical coherence tomography images and clinical factors, including age, sex, and preoperative visual acuity. The predictive accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve of the convolutional neural network model were evaluated. RESULTS: The developed model demonstrated an overall accuracy for visual outcome prediction of 88.68% (95% CI, 79.0%-95.7%) with an area under the receiver operating characteristic curve of 97.8% (95% CI, 86.8%-98.0%), sensitivity of 87.0% (95% CI, 67.9%-95.5%), specificity of 92.9% (95% CI, 77.4%-98.0%), precision of 0.909, recall of 0.870, and F1 score of 0.889. The heatmaps identified the critical area for prediction as the ellipsoid zone of photoreceptors and the superficial retina, which was subjected to tangential traction of the proliferative membrane. CONCLUSION: The novel Heterogeneous Data Fusion Net demonstrated high accuracy in the automated prediction of visual outcomes after weighing and leveraging multiple clinical parameters, including optical coherence tomography images. This approach may be helpful in establishing personalized therapeutic strategies for epiretinal membrane management.

An automatic and accurate deep learning-based neuroimaging pipeline for the neonatal brain.

BACKGROUND: Accurate segmentation of neonatal brain tissues and structures is crucial for studying normal development and diagnosing early neurodevelopmental disorders. However, there is a lack of an end-to-end pipeline for automated segmentation and imaging analysis of the normal and abnormal neonatal brain. OBJECTIVE: To develop and validate a deep learning-based pipeline for neonatal brain segmentation and analysis of structural magnetic resonance images (MRI). MATERIALS AND METHODS: Two cohorts were enrolled in the study, including cohort 1 (582 neonates from the developing Human Connectome Project) and cohort 2 (37 neonates imaged using a 3.0-tesla MRI scanner in our hospital).We developed a deep leaning-based architecture capable of brain segmentation into 9 tissues and 87 structures. Then, extensive validations were performed for accuracy, effectiveness, robustness and generality of the pipeline. Furthermore, regional volume and cortical surface estimation were measured through in-house bash script implemented in FSL (Oxford Centre for Functional MRI of the Brain Software Library) to ensure reliability of the pipeline. Dice similarity score (DSC), the 95th percentile Hausdorff distance (H95) and intraclass correlation coefficient (ICC) were calculated to assess the quality of our pipeline. Finally, we finetuned and validated our pipeline on 2-dimensional thick-slice MRI in cohorts 1 and 2. RESULTS: The deep learning-based model showed excellent performance for neonatal brain tissue and structural segmentation, with the best DSC and the 95th percentile Hausdorff distance (H95) of 0.96 and 0.99 mm, respectively. In terms of regional volume and cortical surface analysis, our model showed good agreement with ground truth. The ICC values for the regional volume were all above 0.80. Considering the thick-slice image pipeline, the same trend was observed for brain segmentation and analysis. The best DSC and H95 were 0.92 and 3.00 mm, respectively. The regional volumes and surface curvature had ICC values just below 0.80. CONCLUSIONS: We propose an automatic, accurate, stable and reliable pipeline for neonatal brain segmentation and analysis from thin and thick structural MRI. The external validation showed very good reproducibility of the pipeline.

Guanylyl cyclase-G is an alarm pheromone receptor in mice.

Many animals respond to threats by releasing alarm pheromones (APs) that warn conspecifics. In mice, detection of the AP 2-sec-butyl-4,5-dihydrothiazole (SBT) is mediated by chemosensory neurons residing in the Grueneberg ganglion (GG) of the anterior nasal region. Although the molecular mechanisms underlying activation of GG neurons by SBT and other substances are still unclear, recent studies have reported an involvement of the transmembrane guanylyl cyclase (GC) subtype GC-G in chemosensory signaling in the GG Here, we show that SBT directly binds with high affinity to the extracellular domain of GC-G and elicits an enhanced enzymatic activity of this protein. In line with this finding, heterologous expression of GC-G renders cells responsive to SBT while activation by SBT was strongly attenuated in GG neurons from GC-G-deficient mice. Consistently, SBT-induced fear-associated behaviors, SBT-evoked elevated blood pressure, and increased serum levels of the stress hormone corticosterone were clearly reduced in GC-G-knockout animals compared to wild-type mice. These observations suggest that GC-G serves as an unusual receptor in GG neurons mediating the detection of the volatile AP substance SBT.

In silico prediction of parkinsonian motor deficits-related neurotoxicants based on the adverse outcome pathway concept.

Exposure to neurotoxicants has been associated with Parkinson's disease (PD). Limited by the clinical variation in the signs and symptoms as well as the slow disease progression, the identification of parkinsonian neurotoxicants relies on animal models. Here, we propose an innovative in silico model for the prediction of parkinsonian neurotoxicants. The model was designed based on a validated adverse outcome pathway (AOP) for parkinsonian motor deficits initiated from the inhibition of mitochondrial complex I. The model consists of a molecular docking model for mitochondrial complex I protein to predict the molecular initiating event and a neuronal cytotoxicity Quantitative Structure-Activity Relationships (QSAR) model to predict the cellular outcome of the AOP. Four known PD-related complex I inhibitors and four non-neurotoxic chemicals were utilized to develop the threshold of the models and to validate the model, respectively. The integrated model showed 100% specificity in ruling out the non-neurotoxic chemicals. The screening of 41 neurotoxicants and complex I inhibitors with the model resulted in 16 chemicals predicted to induce parkinsonian disorder through the molecular initiating event of mitochondrial complex I inhibition. Five of them, namely cyhalothrin, deguelin, deltamethrin, diazepam, and permethrin, are cases with direct evidence linking them to parkinsonian motor deficit-related signs and symptoms. The neurotoxicant prediction model for parkinsonian motor deficits based on the AOP concept may be useful in prioritizing chemicals for further evaluations on PD potential.

Bisphenol B disrupts testis differentiation partly via the estrogen receptor-mediated pathway and subsequently causes testicular dysgenesis in Xenopus laevis.

There is growing concern about adverse effects of bisphenol A alternatives including bisphenol B (BPB) due to their estrogenic activity. However, limited data are available concerning the influences of BPB on male reproductive development in vertebrates, especially in amphibians, which are believed to be susceptible to estrogenic chemicals. The present study investigated the effects of 10, 100 and 1000 nM BPB (2.42, 24.2 and 242 µg/L) on testis development in Xenopus laevis, a model amphibian species for studying gonadal feminization. We found that exposure to BPB from stages 45/46 to 52 resulted in down-regulation of testis-biased gene expression and up-regulation of ovary-biased gene and vitellogenin (vtgb1) expression in gonad-mesonephros complexes (GMCs) of tadpoles at stage 52, coupled with suppressed cell proliferation in testes and reduced gonadal metameres, resembling the effects of 17ß-estradiol. Moreover, an estrogen receptor (ER) antagonist ICI 182780 antagonized BPB-caused up-regulation of ovary-biased gene and vtgb1 expression to some degree, indicating that the effects of BPB on X. laevis testis differentiation could be partly mediated by ER. All observations demonstrate that early exposure to BPB inhibited testis differentiation and exerted certain feminizing effects during gonadal differentiation. When exposure was extended to post-metamorphosis, testes exhibited histological and morphological abnormalities including segmented, discontinuous and fragmented shapes, besides altered sex-dimorphic gene expression. Notably, most of BPB-caused alterations were not concentration-dependent, but the lowest concentration indeed exerted significant effects. Overall, our study for the first time reveals that low concentrations of BPB can disrupt testis differentiation partly due to its estrogenic activity and subsequently cause testicular dysgenesis after metamorphosis, highlighting its reproductive risk to amphibians and other vertebrates including humans. Our finding also implies that estrogenic chemicals-caused testis differentiation inhibition at tadpole stages could predict later testicular dysgenesis after metamorphosis, meaning a possibility of early detection of abnormal testis development caused by estrogenic chemicals.

The study of isotopic enrichment of water in human plasma and erythrocyte.

Life does not sustain without water. For water, there is a natural abundance of stable isotope hydrogen and oxygen. Water molecules get across cell membranes through a plasma membrane protein, named aquaporin. Moreover, the kidney is the main organ to maintain water homeostasis. Here, we study the stable isotopic ratios of hydrogen and oxygen in human blood plasma and erythrocyte corresponding to kidney functions. We extract waters from human plasma and erythrocyte, collected from 110 participants, including 51 clinically stable outpatients with end-stage renal disease (ESRD) and 59 subjects with normal renal function (NRF). We observed that (i) both extracellular (blood plasma) and intracellular (erythrocyte) biology waters are isotopic differences between the ESRD and NRF participants, (ii) the natural abundance of isotopic waters of ESRD is hypo-isotopic, and (iii) the isotopic enrichment of water between erythrocyte and blood plasma are distinct. In addition, we introduce an empirical formula using entropy transformation to describe isotopic water enrichment for biology. Accordingly, the natural abundance of stable isotope water of blood plasma and erythrocyte may be possibly put in practice a new sign for assessments of kidney dysfunctions.

The Configuration-Dependent Anti-Leukemic Effect of Manoalide Stereoisomers: Reignite Research Interest in these Sponge-Derived Sesterterpenoids.

Manoalide was studied as a potential anti-inflammatory agent for the last forty years and more than 200 publications and 180 patents were reported on this compound. However, the configurations at positions 24 and 25 and configuration-dependent bioactivity were not yet studied. In the current report, ten manoalide-like sesterterpenoids were isolated from Luffariella sp. (1-10). These stereoisomers were identified and separated for the first time since 1980 and their configurations at positions 24 and 25 were determined by analyzing their spectroscopic spectra. The configuration-dependent anti-proliferative activity of manoalide derivatives was examined by evaluating their effect on four leukemic cancer cell lines (Molt 4, K562, Sup-T1, and U937). The 24R,25S-isomers exhibited the most potent activity (IC50 0.50-7.67 µM). The anti-proliferative mechanism of action of 24R,25S-manoalide (7) was further studied on Molt 4 cells. Compound 7 exhibited apoptotic activity on Molt 4 cells through the disruption of mitochondrial membrane potential (MMP) and the generation of intracellular reactive oxygen species (ROS). It also inhibited the activity of human topoisomerase I and II. The apoptotic-inducing effect of 7 was further supported by the in vivo experiment by suppressing the volume of xenograft tumor growth (66.11%) compared with the control.

Computational identification of preservatives with potential neuronal cytotoxicity.

Preservatives play a vital role in cosmetics by preventing microbiological contamination for keeping products safe to use. However, a few commonly used preservatives have been suggested to be neurotoxic. Cytotoxicity to neuronal cells is commonly used as the first-tier assay for assessing chemical-induced neurotoxicity. Given the time and resources required for chemical screening, computational methods are attractive alternatives over experimental approaches in prioritizing chemicals prior to further experimental evaluations. In this study, we developed a Quantitative Structure-Activity Relationships (QSAR) model for the identification of potential neurotoxicants. A set of 681 chemicals was utilized to construct a robust prediction model using oversampling and Random Forest algorithms. Within a defined applicability domain, the independent test on 452 chemicals showed a high accuracy of 87.7%. The application of the model to 157 preservatives identified 15 chemicals potentially toxic to neuronal cells. Three of them were further validated by in vitro experiments. The results suggested that further experiments are desirable for assessing the neurotoxicity of the identified preservatives with potential neuronal cytotoxicity.

Effect of hydrophilic and lipophilic statins on early onset cataract: A nationwide case-control study.

BACKGROUND: Statin is biologically plausible in cataract development, but inconclusive associations between statin and cataract are presented in human studies. Given most early onset cataract (EOC) occurs in regions with high cholesterol composition, we therefore aimed to assess the association between statin and EOC. METHODS: A population based case-control study was performed using the Taiwan National Health Insurance Research Database (NHIRD). The case involved patients aged 20-55 years with EOC. Controls were 1:1 matched by age, gender, year of index date, and propensity score estimated from comorbidities and comedications. Statin exposure, including intensity, properties and cumulative exposure one year before the index date were tracked. The odds ratios (ORs) of EOC associated with statin were estimated by conditional logistic regression. RESULTS: A total of 4213 cases and 4213 controls were included. Statins were associated with EOC (OR = 3.257, 95% CI 2.519-4.211). The ORs of cataract was positively associated with cumulative exposure. Subgroup analysis indicated that the ORs of cataract were significant both in lipophilic (OR = 3.485, 95% CI 2.606-4.659) and hydrophilic (OR = 3.241, 95% CI 1.975-5.321) statin users. CONCLUSIONS: Statins were associated with an increased risk of cataract in young populations.

Pediatric non-alcoholic fatty liver disease predicted by anthropometric values through transient elastography.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of pediatric chronic liver disease, which is strongly associated with obesity. Transient elastography, together with anthropometric values including waist-to-height ratio (WHtR) and body mass index (BMI) z-scores are a more precise diagnostic method of NAFLD than ultrasonography. Through transient elastography, we investigate the principal anthropometric values associated with pediatric NAFLD. METHODS: Healthy children between the ages of 6-18 years whose BMIs were ≥85% of normal were recruited as the overweight-and-obese group, and children whose BMIs ranged between 5%-85% were recruited as the control group. Non-alcoholic fatty liver disease was evaluated via transient elastography. BMI z-score and WHtR were measured. RESULTS: A total of 107 (58 overweight-and-obese, 49 control) children were recruited. As evaluated by transient elastography, children in the overweight-and-obese group had significantly higher controlled attenuation parameter and liver stiffness measurement values than the control group. To detect fatty liver, WHtR with a cut-off point of 0.481 and BMI z-score with cut-off point of 1.075 had the best sensitivity and specificity. To identify liver stiffness or inflammation, WHtR with cut-off point of 0.514 and BMI z-score with cut-off point of 1.62 had the best sensitivity and specificity. Controlled attenuation parameter demonstrated a fair correlation with WHtR and BMI z-scores, even in the normal range of these parameters. CONCLUSIONS: Transient elastography together with anthropometric measurements demonstrate that pediatric NAFLD may develop earlier than expected. We present principal anthropometric values associated with pediatric NAFLD.

Prebiotic Iron Originates the Peptidyl Transfer Origin.

The ribosome is responsible for protein synthesis in all living organisms. It is best known to exist around 3.5-3.7 Ga whereat life on Earth inhabited anoxic environment with abundant soluble irons. The RNAs and proteins are the two biopolymers that constitute the ribosome. However, both proteins and RNAs require metal cations to fold and to function. There are four Mg-microcluster (Mg2+-µc) structures conserved in core of large subunit, and the 23S ribosomal RNA (rRNA) was shown to catalyze electron transfer in an anoxic environment in the presence of Fe2+. The Mg2+-µc features two idiosyncratic Mg2+ ions that are chelated and bridged by a common phosphate group and along with that, the adjacent residues of RNA backbone together forming ten-membered chelation ring(s). Here, we utilized four rRNA fragments of the large subunit 23S rRNA of Haloarcula marismortui, that includes the residues that form the four Mg2+-µc's. These four rRNA fragments are shown competent to assemble with Mg2+. Our results show that when these rRNA fragments fold or assembly in the presence of Fe2+ under anoxic conditions, each Fe2+-microcluster can catalyze electron transfer. We propose that Fe2+-microclusters of the ribosome, which use Fe2+ as a cofactor to regulate electron transfer, are pivotal and primordial and may be an origin in evolution of the ribosome.

Chemoresistant ovarian cancer enhances its migration abilities by increasing store-operated Ca2+ entry-mediated turnover of focal adhesions.

BACKGROUND: Among gynecological cancers, ovarian carcinoma has the highest mortality rate, and chemoresistance is highly prevalent in this cancer. Therefore, novel strategies are required to improve its poor prognosis. Formation and disassembly of focal adhesions are regulated dynamically during cell migration, which plays an essential role in cancer metastasis. Metastasis is intricately linked with resistance to chemotherapy, but the molecular basis for this link is unknown. METHODS: Transwell migration and wound healing migration assays were used to analyze the migration ability of ovarian cancer cells. Real-time recordings by total internal reflection fluorescence microscope (TIRFM) were performed to assess the turnover of focal adhesions with fluorescence protein-tagged focal adhesion molecules. SOCE inhibitors were used to verify the effects of SOCE on focal adhesion dynamics, cell migration, and chemoresistance in chemoresistant cells. RESULTS: We found that mesenchymal-like chemoresistant IGROV1 ovarian cancer cells have higher migration properties because of their rapid regulation of focal adhesion dynamics through FAK, paxillin, vinculin, and talin. Focal adhesions in chemoresistant cells, they were smaller and exhibited strong adhesive force, which caused the cells to migrate rapidly. Store-operated Ca2+ entry (SOCE) regulates focal adhesion turnover, and cell polarization and migration. Herein, we compared SOCE upregulation in chemoresistant ovarian cancer cells to its parental cells. SOCE inhibitors attenuated the assembly and disassembly of focal adhesions significantly. Results of wound healing and transwell assays revealed that SOCE inhibitors decreased chemoresistant cell migration. Additionally, SOCE inhibitors combined with chemotherapeutic drugs could reverse ovarian cancer drug resistance. CONCLUSION: Our findings describe the role of SOCE in chemoresistance-mediated focal adhesion turnover, cell migration, and viability. Consequently, SOCE might be a promising therapeutic target in epithelial ovarian cancer.

Correction: Progress of electrospray ionization and rapid evaporative ionization mass spectrometric techniques for the broad-range identification of microorganisms.

Correction for 'Progress of electrospray ionization and rapid evaporative ionization mass spectrometric techniques for the broad-range identification of microorganisms' by Suresh Kumar Kailasa et al., Analyst, 2019, 144, 1073-1103, DOI: 10.1039/C8AN02034E.