Search

It is frequently observed that overparameterized neural networks generalize well. Regarding such phenomena, existing theoretical work mainly devotes to linear settings or fully-connected neural networks. This paper studies the learning ability of an important family of deep neural networks, deep convolutional neural networks (DCNNs), under both underparameterized and overparameterized settings. We establish the first learning rates of underparameterized DCNNs without parameter or function variable structure restrictions presented in the literature. We also show that by adding well-defined layers to a non-interpolating DCNN, we can obtain some interpolating DCNNs that maintain the good learning rates of the non-interpolating DCNN. This result is achieved by a novel network deepening scheme designed for DCNNs. Our work provides theoretical verification of how overfitted DCNNs generalize well. [ABSTRACT FROM AUTHOR]

We investigate precessing and periodic geodesic motions of timelike particles around a black-bounce/traversable wormhole. After obtaining its semi-classic and relativistic periastron advance, we find a preliminary bound on the scale length of such a spactime based on the detected precession of the star S2 around the Galactic Center. We also study periodic orbits around it and find that the variation of the scale length can change the taxonomy of the periodic orbits and cause the transition from a periodic orbit to a quasi-periodic one and vice versa. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRNAs) are critical modulators of various physiological and pathological processes, but their role in cardiac arrhythmias remains yet to be completely understood. Connexin43 (Cx43) is an important cardiac gap junction protein and a potential target of miR-206, and downregulation of Cx43 induces ventricular tachyarrhythmias.Methods: We investigated the effects of miR-206 overexpression on the adult mouse heart and in cardiac arrhythmias. Luciferase activity assay was employed to validate Cx43 as a direct target of miR-206. Expression of Cx43 was measured in cardiac muscle cell line HL-1 securely expressing miR-206. An inducible miR-206 overexpression mouse model was established to evaluate the in vivo effect of miR-206 on Cx43 expression and cardiac rhythm.Results: MiR-206 directly recognised 3'-untranslated region of Cx43 mRNA to inhibit its expression in HL-1 cells. Induction of miR-206 in the adult mouse heart suppressed Cx43 expression, particularly in the atria and ventricle. Importantly, miR-206 overexpression also induced abnormal heart-rate and PR interval, and shortened life-span in the experimental mice.Conclusions: In cardiomyocytes, miR-206 is a upstream regulator of Cx43, and its overexpression downregulates Cx43 to induce abnormal heart-rate and PR interval. [ABSTRACT FROM AUTHOR]

The aim of this experiment was to investigate the protective effects of polysaccharides of sea cucumber Acaudina leucoprocta (ALP) against hydrogen peroxide (H 2 O 2) induced oxidative injury in RAW264.7 cells. Analysis of monosaccharide composition and structure of one fraction from ALP (ALP N) were analyzed by High Performance Liquid Chromatography (HPLC) and Fourier Transform Infrared Spectoscopy (FT-IR). The results showed that ALP N contain sulfate groups, which is sulfated polysaccharides. The results from MTT assay indicated that ALP N could markedly increase viability of cells compared with RAW264.7 cells exposed to H 2 O 2. Moreover, ALP N significantly increased the levels of catalase (CAT), glutathione peroxidase (GSH-P X) and superoxide dismutase (SOD), decreased the production of malondialdehyde (MDA) and lactate dehydrogenase (LDH) in RAW264.7 cells. The data from RT-PCR showed that ALP N (300 μg/mL) could increase the gene expression levels of SOD1 and GPX1. ALP N could also observably increase the protein expression level of Nrf2 and decrease the protein expression level of Keap1 with western blot. Collectively, this study suggested that polysaccharides of sea cucumber Acaudina leucoprocta (ALP) could effectively protect RAW264.7 cells against H 2 O 2 -induced oxidative injury. This protection mechanism may be related to activation of the Nrf2/Keap1 signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract Complex rotorcraft-to-rotorcraft interference problems occur during shipboard operations, and have a negative impact on safety. A vortex-based approach is used here to investigate the flow field and unsteady airloads of a tiltrotor affected by the wake of an upwind tandem rotor. In this work, the blade aerodynamics is modelled using a panel method, and the unsteady behaviour of rotor wakes is modelled using a vortex particle method. The effects of the ship and sea-surfaces are accounted for via a viscous boundary model. The method is applied to a 1/48th scaled model of a CH-46 operating on a model-scale Landing Helicopter Assault ship. The predicted vertical velocities at the location of the downstream V-22 are compared with Computational Fluid Dynamics and experiments carried out at NASA Ames Research Center. The results show that the predicted vertical velocities compare reasonably well with experiments and Computational Fluid Dynamics. A V-22 tilt-rotor placed in the wake of the CH-46 is also simulated, and rolling moments of the V-22 are calculated to show the effect of the upstream CH-46 wake. [ABSTRACT FROM AUTHOR]

Inflammation is connected with a variety of diseases and there is still a need to develop more effective and safer anti-inflammatory drugs. Herein, we synthesized, resolved, and characterized eight enantiopure isomers of yaequinolone J1 (1), yaequinolone J2 (2), 4′-desmethoxyyaequinolone J1 (3), and 4′-desmethoxyyaequinolone J2 (4). The key synthetic steps were extended and 34 racemic analogues modified at the 4-aryl, the N-position, and the pyran ring were designed and synthesized. All the synthesized compounds were evaluated for their anti-inflammatory activities in RAW 264.7 cells of which 13 compounds showed significant inhibition of nitric oxide (NO) production at a concentration of 0.1 μM, which was more potent than that of indomethacin. Furthermore, compounds (−)- 3 , (−)- 4 , 5h, and 6g reduced the production of IL-6 in LPS-stimulated RAW 264.7 cells at a concentration of 50 n M. A preliminary SAR indicated that 3′-Br (5h) , 4′-NO 2 (6g) on 4-phenyl and 3-bromobenzyl (7f) on the N-position were the most effective substituents. This is the first report of the anti-inflammatory yaequinolone alkaloids and the present study provided evidence for exploiting this series of highly efficacious derivatives for new anti-inflammatory agents. [Display omitted] • Yaequinolone fused with an isoprenyl pyran ring reported as a novel chemotype for development of inflammatory inhibitors. • SynThesized eight chiral non-racemic yaequinolones and 34 racemic yaequinolone analogues to establish valuable SARs. • A total of 13 chiral, non-racemic and racemic compounds showed inhibition of NO production at a concentration of 0.1 μM. • Four compounds reduced the production of IL-6 at a concentration of 50 n M. [ABSTRACT FROM AUTHOR]

This study sought to examine grouped and right-censored (GRC) counts of adolescent marijuana use and estimate its temporal trajectories and sociodemographic disparities over almost half a century. After compiling 46 waves of nationally representative data from the Monitoring the Future (MTF) study from 1976 to 2021 (sample size = 491,348), we utilized an innovative modified Poisson (mixture) approach to analyze past-year marijuana use quantified by GRC counts. The overall reduction in incidence rates of marijuana use was attributable to an almost 40% reduction in the risk of marijuana use (with the proportion of at-risk adolescents at 51.36% in 1979 and 31.53% in 2021). Despite substantial changes over the study period, the recent incidence rates for at-risk individuals were similar to those in the early 1980s. Living in an intact family was a protective factor against adolescent marijuana use over time. The incidence rates of marijuana use among at-risk students, especially those from disadvantaged families, remained high over the study period. The modified Poisson (mixture) approach serves as the preferred tool for modeling GRC responses. It is essential to distinguish among risk, at-risk incidence, and overall incidence when assessing substance use and other risky behaviors. [ABSTRACT FROM AUTHOR]

Natural products are well established as an important resource and play an important role in drug discovery. Here, two pyrrolinone-fused benzoazepine alkaloids, (+)-asperazepanones A (1) and B (2) with a 6/7/5 ring system, together with the artifact (−)-asperazepanone A (1), were isolated from the coral-derived Aspergillus candidus fungus. Their structures including absolute configurations were elucidated by extensive spectroscopic methods, single crystal X-ray diffraction, and ECD calculations. Furthermore, total syntheses of (±)-1 and (±)-2 have been achieved starting from the commercially L-aspartic acid diethyl ester hydrochloride and monoethyl malonate in 7 and 8 steps, respectively. The key step in the syntheses was an intramolecular Friedel-Crafts reaction to build the unique tricyclic skeleton. Interestingly, (+)-2 not only showed obviously inhibitory activity against NO production, but also inhibited potent LPS-induced expression of TNF-α and IL-6 at the concentration of 0.1 μM. It thus represents a potentially promising lead for anti-inflammatory drug discovery. Benzoazepine is a well-known pharmacophore presented in several marketed drugs. Here, the authors report the isolation and total syntheses of asperazepanones A and B from coral-derived Aspergillus candidus, two novel pyrrolinone-fused benzoazepine alkaloids with potent anti-inflammatory activities. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the antioxidant effect of seleno-amino-oligosaccharide (Se-AOS) on intestinal porcine epithelial cells (IPEC-1). MTT assay showed that Se-AOS had no effect on the viability of IPEC-1 cells up to a concentration of 9200 μg/L and Se-AOS significantly increased the viability of IPEC-1 cells compared to cells exposed to H 2 O 2 alone. Se-AOS significantly increased the level of superoxide Dismutase (SOD) and decreased the levels of malonic dialdehyde (MDA) and lactate dehydrogenase (LDH) in IPEC-1 cells. The gene expression levels of different antioxidant enzymes dramatically increased by the pretreatment of Se-AOS compared to H 2 O 2 treatment. In addition, the results indicated that Se-AOS up-regulated the intracellular Nrf2 and down-regulated the level of Keap1 by western blot. Taken together, these findings suggested that Se-AOS can protect IPEC-1 cells from oxidative damage through activating the Keap1/Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Metastasis accounts for the most lethal reason for the death of ovarian cancer patients, but remains largely untreated. Epithelial-mesenchymal transition (EMT) is critical for the conversion of early-stage ovarian tumours into metastatic malignancies. Thus the exploration of the signalling pathways promoting EMT would open potential opportunities for the treatment of metastatic ovarian cancer. Herein, the putative role of MDM2 in regulating EMT and metastasis of ovarian cancer SKOV3 cells was investigated.Methods: The regulatory effects by MDM2 on cell motility was emulated by wound-healing and transwell assays. The effects on EMT transition and Smad pathway were studied by depicting the expression levels of epithelial marker E-cadherin as well as key components of Smad pathway. To evaluate the clinical relevance of our findings, the correlation of MDM2 expression levels with the stages of 104 ovarian cancer patients was investigated by immunohistochemistry assay.Results: We demonstrate that MDM2 functions as a key factor to drive EMT and motility of ovarian SKOV3 cells, by facilitating the activation of TGF-β-Smad pathway, which results in the increased transcription of snail/slug and the subsequent loss of E-cadherin levels. Such induction of EMT is sustained in either E3 ligase-depleted MDM2 or E3 ligase inhibitor HLI-373-treated cells, while being impaired by the N-terminal deletion of MDM2, which is also reflected by the inhibitory effects against EMT by Nutlin-3a, the N-terminal targeting agent. The expression levels of MDM2 is highly correlated with the stages of the ovarian cancer patients, and the higher expression of MDM2 together with TGFB are closely correlated with poor prognosis and predict a high risk of ovarian cancer patients.Conclusions: This study suggests that MDM2 activates Smad pathway to promote EMT in ovarian cancer metastasis, and targeting the N-terminal of MDM2 can reprogram EMT and impede the mobility of cancer cells. [ABSTRACT FROM AUTHOR]

Lower global cognitive function scores are a common symptom of autism spectrum disorders ( ASDs). This study investigates the effects of melatonin on hippocampal serine/threonine kinase signaling in an experimental ASD model. We found that chronic melatonin (1.0 or 5.0 mg/kg/day, 28 days) treatment significantly rescued valproic acid ( VPA, 600 mg/kg)-induced decreases in Ca MKII (Thr286), NMDAR1 (Ser896), and PKA (Thr197) phosphorylation in the hippocampus without affecting total protein levels. Compared with control rats, the immunostaining of pyramidal neurons in the hippocampus revealed a decrease in immunolabeling intensity for phospho-Ca MKII (Thr286) in the hippocampus of VPA-treated rats, which was ameliorated by chronic melatonin treatment. Consistent with the elevation of Ca MKII/ PKA/ PKC phosphorylation observed in melatonin-treated rat, long-term potentiation ( LTP) was enhanced after chronic melatonin (5.0 mg/kg) treatment, as reflected by extracellular field potential slopes that increased from 56 to 60 min (133.4 ± 3.9% of the baseline, P < 0.01 versus VPA-treated rats) following high-frequency stimulation (HFS) in hippocampal slices. Accordingly, melatonin treatment also significantly improved social behavioral deficits at postnatal day 50 in VPA-treated rats. Taken together, the increased phosphorylation of Ca MKII/ PKA/ PKC signaling might contribute to the beneficial effects of melatonin on autism symptoms. [ABSTRACT FROM AUTHOR]

Low molecular seleno-aminopolysaccharide (LSA) was synthesized with sodium selenite and low molecular aminopolysaccharide (LA), which is an organic selenium compound. This study is aimed to investigate the protective effect of LSA on the intestinal mucosal barrier in weaning stress rats by detecting the intestinal tissue morphology and function, mucosal thickness and permeability, the structure of MUC2, antioxidant index, the expression level of intracellular transcription factor NF-E2-related factor 2 (Nrf2), and its related factors. The results showed that LSA significantly increased the height of intestinal villi (p < 0.05) and increased the thickness of intestinal mucosa and the number of goblet cells, which indicated that LSA has a protective effect on the intestinal mucosal barrier that is damaged by weaning. Moreover, LSA significantly reduced the level of DAO, D-LA, and LPS compared with the weaning group (p < 0.05), which indicated that LSA reduced the intestinal damage and permeability of weaning rats. In addition, LSA could increase the number and length of glycans chains and the abundance of acid glycans structures in the MUC2 structure, which indicated that LSA alleviated the changes of intestinal mucus protein structure. LSA significantly increased the levels of GSH-Px, SOD, LDH, and CAT, while it decreased the level of MDA in serum and intestinal tissue, which suggested that LSA significantly enhanced the antioxidant capacity and reduced oxidative stress of weaning rats. RT-PCR results showed that LSA significantly increased the expression level of antioxidant genes (GSH-Px, SOD, Nrf2, HO-1), glycosyltransferase genes (GalNT1, GalNT3, GalNT7) and mucin gene (MUC2) in intestinal mucosa (p < 0.05). The results of western blot showed that the LSA activated the Nrf2 signaling pathway by down-regulating the expression of Keap1and up-regulating the expression of Nrf2, and protected the intestinal mucosa from oxidative stress. Overall, LSA could play a protective role in intestinal mucosal barrier of weaning rats by activating the Nrf2 pathway and alleviating the alnormal change of mucin MUC2. [ABSTRACT FROM AUTHOR]