ZLN005 alleviates PBDE-47 induced impairment of mitochondrial translation and neurotoxicity through PGC-1α/ERRα axis.

Recent studies are identified the mitochondria as critical targets of 2, 2', 4, 4'-tetrabromodiphenyl ether (PBDE-47) induced neurotoxicity. This study aimed at examining the impact of PBDE-47 exposure on mitochondrial translation, and its subsequent effect on PBDE-47 neurotoxicity. The Sprague-Dawley (SD) rat model and neuroendocrine pheochromocytoma (PC12) cells were adopted for the measurements of mitochondrial ATP levels, mitochondrial translation products, and expressions of important mitochondrial regulators, such as required meiotic nuclear division 1 (RMND1), estrogen-related receptor α (ERRα), and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). To delve into the role of PGC-1α/ERRα axis in mitochondrial translation, 2-(4-tert-butylphenyl) benzimidazole (ZLN005) was employed. Both cellular and animal model results shown that PBDE-47 impeded PGC-1α/ERRα axis and mitochondrial translation. PBDE-47 suppressed mitochondrial function in rat hippocampus and PC12 cells by decreasing relative mitochondrial DNA (mtDNA) content, mitochondrial translation products, and mitochondrial ATP levels. Particularly, ZLN005 reversed PBDE-47 neurotoxicity by enhancing mitochondrial translation through activation of PGC-1α/ERRα axis, yet suppressing PGC-1α with siRNA attenuates its neuroprotective effect in vitro. In conclusion, this work highlights the importance of mitochondrial translation in PBDE-47 neurotoxicity by presenting results from cellular and animal models and suggests a potential therapeutic approach through activation of PGC-1α/ERRα axis. ENVIRONMENTAL IMPLICATION: PBDEs have attracted extensive attention because of their high lipophilicity, persistence, and detection levels in various environmental media. Increasing evidence has shown that neurodevelopmental disorders in children are associated with PBDE exposure. Several studies have also found that perinatal PBDE exposure can cause long-lasting neurobehavioral abnormalities in experimental animals. Our recent studies have also demonstrated the impact of PBDE-47 exposure on mitochondrial biogenesis and dynamics, leading to memory and neurobehavioral deficits. Therefore, we explore whether the pathological mechanism of PBDE-47-induced neurotoxicity involves the regulation of mitochondrial translation through the PGC-1α/ERRα axis.

N-Sulfonyl amidine polypeptides: new polymeric biomaterials with conformation transition responsive to tumor acidity.

Manipulation of pH responsiveness is a frequently employed tactic in the formulation of trigger-responsive nanomaterials. It offers an avenue for "smart" designs capitalizing on distinctive pH gradients across diverse tissues and intracellular compartments. However, an overwhelming majority of documented functional groups (>80%) exhibit responsiveness solely to the heightened acidic milieu of intracellular pH (about 4.5-5.5). This scenario diverges markedly from the moderately acidic extracellular pH (∼6.8) characteristic of tumor microenvironments. Consequently, systems predicated upon intracellular pH responsiveness are unlikely to confer discernible advantages concerning targeted penetration and cellular uptake at tumor sites. In this study, we elucidated the extracellular pH responsiveness intrinsic to N-sulfonyl amidine (SAi), delineating a method to synthesize an array of SAi-bearing polypeptides (SAi-polypeptides). Notably, we demonstrated the pH-dependent modulation of SAi-polypeptide conformations, made possible by the protonation/deprotonation equilibrium of SAi in response to minute fluctuations in pH from physiological conditions to the extracellular milieu of tumors. This dynamic pH-triggered transition of SAi-polypeptides from negatively charged to neutrally charged side chains at the pH outside tumor cells (∼6.8) facilitated a transition from coil to helix conformations, concomitant with the induction of cellular internalization upon arrival at tumor sites. Furthermore, the progressive acidification of the intracellular environment expedited drug release, culminating in significantly enhanced site-specific chemotherapeutic efficacy compared with free-drug counterparts. The distinct pH-responsive attributes of SAi could aid the design of tumor acidity-responsive applications, thereby furnishing invaluable insights into the realm of smart material design.

Intelligent assessment of atrial fibrillation gradation based on sinus rhythm electrocardiogram and baseline information.

BACKGROUND: Atrial fibrillation (AF) is a progressive arrhythmia that significantly affects a patient's quality of life. The 4S-AF scheme is clinically recommended for AF management; however, the evaluation process is complex and time-consuming. This renders its promotion in primary medical institutions challenging. This retrospective study aimed to simplify the evaluation process and present an objective assessment model for AF gradation. METHODS: In total, 189 12-lead electrocardiogram (ECG) recordings from 64 patients were included in this study. The data were annotated into two groups (mild and severe) according to the 4S-AF scheme. Using a preprocessed ECG during the sinus rhythm (SR), we obtained a synthesized vectorcardiogram (VCG). Subsequently, various features were calculated from both signals, and age, sex, and medical history were included as baseline characteristics. Different machine learning models, including support vector machines, random forests (RF), and logistic regression, were finally tested with a combination of feature selection techniques. RESULTS: The proposed method demonstrated excellent performance in the classification of AF gradation. With an optimized feature set of VCG and baseline features, the RF model achieved accuracy, sensitivity, and specificity of 83.02 %, 80.56 %, and 88.24 %, respectively, under the inter-patient paradigm. CONCLUSION: Our results demonstrate the value of physiological signals in AF gradation evaluation, and VCG signals were effective in identifying mild and severe AF. Considering its low computational complexity and high assessment performance, the proposed model is expected to serve as a useful prognostic tool for clinical AF management.

The role of mTORC1/TFEB axis mediated lysosomal biogenesis and autophagy impairment in fluoride neurotoxicity and the intervention effects of resveratrol.

Elevated exposures to fluoride have been linked to neurological diseases. Identifying mechanisms of fluoride neurotoxicity and finding ways for prevention and treatment of epidemic fluorosis are important issues of public health. In this study, fluoride inhibited TFEB nuclear translocation by activating p-mTORC1/p-p70S6K, thus inhibiting lysosomal biogenesis, leading to dysfunctional lysosome accumulation, which further negatively affected autophagosome and lysosome fusion, thus impairing autophagy degradation, evidenced by the blocked conversion of LC3II to LC3I, and the increased p62 levels. Interestingly, RSV alleviated rats' cognition by improving fluoride-induced nerve damage and promoted lysosomal biogenesis demonstrated by the increased nucleus translocation of TFEB via inhibiting p-mTORC1 and p-p70S6K, the decreased expression of LC3II and p62. Collectively, we clarified the correlation between fluoride neurotoxicity and mTORC1/TFEB-mediated lysosomal biogenesis and autophagy. Meanwhile, RSV appeared to be a promising drug for the prevention and treatment of epidemic fluorosis.

Failure mechanical properties of lumbar intervertebral disc under high loading rate.

BACKGROUND: Lumbar disc herniation (LDH) is the main clinical cause of low back pain. The pathogenesis of lumbar disc herniation is still uncertain, while it is often accompanied by disc rupture. In order to explore relationship between loading rate and failure mechanics that may lead to lumbar disc herniation, the failure mechanical properties of the intervertebral disc under high rates of loading were analyzed. METHOD: Bend the lumbar motion segment of a healthy sheep by 5° and compress it to the ultimate strength point at a strain rate of 0.008/s, making a damaged sample. Within the normal strain range, the sample is subjected to quasi-static loading and high loading rate at different strain rates. RESULTS: For healthy samples, the stress-strain curve appears collapsed only at high rates of compression; for damaged samples, the stress-strain curves collapse both at quasi-static and high-rate compression. For damaged samples, the strengthening stage becomes significantly shorter as the strain rate increases, indicating that its ability to prevent the destruction is significantly reduced. For damaged intervertebral disc, when subjected to quasi-static or high rates loading until failure, the phenomenon of nucleus pulposus (NP) prolapse occurs, indicating the occurrence of herniation. When subjected to quasi-static loading, the AF moves away from the NP, and inner AF has the greatest displacement; when subjected to high rates loading, the AF moves closer to the NP, and outer AF has the greatest displacement. The Zhu-Wang-Tang (ZWT) nonlinear viscoelastic constitutive model was used to describe the mechanical behavior of the intervertebral disc, and the fitting results were in good agreement with the experimental curve. CONCLUSION: Experimental results show that, both damage and strain rate have a significant effect on the mechanical behavior of the disc fracture. The research work in this article has important theoretical guiding significance for preventing LDH in daily life.

Analysis of the relationship between color and natural pigments of tobacco leaves during curing.

Color is one of the most important indicators for the flue-cured tobacco quality. The color change of tobacco has a great relationship with the natural pigments in the tobacco. The relationship between color characteristics and the content of natural pigments in tobacco leaves during curing was investigated. The middle part of variety K326 tobacco was taken at each key time point during the curing process to determine the changes of color characteristics, moisture, pigment and polyphenol content. The results showed that moisture content of wet basis of tobacco gradually decreased from 72 to 18% during the curing process, the b* value increased and then decreased, and the a* value increased significantly. The lutein and ß-carotene content decreased to 63.83 µg/g and 28.3 µg/g, respectively. The total polyphenols content increased to 50.19 mg/g. Meanwhile, the a* value was significantly and positively correlated with polyphenols content and negatively correlated with pigments content. Cluster analysis showed that the samples were divided into three categories: samples with the curing time of 0 h, 24-72 h, and 84-132 h. These results demonstrated that the color change of tobacco during curing process can be divided into three stages from the perspective of chemical composition, which are strongly related to the degradation of pigments and the transformation of polyphenols.

Biochar derived from tobacco waste significantly reduces the accumulations of cadmium and copper in edible parts of two vegetables: an in-situ field study.

Biochar, as a soil amendment, can be applied to remediate heavy metal (HM) contaminated farmland. However, there is little research on the effect of tobacco biochar (TB) derived from tobacco waste on HM controlling in edible parts of vegetables. In this study, the impact of two TB levels on the plant growth, copper (Cu) and cadmium (Cd) accumulation in the edible parts of lettuce and chrysanthemum, and on Cu and Cd bioavailability of rhizosphere soil was investigated through in-situ field experiments. The results showed that TB has rich oxygen containing functional groups, high porosity, high nitrogen adsorption capacity. The addition of 5 t ha-1 and 10 t ha-1 TB significantly increased the shoot biomass of chrysanthemum, but had no effect on the growth of lettuce. Two levels of TB significantly increased the pH value, but decreased the available Cu and Cd concentrations of rhizosphere soil, thereby reducing the Cu and Cd accumulations in the edible parts of lettuce and chrysanthemum. The findings provided effective evidences that TB derived from tobacco waste is an efficient strategy for controlling Cu and Cd accumulation in the edible parts of vegetables to ensure agri-product safety production in HM-polluted farmland.

[Regional CT value in prediction of proximal femoral fracture].

OBJECTIVE: To investigate CT values of cancellous bone in femoral neck in adults over 60 years with proximal femoral fractures. METHODS: From January 2020 to December 2020, a retrospective analysis was performed on 280 subjects aged 60 years or older who underwent bilateral hip CT examination, including 85 males and 195 females, 120 on the left side and 160 on the right side, aged 75 (66, 82) years old. One hundred thirty-six patients with proximal femoral fractures were included in study group and 144 patients without fractures were included in control group. GEOptima CT was used to scan and reconstruct horizontal, coronal and sagittal layers of proximal femur. CT values of cancellous bone in femoral neck were measured and compared between two groups. The relationship between CT values of cancellous bone of femoral neck and proximal femoral fracture was analyzed statistically. RESULTS: In terms of age, fracture group aged 79(73.3, 85.0) years old, non-fracture group aged 69.5 (64.0, 78.8) years old, and had significant difference in age between two groups (P<0.05). In terms of CT value, regional CT value in fracture group was 8.62(-3.62, 27.15) HU, which was lower than that in non-fracture group 34.31(-5.93, 71.74) HU(P<0.05). CT value on coronal view in fracture group was -8.48(-30.96, 17.46) HU, which was lower than that in non-fracture group 40.49(5.55, 80.71) HU (P<0.05). CT value on sagittal view in fracture group was -31.28(-54.91, -5.11) HU, which was lower than that in non-fracture group 7.74(-20.12, 44.54) HU (P<0.05). CT values on horizontal view in fracture group was 0.17(-23.13, 24.60) HU, which was lower than that in non-fracture group 46.40(10.42, 85.18) HU(P<0.05). The mean regional CT values among three planes in the fracture group were lower than those in the non-fracture group. Logistic regression analysis showed coronal CT value was influencing factors of proximal femoral fracture, and it could be written into regression equations that predict probability of fracture. CONCLUSION: In adults aged over 60 years old, CT values of cancellous bone of femoral neck decreased with increasing age. The smaller CT value of cancellous bone of femoral neck, the greater risk of proximal femoral fracture.

SIRT1, a target of miR-708-3p, alleviates fluoride-induced neuronal damage via remodeling mitochondrial network dynamics.

INTRODUCTION: Neurological dysfunction induced by fluoride contamination is still one of major concern worldwide. Recently, neuroprotective roles of silent information regulator 1 (SIRT1) focusing on mitochondrial function have been highlighted. However, what roles SIRT1 exerts and the underlying regulative mechanisms, remain largely uncharacterized in such neurotoxic process of fluoride. OBJECTIVES: We aimed at evaluating the regulatory roles of SIRT1 in human neuroblastoma SH-SY5Y cells and Sprague-Dawley rats with fluoride treatment, and to further identify potential miRNA directly targeting SIRT1. METHODS: Pharmacological suppression of SIRT1 by nicotinamide (NIC) and promotion of SIRT1 by adenovirus (Ad-SIRT1) or resveratrol (RSV) were employed to assess the effects of SIRT1 in mitochondrial dysfunction induced by fluoride. Also, miRNAs profiling and bioinformatic prediction were used to screen the miRNAs which can regulate SIRT1 directly. Further, chemical mimic or inhibitor of chosen miRNA was applied to validate the modulation of chosen miRNA. RESULTS: NIC exacerbated defects in mitochondrial network dynamics and cytochrome c (Cyto C) release-driven apoptosis, contributing to fluoride-induced neuronal death. In contrast, the ameliorative effects were observed when overexpressing SIRT1 by Ad-SIRT1 in vitro or RSV in vivo. More importantly, miR-708-3p targeting SIRT1 directly was identified. And interestingly, moreover, treatment with chemically modified miR-708-3p mimic aggravated, while miR-708-3p inhibitor suppressed fluoride-caused neuronal death. Further confirmedly, overexpressing SIRT1 effectively neutralized miR-708-3p mimic-worsened fluoride neuronal death via correcting mitochondrial network dynamics. On contrary, inhibiting SIRT1 counteracted the promotive effects of miR-708-3p inhibitor against neurotoxic response by fluoride through aggravating abnormal mitochondrial network dynamics. CONCLUSION: These data underscore the functional importance of SIRT1 to mitochondrial network dynamics in neurotoxic process of fluoride and further screen a novel unreported neuronal function of miR-708-3p as an upstream regulator of targeting SIRT1, which has important theoretical implications for a potential therapeutic and preventative target for treatment of neurotoxic progression by fluoride.

[Effectiveness of Kirschner wire fixation and coracoclavicular ligament reconstruction with suture anchor in treatment of Cho type â ¡C distal clavicle fractures].

Objective: To evaluate the effectiveness of Kirschner wire fixation and coracoclavicular ligament reconstruction with suture anchor in the treatment of Cho type ⅡC distal clavicle fractures. Methods: The data of 17 patients with Cho type ⅡC distal clavicular fractures, who were treated with Kirschner wire fixation and coracoclavicular ligament reconstruction with suture anchor between June 2019 and June 2021, was retrospectively analyzed. There were 11 males and 6 females with an average age of 38.7 years (range, 19-72 years). The fractures were caused by falling in 12 cases and traffic accident in 5 cases. All patients had fresh closed fractures. The interval from injury to operation was 1-5 days (mean, 2.6 days). The preoperative injury severity score (ISS) was 6-27 (mean, 10.2). The operation time, intraoperative blood loss, hospital stay, fracture healing, and postoperative complications were analyzed. The shoulder joint function was evaluated by disabilities of the arm, shoulder, and hand (DASH) score and Constant score at last follow-up. Results: All operations were completed successfully. The operation time was 20-50 minutes (mean, 31.6 minutes). The intraoperative blood loss was 30-100 mL (mean, 50.6 mL). The hospital stay was 4-9 days (mean, 5.3 days). All incisions healed by first intention. All patients were followed up 12-16 months (mean, 13 months). All clavicle fractures healed, and the healing time was 8-15 weeks (mean, 11 weeks). No complications such as fracture displacement or nonunion caused by internal fixation failure occurred. During the follow-up, skin irritation caused by the Kirschner wire withdrawal occurred in 3 cases. The Kirschner wires were removed after fracture healing in 17 patients. At last follow-up, the Constant score of shoulder joint was 90-100 (mean, 98.2). The DASH score was 0-10 (mean, 1.5). Conclusion: Kirschner wire fixation combined with coracoclavicular ligament reconstruction with suture anchor in the treatment of Cho type ⅡC distal clavicle fractures has less postoperative complications and slight complications. It is convenient to remove the internal fixator. The Kirschner wire does not fix the distal clavicle fracture through the acromion, which has little effect on shoulder joint function and can obtain good effectiveness.

Peroxiredoxin II regulates exosome secretion from dermal mesenchymal stem cells through the ISGylation signaling pathway.

BACKGROUND: Exosomes are small extracellular vesicles that play important roles in intercellular communication and have potential therapeutic applications in regenerative medicine. Dermal mesenchymal stem cells (DMSCs) are a promising source of exosomes due to their regenerative and immunomodulatory properties. However, the molecular mechanisms regulating exosome secretion from DMSCs are not fully understood. RESULTS: In this study, the role of peroxiredoxin II (Prx II) in regulating exosome secretion from DMSCs and the underlying molecular mechanisms were investigated. It was discovered that depletion of Prx II led to a significant reduction in exosome secretion from DMSCs and an increase in the number of intracellular multivesicular bodies (MVBs), which serve as precursors of exosomes. Mechanistically, Prx II regulates the ISGylation switch that controls MVB degradation and impairs exosome secretion. Specifically, Prx II depletion decreased JNK activity, reduced the expression of the transcription inhibitor Foxo1, and promoted miR-221 expression. Increased miR-221 expression inhibited the STAT signaling pathway, thus downregulating the expression of ISGylation-related genes involved in MVB degradation. Together, these results identify Prx II as a critical regulator of exosome secretion from DMSCs through the ISGylation signaling pathway. CONCLUSIONS: Our findings provide important insights into the molecular mechanisms regulating exosome secretion from DMSCs and highlight the critical role of Prx II in controlling the ISGylation switch that regulates DMSC-exosome secretion. This study has significant implications for developing new therapeutic strategies in regenerative medicine. Video Abstract.

Semi-Supervised Learning for Low-Cost Personalized Obstructive Sleep Apnea Detection Using Unsupervised Deep Learning and Single-Lead Electrocardiogram.

OBJECTIVE: Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder that can lead to a wide range of health issues if left untreated. This study aims to address the lack of research on personalized models for single-lead electrocardiogram (ECG)-based OSA detection, by proposing an automatic semi-supervised algorithm for automated low-cost personalization fine-tuning. METHODS: We utilize a convolutional neural network (CNN)-based auto-encoder (AE) with a modified training objective to detect anomalous region of OSA. An indicator based on model outputs is utilized as a benchmark measure to assign pseudo-labels with confidence to each sample. Finally, we perform validation of the semi-supervised algorithm on the same database and cross-database scenarios. RESULTS: By introducing semi-supervised personalization, the accuracy, AUC, and mean absolute error (MAE) of the general model (GM) of 35 subjects from the same database are improved from 86.3%, 0.915, and 5.178 to 90.3%, 0.948, and 2.593. Simultaneously, in the validation of 25 subjects from a cross-database, the accuracy, AUC, and MAE of the GM are enhanced from 75.6%, 0.800, and 9.149 to 84.3%, 0.881, and 3.509. CONCLUSION: The improved version of AE demonstrates excellent adaptability in identifying abnormal features in OSA, employing a data-driven approach to assign pseudo-labels for unknown data automatically. Additionally, leveraging the pseudo-labels through a semi-supervised fine-tuning strategy provides a solution to overcome the limitation of clinical annotations, facilitating low-cost implementation of personalized models. SIGNIFICANCE: The semi-supervised approach proposed in this article provides a high-performance and annotation-free solution for personalized adjustment of automatic OSA detection.

Depletion of peroxiredoxin II promotes keratinocyte apoptosis and alleviates psoriatic skin lesions via the PI3K/AKT/GSK3ß signaling axis.

Psoriasis is a chronic, systemic immune-mediated disease caused by abnormal proliferation, decreased apoptosis, and over-differentiation of keratinocytes. The psoriatic skin lesions due to abnormal keratinocytes are closely associated with ROS produced by inflammatory cells. Peroxiredoxin II (Prx II) is an efficient antioxidant enzyme, which were highly expressed in skin tissues of psoriasis patient. However, the detailed mechanical functions of Prx II on psoriatic skin remain to be elucidated. Present study showed that depletion of Prx II results in alleviation of symptoms of IMQ-induced psoriasis in mice, but no significant differences in the amounts of serum inflammatory factors. Prx II-knockdown HaCaT cells were susceptible to H2O2-induced apoptosis mediated by Ca2+ release from the endoplasmic reticulum through 1,4,5-triphosphate receptors (IP3Rs), the PI3K/AKT pathway and phosphorylated GSK3ß (Ser9) were significant downregulated. Additionally, significantly reduced sensitivity of Prx II-knockdown HaCaT cells to apoptosis was evident post NAC, 2-APB, BAPTA-AM, SC79 and LiCl treated. These results suggest that Prx II regulated apoptosis of keratinocytes via the PI3K/AKT/GSK3ß signaling axis. Furthermore, treatment with the Prx II inhibitor Conoidin A significantly alleviated psoriatic symptoms in IMQ model mice. These findings have important implications for developing therapeutic strategies through regulate apoptosis of keratinocytes in psoriasis, and Prx II inhibitors may be exploited as a therapeutic drug to alleviate psoriatic symptoms.

Upcycling sulphidic copper tailings into alkali-activated slag materials: effect of the sulfur content.

Sulfidic copper tailings (SCTs) with excessive sulfur content are prone to oxidation, leading to the generation of sulfates and causing compatibility issues with cement. To address this problem, this paper proposes upcycling SCTs into alkali-activated slag (AAS) materials to fully utilize the produced sulfates for slag activation. The influence of the sulfur content of the SCTs compound (quartz, SCTs, and fine pyrite) on the properties of AAS was investigated from various aspects including setting time, compressive strength, hydration products, microstructure, and pore structure. The experimental results showed that adding SCTs compound enabled the generation of S-rich expansive products, such as ettringite, sodium sulfate, and gypsum. Moreover, nano-sized spherical particles were formed and well-distributed in pores or micro-cracks in the microstructure of AAS mortars. Consequently, AAS mortars with SCTs compound developed higher compressive strength at all ages than the blank ones, with an increase of 40.2-144.8% at 3 days, 29.4-115.7% at 7 days, and 29.3-136.3% at 28 days. Furthermore, AAS mortars with SCTs compounds enjoyed significant economic and environmental benefits, as demonstrated by cost-benefit and eco-efficiency analyses. The optimal sulfur content of the SCTs compound was found to be 15%.

Finite Element Analysis of Bonding Property and Flexural Strength of WUHPC-NC Gradient Concrete.

Ultra-high-performance concrete (UHPC) has greater mechanical and durability performance than normal concrete (NC). Using a limited dosage of UHPC on the external surface of NC to form a gradient structure could significantly improve the strength and corrosion resistance of the concrete structure and avoid the problems caused by bulk UHPC. In this work, white ultra-high-performance concrete (WUHPC) was selected as an external protection layer for normal concrete to construct the gradient structure. WUHPC of different strengths were prepared, and 27 gradient WUHPC-NC specimens with different WUHPC strengths and interval times of 0, 10, and 20 h were tested using splitting tensile strength to reveal the bonding properties. Fifteen prism gradient specimens with the size of 100 × 100 × 400 mm and a WUHPC ratio of 1:1, 1:3, and 1:4 were tested using the four-pointed bending method to study the bending performance of the gradient concrete with different WUHPC thicknesses. Finite element models with different WUHPC thicknesses were also built to simulate the cracking behaviors. The results showed that the bonding properties of WUHPC-NC were stronger with less interval time and reached the maximum of 1.5 MPa when the interval was 0 h. Moreover, the bond strength first increased and then decreased with the decline in the strength gap between WUHPC and NC. When the thickness ratios of WUHPC to NC were 1:4, 1:3, and 1:1, the flexural strength of the gradient concrete improved by 89.82%, 78.80%, and 83.31%, respectively. The major cracks rapidly propagated from the 2 cm position to the bottom of the mid-span, and the thickness of 1:4 was the most efficient design. The results simulated by finite element analysis also proved that the elastic strain at the crack propagating point was the minimum and was easier to crack. The simulated results were in good accordance with the experimental phenomenon.

Melatonin protects against developmental PBDE-47 neurotoxicity by targeting the AMPK/mitophagy axis.

The neurotoxicity of 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) is closely linked to mitochondrial abnormalities while mitophagy is vital for mitochondrial homeostasis. However, whether PBDE-47 disrupts mitophagy contributing to impaired neurodevelopment remain elusive. Here, this study showed that neonatal PBDE-47 exposure caused learning and memory deficits in adult rats, accompanied with striatal mitochondrial abnormalities, neuronal apoptosis and the resultant neuronal loss. Mechanistically, PBDE-47 suppressed PINK1/Parkin-mediated mitophagy induction and degradation, inducing mitophagosome accumulation and mitochondrial dysfunction in vivo and in vitro. Additionally, stimulation of mitophagy by adenovirus-mediated Parkin or Autophagy-related protein 7 (Atg7) overexpression aggravated PBDE-47-induced mitophagosome accumulation, mitochondrial dysfunction, neuronal apoptosis and death. Conversely, suppression of mitophagy by the siRNA knockdown of Atg7 rescued PBDE-47-induced detrimental consequences. Importantly, melatonin, a hormone secreted rhythmically by the pineal, improved PBDE-47-caused neurotoxicity via preventing neuronal apoptosis and loss by restoring mitophagic activity and mitochondrial function. These neuroprotective effects of melatonin depended on activation of the AMP-activated protein kinase (AMPK)/Unc-51-like kinase 1 (ULK1) signaling. Collectively, these data indicate that PBDE-47 impairs mitophagy to perturb mitochondrial homeostasis, thus triggering apoptosis, leading to neuronal loss and consequent neurobehavioral deficits. Manipulation of the AMPK-mitophagy axis via melatonin could be a novel therapeutic strategy against developmental PBDE-47 neurotoxicity.

Polymeric Phthalocyanine-Based Nanosensitizers for Enhanced Photodynamic and Sonodynamic Therapies.

Photodynamic therapy and sonodynamic therapy are two highly promising modalities for cancer treatment. The latter holds an additional advantage in deep-tumor therapy owing to the deep penetration of the ultrasonic radiation. The therapeutic efficacy depends highly on the photo/ultrasound-responsive properties of the sensitizers as well as their tumor-localization property and pharmacokinetics. A novel nanosensitizer system based on a polymeric phthalocyanine (pPC-TK) is reported herein in which the phthalocyanine units are connected with cleavable thioketal linkers. Such polymer could self-assemble in water forming nanoparticles with a hydrodynamic diameter of 48 nm. The degradable and flexible thioketal linkers could effectively inhibit the π-π stacking of the phthalocyanine units, rendering the resulting nanoparticles an efficient generator of reactive oxygen species upon light or ultrasonic irradiation. The nanosensitizer could be internalized into cancer cells readily, inducing cell death by efficient photodynamic and sonodynamic effects. The potency is significantly higher than that of the monomeric phthalocyanine (PC-4COOH). The nanosensitizer could also effectively inhibit the growth of tumor in liver tumor-bearing mice by these two therapies without causing noticeable side effects. More importantly, it could also retard the growth of a deep-located orthotopic liver tumor in vivo by sonodynamic therapy.

Secondary Structure in Overcoming Photosensitizers' Aggregation: α-Helical Polypeptides for Enhanced Photodynamic Therapy.

Aggregation caused quenching (ACQ) effect can severely inhibit the application of hydrophobic photosensitizers (PSs) bearing planar and rigid structures. Most of the reported cases utilized random-coiled polymers for the in vivo delivery of PSs, which would inevitably aggravate ACQ effect due to the flexible chains. In this work, the role of polymers' secondary structures (especially α-helical conformation) in overcoming the PSs' aggregation is systemically investigated based on the design of α-helical polypeptides bearing tetraphenylporphyrin (TPP) side chains. Atomistic molecular dynamics simulation, fluorescence quantum yield, and reactive oxygen species (ROS) generation yield are evaluated to demonstrate that α-helical polypeptide backbones can significantly boost both fluorescence quantum yield and ROS by suppressing the π-π stacking interaction between TPP units. The enhanced in vitro and in vivo phototoxicity for helical polypeptides also reveal functions of secondary structures in inhibiting ACQ and improving the membrane activity. Successful in vivo photodynamic therapy (PDT) results in mice bearing H22 tumors showed great potentials for further clinical applications.

Exploring the Applicability of Transfer Learning and Feature Engineering in Epilepsy Prediction Using Hybrid Transformer Model.

OBJECTIVE: Epilepsy prediction algorithms offer patients with drug-resistant epilepsy a way to reduce unintended harm from sudden seizures. The purpose of this study is to investigate the applicability of transfer learning (TL) technique and model inputs for different deep learning (DL) model structures, which may provide a reference for researchers to design algorithms. Moreover, we also attempt to provide a novel and precise Transformer-based algorithm. METHODS: Two classical feature engineering methods and the proposed method which consists of various EEG rhythms are explored, then a hybrid Transformer model is designed to evaluate the advantages over pure convolutional neural networks (CNN)-based models. Finally, the performances of two model structures are analyzed utilizing patient-independent approach and two TL strategies. RESULTS: We tested our method on the CHB-MIT scalp EEG database, the results showed that our feature engineering method gains a significant improvement in model performance and is more suitable for Transformer-based model. In addition, the performance improvement of Transformer-based model utilizing fine-tuning strategies is more robust than that of pure CNN-based model, and our model achieved an optimal sensitivity of 91.7% with false positive rate (FPR) of 0.00/h. CONCLUSION: Our epilepsy prediction method achieves excellent performance and demonstrates its advantage over pure CNN-based structure in TL. Moreover, we find that the information contained in the gamma ( γ ) rhythm is helpful for epilepsy prediction. SIGNIFICANCE: We propose a precise hybrid Transformer model for epilepsy prediction. The applicability of TL and model inputs is also explored for customizing personalized models in clinical application scenarios.