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Review regarding draining likelihood of trace metals, PAHs along with Printed circuit boards from a brownfield located in a flooding area.
Results We included 134 patients, of whom 19 (14.2%) developed any severe illness. CT features on day 0 and day 4, as well as their changes from day 0 to day 4, showed predictive capability. Changes in CT features from day 0 to day 4 performed the best in the prediction (area under the receiver operating characteristic curve = 0.93, 95% confidence interval [CI] 0.87~0.99; C-index=0.88, 95% CI 0.81~0.95). The hazard ratios of PGV and PCV were 1.39 (95% CI 1.05~1.84, P=0.023) and 1.67 (95% CI 1.17~2.38, P=0.005), respectively. CT features, adjusted for age and gender, on day 4 and in terms of changes from day 0 to day 4 outperformed APACHE-II, NLR, and d-dimer. Conclusions CT quantification of pneumonia lesions can early and non-invasively predict the progression to severe illness, providing a promising prognostic indicator for clinical management of COVID-19. © The author(s).Chronic infection by hepatitis B virus (HBV) is associated with high risks of liver fibrosis, cirrhosis and hepatocellular carcinoma. In mouse models of HBV persistence, interleukin 21 (IL-21) has been identified as a potent inducer of viral clearance. Strict hepatotropism makes recombinant HBV (rHBV) vectors ideal for liver-targeting gene delivery. Previously, we established an rHBV vector termed 5c3c, which is highly replicative by itself, but requires HBV envelope proteins provided in trans to produce virions. 5c3c-based rHBV virions are capable of delivering cargo gene expression driven by HBV Sp1 promoter into infected hepatocytes. In this work, we explore the feasibility of using 5c3c-derived rHBV for liver-specific delivery of IL-21 as treatment of chronic HBV infection. Methods 5c3c-derived rHBV replicons harboring mouse or human IL-21 genes (termed 5c3c-mIL-21 and 5c3c-hIL-21 respectively) were constructed and then tested for the production of rHBV virions in vitro and in vivo. 5c3c-mIL-21's anti-HBV effects were determined in chronic HBV mouse model. Furthermore, superinfection by rHBV virions was analysed using HBV-infected HepG2/NTCP cells and human liver chimeric mice. Results 5c3c-mIL-21 and 5c3c-hIL-21 were efficiently replicative and produced enveloped virions when provided with envelope proteins, both in vitro and in vivo. In mouse model of HBV persistence, IL-21 expressed from injected 5c3c-mIL-21 replicon induced complete viral clearance. 5c3c-mIL-21 and 5c3c-hIL-21 virions could infect HepG2/NTCP cells and engender sustained IL-21 expression. Most importantly, IL-21-expressing rHBV virions could superinfect HBV-infected HepG2/NTCP cells and human hepatocytes in human liver chimeric mice, and engender sustained IL-21 expression and rHBV production. Conclusion These data suggest the high potential of 5c3c-derived IL-21-expressing rHBV as a novel therapeutic against chronic HBV infection. © The author(s).Rationale There is a continued need for investigating the roles of microRNAs and their targets on the pathogenesis of pulmonary arterial hypertension (PAH) vascular remodeling. We recently identified the association of myeloid miR-182-3p and its new target, Myeloid-Associated Differentiation Marker (Myadm), with vascular remodeling. Here, we aimed to determine the role of miR-182-3p/Myadm on PAH vascular remodeling and the underlying molecular mechanism. Methods The miR-182-3p/Myadm expression profiles were detected in PAH patients and experimental rodent models. Loss-of-function and gain-of-function studies using gene knock-in or gene knock-out and the combinations of the proteomic technology and genome-wide ChIP-Seq were employed to determine the downstream targets of miR-182-3p/Myadm in response to monocrotaline (MCT)-induced PAH. Results The miR-182-3p/Myadm expression was altered in PAH patients and experimental rodent models. Both miR-182-3p inhibitor and overexpression of Myadm augmented the pathological progression in rats in response to MCT-induced PAH. In contrast, miR-182-3p mimic and Myadm gene knockout attenuated the changes in the hemodynamics and structure of the cardio-pulmonary system in MCT-induced PAH in rats. Myadm mediated the proliferation of pulmonary artery smooth muscle cells (PASMCs) by altering the cell cycle kinase inhibitor (p21/Cip1) expression through the transcription factor Krüppel-like factor 4 (KLF4) translocation into the cytoplasm. Conclusion Our findings indicate the prognostic and therapeutic significance of miR-182-3p in PAH and provide a new regulatory model of the myeloid-derived miR-182-3p/Myadm/KLF4/p21 axis in PAH vascular remodeling. © The author(s).A cluster of patients poisoned by herbal medicine in the 1990s revealed that aristolochic acid (AA) causes kidney failure and upper tract urothelial carcinoma (UTUC). Recent research demonstrated that this was not an isolated incident; on the contrary, AA exposure is widespread in East Asia. This editorial highlights research by Lu and colleagues that investigates clinical characteristics of AA and non-AA UTUCs from 90 patients in Beijing based on the AA mutational signature. The study also detected AA mutations in non-tumor tissue of AA exposed patients and showed that AA mutations can be detected in urine, which might form the basis for non-invasive tests for AA exposure. © The author(s).Chondral and osteochondral defects caused by trauma or pathological changes, commonly progress into total joint degradation, even resulting in disability. The cartilage restoration is a great challenge because of its avascularity and limited proliferative ability. Additionally, precise diagnosis using non-invasive detection techniques is challenging, which increases problems associated with chondral disease treatment. Methods To achieve a theranostic goal, we used an integrated strategy that relies on exploiting a multifunctional nanoprobe based on chitosan-modified Fe3O4 nanoparticles, which spontaneously self-assemble with the oppositely charged small molecule growth factor, kartogenin (KGN). This nanoprobe was used to obtain distinctively brighter T2-weighted magnetic resonance (MR) imaging, allowing its use as a positive contrast agent, and could be applied to obtain accurate diagnosis and osteochondral regeneration therapy. Results This nanoprobe was first investigated using adipose tissue-derived stem cells (ADSCs), and was found to be a novel positive contrast agent that also plays a significant role in stimulating ADSCs differentiation into chondrocytes. This self-assembled probe was not only biocompatible both in vitro and in vivo, contributing to cellular internalization, but was also used to successfully make distinction of normal/damaged tissue in T2-weighted MR imaging. This novel combination was systematically shown to be biosafe via the decrement of apparent MR signals and elimination of ferroferric oxide over a 12-week regeneration period. Conclusion Here, we established a novel method for osteochondral disease diagnosis and reconstruction. Using the Fe3O4-CS/KGN nanoprobe, it is easy to distinguish the defect position, and it could act as a tool for dynamic observation as well as a stem cell-based therapy for directionally chondral differentiation. © The author(s).Reactive oxygen species (ROS)-based photodynamic therapy (PDT) has a widespread application in cancer therapy. Nevertheless, the efficiency of PDT is far from satisfactory. One major impediment is the overexpression of glutathione (GSH) in tumor cells, which could deplete the level of PDT-generated ROS. Herein, we develop a novel type of cytochrome P450 enzyme-mediated auto-enhanced photodynamic co-nanoassembly between clopidogrel (CPG) and photosensitizer pyropheophorbide a (PPa). Methods In this work, we prepare the co-assembled nanoparticles of CPG and PPa (CPG/PPa NPs) by using one-step precipitation method. The assembly mechanism, drug release behavior, GSH consumption, ROS generation, cellular uptake, cytotoxicity of CPG/PPa NPs are investigated in vitro. The mice bearing 4T1 tumor are employed to evaluate in vivo biodistribution and anti-tumor effect of CPG/PPa NPs. Results Such CPG/PPa NPs could disrupt the intracellular redox homeostasis, resulting from the elimination of GSH by CPG active metabolite mediated by cytochrome P450 enzyme (CYP2C19). The in vivo assays reveal that CPG/PPa NPs not only increase the drug accumulation in tumor sites but also significantly suppress tumor growth in BALB/c mice bearing 4T1 tumor. With CPG-mediated GSH consumption and PPa-triggered ROS generation, CPG/PPa NPs show the enhanced PDT treatment effect by breaking intracellular redox balance. Conclusion Our findings provide a valuable knowledge for the rational design of the PDT-based combinational cancer therapy. © The author(s).Gene editing is a versatile technique in biomedicine that promotes fundamental research as well as clinical therapy. The development of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) as a genome editing machinery has accelerated the application of gene editing. However, the delivery of CRISPR components often suffers when using conventional transfection methods, such as viral transduction and chemical vectors, due to limited packaging size and inefficiency toward certain cell types. In this review, we discuss physical transfection methods for CRISPR gene editing which can overcome these limitations. We outline different types of physical transfection methods, highlight novel techniques to deliver CRISPR components, and emphasize the role of micro and nanotechnology to improve transfection performance. We present our perspectives on the limitations of current technology and provide insights on the future developments of physical transfection methods. © The author(s).[This corrects the article DOI 10.7150/thno.18299.]. © The author(s).[This corrects the article DOI 10.7150/thno.35582.]. © The author(s).[This corrects the article DOI 10.7150/thno.9727.]. © The author(s).Non-invasive low-intensity pulsed ultrasound has been employed for direct neuro-modulation. However, its range and effectiveness for different neurological disorders have not been fully elucidated. Methods We used multiple approaches of electrophysiology, immunohistochemistry, and behavioral tests as potential epilepsy treatments in non-human primate model of epilepsy and human epileptic tissues. Low-intensity pulsed ultrasound with a frequency of 750 kHz and acoustic pressure of 0.35 MPa (the spatial peak pulse average intensity, ISPPA = 2.02 W/cm2) were delivered to the epileptogenic foci in five penicillin-induced epileptic monkey models. An ultrasound neuro-modulation system with a frequency of 28 MHz and acoustic pressure of 0.13 MPa (ISPPA = 465 mW/cm2) compatible with patch-clamp systems was used to stimulate the brain slices prepared from fifteen patients with epilepsy. Results After 30 min of low-intensity pulsed ultrasound treatment, total seizure count for 16 hours (sham group 107.7 ± 1.2, ultrasound group 66.0 ± 7.9, P less then 0.01) and seizure frequency per hour (sham group 15.6 ± 1.2, ultrasound group 9.6 ± 1.5, P less then 0.05) were significantly reduced. selleck The therapeutic efficacy and underlying potential mechanism of low-intensity pulsed ultrasound treatment were studied in biopsy specimens from epileptic patients in vitro. Ultrasound stimulation could inhibit epileptiform activities with an efficiency exceeding 65%, potentially due to adjusting the balance of excitatory-inhibitory (E/I) synaptic inputs by the increased activity of local inhibitory neurons. Conclusion Herein, we demonstrated for the first time that low-intensity pulsed ultrasound improves electrophysiological activities and behavioral outcomes in a non-human primate model of epilepsy and suppresses epileptiform activities of neurons from human epileptic slices. The study provides evidence for the potential clinical use of non-invasive low-intensity pulsed ultrasound stimulation for epilepsy treatment. © The author(s).
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