Wireless sensor networks (WSNs), integral components underpinning the infrastructure of the internet of things (IoT), confront escalating threats originating from attempts at malicious jamming. ...Nevertheless, the limited nature of the hardware resources in distributed, low-cost WSNs, such as those for computing power and storage, poses a challenge when implementing complex and intelligent anti-jamming algorithms like deep reinforcement learning (DRL). Hence, in this paper a rapid anti-jamming method is proposed based on imitation learning in order to address this issue. First, on-network nodes obtain expert anti-jamming trajectories using heuristic algorithms, taking historical experiences into account. Second, an RNN neural network that can be used for anti-jamming decision making is trained by mimicking these expert trajectories. Finally, the late-access network nodes receive anti-jamming network parameters from the existing nodes, allowing them to obtain a policy network directly applicable to anti-jamming decision making and thus avoiding redundant learning. Experimental results demonstrate that, compared with traditional Q-learning and random frequency-hopping (RFH) algorithms, the imitation learning-based algorithm empowers late-access network nodes to swiftly acquire anti-jamming strategies that perform on par with expert strategies.
Hypoxia is a common feature of diabetic tissues, which highly correlates to the progression of diabetes. The formation of hypoxic context is induced by disrupted oxygen homeostasis that is ...predominantly driven by vascular remodeling in diabetes. While different types of vascular impairments have been reported, the specific features and underlying mechanisms are yet to be fully understood. Under hypoxic condition, cells upregulate hypoxia-inducible factor-1α (HIF-1α), an oxygen sensor that coordinates oxygen concentration and cell metabolism under hypoxic conditions. However, diabetic context exploits this machinery for pathogenic functions. Although HIF-1α protects cells from diabetic insult in multiple tissues, it also jeopardizes cell function in the retina. To gain a deeper understanding of hypoxia in diabetic complications, we focus on the formation of tissue hypoxia and the outcomes of HIF-1α dysregulation under diabetic context. Hopefully, this review can provide a better understanding on hypoxia biology in diabetes.
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•Diabetes promotes hypoxia by inducing thromus, vascular degradation, oxygen consumption imbalance, and red blood cell impairment.•Hypoxia exerts varied effects on angiogenesis depending on specific cell types involved.•HIF-1α upregulation contributes to diabetic complications in various tissues, while it exhibits protective effect in certain scenario.•Targeting hypoxia and HIF-1α proves effective in alleviating diabetes in mouse models, yet the translational study lags behind.
One of the key issues for the development of electric vehicles (EVs) is the requirement of a supervisory energy management strategy, especially for those with hybrid energy storage systems. An ...adaptive fuzzy logic-based energy management strategy (AFEMS) is proposed in this paper to determine the power split between the battery pack and the ultracapacitor (UC) pack. A fuzzy logic controller is used due to the complex real-time control issue. Furthermore, it does not need the knowledge of the driving cycle ahead of time. The underlying principles of this adaptive fuzzy logic controller are to maximize the system efficiency, to minimize the battery current variation, and to minimize UC state of charge (SOC) difference. NetLogo is used to assess the performance of the proposed method. Compared with other three energy management strategies, the simulation and experimental results show that the proposed AFEMS promises a better comprehensive control performance in terms of the system efficiency, the battery current variation, and differences in the UC SOC, for both congested city driving and highway driving situations.
Enzyme-based host depletion significantly improves the sensitivity of clinical metagenomics. Recent studies found that real-time adaptive sequencing of DNA molecules was achieved using a nanopore ...sequencing machine, which enabled effective enrichment of microbial sequences. However, few studies have compared the enzyme-based host depletion and nanopore adaptive sequencing for microbial enrichment efficiency. To compare the host depletion and microbial enrichment efficiency of enzyme-based and adaptive sequencing methods, the present study collected clinical samples from eight children with respiratory tract infections. The same respiratory samples were subjected to standard methods, adaptive sequencing methods, enzyme-based host depletion methods, and the combination of adaptive sequencing and enzyme-based host depletion methods. We compared the host depletion efficiency, microbial enrichment efficiency, and pathogenic microorganisms detected between the four methods. We found that adaptive sequencing, enzyme-based host depletion and the combined methods significantly enriched the microbial sequences and significantly increased the diversity of microorganisms (p value < 0.001 for each method compared to standard). The highest microbial enrichment efficiency was achieved using the combined method. Compared to the standard method, the combined method increased the microbial reads by a median of 113.41-fold (interquartile range 23.32-327.72, maximum 1812), and the number of genera by a median of 70-fold (interquartile range 56.75-86.75, maximum 164). The combined method detected 6 pathogens in 4 samples with a median read of 547, compared to 5 pathogens in 4 samples with a median read of 4 using the standard method. The combined method is an effective, easy-to-run method for enriching microbial sequences in clinical metagenomics from sputum and bronchoalveolar lavage fluid samples and may improve the sensitivity of clinical metagenomics for other host-derived clinical samples.
With the progressively increasing demand for orthopedic Ti implants, the balance between two primary complications restricting implant applications is needed to be solved: the lack of bone tissue ...integration and biomedical device-associated infections (BAI), where emergence of multiresistance bacteria make it worse. Notably, a combination of silver nanoparticles (AgNPs) and a kind of antibiotic can synergistically inhibit bacterial growth, where a low concentration of AgNPs has been confirmed to promote the proliferation and osteogenesis of osteoblasts. In this work, we built AgNPs/gentamicin (Gen)-embedded silk fibroin (SF)-based biomimetic coatings on orthopedic titanium by a facile dipping-drying circular process and with the assistance of polydopamine (PD). Ag
was reduced to AgNPs by SF under ultraviolet (UV) irradiation, and then they were detected by transmission electron microscope (TEM) images and UV-visible (UV-vis) analyses. Intriguingly, the addition of Gen highly improved the reduction efficiency of Ag
. The antibacterial efficiency of SF-based coatings was examined by challenging them with pathogenic Staphylococcus aureus (S. aureus) bacteria which produced biofilms, and consequently, we found that low concentration loading, durable release of Ag
(28 days), and 10-fold improvement of antibacterial efficiency were achieved for our novel AgNPs- and Gen-embeded silk fibroin coatings. In bacteria and a cells cocultured system, AgNPs/Gen-embedded coatings strongly inhibited adhesion and proliferation of S. aureus, simultaneously improving cell adhesion and growth. To investigate cytocompatibility and osteogenic potential, different coatings were cultured with MC3T3 cells; AgNPs/Gen-embedded coatings showed generally acceptable biocompatibility (cell adhesion, proliferation, and viability) and accelerated osteoblast maturation (alkaline phosphatase production, matrix secretion, and calcification). Expectantly, this novel biofunctional coating will have promising applications in orthopedic and dental titanium implants thanks to its excellently antibacterial, biocompatible, and osteogenic activities.
Transplantation of human pluripotent stem cell (hPSC)-derived neurons is a promising avenue for treating disorders including Parkinson’s disease (PD). Precise control over engrafted cell activity is ...highly desired, as cells do not always integrate properly into host circuitry and can cause suboptimal graft function or undesired outcomes. Here, we show tunable rescue of motor function in a mouse model of PD, following transplantation of human midbrain dopaminergic (mDA) neurons differentiated from hPSCs engineered to express DREADDs (designer receptors exclusively activated by designer drug). Administering clozapine-N-oxide (CNO) enabled precise DREADD-dependent stimulation or inhibition of engrafted neurons, revealing D1 receptor-dependent regulation of host neuronal circuitry by engrafted cells. Transplanted cells rescued motor defects, which could be reversed or enhanced by CNO-based control of graft function, and activating engrafted cells drives behavioral changes in transplanted mice. These results highlight the ability to exogenously and noninvasively control and refine therapeutic outcomes following cell transplantation.
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•CRISPR-mediated DREADD knockin enables precise regulation of hPSC-derived neurons•Engrafted mDA neurons regulate host neuronal circuitry in striatum via D1 receptors•Graft activity can be noninvasively and reversibly controlled by DREADD ligands•Regulation of DREADD-expressing human graft activity dictates animal behavior
Chen et al. show that motor function in PD mice can be reversed or enhanced following transplantation of dopamine neurons differentiated from hPSCs engineered to express DREADDs. Administering CNO noninvasively and reversibly modulates neuronal graft function, highlighting the potential to exogenously control and refine therapeutic outcomes following cell transplantation.
Despite neoadjuvant/conversion chemotherapy, the prognosis of cT4a/bN+ gastric cancer is poor. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in late-stage gastric ...cancer, but their efficacy in the neoadjuvant/conversion setting is unclear. In this single-armed, phase II, exploratory trial (NCT03878472), we evaluate the efficacy of a combination of ICI (camrelizumab), antiangiogenesis (apatinib), and chemotherapy (S-1 ± oxaliplatin) for neoadjuvant/conversion treatment of cT4a/bN+ gastric cancer. The primary endpoints are pathological responses and their potential biomarkers. Secondary endpoints include safety, objective response, progression-free survival, and overall survival. Complete and major pathological response rates are 15.8% and 26.3%. Pathological responses correlate significantly with microsatellite instability status, PD-L1 expression, and tumor mutational burden. In addition, multi-omics examination reveals several putative biomarkers for pathological responses, including RREB1 and SSPO mutation, immune-related signatures, and a peripheral T cell expansion score. Multi-omics also demonstrates dynamic changes in dominant tumor subclones, immune microenvironments, and T cell receptor repertoires during neoadjuvant immunotherapy. The toxicity and post-surgery complications are limited. These data support further validation of ICI- and antiangiogenesis-based neoadjuvant/conversion therapy in large randomized trials and provide candidate biomarkers.
Base editing tools for cytosine to thymine (C-T) conversion enable genome manipulation at single base-pair resolution with high efficiency. Available base editors (BEs) for C-T conversion (CBEs) have ...restricted editing scopes and nonnegligible off-target effects, which limit their applications. Here, by screening diversified lamprey cytidine deaminases, we establish various CBEs with expanded and diversified editing scopes, which could be further refined by various fusing strategies, fusing at either N-terminus or C-terminus of nCas9. Furthermore, off-target analysis reveals that several CBEs display improved fidelity. Our study expands the toolkits for C-T conversion, serves as guidance for appropriate choice and offers a framework for benchmarking future improvement of base editing tools.
Endowing implant surfaces with combined antibacterial and osteogenic properties by drug-loaded coatings has made great strides, but how to achieve the combined excellence of infection-triggered ...bactericidal and in vivo-proven osteogenic activities without causing bacterial resistance still remains a formidable challenge. Herein, antimicrobial peptides (AMPs) with osteogenic fragments were designed and complexed on the surface of silver nanoparticle (AgNP) through hydrogen bonding, and the collagen structure-bionic silk fibroin (SF) was applied to carry AgNPs@ AMPs to achieve infection-triggered antibacterial and osteointegration. As verified by TEM, AMPs contributed to the dispersion and size-regulation of AgNPs, with a particle size of about 20 nm, and a clear protein corona structure was observed on the particle surface. The release curve of silver ion displayed that the SF-based coating owned sensitive pH-responsive properties. In the antibacterial test against S.aureus for up to 21 days, the antibacterial rate had always remained above 99%. Meanwhile, the underlying mechanism was revealed, originating from the destruction of the bacterial cell membranes and ROS generation. The SF-based coating was conducive to the adhesion, diffusion, and proliferation of bone marrow stem cells (BMSCs) on the surface, and promoted the expression of osteogenic genes and collagen secretion. The in vivo implantation results showed that compared with the untreated Ti implants, SF-based coating enhanced osseointegration at week 4 and 8. Overall, the AgNPs@AMPs-loaded SF-based coating presented the ability to synergistically inhibit bacteria and promote osseointegration, possessing tremendous potential application prospects in bone defects and related-infection treatments.
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•AMPs and AgNPs were complexed through hydrogen bonds to form a protein crowns structure.•Silk fibroin matrix was able to maintain the activity of AMPs over 21 d and endow with the infection-trigger release.•The functional coating achieved synergistic antibacterial properties by damaging membrane structure and generating ROS.•The coating displayed acceptable osteogenic properties in vitro and observably promoted osteointegration in vivo.
Paclitaxel (PTX) was discovered more than 50 years ago in 1968. The drug, known as the first herbal-derived chemotherapeutic drug approved, works by inhibiting the cell cycle. However, due to its ...poor water solubility and non-selective toxicity, severe side effects often occur accompanied with the clinical application of drugs. How to enhance the efficacy of paclitaxel has become an urgent problem to researchers. Aiming to provide new ideas for structural modification and drug delivery system development, structural modification of paclitaxel, including the introduction of small molecular fragments or soluble polymers at the C-2' and C-7 sites and nanocarrier-based new generation PTX drugs Abraxane and Lipusu are discussed in this review.
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