Biodegradable multifunctional nanocarriers for pDNA and siRNA delivery

In this thesis, biodegradable non-viral polymeric nucleic acids delivery vectors were characterized concerning biophysicochemical parameters. In the first part of this research, to answer the questions: why the principle of DNA transfection cannot be directly applied for siRNA transfection, we investigated the complexation and aggregation mechanism of nucleic acids/polycations on the atomic and molecular scale. The MD and ITC data showed us the different nature and the different hierarchical mechanism related polycation-siRNA and polycation-pDNA complexes. All our results emphasized one point: lower N/P-ratios are especially effective for polycationic nanocarrier-based siRNA delivery, because siRNA aggregation results in a more uniform and stable complex formation at low N/P ratios already, which lead to increased siRNA delivery efficiency. This could have broad implications for the delivery of siRNA as less toxic and yet efficient delivery systems have been the bottle-neck for the translation of this promising approach into the clinical arena. In chapter 3, novel biodegradable amphiphilic copolymers hy-PEI-g-PCL-b-PEG were prepared by grafting PCL-b-PEG chains onto hyper-branched poly(ethylene imine) as non-viral gene delivery vectors. With the question: how can the graft densities of PCL-b-PEG chains influence the in vitro DNA delivery efficiency, our study began with the characterization of physico-chemical properties and expected that with the introducing of the grafted PCL-b-PEG chains, the in vitro DNA delivery efficiency with the grafted PCL-b-PEG chains could be improved. Of all the experimental results, buffer-capacity has almost exactly the same tendency as transfection efficiency. We assume that in all processes of DNA transfection, the endosomal escape has a really important and rate-limiting role. This opens new perspectives to advance the rational design of new gene delivery systems. The further investigation of these biodegradable grafted amphiphilic copolymers hy-PEI-g-(PCL-b-PEG)n as potential siRNA delivery vectors was showed in chapter 4. The purpose in this section was to enhance the in vivo blood circulation time and siRNA delivery efficiency of biodegradable copolymers polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol) (hyPEI-g-PCL-b-PEG) by introducing high graft densities of PCL-PEG chains. Our study indicated that the effect of PEG on prolonged circulating depends not only on its content in a copolymer (length or percentage), but also on the structure or the shape of the amphiphilic copolymer. We demonstrated that polymeric micelles, which are formed with amphiphilic block polymers have advantages especially for in vivo siRNA delivery, and that the graft density of the amphiphilic chains can enhance the blood circulation, which is a key parameter to promote the development of safe and efficient non-viral polymeric siRNA delivery in vivo. Although the copolymers hy-PEI-g-(PCL-b-PEG)n showed positive results as pDNA and siRNA delivery vectors in chapter 3 and 4, the delivery of gene materials with these non-targeted copolymers is achieved mainly passively by the passive targeting. Therefore, to optimize these polymeric gene delivery vectors with targeting function, in chapter 5, folate conjugated PEI-g-PCL-b-PEG was examined for targeted gene delivery. Lower cytotoxicity was observed for PEI-g-PCL-b-PEG-Fol than PEI-g-PCL-b-PEG and the cellular uptake of polyplexes was enhanced by PEI-g-PCL-b-PEG-Fol in FR over-expressing KB cells compared with those by PEI-g-PCL-b-PEG. Importantly, this enhancement was inhibited by free folic acid, while did not appear in FR-negative A549 cells. All these suggested the specific cell uptake of PEI-g-PCL-b-PEG-Fol/pDNA polyplexes via folate receptor-mediated endocytosis. Consequently, PEI-g-PCL-b-PEG-Fol/pDNA polyplexes revealed higher transfection than PEI-g-PCL-b-PEG/pDNA. Additional studies on gene transfection in vivo and utilizing these described folate-conjugated copolymers for targeted siRNA delivery are in proceeding. In Chapter 6, the novel siRNA delivery systems based on hyperflexible generation 2-4 triazine dendrimers was identified by correlating physico-chemical and biological in vitro and in vivo properties of the complexes with their thermodynamic interaction features simulated by molecular modeling and the influence of dendrimer flexibility has systematically been investigated and discussed. In this study, molecular modeling helped to understand experimental parameters based on the dendrimers’ structural properties and molecular imaging non-invasively predicted the in vivo fate of the complexes, both techniques can efficiently support the rapid development of safe and efficient siRNA formulations that are stable in vivo

Lightweight and Unobtrusive Data Obfuscation at IoT Edge for Remote Inference

Executing deep neural networks for inference on the server-class or cloud backend based on data generated at the edge of Internet of Things is desirable due primarily to the limited compute power of edge devices and the need to protect the confidentiality of the inference neural networks. However, such a remote inference scheme incurs concerns regarding the privacy of the inference data transmitted by the edge devices to the curious backend. This paper presents a lightweight and unobtrusive approach to obfuscate the inference data at the edge devices. It is lightweight in that the edge device only needs to execute a small-scale neural network; it is unobtrusive in that the edge device does not need to indicate whether obfuscation is applied. Extensive evaluation by three case studies of free spoken digit recognition, handwritten digit recognition, and American sign language recognition shows that our approach effectively protects the confidentiality of the raw forms of the inference data while effectively preserving the backend's inference accuracy.Comment: This paper has been accepted by IEEE Internet of Things Journal, Special Issue on Artificial Intelligence Powered Edge Computing for Internet of Thing

Lightweight conductive graphene/thermoplastic polyurethane foams with ultrahigh compressibility for piezoresistive sensing

Lightweight conductive porous graphene/thermoplastic polyurethane (TPU) foams with ultrahigh compressibility were successfully fabricated by using the thermal induced phase separation (TISP) technique. The density and porosity of the foams were calculated to be about 0.11 g cm−3 and 90% owing to the porous structure. Compared with pure TPU foams, the addition of graphene could effectively increase the thickness of the cell wall and hinder the formation of small holes, leading to a robust porous structure with excellent compression property. Meanwhile, the cell walls with small holes and a dendritic structure were observed due to the flexibility of graphene, endowing the foam with special positive piezoresistive behaviors and peculiar response patterns with a deflection point during the cyclic compression. This could effectively enhance the identifiability of external compression strain when used as piezoresistive sensors. In addition, larger compression sensitivity was achieved at a higher compression rate. Due to high porosity and good elasticity of TPU, the conductive foams demonstrated good compressibility and stable piezoresistive sensing signals at a strain of up to 90%. During the cyclic piezoresistive sensing test under different compression strains, the conductive foam exhibited good recoverability and reproducibility after the stabilization of cyclic loading. All these suggest that the fabricated conductive foam possesses great potential to be used as lightweight, flexible, highly sensitive, and stable piezoresistive sensors

Oncological and reproductive outcomes of conization combined with pelvic node evaluation in patients with early-stage cervical cancer: a systematic review and meta-analysis

ObjectiveThis study aims to preliminarily assess the oncological and reproductive outcomes of fertility preservation treatment using conization combined with pelvic node evaluation in young patients with early-stage cervical cancer (ECC) through meta-analysis.MethodsIn this meta-analysis, we analyzed studies published in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), and Clinical Trials. gov that appeared in our search from inception to 0 7/02/2023.ResultsThere were 17 relevant studies with a total of 620 patients included, of which 444 patients received conization combined with pelvic node evaluation. The combined pregnancy rate was 45.4% (95% CI: 0.34–0.57), the combined live birth rate was 33.9% (95% CI: 0.26–0.42), the combined miscarriage rate was 4.8% (95% CI: 0.02–0.092), the combined preterm delivery rate was 5.1% (95% CI: 0.02–0.092), and the combined recurrence rate was 1.9% (95% CI: 0.006–0.035), which did not significantly differ from that of patients who received radical surgery (OR: 0.689, 95% CI: 0.506–0.938).ConclusionCervical conization combined with pelvic lymph node evaluation for fertility preservation in young ECC patients can achieve oncological outcomes similar to radical surgery while improving pregnancy success rates and preserving postoperative fertility. In summary, fertility preservation treatment using cervical conization combined with pelvic lymph node evaluation may be considered as a viable option for young ECC patients with strong fertility preservation desire, resulting in better pregnancy and live birth outcomes.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/#myprospero, identifier PROSPERO (CRD42023423432)

Bose condensation of upper-branch exciton-polaritons in a transferrable microcavity

Exciton-polaritons are composite bosonic quasiparticles arising from the strong coupling of excitonic transitions and optical modes. Exciton-polaritons have triggered wide exploration in the past decades not only due to their rich quantum phenomena such as superfluidity, superconductivity and quantized vortices but also due to their potential applications for unconventional coherent light sources and all-optical control elements. Here, we report the observation of Bose-Einstein condensation of the upper polariton branch in a transferrable WS$_2$ monolayer microcavity. Near the condensation threshold, we observe a nonlinear increase in upper polariton intensity. This sharp increase in intensity is accompanied by a decrease of the linewidth and an increase of the upper polariton temporal coherence, all of which are hallmarks of Bose-Einstein condensation. By simulating the quantum Boltzmann equation, we show that the upper polariton condensation only occurs for a particular range of particle density. We can attribute the creation of Bose condensation of the upper polariton to the following requirements: 1) the upper polariton is more excitonic than the lower one; 2) there is relatively more pumping in the upper branch; and 3) the conversion time from the upper to the lower polariton branch is long compared to the lifetime of the upper polaritons

Tesigo [smart shopping cart]

Tesigo is an automated cart which is designed for carrying goods. It can be used in many areas such as a shopping mall, an airport, and a hospital. Tesigo can target a host and follow the host automatically. So far, there are no others robots like it and we believe both companies and customers will be satisfied with this design. Users can easily control Tesigo by using our mobile App. Our aim is to release users’ hands and give them an easier life

Effects of AMF inoculation on the eco-physiological characteristics of Imperata cylindrica under differing soil nitrogen conditions

Arbuscular mycorrhizal fungi (AMF) play a key role in terrestrial ecosystems, while the ecological restoration application of AMF in mining areas has been progressively gaining attention. This study simulated a low nitrogen (N) environment in copper tailings mining soil to explore inoculative effects of four AMF species on the eco-physiological characteristics of Imperata cylindrica, and provided plant-microbial symbiote with excellent resistance to copper tailings. Results show that N, soil type, AMF species, and associated interactions significantly affected ammonium (NH4  +), nitrate nitrogen (NO3  −), and total nitrogen (TN) content and photosynthetic characteristics of I. cylindrica. Additionally, interactions between soil type and AMF species significantly affected the biomass, plant height, and tiller number of I. cylindrica. Rhizophagus irregularis and Glomus claroideun significantly increased TN and NH4  + content in the belowground components I. cylindrica in non-mineralized sand. Moreover, the inoculation of these two fungi species significantly increased belowground NH4  + content in mineralized sand. The net photosynthetic rate positively correlated to aboveground total carbon (TC) and TN content under the high N and non-mineralized sand treatment. Moreover, Glomus claroideun and Glomus etunicatum inoculation significantly increased both net photosynthetic and water utilization rates, while F. mosseae inoculation significantly increased the transpiration rate under the low N treatment. Additionally, aboveground total sulfur (TS) content positively correlated to the intercellular carbon dioxide (CO2) concentration, stomatal conductance, and the transpiration rate under the low N sand treatment. Furthermore, G. claroideun, G. etunicatum, and F. mosseae inoculation significantly increased aboveground NH4  + and belowground TC content of I. cylindrica, while G. etunicatum significantly increased belowground NH4  + content. Average membership function values of all physiological and ecological I. cylindrica indexes infected with AMF species were higher compared to the control group, while corresponding values of I. cylindrica inoculated with G. claroideun were highest overall. Finally, comprehensive evaluation coefficients were highest under both the low N and high N mineralized sand treatments. This study provides information on microbial resources and plant-microbe symbionts in a copper tailings area, while aiming to improve current nutrient-poor soil conditions and ecological restoration efficiency in copper tailings areas

Efficacy and safety of histone deacetylase inhibitors in peripheral T-cell lymphoma: a systematic review and meta-analysis on prospective clinical trials

BackgroundThe overall survival of peripheral T-cell lymphoma (PTCL) is dismal. Histone deacetylase (HDAC) inhibitors have exhibited promising treatment outcomes for PTCL patients. Therefore, this work aims to systematically evaluate the treatment outcome and safety profile of HDAC inhibitor-based treatment for untreated and relapsed/refractory (R/R) PTCL patients.MethodsThe prospective clinical trials of HDAC inhibitors for the treatment of PTCL were searched on the Web of Science, PubMed, Embase, ClinicalTrials.gov, and Cochrane Library database. The pooled overall response rate, complete response (CR) rate, and partial response rate were measured. The risk of adverse events was evaluated. Moreover, the subgroup analysis was utilized to assess the efficacy among different HDAC inhibitors and efficacy in different PTCL subtypes.ResultsFor untreated PTCL, 502 patients in seven studies were involved, and the pooled CR rate was 44% (95% CI, 39-48%). For R/R PTCL patients, there were 16 studies included, and the CR rate was 14% (95% CI, 11-16%). The HDAC inhibitor-based combination therapy exhibited better efficacy when compared with HDAC inhibitor monotherapy for R/R PTCL patients (P = 0.02). In addition, the pooled CR rate was 17% (95% CI, 13-22%), 10% (95% CI, 5-15%), and 10% (95% CI, 5-15%) in the romidepsin, belinostat, and chidamide monotherapy subgroups, respectively. In the R/R angioimmunoblastic T-cell lymphoma subgroup, the pooled ORR was 44% (95% CI, 35-53%), higher than other subtypes. A total of 18 studies were involved in the safety assessment of treatment-related adverse events. Thrombocytopenia and nausea were the most common hematological and non-hematological adverse events, respectively.ConclusionThis meta-analysis demonstrated that HDAC inhibitors were effective treatment options for untreated and R/R PTCL patients. The combination of HDAC inhibitor and chemotherapy exhibited superior efficacy to HDAC inhibitor monotherapy in the R/R PTCL setting. Additionally, HDAC inhibitor-based therapy had higher efficacy in angioimmunoblastic T-cell lymphoma patients than that in other subtypes

The NLRP3 inflammasome is involved in resident intruder paradigm-induced aggressive behaviors in mice

Background: Aggressive behaviors are one of the most important negative behaviors that seriously endangers human health. Also, the central para-inflammation of microglia triggered by stress can affect neurological function, plasticity, and behavior. NLRP3 integrates stress-related signals and is a key driver of this neural para-inflammation. However, it is unclear whether the NLRP3 inflammasome is implicated in the development of aggressive behaviors.Methods: First, aggressive behavior model mice were established using the resident intruder paradigm. Then, aggressive behaviors were determined with open-field tests (OFT), elevated plus-maze (EPM), and aggressive behavior tests (AT). Moreover, the expression of P2X7R and NLRP3 inflammasome complexes were assessed by immunofluorescence and Western blot. The levels of NLRP3 and inflammatory cytokines were evaluated using enzyme-linked immunosorbent assay (ELISA) kits. Finally, nerve plasticity damage was observed by immunofluorescence, transmission electron microscope, and BrdU staining.Results: Overall, the resident intruder paradigm induced aggressive behaviors, activated the hippocampal P2X7R and NLRP3 inflammasome, and promoted the release of proinflammatory cytokines IL-1β in mice. Moreover, NLRP3 knockdown, administration of P2X7R antagonist (A804598), and IL-1β blocker (IL-1Ra) prevented NLRP3 inflammasome-driven inflammatory responses and ameliorated resident intruder paradigm-induced aggressive behaviors. Also, the resident intruder paradigm promoted the activation of mouse microglia, damaging synapses in the hippocampus, and suppressing hippocampal regeneration in mice. Besides, NLRP3 knockdown, administration of A804598, and IL-1Ra inhibited the activation of microglia, improved synaptic damage, and restored hippocampal regeneration.Conclusion: The NLRP3 inflammasome-driven inflammatory response contributed to resident intruder paradigm-induced aggressive behavior, which might be related to neuroplasticity. Therefore, the NLRP3 inflammasome can be a potential target to treat aggressive behavior-related mental illnesses

Down-Regulation of EBV-LMP1 Radio-Sensitizes Nasal Pharyngeal Carcinoma Cells via NF-κB Regulated ATM Expression

BACKGROUND:The latent membrane protein 1 (LMP1) encoded by EBV is expressed in the majority of EBV-associated human malignancies and has been suggested to be one of the major oncogenic factors in EBV-mediated carcinogenesis. In previous studies we experimentally demonstrated that down-regulation of LMP1 expression by DNAzymes could increase radiosensitivity both in cells and in a xenograft NPC model in mice. RESULTS:In this study we explored the molecular mechanisms underlying the radiosensitization caused by the down-regulation of LMP1 in nasopharyngeal carcinoma. It was confirmed that LMP1 could up-regulate ATM expression in NPCs. Bioinformatic analysis of the ATM ptomoter region revealed three tentative binding sites for NF-κB. By using a specific inhibitor of NF-κB signaling and the dominant negative mutant of IkappaB, it was shown that the ATM expression in CNE1-LMP1 cells could be efficiently suppressed. Inhibition of LMP1 expression by the DNAzyme led to attenuation of the NF-κB DNA binding activity. We further showed that the silence of ATM expression by ATM-targeted siRNA could enhance the radiosensitivity in LMP1 positive NPC cells. CONCLUSIONS:Together, our results indicate that ATM expression can be regulated by LMP1 via the NF-κB pathways through direct promoter binding, which resulted in the change of radiosensitivity in NPCs