Biocompatibility of synthetic nanomaterials and their applications in gene delivery

Nanomedicine is the use of nanoscale or nanostructured materials in medicine that due to their structure have unique medical effects. Prominent applications of nanomedicine are the use of nanomaterials for the delivery of drugs and nucleic acids (to correct gene defects). Nanomaterials offer several attractive features as delivery vehicles: First, their size in the nano-regime endows them with more desirable pharmacokinetic and biodistribution profiles in vivo. Second, they are amenable to diverse chemical engineering that enables loading of a wide range of substances. Third, they can protect therapeutic agents from premature degradation or from inducing undesired side effects. In this thesis, two types of synthetic nanomaterials, namely silica and polythiophene, were investigated for their biocompatibility and applications in gene delivery. In Paper I, human red blood cell hemolysis and premyelocytic leukemia HL-60 cell cytotoxicity induced by silica nanoparticles with distinct physicochemical properties were studied, suggesting that silica nanoparticles potentially induce membrane permeability through a universal mechanism of action. Moreover, plasma protected against silica nanoparticle-induced membrane damage primarily by shielding the surface of silica particles. In Paper II, the cytotoxicity and oxidative stress induced by amorphous silica nanoparticles were compared to nanoparticles with similar size but different chemical compositions. Overexpression of the liver phase II enzyme microsomal glutathione transferase 1 (MGST1) in human breast carcinoma MCF-7 cells reversed the cytotoxicity and oxidative stress induced by some silica nanoparticles but did not protect against the cytotoxic effects induced by zinc oxide nanoparticles. In Paper III, amino-functionalized silica nanoparticles were used to deliver plasmid DNA (pDNA) into human breast carcinoma MCF-7 cells, with the nonporous particles delivering pDNA at higher efficiency than their mesoporous counterparts (with 2.4 nm pore diameter). In Paper IV, polythiophene nanoparticles were used as vectors to deliver small interference RNA (siRNA) into human osteosarcoma U2-OS cells and human cervical carcinoma HeLa cells. The cationic polythiophenes were considerably more efficient delivery vectors than their zwitteronic counterparts. In conclusion, studies to improve the understanding of the biocompatibility and delivery efficiency of nanomaterials, are crucial to assist the rationale design of nanomaterials for delivery applications

Experimental Study on Chinese Athletes’ Physical Distribution in Sanda Competition

Reasonable distribution of physical strength plays a very important role in adversary Sanda competition. According to the physical characteristics of Sanda athletes, this paper studied the physical distribution during Sanda competition. The results are as follows: a) If an athlete’s opponent is physically stronger, then he is not supposed to be recklessly but to take defense-oriented strategies. The athlete has to avoid the opponent’s heavy blow and seize the opportunity to accurately counterattack. b) If his physical strength is equal with the opponent’s, the athlete is supposed to maintain self-physical strength, and try to consume opponent physically. c) If the athlete is physically stronger, then he should actively attack, but not rampage. Two specific tactics are proposed: i) try to consume the opponent’s strength if the opponent is very easily excited or impetuous; ii) try to use defensive strategies if the opponent less attack

Self-Presentation on the Web: Agencies Serving Abused and Assaulted Women

Objectives. We examined the content and usability of the Web sites of agencies serving women victims of violence. Methods. We entered the names of a systematic 10% sample of 3774 agencies listed in 2 national directories into a search engine. We took (in April 2012) and analyzed screenshots of the 261 resulting home pages and the readability of 193 home and first-level pages. Results. Victims (94%) and donors (68%) were the primary intended audiences. About one half used social media and one third provided cues to action. Almost all (96.4%) of the Web pages were rated “fairly difficult” to “very confusing” to read, and 81.4% required more than a ninth-grade education to understand. Conclusions. The service and marketing functions were met fairly well by the agency home pages, but usability (particularly readability and offer of a mobile version) and efforts to increase user safety could be improved. Internet technologies are an essential platform for public health. They are particularly useful for reaching people with stigmatized health conditions because of the anonymity allowed. The one third of agencies that lack a Web site will not reach the substantial portion of the population that uses the Internet to find health information and other resources

Preparation, structural and magnetic characterization of trinuclear and one-dimensional cyanide-bridged Co(III)-Cu(II) complexes

341-345By employing two trans-dicyanocobolt(III) building blocks K[Co(bpb)(CN)2] (bpb2- = 1,2-bis(pyridine-2-carboxamido)benzenate), K[Co(bpmb)(CN)2] (bpmb2- = 1,2-bis(pyridine-2-carboxamido)-4-methyl-benzenate) and one 14-membered macrocycle Cu(II) compound as assembling segment, two cyanide-bridged CoIII-CuII complexes {{[Cu(cyclam)][Co(bpb)(CN)2]}ClO4}n·nCH3OH·nH2O (1) and {[Cu(cyclam)][Co(bpmb)(CN)2]2}·4H2O (2) (cyclam = 1,4,8,11-tetraazacyclotetradecane) have been successfully prepared and characterized by elemental analysis, IR spectroscopy and X-ray structure determination. Single X-ray diffraction analysis shows that complex 1 can be structurally characterized as one-dimensional cationic single chain consisting of alternating units of [Cu(cyclam)]2+ and [Co(bpb)(CN)2]- with free ClO4- as balanced anion, while complex 2 presents cyanide-bridged neutral trinuclear bimetallic structure containing Co2Cu core, giving clear information that the substitute group on the cyanide precursor has obvious influence on the structure type of the target compound. Investigation over magnetic properties of complex 1 reveals the weak antiferromagnetic coupling between the neighboring Cu(II) ions through the diamagnetic cyanide building block

Patients with myasthenia gravis with acute onset of dyspnea: predictors of progression to myasthenic crisis and prognosis

Background: Life-threatening myasthenic crisis (MC) occurs in 10–20% of the patients with myasthenia gravis (MG). It is important to identify the predictors of progression to MC and prognosis in the patients with MG with acute exacerbations. Objective: This study aimed to explore the predictors of progression to MC in the patients with MG with acute onset of dyspnea and their short-term and long-term prognosis. Methods: This study is a retrospective cohort study. We collected and analyzed data on all the patients with MG with acute dyspnea over a 10-year period in a single center using the univariate and multivariate analysis. Results: Eighty-six patients with MG were included. In their first acute dyspnea episodes, 36 (41.9%) episodes eventually progressed to MC. A multivariate analysis showed that the early-onset MG (adjusted OR: 3.079, 95% CI 1.052–9.012) and respiratory infection as a trigger (adjusted OR: 3.926, 95% CI 1.141–13.510) were independent risk factors for the progression to MC, while intravenous immunoglobulin (IVIg) treatment prior to the mechanical ventilation (adjusted OR: 0.253, 95% CI 0.087–0.732) was a protective factor. The prognosis did not significantly differ between the patients with and without MC during the MG course, with a total of 45 (52.3%) patients reaching post-intervention status better than minimal manifestations at the last follow-up. Conclusion: When treating the patients with MG with acute dyspnea, the clinicians should be aware of the risk factors of progression to MC, such as early-onset MG and respiratory infection. IVIg is an effective treatment. With proper immunosuppressive therapy, this group of patients had an overall good long-term prognosis

Association between clinical factors and result of immune checkpoint inhibitor related myasthenia gravis: a single center experience and systematic review

Background: Neurological immune-related adverse events (nirAEs) are rare toxicities of immune-checkpoint inhibitors (ICI). With the increase use of ICIs, incidence of nirAEs is growing, among which ICI related MG (irMG) is causing high fatality rate. Given the limited evidence, data from a large cohort of patients with irMG is needed to aid in recognition and management of this fatal complication. Objective: This study aimed to summarize clinical characteristics of irMG and explore predictors of irMG clinical outcome. Methods: We summarized our institution's patients who were diagnosed as irMG between Sep 2019 and Oct 2021. We systematically reviewed the literature through Oct 2021 to identify all similar reported patients who met inclusion criteria. As the control group, patients with idiopathic MG were used. We collected data on clinical features, management, and outcomes of both irMG and idioMG cases. Further statistical analysis was conducted. Results: Sixty three irMG patients and 380 idioMG patients were included in the final analysis. For irMG patients, six were from our institution while the rest 57 were from reported cases. The average age of irMG patients is 70.16 years old. Forty three were male. Average time from first ICI injection to symptom onset was 5.500 weeks. Eleven patients had a past history of MG. Higher MGFA classification and higher QMGS rates were observed in irMG patients compared to idioMG patients. For complication, more irMG patients had myositis or myocarditis overlapping compared to idioMG patients. The most commonly used treatment was corticosteroids for both idioMG and irMG. Twenty one patients (35%) with irMG had unfavorable disease outcome. Single variate and multivariate binary logistic regression proved that association with myocarditis, high MGFA classification or QMGS rates at first visit were negatively related to disease outcome in irMG patients. Conclusion: irMG is a life-threatening adverse event. irMG has unique clinical manifestations and clinical outcome compared to idioMG. When suspicious, early evaluation of MGFA classification, QMGS rates and myositis/myocarditis evaluation are recommended

DFlow: Efficient Dataflow-based Invocation Workflow Execution for Function-as-a-Service

The Serverless Computing is becoming increasingly popular due to its ease of use and fine-grained billing. These features make it appealing for stateful application or serverless workflow. However, current serverless workflow systems utilize a controlflow-based invocation pattern to invoke functions. In this execution pattern, the function invocation depends on the state of the function. A function can only begin executing once all its precursor functions have completed. As a result, this pattern may potentially lead to longer end-to-end execution time. We design and implement the DFlow, a novel dataflow-based serverless workflow system that achieves high performance for serverless workflow. DFlow introduces a distributed scheduler (DScheduler) by using the dataflow-based invocation pattern to invoke functions. In this pattern, the function invocation depends on the data dependency between functions. The function can start to execute even its precursor functions are still running. DFlow further features a distributed store (DStore) that utilizes effective fine-grained optimization techniques to eliminate function interaction, thereby enabling efficient data exchange. With the support of DScheduler and DStore, DFlow can achieving an average improvement of 60% over CFlow, 40% over FaaSFlow, 25% over FaasFlowRedis, and 40% over KNIX on 99%-ile latency respectively. Further, it can improve network bandwidth utilization by 2x-4x over CFlow and 1.5x-3x over FaaSFlow, FaaSFlowRedis and KNIX, respectively. DFlow effectively reduces the cold startup latency, achieving an average improvement of 5.6x over CFlow and 1.1x over FaaSFlowComment: 22 pages, 13 figure

Long-term efficacy of non-steroid immunosuppressive agents in anti-muscle-specific kinase positive myasthenia gravis patients: a prospective study

Background and Purpose: Anti-muscle-specific kinase (MuSK) positive myasthenia gravis (MG) is characterized by a high relapsing rate, thus, choosing the appropriate oral drug regimen is a challenge. This study aimed to evaluate the efficacy of oral immunosuppressants (IS) in preventing relapse in MuSK-MG. Methods: This prospective cohort observational study included patients with MuSK-MG at Peking Union Medical College Hospital between January 1, 2018, and November 15, 2021. The patients were divided into 2 groups: those with (IS+) or without (IS-) non-steroid immunosuppressive agents. The primary outcome was relapsed at follow-up, and the log-rank test was used to compare the proportion of maintenance-free relapse between the groups; hazard ratio (HR) was calculated using the Cox proportional hazards models. Results: Fifty-three of 59 patients with MuSK-MG were included in the cohort, 14 were in the IS+ group, and 39 were in the IS- group. Twenty-four cases in the cohort experienced relapse at least once; the relapse rate was 2/14 (14.3%) in the IS+ group and 22/39 (56.4%) in the IS- group. At the end of follow-up, the proportion of maintenance-free relapse was significantly different between the two groups (log-rank χ2 = 4.94, P = 0.02). Of all the potential confounders, only the use of IS was associated with a reduced risk of relapse. The HR for relapse among patients in the IS+ group was 0.21 (95%CI 0.05–0.58) and was 0.23 (95%CI 0.05–0.93) in a model adjusted for age, sex, relapse history, highest Myasthenia Gravis Foundation of America (MGFA), and accumulated time of steroid therapy. Conclusions: This study provides evidence that oral non-steroid immunosuppressive agents may be beneficial in reducing relapse in patients with MuSK-MG

Iron metabolism patterns in non-anemic patients with myasthenia gravis: a cross-sectional and follow-up study

Background and purpose: Iron metabolism in myasthenia gravis (MG) and factors associated with it are explored by few published studies. Therefore, this study aimed to compare iron metabolism patterns between patients with MG and healthy individuals as well as between the same group of patients before and after immunotherapy, and to identify predictors of iron metabolism disorders in MG. Materials and methods: For this study, 105 patients and healthy individuals were included at baseline, after which paired parametric and non-parametric tests were adopted to compare their iron metabolism patterns, and multivariate binary logistic regression was used to identify predictors of iron metabolism disorders. Patients with MG were then followed up for 12 ± 3 months to explore alterations in their iron metabolism patterns after starting immunotherapy with the help of paired tests. Results: Non-anemic immunotherapy-naive patients with MG had significantly lower serum iron (SI) and transferrin saturation (TS) levels than healthy individuals. Premenopausal female was significantly associated with SI < 65 µg/dL and iron deficiency in these patients. However, iron metabolism parameters did not significantly alter after around 12 months of immunotherapy in patients with MG. Conclusion: Iron inadequacy was present in patients with MG, particularly premenopausal female patients, and it would hardly improve after immunotherapy. Given the significant role of iron in human body, it should be given more attention in patients with MG