ABSTRACT
In the swiftly evolving business landscape, digital transformation (DT) has emerged as a crucial strategy for firms to gain a competitive edge. Despite the abundance of literature on DT in firms, there remains a dearth of empirical research that defines and analyzes crucial antecedents of small and medium-sized enterprises' (SMEs) DT from an internal perspective. To fill this research gap, this study examines the correlation between organizational agility and digital capability in cultivating SMEs' DT while also evaluating top management support as a moderating variable through the lens of internal factors of SMEs. The results indicate that both organizational agility and digital capability have a positive impact on SMEs' DT, with organizational agility significantly influencing digital capability. Furthermore, the findings highlight that digital capability serves as a mediator between organizational agility and SMEs' DT. In addition, top management support plays a moderating role in these relationships to a certain extent. Additionally, we explicate the concept of digital capabilities from the perspective of dynamic capability. Our study contributes to an enhanced understanding of the effect of organizational agility and digital capability on SMEs' DT, as well as the role of top management support. We provide recommendations for managers to enhance organizational agility and suggest that SMEs should improve their digital thinking to better perceive digital technology changes, enhance digital operation capabilities, and better integrate digital resources.
ABSTRACT
Non-destructive measurements of low-intensity charged particle beams are particularly challenging for beam diagnostics. At the Heavy Ion Accelerator Facility in Lanzhou (HIRFL), beams with weak currents below 1 µA are often provided for experiments. The detection of such low beam current is below the threshold of typical standard beam current transformers. Therefore, a low-intensity monitoring system is developed by using a sensitive capacitive pick-up (PU) and low-noise electronics. This device measures beam currents by digitally analyzing the amplitude of the PU signals using a homodyne detection scheme. During lab tests, the amplitude nonlinearity is <0.5% in the operational range of 1 nA-45 µA and the amplitude resolution is 0.94 nA. At present, four measurement systems for low beam currents are installed at HIRFL for the monitoring of standard operating conditions with low beam currents below 1 µA. After an absolute calibration with a Faraday cup, it can be used for accurate beam intensity measurement with a current resolution of about 1 nA.
ABSTRACT
In cocreating value with other organizations, nonprofit organizations may face multiple management challenges, posed by multistakeholder global innovation networks. Since these have not yet been systematically studied by academics, this study explores how nonprofit organizations can promote the cocreation of value in multistakeholder global innovation networks. Adopting a longitudinal single-case study approach from the perspective of network orchestration theory, this work deeply analyzes how nonprofit organizations can promote the evolution of the global innovation network of the COVID-19 vaccine under the COVAX program. The results show that nonprofits need to successively address the dilemmas of legitimacy, direction, and heterogeneity in constructing global innovation networks and that to solve these stage dilemmas, orchestrators must successively function as network architects, liaisons, and leaders to direct the implementation of network actions using trusted, leveraged, and adapted orchestration logics. This paper further proposes a model of the orchestration process and mechanisms by which nonprofit organizations facilitate multistakeholder global innovation networks. Theoretically, this study therefore extends network orchestration theory by summarizing the mechanisms and orchestration logics by which NPOs construct and develop networks when they act as orchestrators. From a practical perspective, this study also provides guidance for future unexpected global public health crises, improving the global community's ability to combat them.
ABSTRACT
The Islamic Republic of Pakistan has been a mere victim of climate change in recent years. The country needs emergency measures at every level to mitigate environmental dilapidation. The role of enterprises in the country's environmental efforts is critical. In this regard, the hotel sector is known for its outsized carbon footprint. Knowing this, the current study aims to improve a hotel enterprise's environmental performance (ENP) as an outcome of corporate social responsibility (CSR). The study also considers the mediating role of pro-environmental behavior (PEB) of employees and the moderating role of altruistic values (ALT). A hypothesized model was developed, which was validated by employing the structural equation modeling technique. The empirical results confirmed that CSR, directly and indirectly (through PEB), positively induces the ENP of a hotel enterprise. Whereas the conditional indirect role of ALT was also found significant. The study offers different implications for theory and practice, among which one important takeaway for the hotel sector is to realize the importance of employees to spur ENP of a hotel enterprise through their eco-friendly behavior. At the same time, the current work also advances the theory by highlighting the moderating role of ALT between the indirect relationship of CSR and ENP.
ABSTRACT
A diagonal-cut type beam position monitor (BPM) has been developed for the High Intensity Heavy-Ion Accelerator Facility (HIAF) project at the Institute of Modern Physics. Compared with other types of BPMs, the diagonal-cut type BPM has almost perfect position linearity, i.e., no non-linear correction required, which is advantageous for beams that are transversally large and have a complex charge distribution. The key parameters for the diagonal-cut type BPM have been simulated and optimized in detail and systematically herein. It was found that the crosstalk is improved by â¼10 dB at 160 MHz by insertion of a separate ring between two horizontal or vertical electrodes of the BPM made of stainless steel with vacuum as a dielectric. Furthermore, the longitudinal and transverse numerical simulation to evaluate the beam impedance on the diagonal-cut type BPM has been performed. The results for the crosstalk, position sensitivity, and electrode capacitance to ground obtained from simulations and laboratory measurements agree well. The vacuum of the BPM prototype after baking out at 250 °C for 72 h is better than 1.0 × 10-11 mbar. The simulated and on-line measured BPM output signal magnitude results are consistent with each other. This diagonal-cut type BPM structure will be considered for application to the HIAF project as a priority.
ABSTRACT
The unique electron deficiency and coordination property of boron led to a wide range of applications in chemistry, energy research, materials science and the life sciences. The use of boron-containing compounds as pharmaceutical agents has a long history, and recent developments have produced encouraging strides. Boron agents have been used for both radiotherapy and chemotherapy. In radiotherapy, boron neutron capture therapy (BNCT) has been investigated to treat various types of tumors, such as glioblastoma multiforme (GBM) of brain, head and neck tumors, etc. Boron agents playing essential roles in such treatments and other well-established areas have been discussed elsewhere. Organoboron compounds used to treat various diseases besides tumor treatments through BNCT technology have also marked an important milestone. Following the clinical introduction of bortezomib as an anti-cancer agent, benzoxaborole drugs, tavaborole and crisaborole, have been approved for clinical use in the treatments of onychomycosis and atopic dermatitis. Some heterocyclic organoboron compounds represent potentially promising candidates for anti-infective drugs. This review highlights the clinical applications and perspectives of organoboron compounds with the natural boron atoms in disease treatments without neutron irradiation. The main topic focuses on the therapeutic applications of organoboron compounds in the diseases of tuberculosis and antifungal activity, malaria, neglected tropical diseases and cryptosporidiosis and toxoplasmosis.
Subject(s)
Boron/chemistry , Boron/metabolism , Boron/pharmacology , Anti-Bacterial Agents/pharmacology , Antiparasitic Agents/pharmacology , Boron Neutron Capture Therapy/methods , Boron Neutron Capture Therapy/trends , Bortezomib/therapeutic use , Brain Neoplasms/drug therapy , Cryptosporidiosis/drug therapy , Dermatitis, Atopic/drug therapy , Eczema/drug therapy , Glioblastoma/drug therapy , Humans , Malaria/drug therapy , Onychomycosis/drug therapy , Toxoplasmosis/drug therapy , Tuberculosis/drug therapyABSTRACT
Background and Aims: Emitasvir is a new type of hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor, and the data of phase 2 trial has shown emitasvir-sofosbuvir to have good safety and tolerance. We conducted this phase 3 trial to further verify the efficacy and safety. Methods: We evaluated the antiviral activity and safety of a 12-week regimen of emitasvir phosphate (100 mg) combined with sofosbuvir (400 mg) once daily in non-cirrhotic patients with genotype 1 HCV infection. The primary endpoint was a sustained virological response at 12 weeks (SVR12) after the end of treatment. Results: Of the 362 patients enrolled in the trial, 39.8% were male, 99.2% had HCV genotype 1b, 0.8% had genotype 1a and 79.8% were treatment-naïve. The average age was 47.2 years. All patients completed the treatment and follow-up. All 3 patients with genotype 1a achieved SVR. Two genotype 1b treatment-naïve patients experienced virologic relapse. The rate of SVR12 was 99.7% (358/359), and SVR24 was 99.4% (357/359) in genotype 1b. Overall, 36.2% had resistance-associated substitutions (RASs) in NS5A and 98.3% had RASs in NS5B at baseline. The RASs at baseline had no effect on the rates of response. Serious adverse events were reported in 16 patients and were not related to emitasvir-sofosbuvir. Most adverse events did not require therapy. Conclusions: The 12 weeks of treatment with emitasvir-sofosbuvir was a highly efficient and safe treatment for a wide range of patients with HCV genotype 1b infection without cirrhosis, who had not been treated or who had been treated with interferon-based regimen previously.
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We report herein the synthesis of novel ring-fused pyrazoloamino pyridine/pyrimidine derivatives as potential FAK inhibitors and the evaluation of pharmaceutical activity against five cancer cell lines (MDA-MB-231, BXPC-3, NCI-H1975, DU145 and 786O). Generally, the majority of compounds displayed strong anti-FAK enzymatic potencies (IC50 < 1 nM) and could effectively inhibit several class of cancer cell lines within the concentration of 3 µM in comparison with GSK2256098 as a reference. Among them, compound 4o is considered to be the most effective due to high sensitivity in antiproliferation. In culture, 4o could not only inhibit FAK Y397 phosphorylation in MDA-MB-231 cell line, but also trigger apoptosis in a dose-dependent manner. Furthermore, computational docking analysis also suggested that 4o and TAE-226 displayed the similar interaction with FAK kinase domain.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Focal Adhesion Kinase 1/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Pyrimidines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Focal Adhesion Kinase 1/metabolism , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemistry , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
Yimitasvir is a novel, oral hepatitis C virus (HCV) non-structural protein 5A inhibitor for the treatment of chronic HCV genotype 1 infection. The objective of this analysis was to develop a population pharmacokinetic model of yimitasvir in Chinese healthy volunteers and HCV infection patients. The model was performed using data from 219 subjects across six studies. Nonlinear mixed effects models were developed using Phoenix NLME software. The covariates were evaluated using a stepwise forward inclusion (p < 0.01) and then a backward exclusion procedure (p < 0.001). A two-compartment model with sequential zero-first order absorption and first-order elimination reasonably described yimitasvir pharmacokinetics (PK). The apparent oral clearance and central volume of distribution were 13.8 l·h-1 and 188 l, respectively. The bioavailability (F) of yimitasvir decreased 12.9% for each 100 mg dose increase. Food was found to affect absorption rate (Ka) and F. High-fat meal decreased Ka and F by 90.9% and 38.5%, respectively. Gender and alanine aminotransferase were identified as significant covariates on apparent oral clearance. Female subjects had lower clearance than male subjects. Zero-order absorption duration was longer in healthy volunteers (2.17 h) than that in patients (1.43 h). The population pharmacokinetic model described yimitasvir PK profile well. Food decreased Ka and F significantly, so it was recommended to take yimitasvir at least 2 h before or after a meal. Other significant covariates were not clinically important.
ABSTRACT
We have previously demonstrated the pivotal role of Jnk-mediated Irf-3/c-Jun in regulating nuclear factor kappa-Β ligand (RANKL)-induced osteoclastogenesis. Here, we demonstrated that proanthocyanidins (PACs) target Irf-3 to alleviate breast cancer-induced activation of osteoclasts. We also found that PACs induced apoptosis of osteoclast precursors by upregulating the ratio of bax/bcl-2 and activating caspase-3 activity. Such bone protective effect also could be observed in a bone metastasis model of breast cancer. These findings provided a novel therapeutic intervention targeting abnormal bone metabolism to alleviate bone metastasis of breast cancer.
Subject(s)
Bone Neoplasms/drug therapy , Bone Neoplasms/secondary , Breast Neoplasms/pathology , Interferon Regulatory Factor-3/metabolism , Proanthocyanidins/pharmacology , Proto-Oncogene Proteins c-jun/metabolism , Animals , Apoptosis/drug effects , Bone Neoplasms/metabolism , Cell Line, Tumor , Culture Media, Conditioned/pharmacology , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Interferon Regulatory Factor-3/genetics , Male , Mice, Inbred BALB C , Mice, Inbred C57BL , Osteoclasts/drug effects , Osteoclasts/metabolism , Osteogenesis/drug effects , Osteogenesis/physiology , Proto-Oncogene Proteins c-jun/geneticsABSTRACT
BACKGROUND AND OBJECTIVES: Yimitasvir is a novel oral hepatitis C virus non-structural protein 5A (NS5A) inhibitor. The aims of this first-in-human study were to evaluate the safety, tolerability and pharmacokinetics of single and multiple doses of yimitasvir in healthy adult Chinese volunteers and to assess the effect of food on yimitasvir pharmacokinetics. METHODS: Randomized, double-blind, placebo-controlled, single-ascending-dose (30, 100, 200 and 400 mg) and multiple-ascending-dose (100 and 200 mg once daily for 7 days) studies were performed in 32 and 24 subjects, respectively, in male and female adults. Additionally, the effect of food on yimitasvir pharmacokinetics was assessed with a crossover study in 15 male subjects. RESULTS: Yimitasvir was absorbed slowly after oral administration with a median time to maximum plasma concentration (Tmax) of 3.5-4.0 h. Increases in the maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to the last measurable time point (AUC0-t) were proportional to the dose of yimitasvir over a dose range of 30-100 mg, while increases were less than dose proportional over a dose range of 200-400 mg in part 1, indicating that absorption at the 200-mg dose was nearly saturated. The geometric mean terminal half-life of yimitasvir was 13.4-19.7 h in each cohort, supporting once-daily dosing. Faecal excretion of parent yimitasvir was the major route of elimination. Steady state was achieved following 5 days of dosing with minimal accumulation. A standardized high-fat meal decreased the rate and extent of absorption. All doses of yimitasvir were well tolerated. CONCLUSIONS: Yimitasvir, at single doses of 30-400 mg and multiple doses of 100-200 mg for 7 days, was well tolerated in healthy Chinese subjects. The results of this study formed the basis for the dosing schemes evaluated in a phase Ib study and subsequent phase II and phase III clinical studies. CLINICAL TRIAL REGISTRATION: This study was registered at the China Food and Drug Administration (Registration numbers: 2014L02064 and 2014L02065) and at http://www.chictr.org.cn (Nos. CTR20140854, CTR20150048 and CTR20150123).
Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C/drug therapy , Organic Chemicals/therapeutic use , Administration, Oral , Adolescent , Adult , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Cross-Over Studies , Female , Humans , Male , Middle Aged , Organic Chemicals/adverse effects , Organic Chemicals/pharmacokinetics , Young AdultABSTRACT
Boron-containing compounds are essential micronutrients for animals and plants despite their low-level natural occurrence. They can strengthen the cell walls of the plants and they play important role in supporting bone health. However, surprisingly, boron-containing compounds are seldom found in pharmaceutical drugs. In fact, there are no inherent disadvantages reported so far in terms of the incorporation of boron into medicines. Indeed, drugs based on boron-containing compounds, such as tavaborole (marked name Kerydin) and bortezomib (trade name Velcade) have been investigated and they are used in clinical treatment. In addition, following the advanced development of boron neutron capture therapy and a new emerging proton boron fusion therapy, more boron-containing medicinals are to be expected. This review discusses the current status and perspectives of delivery strategy for boron-containing drugs.
ABSTRACT
The development, performance, and testing of the longitudinal bunch shape monitor, namely, the Fast Faraday Cup (FFC), are presented in this paper. The FFC is an invasive instrument controlled by a stepper motor, and its principle of operation is based on a strip line structure. The longitudinal bunch shape was determined by sampling a small part of the beam hitting the strip line through a 1-mm hole. The rise time of the detector reached 24 ps. To accommodate experiments that utilize high-intensity beams, the materials of the bunch shape monitor were chosen to sustain high temperatures. Water cooling was also integrated in the detector system to enhance heat transfer and prevent thermal damage. We also present an analysis of the heating caused by the beam. The bunch shape monitor has been installed and commissioned at the China ADS proton LINAC Injector II.
ABSTRACT
This study used the MG-63 osteosarcoma cell line to investigate the demethylation of the phosphate and tension homolog (PTEN) gene promoter and the change in PTEN gene expression levels, which are caused by the methylation inhibitor 5-azacytidine (5-Zac), and the association between the two. Different concentrations of 5-Zac (0, 5 and 10 µmol/l) were added into the MG-63 cell culture medium and the cells were cultured for 72 h. The following techniques were performed on the cells: Western blot analysis to detect the PTEN protein; reverse transcription-polymerase chain reaction (PCR) to detect the mRNA transcription levels of the PTEN gene; flow cytometry to detect the cell apoptotic rate; and sodium bisulfate to deal with the DNA of each group. The genes of the PTEN promoter and the transcription factors specificity protein 1 (Sp1) and Myc were PCR amplified and transformed into Escherichia coli, then a number of clones were selected for sequencing and the methylation status of the amplified PTEN promoter fragment was detected. Following culture of the MG-63 cells with 5-Zac at concentrations of 0, 5 and 10 µmol/l for 72 h, the expression levels of PTEN protein in each group were gradually increased, presenting a concentration-dependent effect: Group 0 µmol/l compared with groups 5 and 10 µmol/l, P<0.05; and group 5 µmol/l compared with group 10 µmol/l, P=0.007. The mRNA expression levels of the PTEN gene significantly increased. The apoptotic rates of groups 0, 5 and 10 µmol/l were 0.69±0.42, 2.50±0.30 and 6.59±0.62%, and significant differences (P<0.01) were observed between every two groups. The bisulfate DNA sequencing results of three groups showed that, following the treatment with 5-Zac, the binding of the CG site to transcription factors was affected by demethylation. The average rate of demethylation indicated a statistical difference among the three groups. In conclusion, the methylation inhibitor 5-Zac leads to a significant increase in the expression levels of the tumor suppressor gene PTEN in the MG-63 osteosarcoma cell line in vitro. The expression levels of mRNA and the cellular apoptotic rate were also increased. The elevated activation and expression levels of the PTEN gene may be associated with the low methylation levels of the CG site that binds to the transcription factors Sp1 and Myc in the PTEN gene promoter, and they promote the combination of the transcription factors and the gene promoter.
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A nanoparticle-based strategy has been demonstrated using structurally-tailored tert-butylcalixarenes immobilized on gold nanoparticles to tune the guest access to the calixarene cone cavity for cationic recognition. This strategy exploits the interparticle charge-induced aggregation upon selective capture of metal cations into the nanoparticle-immobilized tert-butylcalixarenes, which produces calorimetric changes for the detection. A possible pathway for the binding of M(n+) into the t-BCA structure and the interparticle interaction is proposed for the formation of an electric double layer inducing the interparticle association responsible for the red-shifted surface plasmon resonance band of the nanoparticles. The value of this class of calorimetric nanoprobes will be in the area of designing advanced host-guest probes using a variety of calixarene ligands for ionic recognition in a simplistic detection format.
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OBJECTIVE: To investigate the method and clinical effect of the expandable intramedullary nails on fractures of extremities. METHODS: Nineteen cases of extremities long tubular bone fractures were treated with Fixion expandable intramedullary nails. RESULTS: Nineteen cases were followed up for 4-18 months,all cases healed without any complications. CONCLUSION: The application of expandable intramedullary nails in the treatment of extremity fractures has the advantages of little trauma, simple operation, rigid fixation and high healing rate. It is a good treatment for fractures of extremities.