Facile fabrications of poly (acrylic acid)-mesoporous zinc phosphate/polydopamine Janus nanoparticles as a biosafe photothermal therapy agent and a pH/NIR-responsive drug carrier.

Balancing biocompatibility and drug-loading efficiency in nanoparticles presents a significant challenge. In this study, we describe the facile fabrication of poly (acrylic acid)-mesoporous zinc phosphate/polydopamine (PAA-mZnP/PDA) Janus nanoparticles (JNPs). The PDA half-shell itself can serve as a photothermal agent for photothermal therapy (PTT), as well as to offers sites for polyethylene glycol (PEG) to enhance biocompatibility. Concurrently, the mesoporous ZnP core allows high loading of doxorubicin (DOX) for chemotherapy and the Cy5.5 dye for fluorescence imaging. The resultant PAA-mZnP/PDA-PEG JNPs exhibit exceptional biocompatibility, efficient drug loading (0.5 mg DOX/1 mg JNPs), and dual pH/NIR-responsive drug release properties. We demonstrate the JNPs' satisfactory anti-cancer efficacy, highlighting the synergistic effects of chemotherapy and PTT. Furthermore, the potential for synergistic fluorescence imaging-guided chemo-phototherapy in cancer treatment is illustrated. Thus, this work exemplifies the development of biosafe, multifunctional JNPs for advanced applications in cancer theranostics. STATEMENT OF SIGNIFICANCE: Facile fabrication of monodispersed nanomedicine with multi-cancer killing modalities organically integrated is nontrivial and becomes more challenging under the biocompatibility requirement that is necessary for the practical applications of nanomedicines. In this study, we creatively designed PAA-mZnP/PDA JNPs and fabricated them under mild conditions. Our method reliably yields uniform JNPs with excellent monodispersity. To maximize functionalities, we achieve fourfold advantages including efficient drug/fluorescent dye loading, PTT, pH/NIR dual-responsive properties, and optimal biocompatibility. The as-fabricated JNPs exhibit satisfactory anti-cancer performance both in vitro and in vivo, and demonstrate the potential of JNPs in fluorescence imaging-guided synergistic cancer chemo-phototherapy. Overall, our research establishes a pathway in versatile inorganic/polymer JNPs for enhanced cancer diagnosis and therapy.

Burden of Cardiovascular Diseases in China, 1990-2016: Findings From the 2016 Global Burden of Disease Study.

Importance: Cardiovascular disease (CVD) remains the top cause of death in China. To our knowledge, no consistent and comparable assessments of CVD burden have been produced at subnational levels, and little is understood about the spatial patterns and temporal trends of CVD in China. Objective: To determine the national and province-level burden of CVD from 1990 to 2016 in China. Design, Setting, and Participants: Following the methodology framework and analytical strategies used in the 2016 Global Burden of Disease study, the mortality, prevalence, and disability-adjusted life-years (DALYs) of CVD in the Chinese population were examined by age, sex, and year and according to 10 subcategories. Estimates were produced for all province-level administrative units of mainland China, Hong Kong, and Macao. Exposures: Residence in China. Main Outcomes and Measures: Mortality, prevalence, and DALYs of CVD. Results: The annual number of deaths owing to CVD increased from 2.51 million to 3.97 million between 1990 and 2016; the age-standardized mortality rate fell by 28.7%, from 431.6 per 100 000 persons in 1990 to 307.9 per 100 000 in 2016. Prevalent cases of CVD doubled since 1990, reaching nearly 94 million in 2016. The age-standardized prevalence rate of CVD overall increased significantly from 1990 to 2016 by 14.7%, as did rates for ischemic heart disease (19.1%), ischemic stroke (36.6%), cardiomyopathy and myocarditis (23.1%), and endocarditis (26.7%). Substantial reduction in the CVD burden, as measured by age-standardized DALY rate, was observed from 1990 to 2016 nationally, with a greater reduction in women (43.7%) than men (24.7%). There were marked differences in the spatial patterns of mortality, prevalence, and DALYs of CVD overall as well as its main subcategories, including ischemic heart disease, hemorrhagic stroke, and ischemic stroke. The CVD burden appeared to be lower in coastal provinces with higher economic development. The between-province gap in relative burden of CVD increased from 1990 to 2016, with faster decline in economically developed provinces. Conclusions and Relevance: Substantial discrepancies in the total CVD burden and burdens of CVD subcategories have persisted between provinces in China despite a relative decrease in the CVD burden. Geographically targeted considerations are needed to tailor future strategies to enhance CVD health throughout China and in specific provinces.

The KP1_4563 gene is regulated by the cAMP receptor protein and controls type 3 fimbrial function in Klebsiella pneumoniae NTUH-K2044.

Klebsiella pneumoniae (K. pneumoniae) is an opportunistic pathogen that can adhere to host cells or extracellular matrix via type 1 and type 3 fimbriae. KP1_4563 is a gene encoding a hypothetical protein in K. pneumoniae NTUH-K2044. KP1_4563 is located between the type 1 and type 3 fimbrial gene clusters and is likely associated with fimbrial function given its putative conserved domains of unknown function (DUF1471). Cyclic AMP receptor protein (CRP) regulates virulence-related gene expression and is a crucial transcriptional regulator in many bacteria. The predicted DNA recognition motif of CRP is present in the KP1_4563 promoter region. This study aimed to investigate the function of KP1_4563 in fimbriae and its transcriptional regulation mechanism by CRP. We generated Kp-Δ4563 mutant and complementation strains. We utilized phenotype and adhesion assays to evaluate the role of KP1_4563 in fimbriae. We conducted quantitative RT-PCR (qRT-PCR), LacZ fusion, electrophoretic mobility shift, and DNase I footprinting assays to study the transcriptional regulation of KP1_4563 gene by CRP. We found that KP1_4563 negatively regulates the function of type 3 fimbriae. Compared with NTUH-K2044, the absence of KP1_4563 enhanced the ability of Kp-Δ4563 to adhere to A549 cells. CRP negatively regulates KP1_4563 by directly binding to its promoter region. KP1_4563 plays an important role in type 3 fimbrial function. This novel insight will assist in the development of strategies for preventing K. pneumoniae infection.

Influence of cAMP receptor protein (CRP) on bacterial virulence and transcriptional regulation of allS by CRP in Klebsiella pneumoniae.

cAMP receptor protein (CRP) is one of the most important transcriptional regulators, which can regulate large quantities of operons in different bacteria. The gene allS was well-known as allantoin-utilizing capability and involving in bacterial virulence in Klebsiella pneumoniae (K. pneumoniae). The specific DNA recognition motif of transcription regulator CRP was found in allS promoter region. Therefore, this study is aimed to investigate the function of CRP on virulence and its transcriptional regulation mechanism to gene allS in K. pneumoniae. The wild-type (WT) K. pneumoniae NTUH-2044, crp knockout (Kp-Δcrp) and the complemented knockout (KpC-Δcrp) strains were used to determine the function of crp gene. The lacZ fusion, qRT-PCR, electrophoretic mobility shift and DNase I footprinting assays were performed to study the transcriptional regulation of CRP on allS. The result showed a decreased virulence in crp knockout strain. Complement through supplementing crp fragment in expression plasmid partially restore virulence of knockout bacteria. The CRP could bind to the allS promoter-proximal region and the binding site was further refined to be located from 60bp to 94bp upstream of the allS promoter. Based on these results, we proposed that CRP is an essential virulence regulator and knock out of crp gene will result in reduced virulence in K. pneumoniae. In the meantime, the transcription of gene allS is positively regulated by CRP via directly binding to upstream of allS promoter.