Solvent Effects Used for Optimal Simultaneous Analysis of Amino Acids via 19F NMR Spectroscopy.

19F NMR has been extensively used in simultaneous analysis of multicomponent due to its 100% natural isotope abundance, high NMR-sensitivity, and wide-range chemical shifts. The solvent effects are usually observed in NMR spectroscopy and cause large changes in 19F chemical shifts. Herein, we propose that the simultaneous analysis of a complex mixture can be achieved using solvent effects via 19F NMR spectroscopy, such as a mixture solution of amino acids (AAs). AAs are not only cell-signaling molecules, but are also considered as biomarkers of some diseases. Hence, the analysis of AAs is important for human health and the diagnosis of diseases. In this work, the key to the success of sensing 19 biogenic AAs is the use of 2-fluorobenzaldehyde (2FBA) as a highly sensitive derivatizing agent and solvent effects to produce distinguishable 19F NMR signals. As a result, the resolution of 19F NMR spectroscopy of multiple 2FBA-labeled AAs is obviously higher than other methods based on 19F NMR. Moreover, 14 and 18 AAs can be satisfactorily differentiated and unambiguously identified in different complicated media supporting the growth of mammalian cells. Furthermore, quantification of the concentration of AAs can be made, and the limit of detection reaches 10 µM. Our work provides new insights into the simultaneous analysis of a multicomponent mixture based on solvent effects by 19F NMR spectroscopy.

Investigation of the Relationship between Electronic Structures and Bioactivities of Polypyridyl Ru(II) Complexes.

Ruthenium (Ru)-based organometallic drugs have gained attention as chemotherapeutic and bioimaging agents due to their fewer side effects and excellent physical optical properties. Tuning the electronic structures of Ru complexes has been proven to increase the cytotoxicity of cancer cells and the luminescent efficiency of the analytical probes. However, the relationship between electronic structures and bioactivities is still unclear due to the potential enhancement of both electron donor and acceptor properties. Thus, we investigated the relationship between the electronic structures of Ru(II) complexes and cytotoxicity by optimizing the electron-withdrawing (complex 1), electron-neutral (complex 2), and electron-donating (complex 3) ligands through DFT calculations, bioactivities tests, and docking studies. Our results indicated that it was not sufficient to consider only either the effect of electron-withdrawing or electron-donating effects on biological activities instead of the total electronic effects. Furthermore, these complexes with electron-donating substituents (complex 3) featured unique "off-on" luminescent emission phenomena caused by the various "HOMO-LUMO" distributions when they interacted with DNA, while complex with electron-withdrawing substituent showed an "always-on" signature. These findings offer valuable insight into the development of bifunctional chemotherapeutic agents along with bioimaging ability.

Transcriptional Regulation of Female and Male Flower Bud Initiation and Development in Pecan (Carya illinoensis).

Pecan (Carya illinoensis) nuts are delicious and rich in unsaturated fatty acids, which are beneficial for human health. Their yield is closely related to several factors, such as the ratio of female and male flowers. We sampled and paraffin-sectioned female and male flower buds for one year and determined the stages of initial flower bud differentiation, floral primordium formation, and pistil and stamen primordium formation. We then performed transcriptome sequencing on these stages. Our data analysis suggested that FLOWERING LOCUS T (FT) and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 play a role in flower bud differentiation. J3 was highly expressed in the early stage of female flower buds and may play a role in regulating flower bud differentiation and flowering time. Genes such as NF-YA1 and STM were expressed during male flower bud development. NF-YA1 belongs to the NF-Y transcription factor family and may initiate downstream events leading to floral transformation. STM promoted the transformation of leaf buds to flower buds. AP2 may have been involved in the establishment of floral meristem characteristics and the determination of floral organ characteristics. Our results lay a foundation for the control and subsequent regulation of female and male flower bud differentiation and yield improvement.

The initiation, exploration, and development of hospital-based health technology assessment in China: 2005 ‒ 2022.

A hospital-based health technology assessment (HB-HTA) can provide the evidence needed to inform clinical decisions at the administrative level. With the implementation of a new round of medical and health care system reforms in China, such as the abolition of medical mark-ups, adoption of modern hospital management systems, reform of diagnosis related groups (DRGs) payment, and performance evaluations for public hospitals, medical institutions increasingly need HB-HTA. The development of HB-HTA in China can be divided into three phases: An initiation phase (2005-2014), a preliminary exploratory phase (2015-2017), and a rapid development phase (2018-present). HB-HTA has been used to manage medical consumables, medical devices, and medicines, but there are still problems and challenges in terms of concept recognition, the mode of development, and limited professionals and data. To promote and use HB-HTA in developing countries, we have identifies the development paths and recommendations for implementation based on a case study in China, which can be summarized as follows: enhancing the top-level design of HB-HTA, formulating HB-HTA guidelines, further promoting the main ideas of HB-HTA, concentrating on the training of evaluation personnel, establishing an HB-HTA network and paying attention to the flexibility of HB-HTA in the application process, and multi- stakeholder participation.

Increasing the cytotoxicity of Ru(II) polypyridyl complexes by tuning the electron-donating ability of 1,10-phenanthroline ligands.

Ruthenium (Ru)-based chemotherapeutic agents are a choice to replace traditional platinum-containing metallodrugs due to fewer side effects. It has been proved that the mechanism of Ru complex drugs is to highly likely bind with DNA and certain proteins, which also highly depends on the electronic structures of Ru complexes. However, the relationship between electronic properties and chemotherapeutic activities has not yet been completely systemically investigated, which limits the effective drug design strategies. Herein, we propose that increasing the electron densities of Ru would enhance the nucleophilic substitution rate of chlorine atoms (Cl) on Ru, providing better bioactivity against both amino acids and nucleic acids. A series of complexes with various optimized electron-donating groups (EDGs) were synthesized according to DFT calculations. In addition, kinetics substitution with L-histidine, DNA binding experiments, and cell cytotoxicity studies verified our assumptions. Surprisingly, these complexes could also be potential cellular imaging probes via an unprecedented "off-on" light-switching mechanism of living cells, which was caused by the "HOMO-LUMO" distribution changes of Ru complexes after interaction with DNA. Accordingly, the reactivity and selectivity demonstrated by these compounds support the further development of these Ru complexes in cancer treatments and afford strategic perspectives on the development of metal complexes as chemotherapeutic agents and bioimaging probes.

Molecular docking and antihypertensive effects of a novel angiotensin-I converting enzyme inhibitory peptide from yak bone.

A novel angiotensin-converting enzyme (ACE) inhibitory peptide ser-ala-ser-val-ile-pro-val-ser-ala-val-arg-ala (SASVIPVSAVRA) was purified and identified from yak bone by Electrospray Ionization-Time of Flight-Mass Spectrometry (ESI-TOF-MS). Results in vitro showed that the peptide exhibited strong ACE inhibition activities with an IC50 of 54.22 µM. Molecular docking results showed the binding between the peptide SASVIPVSAVRA and ACE mainly driven by van der Waals forces, hydrogen bonds and metal receptor. Interestingly, the ACE inhibition activities of the peptide increased about 19% after digestion, but none of its metabolites showed stronger activity than it. The in vivo experiment showed that the antihypertensive effect of peptide SASVIPVSAVRA at dose of 30 mg/kg is nearly equal to Captopril at dose of 10 mg/kg to spontaneously hypertensive rats (SHRs). The antihypertensive effect mechanism of SASVIPVSAVRA should be further studied through plasma metabolomics and bioanalysis. Structure analysis of amino acids and peptides produced during digestion may help better understand the antihypertensive effect of peptides.

The additive effect of biochar amendment and simulated nitrogen deposition stimulates the plant height, photosynthesis and accumulation of NPK in pecan (Carya illinoinensis) seedlings.

This work investigated the effective doses of biochar (BC) amendment with simulated nitrogen deposition on the stimulation of pecan (Carya illinoinensis) growth. A total of nine conditions combining three levels of BC-BC0, 0 t ha-1 year-1; BC20, 20 t ha-1 year-1; and BC40, 40 t ha-1 year-1-and three levels of simulated nitrogen deposition-N0, 0 kg N ha-1 year-1; N50, 50 kg N ha-1 year-1; and N150, 150 kg N ha-1 year-1-were applied throughout 1 year on the pecan-grafted seedlings of cultivar 'Pawnee'. The growth, photosynthesis, chlorophyll and nutrient content in the seedlings were measured. The soil bulk density, pH, nitrogen content and enzymatic activities were also measured. Biochar amendment reduced soil bulk density and elevated soil pH. Meanwhile, aided by BC amendment, the inorganic nitrogen content and enzyme activities increased with increasing doses of nitrogen. In the absence of BC amendment, the seedlings' height, photosynthesis and chlorophyll pigments were only stimulated by a low level of simulated nitrogen deposition (N50), whereas a high level of simulated nitrogen deposition (N150) impeded the growth. The seedlings improved the most under the combined treatment of BC20N150, wherein the seedling heights, photosynthesis and total chlorophyll improved by 22 %, 70 % and 40 %, respectively, compared to those treated solely with BC20. Further increase of nitrogen retention in the soil by the BC40 did not further improve the growth of the seedlings, suggesting the possible mechanisms involve nutrient uptake and usage dynamic in the seedlings. The BC amendment alleviated the antagonist effect from simulated nitrogen deposition that suppressed the absorption of phosphorus, potassium and iron. The effect of applying both BC amendment and simulated nitrogen deposition to the growth of seedlings was additive at fertilizing tree species.

An Exploratory Study of the Use of the Electronic Health Records of Hypertensive Patients to Support the Primary Prevention of Stroke in Shanghai.

BACKGROUND: The value of identifying and targeting population demographics at high risk of stroke based on patient-reported outcomes (PROs) with electronic health records (EHRs) in Shanghai is largely undiscovered. AIM: To test the hypothesis that establishing an evidence-based support system composed of PROs integrated with EHRs could be effective at identifying individuals at high risk of suffering from stroke. METHODS: The patients included in this study joined the hypertensive patient management system from 2014 to 2018. We merged the Hypertension Patients Management Database and the Diabetes Mellitus Patients Management Database of Shanghai Jiading district, then kept the hypertension patients with or without diabetes. We subsequently performed a screen analysis utilizing EHRs to target the population with any risk factor for stroke, namely, hypertension, diabetes mellitus, obesity, smoking and physical inactivity. We also calculated the distribution of each risk factor and the combinations of risk factors. RESULTS: In the Jiading District of Shanghai, 46,580 hypertensive patients with complete baseline information joined the hypertensive patient management system from 2014 to 2018. The majority of the patients were aged above 60 years old. Physical inactivity (83.24%), smoking (24.07%), diabetes (16.87%), and obesity (12.23%) were highly prevalent in hypertensive participants. Approximately 4377 patients were diagnosed with hypertension exclusively, accounting for 9.70% of the total number of patients in this study. Meanwhile, approximately 52.47% of the patients were diagnosed with two concurrent risk factors, and 38.13% of the patients had hypertension, meaning that 17,762 patients could be labeled as the high-risk population for stroke according to the criteria established by the National Stroke Screening Survey. CONCLUSION: Our exploratory findings demonstrate the feasibility of pinpointing and targeting populations at high risk of stroke using the EHRs of hypertensive patients.

"4+7" city drug volume-based purchasing and using pilot program in China and its impact.

In order to deepen the health system reform and improve the mechanism for the formation of drug prices, in January 2019, the General Office of the State Council of the People's Republic of China issued the "National centralized drug purchasing and using pilot program", selected 11 cities in mainland China to carry out "4+7" city drug volume based purchasing pilot work. This paper introduces the specific implementation plan, organizational structure and drug selection process of China's "4+7" city drug volume-based purchasing pilot work, and expounds the initial effects, existing problems and policy development after the implementation of the policy. After the implementation of the policy, the prices of 25 selected drugs were significantly lower, compared with the minimum purchase price of the same drugs in 11 pilot cities in 2017, the average drop was 52%. After the pilot scope was extended to the nation, compared with the minimum purchase price of the Union in 2018, the proposed price of the 25 drugs have an average price drop of 59%, compared with the selected price of the "4+7" pilot cities, the average price drop was 25%, and the price of drugs dropped further. By the end of August 2019, the implementation progress of 25 selected drugs in the "4+7" city drug volume-based purchasing was better than expected, the burden of patients' drug expenses was reduced, and the pilot work was beginning to bear fruit. The long-term influence and effect of the "4+7" city drug volume-based purchasing and policy implementation after the expansion needs to be further observed.

Association between social health insurance and choice of hospitals among internal migrants in China: a national cross-sectional study.

OBJECTIVES: There is a tendency to pursue higher-level hospitalisation services in China, especially for internal migrants. This study aims to investigate the choices of hospitalisation services among internal migrants, and evaluate the association between social health insurance and hospitalisation choices. METHODS: Data were from a 2014 nationally representative cross-sectional sample of internal migrants aged 15-59 years in China. Descriptive analyses were used to perform the distribution of healthcare facility levels for hospitalisation services, and multinomial logistic regression was applied to examine the association between social health insurance and hospitalisation choices. RESULTS: Of the 6121 inpatient care users, only 11.50% chose the primary healthcare facilities for hospitalisation services, 44.91% chose the secondary hospitals and 43.59% preferred the tertiary hospitals. The choices presented large regional variations across the country. Compared with the uninsured, social health insurance had no statistically significant effect on patient choices of healthcare facility levels among internal migrants in China, whereas socioeconomic status was positively associated with the choices. CONCLUSIONS: Social health insurance had little influence on the hospital choice among the internal migrants. Thus, social health insurance should be consolidated and portable to enhance the proper incentive of health insurance on healthcare seeking behaviours.

A Druggable TCF4- and BRD4-Dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNAi screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETis) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers. BETis retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy.

Perinatal transmission and viral evolution of hepatitis C virus quasispecies in infants coinfected with HIV.

OBJECTIVES: Three HIV/hepatitis C virus (HCV)-coinfected children and the mothers of 2 were studied to examine the nature of perinatal HCV infection in HIV-coinfected infants and to assess the evolution of viral quasispecies thereafter. Sequences of the hypervariable region in the N terminus of the E2/NS1 region (HVR-1) of the children and their mothers were compared. HCV quasispecies changes in the infants were tracked over several years. METHODS: Sequence similarity comparisons and phylogenetic trees were derived from cDNA of plasma isolates. Quantitation of plasma HCV and HIV was performed in the children, as well as CD4 T-cell percentage and liver transaminases. RESULTS: Phylogenetic analysis of the mother-child pairs suggested that transmission of multiple dominant and nondominant variants identified in the mother were seen. HCV diversification in the children was seen as early as 2 months of life. The child with the best immune status and HIV control demonstrated the most diversification throughout. CONCLUSION: Multiples HCV variants transmitted from mother to child and their early changes in the child may be related to maternal antibody. Variation after the 1st year of life may reflect immunologic pressure from the child. There was no trend suggesting that the presence or absence of selective immunologic pressure affected HCV load or liver transaminase values.