The characterization of process‐related impurities and forced degradants of alogliptin benzoate (Alb) in bulk drugs and a stability‐indicating HPLC method for the separation and quantification of all ...the impurities were investigated. Alb was found to be unstable under acid and alkali stress conditions and two major degradation products (Imp‐F and Imp‐G) were observed. The optimum separation was achieved on Kromasil C₁₈ (250 × 4.6 mm, 5 μm) using 0.1% perchloric acid (pH adjusted to 3.0 with triethylamine) and acetonitrile as a mobile phase in gradient mode. The proposed method was found to be stability indicating, precise, linear (0.10–75.0 μg/mL), accurate, sensitive, and robust for the quantitation of Alb and its process‐related substances and degradation products. The structures of 11 impurities were characterized and confirmed by NMR spectroscopy, MS, and IR spectroscopy, and the most probable formation mechanisms of all impurities were proposed according to the synthesis route.
Background: Metagenomic Next Generation Sequencing (mNGS) has the potential to detect pathogens rapidly. We aimed to assess the diagnostic performance of mNGS in hospitalized patients with suspected ...sepsis and evaluate its role in guiding antimicrobial therapy. Methods: A multicenter, prospective cohort study was performed. We enrolled patients with suspected sepsis, collected clinical characteristics and blood samples, and recorded the 30-day survival. Diagnostic efficacy of mNGS test and blood culture was compared, and the clinical impact of mNGS on antibiotic regimen modification was analyzed. Results: A total of 277 patients were enrolled, and 162 were diagnosed with sepsis. The mortality was 44.8% (121/270). The mNGS test exhibited shorter turn-out time (27.0 (26.0, 29.0) vs. 96.0 (72.0, 140.3) hours, p < 0.001) and higher sensitivity (90.5% vs. 36.0%, p < 0.001) compared with blood culture, especially for fungal infections. The mNGS test showed better performance for patients with mild symptoms, prior antibiotic use, and early stage of infection than blood culture, and was capable of guiding antibiotic regimen modification and improving prognosis. Higher reads of pathogens detected by mNGS were related to 30-day mortality (p = 0.002). Conclusions: Blood mNGS testing might be helpful for early etiological diagnosis of patients with suspected sepsis, guiding the antibiotic regimen modification and improving prognosis.
•The environment friendly C3H5NaO3 is acted as complexing agent to replace NH3⋅H2O.•MCO3 precursor is synthesized via using co-precipitation method.•Mixtures of MCO3 and LiOH⋅H2O are calcined to form ...cathodes with various Co contents.•Lattice parameters c/a ratio for cathode material increases with the Co increment increasing.•Li1.2Mn0.51Ni0.19Co0.1O2 cathode shows the best electrochemical properties.
MCO3 precursors are synthesized via co-precipitation method using NaCO3 as the precipitation, and the environment friendly C3H5NaO3 is acted as complexing agent to replace NH3⋅H2O. And then the mixtures of MCO3 precursors and LiOH⋅H2O are calcined at 950°C to form Li1.2Mn0.52−0.5xNi0.2−0.5xCo0.08+xO2 cathode materials with different Co increments. The influence of Co increment on the microstructure and electrochemical properties of Li1.2Mn0.52−0.5xNi0.2−0.5xCo0.08+xO2 cathode materials has been analyzed. The results show that the c/a ratio for cathode material becomes higher, and then the layered structure becomes better when the Co increment increases. Among them, Li1.2Mn0.51Ni0.19Co0.1O2 (x=0.02) shows the best electrochemical properties with the initial discharge capacity of 261.0mAhg−1, capacity retention of 99.4% (189.9mAhg−1) after 100 cycles at the charging and discharging current density of 100mAg−1 and highest discharge capacity of 157.6mAhg−1 at the discharging current density of 400mAg−1.
Abstract Paclitaxel (taxol) is a widely used chemo-drug for many solid tumors, while continual taxol treatment is revealed to stimulate tumor dissemination. We previously found that a small molecule ...inhibitor of miR-21, termed AC1MMYR2, had the potential to impair tumorigenesis and metastasis. The aim of this study was to investigate whether combining AC1MMYR2 with taxol could be explored as a means to limit tumor metastasis. Here we showed that abnormal activation of miR-21/CDK5 axis was associated with breast cancer lymph node metastasis, which was also contribute to high dose taxol-induced invasion and epithelial mesenchymal transition (EMT) in both breast cancer cell line MDA-MB-231 and glioblastoma cell line U87VIII. AC1MMYR2 attenuated CDK5 activity by functional targeting CDK5RAP1, CDK5 activator p39 and target p-FAKser732 . A series of in vitro assays indicated that treatment of AC1MMYR2 combined with taxol suppressed tumor migration and invasion ability in both MDA-MB-231 and U87VIII cell. More importantly, combination therapy impaired high-dose taxol induced invadopodia, and EMT markers including β-catenin, E-cadherin and vimentin. Strikingly, a significant reduction of lung metastasis in mice was observed in the AC1MMYR2 plus taxol treatment. Taken together, our work demonstrated that AC1MMYR2 appeared to be a promising strategy in combating taxol induced cancer metastasis by targeting miR-21/CDK5 axis, which highlighted the potential for development of therapeutic modalities for better clinic taxol application.
Abstract
One of the best ways to control COVID-19 is vaccination. Among the various SARS-CoV-2 vaccines, inactivated virus vaccines have been widely applied in China and many other countries. To ...understand the underlying protective mechanism of these vaccines, it is necessary to systematically analyze the humoral responses that are triggered. By utilizing a SARS-CoV-2 microarray with 21 proteins and 197 peptides that fully cover the spike protein, antibody response profiles of 59 serum samples collected from 32 volunteers immunized with the inactivated virus vaccine BBIBP-CorV were generated. For this set of samples, the microarray results correlated with the neutralization titers of the authentic virus, and two peptides (S1-5 and S2-22) were identified as potential biomarkers for assessing the effectiveness of vaccination. Moreover, by comparing immunized volunteers to convalescent and hospitalized COVID-19 patients, the N protein, NSP7, and S2-78 were identified as potential biomarkers for differentiating COVID-19 patients from individuals vaccinated with the inactivated SARS-CoV-2 vaccine. The comprehensive profile of humoral responses against the inactivated SARS-CoV-2 vaccine will facilitate a deeper understanding of the vaccine and provide potential biomarkers for inactivated virus vaccine-related applications.
A novel rational-fraction dispersion model is proposed for simulation of optical properties of arbitrary linear dispersive media over a wide wavelength range. A generally applicable method is ...proposed for estimating the parameters of this model. It is demonstrated that the rational-fraction dispersion model can fit the relative permittivity data of a material accurately and efficiently in a wide wavelength range. The new model is implemented in the finite-difference time-domain method and is applied as a powerful and computationally efficient tool for simulating nano-particles of dispersive materials in a wide wavelength range of light.
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•3D structures with vast pores of HTNTs/Ti increase dispersion of N,F and others.•Nitrogen and fluorine was doped to improve PEC performance under visible light.•N,F-TiO2NTs/Ti has ...high sensitivity, low detection limit and wide detection range.
Photoelectrochemical (PEC) sensor stimulated by visible light has wide developing prospect in biosensor field due to its sensitivity and low detection limit. Via hydrothermal treatment, Ti supported hydrogen titanate nanotubes were prepared and exhibited fine 3D structure with vast pores (HTNTs/Ti). Further nitrogen and fluorine doping induced improved PEC performance under visible light. The surface morphology, composition and structure of the fabricated N, F-codoped TiO2 nanotubes/Ti (N, F-TiO2NTs/Ti) were analyzed by SEM, TEM, XRD and XPS. The PEC sensitivity of the N, F-TiO2NTs/Ti electrodes for glucose showed that the linear range for glucose was 0.5–3.0 μM, the detection sensitivity was 51.56 μA·mM−1·cm−2, and the detection limit (LOD) was 0.3230 μM. Compared with the similar HTNTs/Ti-based enzymatic sensor, the N, F-TiO2NTs/Ti exhibited better sensitivity for glucose, and was potential for biomedical applications for its stable properties and implanting potentiality.
The interaction between K48-linked ubiquitin (Ub) chain and Rpn13 is important for proteasomal degradation of ubiquitinated substrate proteins. Only the complex structure between the N-terminal ...domain of Rpn13 (Rpn13
) and Ub monomer has been characterized, while it remains unclear how Rpn13 specifically recognizes K48-linked Ub chain. Using single-molecule FRET, here we show that K48-linked diubiquitin (K48-diUb) fluctuates among distinct conformational states, and a preexisting compact state is selectively enriched by Rpn13
. The same binding mode is observed for full-length Rpn13 and longer K48-linked Ub chain. Using solution NMR spectroscopy, we have determined the complex structure between Rpn13
and K48-diUb. In this structure, Rpn13
simultaneously interacts with proximal and distal Ub subunits of K48-diUb that remain associated in the complex, thus corroborating smFRET findings. The proximal Ub interacts with Rpn13
similarly as the Ub monomer in the known Rpn13
:Ub structure, while the distal Ub binds to a largely electrostatic surface of Rpn13
. Thus, a charge-reversal mutation in Rpn13
weakens the interaction between Rpn13 and K48-linked Ub chain, causing accumulation of ubiquitinated proteins. Moreover, physical blockage of the access of the distal Ub to Rpn13
with a proximity-attached Ub monomer can disrupt the interaction between Rpn13 and K48-diUb. Taken together, the bivalent interaction of K48-linked Ub chain with Rpn13 provides the structural basis for Rpn13 linkage selectivity, which opens a new window for modulating proteasomal function.
To observe the changes of Nogo/NgR and Rho/ROCK signaling pathway-related gene and protein expression in rats with spinal cord injury (SCI) treated with electroacupuncture (EA) and to further ...investigate the possible mechanism of EA for treating SCI.
Allen's method was used to create the SCI rat model. Sixty-four model rats were further subdivided into four subgroups, namely, the SCI model group (SCI), EA treatment group (EA), blocking agent Y27632 treatment group (Y27632) and EA+blocking agent Y27632 treatment group (EA+Y), according to the treatment received. The rats were subjected to EA and/or blocking agent Y27632 treatment. After 14 days, injured spinal cord tissue was extracted for analysis. The mRNA and protein expression levels were determined by real-time fluorescence quantitative PCR and Western blotting, respectively. Cell apoptosis changes in the spinal cord were evaluated by in situ hybridization. Hindlimb motor function in the rats was evaluated by Basso-Beattie-Bresnahan assessment methods.
Except for RhoA protein expression, compared with the SCI model group, EA, blocking agent Y27632 and EA+blocking agent Y27632 treatment groups had significantly reduced mRNA and protein expression of Nogo-A, NgR, LINGO-1, RhoA and ROCK II in spinal cord tissues, increased mRNA and protein expression of MLCP, decreased p-MYPT1 protein expression and p-MYPT1/MYPT1 ratio, and caspase3 expression, and improved lower limb movement function after treatment for 14 days (P<0.01 or <0.05). The combination of EA and the blocking agent Y27632 was superior to EA or blocking agent Y27632 treatment alone (P < 0.01 or <0.05).
EA may have an obvious inhibitory effect on the Nogo/NgR and Rho/ROCK signaling pathway after SCI, thereby reducing the inhibition of axonal growth, which may be a key mechanism of EA treatment for SCI.
Cassava flour (CF) was used as a raw material to replace wheat flour (WF) at levels of 0% (control), 10%, 20%, 30%, 40%, and 50% to prepare wheat–cassava composite flour (W-CF) and dough. The effects ...of different CF substituting levels on the functional properties of the W-CF and dough were investigated. The results show that an increase in CF led to a decrease in the moisture, protein, fat, and b* values of W-CF. The crude fiber, ash, starch, L*, a* values, iodine blue value (IBV), and swelling power (SP) of the composite flour increased gradually. It was found that the water absorption, hardness, and chewiness of the W-CF dough increased with an increase in the CF substitution level. A different trend could be observed with the springiness and cohesiveness of the W-CF dough. The resistance to extension, extensibility, and the extended area of the W-CF dough at all substitution levels was significantly lower than that of the WF dough. The elasticity and cohesiveness of the dough tended to increase for CF content from 10% to 30%, followed by a decrease at a higher replacement. Pearson correlation analysis indicated that the substitution levels of CF had a significant influence on the proximate analysis and functional properties of the W-CF and dough. This study will provide important information on choosing CF substitution levels for different products.
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