Background
Kazal-type serine protease inhibitors play a role in physiological processes such as blood coagulation and fibrinolysis. The amino acid residues at the P1 site are different, and they ...inhibit different types of proteases. The inhibitory mechanism of the protease in the salivary glands of
Poecilobdella manillensis
is still unclear.
Methods and results
Based on cloning, prokaryotic expression and bioinformatics analysis, we studied the role of Kazal-type serine protease inhibitors in
P. manillensis
and analyzed their expression by quantitative real-time PCR. The results suggested that the recombinant protein was successfully expressed in the supernatant when a prokaryotic expression vector was constructed and induced with 0.2 mmol/L IPTG at 37 °C for 4 h, and the enzymatic activity was determined. The mature protein encodes 91 amino acids and has a relative molecular weight of 9929.32 Da, and after removing the signal peptide, the theoretical isoelectric point was 8.79. It is an unstable protein without a transmembrane domain. The mature protein contains two Kazal-type domains, in which all P1 residues are Lys, consisting of an α helix and three antiparallel β sheets. The upregulated expression of the mRNA was induced after a meal was provided, and the results showed an increasing and then decreasing trend.
Conclusions
Taken together, the results indicate that mature proteins from
P. manillensis
inhibit thrombin activity, laying the foundation for the subsequent in-depth study of the function of genes encoding Kazal-type serine protease inhibitors.
Highlights
The
pmKPI
cDNA from salivary glands of
Poecilobdella manillensis
was cloned and expressed.
pmKPI proteins can inhibit thrombin activity.
pmKPI
mRNA expression was upregulated after a meal was provided, showing an increasing and then decreasing trend.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This study aims to elucidate the underlying mechanism of grain boundary serration and investigate its effects on hot workability of U720Li superalloy. Industrial scale as-cast ingots were subjected ...to heat treatments at 1180 °C followed by different cooling rates (15 °C/s, 0.1 °C/s, 0.02 °C/s and 0.003 °C/s) prior hot deformation. With 15 °C/s fast cooling, samples possessed straight boundaries and fine L12 structured γ’ particles dispersion. When the cooling rate was decreased to 0.1 °C/s and below, continuous and discontinuous precipitation of the γ' phase led to the formations of Type-I and Type-II grain boundary serrations, respectively. Lamellar γ/γ’ behind the mobile grain boundary was observed for Type-II boundary, which exhibited larger degree of undulation than that of Type-I boundary. With increasing fractions of Type-II boundary, the hot formability of U720Li was significantly improved during compression tests at 1000 °C; 70 % reduction ratio (true strain=1.2) could be achieved without crack formation. This work presents a simple process route to improve the hot deformability of U720Li fabricated on an industrial scale.
•Grain boundary serrations can be controlled by cooling rate during heat treatment.•Serrations are associated with continuous and discontinuous precipitations.•Type-II serrations can possess greater undulation than that of Type-I serrations.•Type-II serrations result 70 % reduction ratio without cracking during compression.•Serrations can reduce local strain concentration and inhibit crack propagation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hypoxia is one of the most common physiological stressors in shrimp farming. Post-transcriptional regulation by microRNAs has been recognized as a ubiquitous strategy to enable transient phenotypic ...plasticity and adaptation to stressful environment, but involvement of microRNAs in hypoxia stress response of penaeid shrimp remains elusive. In this study, small RNA sequencing and comparative transcriptomic analysis was conducted to construct a comprehensive microRNA dataset for the whiteleg shrimp Litopenaeus vannamei exposed to hypoxia challenge. A total of 3324 known miRNAs and 8 putative novel miRNAs were identified, providing a valuable resource for future investigation on the functional mechanism of miRNAs in shrimp. Upon hypoxia, 1213 miRNAs showed significant differential expression, and many well-known miRNAs involved in hypoxia tolerance such as miR-210, let-7, miR-143 and miR-101 were identified. Remarkably, the vast majority of these miRNAs were up-regulated, suggesting that up-regulation of miRNAs may represent an effective strategy to inhibit protein translation under stressful hypoxic condition. The differentially expressed miRNAs were potentially targeting a wide variety of genes, including those with essential roles in hypoxia tolerance such as HIF1a and p53. GO and KEGG enrichment analysis further revealed that a broad range of biological processes and metabolic pathways were over-represented. Several GO terms associated with gene transcription and translation and KEGG pathways related to cytoskeleton remodeling, immune defense and signaling transduction were enriched, highlighting the crucial roles of these cellular events in the adaptation to hypoxia. Taken together, our study revealed that the differentially expressed miRNAs may regulate host response to hypoxia by modulating the expression of stress response genes such as HIF1a and p53 and affecting key cellular events involved in hypoxia adaptation. The findings would expand our knowledge of the biochemical and molecular underpinnings of hypoxia response strategies used by penaeid shrimp, and contribute to a better understanding of the molecular mechanisms of hypoxia tolerance in decapod crustaceans.
•A comprehensive miRNA dataset was constructed for L. vannamei.•A large number of miRNAs including miR-210, let-7, miR-143 and miR-101 were responsive to hypoxia.•Induction of miRNAs appeared as a potential strategy to limit protein translation under stressful hypoxia condition.•The miRNAs potentially targeted a variety of genes including HIF1a and p53.•Key biological processes and pathways related to hypoxia adaptation were identified.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
To observe the effect of zoledronic acid on the reduction of acute bone loss and fracture rate in elderly postoperative patients with intertrochanteric fracture.
Methods
From August 2012 to ...January 2015, a total of 482 patients with senile osteoporotic femoral intertrochanteric fracture, who accepted proximal femoral intramedullary fixation under anesthesia were analysed. The patients were divided into two groups. Treatment group (353 cases) were treated with 100 mL/5 mg of zoledronic acid injection in 1 week after operation, as well as orally taken 600 mg/d of calcium carbonate and active vitamin D3 400 IU/d. Control group (129 cases) were given the same dose of calcium carbonate and active vitamin D3 orally. Efficacy evaluation were conducted during different periods of medication
Results
Compared with pre‐medication, indexes of bone metabolism (TARP‐5b, CTX) in the treatment group were brought down, especially significantly statistically different after 12 months of medication. The treatment group performed superior to control group in alleviating the pain of back and posture changing (P < 0.05), improving bone density (P < 0.05), depressing re‐fracture rate (P < 0.01) after 24 months of medication. In addition, BP, PF and MH dimension scores were demonstrated with statistical significance (P < 0.05).
Conclusions
The application of zoledronic acidin elderly postoperative patients with intertrochanteric fracture can not only relieve acute bone loss, reduce the incidence rate of re‐fracture, alleviate osteoporosis pain and the pain from osteoporotic fracture, but also improve bone metabolism and quality of life, which may offer an acceptable clinical opinion
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra and loss of DA transmission in the striatum, thus making ...cell transplantation an effective treatment strategy. Here, we develop a cellular therapy based on induced pluripotent stem cell (iPSC)-derived midbrain organoids. By transplanting midbrain organoid cells into the striatum region of a 6-OHDA-lesioned PD mouse model, we found that the transplanted cells survived and highly efficiently differentiated into DA neurons. Further, using a dopamine sensor, we observed that the differentiated human DA neurons could efficiently release dopamine and were integrated into the neural network of the PD mice. Moreover, starting from four weeks after transplantation, the motor function of the transplanted mice could be significantly improved. Therefore, cell therapy based on iPSC-derived midbrain organoids can be a potential strategy for the clinical treatment of PD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A meta-analysis was performed to compare KRAS gene mutations in colorectal cancer tissue samples with primary and metastatic colorectal cancers. A total of 19 publications with 986 paired primary and ...distant metastases and 171 paired primary and lymph node metastases showed that KRAS genotype was highly concordant in primary and distant metastatic tumors, indicating that either type of tumor tissue could be useful as a source to detect KRAS mutations for selection of anti-EGFR therapy. However, lymph-node-metastatic tumors might not be suitable for diagnostic analysis of KRAS mutations due to an obvious discordant rate between primary and lymph-node-metastatic tumors.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Four new tellurites were hydrothermally synthesized by the adjustment of different alkali-metal ions, and all of the compounds demonstrate 2D layer structures. Rb2Te4O9·2H2O in centrosymmetric space ...group Pccn features a new Te4O9∞ 2– anion sheet consisting of rare Te8O2212– groups. RbNaTe8O14(OH)6·8H2O in CS space group P1̅ exhibits a Te4O9∞ 2– anion layer by linkage of the TeO3 and TeO4 units. NaPb4Te4O12F located in CS space group P4/n displays an unusual PbTeO3∞ neutral layer made up of PbO3 and TeO3 trigonal pyramids. RbK3Te8O18·5H2O lying in noncentrosymmetric (NCS) space group Cc shows a Te4O9∞ 2– anion layer composed of the TeO3 and TeO4 units; its second-harmonic-generation response is about 0.2 times that of KH2PO4; structure analysis and local dipole moment calculation verify that the weak polarization mostly from the Te4O9∞ 2– layer results from the inverse arrangement of TeO n units, and further theoretical calculation confirms that TeO n groups dominate the band gap of RbK3Te8O18·5H2O and optical properties. Meanwhile, systematic analyses of a series of metal tellurites reveal that the alkali-metal cations exert a considerable impact on polarization of the crystal structures, which puts forward a feasible idea about the design of new NCS materials.
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IJS, KILJ, NUK, PNG, UL, UM
Apatinib is a tyrosine kinase inhibitor (TKI) that selectively inhibits the vascular endothelial growth factor receptor-2. A weighted pooled analysis was performed to evaluate the clinical outcome, ...efficacy, and toxicity of apatinib in patients with advanced nonsmall cell lung cancer (NSCLC) that failed prior treatment with chemotherapy or epidermal growth factor receptor-TKIs (EGFR-TKIs).
The literature published in PubMed, Embase, and Cochrane Library databases was searched (from inception to November 30, 2017) for eligible trials using the following search terms: apatinib AND (lung cancer OR NSCLC). Meeting abstracts were also reviewed to identify appropriate studies. Inclusion criteria were as follows: prospective or retrospective studies that evaluated efficacy and/or safety of apatinib in patients with advanced NSCLC that failed prior chemotherapy or EGFR-TKIs; primary outcome included one of these endpoints, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), or adverse events (AEs); English language; and number of cases in the study ≥10 cases.
A total of 457 patients with advanced NSCLC were treated with apatinib in 14 studies (10 retrospective and 4 prospective studies) and were included in this pooled analysis. The pooled median PFS was 4.77 months 95% confidence interval (CI), 4.11-5.00 in all groups, 4.80 months (95% CI, 4.65-4.95) in the 750 mg apatinib (high-dose) group, and 3.88 months (95% CI, 3.11-4.65) in the 250 to 500 mg apatinib (low-dose) group. Median PFS stratified by single apatinib therapy or apatinib combined with continuous EGFR-TKIs was 4.76 months (95% CI, 3.66-5.06) and 5.20 months (95% CI, 3.66-6.74), respectively. The pooled median OS, ORR, and DCR values were 6.85 months, 18%, and 72%, respectively; pooled median ORR and DCR were 15% and 72% in the 750 mg apatinib group versus 20% and 72% in the 250 to 500 mg apatinib group. ORR and DCR stratified by therapeutic regimens were 14% and 70% for single-agent apatinib, 29% and 88% for apatinib combined with continuous EGFR-TKIs, and 26% and 63% for apatinib combined with chemotherapy, respectively. The pooled AE rates of grade 3/4 were hypertension (7%), proteinuria (3%), hand-foot-skin reaction (6%), fatigue (4%), decreased appetite (1.1%), oral mucositis (3%), and thrombocytopenia (3%).
Apatinib has promising antitumor activity and manageable toxicity profile in patients with advanced NSCLC that failed prior chemotherapy or EGFR-TKIs. This result needs to be confirmed through the ongoing Phase III clinical trial.
Docetaxel was used to treat metastatic CRPC patients. However, Doc resistance in prostate cancer (PCa) hinders its clinical application.
To understand the underlying mechanisms by which Doc ...resistance is developed and to find novel therapeutic target to cure Doc resistant PCa has clinical importance.
We established Doc resistant cell lines and explored the role of Ezh2 in the development of Doc resistance by overexpressing its cDNA or using its inhibitor.
We found that Ezh2 was induced in our established Doc resistant (DocR) cells, which was attributable to the silenced expression of miR-101-3p and miR-138-5p. Blockage of Ezh2 activity by either inhibitor or miRNA mimics could overcome Doc resistance by suppressing Doc-induced cancer stem cells populations. Mechanistically, Ezh2 activity was required for the induced expression of Nanog, Sox2 and CD44 upon Doc treatment.
Targeting Ezh2 could overcome Doc resistance.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Climate warming affects rice growth at different phenological stages, thereby increasing rice chalkiness and protein content and reducing eating and cooking quality (ECQ). The structural and ...physicochemical properties of rice starch played important roles in determining rice quality. However, differences in their response to high temperature during the reproductive stage have been rarely studied. In the present study, they were evaluated and compared between two contrasting natural temperature field conditions, namely, high seasonal temperature (HST) and low seasonal temperature (LST), during the reproductive stage of rice in 2017 and 2018. Compared with LST, HST significantly deteriorated rice quality, including increased grain chalkiness, setback, consistence, and pasting temperature and reduced taste values. HST considerably reduced the total starch and increased the protein content. Likewise, HST significantly reduced the short amylopectin chains degree of polymerization (DP) <12 and increased the long amylopectin chains (DP > 12) and relative crystallinity. The starch structure, total starch content, and protein content explained 91.4%, 90.4%, and 89.2% of the total variations in pasting properties, taste value, and grain chalkiness degree, respectively. In conclusion, we suggested that rice quality variations were closely associated with the changes in chemical composition content (total starch and protein content) and starch structure in response to HST. These results indicated that we should improve the resistance of rice to high temperature during the reproductive stage to improve the fine structure of rice starch in further breeding and practice.
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