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Proceedings of the National Academy of... Oct 2015The complement system has evolved to annul pathogens, but its improper regulation is linked with diseases. Efficient regulation of the system is primarily provided by a...
The complement system has evolved to annul pathogens, but its improper regulation is linked with diseases. Efficient regulation of the system is primarily provided by a family of proteins termed regulators of complement activation (RCA). The knowledge of precise structural determinants of RCA proteins critical for imparting the regulatory activities and the molecular events underlying the regulatory processes, nonetheless, is still limited. Here, we have dissected the structural requirements of RCA proteins that are crucial for one of their two regulatory activities, the cofactor activity (CFA), by using the Kaposi's sarcoma-associated herpesvirus RCA homolog Kaposica as a model protein. We have scanned the entire Kaposica molecule by sequential mutagenesis using swapping and site-directed mutagenesis, which identified residues critical for its interaction with C3b and factor I. Mapping of these residues onto the modeled structure of C3b-Kaposica-factor I complex supported the mutagenesis data. Furthermore, the model suggested that the C3b-interacting residues bridge the CUB (complement C1r-C1s, Uegf, Bmp1) and MG2 (macroglobulin-2) domains of C3b. Thus, it seems that stabilization of the CUB domain with respect to the core of the C3b molecule is central for its CFA. Identification of CFA-critical regions in Kaposica guided experiments in which the equivalent regions of membrane cofactor protein were swapped into decay-accelerating factor. This strategy allowed CFA to be introduced into decay-accelerating factor, suggesting that viral and human regulators use a common mechanism for CFA.
Topics: Complement C3b; Complement Factor I; Herpesvirus 8, Human; Humans; Models, Molecular; Multiprotein Complexes; Protein Structure, Quaternary; Protein Structure, Tertiary; Viral Proteins
PubMed: 26420870
DOI: 10.1073/pnas.1506449112 -
Scientific Reports Mar 2020Ecological degradation impedes sustainable development in Southwest China, and artificial afforestation has been a key strategy of the Government of China to effectively...
Ecological degradation impedes sustainable development in Southwest China, and artificial afforestation has been a key strategy of the Government of China to effectively curb it. However, the water consumed by large-scale afforestation has a huge impact on water supply in Southwest China, which also arise a new challenge causing severe drought here recently. In order to determine the impact of artificial afforestation on the region, this study conducts spatiotemporal, abrupt change, and correlation and regression analyses. Results show that although water resources fluctuate, they exhibit a general declining trend. Especially after 2000, water resources showed a significant downward trend. In terms of spatial tendency, there has been an obvious decrease in water resources in the Sichuan Basin, the mountainous region of eastern Chongqing, and the Yunnan-Guizhou Plateau. Due to extensive afforestation and vegetation cover growth, there has been an increase in most trends of forest-shrub ecosystems, resulting in substantially enhanced evapotranspiration effects. The uptake of water by afforestation in Southwest China could reach 40.42 billion m, which is equivalent to 10.69% of its annul available water supply (1980-2015). Generally, afforestation disrupts the water balance of the region. This study recommends substituting afforestation for natural restoration or, at the very least, selecting vegetation that requires less water for the restoration of the ecological environment of Southwest China, which provide scientific method for regional sustainable development.
PubMed: 32139773
DOI: 10.1038/s41598-020-61108-w -
Pathology International Aug 2019Humoral factors from cancer-associated fibroblasts (CAFs) reportedly affect epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance in cancer...
Secretion of high amounts of hepatocyte growth factor is a characteristic feature of cancer-associated fibroblasts with EGFR-TKI resistance-promoting phenotype: A study of 18 cases of cancer-associated fibroblasts.
Humoral factors from cancer-associated fibroblasts (CAFs) reportedly affect epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance in cancer cells with EGFR mutations. The aim of this study was to identify the robust humoral factors secreted from CAFs that induce the primary resistance to EGFR-TKI. We evaluated the EGFR-TKI sensitivity of EGFR-mutant lung adenocarcinoma cell line (PC-9) treated with condition media (CM) from 18 cases of CAFs and matched non-cancerous-tissue-associated fibroblasts (NCAFs). We measured the expression levels of hepatocyte growth factor (HGF), interleukin-6, fibroblast growth factor-2, insulin-like growth factor-1, and vascular endothelial growth factor-A in CAFs and NCAFs. We examined whether HGF neutralizing antibody could annul the EGFR-TKI resistance induced by CM from CAFs. Compared to CM from NCAFs, CM from CAFs increased the resistance of PC-9 cells to EGFR-TKI in five out of 18 cases. Relative expression ratio of HGF messenger RNA was significantly higher in these five CAFs compared to others (P = 0.0013), whereas other cytokines were not. In four of these five cases, the addition of HGF neutralizing antibody significantly decreased the survival ratio of PC-9 cells. This study suggests that the secretion of higher amounts of HGF is the robust feature of EGFR-TKI resistance-promoting CAFs.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Cancer-Associated Fibroblasts; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; ErbB Receptors; Female; Hepatocyte Growth Factor; Humans; Lung Neoplasms; Male; Middle Aged; Phenotype; Protein Kinase Inhibitors
PubMed: 31339210
DOI: 10.1111/pin.12838 -
Risk Analysis : An Official Publication... Oct 2020Operational risk management of autonomous vehicles in extreme environments is heavily dependent on expert judgments and, in particular, judgments of the likelihood that...
Operational risk management of autonomous vehicles in extreme environments is heavily dependent on expert judgments and, in particular, judgments of the likelihood that a failure mitigation action, via correction and prevention, will annul the consequences of a specific fault. However, extant research has not examined the reliability of experts in estimating the probability of failure mitigation. For systems operations in extreme environments, the probability of failure mitigation is taken as a proxy of the probability of a fault not reoccurring. Using a priori expert judgments for an autonomous underwater vehicle mission in the Arctic and a posteriori mission field data, we subsequently developed a generalized linear model that enabled us to investigate this relationship. We found that the probability of failure mitigation alone cannot be used as a proxy for the probability of fault not reoccurring. We conclude that it is also essential to include the effort to implement the failure mitigation when estimating the probability of fault not reoccurring. The effort is the time taken by a person (measured in person-months) to execute the task required to implement the fault correction action. We show that once a modicum of operational data is obtained, it is possible to define a generalized linear logistic model to estimate the probability a fault not reoccurring. We discuss how our findings are important to all autonomous vehicle operations and how similar operations can benefit from revising expert judgments of risk mitigation to take account of the effort required to reduce key risks.
PubMed: 32562315
DOI: 10.1111/risa.13539 -
Materials Science & Engineering. C,... May 2021The recently proposed concept of quaternary bioreceptivity applies to substrates treated with coating materials and it is considered in the present study with the alga...
The recently proposed concept of quaternary bioreceptivity applies to substrates treated with coating materials and it is considered in the present study with the alga Bracteacoccus minor and the cyanobacterium Nostoc sp. onto granite specimens treated with ethyl silicate and nano-sized silica doped with different amounts of TiO (0, 0.5, 1 and 3 wt%). The findings showed a lack of correlation between the amount of TiO and the level of colonization (main bioreceptivity estimator) to the presence of cracks on the surface, which annul the biocidal power of TiO. Crack formation, which depends on the mechanical properties, greatly influences the bioreceptivity of the material. Thus, the cracks provided anchor points where water is retained, in turn strongly influencing the early stages of colonization kinetics, to a greater extent than the biocidal power of TiO, which will probably increase as the biofilm develops over the entire surface. In addition, although the cracks were more abundant and wider in the ethyl silicate-based consolidant, the nano-sized silica provided better anchoring points, making the material treated with the corresponding consolidant more bioreceptive.
Topics: Biofilms; Construction Materials; Ecosystem; Humans; Titanium
PubMed: 33947552
DOI: 10.1016/j.msec.2021.112058 -
Scientific Reports Oct 2018In this study, the horizontal eddy heat flux in the upper mixed-layer in the South China Sea (SCS) is derived from satellite-derived observational data of sea surface...
In this study, the horizontal eddy heat flux in the upper mixed-layer in the South China Sea (SCS) is derived from satellite-derived observational data of sea surface height anomalies and optimally interpolated sea surface temperature, as well as a reanalysis dataset of mixed-layer depth. The long-term heat flux shows a northward transport on the west side of the SCS, comparable with that in the Kuroshio extension with strong eddy activities. The eddy flux in the SCS has a prominent semi-annual cycle and becomes the strongest in winter and summer with the inflow flux in the south and the outflow in the northwest into the East China Sea through the Taiwan Strait. The semi-annual cycle is related to the strong semi-annul variabilities of the velocity and the temperature in areas southeast of Vietnam and in the northern SCS, respectively. In some areas of the SCS, the eddy heat flux can reach more than ~ 60% of the mean flow heat flux. The convergence of the eddy flux indicates that heat accumulates southeast of Vietnam, which may result in heat storage increases in the upper mixed-layer.
PubMed: 30341357
DOI: 10.1038/s41598-018-33803-2 -
Reproductive Health Matters Nov 2014While women in Mexico City can access free, safe and legal abortion during the first trimester, women in other Mexican states face many barriers. To complicate matters,...
While women in Mexico City can access free, safe and legal abortion during the first trimester, women in other Mexican states face many barriers. To complicate matters, between 2008 and 2009, 16 state constitutions were amended to protect life from conception. While these reforms do not annul existing legal abortion indications, they have created additional obstacles for women. Health providers increasingly report women who seek life-saving care for complications such as haemorrhage to the police, and some cases eventually end up in court. The Grupo de Información en Reproducción Elegida (GIRE) has successfully litigated such cases in state courts, with positive outcomes. However, state courts have mainly focused on procedural issues. The Mexican Supreme Court ruling supporting Mexico City's law has had a positive effect, but a stronger stance is needed. This paper discusses the constitutional framework and jurisprudence regarding abortion in Mexico, and the recent Costa Rica decision of the Inter-American Court of Human Rights. We assert that Mexican states must guarantee women's access to abortion on the legal grounds established in law. We continue to support litigation at the state level to oblige courts to exonerate women prosecuted for illegal abortion. Advocacy should, of course, also address the legislative and executive branches, while working simultaneously to set legal precedents on abortion.
Topics: Abortion, Criminal; Abortion, Induced; Adolescent; Costa Rica; Criminal Law; Female; Health Services Accessibility; Human Rights; Humans; Mexico; Pregnancy
PubMed: 25555763
DOI: 10.1016/S0968-8080(14)44800-6