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PurposeMonogenic disorders can present clinically heterogeneous symptoms. We hypothesized that in patients with a monogenic disorder caused by a large deletion, frequently additional loss-of-function (LOF)-intolerant genes are affected, potentially contributing to the phenotype.MethodsWe investigated the LOF-intolerant gene distribution across the genome and its association with benign population and pathogenic classified deletions from individuals with presumably monogenic disorders. For people with presumably monogenic epilepsy, we compared Human Phenotype Ontology terms in people with large and small deletions.ResultsWe identified LOF-intolerant gene dense regions that were enriched for ClinVar and depleted for population copy number variants. Analysis of data from >143,000 individuals with a suspected monogenic disorder showed that 2.5% of haploinsufficiency disorder–associated deletions can affect at least 1 other LOF-intolerant gene. Focusing on epilepsy, we observed that 13.1% of pathogenic and likely pathogenic ClinVar deletions <3 megabase pair, covering the diagnostically most relevant genes, affected at least 1 additional LOF-intolerant gene. Those patients have potentially more complex phenotypes with increasing deletion size.ConclusionWe could systematically show that large deletions frequently affected admditional LOF-intolerant genes in addition to the established disease gene. Further research is needed to understand how additional potential disease-relevant genes influence monogenic disorders to improve clinical care and the efficacy of targeted therapies.  相似文献   
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We previously found that circulating β2‐glycoprotein I inhibits human endothelial cell migration, proliferation, and angiogenesis by diverse mechanisms. In the present study, we investigated the antitumor activities of β2‐glycoprotein I using structure‐function analysis and mapped the critical region within the β2‐glycoprotein I peptide sequence that mediates anticancer effects. We constructed recombinant cDNA and purified different β2‐glycoprotein I polypeptide domains using a baculovirus expression system. We found that purified β2‐glycoprotein I, as well as recombinant β2‐glycoprotein I full‐length (D12345), polypeptide domains I‐IV (D1234), and polypeptide domain I (D1) significantly inhibited melanoma cell migration, proliferation and invasion. Western blot analyses were used to determine the dysregulated expression of proteins essential for intracellular signaling pathways in B16‐F10 treated with β2‐glycoprotein I and variant recombinant polypeptides. Using a melanoma mouse model, we found that D1 polypeptide showed stronger potency in suppressing tumor growth. Structural analysis showed that fragments A and B within domain I would be the critical regions responsible for antitumor activity. Annexin A2 was identified as the counterpart molecule for β2‐glycoprotein I by immunofluorescence and coimmunoprecipitation assays. Interaction between specific amino acids of β2‐glycoprotein I D1 and annexin A2 was later evaluated by the molecular docking approach. Moreover, five amino acid residues were selected from fragments A and B for functional evaluation using site‐directed mutagenesis, and P11A, M42A, and I55P mutations were shown to disrupt the anti‐melanoma cell migration ability of β2‐glycoprotein I. This is the first study to show the therapeutic potential of β2‐glycoprotein I D1 in the treatment of melanoma progression.  相似文献   
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Introduction and objectivesRelease kinetics of high-sensitivity cardiac troponin (hs-cTn) T and I in patients with acute myocardial infarction (AMI) are incompletely understood. We aimed to assess whether hs-cTnT/I release in early AMI is near linear.MethodsIn a prospective diagnostic multicenter study the acute release of hs-cTnT and hs-cTnI within 1 and 2 hours from presentation to the emergency department was quantified using 3 hs-cTnT/I assays in patients with suspected AMI. The primary endpoint was correlation between hs-cTn changes from presentation to 1 hour vs changes from presentation to 2 hours, among all AMI patients and different prespecified subgroups. The final diagnosis was adjudicated by 2 independent cardiologists, based on serial hs-cTnT from the serial study blood samples and additional locally measured hs-cTn values.ResultsAmong 2437 patients with complete hs-cTnT data, AMI was the adjudicated diagnosis in 376 patients (15%). For hs-cTnT, the correlation coefficient between 0- to 1-hour change and 0- to 2 hour change was 0.931 (95%CI, 0.916-0.944), P < .001. Similar findings were obtained with hs-cTnI (Architect) with correlation coefficients between 0- to 1-hour change and 0- to 2 hour change of 0.969 and hs-cTnI (Centaur) of 0.934 (P < .001 for both). Findings were consistent among type 1 and type 2 AMI and in the subgroup of patients presenting very early after chest pain onset.ConclusionsPatients presenting with early AMI showed a near linear release of hs-cTnT and hs-cTnI. This near linearity provides the pathophysiological basis for rapid diagnostic algorithms using 0- to 1-hour changes as surrogates for 0- to 2 hour or 0- to 3 hour changes.Registered at ClinicalTrials.gov (Identifier: NCT00470587).  相似文献   
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Proteolytic cleavage of the hemagglutinin (HA) of influenza virus by host trypsin-like proteases is required for viral infectivity. Some serine proteases are capable of cleaving influenza virus HA, whereas some serine protease inhibitors (serpins) inhibit the HA cleavage in various cell types. Kallikrein-related peptidase 1 (KLK1, also known as tissue kallikrein) is a widely distributed serine protease. Kallistatin, a serpin synthesized mainly in the liver and rapidly secreted into the circulation, forms complexes with KLK1 and inhibits its activity. Here, we investigated the roles of KLK1 and kallistatin in influenza virus infection. We show that the levels of KLK1 increased, whereas those of kallistatin decreased, in the lungs of mice during influenza virus infection. KLK1 cleaved H1, H2, and H3 HA molecules and consequently enhanced viral production. In contrast, kallistatin inhibited KLK1-mediated HA cleavage and reduced viral production. Cells transduced with the kallistatin gene secreted kallistatin extracellularly, which rendered them more resistant to influenza virus infection. Furthermore, lentivirus-mediated kallistatin gene delivery protected mice against lethal influenza virus challenge by reducing the viral load, inflammation, and injury in the lung. Taking the data together, we determined that KLK1 and kallistatin contribute to the pathogenesis of influenza virus by affecting the cleavage of the HA peptide and inflammatory responses. This study provides a proof of principle for the potential therapeutic application of kallistatin or other KLK1 inhibitors for influenza. Since proteolytic activation also enhances the infectivity of some other viruses, kallistatin and other kallikrein inhibitors may be explored as antiviral agents against these viruses.  相似文献   
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Newly developed high-speed, synchrotron-based X-ray computed microtomography enabled us to directly image pore-scale displacement events in porous rock in real time. Common approaches to modeling macroscopic fluid behavior are phenomenological, have many shortcomings, and lack consistent links to elementary pore-scale displacement processes, such as Haines jumps and snap-off. Unlike the common singular pore jump paradigm based on observations of restricted artificial capillaries, we found that Haines jumps typically cascade through 10–20 geometrically defined pores per event, accounting for 64% of the energy dissipation. Real-time imaging provided a more detailed fundamental understanding of the elementary processes in porous media, such as hysteresis, snap-off, and nonwetting phase entrapment, and it opens the way for a rigorous process for upscaling based on thermodynamic models.  相似文献   
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Reevesioside F, isolated from Reevesia formosana, induced anti-proliferative activity that was highly correlated with the expression of Na+/K+-ATPase α3 subunit in several cell lines, including human leukemia HL-60 and Jurkat cells, and some other cell lines. Knockdown of α3 subunit significantly inhibited cell apoptosis suggesting a crucial role of the α3 subunit. Reevesioside F induced a rapid down-regulation of survivin protein, followed by release of cytochrome c from mitochondria and loss of mitochondrial membrane potential (ΔΨm). Further examination demonstrated the mitochondrial damage in leukemic cells through Mcl-1 down-regulation, Noxa up-regulation and an increase of the formation of truncated Bid, tBim and a 23-kDa cleaved Bcl-2 fragment. Furthermore, reevesioside F induced an increase of mitochondria-associated acetyl α-tubulin that may also contribute to apoptosis. The caspase cascade was profoundly activated by reevesioside F. Notably, the specific caspase-3 inhibitor z-DEVD-fmk significantly blunted reevesioside F-induced loss of ΔΨm and apoptosis, suggesting that caspase-3 activation may further amplify mitochondrial damage and apoptotic signaling cascade. In spite of being a cardiac glycoside, reevesioside F did not increase the intracellular Ca2+ levels. Moreover, CGP-37157 which blocked Na+/Ca2+ exchanger on plasma membrane and mitochondria did not modify reevesioside F-mediated effect. In summary, the data suggest that reevesioside F induces apoptosis through the down-regulation of survivin and Mcl-1, and the formation of pro-apoptotic fragments from Bcl-2 family members. The loss of ΔΨm and mitochondrial damage are responsible for the activation of caspases. Moreover, the amplification of caspase-3-mediated signaling pathway contributes largely to the execution of apoptosis in leukemic cells.  相似文献   
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