79 research outputs found
Toward Compilation of Balanced Protein Stability Data Sets: Flattening the G Curve through Systematic Enrichment
No full textOften studies analyzing stability
data sets and/or predictors ignore
neutral mutations and use a binary classification scheme labeling
only destabilizing and stabilizing mutations. Recognizing that highly
concentrated neutral mutations interfere with data set quality, we
have explored three protein stability data sets: S2648, PON-tstab,
and the symmetric Ssym that differ in size and quality.
A characteristic leptokurtic shape in the ΔΔG distributions of all three data sets including the curated and symmetric
ones was reported due to concentrated neutral mutations. To further
investigate the impact of neutral mutations on ΔΔG predictions, we have comprehensively assessed the performance
of 11 predictors on the PON-tstab data set. Correlation and error
analyses showed that all of the predictors performed the best on the
neutral mutations, while their performance became gradually worse
as the ΔΔG of the mutations departed
further from the neutral zone regardless of the direction, implying
a bias toward dense mutations. To this end, after unraveling the role
of concentrated neutral mutations in biases of stability data sets,
we described a systematic enrichment approach to balance the ΔΔG distributions. Before enrichment, mutations were clustered
based on their biochemical and/or structural features, and then three
mutations were selected from every 2 kcal/mol of each cluster. Upon
implementation of this approach by distinct clustering schemes, we
generated five subsets varying in size and ΔΔG distributions. All subsets showed improved ΔΔG and frequency distributions. We ultimately reported that
the errors toward enriched subsets were higher than those toward the
parent data sets, confirming the enrichment of difficult-to-predict
mutations in the subsets. In summary, we elaborated the prediction
bias toward a concentrated neutral zone and also implemented a rational
strategy to tackle this and other forms of biases. Ultimately, this
study equipping us with an extended view of shortcomings of stability
data sets is a step taken toward development of an unbiased predictor
Thermostability of the PYL–PP2C Heterodimer Is Dependent on Magnesium: <i>In Silico</i> Insights into the Link between Heat Stress Response and Magnesium Deficiency in Plants
No full textAFFIPred: AlphaFold2 structure\u2010based Functional Impact Prediction of missense variations
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Assessment of antiangiogenic effect of imatinib mesylate on vestibular schwannoma tumors using in vivo corneal angiogenesis assay Laboratory investigation
No full textObject. Angiogenesis and the platelet-derived growth factor (PDGF) pathway are active in the pathogenesis of vestibular schwannomas (VSs). The purpose of this study was to test whether imatinib mesylate (Gleevec), a PDGF receptor (PDGFR) blocker, reduces angiogenic capacity in sporadic VS and in VS associated with neurofibromatosis Type 2 (NF2) using a conical angiogenesis assay. Methods. From 121 VS tissue samples stored in the tumor bank at the Marmara University Institute of Neurological Sciences, 10 samples (6 from sporadic cases, 4 from NF2-associated cases) were selected at random for use in this study. Expression of PDGF-A and PDGF-B and their receptors was evaluated in sporadic and NF2-associated VS as well as in glioblastoma (GBM) and normal brain tissue by means of immunohistochemistry and Western blot analysis. Corneal angiogenesis assay was then used to evaluate the angiogenic capacity of tissue specimens from sporadic and NF2-associated VS with and without imatinib treatment as well as positive and negative controls (GBM and normal brain tissue). Results. The angiogenic potential of the sporadic and NF2-associated VS tumor tissue differed significantly from that of the positive and negative control tissues (p < 0.05). Furthermore, NF2-associated VS showed significantly lower angiogenic potential than sporadic VS (p < 0.05). Imatinib treatment significantly reduced the angiogenic potential in both the sporadic VS and the NF2-associated VS groups. The level of PDGF-A and PDGFR-alpha as well as PDGF-B and PDGFR-beta expression in sporadic VS and NF2-associated VS also differed significantly (p < 0.05) from the levels in controls. Additionally the level of PDGFR-beta was significantly higher in sporadic VS than in NF2-associated VS (p < 0.05). Conclusions. The findings of this study indicate that NF2-associated VS has significantly more angiogenic potential than sporadic VS and normal brain tissue. Additionally, imatinib reduces the angiogenic activity of both sporadic and NF2-associated VS. The authors conclude that imatinib may be a potential treatment for VS, especially for NF2-associated lesions that cannot be cured with resection or radiosurgery. (http://thejns.org/doi/abs/10.3171/2012.6.JNS112263
Gamma Knife Radiosurgery Inhibits Angiogenesis of Meningiomas: In Vivo Rat Corneal Assay
No full textOBJECTIVE: The aim of this study is to reveal inhibitory effect of gamma knife irradiation on angiogenesis of meningiomas using rat corneal angiogenesis assay. METHODS: A total of 72 rats were divided into three preliminary groups. Each group, consisting of 24 rats, was implanted to World Health Organization (WHO) grade I (typical), grade II (atypical), and grade III (malignant) meningioma. Each of these three preliminary groups of 24 rats, were then divided into four subgroups, each consisting of 6 rats and subsequently irradiated by gamma knife with dose prescriptions of 0, 14, 18, and 22 Gy. The numbers of vessels that developed around the micropockets of the corneas were counted and photographed on days 5, 10, 15, and 20. RESULTS: For WHO grade I meningiomas, 18 and 22 Gy doses (P < 0.001), and for grade II meningiomas, the 22-Gy (P 0.021) dose were found to inhibit tumor-induced angiogenesis compared with the radiation-free control group. For grade III meningiomas, there was no statistical difference with the control group in any of the doses applied. Our findings demonstrate that gamma knife irradiation may suppress the angiogenic activity of WHO grades I and II meningiomas but not of the grade III meningiomas. CONCLUSIONS: For the first time, this study provides an experimental data to show the antiangiogenic effect of gamma knife irradiation on meningiomas
Controlled release of imatinib mesylate from PLGA microspheres inhibit craniopharyngioma mediated angiogenesis
No full textPoly(lactic-co-glycolic acid) microspheres loaded with imatinib mesylate has been developed as a new therapeutic strategy to prevent craniopharyngioma recurrence. Microspheres composed of different lactic/glycolic acid ratios, molecular weights and drug compositions were synthesized and loaded with imatinib mesylate by modified double-emulsion/solvent evaporation technique and subsequently characterized by particle-size distribution, scanning electron microscopy, encapsulation efficiency and in vitro drug release. Inhibitory potential of imatinib containing microspheres on tumor neovascularization was investigated on craniopharyngioma tumor samples by rat cornea angiogenesis assay. Results showed that microspheres in different LA:GA ratios [LA:GA 50:50 (G50), 75:25 (G25), 85:15 (G15)] considerably reduced neovascularization induced by recurrent tumor samples in an in vivo angiogenesis assay (P < 0.01). Our data indicate that local delivery of imatinib mesylate to the post-surgical tumoral cavity using biodegradable microspheres may be a promising biologically selective approach to prevent the recurrence of craniopharyngiomas, via inhibition of neovascularization
The ANS fluorescence at 460 nm.
No full text<p>The closed circles show the fluorescence from the lipases in 5 mM Tris-Cl at pH 7.0 and the open circles show the effect of 2-propanol. </p
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