Mapping the ligand binding landscape

The interaction between a ligand and a protein involves a multitude of conformational states. To achieve a particular deeply-bound pose the ligand must search across a rough free energy landscape, with many metastable minima. Creating maps of the ligand binding landscape is a great challenge, as binding and release events typically occur on timescales that are beyond the reach of molecular simulation. The WExplore enhanced sampling method is well-suited to build these maps, as it is designed to broadly explore free-energy landscapes, and is capable of simulating ligand release pathways that occur on timescales as long as minutes.

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Promising Scandium Radionuclides for Nuclear Medicine: A Review on the Production and Chemistry up to In Vivo Proofs of Concept

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


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Nanoscale topography and poroelastic properties of model tissue breast gland basement membranes

Basement membranes (BMs) are thin layers of condensed extracellular matrix proteins serving as permeability filters, cellular anchoring sites, and barriers against cancer cell invasion. It is believed that their biomechanical properties play a crucial role in determining cellular behavior and response, especially in mechanically active tissues like breast glands. In spite of this, so far relatively little attention has been dedicated to their analysis due to the difficulty of isolating and handling such thin layers of material.

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The Dual Nature of Mimicry: Organismal Form and Beholder’s Eye

Abstract

Mimicry is often cited as a compelling demonstration of the power of natural selection. By adopting signs of a protected model, mimics usually gain a reproductive advantage by minimising the likelihood of being preyed upon. Yet while natural selection plays a role in the evolution of mimicry, it can be doubted whether it fully explains it. Mimicry is mediated by the emergence of formally analogous patterns (visual, olfactory, or acoustic) between unrelated organisms and by the fact that these patterns are meaningfully perceived as similar. The perception of similarity is always perceiver-dependent. Similarities between for instance colours are psychophysical phenomena, and their existence is conditioned by an intimate interdependence between perceivers and perceptible reality. In this sense, mimicry is by its very nature dualistic. The analogy in form needed to establish a mimicry does not emerge out of the blue. It depends on the ecological context and the morphogenetic potential of a species. In our proposal, we take into account both the developmental generators of formally analogous structures and the perceptual and cognitive processes that lead to the emergence of mimicry. We show that some of the rather controversial and nowadays largely neglected ideas found in non-Anglo-Saxon literature on mimicry (e.g. writings by Th. Eimer, F. Heikertinger, or N. Vavilov) deserve closer attention. We suggest that the diversity of mimicry types is due to differences in variational properties of form-generating and perceptual systems among diverse groups of organisms. We also anticipate that processes studied within social psychology and emotion research (such as the formation of a first impression or activation of the fear module) probably take place, at least in a simplified form, also in non-human animals. Finally, we argue that these meaning-attributive processes underlie the functionality of mimicry.

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Cancers, Vol. 10, Pages 365: Oncobox Bioinformatical Platform for Selecting Potentially Effective Combinations of Target Cancer Drugs Using High-Throughput Gene Expression Data

Cancers, Vol. 10, Pages 365: Oncobox Bioinformatical Platform for Selecting Potentially Effective Combinations of Target Cancer Drugs Using High-Throughput Gene Expression Data

Cancers doi: 10.3390/cancers10100365

Authors: Maxim Sorokin Roman Kholodenko Maria Suntsova Galina Malakhova Andrew Garazha Irina Kholodenko Elena Poddubskaya Dmitriy Lantsov Ivan Stilidi Petr Arhiri Andreyan Osipov Anton Buzdin

Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs.

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Rab14 overexpression regulates gemcitabine sensitivity through regulation of Bcl-2 and mitochondrial function in pancreatic cancer

Abstract

Rab family protein Rab14 has been implicated in the development of human cancers. To date, its expression pattern, biological function, and potential mechanism in pancreatic cancer have not been explored. In this study, we analyzed Rab14 expression in 103 cases of pancreatic cancer tissues using immunohistochemistry (IHC) and found that Rab14 was overexpressed in 41/103 cases (39.8%). Rab14 overexpression correlated with the advanced stage. Moreover, elevated Rab14 levels indicated poor prognosis of patients with pancreatic cancers. We used BxPC-3 and Capan-2 respectively for plasmid and siRNA transfection. MTT and colony formation assays showed that Rab14 transfection increased cell proliferation and colony formation in BxPC-3 cells. Rab14 siRNA knockdown inhibits proliferation and colony formation ability in Capan-2 cell line. Cell cycle analysis showed that Rab14 facilitated cell cycle progression. Matrigel invasion assay showed that Rab14 promoted BxPC-3 cell invasion while its depletion inhibited Capan-2 cell invasion. In addition, MTT and AnnexinV/PI analysis demonstrated that overexpression of Rab14 reduced gemcitabine sensitivity which conversely was increased by Rab14 knockdown. We also demonstrated that Rab14 upregulated mitochondrial membrane potential (MMP) while its depletion downregulated MMP during gemcitabine treatment. In addition, western blotting revealed that Rab14 overexpression upregulated cyclin D1, cyclin A, cyclin E, p-Rb, and Bcl-2 and downregulated p21. Rab14 also downregulated caspase3, PARP cleavage, and cytochrome c release. In conclusion, our data indicated that Rab14 was overexpressed in pancreatic cancer and promotes growth and gemcitabine resistance, possibly through regulation of mitochondrial function and Bcl-2.

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Development of pseudo-subarachnoid hemorrhage secondary to hypoxic-ischemic injury due to bleeding pulmonary arterio-venous malformation

The computed tomography (CT) finding of a pseudo-subarachnoid hemorrhage (SAH) may lead the treating physician into a diagnostic dilemma. We present a case of a pseudo-SAH in a patient with post-resuscitative ...

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