IMAGE: A New Tool for the Prediction of Transcription Factor Binding Sites

IMAGE is an application tool, based on the vector quantization method, aiding the discovery of nucleotidic sequences corresponding to Transcription Factor binding sites. Starting from the knowledge of regulation regions of a number of co-expressed genes, the software is able to predict the occurrence of specific motifs of different lengths (starting from 6 base pairs) with a defined number of punctual mutations

Category Theoretic Analysis of Hierarchical Protein Materials and Social Networks

Materials in biology span all the scales from Angstroms to meters and typically consist of complex hierarchical assemblies of simple building blocks. Here we describe an application of category theory to describe structural and resulting functional properties of biological protein materials by developing so-called ologs. An olog is like a “concept web” or “semantic network” except that it follows a rigorous mathematical formulation based on category theory. This key difference ensures that an olog is unambiguous, highly adaptable to evolution and change, and suitable for sharing concepts with other olog. We consider simple cases of beta-helical and amyloid-like protein filaments subjected to axial extension and develop an olog representation of their structural and resulting mechanical properties. We also construct a representation of a social network in which people send text-messages to their nearest neighbors and act as a team to perform a task. We show that the olog for the protein and the olog for the social network feature identical category-theoretic representations, and we proceed to precisely explicate the analogy or isomorphism between them. The examples presented here demonstrate that the intrinsic nature of a complex system, which in particular includes a precise relationship between structure and function at different hierarchical levels, can be effectively represented by an olog. This, in turn, allows for comparative studies between disparate materials or fields of application, and results in novel approaches to derive functionality in the design of de novo hierarchical systems. We discuss opportunities and challenges associated with the description of complex biological materials by using ologs as a powerful tool for analysis and design in the context of materiomics, and we present the potential impact of this approach for engineering, life sciences, and medicine.Presidential Early Career Award for Scientists and Engineers (N000141010562)United States. Army Research Office. Multidisciplinary University Research Initiative (W911NF0910541)United States. Office of Naval Research (grant N000141010841)Massachusetts Institute of Technology. Dept. of MathematicsStudienstiftung des deutschen VolkesClark BarwickJacob Luri

Rationally Designed Turn Promoting Mutation in the Amyloid-β Peptide Sequence Stabilizes Oligomers in Solution

Enhanced production of a 42-residue beta amyloid peptide (Aβ42) in affected parts of the brain has been suggested to be the main causative factor for the development of Alzheimer's Disease (AD). The severity of the disease depends not only on the amount of the peptide but also its conformational transition leading to the formation of oligomeric amyloid-derived diffusible ligands (ADDLs) in the brain of AD patients. Despite being significant to the understanding of AD mechanism, no atomic-resolution structures are available for these species due to the evanescent nature of ADDLs that hinders most structural biophysical investigations. Based on our molecular modeling and computational studies, we have designed Met35Nle and G37p mutations in the Aβ42 peptide (Aβ42Nle35p37) that appear to organize Aβ42 into stable oligomers. 2D NMR on the Aβ42Nle35p37 peptide revealed the occurrence of two β-turns in the V24-N27 and V36-V39 stretches that could be the possible cause for the oligomer stability. We did not observe corresponding NOEs for the V24-N27 turn in the Aβ21–43Nle35p37 fragment suggesting the need for the longer length amyloid peptide to form the stable oligomer promoting conformation. Because of the presence of two turns in the mutant peptide which were absent in solid state NMR structures for the fibrils, we propose, fibril formation might be hindered. The biophysical information obtained in this work could aid in the development of structural models for toxic oligomer formation that could facilitate the development of therapeutic approaches to AD

Nanomechanical properties of α-synuclein amyloid fibrils: a comparative study by nanoindentation, harmonic force microscopy, and Peakforce QNM

We report on the use of three different atomic force spectroscopy modalities to determine the nanomechanical properties of amyloid fibrils of the human α-synuclein protein. α-Synuclein forms fibrillar nanostructures of approximately 10 nm diameter and lengths ranging from 100 nm to several microns, which have been associated with Parkinson's disease. Atomic force microscopy (AFM) has been used to image the morphology of these protein fibrils deposited on a flat surface. For nanomechanical measurements, we used single-point nanoindentation, in which the AFM tip as the indenter is moved vertically to the fibril surface and back while the force is being recorded. We also used two recently developed AFM surface property mapping techniques: Harmonic force microscopy (HarmoniX) and Peakforce QNM. These modalities allow extraction of mechanical parameters of the surface with a lateral resolution and speed comparable to tapping-mode AFM imaging. Based on this phenomenological study, the elastic moduli of the α-synuclein fibrils determined using these three different modalities are within the range 1.3-2.1 GPa. We discuss the relative merits of these three methods for the determination of the elastic properties of protein fibrils, particularly considering the differences and difficulties of each method

A cytoarchitectonic and myeloarchitectonic study of the insular cortex of the bull, Bos taurus.

The mammalian Insula is characterised by considerable morphologic variability, however, it shows a cytoarchitectonic homogeneity within the species so far studied. Three cytoarchitectonic areas are generally recognisable in the Insula: an "agranular", a "dysgranular" and a "granular" area. The numerous functions attributed to the Insula (visceral sensory, visceral motor, somatosensorial, supplementary motor area, area speech and/or language related, etc.) have recently attracted renewed interest. Considering the involvement of the Insula in the control of gastroenteric motility and the structural and functional complexity of this region in ruminants, it seemed interesting to analyse the cyto- and myelo-architectonic arrangement of the Insula of the bull, Bos taurus. Unlike that of the other species described, all the insular Neocortex of the bull, is of the "agranular" type. The latter includes at least four variants that differ according to the organisation of the cortical layer pattern. Considering the available evidence in laboratory animals and primates of a role played by the agranular insular cortex in gastroenteric motility control, the trademark presence of a very much extended insular agranular cortex in the Insula of the bull may be related to the necessity of motor activity control of a gastroenteric complex that is extensively more developed than in the monogastric species

Mechanical properties of single molecules: a theoretical approach.

The substantial homogeneity and the consequent conformational degeneracy of the nucleotide residues along DNA double helix have allowed great progress in the knowledge of the molecular mechanisms that control the functional organization of the genome. DNA plays a crucial role in the management of the informational content that the nucleotide sequence holds. Inside the cell, DNA actively interacts with proteins involved in replication, transcription, repair, and regulation processes. During these processes, the DNA transforms between packed and unpacked architectures, like that of chromatin or other higher-order structures morphing into shapes with structural spikes alternative to the canonical B-form in connection with biological events as in replication bubbles, hairpins or in G-quadruplex structures. The base sequence encodes the dynamics of these transformations from the atomic to the nanometer scale length, and over higher spatial scales. In fact, although an important part of the DNA informational content acts locally, it exerts its functions as collective properties of relatively long sequences and manifests as static and dynamic curvature. Such superstructural features are an intrinsic property of the sequence and are recognized and amplified by protein binding. This large-scale structural amplification influences in deterministic way DNA high scale functions by integrating sequence-dependent curvature effects and local binding of different factors