Computational and experimental methodology for site-matched investigations of the influence of mineral mass fraction and collagen orientation on the axial indentation modulus of lamellar bone

Relationships between mineralization, collagen orientation and indentation modulus were investigated in bone structural units from the mid-shaft of human femora using a site-matched design. Mineral mass fraction, collagen fibril angle and indentation moduli were measured in registered anatomical sites using backscattered electron imaging, polarized light microscopy and nano-indentation, respectively. Theoretical indentation moduli were calculated with a homogenization model from the quantified mineral densities and mean collagen fibril orientations. The average indentation moduli predicted based on local mineralization and collagen fibers arrangement were not significantly different from the average measured experimentally with nanoindentation (p=0.9). Surprisingly, no substantial correlation of the measured indentation moduli with tissue mineralization and/or collagen fiber arrangement was found. Nano-porosity, micro-damage, collagen cross-links, non-collagenous proteins or other parameters affect the indentation measurements. Additional testing/simulation methods need to be considered to properly understand the variability of indentation moduli, beyond the mineralization and collagen arrangement in bone structural units.

SUSYFLAVOR v2: A Computational tool for FCNC and CP-violating processes in the MSSM

We present SUSY_FLAVOR version 2 — a Fortran 77 program that calculates low-energy flavor observables in the general R-parity conserving MSSM. For a set of MSSM parameters as input, the code gives predictions for: 1. Electric dipole moments of the leptons and the neutron. 2. Anomalous magnetic moments (i.e. g − 2) of the leptons. 3. Radiative lepton decays (μ → eγ and τ → μγ , eγ ). 4. Rare Kaon decays (K0 L → π0 ¯νν and K+ → π+ ¯νν). 5. Leptonic B decays (Bs,d → l+l−, B → τ ν and B → Dτ ν). 6. Radiative B decays (B → ¯ Xsγ ). 7. ΔF = 2 processes ( ¯ K0–K0, ¯D–D, ¯Bd–Bd and ¯Bs–Bs mixing). Comparing to SUSY_FLAVOR v1, where the matching conditions were calculated strictly at one-loop level, SUSY_FLAVOR v2 performs the resummation of all chirally enhanced corrections, i.e. takes into account the enhanced effects from tan β and/or large trilinear soft mixing terms to all orders in perturbation theory. Also, in SUSY_FLAVOR v2 new routines calculation of B → (D)τ ν, g − 2, radiative lepton decays and Br(l → l′γ ) were added. All calculations are done using exact diagonalization of the sfermion mass matrices. The program can be obtained from http://www.fuw.edu.pl/susy_flavor.

Notes on a Queer Brain: Can there be a Critical Research on Sex/Gender in Neuroscience?

Anelis Kaiser is associate researcher at the Center for Cognitive Science at the University of Freiburg, Germany. Dr. Kaiser recently co-edited a special issue of the journal Neuroethics on gender and brain science. She is co-founder (with Isabelle Dussauge) of the interdisciplinary network NeuroGenderings, which brings together experts from the brain sciences, the humanities and science studies (STS) to critically study the sexed brain. She has published on sex and gender as constructed categories in science as well as on the topics of multilingualism and language processing in the brain. Co-sponsored with the Center for Lesbian and Gay Studies. - See more at: http://www.gc.cuny.edu/Page-Elements/Academics-Research-Centers-Initiatives/Centers-and-Institutes/Center-for-the-Study-of-Women-and-Society/Center-Events#sthash.bDeBg5fk.dpuf

Short-Term Plasticity in a Computational Model of the Tail-Withdrawal Circuit in Aplysia.

The tail-withdrawal circuit of Aplysia provides a useful model system for investigating synaptic dynamics. Sensory neurons within the circuit manifest several forms of synaptic plasticity. Here, we developed a model of the circuit and investigated the ways in which depression (DEP) and potentiation (POT) contributed to information processing. DEP limited the amount of motor neuron activity that could be elicited by the monosynaptic pathway alone. POT within the monosynaptic pathway did not compensate for DEP. There was, however, a synergistic interaction between POT and the polysynaptic pathway. This synergism extended the dynamic range of the network, and the interplay between DEP and POT made the circuit responded preferentially to long-duration, low-frequency inputs.

Tracking the Flow of Information through the Hippocampal Formation in the Rat

The hippocampus receives input from upper levels of the association cortex and is implicated in many mnemonic processes, but the exact mechanisms by which it codes and stores information is an unresolved topic. This work examines the flow of information through the hippocampal formation while attempting to determine the computations that each of the hippocampal subfields performs in learning and memory. The formation, storage, and recall of hippocampal-dependent memories theoretically utilize an autoassociative attractor network that functions by implementing two competitive, yet complementary, processes. Pattern separation, hypothesized to occur in the dentate gyrus (DG), refers to the ability to decrease the similarity among incoming information by producing output patterns that overlap less than the inputs. In contrast, pattern completion, hypothesized to occur in the CA3 region, refers to the ability to reproduce a previously stored output pattern from a partial or degraded input pattern. Prior to addressing the functional role of the DG and CA3 subfields, the spatial firing properties of neurons in the dentate gyrus were examined. The principal cell of the dentate gyrus, the granule cell, has spatially selective place fields; however, the behavioral correlates of another excitatory cell, the mossy cell of the dentate polymorphic layer, are unknown. This report shows that putative mossy cells have spatially selective firing that consists of multiple fields similar to previously reported properties of granule cells. Other cells recorded from the DG had single place fields. Compared to cells with multiple fields, cells with single fields fired at a lower rate during sleep, were less likely to burst, and were more likely to be recorded simultaneously with a large population of neurons that were active during sleep and silent during behavior. These data suggest that single-field and multiple-field cells constitute at least two distinct cell classes in the DG. Based on these characteristics, we propose that putative mossy cells tend to fire in multiple, distinct locations in an environment, whereas putative granule cells tend to fire in single locations, similar to place fields of the CA1 and CA3 regions. Experimental evidence supporting the theories of pattern separation and pattern completion comes from both behavioral and electrophysiological tests. These studies specifically focused on the function of each subregion and made implicit assumptions about how environmental manipulations changed the representations encoded by the hippocampal inputs. However, the cell populations that provided these inputs were in most cases not directly examined. We conducted a series of studies to investigate the neural activity in the entorhinal cortex, dentate gyrus, and CA3 in the same experimental conditions, which allowed a direct comparison between the input and output representations. The results show that the dentate gyrus representation changes between the familiar and cue altered environments more than its input representations, whereas the CA3 representation changes less than its input representations. These findings are consistent with longstanding computational models proposing that (1) CA3 is an associative memory system performing pattern completion in order to recall previous memories from partial inputs, and (2) the dentate gyrus performs pattern separation to help store different memories in ways that reduce interference when the memories are subsequently recalled.

Computational selection of inhibitors of Abeta aggregation and neuronal toxicity.

Alzheimer's disease (AD) is characterized by the cerebral accumulation of misfolded and aggregated amyloid-beta protein (Abeta). Disease symptoms can be alleviated, in vitro and in vivo, by 'beta-sheet breaker' pentapeptides that reduce plaque load. However the peptide nature of these compounds, made them biologically unstable and unable to penetrate membranes with high efficiency. The main goal of this study was to use computational methods to identify small molecule mimetics with better drug-like properties. For this purpose, the docked conformations of the active peptides were used to identify compounds with similar activities. A series of related beta-sheet breaker peptides were docked to solid state NMR structures of a fibrillar form of Abeta. The lowest energy conformations of the active peptides were used to design three dimensional (3D)-pharmacophores, suitable for screening the NCI database with Unity. Small molecular weight compounds with physicochemical features and a conformation similar to the active peptides were selected, ranked by docking and biochemical parameters. Of 16 diverse compounds selected for experimental screening, 2 prevented and reversed Abeta aggregation at 2-3microM concentration, as measured by Thioflavin T (ThT) fluorescence and ELISA assays. They also prevented the toxic effects of aggregated Abeta on neuroblastoma cells. Their low molecular weight and aqueous solubility makes them promising lead compounds for treating AD.

Short-Term Plasticity in a Computational Model of the Tail-Withdrawal Circuit in Aplysia.

The tail-withdrawal circuit of Aplysia provides a useful model system for investigating synaptic dynamics. Sensory neurons within the circuit manifest several forms of synaptic plasticity. Here, we developed a model of the circuit and investigated the ways in which depression (DEP) and potentiation (POT) contributed to information processing. DEP limited the amount of motor neuron activity that could be elicited by the monosynaptic pathway alone. POT within the monosynaptic pathway did not compensate for DEP. There was, however, a synergistic interaction between POT and the polysynaptic pathway. This synergism extended the dynamic range of the network, and the interplay between DEP and POT made the circuit responded preferentially to long-duration, low-frequency inputs.

Computational identification and functional validation of regulatory motifs in cartilage-expressed genes.

Chondrocyte gene regulation is important for the generation and maintenance of cartilage tissues. Several regulatory factors have been identified that play a role in chondrogenesis, including the positive transacting factors of the SOX family such as SOX9, SOX5, and SOX6, as well as negative transacting factors such as C/EBP and delta EF1. However, a complete understanding of the intricate regulatory network that governs the tissue-specific expression of cartilage genes is not yet available. We have taken a computational approach to identify cis-regulatory, transcription factor (TF) binding motifs in a set of cartilage characteristic genes to better define the transcriptional regulatory networks that regulate chondrogenesis. Our computational methods have identified several TFs, whose binding profiles are available in the TRANSFAC database, as important to chondrogenesis. In addition, a cartilage-specific SOX-binding profile was constructed and used to identify both known, and novel, functional paired SOX-binding motifs in chondrocyte genes. Using DNA pattern-recognition algorithms, we have also identified cis-regulatory elements for unknown TFs. We have validated our computational predictions through mutational analyses in cell transfection experiments. One novel regulatory motif, N1, found at high frequency in the COL2A1 promoter, was found to bind to chondrocyte nuclear proteins. Mutational analyses suggest that this motif binds a repressive factor that regulates basal levels of the COL2A1 promoter.

A new methodical approach in neuroscience: assessing inter-personal brain coupling using functional near-infrared imaging (fNIRI) hyperscanning

Since the first demonstration of how to simultaneously measure brain activity using functional magnetic resonance imaging (fMRI) on two subjects about 10 years ago, a new paradigm in neuroscience is emerging: measuring brain activity from two or more people simultaneously, termed "hyperscanning". The hyperscanning approach has the potential to reveal inter-personal brain mechanisms underlying interaction-mediated brain-to-brain coupling. These mechanisms are engaged during real social interactions, and cannot be captured using single-subject recordings. In particular, functional near-infrared imaging (fNIRI) hyperscanning is a promising new method, offering a cost-effective, easy to apply and reliable technology to measure inter-personal interactions in a natural context. In this short review we report on fNIRI hyperscanning studies published so far and summarize opportunities and challenges for future studies.

A longitudinal study of Type-B aortic dissection and endovascular repair scenarios: computational analyses

Conservative medical treatment is commonly first recommended for patients with uncomplicated Type-B aortic dissection (AD). However, if dissection-related complications occur, endovascular repair or open surgery is performed. Here we establish computational models of AD based on radiological three-dimensional images of a patient at initial presentation and after 4-years of best medical treatment (BMT). Computational fluid dynamics analyses are performed to quantitatively investigate the hemodynamic features of AD. Entry and re-entries (functioning as entries and outlets) are identified in the initial and follow-up models, and obvious variations of the inter-luminal flow exchange are revealed. Computational studies indicate that the reduction of blood pressure in BMT patients lowers pressure and wall shear stress in the thoracic aorta in general, and flattens the pressure distribution on the outer wall of the dissection, potentially reducing the progressive enlargement of the false lumen. Finally, scenario studies of endovascular aortic repair are conducted. The results indicate that, for patients with multiple tears, stent-grafts occluding all re-entries would be required to effectively reduce inter-luminal blood communication and thus induce thrombosis in the false lumen. This implicates that computational flow analyses may identify entries and relevant re-entries between true and false lumen and potentially assist in stent-graft planning.