Patients’ Perceptions of Memory Functioning Before and After Surgical Intervention to Treat Medically Refractory Epilepsy.

Purpose:One risk associated with epilepsy surgery is memory loss, but perhaps more important is how patients perceive changes in their memories. This longitudinal study evaluated changes in memory self-reports and investigated how self-reports relate to changes on objective memory measures in temporal or extratemporal epilepsy patients who underwent surgery. Methods: Objective memory (Wechsler Memory Scale–Revised) and subjective memory self-reports (Memory Assessment Clinics Self-Rating Scale) were individually assessed for 136 patients ∼6 months before and 6 months after surgery. A measure of depressive affect (Beck Depression Inventory–2nd Edition) was used to control variance attributable to emotional distress. Results: Despite a lack of significant correlational relationships between objective and subjective memory for the entire sample, significant correlations between objective memory scores and self-reports did emerge for a subset of patients who evidenced memory decline. Differences also were found in the subjective memory ratings of temporal lobe versus extratemporal patients. Temporal lobe patients rated their memories more negatively than did extratemporal patients and were more likely to report significant improvements in their memory after surgery. Conclusions: In general, patients were not accurate when rating their memories compared to other adults. However, patients with significant declines in their memories were sensitive to actual changes in their memories over time relative to their own personal baselines

A novel μCT analysis reveals different responses of bioerosion and secondary accretion to environmental variability

Corals build reefs through accretion of calcium carbonate (CaCO3) skeletons, but net reef growth also depends on bioerosion by grazers and borers and on secondary calcification by crustose coralline algae and other calcifying invertebrates. However, traditional field methods for quantifying secondary accretion and bioerosion confound both processes, do not measure them on the same time-scale, or are restricted to 2D methods. In a prior study, we compared multiple environmental drivers of net erosion using pre- and post-deployment micro-computed tomography scans (μCT; calculated as the % change in volume of experimental CaCO3 blocks) and found a shift from net accretion to net erosion with increasing ocean acidity. Here, we present a novel μCT method and detail a procedure that aligns and digitally subtracts pre- and post-deployment μCT scans and measures the simultaneous response of secondary accretion and bioerosion on blocks exposed to the same environmental variation over the same time-scale. We tested our method on a dataset from a prior study and show that it can be used to uncover information previously unattainable using traditional methods. We demonstrated that secondary accretion and bioerosion are driven by different environmental parameters, bioerosion is more sensitive to ocean acidity than secondary accretion, and net erosion is driven more by changes in bioerosion than secondary accretion

Invariant computations in local cortical networks with balanced excitation and inhibition

[Abstract] Cortical computations critically involve local neuronal circuits. The computations are often invariant across a cortical area yet are carried out by networks that can vary widely within an area according to its functional architecture. Here we demonstrate a mechanism by which orientation selectivity is computed invariantly in cat primary visual cortex across an orientation preference map that provides a wide diversity of local circuits. Visually evoked excitatory and inhibitory synaptic conductances are balanced exquisitely in cortical neurons and thus keep the spike response sharply tuned at all map locations. This functional balance derives from spatially isotropic local connectivity of both excitatory and inhibitory cells. Modeling results demonstrate that such covariation is a signature of recurrent rather than purely feed-forward processing and that the observed isotropic local circuit is sufficient to generate invariant spike tuning

LEMS: a language for expressing complex biological models in concise and hierarchical form and its use in underpinning NeuroML 2.

Computational models are increasingly important for studying complex neurophysiological systems. As scientific tools, it is essential that such models can be reproduced and critically evaluated by a range of scientists. However, published models are currently implemented using a diverse set of modeling approaches, simulation tools, and computer languages making them inaccessible and difficult to reproduce. Models also typically contain concepts that are tightly linked to domain-specific simulators, or depend on knowledge that is described exclusively in text-based documentation. To address these issues we have developed a compact, hierarchical, XML-based language called LEMS (Low Entropy Model Specification), that can define the structure and dynamics of a wide range of biological models in a fully machine readable format. We describe how LEMS underpins the latest version of NeuroML and show that this framework can define models of ion channels, synapses, neurons and networks. Unit handling, often a source of error when reusing models, is built into the core of the language by specifying physical quantities in models in terms of the base dimensions. We show how LEMS, together with the open source Java and Python based libraries we have developed, facilitates the generation of scripts for multiple neuronal simulators and provides a route for simulator free code generation. We establish that LEMS can be used to define models from systems biology and map them to neuroscience-domain specific simulators, enabling models to be shared between these traditionally separate disciplines. LEMS and NeuroML 2 provide a new, comprehensive framework for defining computational models of neuronal and other biological systems in a machine readable format, making them more reproducible and increasing the transparency and accessibility of their underlying structure and properties

libNeuroML and PyLEMS: using Python to combine procedural and declarative modeling approaches in computational neuroscience.

NeuroML is an XML-based model description language, which provides a powerful common data format for defining and exchanging models of neurons and neuronal networks. In the latest version of NeuroML, the structure and behavior of ion channel, synapse, cell, and network model descriptions are based on underlying definitions provided in LEMS, a domain-independent language for expressing hierarchical mathematical models of physical entities. While declarative approaches for describing models have led to greater exchange of model elements among software tools in computational neuroscience, a frequent criticism of XML-based languages is that they are difficult to work with directly. Here we describe two Application Programming Interfaces (APIs) written in Python (http://www.python.org), which simplify the process of developing and modifying models expressed in NeuroML and LEMS. The libNeuroML API provides a Python object model with a direct mapping to all NeuroML concepts defined by the NeuroML Schema, which facilitates reading and writing the XML equivalents. In addition, it offers a memory-efficient, array-based internal representation, which is useful for handling large-scale connectomics data. The libNeuroML API also includes support for performing common operations that are required when working with NeuroML documents. Access to the LEMS data model is provided by the PyLEMS API, which provides a Python implementation of the LEMS language, including the ability to simulate most models expressed in LEMS. Together, libNeuroML and PyLEMS provide a comprehensive solution for interacting with NeuroML models in a Python environment

Hormonal control of p53 and chemoprevention

Improvements in the detection and treatment of breast cancer have dramatically altered its clinical course and outcome. However, prevention of breast cancer remains an elusive goal. Parity, age of menarche, and age at menopause are major risk factors drawing attention to the important role of the endocrine system in determining the risk of breast cancer, while heritable breast cancer susceptibility syndromes have implicated tumor suppressor genes as important targets. Recent work demonstrating hormonal modulation of the p53 tumor suppressor pathway draws together these established determinants of risk to provide a model of developmental susceptibility to breast cancer. In this model, the mammary epithelium is rendered susceptible due to impaired p53 activity during specific periods of mammary gland development, but specific endocrine stimuli serve to activate p53 function and to mitigate this risk. The results focus attention on p53 as a molecular target for therapies to reduce the risk of breast cancer

cExternal beam radiation results in minimal changes in post void residual urine volumes during the treatment of clinically localized prostate cancer

<p>Abstract</p> <p>Background</p> <p>To evaluate the impact of external beam radiation therapy (XRT) on weekly ultrasound determined post-void residual (PVR) urine volumes in patients with prostate cancer.</p> <p>Methods</p> <p>125 patients received XRT for clinically localized prostate cancer. XRT was delivered to the prostate only (n = 66) or if the risk of lymph node involvement was greater than 10% to the whole pelvis followed by a prostate boost (n = 59). All patients were irradiated in the prone position in a custom hip-fix mobilization device with an empty bladder and rectum. PVR was obtained at baseline and weekly. Multiple clinical and treatment parameters were evaluated as predictors for weekly PVR changes.</p> <p>Results</p> <p>The mean patient age was 73.9 years with a mean pre-treatment prostate volume of 53.3 cc, a mean IPSS of 11.3 and a mean baseline PVR of 57.6 cc. During treatment, PVR decreased from baseline in both cohorts with the absolute difference within the limits of accuracy of the bladder scanner. Alpha-blockers did not predict for a lower PVR during treatment. There was no significant difference in mean PVR urine volumes or differences from baseline in either the prostate only or pelvic radiation groups (p = 0.664 and p = 0.458, respectively). Patients with a larger baseline PVR (>40 cc) had a greater reduction in PVR, although the greatest reduction was seen between weeks one and three. Patients with a small PVR (<40 cc) had no demonstrable change throughout treatment.</p> <p>Conclusion</p> <p>Prostate XRT results in clinically insignificant changes in weekly PVR volumes, suggesting that radiation induced bladder irritation does not substantially influence bladder residual urine volumes.</p

Suppression of TGFβ-Induced Epithelial-Mesenchymal Transition Like Phenotype by a PIAS1 Regulated Sumoylation Pathway in NMuMG Epithelial Cells

Epithelial-mesenchymal-transition (EMT) is a fundamental cellular process that is critical for normal development and tumor metastasis. The transforming growth factor beta (TGFβ) is a potent inducer of EMT like effects, but the mechanisms that regulate TGFβ-induced EMT remain incompletely understood. Using the widely employed NMuMG mammary epithelial cells as a model to study TGFβ-induced EMT, we report that TGFβ downregulates the levels of the SUMO E3 ligase PIAS1 in cells undergoing EMT. Gain and loss of function analyses indicate that PIAS1 acts in a SUMO ligase dependent manner to suppress the ability of TGFβ to induce EMT in these cells. We also find that TGFβ inhibits sumoylation of the PIAS1 substrate SnoN, a transcriptional regulator that antagonizes TGFβ-induced EMT. Accordingly, loss of function mutations of SnoN sumoylation impair the ability of SnoN to inhibit TGFβ-induced EMT in NMuMG cells. Collectively, our findings suggest that PIAS1 is a novel negative regulator of EMT and reveal that inhibition of the PIAS1-SnoN sumoylation pathway represents a key mechanism by which TGFβ induces EMT, with important implications in normal development and tumor metastasis

The association of APOE genotype and cognitive decline in interaction with risk factors in a 65–69 year old community sample

<p>Abstract</p> <p>Background</p> <p>While the evidence of an association between the apolipoprotein E (<it>APOE</it>) <it>*E4 </it>allele and Alzheimer's disease is very strong, the effect of the <it>*E4 </it>allele on cognitive decline in the general population is more equivocal. A cross-sectional study on the lifespan effects of the <it>*E4 </it>allele <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> failed to find any effect of the <it>*E4 </it>allele on cognitive performance at ages 20–24, 40–44 or 60–64 years.</p> <p>Methods</p> <p>In this four year follow-up study, we reexamine the effect of <it>*E4 </it>in the sample of 2,021 individuals, now aged 65–69 years.</p> <p>Results</p> <p>Performance on the Mini-Mental State Examination (MMSE) was significantly poorer for <it>*E4 </it>homozygotes than heterozygotes or non-carriers. The effects of the <it>*E4 </it>genotype on cognitive decline over four years were found on the MMSE and Symbol-Digit Modalities test but only when controlling for risk factors such as head injury and education. Analyses were repeated with the exclusion of participants diagnosed with a mild cognitive disorder, with little change.</p> <p>Conclusion</p> <p>It is possible that <it>*E4 </it>carriers become vulnerable to greater cognitive decline in the presence of other risk factors at 65–69 years of age.</p

Severe infections emerge from commensal bacteria by adaptive evolution

Bacteria responsible for the greatest global mortality colonize the human microbiota far more frequently than they cause severe infections. Whether mutation and selection among commensal bacteria are associated with infection is unknown. We investigated de novo mutation in 1163 Staphylococcus aureus genomes from 105 infected patients with nose colonization. We report that 72% of infections emerged from the nose, with infecting and nose-colonizing bacteria showing parallel adaptive differences. We found 2.8-to-3.6-fold adaptive enrichments of protein-altering variants in genes responding to rsp, which regulates surface antigens and toxin production; agr, which regulates quorum-sensing, toxin production and abscess formation; and host-derived antimicrobial peptides. Adaptive mutations in pathogenesis-associated genes were 3.1-fold enriched in infecting but not nose-colonizing bacteria. None of these signatures were observed in healthy carriers nor at the species-level, suggesting infection-associated, short-term, within-host selection pressures. Our results show that signatures of spontaneous adaptive evolution are specifically associated with infection, raising new possibilities for diagnosis and treatment