Validation of machine learning models to detect amyloid pathologies across institutions.

Semi-quantitative scoring schemes like the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) are the most commonly used method in Alzheimer's disease (AD) neuropathology practice. Computational approaches based on machine learning have recently generated quantitative scores for whole slide images (WSIs) that are highly correlated with human derived semi-quantitative scores, such as those of CERAD, for Alzheimer's disease pathology. However, the robustness of such models have yet to be tested in different cohorts. To validate previously published machine learning algorithms using convolutional neural networks (CNNs) and determine if pathological heterogeneity may alter algorithm derived measures, 40 cases from the Goizueta Emory Alzheimer's Disease Center brain bank displaying an array of pathological diagnoses (including AD with and without Lewy body disease (LBD), and / or TDP-43-positive inclusions) and levels of Aβ pathologies were evaluated. Furthermore, to provide deeper phenotyping, amyloid burden in gray matter vs whole tissue were compared, and quantitative CNN scores for both correlated significantly to CERAD-like scores. Quantitative scores also show clear stratification based on AD pathologies with or without additional diagnoses (including LBD and TDP-43 inclusions) vs cases with no significant neurodegeneration (control cases) as well as NIA Reagan scoring criteria. Specifically, the concomitant diagnosis group of AD + TDP-43 showed significantly greater CNN-score for cored plaques than the AD group. Finally, we report that whole tissue computational scores correlate better with CERAD-like categories than focusing on computational scores from a field of view with densest pathology, which is the standard of practice in neuropathological assessment per CERAD guidelines. Together these findings validate and expand CNN models to be robust to cohort variations and provide additional proof-of-concept for future studies to incorporate machine learning algorithms into neuropathological practice

The Flexure-based Microgap Rheometer (FMR)

Submitted to J. Rheol.We describe the design and construction of a new microrheometer designed to facilitate the viscometric study of complex fluids with very small sample volumes (1-10 μl)and gaps of micrometer dimensions. The Flexure-based Microgap Rheometer (FMR) is a shear-rate-controlled device capable of measuring the shear stress in a plane Couette configuration with directly-controlled gaps between 1 μm and 200 μm. White light interferometry and a three-point nanopositioning stage using piezo-stepping motors are used to control the parallelism of the upper and lower shearing surfaces which are constructed from glass optical flats. A compound flexure system is used to hold the fluid sample testing unit between a drive spring connected to an ‘inchworm’ motor and an independent sensor spring. Displacements in the sensing flexure are detected using an inductive proximity sensor. Ready optical access to the transparent shearing surfaces enables monitoring of the structural evolution in the gap with a long working-distance video-microscope. This configuration then allows us to determine the microgap-dependent flow behavior of complex fluids over 5 decades of shear rate. We demonstrate the capability of the FMR by characterizing the complex stress and gap dependent flow behavior of a typical microstructured food product (mayonnaise) over the range of gaps from 8 to 100 μm and stresses from 10 to 1500 Pa. We correlate the gap-dependent rheological response to the microstructure of the emulsion and changes induced in the material by prolonged shearing.Dupont MIT Allianc

Setdb1-mediated H3K9 methylation is enriched on the inactive X and plays a role in its epigenetic silencing

Background: The presence of histone 3 lysine 9 (H3K9) methylation on the mouse inactive X chromosome has been controversial over the last 15 years, and the functional role of H3K9 methylation in X chromosome inactivation in any species has remained largely unexplored. Results: Here we report the first genomic analysis of H3K9 di- and tri-methylation on the inactive X: we find they are enriched at the intergenic, gene poor regions of the inactive X, interspersed between H3K27 tri-methylation domains found in the gene dense regions. Although H3K9 methylation is predominantly non-genic, we find that depletion of H3K9 methylation via depletion of H3K9 methyltransferase Set domain bifurcated 1 (Setdb1) during the establishment of X inactivation, results in failure of silencing for around 150 genes on the inactive X. By contrast, we find a very minor role for Setdb1-mediated H3K9 methylation once X inactivation is fully established. In addition to failed gene silencing, we observed a specific failure to silence X-linked long-terminal repeat class repetitive elements. Conclusions: Here we have shown that H3K9 methylation clearly marks the murine inactive X chromosome. The role of this mark is most apparent during the establishment phase of gene silencing, with a more muted effect on maintenance of the silent state. Based on our data, we hypothesise that Setdb1-mediated H3K9 methylation plays a role in epigenetic silencing of the inactive X via silencing of the repeats, which itself facilitates gene silencing through alterations to the conformation of the whole inactive X chromosome.Andrew Keniry, Linden J. Gearing, Natasha Jansz, Joy Liu, Aliaksei Z. Holik, Peter F. Hickey, Sarah A. Kinkel, Darcy L. Moore, Kelsey Breslin, Kelan Chen, Ruijie Liu, Catherine Phillips, Miha Pakusch, Christine Biben, Julie M. Sheridan, Benjamin T. Kile, Catherine Carmichael, Matthew E. Ritchie, Douglas J. Hilton and Marnie E. Blewit

‘I think I'm more free with them'—Conflict, Negotiation and Change in Intergenerational Relations in African Families Living in Britain

While the family is increasingly being recognised as pivotal to migration, there remain too few studies examining how migration impacts on intergenerational relationships. Although traditional intergenerational gaps are intensified by migration, arguably there has been an over-emphasis on the divisions between ‘traditional’ parents and ‘modern’ children at the expense of examining the ways in which both generations adapt. As Foner and Dreby [2011. “Relations Between the Generations in Immigrant Families.” Annual Review of Sociology 37: 545–564] stress, the reality of post-migration intergenerational relations is inevitably more complex, requiring the examination of both conflict and cooperation. This article contributes to this growing literature by discussing British data from comparative projects on intergenerational relations in African families (in Britain, France and South Africa). It argues that particular understandings can be gained from examining the adaptation of parents and parenting strategies post-migration and how the reconfiguration of family relations can contribute to settlement. By focusing on how both parent and child generations engage in conflict and negotiation to redefine their relationships and expectations, it offers insight into how families navigate and integrate the values of two cultures. In doing so, it argues that the reconfiguration of gender roles as a result of migration offers families the space to renegotiate their relationships and make choices about what they transmit to the next generation

Pioglitazone administration alters ovarian gene expression in aging obese lethal yellow mice

<p>Abstract</p> <p>Background</p> <p>Women with polycystic ovary syndrome (PCOS) are often treated with insulin-sensitizing agents, e.g. thiazolidinediones (TZD), which have been shown to reduce androgen levels and improved ovulatory function. Acting via peroxisome proliferator-activated receptor (PPAR) gamma, TZD alter the expression of a large variety of genes. Lethal yellow (LY; C57BL/6J Ay/a) mice, possessing a mutation (Ay) in the agouti gene locus, exhibit progressive obesity, reproductive dysfunction, and altered metabolic regulation similar to women with PCOS. The current study was designed to test the hypothesis that prolonged treatment of aging LY mice with the TZD, pioglitazone, alters the ovarian expression of genes that may impact reproduction.</p> <p>Methods</p> <p>Female LY mice received daily oral doses of either 0.01 mg pioglitazone (n = 4) or an equal volume of vehicle (DMSO; n = 4) for 8 weeks. At the end of treatment, ovaries were removed and DNA microarrays were used to analyze differential gene expression.</p> <p>Results</p> <p>Twenty-seven genes showed at least a two-fold difference in ovarian expression with pioglitazone treatment. These included leptin, angiopoietin, angiopoietin-like 4, Foxa3, PGE1 receptor, resistin-like molecule-alpha (RELM), and actin-related protein 6 homolog (ARP6). For most altered genes, pioglitazone changed levels of expression to those seen in untreated C57BL/6J(a/a) non-mutant lean mice.</p> <p>Conclusion</p> <p>TZD administration may influence ovarian function via numerous diverse mechanisms that may or may not be directly related to insulin/IGF signaling.</p