Patterns of progressive atrophy vary with age in Alzheimer's disease patients

Age is not only the greatest risk factor for Alzheimer's disease (AD) but also a key modifier of disease presentation and progression. Here, we investigate how longitudinal atrophy patterns vary with age in mild cognitive impairment (MCI) and AD. Data comprised serial longitudinal 1.5-T magnetic resonance imaging scans from 153 AD, 339 MCI, and 191 control subjects. Voxel-wise maps of longitudinal volume change were obtained and aligned across subjects. Local volume change was then modeled in terms of diagnostic group and an interaction between group and age, adjusted for total intracranial volume, white-matter hyperintensity volume, and apolipoprotein E genotype. Results were significant at p < 0.05 with family-wise error correction for multiple comparisons. An age-by-group interaction revealed that younger AD patients had significantly faster atrophy rates in the bilateral precuneus, parietal, and superior temporal lobes. These results suggest younger AD patients have predominantly posterior progressive atrophy, unexplained by white-matter hyperintensity, apolipoprotein E, or total intracranial volume. Clinical trials may benefit from adapting outcome measures for patient groups with lower average ages, to capture progressive atrophy in posterior cortices

A new multicompartmental reaction-diffusion modeling method links transient membrane attachment of E. coli MinE to E-ring formation

Many important cellular processes are regulated by reaction-diffusion (RD) of molecules that takes place both in the cytoplasm and on the membrane. To model and analyze such multicompartmental processes, we developed a lattice-based Monte Carlo method, Spatiocyte that supports RD in volume and surface compartments at single molecule resolution. Stochasticity in RD and the excluded volume effect brought by intracellular molecular crowding, both of which can significantly affect RD and thus, cellular processes, are also supported. We verified the method by comparing simulation results of diffusion, irreversible and reversible reactions with the predicted analytical and best available numerical solutions. Moreover, to directly compare the localization patterns of molecules in fluorescence microscopy images with simulation, we devised a visualization method that mimics the microphotography process by showing the trajectory of simulated molecules averaged according to the camera exposure time. In the rod-shaped bacterium _Escherichia coli_, the division site is suppressed at the cell poles by periodic pole-to-pole oscillations of the Min proteins (MinC, MinD and MinE) arising from carefully orchestrated RD in both cytoplasm and membrane compartments. Using Spatiocyte we could model and reproduce the _in vivo_ MinDE localization dynamics by accounting for the established properties of MinE. Our results suggest that the MinE ring, which is essential in preventing polar septation, is largely composed of MinE that is transiently attached to the membrane independently after recruited by MinD. Overall, Spatiocyte allows simulation and visualization of complex spatial and reaction-diffusion mediated cellular processes in volumes and surfaces. As we showed, it can potentially provide mechanistic insights otherwise difficult to obtain experimentally

Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation

A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach

Brain multiplexes reveal morphological connectional biomarkers fingerprinting late brain dementia states

Accurate diagnosis of mild cognitive impairment (MCI) before conversion to Alzheimer\u27s disease (AD) is invaluable for patient treatment. Many works showed that MCI and AD affect functional and structural connections between brain regions as well as the shape of cortical regions. However, \u27shape connections\u27 between brain regions are rarely investigated -e.g., how morphological attributes such as cortical thickness and sulcal depth of a specific brain region change in relation to morphological attributes in other regions. To fill this gap, we unprecedentedly design morphological brain multiplexes for late MCI/AD classification. Specifically, we use structural T1-w MRI to define morphological brain networks, each quantifying similarity in morphology between different cortical regions for a specific cortical attribute. Then, we define a brain multiplex where each intra-layer represents the morphological connectivity network of a specific cortical attribute, and each inter-layer encodes the similarity between two consecutive intra-layers. A significant performance gain is achieved when using the multiplex architecture in comparison to other conventional network analysis architectures. We also leverage this architecture to discover morphological connectional biomarkers fingerprinting the difference between late MCI and AD stages, which included the right entorhinal cortex and right caudal middle frontal gyrus

2-Octyl-cyanoacrylate for wound closure in cervical and lumbar spinal surgery

It is claimed that wound closure with 2-octyl-cyanoacrylate has the advantages that band-aids are not needed in the postoperative period, that the wound can get in contact with water and that removal of stitches is not required. This would substantially enhance patient comfort, especially in times of reduced in-hospital stays. Postoperative wound infection is a well-known complication in spinal surgery. The reported infection rates range between 0% and 12.7%. The question arises if the advantages of wound closure with 2-octyl-cyanoacrylate in spinal surgery are not surpassed by an increase in infection rate. This study has been conducted to identify the infection rate of spinal surgery if wound closure was done with 2-octyl-cyanoacrylate. A total of 235 patients with one- or two-level surgery at the cervical or lumbar spine were included in this prospective study. Their pre- and postoperative course was evaluated. Analysis included age, sex, body mass index, duration and level of operation, blood examinations, 6-week follow-up and analysis of preoperative risk factors. The data were compared to infection rates of similar surgeries found in a literature research and to a historical group of 503 patients who underwent wound closure with standard skin sutures after spine surgery. With the use of 2-octyl-cyanoacrylate, only one patient suffered from postoperative wound infection which accounts for a total infection rate of 0.43%. In the literature addressing infection rate after spine surgery, an average rate of 3.2% is reported. Infection rate was 2.2% in the historical control group. No risk factor could be identified which limited the usage of 2-octyl-cyanoacrylate. 2-Octyl-cyanoacrylate provides sufficient wound closure in spinal surgery and is associated with a low risk of postoperative wound infection

Three-Dimensional Stochastic Off-Lattice Model of Binding Chemistry in Crowded Environments

Molecular crowding is one of the characteristic features of the intracellular environment, defined by a dense mixture of varying kinds of proteins and other molecules. Interaction with these molecules significantly alters the rates and equilibria of chemical reactions in the crowded environment. Numerous fundamental activities of a living cell are strongly influenced by the crowding effect, such as protein folding, protein assembly and disassembly, enzyme activity, and signal transduction. Quantitatively predicting how crowding will affect any particular process is, however, a very challenging problem because many physical and chemical parameters act synergistically in ways that defy easy analysis. To build a more realistic model for this problem, we extend a prior stochastic off-lattice model from two-dimensional (2D) to three-dimensional (3D) space and examine how the 3D results compare to those found in 2D. We show that both models exhibit qualitatively similar crowding effects and similar parameter dependence, particularly with respect to a set of parameters previously shown to act linearly on total reaction equilibrium. There are quantitative differences between 2D and 3D models, although with a generally gradual nonlinear interpolation as a system is extended from 2D to 3D. However, the additional freedom of movement allowed to particles as thickness of the simulation box increases can produce significant quantitative change as a system moves from 2D to 3D. Simulation results over broader parameter ranges further show that the impact of molecular crowding is highly dependent on the specific reaction system examined

Diffusion in crowded biological environments: applications of Brownian dynamics

Biochemical reactions in living systems occur in complex, heterogeneous media with total concentrations of macromolecules in the range of 50 - 400 mgml. Molecular species occupy a significant fraction of the immersing medium, up to 40% of volume. Such complex and volume-occupied environments are generally termed 'crowded' and/or 'confined'. In crowded conditions non-specific interactions between macromolecules may hinder diffusion - a major process determining metabolism, transport, and signaling. Also, the crowded media can alter, both qualitatively and quantitatively, the reactions in vivo in comparison with their in vitro counterparts. This review focuses on recent developments in particle-based Brownian dynamics algorithms, their applications to model diffusive transport in crowded systems, and their abilities to reproduce and predict the behavior of macromolecules under in vivo conditions

Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer

BACKGROUND: Delta-like ligand 4 (Dll4) is a Notch ligand that is upregulated by hypoxia and vascular endothelial growth factor-A (VEGF-A) and is reported to have a role in tumor angiogenesis. Evidence from xenograft studies suggests that inhibiting Dll4-Notch signalling may overcome resistance to anti-VEGF therapy. The aim of this study was to characterise the expression of Dll4 in colon cancer and to assess whether it is associated with markers of hypoxia and prognosis. METHOD: In all, 177 colon cancers were represented in tissue microarrays. Immunohistochemistry was performed using validated antibodies against Dll4, VEGF, hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, prolyl hydroxylase (PHD)1, PHD2, PHD3 and carbonic anhydrase 9 (CA9). RESULTS: The expression of Dll4 was observed preferentially in the endothelium of 71% (125 out of 175) of colon cancers, but not in the endothelium adjacent to normal mucosa (none out of 107, P&lt;0.0001). The expression of VEGF was significantly associated with HIF-2alpha (P&lt;0.0001) and Dll4 (P=0.010). Only HIF-2alpha had a significant multivariate prognostic effect (hazard ratio 1.61, 95% confidence interval 1.01-2.57). Delta-like ligand 4 was also expressed by neoplastic cells, particularly neoplastic goblet cells. CONCLUSION: Endothelial expression of Dll4 is not a prognostic factor, but is significantly associated with VEGF. Assessing endothelial Dll4 expression may be critical in predicting response to anti-VEGF therapies

Marine Biodiversity of Aotearoa New Zealand

The marine-biodiversity assessment of New Zealand (Aotearoa as known to Māori) is confined to the 200 nautical-mile boundary of the Exclusive Economic Zone, which, at 4.2 million km2, is one of the largest in the world. It spans 30° of latitude and includes a high diversity of seafloor relief, including a trench 10 km deep. Much of this region remains unexplored biologically, especially the 50% of the EEZ deeper than 2,000 m. Knowledge of the marine biota is based on more than 200 years of marine exploration in the region. The major oceanographic data repository is the National Institute of Water and Atmospheric Research (NIWA), which is involved in several Census of Marine Life field projects and is the location of the Southwestern Pacific Regional OBIS Node; NIWA is also data manager and custodian for fisheries research data owned by the Ministry of Fisheries. Related data sources cover alien species, environmental measures, and historical information. Museum collections in New Zealand hold more than 800,000 registered lots representing several million specimens. During the past decade, 220 taxonomic specialists (85 marine) from 18 countries have been engaged in a project to review New Zealand's entire biodiversity. The above-mentioned marine information sources, published literature, and reports were scrutinized to give the results summarized here for the first time (current to 2010), including data on endemism and invasive species. There are 17,135 living species in the EEZ. This diversity includes 4,315 known undescribed species in collections. Species diversity for the most intensively studied phylum-level taxa (Porifera, Cnidaria, Mollusca, Brachiopoda, Bryozoa, Kinorhyncha, Echinodermata, Chordata) is more or less equivalent to that in the ERMS (European Register of Marine Species) region, which is 5.5 times larger in area than the New Zealand EEZ. The implication is that, when all other New Zealand phyla are equally well studied, total marine diversity in the EEZ may be expected to equal that in the ERMS region. This equivalence invites testable hypotheses to explain it. There are 177 naturalized alien species in New Zealand coastal waters, mostly in ports and harbours. Marine-taxonomic expertise in New Zealand covers a broad number of taxa but is, proportionately, at or near its lowest level since the Second World War. Nevertheless, collections are well supported by funding and are continually added to. Threats and protection measures concerning New Zealand's marine biodiversity are commented on, along with potential and priorities for future research