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Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.
Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.
Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.
This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.
Two radiocarbon (14C) excursions are caused by an increase of incoming cosmic rays on a short time scale found in the Late Holocene (AD 774–775 and AD 993–994), which are widely explained as due to extreme solar proton events (SPE). In addition, a larger event has also been reported at 5480 BC (Miyake et al. 2017a), which is attributed to a special mode of a grand solar minimum, as well as another at 660 BC (Park et al. 2017). Clearly, other events must exist, but could have different causes. In order to detect more such possible events, we have identified periods when the 14C increase rate is rapid and large in the international radiocarbon calibration (IntCal) data (Reimer et al. 2013). In this paper, we follow on from previous studies and identify a possible excursion starting at 814–813 BC, which may be connected to the beginning of a grand solar minimum associated with the beginning of the Hallstatt period, which is characterized by relatively constant 14C ages in the period from 800–400 BC. We compare results of annual 14C measurements from tree rings of sequoia (California) and cedar (Japan), and compare these results to other identified excursions, as well as geomagnetic data. We note that the structure of the increase from 813 BC is similar to the increase at 5480 BC, suggesting a related origin. We also assess whether there are different kinds of events that may be observed and may be consistent with different types of solar phenomena, or other explanations.
The hoard of silver plate known as the Vinkovci treasure (or the Cibalae treasure, after the Roman name for the town) was discovered on March 23, 2012, during rescue excavations in the town of Vinkovci (Colonia Aurelia Cibalae) in the Vukovar-Srijem county of E Croatia (fig. 1). It is one of the most significant late Roman discoveries of the new millennium, and the first major 4th-c. A.D. assemblage of silver plate to be unearthed for at least half a century (the Seuso treasure was probably found in the late 1970s, and although new pieces of the Kaiseraugst treasure emerged in the 1990s the original discovery was made in 1961). This interim report on the treasure is based upon the results of research conducted by the authors in the 4 years that have passed since it came to light.
The modeling of deformation in snow-pack of realistic geometry is reported. Experimentally measured deformation rates are compared with corresponding rates predicted from a finite-element model developed using local stratigraphy in the experimental area. Specifically designed deformation gages placed on an avalanche-sensitive snow slope at Berthoud Pass, Colorado, during the winter of 1972-73, were used to measure the experimental values. The finite-element code, based upon a plane-strain idealization, was used to model the steady-state flow of the slope. The program incorporates visco-elastic properties of the snow-pack, snow-layer stratigraphy, and the orthotropic properties of snow when both tension and compression components of stress act at a point. The degree of correlation between experimental and computed values of deformation rates is reported, and limitations of the analysis in conjunction with the type of experimental data taken are discussed.
Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain-CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource.
Two radiocarbon excursions (AD 774–775 and AD 993–994) occurred due to an increase of incoming cosmic rays on a short timescale. The most plausible cause of these events is considered to be extreme solar proton events (SPE). It is possible that there are other annual 14C excursions in the past that have yet to be confirmed. In order to detect more of these events, we measured the 14C contents in bristlecone pine tree-ring samples during the periods when the rate of 14C increase in the IntCal data is large. We analyzed four periods every other year (2479–2455 BC, 4055–4031 BC, 4465–4441 BC, and 4689–4681 BC), and found no anomalous 14C excursions during these periods. This study confirms that it is important to do continuous measurements to find annual cosmic-ray events at other locations in the tree-ring record.
A sample with a radiocarbon concentration estimated to be greater than 105 times Modern was inadvertently graphitized and measured in the Xi'an AMS system last year. Both the sample preparation lines and the ion source system were seriously contaminated and a series of cleaning procedures were carried out to remove the contamination from them. After repeated and careful cleaning as well as continuous flushing with dead CO2 gas, both systems have recovered from the contamination event. The machine background is back to 2.0 x 10–16 and the chemical blank is beyond 50 kyr.
We show how estimates of parameters characterizing inflation-based theories of structure formation localized over the past year when large scale structure (LSS) information from galaxy and cluster surveys was combined with the rapidly developing cosmic microwave background (CMB) data, especially from the recent Boomerang and Maxima balloon experiments. All current CMB data plus a relatively weak prior probability on the Hubble constant, age and LSS points to little mean curvature (Ωtot = 1.08±0.06) and nearly scale invariant initial fluctuations (ns = 1.03±0.08), both predictions of (non-baroque) inflation theory. We emphasize the role that degeneracy among parameters in the Lpk = 212 ± 7 position of the (first acoustic) peak plays in defining the Ωtot range upon marginalization over other variables. Though the CDM density is in the expected range (Ωcdmh2 = 0.17 ± 0.02), the baryon density Ωbh2 = 0.030 ± 0.005 is somewhat above the independent 0.019 ± 0.002 nucleosynthesis estimates. CMB+LSS gives independent evidence for dark energy (ΩΛ = 0.66 ± 0.06) at the same level as from supernova (SN1) observations, with a phenomenological quintessence equation of state limited by SN1+CMB+LSS to wQ < −0.7 cf. the wQ=−1 cosmological constant case.
We report on the analysis of virtual powder-diffraction patterns from serial femtosecond crystallography (SFX) data collected at an X-ray free-electron laser. Different approaches to binning and normalizing these patterns are discussed with respect to the microstructural characteristics which each highlights. Analysis of SFX data from a powder of Pr0.5Ca0.5MnO3 in this way finds evidence of other trace phases in its microstructure which was not detectable in a standard powder-diffraction measurement. Furthermore, a comparison between two virtual powder pattern integration strategies is shown to yield different diffraction peak broadening, indicating sensitivity to different types of microstrain. This paper is a first step in developing new data analysis methods for microstructure characterization from serial crystallography data.
Biogenic nitrogen (N2) and nitrous oxide (N2O) accumulations were measured in groundwater, streams and the vadose zone of small agricultural watersheds in the Mid-Atlantic USA. In general, N2 and N2O in excess of atmospheric equilibrium were found in groundwater virtually everywhere that was sampled. Excess N2 in groundwater ranged from undetectable to 616 μmol N2-N/l, the latter representing c. 50% of background N2. The N2O-N concentrations varied from undetectable to 75 μm, and usually greatly exceeded values at atmospheric equilibrium (25–30 nM); however, N2O was generally 1–10% of excess N2. Intermediate levels of deficit and excess N2 in flowing streams (−65 to +250 μmol N2-N/L) resulting from both abiotic and biotic processes were also measured. In vadose zone gases, multiple N2/Ar gas profiles were measured which exhibited seasonal variations with below atmospheric values when the soil was warming in spring/summer and above atmospheric values when groundwater was cooling in fall/winter. Both abiotic and biotic processes contributed to the excess N2 and N2O that was observed. The current data indicate that large concentrations of excess N gases can accumulate within soil, groundwater, and streams of agriculturally dominated watersheds. When excess N gases are exchanged with the atmosphere, the net fluxes to the atmosphere may represent an important loss term for watershed N budgets.
Three major lithographic applications have emerged for electron beam exposure tools: optical mask fabrication, direct writing for device fabrication, and more recently projection e-beam printing. The traditional mask making process uses poly(butenesulfone) resist. A wet etch process was adopted to generate patterns on chrome. Recently, shrinking dimensions, optical proximity correction features, and the complexity of phase shift masks have forced the industry to a chrome dry etch process. ZEP, a poly(methyl α-chloroacrylate-co-α-methylstyrene) based resist, has been well accepted for most of the >180 nm device mask making. The acceptance of ZEP comes in spite of its low contrast, marginal etch resistance, organic solvent development, and concerns of resist heating associated with its high dose requirements. These issues have spawned interest in using chemically amplified resist (CAR) systems for direct write and mask making applications. We have developed a high contrast resist based on ketal protecting groups, KRS-XE, which is robust against airborne contamination and can be used for all forms of e-beam exposure in both chrome mask and silicon processing. This high contrast resist is processed with aqueous base developer and has a wide bake latitude. The development of KRS-XE has provided the capability of fabricating chrome masks for future generation (< 180 nm) devices and has potential for use with projection beam exposure systems.
Richard A. Lang, Divisions of Developmental Biology and Ophthalmology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati,
John W. McAvoy, Save Sight Institute and Department of Anatomy and Histology, University of Sydney, Sydney Eye Hospital, Macquarie Street, GPO Box 4337, Sydney 2001, Australia
How the lens develops and acquires its distinctive morphology and growth patterns has been a major research focus for developmental biologists. Growth factors are known to play key roles in influencing cell behavior and cell fates during development. In recent years researchers have identified some of the growth factor families involved in regulating the processes of lens induction, morphogenesis, and growth. The aim of this chapter is to review the current state of knowledge in this key area of lens research.
The lens develops from head ectoderm that is associated with an evagination of the developing brain: the optic vesicle (Fig. 11.1). Soon after these two tissues become associated, the presumptive lens ectoderm grows and thickens to form the lens placode. Subsequent invagination of the placode forms the lens pit, which later closes to form the lens vesicle. Cells in the posterior segment of the lens vesicle, next to the optic cup, elongate to form the primary fibers, whereas cells in the anterior segment of the vesicle differentiate into epithelial cells. These divergent fates of embryonic lens cells give the lens its distinctive polarity. From this stage onwards, the lens grows by continued proliferation of epithelial cells and differentiation of fiber cells. Proliferation initially occurs throughout the lens epithelial compartment but during development becomes progressively restricted to a band of cells above the equator, known as the germinative zone. Progeny of divisions that shift below the equator enter the transitional zone and elongate to give rise to secondary fibers.
The cellular mechanisms that underlie the initiation and propagation of the peristaltic contractions, which transport urine from the kidney to the bladder for storage, remain little understood. Extracellular and intracellular microelectrode recordings have identified two populations of smooth muscle cells as well as a population of renal interstitial cells (RICs) that all display spontaneous electrical activity. By analogy with the heart it has been proposed that atypical smooth muscle cells, preferentially located in the very proximal regions of the renal pelvis, generate the essential pacemaker signal. These pacemaker potentials propagate to neighbouring typical smooth muscle cells or RICs to trigger action potential discharge. These action potentials then propagate distally to trigger other bundles of typical smooth muscle cells. The frequency of action potential discharge and contraction decreases as the relative number of RICs and atypical smooth muscle cells compared to typical smooth muscle cells decreases with distance from the renal fornix. It is clear that functional capsaicin-sensitive sensory afferents and the endogenous release of both tachykinins and prostaglandins are essential in the maintenance of normal peristalsis, as well as in monitoring and responding to any chemical or mechanical stimulation. However, the cellular mechanisms underlying the action of these endogenously-released agents remain to be elucidated. Experimental Physiology (2002) 87.2, 129-146.
This article deals with the modification of self-statements as a specific strategy in cognitive therapy. A method is described in which patients modify their self-talk by reading aloud positive self-statements that are incompatible with original self-deprecatory thoughts. Next, several cases are presented that illustrate how this intervention can effectively be integrated in the treatment of various disorders. In the discussion, the indications for using this intervention are considered and compared to other cognitive strategies.
A case of prostatic adenocarcinoma presenting with dysphagia due to a tonsillar metastasis is described. Details of the clinical history, histopathological and autopsy findings are presented. A review of the literature suggests that this is only the second description of such an occurrence.
The present paper considers methods for computing moments connected with subcritical multitype branching processes. By stressing the interplay between moment and cumulant structure, it is possible to prove simultaneously the existence of the moments. The kinds of moments considered are those arising in (1) times to extinction, (2) ultimate numbers of particles starting from a single particle, and (3) equilibrium numbers of particles for subcritical processes experiencing immigration.
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