A comprehensive resource for induced pluripotent stem cells from patients with primary tauopathies

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies

A comparison of the pyrolysis of olive kernel biomass in fluidised and fixed bed conditions

The use of thermogravimetric analysis to describe biomass kinetics often uses bench top thermogravimetric analyser (TGA) analysers which are only capable of low heating rates. The aim of this research was to compare experimental fast pyrolysis of Olive kernels in a bespoke laboratory thermogravimetric fluidised bed reactor (TGFBR) characterised by rapid heating rates at high flow rates, compared to a smaller bench scale fixed bed TGA system. The pyrolysis in the TGFBR was analysed by using the isothermal kinetic approach and it was theorised that the pyrolysis decomposition reactions occurred by two mechanisms depending on the temperature, resulting in an activation energy of 67.4 kJ/mol at temperatures below 500 °C. For comparison, a bench scale TGA was used to look at the thermal behaviour in different fixed bed thermal conditions giving a higher activation energy of 74.4 kJ/mol due to the effect of external particle gas diffusion. The effect of biomass particle size (0.3–4.0 mm) on the conversion of biomass at different temperatures, was investigated between 300 and 660 °C in the TGFBR. The results suggested inhibition of internal gas diffusion was more important at lower temperatures, but in comparison had no significant effect when measured in the fixed bed TGA at lower heating rates. Bench top TGA analysis of pyrolysis is a rapid and valuable method, but is limited by smaller sample sizes and lower heating rates. In comparison, the conditions encountered with the laboratory scale TGFBR are more likely to be relevant to larger scale systems where heat distribution, heat transfer and mass diffusion effects play major roles in the reactivity of biomass

Domesticating the mountains: The palaeoecology of changing resource management during the Mid- to early Late Holocene in southeast Anatolia and Kurdish Iraq

This thesis sets out to answer three questions using the primary datasets of sedimentary and phytolith evidence. The questions relate to how local environmental change can be seen in these datasets, how resource and land use can be discerned in the sedimentary and phytolith records and finally, how these datasets can be used to elucidate on human modification of the environment and subsequent ecological and cultural inheritances using the framework of cultural niche construction. In addition, a new protocol for establishing land surfaces in offsite samples and differentiating been regional and local phytolith signals is also introduced. On and offsite samples were taken from two sites, Hirbemerdon Tepe in southeastern Anatolia and Bakr Awa in Iraqi Kurdistan. The thesis concludes that the combination of the two methods provides an effective way to understand local environmental change, resource and land use. It also shows that, despite drawbacks of using offsite data, which may be fragmentary at times, sedimentary and phytolith evidence can be used to understand and describe human modification of the environment and should be considered when addressing questions about the human environment- relationship, using the cultural niche construction approach. Finally, although the land surface protocol needs much refinement, it shows much promise as a tool for understanding environmental and vegetation change as well as resource and land use

KCNQ/M currents in sensory neurons: Significance for pain therapy

Neuronal hyperexcitability is a feature of epilepsy and both inflammatory and neuropathic pain. M currents [I-K(M)] play a key role in regulating neuronal excitability, and mutations in neuronal KCNQ2/3 subunits, the molecular correlates of I-K(M), have previously been linked to benign familial neonatal epilepsy. Here, we demonstrate that KCNQ/M channels are also present in nociceptive sensory systems. I-K(M) was identified, on the basis of biophysical and pharmacological properties, in cultured neurons isolated from dorsal root ganglia (DRGs) from 17-d-old rats. Currents were inhibited by the M-channel blockers linopirdine (IC50, 2.1 muM) and XE991 (IC50, 0.26 muM) and enhanced by retigabine (10 muM). The expression of neuronal KCNQ subunits in DRG neurons was confirmed using reverse transcription-PCR and single-cell PCR analysis and by immunofluorescence. Retigabine, applied to the dorsal spinal cord, inhibited C and Adelta fiber-mediated responses of dorsal horn neurons evoked by natural or electrical afferent stimulation and the progressive "windup" discharge with repetitive stimulation in normal rats and in rats subjected to spinal nerve ligation. Retigabine also inhibited responses to intrapaw application of carrageenan in a rat model of chronic pain; this was reversed by XE991. It is suggested that I-K(M) plays a key role in controlling the excitability of nociceptors and may represent a novel analgesic target

CFD analysis of the fluidised bed hydrodynamic behaviour inside an isothermal gasifier with different perforated plate distributors

The hydrodynamic behaviour of gas-solid mixtures inside Bed Fluidised Beds (BFB) gasifiers has a major impact on the gasification process due to particles - gas and particle - particle contact mechanisms. The Discrete Phase Model DPM with Multiphase Particle-in-Cell method MPPIC was used as a CFD approach to study the hydrodynamic behaviour of an 800 height x 83 mm φ prototype fluidised bed gasifier with 4 different perforated plate distributors. In terms of bubble forming, pressure drop and superficial velocity, the type D distributor, i.e. triangular, had the best performance among the other types and in turn better bed height and bed movement, thus allowing best fluidisation performance as a consequence of better flow distribution

Mid- to late-Holocene archaeology, environment and climate in the northeast Kurdistan region of Iraq

This work presents new data from phytolith and speleothem analyses that cover the middle to late Holocene from northeastern Iraq in the Kurdistan region. Coupling these data with previous work, we demonstrate how the region’s environment and climate developed during a time when agriculture became not only established but settlements started to transform into larger urban areas. Results demonstrate a wetter phase during the middle Holocene relative to the present period; a highly seasonal climate with one rainy season is also suggested between 8025 ± 38 and 6977 ± 219 BP. Phytoliths not only suggest a relatively wet environment but they also indicate a diversity of plants used for settlement activity. Sedimentary results complement the indication of a relatively wetter middle Holocene. Archaeologically, terraced construction found in Gurga Chiya and the presence of drought tolerant crops suggest adaptation to stronger, seasonal rains and seasonal droughts in the middle Holocene. Sedimentary, phytolith, and speleothem results suggest relatively drier late-Holocene conditions, although the region continued to be conducive for rainfed agriculture

Multivariate GWAS of Alzheimer\u27s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

BACKGROUND: Genome-wide association studies (GWAS) of Alzheimer\u27s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. METHODS: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. RESULTS: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. CONCLUSIONS: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine

Rotational Broadening and Doppler Tomography of the Quiescent X-Ray Nova Centaurus X-4

We present high and intermediate resolution spectroscopy of the X-ray nova Centaurus X-4 during its quiescent phase. Our analysis of the absorption features supports a K3-K5V spectral classification for the companion star, which contributes approximately 75 % of the total flux at Halpha. Using the high resolution spectra we have measured the secondary star's rotational broadening to be V_rot*sin(i) = 43 +/- 6 km/s and determined a binary mass ratio of q=0.17 +/- 0.06. Combining our results for K_2 and q with the published limits for the binary inclination, we constrain the mass of the compact object and the secondary star to the ranges 0.49 < M_1 < 2.49 Msun and 0.04 < M_2 < 0.58 Msun. A Doppler image of the Halpha line shows emission coming from the secondary star, but no hotspot is present. We discuss the possible origins of this emission.Comment: 10 pages, 4 figures, accepted by MNRA

Structural, functional, and metabolic alterations in human cerebrovascular endothelial cells during toxoplasma gondii infection and amelioration by verapamil in vitro

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Toxoplasma gondii (T. gondii), the causative agent of toxoplasmosis, is a frequent cause of brain infection. Despite its known ability to invade the brain, there is still a dire need to better understand the mechanisms by which this parasite interacts with and crosses the blood–brain barrier (BBB). The present study revealed structural and functional changes associated with infection and replication of T. gondii within human brain microvascular endothelial cells (BMECs) in vitro. T. gondii proliferated within the BMECs and disrupted the integrity of the cerebrovascular barrier through diminishing the cellular viability, disruption of the intercellular junctions and increasing permeability of the BMEC monolayer, as well as altering lipid homeostasis. Proton nuclear magnetic resonance (1H NMR)-based metabolomics combined with multivariate data analysis revealed profiles that can be attributed to infection and variations in the amounts of certain metabolites (e.g., amino acids, fatty acids) in the extracts of infected compared to control cells. Notably, treatment with the Ca2+ channel blocker verapamil rescued BMEC barrier integrity and restricted intracellular replication of the tachyzoites regardless of the time of treatment application (i.e., prior to infection, early-and late-infection). This study provides new insights into the structural and functional changes that accompany T. gondii infection of the BMECs, and sheds light upon the ability of verapamil to inhibit the parasite proliferation and to ameliorate the adverse effects caused by T. gondii infection

Barriers and enablers for scaled-up adoption of compressed earth blocks in Egypt

This dataset is a summary of the anonymized responses from the survey participants and interviewees for the paper titled: "Barriers and enablers for scaled-up adoption of compressed earth blocks in Egypt" https://doi.org/10.1080/09613218.2023.223713