Variations in the FRA10AC1 Fragile Site and 15q21 Are Associated with Cerebrospinal Fluid Aβ1-42 Level

Proteolytic fragments of amyloid and post-translational modification of tau species in Cerebrospinal fluid (CSF) as well as cerebral amyloid deposition are important biomarkers for Alzheimer’s Disease. We conducted genome-wide association study to identify genetic factors influencing CSF biomarker level, cerebral amyloid deposition, and disease progression. The genome-wide association study was performed via a meta-analysis of two non-overlapping discovery sample sets to identify genetic variants other than APOE ε4 predictive of the CSF biomarker level (Aβ_1–42, t-Tau, p-Tau_181P, t-Tau:Aβ_1–42 ratio, and p-Tau_181P:Aβ_1–42 ratio) in patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Loci passing a genome-wide significance threshold of P < 5 x 10⁻⁸ were followed-up for replication in an independent sample set. We also performed joint meta-analysis of both discovery sample sets together with the replication sample set. In the discovery phase, we identified variants in FRA10AC1 associated with CSF Aβ_1–42 level passing the genome-wide significance threshold (directly genotyped SNV rs10509663 P _FE = 1.1 x 10⁻⁹, imputed SNV rs116953792 P _FE = 3.5 x 10⁻¹⁰), rs116953792 (P _one-sided = 0.04) achieved replication. This association became stronger in the joint meta-analysis (directly genotyped SNV rs10509663 P _FE = 1.7 x 10⁻⁹, imputed SNV rs116953792 P _FE = 7.6 x 10⁻¹¹). Additionally, we identified locus 15q21 (imputed SNV rs1503351 P _FE = 4.0 x 10⁻⁸) associated with CSF Aβ_1–42 level. No other variants passed the genome-wide significance threshold for other CSF biomarkers in either the discovery sample sets or joint analysis. Gene set enrichment analyses suggested that targeted genes mediated by miR-33, miR-146, and miR-193 were enriched in various GWAS analyses. This finding is particularly important because CSF biomarkers confer disease susceptibility and may be predictive of the likelihood of disease progression in Alzheimer’s Disease.     

Climatic and Catchment-Scale Predictors of Chinese Stream Insect Richness Differ between Taxonomic Groups

Little work has been done on large-scale patterns of stream insect richness in China. We explored the influence of climatic and catchment-scale factors on stream insect (Ephemeroptera, Plecoptera, Trichoptera; EPT) richness across mid-latitude China. We assessed the predictive ability of climatic, catchment land cover and physical structure variables on genus richness of EPT, both individually and combined, in 80 mid-latitude Chinese streams, spanning a 3899-m altitudinal gradient. We performed analyses using boosted regression trees and explored the nature of their influence on richness patterns. The relative importance of climate, land cover, and physical factors on stream insect richness varied considerably between the three orders, and while important for Ephemeroptera and Plecoptera, latitude did not improve model fit for any of the groups. EPT richness was linked with areas comprising high forest cover, elevation and slope, large catchments and low temperatures. Ephemeroptera favoured areas with high forest cover, medium-to-large catchment sizes, high temperature seasonality, and low potential evapotranspiration. Plecoptera richness was linked with low temperature seasonality and annual mean, and high slope, elevation and warm-season rainfall. Finally, Trichoptera favoured high elevation areas, with high forest cover, and low mean annual temperature, seasonality and aridity. Our findings highlight the variable role that catchment land cover, physical properties and climatic influences have on stream insect richness. This is one of the first studies of its kind in Chinese streams, thus we set the scene for more in-depth assessments of stream insect richness across broader spatial scales in China, but stress the importance of improving data availability and consistency through time.     

Indirect co-culture of lung carcinoma cells with hyperthermia-treated mesenchymal stem cells influences tumor spheroid growth in a collagen-based 3-dimensional microfluidic model

BackgroundMesenchymal stem cells (MSCs) have paradoxically been reported to exert either pro- or anti-tumor effects in vitro. Hyperthermia, in combination with chemotherapy, has tumor-inhibiting effects; however, its role, together with MSCs, so far is not well understood. Furthermore, a lot of research is conducted using conventional 2-dimensional in vitro models that do not mimic the actual tumor microenvironment.AimIn light of this fact, an indirect method of co-culturing human amniotic membrane-derived MSCs (AMMSCs) with collagen-encapsulated human lung carcinoma cells (A549) was performed using a 3-dimensional (3D) tumor-on-chip device.MethodsThe conditioned medium of AMMSCs (AMMSC-CM) or heat-treated AMMSCs (heat-AMMSC-CM) was utilized to create indirect co-culture conditions. Tumor spheroid growth characterization, immunocytochemistry and cytotoxicity assays, and anti-cancer peptide (P1) screening were performed to determine the effects of the conditioned medium.ResultsThe A549 cells cultured inside the 3D microfluidic chip developed into multicellular tumor spheroids over five days of culture. The AMMSC-CM, contrary to previous reports claiming its tumor-inhibiting potential, led to significant proliferation of tumor spheroids. Heat-AMMSC-CM led to reductions in both spheroid diameter and cell proliferation. The medium containing the P1 peptide was found to be the least cytotoxic to tumor spheroids in co-culture compared with the monoculture and heat-co-culture groups.ConclusionsHyperthermia, in combination with the anticancer peptide, exhibited highest cytotoxic effects. This study highlights the growing importance of 3D microfluidic tumor models for testing stem-cell-based and other anti-cancer therapies.     

Selection of plant growth-promoting Pseudomonas spp. that enhanced productivity of soybean-wheat cropping system in Central India

The aim of this investigation was to select effective Pseudomonas sp. strains that can enhance the productivity of soybean-wheat cropping systems in Vertisols of Central India. Out of 13 strains of Pseudomonas species tested in vitro, only five strains displayed plant growth-promoting (PGP) properties. All the strains significantly increased soil enzyme activities, except acid phosphatase, total system productivity, and nutrient uptake in field evaluation; soil nutrient status was not significantly influenced. Available data indicated that six strains were better than the others. Principal component analysis (PCA) coupled cluster analysis of yield and nutrient data separated these strains into five distinct clusters with only two effective strains, GRP3 and HHRE81 in cluster IV. In spite of single cluster formation by strains GRP3 and HHRE81, they were diverse owing to greater intracluster distance (4.42) between each other. These results suggest that the GRP3 and HHRE81 strains may be used to increase the productivity efficiency of soybean-wheat cropping systems in Vertisols of Central India. Moreover, the PCA coupled cluster analysis tool may help in the selection of other such strains.     

Kinetin Supplementation Modifies Chromium (VI) Induced Alterations in Growth and Ammonium Assimilation in Pea Seedlings

In the present study, impact of kinetin (KN; 10 and 100 μM) supplementation on growth, ammonium (NH(4)(+)) assimilation and antioxidant system in pea under hexavalent chromium toxicity (Cr VI; 50, 100 and 250 μM) was investigated. Chromium decreased growth, protein, and nitrogen, and activity of glutamine synthetase (GS) and glutamate synthase (GOGAT) while it increased NH(4)(+) content and activity of glutamate dehydrogenase (GDH). Kinetin at 100 μM decreased growth and NH(4)(+) assimilation, and together with Cr, it increased Cr toxicity. Chromium and 100 μM KN increased superoxide dismutase (SOD) and ascorbate peroxidase (APX) activities while decreasing activities of catalase (CAT), glutathione reductase (GR) and dehydroascorbate reductase (DHAR). Ascorbate and glutathione levels were decreased by Cr and 100 μM KN. In contrast, supplementation of 10 μM KN under Cr (VI) toxicity, protected NH(4)(+) assimilation and promoted growth of pea by increasing levels of some of the antioxidants i.e., CAT, GR, DHAR, ascorbate and glutathione. Results showed that 10 μM KN increases Cr tolerance while 100 μM KN exhibited opposite responses. These results could contribute to an understanding of the mechanisms of KN-mediated dual influence on metal tolerance in crop plants.     

A new PMHS model for lumbar spine injuries during vertical acceleration

Ejection from military aircraft exerts substantial loads on the lumbar spine. Fractures remain common, although the overall survivability of the event has considerably increased over recent decades. The present study was performed to develop and validate a biomechanically accurate experimental model for the high vertical acceleration loading to the lumbar spine that occurs during the catapult phase of aircraft ejection. The model consisted of a vertical drop tower with two horizontal platforms attached to a monorail using low friction linear bearings. A total of four human cadaveric spine specimens (T12-L5) were tested. Each lumbar column was attached to the lower platform through a load cell. Weights were added to the upper platform to match the thorax, head-neck, and upper extremity mass of a 50th percentile male. Both platforms were raised to the drop height and released in unison. Deceleration characteristics of the lower platform were modulated by foam at the bottom of the drop tower. The upper platform applied compressive inertial loads to the top of the specimen during deceleration. All specimens demonstrated complex bending during ejection simulations, with the pattern dependent upon the anterior-posterior location of load application. The model demonstrated adequate inter-specimen kinematic repeatability on a spinal level-by-level basis under different subfailure loading scenarios. One specimen was then exposed to additional tests of increasing acceleration to induce identifiable injury and validate the model as an injury-producing system. Multiple noncontiguous vertebral fractures were obtained at an acceleration of 21 g with 488 g/s rate of onset. This clinically relevant trauma consisted of burst fracture at L1 and wedge fracture at L4. Compression of the vertebral body approached 60% during the failure test, with -6,106 N axial force and 168 Nm flexion moment. Future applications of this model include developing a better understanding of the vertebral injury mechanism during pilot ejection and developing tolerance limits for injuries sustained under a variety of different vertical acceleration scenarios.