Aims/hypothesis Raised maternal plasma total homocysteine (tHcy) concentrations predict small size at birth, which is a risk factor for type 2 diabetes mellitus. We studied the association between ...maternal vitamin B₁₂, folate and tHcy status during pregnancy, and offspring adiposity and insulin resistance at 6 years. Methods In the Pune Maternal Nutrition Study we studied 700 consecutive eligible pregnant women in six villages. We measured maternal nutritional intake and circulating concentrations of folate, vitamin B₁₂, tHcy and methylmalonic acid (MMA) at 18 and 28 weeks of gestation. These were correlated with offspring anthropometry, body composition (dual-energy X-ray absorptiometry scan) and insulin resistance (homeostatic model assessment of insulin resistance HOMA-R) at 6 years. Results Two-thirds of mothers had low vitamin B₁₂ (<150 pmol/l), 90% had high MMA (>0.26 μmol/l) and 30% had raised tHcy concentrations (>10 μmol/l); only one had a low erythrocyte folate concentration. Although short and thin (BMI), the 6-year-old children were relatively adipose compared with the UK standards (skinfold thicknesses). Higher maternal erythrocyte folate concentrations at 28 weeks predicted higher offspring adiposity and higher HOMA-R (both p < 0.01). Low maternal vitamin B₁₂ (18 weeks; p = 0.03) predicted higher HOMA-R in the children. The offspring of mothers with a combination of high folate and low vitamin B₁₂ concentrations were the most insulin resistant. Conclusions/interpretation Low maternal vitamin B₁₂ and high folate status may contribute to the epidemic of adiposity and type 2 diabetes in India.
The CRISPR-Cas9 system is a powerful tool for genome editing, which allows the precise modification of specific DNA sequences. Many efforts are underway to use the CRISPR-Cas9 system to ...therapeutically correct human genetic diseases
. The most widely used orthologs of Cas9 are derived from Staphylococcus aureus and Streptococcus pyogenes
. Given that these two bacterial species infect the human population at high frequencies
, we hypothesized that humans may harbor preexisting adaptive immune responses to the Cas9 orthologs derived from these bacterial species, SaCas9 (S. aureus) and SpCas9 (S. pyogenes). By probing human serum for the presence of anti-Cas9 antibodies using an enzyme-linked immunosorbent assay, we detected antibodies against both SaCas9 and SpCas9 in 78% and 58% of donors, respectively. We also found anti-SaCas9 T cells in 78% and anti-SpCas9 T cells in 67% of donors, which demonstrates a high prevalence of antigen-specific T cells against both orthologs. We confirmed that these T cells were Cas9-specific by demonstrating a Cas9-specific cytokine response following isolation, expansion, and antigen restimulation. Together, these data demonstrate that there are preexisting humoral and cell-mediated adaptive immune responses to Cas9 in humans, a finding that should be taken into account as the CRISPR-Cas9 system moves toward clinical trials.
In multiple myeloma malignant plasma cells expand within the bone marrow. Since this site is well-perfused, a rapid dissemination of "fitter" clones may be anticipated. However, an imbalanced ...distribution of multiple myeloma is frequently observed in medical imaging. Here, we perform multi-region sequencing, including iliac crest and radiology-guided focal lesion specimens from 51 patients to gain insight into the spatial clonal architecture. We demonstrate spatial genomic heterogeneity in more than 75% of patients, including inactivation of CDKN2C and TP53, and mutations affecting mitogen-activated protein kinase genes. We show that the extent of spatial heterogeneity is positively associated with the size of biopsied focal lesions consistent with regional outgrowth of advanced clones. The results support a model for multiple myeloma progression with clonal sweeps in the early phase and regional evolution in advanced disease. We suggest that multi-region investigations are critical to understanding intra-patient heterogeneity and the evolutionary processes in multiple myeloma.In multiple myeloma, malignant cells expand within bone marrow. Here, the authors use multi-region sequencing in patient samples to analyse spatial clonal architecture and heterogeneity, providing novel insight into multiple myeloma progression and evolution.
The ability of cells to orient in response to mechanical stimuli is essential to embryonic development, cell migration, mechanotransduction, and other critical physiologic functions in a range of ...organs. Endothelial cells, fibroblasts, mesenchymal stem cells, and osteoblasts all orient perpendicular to an applied cyclic stretch when plated on stretchable elastic substrates, suggesting a common underlying mechanism. However, many of these same cells orient parallel to stretch in vivo and in 3D culture, and a compelling explanation for the different orientation responses in 2D and 3D has remained elusive. Here, we conducted a series of experiments designed specifically to test the hypothesis that differences in strains transverse to the primary loading direction give rise to the different alignment patterns observed in 2D and 3D cyclic stretch experiments (“strain avoidance”). We found that, in static or low-frequency stretch conditions, cell alignment in fibroblast-populated collagen gels correlated with the presence or absence of a restraining boundary condition rather than with compaction strains. Cyclic stretch could induce perpendicular alignment in 3D culture but only at frequencies an order of magnitude greater than reported to induce perpendicular alignment in 2D. We modified a published model of stress fiber dynamics and were able to reproduce our experimental findings across all conditions tested as well as published data from 2D cyclic stretch experiments. These experimental and model results suggest an explanation for the apparently contradictory alignment responses of cells subjected to cyclic stretch on 2D membranes and in 3D gels.
Aims The ability to suppress soil nitrification through the release of nitrification inhibitors from plant roots is termed 'biological nitrification inhibition' (BNI). Here, we aimed at the ...quantification and characterization of the BNI function in sorghum that included inhibitor production, their chemical identity, functionality and factors regulating their release. Methods Sorghum was grown in solution culture and root exúdate was collected using aerated NH₄Cl solutions. A bioluminescence assay using recombinant Nitrosomonas europaea was employed to determine the BNI activity. Activity-guided Chromatographie fractionation was used to isolate biological nitrification inhibitors (BNIs). The chemical structure was analyzed using NMR and mass spectrometry; pH-stat systems were deployed to analyze the role of rhizosphere pH on BNIs release. Results Sorghum roots released two categories of BNIs: hydrophilic- and hydrophobic-BNIs. The release rates for hydrophilic- and hydrophobic- BNIs ranged from 10 to 25 ATUg⁻¹ root dwt. d⁻¹. Addition of hydrophilic BNIs (10 ATUg⁻¹ soil) significantly inhibited soil nitrification (40 % inhibition) during a 30-d incubation test. Two BNI compounds isolated were: sakuranetin (ED₈₀ 0.6 µM; isolated from hydrophilic-BNIs fraction) and sorgoleone (ED₈₀ 13.0 µM; isolated from hydrophobic-BNIs fraction), which inhibited Nitrosomonas by blocking AMO and HAO enzymatic pathways. The BNIs release required the presence of NH₄⁺ in the root environment and the stimulatory effect of NH₄⁺ lasted 24 h. Unlike the hydrophobic-BNIs, the release of hydrophilic-BNIs declined at a rhizosphere pH >5.0; nearly 80 % of hydrophilic-BNI release was suppressed at pH ≥7.0. The released hydrophilic-BNIs were functionally stable within a pH range of 5.0 to 9.0. Sakuranetin showed a stronger inhibitory activity (ED₅₀ 0.2 µM) than methyl 3-(4-hydroxyphenyl) propionate (MHPP) (ED₅₀ 100 µM) (isolated from hydrophilic-BNIs fraction) in the in vitro culture-bioassay, but the activity was non-functional and ineffective in the soil-assay. Conclusions There is an urgent need to identify sorghum genetic stocks with high potential to release functional-BNIs for suppressing nitrification and to improve nitrogen use efficiency in sorghum-based production systems.
TUNNEL MODELING USING MOBILE MAPPING LIDAR POINTS
The international archives of the photogrammetry, remote sensing and spatial information sciences/International archives of the photogrammetry, remote sensing and spatial information sciences,
2021
Conference Proceeding
Abstract We present a revised strategy for Indian DEMO in the context of new technologies and concepts in fusion research. The central idea behind the new strategy is that the power plant is a ...reactor-park consisting of multiple, preferably compact, reactors with moderate fusion power (∼1000 MW) with 35%–50% availability for each. The DEMO is a single net electricity producing unit that becomes the basis for replication into multiple units on a commercial scale. One of the key enablers for the revised strategy is the emergence of high-temperature superconductors for high field magnets. For a steady-state burn we show that there exists an optimum regime of plasma β and confinement where the fusion gain is maximum. Thus, we adopt a strategy with moderate confinement regimes and plasma β . This makes current drive a necessity for the reactors. Based on these considerations a four-stage approach to DEMO is proposed. It is argued that an electricity producing pilot plant (PP) with fusion power of 200 MW–300 MW is needed before the DEMO to establish the power performance, tritium breeding and its re-use over sufficiently long pulses. An integrated test facility must precede the pilot to test and qualify the technologies for the pilot stage. The revised approach takes into account realistic assumptions on power balance, current drive efficiency and magnet lifetime-dose; factors that pose constraints in identifying potential reactor configurations. Parameter choices for possible options for the integrated test facility (Fusion Engineering Science and Test), PP and DEMO are presented that can be used to initiate conceptual designs and directed R&D.
Soils around the planet creep, despite wide variations in particle properties and environments. This sub‐yield “flow” of soil interacts with a variety of boundaries, in terms of geometry and ...friction. Here we explore the veracity of recent observations of undisturbed, gravity‐driven creep, by testing a suite of materials and boundary configurations in an experimental hillslope. Using an optical interferometry technique, we demonstrate that creep is a generic relaxation process whose qualitative dynamics are insensitive to grain properties. Velocity profiles are exponential, albeit with a defect near the no‐slip boundary. Quantitative patterns such as spatial variability and magnitude of strain rates, however, are exquisitely sensitive to the details of the experiment. The emerging picture is that creep is accomplished by localized plastic failure, which induces an elastic redistribution. Similar patterns have been observed in model glasses and on earthquake faults, indicating that sub‐yield relaxation in disordered materials may share common physics.
Plain Language Summary
A while ago, we poured some glass beads into a box. Even days after we were done pouring, the grains still moved—but really slowly. This is creep. Our observations of “undisturbed” creep have aroused surprise and also suspicion from fellow geoscientists—in particular because experiments were conducted using glass beads, while natural soil particles are more angular and sometimes sticky. To help convince everyone that creep is robust, we dumped a bunch of different materials into an acrylic box over and over again. Sand, espresso grounds, yeast, clay—you name it, we dumped it. It all creeps, and it doesn't really matter whether the boundaries are smooth or rough.
Key Points
Soil slowly creeps downhill due to gravity alone
Creep dynamics are robust across a range of granular materials and boundary roughness
Granular creep is similar to creep in glass and also localized slip along faults
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