The genome and gene editing system of sea barleygrass provide a novel platform for cereal domestication and stress tolerance studies

The tribe Triticeae provides important staple cereal crops and contains elite wild species with wide genetic diversity and high tolerance to abiotic stresses. Sea barleygrass (Hordeum marinum Huds.), a wild Triticeae species, thrives in saline marshlands and is well known for its high tolerance to salinity and waterlogging. Here, a 3.82-Gb high-quality reference genome of sea barleygrass is assembled de novo, with 3.69 Gb (96.8%) of its sequences anchored onto seven chromosomes. In total, 41 045 high-confidence (HC) genes are annotated by homology, de novo prediction, and transcriptome analysis. Phylogenetics, non-synonymous/synonymous mutation ratios (Ka/Ks), and transcriptomic and functional analyses provide genetic evidence for the divergence in morphology and salt tolerance among sea barleygrass, barley, and wheat. The large variation in post-domestication genes (e.g. IPA1 and MOC1) may cause interspecies differences in plant morphology. The extremely high salt tolerance of sea barleygrass is mainly attributed to low Na+ uptake and root-to-shoot translocation, which are mainly controlled by SOS1, HKT, and NHX transporters. Agrobacterium-mediated transformation and CRISPR/Cas9-mediated gene editing systems were developed for sea barleygrass to promote its utilization for exploration and functional studies of hub genes and for the genetic improvement of cereal crops

Novel Anatomic Endpoints For The Study Of Geographic Atrophy Secondary To Non-Exudative Age-Related Macular Degeneration

Geographic atrophy (GA) is the end stage of nonexudative age-related macular degeneration, affecting more than 5 million patients worldwide. The enlargement rate of GA area is the most common primary endpoint in clinical trials aiming to slow GA progression. However, this endpoint varies widely across patients with different GA morphology and is also poorly associated with patients’ visual acuity (VA). We aimed to develop an anatomic endpoint that is independent of GA morphology, and that correlates with VA in eyes with GA.We manually delineated GA on 1654 fundus photographs of 365 eyes from the Age-Related Eye Disease Study (median follow-up duration = 4 years). We calculated GA area growth rate for each eye based on the first and last visit. GA perimeter-adjusted growth rate (mm/year) was defined as the ratio between GA area growth rate (mm2/year) and mean GA perimeter (mm) between the first and last visit for each eye. We measured GA areas in 9 macular subfields and correlated them with VA via a mixed-effects model. We determined the optimal diameter for the central zone by varying the diameter from 0 to 10 mm until the highest r2 between GA area in the central zone and VA was achieved. We measured the residual area in the optimal central zone and calculated central residual effective radius as square root of (residual area/π). GA area growth rate was strongly correlated with mean GA perimeter (r2 = 0.66). GA area growth rate was associated with baseline GA area (r2 = 0.39, P \u3c 0.001), lesion number (r2 = 0.10, P \u3c 0.001), and circularity index (r2 = 0.28, P \u3c 0.001). In comparison, GA perimeter-adjusted growth rate (0.098 ± 0.062 mm/year) was uncorrelated with baseline GA area (r2 = 0.005, P = 0.20), lesion number (r2 = 0.00009, P = 0.86), and circularity index (r2 = 0.007, P = 0.14). Total GA area correlated poorly with VA (r2 = 0.07). Among GA areas in 9 subfields, only GA area in the central zone was independently associated with VA (P \u3c 0.001). GA area in the central 1-mm-diameter zone correlated best with VA (r2 = 0.45). On average, full GA coverage of the central zone corresponded to 34.8 letters decline in VA. The decline rate of central residual area was associated with baseline residual area (P = 0.008), but a transformation from central residual area to central residual effective radius eliminated this relationship (P = 0.51). After the introduction of horizontal translation factors to each dataset, central residual effective radius declined linearly over approximately 13 years (r2 = 0.80) at a mean rate of 0.038 mm/year. In conclusion, GA perimeter-adjusted growth rate is uncorrelated with GA morphology (i.e., lesion size, number, and circularity) and may serve as a sensitive and reliable anatomic endpoint in future clinical trials. GA area in the central 1-mm-diameter zone was significantly correlated with VA. The residual effective radius in this central zone declined consistently over time and may serve as another endpoint for future trials

An In Silica Model for RPE Loss Patterns in Choroideremia

PurposeTo use empirical data to develop a model of cell loss in choroideremia that predicts the known exponential rate of RPE loss and central, scalloped preservation pattern seen in this disease.MethodsA computational model of RPE loss was created in Python 3.7, which constructed an array of RPE cells clusters, binarized as either live or atrophic. Two rules were applied to this model: the background effect gave each cell a chance of dying defined by a background function, and the neighbor effect increased the chance of RPE cell death if a neighbor were dead. The known anatomic distribution of rods, RPE, choriocapillaris density, amacrine, ganglion, and cone cells were derived from the literature and applied to this model. Atrophy growth rates were measured over arbitrary time units and fit to the known exponential decay model. The main outcome measures: included topography of atrophy over time and fit of simulated residual RPE area to exponential decay.ResultsA background effect alone can simulate exponential decay, but does not simulate the central island preservation seen in choroideremia. An additive neighbor effect alone does not simulate exponential decay. When the neighbor effect multiplies the background effect using the rod density function, our model follows an exponential decay, similar to previous observations. Also, our model predicts a residual island of RPE that resembles the topographic distribution of residual RPE seen in choroideremia.ConclusionsThe pattern of RPE loss in choroideremia can be predicted by applying simple rules. The RPE preservation pattern typically seen in choroideremia may be related to the underlying pattern of rod density. Further studies are needed to validate these findings

Subretinal Drusenoid Deposit Formation: Insights From Turing Patterns

PurposeThe purpose of this study was to demonstrate that the organized formation of subretinal drusenoid deposits (SDDs) may be a Turing pattern.MethodsA Java-based computational model of an inferred reaction-diffusion system using paired partial differential equations was used to create topographic images. Reaction kinetics were varied to illustrate a spectrum of pattern development, which were then compared to dot-like, reticular, and confluent SDD patterns observed clinically.ResultsA reaction-diffusion system using two agents, one an "activator" that increases its own production, and the other an "inhibitor" that decreases the activator's production, can create patterns that match the spectrum of topographic appearance of organized SDD. By varying a single parameter, the strength of the activator, the full spectrum of clinically observed SDD patterns can be generated. A new pattern, confluence with holes, is predicted and identified in one case example.ConclusionsThe formation of clinically significant SDD and its different patterns can be explained using Turing patterns obtained by simulating a two-component reaction-diffusion system.Translational relevanceThis model may be able to guide future risk stratification for patients with SDD, and provide mechanistic insights into the cause of the disease

Identification of microRNAs Responding to Aluminium, Cadmium and Salt Stresses in Barley Roots

Plants are frequently exposed to various abiotic stresses, including aluminum, cadmium and salinity stress. Barley (Hordeum vulgare) displays wide genetic diversity in its tolerance to various abiotic stresses. In this study, small RNA and degradome libraries from the roots of a barley cultivar, Golden Promise, treated with aluminum, cadmium and salt or controls were constructed to understand the molecular mechanisms of microRNAs in regulating tolerance to these stresses. A total of 525 microRNAs including 198 known and 327 novel members were identified through high-throughput sequencing. Among these, 31 microRNAs in 17 families were responsive to these stresses, and Gene Ontology (GO) analysis revealed that their targeting genes were mostly highlighted as transcription factors. Furthermore, five (miR166a, miR166a-3p, miR167b-5p, miR172b-3p and miR390), four (MIR159a, miR160a, miR172b-5p and miR393) and three (miR156a, miR156d and miR171a-3p) microRNAs were specifically responsive to aluminum, cadmium and salt stress, respectively. Six miRNAs, i.e., miR156b, miR166a-5p, miR169a, miR171a-5p, miR394 and miR396e, were involved in the responses to the three stresses, with different expression patterns. A model of microRNAs responding to aluminum, cadmium and salt stresses was proposed, which may be helpful in comprehensively understanding the mechanisms of microRNAs in regulating stress tolerance in barley

A hierarchical Bayesian entry time realignment method to study the long-term natural history of diseases

A major question in clinical science is how to study the natural course of a chronic disease from inception to end, which is challenging because it is impractical to follow patients over decades. Here, we developed BETR (Bayesian entry time realignment), a hierarchical Bayesian method for investigating the long-term natural history of diseases using data from patients followed over short durations. A simulation study shows that BETR outperforms an existing method that ignores patient-level variation in progression rates. BETR, when combined with a common Bayesian model comparison tool, can identify the correct disease progression function nearly 100% of the time, with high accuracy in estimating the individual disease durations and progression rates. Application of BETR in patients with geographic atrophy, a disease with a known natural history model, shows that it can identify the correct disease progression model. Applying BETR in patients with Huntington's disease demonstrates that the progression of motor symptoms follows a second order function over approximately 20 years

A novel membrane for DMFC - Na.sub.2Ti.sub.3O.sub.7 Nanotubes/Nafion.sup.[R] composite membrane: Performances studies

Systematic experiments have been carried out to study the performance of the novel sodium titanate (Na.sub.2Ti.sub.3O.sub.7) nanotube/Nafion.sup.[R] composite membrane (5 wt% Na.sub.2Ti.sub.3O.sub.7) in a single direct methanol fuel cell (DMFC) at different operating temperatures, methanol concentrations, air flow rates, methanol flow rates, and cathode humidification temperatures. The experimental results showed that the composite membrane outperform pure Nafion.sup.[R] membranes with the same thickness, Nafion.sup.[R]112, under all the operating conditions. Furthermore, under some operating conditions, the new composite membranes even outperform Nafion.sup.[R]117, a much thicker membrane. These experimental results have proved that the new composite membrane is superior to pure Nafion.sup.[R] membrane in DMFCs and the addition of Na.sub.2Ti.sub.3O.sub.7 nanotubes into Nafion.sup.[R] is an effective way to improve membrane performances.Academi

Associations of systemic health and medication use with the enlargement rate of geographic atrophy in age-related macular degeneration.

BACKGROUND: The associations of geographic atrophy (GA) progression with systemic health status and medication use are unclear. METHODS: We manually delineated GA in 318 eyes in the Age-Related Eye Disease Study. We calculated GA perimeter-adjusted growth rate as the ratio between GA area growth rate and mean GA perimeter between the first and last visit for each eye (mean follow-up=5.3 years). Patients history of systemic health and medications was collected through questionnaires administered at study enrolment. We evaluated the associations between GA perimeter-adjusted growth rate and 27 systemic health factors using univariable and multivariable linear mixed-effects regression models. RESULTS: In the univariable model, GA perimeter-adjusted growth rate was associated with GA in the fellow eye at any visit (p=0.002), hypertension history (p=0.03), cholesterol-lowering medication use (p<0.001), beta-blocker use (p=0.02), diuretic use (p<0.001) and thyroid hormone use (p=0.03). Among the six factors, GA in the fellow eye at any visit (p=0.008), cholesterol-lowering medication use (p=0.002), and diuretic use (p<0.001) were independently associated with higher GA perimeter-adjusted growth rate in the multivariable model. GA perimeter-adjusted growth rate was 51.1% higher in patients with versus without cholesterol-lowering medication use history and was 37.8% higher in patients with versus without diuretic use history. CONCLUSIONS: GA growth rate may be associated with the fellow eye status, cholesterol-lowering medication use, and diuretic use. These possible associations do not infer causal relationships, and future prospective studies are required to investigate the relationships further