It is possible to estimate the prior probability of pathogenicity for germline disease gene variants based on bioinformatic prediction of variant effect/s. However, routinely used approaches have likely led to the underestimation and underreporting of variants located outside donor and acceptor splice site motifs that affect mRNA processing. This review presents information about hereditary cancer gene germline variants, outside native splice sites, with experimentally validated splicing effects. We list 81 exonic variants that impact splicing regulatory elements in BRCA1, BRCA2, MLH1, MSH2, MSH6 and PMS2. We utilized a pre-existing large-scale BRCA1 functional dataset to map functional splicing regulatory elements, assess the relative performance of different tools to predict effects of 283 variants on such elements, and develop a generic workflow to prioritize variants that may impact splicing regulatory elements. We also describe rare examples of intronic variants that impact branchpoint sites and create pseudoexons. We discuss the challenges in predicting variant effect on branchpoint site usage and pseudoexonization, and suggest strategies to improve the bioinformatic prioritization of such variants for experimental validation. Importantly, our review highlights the importance of considering impact of variants outside donor and acceptor motifs on mRNA splicing and disease causation.

Population dynamics models combine density-dependence and environmental effects. Ignoring sampling uncertainty might lead to biased estimation of the strength of density-dependence. This is typically addressed using state-space model approaches, which integrate sampling error and population process estimates. Such models seldom include an explicit link between the sampling procedures and the true abundance, which is common in capture-recapture settings. However, many of the models proposed to estimate abundance in the presence of heterogeneity lead to incomplete likelihood functions and cannot be straightforwardly included in state-space models. We assessed the importance of estimating sampling error explicitly by taking an intermediate approach between ignoring uncertainty in abundance estimates and fully specified state-space models for density-dependence estimation based on autoregressive processes. First, we estimated individual capture probabilities based on a heterogeneity model, using a conditional multinomial likelihood, followed by a Horvitz-Thompson estimate for abundance. Second, we estimated coefficients of autoregressive models for the log abundance. Inference was performed using the methodology of integrated nested Laplace approximation (INLA). We performed an extensive simulation study to compare our approach with estimates disregarding capture history information, and using R-package VGAM, for different parameter specifications. The methods were then applied to a real dataset of gray-sided voles Myodes rufocanus from Northern Norway. We found that density-dependence estimation was improved when explicitly modelling sampling error in scenarios with low innovation variances, in which differences in coverage reached up to 8% in estimating the coefficients of the autoregressive processes. In this case, the bias also increased assuming a Poisson distribution in the observational model. For high innovation variances, the differences between methods were small and it appeared less important to model heterogeneity.

1. The reduction of plant diversity following eutrophication threatens many ecosystems worldwide. Yet, the mechanisms by which species are lost following nutrient enrichment are still not completely understood, nor are the details of when such mechanisms act during the growing season, which hampers understanding and the development of mitigation strategies. 2. Using a common garden competition experiment, we found that early-season differences in growth rates among five perennial grass species measured in monoculture predicted short-term competitive dominance in pairwise combinations and that this effect was stronger under a fertilisation treatment. 3. We also examined the role of early-season growth rate in determining the outcome of competition along an experimental nutrient gradient in an alpine meadow. Early differences in growth rate between species predicted short-term competitive dominance under both ambient and fertilized conditions and competitive exclusion under fertilized conditions. 4. The results of these two studies suggests that plant species growing faster during the early stage of the growing season gain a competitive advantage over species that initially grow more slowly, and that this advantage is magnified under fertilisation. This finding is consistent with the theory of asymmetric competition for light in which fast-growing species can intercept incident light and hence outcompete and exclude slower-growing (and hence shorter) species. We predict that the current chronic nutrient inputs into many terrestrial ecosystems worldwide will reduce plant diversity and maintain low biodiversity state by continuously favouring fast-growing species. Biodiversity management strategies should focus on controlling nutrient inputs and reducing the growth of fast-growing species early in the season.

Continuity in research group collective knowledge is critical for running a successful research program but in an undergraduate research lab, this can be particularly challenging. A wiki site dedicated to the research laboratory, a lab wiki, can bridge gaps in student-to-student knowledge transfer and contribute to longevity of a research program. A lab wiki is an organized, easily accessible, collaborative resource that can contain tutorials, group-specific directions, links to resources and guides to writing papers or proposals. The wiki language is easy for students to pick up and contributes to their participation in preserving group knowledge. This tutorial introduces the concept of a lab wiki, the advantages of it, example content and practical implementation advice.

As issues surrounding depleting fossil fuels, climate change, and various other environmental impacts are becoming more prevalent, there is a growing interest in technological shifts toward a bio-based economy. Various advanced biotechnological tools have been developed to customize cell factories for the production of a wide range of complex fine chemicals from renewable feedstock. Herein, we report development of a microbial bioprocess for high-level and potentially economical production of 5-aminolevulinic acid (5-ALA), a valuable non-proteinogenic amino acid with multiple applications in medical, agricultural, and food industries, using Escherichia coli as a cell factory. We first implemented the Shemin (i.e., C4) pathway for heterologous 5-ALA biosynthesis in E. coli. To reduce, but not to abolish, the carbon flux toward essential tetrapyrrole/porphyrin biosynthesis, we applied Clustered Regularly Interspersed Short Palindromic Repeats interference (CRISPRi) to repress hemB expression, leading to extracellular 5-ALA accumulation. We then applied metabolic engineering strategies to direct more dissimilated carbon flux toward the key precursor of succinyl-CoA for enhanced 5-ALA biosynthesis. Using these engineered E. coli strains for bioreactor cultivation, we successfully demonstrated high-level 5-ALA biosynthesis solely from glycerol (~30 g l-1) under both microaerobic and aerobic conditions, achieving up to 5.95 g l-1 (36.9% yield) and 6.93 g l-1 (50.9% yield) 5-ALA, respectively. This study represents one of the most effective bio-based production of 5-ALA from a structurally unrelated carbon to date, highlighting the importance of integrated strain engineering and bioprocessing strategies to enhance bio-based production.

Letter to the Editor, BJOG Exchange

Objective: To determine whether planned cesarean section (CS) for a second delivery protects anal continence in women with obstetrical anal sphincter lesions. Design: Randomized trial. Setting: 6 maternity units in the Paris area. Sample : Women at high risk of sphincter lesions (first delivery with 3d degree laceration and/or forceps) but no symptomatic anal incontinence. Methods : Endoanal ultrasound was performed in the third trimester of the second pregnancy. Women with sphincter lesions were randomized to planned CS or vaginal delivery (VD). Main outcome measures : Anal continence at 6 months post-partum. Secondary outcomes were urinary continence, sexual morbidity, maternal and neonatal morbidities and worsening of external sphincter lesions. Results : Anal sphincter lesions were detected by ultrasound in 264/434 women enrolled (60.8%) ; 112 were randomized to planned VD and 110 to planned CS. At 6-8 weeks after delivery, there was no significant difference in anal continence between the 2 groups. At 6 months after delivery, median Vaizey scores of anal continence were 1 [IQR 0-4] in the CS group and 1 [IQR 0-3] in the VD group (p = 0.34). There were no significant differences for urinary continence, sexual functions or for other maternal and neonatal morbidities. Conclusions : In women with asymptomatic obstetrical anal sphincter lesions diagnosed by ultrasound, planning a CS had no significant impact on anal continence 6 months after the second delivery. These results do not support advising systematic CS for this indication.

Most new cryptic species are described using conventional tree- and distance-based species delimitation methods (SDMs), which rely on phylogenetic arrangements and measures of genetic divergence. However, although numerous factors such as spatial population structure and gene flow are known to confound phylogenetic and species delimitation inferences, the influence of these processes on species estimation is rarely evaluated. Using large amounts of exons, introns, and ultraconserved elements obtained using the FrogCap sequence-capture protocol, we compared conventional SDMs with more robust genomic analyses that assesses spatial population structure and gene flow to characterize species boundaries in a Southeast Asian frog complex (Pulchrana picturata). Our results showed that gene flow and introgression can produce phylogenetic patterns and levels of divergence that resemble distinct species (up to 10% divergent in mitochondrial DNA). Hybrid populations were inferred as independent (singleton) clades that were highly divergent from adjacent populations (7–10%) and unusually similar (<3%) to allopatric populations. Such anomalous patterns are not uncommon in Southeast Asian amphibians, which brings into question whether the high cryptic diversity observed in other amphibian groups reflect distinct cryptic species—or, instead, highly structured and admixed metapopulation lineages. Our results also provide an alternative explanation to the conundrum of divergent (sometimes non-sister) sympatric lineages―a pattern that has been celebrated as indicative of true cryptic speciation. Based on these findings, we recommend that species delimitation of continuously distributed “cryptic” groups should not rely solely on conventional SDMs but should necessarily examine spatial population structure and gene flow to avoid taxonomic inflation.

Accurate prediction of protein secondary structure (alpha-helix, beta-strand and coil) is a crucial step for protein inter-residue contact prediction and ab initio tertiary structure prediction. In a previous study, we developed a deep belief network-based protein secondary structure method (DNSS1) and successfully advanced the prediction accuracy beyond 80%. In this work, we developed multiple advanced deep learning architectures (DNSS2) to further improve secondary structure prediction. The major improvements over the DNSS1 method include (i) designing and integrating six advanced one-dimensional deep convolutional/recurrent/residual/memory/fractal/inception networks to predict secondary structure, and (ii) using more sensitive profile features inferred from Hidden Markov model (HMM) and multiple sequence alignment (MSA). Most of the deep learning architectures are novel for protein secondary structure prediction. DNSS2 was systematically benchmarked on two independent test datasets with eight state-of-art tools and consistently ranked as one of the best methods. Particularly, DNSS2 was tested on the 82 protein targets of 2018 CASP13 experiment and achieved the best Q3 score of 83.74% and SOV score of 72.46%. DNSS2 is freely available at: https://github.com/multicom-toolbox/DNSS2.

Extreme droughts of increased frequency due to climate change poses great challenges to the sustainability of plantations in drylands worldwide. Millions of plantations on China’s Loess Plateau which are mainly in drylands are threatened by serious degradation due to water scarcity. Here we aim to disentangle the impacts of combinations of terracing and mulching on water use strategy and its response to extreme droughts in a rainfed jujube (Ziziphus jujuba) plantation on the semiarid Loess Plateau, using three-year in situ field observations. Pruned jujube branches and maize straw were mulched on half-moon terraces to form two combined treatments, referred to as JBT and MST, respectively. The efficacy of these two combinations on the water use strategy of jujube trees was compared with terracing alone (SHT) and control (no terrace). We found that extreme drought clearly reduced soil water storage (SWS) under all treatments. However, the combined treatments showed significantly (P<0.05) higher SWS than the SHT and control. Furthermore, the combined treatments enhanced soil water use in deep layers during both normal and drought years, thus helping jujube trees to resist droughts. Moreover, the extreme drought significantly reduced transpiration whereas the moderate drought increased transpiration at both seasonal and annual scales. Nonetheless, the combined treatments were associated with enhanced transpiration compared to the SHT and control during drought periods. Finally, jujube trees exhibited isohydric behavior which also helped them to cope with prolonged droughts. Overall, the findings here may provide insights into land management of dryland plantations worldwide under climate change.

This article focuses on studying mild solutions of an original frac- tional partial differential equation disturbed by multiplicative white noise. We employ techniques of semi group theory, Hausdorff measure, and Darbo xed point theorem.

In this paper, we consider an electromagnetic obstacle scattering problem in a piecewise homogeneous medium. We assume that the incident field is the electromagnetic plane wave and the obstacle consists of metallic and nonmetallic parts. We firstly establish uniqueness and existence for the solution to the electromagnetic obstacle scattering problem. Then we prove that the electric far field pattern satisfies the reciprocity relation and the set of electric far field patterns is complete in a Hilbert space. These results have an important bearing on the solution of the inverse electromagnetic scattering problem i.e. determination of the shape of the obstacle from the knowledge of the electric far field patterns.

The lower bound decay rate of global solution to the compressible viscous quantum magnetohydrodynamic model in three-dimensional whole space under the $H^5\times H^4\times H^4$ framework is investigated in this paper. We firstly show that the lower bound of decay rate for the density, velocity and magnetic field converging to the equilibrium state (1,0,0) in $L^2$-norm is $(1+t)^{-\frac{3}{4}}$ when the initial data satisfies some low frequency assumption. Moreover, we prove that the lower bound of decay rate of $k(k\in [1,3])$ order spatial derivative for the density, velocity and magnetic field converging to the equilibrium state (1,0,0) in $L^2$-norm is $(1+t)^{-\frac{3+2k}{4}}$. Then we show that the lower bound of decay rate for the time derivatives of density and velocity converging to zero in $L^2$-norm is $(1+t)^{-\frac{5}{4}}$, but the lower bound of decay rate for the time derivative of magnetic field converging to zero in $L^2$-norm is $(1+t)^{-\frac{7}{4}}$.

In this paper, using the Lyapunov-like functions, the practical stability with respect to part of the variables of fractional-order nonlinear systems depending on a small parameter is studied.

We investigate mixed type boundary-transmission problems of the generalized thermo-electro-magneto elasticity (GTEME) theory for complex elastic anisotropic layered structures containing interfacial cracks. This type of problems are described mathematically by systems of partial differential equations with appropriate transmission and boundary conditions for six dimensional unknown physical field (three components of the displacement vector, electric potential function, magnetic potential function, and temperature distribution function). We apply the potential method and the theory of pseudodifferential equations and prove uniqueness and existence theorems of solutions to different type mixed boundary-transmission problems in appropriate Sobolev spaces. We analyze smoothness properties of solutions near the edges of interfacial cracks and near the curves where different type boundary conditions collide.

The widespread construction of photovoltaic (PV) power stations within northwest China poses an environmental threat because of severe wind erosion and land degradation attributed to unique wind control issues caused by the power stations. In this study, various engineering (E), plant (V), and biocrust (B) treatments were evaluated for their effectiveness in the reduction of wind erosion. The placement of solar panels with wide wind inlets and narrow wind outlets caused wind velocity reductions at the inlet that sharply increased at the outlet and formed distinct zones of deflation, direct shear abrasion (DSA), and deposition. The engineering treatments reduced the wind velocities and sand transport rates, in comparison to the control with E4 (DSA zone + a gravel/deposition zone + red clay) being the most effective with an 87% reduction in the total sand transport rate. Both plant treatments V1 (Sedum aizoon L.) and V2 (Pennisetum alopecuroides (L.) Spreng) increased the aerodynamic roughness, and decreased the sand transport rates and the sand erosion-deposition budget under or between the solar panels. Treatment B2 (moss crust) decreased the sand transport rate and sand erosion-deposition budget under the solar panels in comparison to the control. All the treatments had effects on reducing wind erosion, and we strongly recommend the use of moss crust, gravel mulch, and red clay mulch in the deflation zones, DSA zones, and deposition zones, respectively, to control the severe wind erosion at these PV power stations located in sandy areas.

We use adaptive dynamics models to study how changes in the abiotic environment affect patterns of evolutionary dynamics and diversity in evolving communities of organisms with complex phenotypes. The models are based on the logistic competition model and environmental changes are implemented as a temporal change of the carrying capacity as a function of phenotype. In general we observe that environmental changes cause a reduction in the number of species, in total population size, and in phenotypic diversity. The rate of environmental change is crucial for determining whether a community survives or undergoes extinction. Until some critical rate of environmental changes, species are able to follow evolutionarily the shifting phenotypic optimum of the carrying capacity, and many communities adapt to the changing conditions and converge to new stationary states. When environmental changes stop, such communities gradually restore their initial phenotypic diversity.

Satellite-based solar-induced chlorophyll fluorescence (SIF) has the potential for an early detection and accurate impact assessment of meteorological drought on vegetation photosynthesis. However, how the response of satellite SIF to meteorological drought varies under different climatic conditions and biome types remains poorly understood. In this study, we determined the drought time-scale at which the vegetation photosynthesis response was highest based on the standardized precipitation evapotranspiration index (SPEI) and satellite SIF, and examined how the sensitivity of SIF signals from different ecosystems to drought varied along an aridity gradient in northern China. The results showed that spatial variability of the annual maximum SIF was constrained by wetness conditions and biome types. Annual maximum SIF was positively correlated with SPEI in 57.9% of vegetated lands (P < 0.05). 34.8% of humid ecosystems were characterized by a significant SIF-SPEI correlation (P < 0.05). This percentage reached 44%, 71.4% and 86.2% for arid, sub-humid and semi-arid ecosystems, respectively. The variation of SIF-SPEI correlations was a Gaussian function of the aridity index (AI), with the highest SIF-SPEI correlation appearing in the AI bin of 0.4 (0.37-0.46). The drivers for this pattern were vegetation composition and water availability. The variation of SIF time-scales in response to SPEI was a linear function of the AI, but the slope varied among biomes. To summarize with increasing aridity drought-induced declines in vegetation photosynthesis will be quicker and more significant.