The wheat group has evolved through allopolyploidization, namely, through hybridization among species from the plant genera Aegilops and Triticum followed by genome doubling. This speciation process ...has been associated with ecogeographical expansion and with domestication. In the past few decades, we have searched for explanations for this impressive success. Our studies attempted to probe the bases for the wide genetic variation characterizing these species, which accounts for their great adaptability and colonizing ability. Central to our work was the investigation of how allopolyploidization alters genome structure and expression. We found in wheat that allopolyploidy accelerated genome evolution in two ways: (1) it triggered rapid genome alterations through the instantaneous generation of a variety of cardinal genetic and epigenetic changes (which we termed "revolutionary" changes), and (2) it facilitated sporadic genomic changes throughout the species' evolution (i.e., evolutionary changes), which are not attainable at the diploid level. Our major findings in natural and synthetic allopolyploid wheat indicate that these alterations have led to the cytological and genetic diploidization of the allopolyploids. These genetic and epigenetic changes reflect the dynamic structural and functional plasticity of the allopolyploid wheat genome. The significance of this plasticity for the successful establishment of wheat allopolyploids, in nature and under domestication, is discussed.
Homologous recombination (HR) between parental chromosomes occurs stochastically. Here, we report on targeted recombination between homologous chromosomes upon somatic induction of DNA double-strand ...breaks (DSBs) via CRISPR-Cas9. We demonstrate this via a visual and molecular assay whereby DSB induction between two alleles carrying different mutations in the PHYTOENE SYNTHASE (PSY1) gene results in yellow fruits with wild type red sectors forming via HR-mediated DSB repair. We also show that in heterozygote plants containing one psy1 allele immune and one sensitive to CRISPR, repair of the broken allele using the unbroken allele sequence template is a common outcome. In another assay, we show evidence of a somatically induced DSB in a cross between a psy1 edible tomato mutant and wild type Solanum pimpinellifolium, targeting only the S. pimpinellifolium allele. This enables characterization of germinally transmitted targeted somatic HR events, demonstrating that somatically induced DSBs can be exploited for precise breeding of crops.
The evolvement of duplicated gene loci in allopolyploid plants has become the subject of intensive studies. Most duplicated genes remain active in neoallopolyploids contributing either to a ...favourable effect of an extra gene dosage or to the build-up of positive inter-genomic interactions when genes or regulation factors on homoeologous chromosomes are divergent. However, in a small number of loci (about 10%), genes of only one genome are active, while the homoeoalleles on the other genome(s) are either eliminated or partially or completely suppressed by genetic or epigenetic means. For several traits, the retention of controlling genes is not random, favouring one genome over the other(s). Such genomic asymmetry is manifested in allopolyploid wheat by the control of various morphological and agronomical traits, in the production of rRNA and storage proteins, and in interaction with pathogens. It is suggested that the process of cytological diploidization leading to exclusive intra-genomic meiotic pairing and, consequently, to complete avoidance of inter-genomic recombination, has two contrasting effects. Firstly, it provides a means for the fixation of positive heterotic inter-genomic interactions and also maintains genomic asymmetry resulting from loss or silencing of genes. The possible mechanisms and evolutionary advantages of genomic asymmetry are discussed.
The Omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially identified in November 2021 in South Africa and Botswana, as well as in a sample from a ...traveller from South Africa in Hong Kong
. Since then, Omicron has been detected globally. This variant appears to be at least as infectious as Delta (B.1.617.2), has already caused superspreader events
, and has outcompeted Delta within weeks in several countries and metropolitan areas. Omicron hosts an unprecedented number of mutations in its spike gene and early reports have provided evidence for extensive immune escape and reduced vaccine effectiveness
. Here we investigated the virus-neutralizing and spike protein-binding activity of sera from convalescent, double mRNA-vaccinated, mRNA-boosted, convalescent double-vaccinated and convalescent boosted individuals against wild-type, Beta (B.1.351) and Omicron SARS-CoV-2 isolates and spike proteins. Neutralizing activity of sera from convalescent and double-vaccinated participants was undetectable or very low against Omicron compared with the wild-type virus, whereas neutralizing activity of sera from individuals who had been exposed to spike three or four times through infection and vaccination was maintained, although at significantly reduced levels. Binding to the receptor-binding and N-terminal domains of the Omicron spike protein was reduced compared with binding to the wild type in convalescent unvaccinated individuals, but was mostly retained in vaccinated individuals.
Summary
Background
Hand involvement in systemic sclerosis (SSc) is at the core of the disease, with a substantial impact on both functional aspects and quality of life. There is no patient‐reported ...outcome (PRO) scale globally assessing hand involvement in SSc.
Objectives
To develop and validate a PRO scale, the Hand scleroDerma lived Experience (HAnDE) scale, to assess the lived experience of hand involvement in patients with SSc.
Methods
This was an exploratory sequential mixed‐methods study with two phases: (i) PRO development through an inductive process to analyse the structure of lived experience, involving 21 patients with SSc; and (ii) PRO validation by assessing the psychometric properties of the scale among 105 patients with SSc.
Results
Phase 1 enabled us to generate the 18‐item provisional scale. From Phase 2, the mean (SD) total score of the scale was 29·16 (16·15). The item reduction process retained 16 items with five levels of answers (range 0–64). Internal consistency of the 16‐item version was excellent (Cronbach’s alpha = 0·946). Construct validity was very good, principal component analysis pointing towards a unidimensional instrument, with one factor explaining 56% of the variance, and concurrent validity being confirmed: Cochin Hand Function Scale r = 0·66; Health Assessment Questionnaire – Disability index r = 0·58; Hospital Anxiety and Depression Scale, anxiety r = 0·51, depression r = 0·4; Mouth Handicap in Systemic Sclerosis scale r = 0·61; 36‐Item Short Form Health Survey, physical component r = –0·48, mental component r = –0·46; and Kapandji score r = –0·46. The correlations were statistically significant (P < 0·05).
Conclusions
We propose, for future trials and clinical practice in SSc, a new PRO, the HAnDE scale, that assesses all the dimensions – functional, aesthetic, relational, existential and emotional – of the lived experience of hand involvement in SSc.
What is already known about this topic?
Hand involvement in systemic sclerosis (SSc) is at the core of the disease, with a substantial impact on both functional aspects and quality of life.
There is no patient‐reported outcome (PRO) scale globally assessing hand involvement in SSc.
What does this study add?
The Hand scleroDerma lived Experience (HAnDE) scale is the first PRO scale assessing the overall impact of hand involvement in SSc.
What are the clinical implications of this work?
The HAnDE scale could be of interest both in clinical trials and daily clinical practice.
It could reduce patient–physician discrepancy regarding management of the disease, especially concerning hand involvement.
Linked Comment: M. Hughes and C.P. Denton. Br J Dermatol 2022; 186:11–12.
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Inferring precise phenotypic patterns from population-scale clinical data is a core computational task in the development of precision, personalized medicine. The traditional approach uses supervised ...learning, in which an expert designates which patterns to look for (by specifying the learning task and the class labels), and where to look for them (by specifying the input variables). While appropriate for individual tasks, this approach scales poorly and misses the patterns that we don't think to look for. Unsupervised feature learning overcomes these limitations by identifying patterns (or features) that collectively form a compact and expressive representation of the source data, with no need for expert input or labeled examples. Its rising popularity is driven by new deep learning methods, which have produced high-profile successes on difficult standardized problems of object recognition in images. Here we introduce its use for phenotype discovery in clinical data. This use is challenging because the largest source of clinical data - Electronic Medical Records - typically contains noisy, sparse, and irregularly timed observations, rendering them poor substrates for deep learning methods. Our approach couples dirty clinical data to deep learning architecture via longitudinal probability densities inferred using Gaussian process regression. From episodic, longitudinal sequences of serum uric acid measurements in 4368 individuals we produced continuous phenotypic features that suggest multiple population subtypes, and that accurately distinguished (0.97 AUC) the uric-acid signatures of gout vs. acute leukemia despite not being optimized for the task. The unsupervised features were as accurate as gold-standard features engineered by an expert with complete knowledge of the domain, the classification task, and the class labels. Our findings demonstrate the potential for achieving computational phenotype discovery at population scale. We expect such data-driven phenotypes to expose unknown disease variants and subtypes and to provide rich targets for genetic association studies.
The clear-cut experimental identification of Majorana bound states in transport measurements still poses experimental challenges. We here show that the zero-energy Majorana state formed at a junction ...of three topological superconductor wires is directly responsible for giant shot noise amplitudes, in particular at low voltages and for small contact transparency. The only intrinsic noise limitation comes from the current-induced dephasing rate due to multiple Andreev reflection processes.
Meiotic recombination is tightly regulated by cis- and trans-acting factors. Although DNA methylation and chromatin remodeling affect chromosome structure, their impact on meiotic recombination is ...not well understood. To study the effect of DNA methylation on the landscape of chromosomal recombination, we analyzed meiotic recombination in the decreased DNA methylation 1 (ddm1) mutant. DDM1 is a SWI2/SNF2-like chromatin-remodeling protein necessary for DNA methylation and heterochromatin maintenance in Arabidopsis thaliana. The rate of meiotic recombination between markers located in euchromatic regions was significantly higher in both heterozygous (DDM1/ddm1) and homozygous (ddm1/ddm1) backgrounds than in WT plants. The effect on recombination was similar for both male and female meiocytes. Contrary to expectations, ddm1 had no effect on the number of crossovers between markers in heterochromatic pericentric regions that underwent demethylation. These results are surprising, because the pericentromeric regions are hypermethylated and were expected to be the regions most affected by demethylation. Thus, DDM1 loss of function may trigger changes that enhance meiotic recombination in euchromatin regions but are not sufficient to induce the same events in heterochromatic segments. This work uncovers the repressive role of methylation on meiotic recombination in euchromatic regions and suggests that additional factors may have a role in controlling the suppression of recombination in heterochromatin.
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