S-acylation stabilizes ligand-induced receptor kinase complex formation during plant pattern-triggered immune signalling

SummaryPlant receptor kinases are key transducers of extracellular stimuli, such as the presence of beneficial or pathogenic microbes or secreted signalling molecules. Receptor kinases are regulated by numerous post-translational modifications. Here, using the immune receptor kinases FLS2 and EFR, we show that S-acylation at a cysteine conserved in all plant receptor kinases is crucial for function. S-acylation involves the addition of long-chain fatty acids to cysteine residues within proteins, altering their biophysical properties and behaviour within the membrane environment. We observe S-acylation of FLS2 at C-terminal kinase domain cysteine residues within minutes following perception of its ligand flg22, in a BAK1 co-receptor dependent manner. We demonstrate that S-acylation is essential for FLS2-mediated immune signalling and resistance to bacterial infection. Similarly, mutating the corresponding conserved cysteine residue in EFR supressed elf18 triggered signalling. Analysis of unstimulated and activated FLS2-containing complexes using microscopy, detergents and native membrane DIBMA nanodiscs indicates that S-acylation stabilises and promotes retention of activated receptor kinase complexes at the plasma membrane to increase signalling efficiency

Systematic review of facilitated communication 2014–2018 finds no new evidence that messages delivered using facilitated communication are authored by the person with disability

Background and aims Facilitated Communication (FC) is a technique that involves a person with a disability pointing to letters, pictures, or objects on a keyboard or on a communication board, typically with physical support from a “facilitator”. Proponents claim that FC reveals previously undetected literacy and communication skills in people with communication disability. However, systematic reviews conducted up to 2014 reveal no evidence that the messages generated using FC are authored by the person with a disability. This study aimed to conduct a systematic review of the literature on FC published between 2014 and 2018 to inform the 2018 update of the 1995 American Speech-Language-Hearing Association Position Statement on FC. Method A systematic search was undertaken to locate articles about FC in English published in the peer reviewed literature since 2014; and to classify these according to the study design for analysis. Studies meeting the inclusion criteria were classified according to four categories of evidence: (a) quantitative experimental data pertaining to authorship, (b) quantitative descriptive data on messages produced using FC, (c) qualitative data, or (d) commentary material on FC. Main contribution In total, 18 studies met the inclusion criteria. There were no new empirical studies and no new descriptive quantitative studies addressing the authorship of messages delivered using FC. Three new qualitative studies qualified for inclusion; these did not first establish authorship. Of the 15 new commentary papers on FC located, 14 were critical and one was non-critical. The results could be used to inform the development or update of current position statements on FC held locally, nationally, and globally. Conclusion There are no new studies on authorship and there remains no evidence that FC is a valid form of communication for individuals with severe communication disabilities. There continue to be no studies available demonstrating that individuals with communication disabilities are the authors of the messages generated using FC. Furthermore, there is substantial peer-reviewed literature that is critical of FC and warns against its use. Implications FC continues to be contested in high profile court cases and its use promoted in school settings and workshops at university campuses in the US. Our empty systematic review will influence both clinical practice and future clinical guidance; most immediately the American Speech-Language-Hearing Association Position Statement on FC and any future guidance issued by the 19 associations worldwide with positions against FC. </jats:sec

De novo Assembly and Analysis of the Chilean Pencil Catfish Trichomycterus areolatus Transcriptome

Trichomycterus areolatus is an endemic species of pencil catfish that inhabits the riffles and rapids of many freshwater ecosystems of Chile. Despite its unique adaptation to Chile’s high gradient watersheds and therefore potential application in the investigation of ecosystem integrity and environmental contamination, relatively little is known regarding the molecular biology of this environmental sentinel. Here, we detail the assembly of the Trichomycterus areolatus transcriptome, a molecular resource for the study of this organism and its molecular response to the environment. RNA-Seq reads were obtained by next-generation sequencing with an Illumina® platform and processed using PRINSEQ. The transcriptome assembly was performed using TRINITY assembler. Transcriptome validation was performed by functional characterization with KOG, KEGG, and GO analyses. Additionally, differential expression analysis highlights sex-specific expression patterns, and a list of endocrine and oxidative stress related transcripts are included

Discovery of AZD-2098 and AZD-1678, two potent and bioavailable CCR4 receptor antagonists

N-(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in a CCR4 receptor antagonist high throughput screen (HTS) of a sub-set of the AstraZeneca compound bank. As a hit with a lead-like profile, it was an excellent starting point for a CCR4 receptor antagonist program and enabled the rapid progression through the Lead Identification and Lead Optimization phases resulting in the discovery of two bioavailable CCR4 receptor antagonist candidate drugs

How much exposure to English is necessary for a bilingual toddler to perform like a monolingual peer in language tests?

Background Bilingual children are under-referred due to an ostensible expectation that they lag behind their monolingual peers in their English acquisition. The recommendations of the Royal College of Speech and Language Therapists (RCSLT) state that bilingual children should be assessed in both the languages known by the children. However, despite these recommendations, a majority of speech and language professionals report that they assess bilingual children only in English as bilingual children come from a wide array of language backgrounds and standardized language measures are not available for the majority of these. Moreover, even when such measures do exist, they are not tailored for bilingual children. Aims It was asked whether a cut-off exists in the proportion of exposure to English at which one should expect a bilingual toddler to perform as well as a monolingual on a test standardized for monolingual English-speaking children. Methods & Procedures Thirty-five bilingual 2;6-year-olds exposed to British English plus an additional language and 36 British monolingual toddlers were assessed on the auditory component of the Preschool Language Scale, British Picture Vocabulary Scale and an object-naming measure. All parents completed the Oxford Communicative Development Inventory (Oxford CDI) and an exposure questionnaire that assessed the proportion of English in the language input. Where the CDI existed in the bilingual's additional language, these data were also collected. Outcomes & Results Hierarchical regression analyses found the proportion of exposure to English to be the main predictor of the performance of bilingual toddlers. Bilingual toddlers who received 60% exposure to English or more performed like their monolingual peers on all measures. K-means cluster analyses and Levene variance tests confirmed the estimated English exposure cut-off at 60% for all language measures. Finally, for one additional language for which we had multiple participants, additional language CDI production scores were significantly inversely related to the amount of exposure to English. Conclusions & Implications Typically developing 2;6-year-olds who are bilingual in English and an additional language and who hear English 60% of the time or more, perform equivalently to their typically developing monolingual peers

Jumping to the wrong conclusions? An investigation of the mechanisms of reasoning errors in delusions

Understanding how people with delusions arrive at false conclusions is central to the refinement of cognitive behavioural interventions. Making hasty decisions based on limited data ('jumping to conclusions', JTC) is one potential causal mechanism, but reasoning errors may also result from other processes. In this study, we investigated the correlates of reasoning errors under differing task conditions in 204 participants with schizophrenia spectrum psychosis who completed three probabilistic reasoning tasks. Psychotic symptoms, affect, and IQ were also evaluated. We found that hasty decision makers were more likely to draw false conclusions, but only 37% of their reasoning errors were consistent with the limited data they had gathered. The remainder directly contradicted all the presented evidence. Reasoning errors showed task-dependent associations with IQ affect, and psychotic symptoms. We conclude that limited data-gathering contributes to false conclusions but is not the only mechanism involved. Delusions may also be maintained by a tendency to disregard evidence. Low IQ and emotional biases may contribute to reasoning errors in more complex situations. Cognitive strategies to reduce reasoning errors should therefore extend beyond encouragement to gather more data, and incorporate interventions focused directly on these difficulties

S-acylation stabilizes ligand-induced receptor kinase complex formation during plant pattern-triggered immune signaling

Plant receptor kinases are key transducers of extracellular stimuli, such as the presence of beneficial or pathogenic microbes or secreted signaling molecules. Receptor kinases are regulated by numerous post-translational modifications.1,2,3 Here, using the immune receptor kinases FLS24 and EFR,5 we show that S-acylation at a cysteine conserved in all plant receptor kinases is crucial for function. S-acylation involves the addition of long-chain fatty acids to cysteine residues within proteins, altering their biochemical properties and behavior within the membrane environment.6 We observe S-acylation of FLS2 at C-terminal kinase domain cysteine residues within minutes following the perception of its ligand, flg22, in a BAK1 co-receptor and PUB12/13 ubiquitin ligase-dependent manner. We demonstrate that S-acylation is essential for FLS2-mediated immune signaling and resistance to bacterial infection. Similarly, mutating the corresponding conserved cysteine residue in EFR suppressed elf18-triggered signaling. Analysis of unstimulated and activated FLS2-containing complexes using microscopy, detergents, and native membrane DIBMA nanodiscs indicates that S-acylation stabilizes, and promotes retention of, activated receptor kinase complexes at the plasma membrane to increase signaling efficiency