Chitin perception in plasmodesmata characterizes submembrane immune-signaling specificity in plants

The plasma membrane (PM) is composed of heterogeneous subdomains, characterized by differences in protein and lipid composition. PM receptors can be dynamically sorted into membrane domains to underpin signaling in response to extracellular stimuli. In plants, the plasmodesmal PM is a discrete microdomain that hosts specific receptors and responses. We exploited the independence of this PM domain to investigate how membrane domains can independently integrate a signal that triggers responses across the cell. Focusing on chitin signaling, we found that responses in the plasmodesmal PM require the LysM receptor kinases LYK4 and LYK5 in addition to LYM2. Chitin induces dynamic changes in the localization, association, or mobility of these receptors, but only LYM2 and LYK4 are detected in the plasmodesmal PM. We further uncovered that chitin-induced production of reactive oxygen species and callose depends on specific signaling events that lead to plasmodesmata closure. Our results demonstrate that distinct membrane domains can integrate a common signal with specific machinery that initiates discrete signaling cascades to produce a localized response

Khresmoi Professional: Multilingual Semantic Search for Medical Professionals

There is increasing interest in and need for innovative solutions to medical search. In this paper we present the EU funded Khresmoi medical search and access system, currently in year 3 of 4 of development across 12 partners . The Khresmoi system uses a component based architecture housed in the cloud to allow for the development of several innovative applications to support target users medical information needs. The Khresmoi search systems based on this architecture have been designed to support the multilingual and multimod al information needs of three target groups the general public, general practitioners and consultant radiologists. In this paper we focus on the presentation of the systems to support the latter two groups using semantic, multilingual text and image based (including 2D and 3D radiology images) search

BLOOM: A 176B-Parameter Open-Access Multilingual Language Model

Large language models (LLMs) have been shown to be able to perform new tasks based on a few demonstrations or natural language instructions. While these capabilities have led to widespread adoption, most LLMs are developed by resource-rich organizations and are frequently kept from the public. As a step towards democratizing this powerful technology, we present BLOOM, a 176B-parameter open-access language model designed and built thanks to a collaboration of hundreds of researchers. BLOOM is a decoder-only Transformer language model that was trained on the ROOTS corpus, a dataset comprising hundreds of sources in 46 natural and 13 programming languages (59 in total). We find that BLOOM achieves competitive performance on a wide variety of benchmarks, with stronger results after undergoing multitask prompted finetuning. To facilitate future research and applications using LLMs, we publicly release our models and code under the Responsible AI License

Khresmoi – multilingual semantic search of medical text and images

The Khresmoi project is developing a multilingual multimodal search and access system for medical and health information and documents. This scientific demonstration presents the current state of the Khresmoi integrated system, which includes components for text and image annotation, semantic search, search by image similarity and machine translation. The flexibility in adapting the system to varying requirements for different types of medical information search is demonstrated through two instantiations of the system, one aimed at medical professionals in general and the second aimed at radiologists. The key innovations of the Khresmoi system are the integration of multiple software components in a flexible scalable medical search system, the use of annotation cycles including manual correction to improve semantic search, and the possibility to do large scale visual similarity search on 2D and 3D (CT, MR) medical images

Khresmoi: Multimodal Multilingual Medical Information Search

Khresmoi is a European Integrated Project developing a multilingual multimodal search and access system for medical and health information and documents. It addresses the challenges of searching through huge amounts of medical data, including general medical information available on the internet, as well as radiology data in hospital archives. It is developing novel semantic search and visual search techniques for the medical domain. At the MIE Village of the Future, Khresmoi proposes to have two interactive demonstrations of the system under development, as well as an overview oral presentation and potentially some poster presentation

Regulation of plasmodesmal receptor sorting and signalling by membrane scaffolds – the role of tetraspanins and flotillins

Plants can perceive and respond to the presence of microorganisms such as fungi and bacteria in their environment. One way for plants to perceive the presence of fungi is to detect the fungal cell wall component chitin, via pattern recognition receptors (PRR). During the perception of pathogens, plant cells close the membrane lined channels connecting the cytoplasm of adjacent cells (plasmodesmata) by depositing callose in the cell wall, and thereby restrict the molecular flux between neighbouring cells. Three different PRR are necessary for chitin-triggered plasmodesmal closure in Arabidopsis: LYSM DOMAIN GPIANCHORED PROTEIN 2 (LYM2), LYSM-CONTAINING RECEPTOR-LIKE KINASE 4 (LYK4), and LYSM-CONTAINING RECEPTOR-LIKE KINASE 5 (LYK5). Out of those three, only LYM2 is enriched at plasmodesmata, and chitin triggers a further increase of this enrichment. However, the molecular mechanisms underlying this process remain to be elucidated. In this thesis I explore prerequisites and characteristics necessary to achieve this plasmodesmal localisation. I further show that all three receptors LYM2, LYK4 and LYK5 associate with each other in planta, and investigate how LYK5 could be important for chitintriggered plasmodesmal closure, even though it is absent at plasmodesmata itself. I further demonstrate that not only receptors but also proteins of two different scaffolding families — the tetraspanins and flotillins — are necessary for these responses. Both of these families are known for their presence and orchestration of specialised membrane domains such as nanodomains. My data reveal that they are also important for signalling responses at the specialised plasmodesmal PM microdomain. I show how both tetraspanins and flotillins are necessary to achieve chitin-triggered ROS bursts, plasmodesmal regulation, as well as plant resistance against pathogenic fungi comparable to wild-type plants. Together, the data presented in this work generate new insights on how chitin-triggered signalling processes depend on different receptors, and also on their partner scaffolding proteins, thereby creating new hypotheses and opportunities for future investigations

Incidence of Exposure of Patients in the United States to Multiple Drugs for Which Pharmacogenomic Guidelines Are Available

<div><p>Pre-emptive pharmacogenomic (PGx) testing of a panel of genes may be easier to implement and more cost-effective than reactive pharmacogenomic testing if a sufficient number of medications are covered by a single test and future medication exposure can be anticipated. We analysed the incidence of exposure of individual patients in the United States to multiple drugs for which pharmacogenomic guidelines are available (PGx drugs) within a selected four-year period (2009–2012) in order to identify and quantify the incidence of pharmacotherapy in a nation-wide patient population that could be impacted by pre-emptive PGx testing based on currently available clinical guidelines. In total, 73 024 095 patient records from private insurance, Medicare Supplemental and Medicaid were included. Patients enrolled in Medicare Supplemental age > = 65 or Medicaid age 40–64 had the highest incidence of PGx drug use, with approximately half of the patients receiving at least one PGx drug during the 4 year period and one fourth to one third of patients receiving two or more PGx drugs. These data suggest that exposure to multiple PGx drugs is common and that it may be beneficial to implement wide-scale pre-emptive genomic testing. Future work should therefore concentrate on investigating the cost-effectiveness of multiplexed pre-emptive testing strategies.</p></div

Incidence of exposure to drugs for which pre-emptive pharmacogenomic testing is available.

<p>Incidence of exposure to drugs for which pre-emptive pharmacogenomic testing is available.</p

Number of expected drug-phenotype co-occurrences of highest priority according to CPIC guidelines (CPIC level A) or high clinical significance according to DPWG guidelines (DPWG clinical significance classes C–F) within the observed four-year time window.

<p>PGx drugs included in all estimations: amitriptyline, azathioprine, clomipramine, clopidogrel, doxepin, glimepiride, haloperidol, imipramine, mercaptopurine, metoprolol, nortriptyline, paroxetine, propafenone, risperidone sertraline, tamoxifen, thioguanine, tramadol, venlafaxine. Estimations which additionally included codeine are shown for comparison. The rationale for including / excluding drug substances is described in the Methods section (‘Drug substances included in the estimation’).</p