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The amide moiety of peptides can be replaced for example by a triazole moiety, which is considered to be bioisosteric. Therefore, the carbonyl moiety of an amino acid has to be replaced by an alkyne in order to provide a precursor of such peptidomimetics. As most amino acids have a chiral center at C α , such amide bond surrogates need a chiral moiety. Here the asymmetric synthesis of a set of 24 N -sulfinyl propargylamines is presented. The condensation of various aldehydes with Ellman’s chiral sulfinamide provides chiral N- sulfinylimines, which were reacted with (trimethylsilyl)ethynyllithium to afford diastereomerically pure N -sulfinyl propargylamines. Diverse functional groups present in the propargylic position resemble the side chain present at the C α of amino acids. Whereas propargylamines with (cyclo)alkyl substituents can be prepared in a direct manner, residues with polar functional groups require suitable protective groups. The presence of particular functional groups in the side chain in some cases leads to remarkable side reactions of the alkyne moiety. Thus, electron-withdrawing substituents in the C α -position facilitate a base induced rearrangement to α,β-unsaturated imines, while azide-substituted propargylamines form triazoles under surprisingly mild conditions. A panel of propargylamines bearing fluoro or chloro substituents, polar functional groups, or basic and acidic functional groups is accessible for the use as precursors of peptidomimetics.

Flexible and stretchable strain sensors are an important development for measuring various movements and forces and are increasingly used in a wide range of smart textiles. For example, strain sensors can be used to measure the movements of arms, legs or individual joints. Thereby, most strain sensors are capable of detecting large movements with a high sensitivity. Very few are able to measure small movements, i.e., strains of less than 5%, with a high sensitivity, which is necessary to carry out important health measurements, such as breathing, bending, heartbeat, and vibrations. This research deals with the development of strain sensors capable of detecting strain of 1% with a high sensitivity. For this purpose, a total of six commercially available metallic yarns were coated with a carbon-containing silicone coating. The process is based on a vertical dip-coating technology with a self-printed 3D coating bath. Afterwards, the finished yarns were interlooped and stretched by 1% while electrical resistance measurements were carried out. It was shown that, although the coating reduced the overall conductivity of the yarns, it also improved their sensitivity to stress. Conclusively, highly sensitive strain sensors, designed specially for small loads, were produced by a simple coating set-up and interlooping structure of the sensory yarns, which could easily be embedded in greater textile structures for wearable electronics.

Police refused to release the names of the accused, but it is believed the man had been friends with Ms [Linda Roberts] for more than 10 years. It is also believed he had helped Ms Roberts' friends and relatives scour bushland on Brisbane's south side for any trace of the receptionist. Ms Roberts' boyfriend Chris Piero said he went indoor rock- climbing every week with the accused man. He said he did not believe the man could be responsible. VICTIM and accused . . . receptionist Linda Roberts, left, and the couple accused of her murder are taken to Brisbane City watchhouse yesterday. The pair allegedly had dinner with Ms Roberts the night she vanished.; Photo: Photo

Abnormalities of the arterial valves, including bicuspid aortic valve (BAV) are amongst the most common congenital defects and are a significant cause of morbidity as well as predisposition to disease in later life. Despite this, and compounded by their small size and relative inaccessibility, there is still much to understand about how the arterial valves form and remodel during embryogenesis, both at the morphological and genetic level. Here we set out to address this in human embryos, using Spatial Transcriptomics (ST). We show that ST can be used to investigate the transcriptome of the developing arterial valves, circumventing the problems of accurately dissecting out these tiny structures from the developing embryo. We show that the transcriptome of CS16 and CS19 arterial valves overlap considerably, despite being several days apart in terms of human gestation, and that expression data confirm that the great majority of the most differentially expressed genes are valve-specific. Moreover, we show that the transcriptome of the human arterial valves overlaps with that of mouse atrioventricular valves from a range of gestations, validating our dataset but also highlighting novel genes, including four that are not found in the mouse genome and have not previously been linked to valve development. Importantly, our data suggests that valve transcriptomes are under-represented when using commonly used databases to filter for genes important in cardiac development; this means that causative variants in valve-related genes may be excluded during filtering for genomic data analyses for, for example, BAV. Finally, we highlight “novel” pathways that likely play important roles in arterial valve development, showing that mouse knockouts of RBP1 have arterial valve defects. Thus, this study has confirmed the utility of ST for studies of the developing heart valves and broadens our knowledge of the genes and signalling pathways important in human valve development.

Interleukin (IL)-17a has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Studies suggest that IL-17a promotes behavioral changes in experimental models of autism and aggregation behavior in worms. Here, through a cellular and molecular characterization of meningeal γδ17 T cells, we defined the nearest central nervous system–associated source of IL-17a under homeostasis. Meningeal γδ T cells express high levels of the chemokine receptor CXCR6 and seed meninges shortly after birth. Physiological release of IL-17a by these cells was correlated with anxiety-like behavior in mice and was partially dependent on T cell receptor engagement and commensal-derived signals. IL-17a receptor was expressed in cortical glutamatergic neurons under steady state and its genetic deletion decreased anxiety-like behavior in mice. Our findings suggest that IL-17a production by meningeal γδ17 T cells represents an evolutionary bridge between this conserved anti-pathogen molecule and survival behavioral traits in vertebrates. IL-17a is an evolutionarily conserved cytokine with behavior-modulating roles in the central nervous system. Kipnis and colleagues characterize a population of meningeal γδ17 T cells that use IL-17a to elicit anxiety-like behavior through cortical glutamatergic neurons.

SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.

Objective To report on the demographic data from the first 18 months of enrollment to an international registry on autoinflammatory diseases in the context of the Eurofever project. Methods A web-based registry collecting baseline and clinical information on autoinflammatory diseases and related conditions is available in the member area of the PRINTO web-site. Anonymised data were collected with standardised forms. Results 1880 (M:F=916:964) individuals from 67 centers in 31 countries have been entered in the Eurofever registry. Most of the patients (1388; 74%), reside in western Europe, 294 (16%) in the eastern and southern Mediterranean region (Turkey, Israel, North Africa), 106 (6%) in eastern Europe, 54 in Asia, 27 in South America and 11 in Australia. In total 1049 patients with a clinical diagnosis of a monogenic autoinflammatory diseases have been enrolled; genetic analysis was performed in 993 patients (95%): 703 patients have genetically confirmed disease and 197 patients are heterozygous carriers of mutations in genes that are mutated in patients with recessively inherited autoinflammatory diseases. The median diagnosis delay was 7.3 years (range 0.3–76), with a clear reduction in patients born after the identification of the first gene associated with autoinflammatory diseases in 1997. Conclusions A shared online registry for patients with autoinflammatory diseases is available and enrollment is ongoing. Currently, there are data available for analysis on clinical presentation, disease course, and response to treatment, and to perform large scale comparative studies between different conditions.

Rapidly changing abiotic conditions, particularly temperature variations, pose adaptation challenges to many animal communities across the globe. Lanice conchilega , a key polychaete in the ecosystem of the German Wadden Sea, faces an increasing threat hampered by its limited mobility. The microbiome can alleviate stress, alter local environmental conditions, and provide new metabolic capabilities, contributing to host adaptation. To understand the potential roles of the microbiome of L. conchilega , we analysed a broad sample set via 16 S rRNA gene amplicon sequencing. We compared the bacterial composition of the microbiome of L. conchilega with that of the surrounding sediment, and the effect of seasonality, zonation, tidal, and diurnal cycles. Our findings reveal a set of ASVs exclusive to the microbiome of L. conchilega . Community composition was mostly shaped by seasonality, slightly influenced by zonation, day/night cycles, and tides. Notably, Endozoicomonas ASVs were found only in the L. conchilega microbiome and were particularly abundant during summer. These bacteria, known for their symbiotic relationships, broad metabolic capabilities, and linked to heat resistance in corals, are predicted to contribute unique metabolic functions in L. conchilega . This work provides novel insights into the host-microbiome relationship of L. conchileg a and highlights the potential role of symbionts in the environmental adaptation of these and similar animals.

The growth of freshly formed aerosol particles can be the bottleneck in their survival to cloud condensation nuclei. It is therefore crucial to understand how particles grow in the atmosphere. Insufficient experimental data has impeded a profound understanding of nano-particle growth under atmospheric conditions. Here we study nano-particle growth in the CLOUD (Cosmics Leaving OUtdoors Droplets) chamber, starting from the formation of molecular clusters. We present measured growth rates at sub-3 nm sizes with different atmospherically relevant concentrations of sulphuric acid, water, ammonia and dimethylamine. We find that atmospheric ions and small acid-base clusters, which are not generally accounted for in the measurement of sulphuric acid vapour, can participate in the growth process, leading to enhanced growth rates. The availability of compounds capable of stabilizing sulphuric acid clusters governs the magnitude of these effects and thus the exact growth mechanism. We bring these observations into a coherent framework and discuss their significance in the atmosphere. The growth rates of freshly formed aerosol particles influence what fraction of these can reach sizes large enough to affect cloud formation and climate. Here, the authors show that the nano-particle growth in a sulphuric acid containing system can be enhanced by the presence of ions or small acid-base clusters.

This article is an update of the best practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes published in 2010 in BMC Medical Genetics [1]. The update takes into account developments in terms of techniques, differential diagnoses and (especially) reporting standards. It highlights the advantages and disadvantages of each method and moreover, is meant to facilitate the interpretation of the obtained results - leading to improved standardised reports.