A bifurcated pathway to thiazoles and imidazoles using a modular flow microreactor

A scalable method for the preparation of 4,5-disubstituted thiazoles and imidazoles as distinct regioisomeric products using a modular flow microreactor has been devised. The process makes use of microfluidic reaction chips and packed immobilized-reagent columns to effect bifurcation of the reaction pathway.

A flow reactor process for the synthesis of peptides utilizing immobilized reagents, scavengers and catch and release protocols

A general flow process for the multi-step assembly of peptides has been developed and this procedure has been used to successfully construct a series of Boc, Cbz and Fmoc N-protected dipeptides in excellent yields and purities, including an extension of the method to enable the preparation of a tripeptide derivative.

It is always on your mind: experiences and perceptions of falling of older people and their carers and the potential of a mobile falls detection device

Background. Falls and fear of falling present a major risk to older people as both can affect their quality of life and independence. Mobile assistive technologies (AT) fall detection devices may maximise the potential for older people to live independently for as long as possible within their own homes by facilitating early detection of falls. Aims. To explore the experiences and perceptions of older people and their carers as to the potential of a mobile falls detection AT device. Methods. Nine focus groups with 47 participants including both older people with a range of health conditions and their carers. Interviews were audio recorded, transcribed verbatim, and thematically analysed. Results. Four key themes were identified relating to participants’ experiences and perceptions of falling and the potential impact of a mobile falls detector: cause of falling, falling as everyday vulnerability, the environmental context of falling, and regaining confidence and independence by having a mobile falls detector. Conclusion. The perceived benefits of a mobile falls detector may differ between older people and their carers. The experience of falling has to be taken into account when designing mobile assistive technology devices as these may influence perceptions of such devices and how older people utilise them.

Aircraft routing with minimal climate impact: the REACT4C climate cost function modelling approach (V1.0)

In addition to CO2, the climate impact of aviation is strongly influenced by non-CO2 emissions, such as nitrogen oxides, influencing ozone and methane, and water vapour, which can lead to the formation of persistent contrails in ice-supersaturated regions. Because these non-CO2 emission effects are characterised by a short lifetime, their climate impact largely depends on emission location and time; that is to say, emissions in certain locations (or times) can lead to a greater climate impact (even on the global average) than the same emission in other locations (or times). Avoiding these climate-sensitive regions might thus be beneficial to climate. Here, we describe a modelling chain for investigating this climate impact mitigation option. This modelling chain forms a multi-step modelling approach, starting with the simulation of the fate of emissions released at a certain location and time (time-region grid points). This is performed with the chemistry–climate model EMAC, extended via the two submodels AIRTRAC (V1.0) and CONTRAIL (V1.0), which describe the contribution of emissions to the composition of the atmosphere and to contrail formation, respectively. The impact of emissions from the large number of time-region grid points is efficiently calculated by applying a Lagrangian scheme. EMAC also includes the calculation of radiative impacts, which are, in a second step, the input to climate metric formulas describing the global climate impact of the emission at each time-region grid point. The result of the modelling chain comprises a four-dimensional data set in space and time, which we call climate cost functions and which describes the global climate impact of an emission at each grid point and each point in time. In a third step, these climate cost functions are used in an air traffic simulator (SAAM) coupled to an emission tool (AEM) to optimise aircraft trajectories for the North Atlantic region. Here, we describe the details of this new modelling approach and show some example results. A number of sensitivity analyses are performed to motivate the settings of individual parameters. A stepwise sanity check of the results of the modelling chain is undertaken to demonstrate the plausibility of the climate cost functions.

Dysregulated circulating dendritic cell function in ulcerative colitis is partially restored by probiotic strain Lactobacillus casei Shirota

BACKGROUND: Dendritic cells regulate immune responses to microbial products and play a key role in ulcerative colitis (UC) pathology. We determined the immunomodulatory effects of probiotic strain Lactobacillus casei Shirota (LcS) on human DC from healthy controls and active UC patients. METHODS: Human blood DC from healthy controls (control-DC) and UC patients (UC-DC) were conditioned with heat-killed LcS and used to stimulate allogeneic T cells in a 5-day mixed leucocyte reaction. RESULTS: UC-DC displayed a reduced stimulatory capacity for T cells (P < 0.05) and enhanced expression of skin-homing markers CLA and CCR4 on stimulated T cells (P < 0.05) that were negative for gut-homing marker β7. LcS treatment restored the stimulatory capacity of UC-DC, reflecting that of control-DC. LcS treatment conditioned control-DC to induce CLA on T cells in conjunction with β7, generating a multihoming profile, but had no effects on UC-DC. Finally, LcS treatment enhanced DC ability to induce TGFβ production by T cells in controls but not UC patients. CONCLUSIONS: We demonstrate a systemic, dysregulated DC function in UC that may account for the propensity of UC patients to develop cutaneous manifestations. LcS has multifunctional immunoregulatory activities depending on the inflammatory state; therapeutic effects reported in UC may be due to promotion of homeostasis.

Exogenous alpha-Synuclein decreases raft partitioning of Cav2.2 channels inducing dopamine release

alpha-Synuclein is thought to regulate neurotransmitter release through multiple interactions with presynaptic proteins, cytoskeletal elements, ion channels, and synaptic vesicles membrane. alpha-Synuclein is abundant in the presynaptic compartment, and its release from neurons and glia has been described as responsible for spreading of alpha-synuclein-derived pathology. alpha-Synuclein-dependent dysregulation of neurotransmitter release might occur via its action on surface-exposed calcium channels. Here, we provide electrophysiological and biochemical evidence to show that alpha-synuclein, applied to rat neurons in culture or striatal slices, selectively activates Cav2.2 channels, and said activation correlates with increased neurotransmitter release. Furthermore, in vivo perfusion of alpha-synuclein into the striatum also leads to acute dopamine release. We further demonstrate that alpha-synuclein reduces the amount of plasma membrane cholesterol and alters the partitioning of Cav2.2 channels, which move from raft to cholesterol-poor areas of the plasma membrane. We provide evidence for a novel mechanism through which alpha-synuclein acts from the extracellular milieu to modulate neurotransmitter release and propose a unifying hypothesis for the mechanism of alpha-synuclein action on multiple targets: the reorganization of plasma membrane microdomains.

Neuroanatomy of individual differences in language in adult males with autism

One potential source of heterogeneity within autism spectrum conditions (ASC) is language development and ability. In 80 high-functioning male adults with ASC, we tested if variations in developmental and current structural language are associated with current neuroanatomy. Groups with and without language delay differed behaviorally in early social reciprocity, current language, but not current autistic features. Language delay was associated with larger total gray matter (GM) volume, smaller relative volume at bilateral insula, ventral basal ganglia, and right superior, middle, and polar temporal structures, and larger relative volume at pons and medulla oblongata in adulthood. Despite this heterogeneity, those with and without language delay showed significant commonality in morphometric features when contrasted with matched neurotypical individuals (n = 57). In ASC, better current language was associated with increased GM volume in bilateral temporal pole, superior temporal regions, dorsolateral fronto-parietal and cerebellar structures, and increased white matter volume in distributed frontal and insular regions. Furthermore, current language–neuroanatomy correlation patterns were similar across subgroups with or without language delay. High-functioning adult males with ASC show neuroanatomical variations associated with both developmental and current language characteristics. This underscores the importance of including both developmental and current language as specifiers for ASC, to help clarify heterogeneity.

Avoiding the dark side of positive online consumer reviews: enhancing reviews' usefulness for high risk-averse travelers

The influence of positive online consumer reviews on a traveler's decision making remains unclear. To better understand the perceived usefulness of online reviews, this study conducts two experiments using positive and negative online consumer reviews. Study results suggest that high risk-averse travelers find negative online reviews more useful than positive reviews. For positive online reviews, high-risk averse travelers feel expert reviewers' postings, travel product pictures, and well-known brand names enhance usefulness of the positive online reviews. These findings offer interesting implications for both marketing theory and practice.

Do online hotel rating schemes influence booking behaviours?

Travelers’ hotel booking behaviors increasingly depend on peers' opinions and online ratings. This study investigates the effects of online hotel ratings on travelers' attitudes toward the hotel and booking intentions, using a 2 × 2 experimental research design. The results suggest that online rating lists are more useful and credible when published by well-known online travel communities (e.g., TripAdvisor). More favorable attitudes toward a hotel and higher booking intentions emerge when the hotel appears in best hotels lists. Finally, for the entries on best hotels lists, better attitudes and higher booking intentions result if the list is published on a well-known online travel community (Tripadvisor), whereas for entries on a worst hotel list, attitudes and booking intentions decrease even further if the list appears on TripAdvisor.

Volatile profile of Spanish Cistus plants as sources of antimicrobials for industrial applications

Cistus is a plant genus traditionally used in folk medicine as remedy for several microbial disorders and infections. The abundance of Cistus spp. in the Iberian Peninsula together with their ability to renew after wildfire contribute to their profitability as suppliers of functional ingredients. The aim of this study was to provide a comprehensive characterization of the volatile profile of different Cistus plants grown in Spain:Cistus ladanifer L., Cistus albidus L., Cistus salviifolius L., and Cistus clusii Dunal (the latter has not been studied before). A system combining headspace solid-phase microextraction and gas chromatography coupled to mass spectrometry (HS-SPME-GC–MS) was implemented; thereby, the volatile compounds were extracted and analyzed in a fast, reliable and environment-friendly way. A total of 111 volatile compounds were identified, 28 of which were reported in Cistus for the first time. The most abundant components of the samples (mono and sesquiterpenes) have been previously reported as potent antimicrobial agents. Therefore, this work reveals the potential use of the Cistus spp. studied as natural sources of antimicrobial compounds for industrial production of cosmeceuticals, among other applications.

The impact of career capital on expatriates’ perceived marketability

We examine how the development of three types of career capital (knowing how, knowing whom, and knowing why) during an international assignment affects the perceived marketability of organizational expatriates. Using the perceived marketability perspective and long-term follow-up data, we show that knowing how is seen as the most transferable type of career capital, while the development of other aspects of career capital has little impact on perceived marketability. We also show that career capital development is more recognized in the external market than by current employers. Our findings expand our understanding of long-term career marketability among people who have completed international assignments.

Growth factor receptor-bound protein 2 contributes to (hem)immunoreceptor tyrosine-based activation motif-mediated signaling in platelets

Rationale: Platelets are anuclear cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity but may also cause pathological vessel occlusion. One major pathway of platelet activation is triggered by 2 receptors that signal through an (hem)immunoreceptor tyrosine-based activation motif (ITAM), the activating collagen receptor glycoprotein (GP) VI and the C-type lectin-like receptor 2 (CLEC-2). Growth factor receptor–bound protein 2 (Grb2) is a ubiquitously expressed adapter molecule involved in signaling processes of numerous receptors in different cell types, but its function in platelets and MKs is unknown. Objective: We tested the hypothesis that Grb2 is a crucial adapter protein in (hem)immunoreceptor tyrosine-based activation motif signaling in platelets. Methods and Results: Here, we show that genetic ablation of Grb2 in MKs and platelets did not interfere with MK differentiation or platelet production. However, Grb2-deficiency severely impaired glycoprotein VI–mediated platelet activation because of defective stabilization of the linker of activated T-cell (LAT) signalosome and activation of downstream signaling proteins that resulted in reduced adhesion, aggregation, and coagulant activity on collagen in vitro. Similarly, CLEC-2–mediated signaling was impaired in Grb2-deficient platelets, whereas the cells responded normally to stimulation of G protein–coupled receptors. In vivo, this selective (hem)immunoreceptor tyrosine-based activation motif signaling defect resulted in prolonged bleeding times but affected arterial thrombus formation only after concomitant treatment with acetylsalicylic acid, indicating that defective glycoprotein VI signaling in the absence of Grb2 can be compensated through thromboxane A2–induced G protein–coupled receptor signaling pathways. Conclusions: These results reveal an important contribution of Grb2 in (hem)immunoreceptor tyrosine-based activation motif signaling in platelets in hemostasis and thrombosis by stabilizing the LAT signalosome.

Atypically rightward cerebral asymmetry in male adults with autism stratifies individuals with and without language delay

In humans, both language and fine motor skills are associated with left-hemisphere specialization, whereas visuospatial skills are associated with right-hemisphere specialization. Individuals with autism spectrum conditions (ASC) show a profile of deficits and strengths that involves these lateralized cognitive functions. Here we test the hypothesis that regions implicated in these functions are atypically rightward lateralized in individuals with ASC and, that such atypicality is associated with functional performance. Participants included 67 male, right-handed adults with ASC and 69 age- and IQ-matched neurotypical males. We assessed group differences in structural asymmetries in cortical regions of interest with voxel-based analysis of grey matter volumes, followed by correlational analyses with measures of language, motor and visuospatial skills. We found stronger rightward lateralization within the inferior parietal lobule and reduced leftward lateralization extending along the auditory cortex comprising the planum temporale, Heschl's gyrus, posterior supramarginal gyrus, and parietal operculum, which was more pronounced in ASC individuals with delayed language onset compared to those without. Planned correlational analyses showed that for individuals with ASC, reduced leftward asymmetry in the auditory region was associated with more childhood social reciprocity difficulties. We conclude that atypical cerebral structural asymmetry is a potential candidate neurophenotype of ASC

Do online hotel rating schemes influence booking behaviors?

Travelers’ hotel booking behaviors increasingly depend on peers' opinions and online ratings. This study investigates the effects of online hotel ratings on travelers' attitudes toward the hotel and booking intentions, using a 2 × 2 experimental research design. The results suggest that online rating lists are more useful and credible when published by well-known online travel communities (e.g., TripAdvisor). More favorable attitudes toward a hotel and higher booking intentions emerge when the hotel appears in best hotels lists. Finally, for the entries on best hotels lists, better attitudes and higher booking intentions result if the list is published on a well-known online travel community (Tripadvisor), whereas for entries on a worst hotel list, attitudes and booking intentions decrease even further if the list appears on TripAdvisor.

Using palaeo-climate comparisons to constrain future projections in CMIP5

We present a selection of methodologies for using the palaeo-climate model component of the Coupled Model Intercomparison Project (Phase 5) (CMIP5) to attempt to constrain future climate projections using the same models. The constraints arise from measures of skill in hindcasting palaeo-climate changes from the present over three periods: the Last Glacial Maximum (LGM) (21 000 yr before present, ka), the mid-Holocene (MH) (6 ka) and the Last Millennium (LM) (850–1850 CE). The skill measures may be used to validate robust patterns of climate change across scenarios or to distinguish between models that have differing outcomes in future scenarios. We find that the multi-model ensemble of palaeo-simulations is adequate for addressing at least some of these issues. For example, selected benchmarks for the LGM and MH are correlated to the rank of future projections of precipitation/temperature or sea ice extent to indicate that models that produce the best agreement with palaeo-climate information give demonstrably different future results than the rest of the models. We also explore cases where comparisons are strongly dependent on uncertain forcing time series or show important non-stationarity, making direct inferences for the future problematic. Overall, we demonstrate that there is a strong potential for the palaeo-climate simulations to help inform the future projections and urge all the modelling groups to complete this subset of the CMIP5 runs.