Chloride ions are efficient catalysts for the synthesis of phosgene from carbon monoxide and elemental chlorine at room temperature and atmospheric pressure. Control experiments rule out a radical mechanism and highlight the role of triethylmethylammonium trichloride, [NEt3Me][Cl3], as active species. In the catalytic reaction, commercially available [NEt3Me]Cl reacts with Cl2 to form [NEt3Me][Cl3], enabling the insertion of CO into an activated Cl─Cl bond with a calculated energy barrier of 56.9 to 77.6 kJ mol−1. As [NEt3Me]Cl is also a useful chlorine storage medium, it could serve as a catalyst for phosgene production and as chlorine storage in a combined industrial process.

Aim To determine the potential anti-inflammatory effect of a multimodal periodic fasting programme on surrogate parameters of periodontal inflammation in hospitalized patients diagnosed for metabolic syndrome (MetS). Material and methods A total of 47 patients were recruited and hospitalized in an integrative ward for an intensified two-week multimodal fasting, diet and lifestyle programme. Patients were periodontally examined at baseline (t1), after the 2-week fasting protocol (t2) and, subsequently, 4 months after fasting (t3). The following parameters were determined: periodontal screening index (PSI), bleeding on probing (BOP), gingival crevicular fluid volume (GCF), plaque index (PI), C-reactive protein (CRP), blood pressure (BP), waist circumference (WC), fasting glucose (FGLU), triglycerides (TRG), high-density lipoprotein (HDL) and HbA1c. Results A total of 28 female and 8 male patients fulfilled the defined criteria for MetS and were analysed separately by gender. At t2, BOP and GCF were reduced when compared to t1 (median: t2 = 39; t1 = 33.1%; p p = .02, respectively). BOP reduction correlated to FGLU (R = .37, p = .049) and weight reduction (R = .4, p = .04). Conclusion This study showed for the first time that clinically supervised periodic fasting in female patients with MetS may facilitate the reduction of periodontal inflammation.

Background Nonalcoholic steatohepatitis has become one of the leading causes of liver transplantation. The development of steatosis, as well as the link to inflammation and fibrosis, after transplantation remain poorly understood. The aim of this analysis was to evaluate the influence of obesity on histopathological changes of the graft during long-term follow-up. Methods A total of 1494 longitudinal liver biopsies of 271 recipients were evaluated during a follow-up period of 5 to 10 years. Clinical and laboratory parameters as well as histopathological categories of steatosis, inflammation, and fibrosis were explored by routine protocol biopsies. Results The BMI and prevalence of diabetes mellitus significantly increased after transplantation (P < .01). Diabetes and de novo obesity were significantly associated with the degree of graft steatosis. There was no correlation between former steatosis and inflammation or fibrosis. Inflammation was a precursor of fibrosis, and fibrosis increased over the first 3 years (P < .01). No severe graft dysfunction was observed. Conclusion Obesity and diabetes mellitus correlated with higher grades of steatosis and de novo steatosis after transplantation. Metabolic syndrome must be considered as a serious post-transplant complication that can cause histopathological alteration. However, the progress from steatosis to steatohepatitis is not as common as expected.

Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80-540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.

Background: Due to extensive clinical and genetic heterogeneity of intellectual disability (ID) syndromes, the process of diagnosis is very challenging even for expert clinicians. Despite recent advancements in molecular diagnostics methodologies, a significant fraction of ID patients remains without a clinical diagnosis.

Methods, results, and conclusions: Here, in a prospective study on a cohort of 21 families (trios) with a child presenting with ID of unknown etiology, we executed phenotype-driven bioinformatic analysis method, PhenIX, utilizing targeted next-generation sequencing (NGS) data and Human Phenotype Ontology (HPO)-encoded phenotype data. This approach resulted in clinical diagnosis for eight individuals presenting with atypical manifestations of Rubinstein-Taybi syndrome 2 (MIM 613684), Spastic Paraplegia 50 (MIM 612936), Wiedemann-Steiner syndrome (MIM 605130), Cornelia de Lange syndrome 2 (MIM 300590), Cerebral creatine deficiency syndrome 1 (MIM 300352), Glass Syndrome (MIM 612313), Mental retardation, autosomal dominant 31 (MIM 616158), and Bosch-Boonstra-Schaaf optic atrophy syndrome (MIM 615722).

Aim: Dry skin is one of the most frequent cutaneous problems in aged long-term care residents. Although it is clinically relevant, the impact on quality of life is unclear. The objective was to measure well-being, sleep quality and itch in nursing home residents being 65 years and older and to explore possible associations with demographics, dry skin and skincare habits.

Design: Multicentre, observational, cross-sectional.

Methods: Sleep quality was assessed with the Richards-Campbell Sleep Quality Questionnaire, well-being with the WHO-Five Well-being Index and itch with the 5-D Itch scale. Skin dryness was measured using the Overall Dry Skin score.

Results: A total of 51 residents were included. The item scores of the sleep quality and itch questionnaires were strongly associated with each other. Demographics, dry skin and skincare habits were not associated with the questionnaires. It is unclear whether basic skincare activities can improve the quality of life in this population.

Background: Cardiomyopathies are heterogeneous diseases with clinical presentations varying from asymptomatic to life-threatening events, including severe heart failure and sudden cardiac death. The role of underlying genetic and disease-modulating factors in children and adolescents is relatively unknown. In this prospective study, in-depth phenotypic and genetic characterization of pediatric patients with primary cardiomyopathy and their first-degree family members (FMs) was performed. Outcome was assessed to identify clinical risk factors.

Methods and Results: Sixty index patients with primary cardiomyopathy (median age: 7.8 years) and 124 FMs were enrolled in the RIKADA (Risk Stratification in Children and Adolescents with Primary Cardiomyopathy) study. Family screening included cardiac workup and genetic testing. Using cardiologic screening, we identified 17 FMs with cardiomyopathies and 30 FMs with suspected cardiomyopathies. Adverse events appeared in 32% of index patients and were more common in those with lower body surface area (P=0.019), increased NT-proBNP (N-terminal pro-brain natriuretic peptide; P<0.001), and left ventricular dysfunction (P<0.001) and dilatation (P=0.005). The worst prognosis was observed in dilated and restrictive cardiomyopathies. Genetic variants of interest were detected in patients (79%) and FMs (67%). In all 15 families with at least 1 FM with cardiomyopathy, we found a variant of interest in the index patient. Increased number of variants of interest per patient was associated with adverse events (P=0.021). Late gadolinium enhancement was related to positive genotypes in patients (P=0.041).

Conclusions: Lower body surface area, increased NT-proBNP, left ventricular dysfunction or dilatation, late gadolinium enhancement, and increased number of variants of interest were associated with adverse outcome and should be considered for risk assessment in pediatric primary cardiomyopathies.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT03572569.

Epoxides derived from arachidonic acid (AA) are released during exercise and may contribute to vasodilation. However, exercise may also affect circulating levels of other epoxides derived from cytochromes P450 (CYP) monooxygenase and lipoxygenase (LOX) pathways, many of whose exhibit cardiovascular activity in vitro. The effects of exercise on their levels have not been documented. We tested the hypothesis that acute, maximal exercise would influence the plasma concentrations of these vasoactive substances. We measured plasma CYP and LOX mediators derived from both the n - 3 and n - 6 fatty acid (FA) classes in healthy volunteers before, during and after short-term exhaustive exercise. Lipid mediators were profiled by means of LC-MS/MS tandem mass spectrometry. A maximal Bruce treadmill test was performed to voluntary exhaustion. Exhaustive exercise increased the circulating levels of epoxyoctadecenoic (12,13-EpOME), dihydroxyeicosatrienoic (5,6-DHET), dihydroxyeicosatetraenoic acids (5,6-DiHETE, 17,18-DiHETE), but had no effect on the majority of CYP and LOX metabolites. Although our calculations of diol/epoxide ratios revealed preferred hydrolysis of epoxyeicosatrienoic acids (EEQs) into their diols (DiHETEs), this hydrolysis was resistant to maximal exercise. Our study is the first documentation that bioactive endogenous n - 3 and n - 6 CYP lipid mediators are released by short-term exhaustive exercise in humans. In particular, the CYP epoxy-metabolite status, 12,13-EpOME/DiHOME, 5,6-EET/DHET, 5,6-EEQ/DiHETE and 17,18-EEQ/DiHETE may contribute to the cardiovascular response during maximal exercise.

This article attempts to draw attention to the social choices of the earliest farming societies, evaluating new and old settlement data from the Early Neolithic of Thessaly in Greece. We examine the inhabitation of landscapes, the organisation of the inhabited spaces and the human–landscape interaction as a framework for the creation of a socialised environment. Taking into account aspects such as settlement location, duration, architecture and intra- and intersite arrangements, this study shows that the observed diversity in space and time reflects alternative modes of settlement and land use, variations in notions of permanence and continuity and different modalities of the adoption and meaning of new socioeconomic practices. This evidence challenges traditional interpretations of simplicity, homogeneity and change as being induced from outside and calls for a new reading of the Early Neolithic. We argue that the model of a single and uniform development, deriving from concepts of diffusionism and evolutionism, does not hold in Neolithic Thessaly (or in Greece). Instead, Neolithisation was a contextual process that involved human awareness and different choices, and that the social landscape created by the pioneering farming societies set the stage for all kinds of different developments that occurred in later phases.

This article uses a person-environment fit perspective to investigate whether and how educational background and general trust are related to fit (or not) with university life as well as to criteria of subjective academic success and well-being. To analyze how students perceive fit with their university, we measured their perception of exclusion and their affective commitment. The sample includes N = 424 students from two German universities, about half of whom have at least one parent with tertiary education. The results show that especially general trust is related to the subjective criteria of academic success, and that this relationship is mediated by the perception of exclusion, on the one hand, and by the affective commitment, on the other hand. A comparison of the two mediators shows that the perception of exclusion is particularly potent in terms of predicting satisfaction with coping with study demands and general well-being. We discuss the results in terms of their significance to the future diversity management at universities for overcoming social inequality and increasing social inclusion.

Cold-priming uncouples cold and light regulation of otherwise tightly co-regulated genes. In this study, we focused on the early regulatory processes in Arabidopsis within the first 2 h in cold and in high light after a 5-d lag-phase at 20 °C and 24 h cold-priming at 4 °C. Priming quickly modified gene expression in a trigger-specific manner. In the early stress-response phase during cold and high-light triggering, it reduced the regulatory amplitudes of many up- and down-regulated genes. A third of the priming-regulated genes were jasmonate-sensitive, including the full set of genes required for oxylipin biosynthesis. Analysis of wild-type and mutant plants based on qPCR demonstrated that biosynthesis of the jasmonic acid (JA) precursor 12-oxo phytenoic acid (OPDA) relative to the availability of JA dampened the response of the genes for oxylipin biosynthesis. In oxylipin biosynthetic mutants, cold-priming more strongly affected genes involved in the biosynthesis of OPDA than in its conversion to JA. In addition, priming-dependent dampening of the triggering response was more linked to OPDA than to regulation of the JA concentration. Spray application of OPDA prior to triggering counteracted the priming effect. Regulation of the oxylipin hub was controlled by modulation of the oxylipin-sensitivity of the genes for OPDA biosynthesis, but it was insensitive to priming-induced accumulation of thylakoid ascorbate peroxidase, thus identifying a parallel-acting cold-priming pathway.

The EU is surrounded by areas of limited statehood (ALS) and contested orders (CO) in its southern and eastern neighbourhood. Resilience has become a focus of attention in the academic debate on how to successfully deal with ALS and CO. Moreover, resilience-building is a new cornerstone in the EU’s foreign and security policy. However, to what extent is resilience a mechanism to cope with ALS and CO? What are the sources of resilience? To what extent does the EU act as a resilience builder or spoiler in its neighbourhood? By presenting a new conceptual framework for analysing the interplay between risks, resilience, and governance breakdown/violent conflict as well as through in-depth empirical evidence, this special issue puts forward three key arguments. First, resilience is a key mechanism to prevent governance breakdown and violent conflict in the EU’s neighbourhood. Second, three sources are key in building resilience: Social trust within societies and communities, legitimacy of (state and non-state) governance actors and institutions, as well as effective, fair, and inclusive governance institutions. Third, if external actors, such as the EU, seek to build resilience, they need to factor in long-time horizons, in-depth local knowledge, and a clearly designed strategy.

El artículo aborda la comunalización del cuidado y el sostenimiento de la vida en condiciones de crisis. Partiendo de investigación cualitativa acerca de los procesos de reproducción en una localidad periférica de la costa manabita tras el terremoto de 2016 en Ecuador, el texto discute la potencia y los límites de la acción comunitaria. Ésta se rearticula cuando lo que resguarda el diario vivir -cobijo, alimentación, salud, educación, agua, etc.- colapsa. Inmersa en un contexto histórico de explotación laboral y territorial y de una limitada acción estatal, la población pone en marcha dinámicas de cooperación y cogestión en distintos frentes, y transforma las que operaban previamente. Discutiendo con la literatura sobre cuidado, comunidad y común desde el feminismo y la que trabaja sobre vulnerabilidad, riesgo y desastres, la pregunta central que motiva la reflexión es: ¿qué informa el análisis de este tipo de crisis sobre las prácticas comunales de reproducción social?

Different solar system objects display variable abundances of neutron-rich isotopes such as 54Cr, 50Ti, and 48Ca, which are commonly attributed to a heterogeneous distribution of presolar grains in different domains of the solar system. Here, we show that the heterogeneity of 54Cr/52Cr and the correlation of 54Cr/52Cr with Fe/Cr in metal fractions of EH3 chondrites and in inner solar system bodies can be attributed to variable irradiation of dust grains by solar energetic particles and variable mixing of irradiated material in the different domains of the inner solar nebula. The isotope variations in inner solar system objects can be generated by ~300 y long local irradiation of mm- to cm-sized solids with average solar energetic particle fluxes of ~105 times the modern value. The relative homogeneity of 53Cr/52Cr in inner solar system objects can be a consequence of the production of 53Mn by the early irradiation of dust, evaporation, and nebula-wide homogenization of Mn due to high temperatures, followed by Mn/Cr fractionation within the first few million years of the solar system. The 54Cr/52Cr of the Earth can be produced by irradiated pebbles and <15 wt% of CI chondrite like material. Alternatively, Earth may contain only a few % of CI chondrite like material but then must have an Fe/Cr ratio 10–15% higher than CI chondrites.

The online real-time particle size analysis of the microencapsules manufacturing process using the continuous solvent evaporation method was performed using focused beam reflectance measurement (FBRM). In this paper, we use FBRM measurements to investigate the effects of polymer type and compare the size distributions to those obtained using other sizing methods such as optical microscope and laser diffraction. FBRM was also utilized to measure the length-weighted chord length distribution (CLD) and particle size distribution (PSD) online during particle solidification, which could not be done with laser diffraction or nested sieve analysis. The chord lengths and CLD data were taken at specific times using an online FBRM probe mounted below the microparticle. The timing of the FBRM determinations was coordinated with the selection of microparticle samples for particle size analysis by optical microscope and laser diffraction calculation as a reference. For all three produced batches tested, FBRM, laser diffraction, and sieve analysis yielded similar results. Hardening time for the transformation of emulsion droplets into solid microparticles occurred within the first 10.5, 19, 25, 30, and 55 min, according to FBRM results. The FBRM CLDs revealed that a larger particle size mean resulted in a longer CLD and a lower peak of particle number. The FBRM data revealed that the polymer type had a significant impact on microparticle CLD and the transformation process.

This study attempted to evaluate the groundwater quality, with a special emphasis on nutrients, of a riverine coastal island near Kodungallur, Kerala. Water quality parameters were analyzed in the collected samples over pre- and post-monsoon seasons. A considerable variation in groundwater chemistry was observed in the two periods. During pre-monsoon season, many wells were contaminated with TDS, Cl, Fe, Ca and Mg in certain locations. Whereas, post-monsoon water was relatively fresh, indicating the dilution process as well as aquifer recharge by the monsoon rain and consequent regression of saline water. A higher concentration of Fe was observed in the pre-monsoon season (41%) than in the post-monsoon season (24%). Nitrate and phosphates were analyzed to assess the nutrients and the observed concentration was below their corresponding permissible limits. Results show that overexploitation of the aquifer as well as the decreased flow of the River Periyar during the pre-monsoon period increased the threat from seawater intrusion and groundwater contamination. An interesting groundwater recharge mechanism locally known as backwashing—the diversion of rainwater from rooftops to dug wells—is being practiced in the study area and has been found to be effective in raising water levels and improving water quality.

We demonstrate the application of the transition manifold framework to the late-stage fibrillation process of the NFGAILS peptide, a amyloidogenic fragment of the human islet amyloid polypeptide (hIAPP). This framework formulates machine learning methods for the analysis of multi-scale stochastic systems from short, massively parallel molecular dynamical simulations. We identify key intermediate states and dominant pathways of the process. Furthermore, we identify the optimally timescale-preserving reaction coordinate for the dock-lock process to a fixed pre-formed fibril and show that it exhibits strong correlation with the mean native hydrogen-bond distance. These results pave the way for a comprehensive model reduction and multi-scale analysis of amyloid fibrillation processes.

During vegetative growth plants pass from a juvenile to an adult phase causing changes in shoot morphology. This vegetative phase change is primarily regulated by the opposite actions of two microRNAs, the inhibitory miR156 and the promoting miR172 as well as their respective target genes, constituting the age pathway. Here we show that the phytohormone cytokinin promotes the juvenile-to-adult phase transition through regulating components of the age pathway. Reduction of cytokinin signalling substantially delayed the transition to the adult stage. tZ-type cytokinin was particularly important as compared to iP- and the inactive cZ-type cytokinin, and root-derived tZ influenced the phase transition significantly. Genetic and transcriptional analyses indicated the requirement of SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) transcription factors and miR172 for cytokinin activity. Two miR172 targets, TARGET OF EAT1 (TOE1) and TOE2 encoding transcriptional repressors were necessary and sufficient to mediate the influence of cytokinin on vegetative phase change. This cytokinin pathway regulating plant aging adds to the complexity of the regulatory network controlling the juvenile-to-adult phase transition and links cytokinin to miRNA action.

High amounts of glycosaminoglycans (GAG) such as hyaluronan (HA) occur in connective tissues. There is nowadays increasing evidence that a “sulfation code” exists which mediates numerous GAG functions. High molecular weight and inhomogeneity of GAG, however, aggravated detailed studies. Thus, synthetic oligosaccharides were urgently required. We will review here chemoenzymatic and analytic strategies to provide defined sulfated and anomerically modified GAG oligosaccharides of the HA type. Representative studies of protein/GAG interactions by (bio)chemical and biophysical methods are reported yielding novel insights into GAG-protein binding. Finally, the biological conclusions and in vivo applications of defined sulfated GAG oligosaccharides will be discussed.

The transition from traditional fuel-based bus transportation towards electric bus systems is regarded as a beacon of hope for emission-free public transport. In this study, we focus on battery electric bus systems, in which charging is possible at a variety of locations distributed at terminal stations over the entire bus network. In such systems, two intertwined planning problems to be considered are charging location planning and electric vehicle scheduling. We account for the interdependent nature of both planning problems by adopting a simultaneous optimization perspective. Acknowledging the existence of parameter uncertainty in such complex planning situations, which is rooted in potential changes of values of several environmental factors, we analyze the solution sensitivity to several of these factors in order to derive methodological guidance for decision makers in public transportation organizations. Based on the formulation of a new mathematical model and the application of a variable neighborhood search metaheuristic, we conduct sensitivity analysis by means of numerical experiments drawing on real-world data. The experiments reveal that it is not possible to identify persistent structures for charging locations by an a priori analysis of the problem instances, so that rather a simultaneous optimization is necessary. Furthermore, the experiments show that the configuration of electric bus systems reacts sensitively to parameter changes.