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Background/objectives: Attitudes towards COVID-19 vaccination vary globally, influenced by political and cultural factors. This research aimed to assess the views of people without a healthcare qualification in Europe on COVID-19 vaccination safety, effectiveness, and necessity as well as how well informed they felt. The secondary outcomes focused on how respondents' views were affected by demographic and context factors and included a comparison by country of the level of feeling well informed. Methods: A mixed-method cross-sectional online survey in eight European countries, using convenience sampling. Results : A total of 1008 adults completed the survey, 60% of whom were female. While only 44.1% considered the vaccines safe, 43.5% effective, and 44.9% necessary, 80.0% had been vaccinated. Four in ten adults strongly agreed that they were well informed, while over a quarter did not answer the question. Younger respondents, well-informed individuals, and German respondents were more inclined to perceive COVID-19 vaccination as both effective and necessary. Conclusions : Motivations for vaccination included perceived health and social benefits, while concerns included a preference for "natural immunity", the rapid development of the vaccine, and potential unknown long-term effects. A correlation existed between respondents feeling well informed about the different COVID-19 vaccines in their country and the likelihood of having been vaccinated.

Introduction: The societal costs of dementia and cognitive decline are substantial and likely to increase during the next decades due to the increasing number of people in older age groups. The aim of this multicenter cluster-randomized controlled trial was to assess the cost-effectiveness of a multi-domain intervention to prevent cognitive decline in older people who are at risk for dementia., Methods: We used data from a multi-centric, two-armed, cluster-randomized controlled trial ( AgeWell.de trial, ID: DRKS00013555). Eligible participants with increased dementia risk at baseline (Cardiovascular Risk Factors, Aging, and Incidence of Dementia/CAIDE Dementia Risk Score ≥ 9), 60-77 years of age, were recruited by their general practitioners, and assigned randomly to a multi-domain lifestyle intervention or general health advice. We performed a cost-effectiveness analysis from the societal perspective. The time horizon was 2 years. Health care utilization was measured using the "Questionnaire for Health-Related Resource Use in Older Populations." As effect measure, we used quality-adjusted life-years (QALYs) based on the 5-level EQ-5D version (EQ-5D-5L). We calculated the incremental cost-effectiveness ratios (ICER) and cost-effectiveness acceptability curves (CEAC) using the net-benefit approach. Exploratory analyses considering women and the EQ visual analogue scale (EQ VAS) were conducted., Results: Data were available for 819 participants (mean age 69.0 [standard deviation (SD)5-level EQ-5D version 4.9]); 378 were treated in the intervention group and 441 in the control group. The participants in the intervention group caused higher costs (+€445.88 [SD: €1,244.52]) and gained additional effects (+0.026 QALY [SD: 0.020]) compared to the participants in the control group (the difference was statistically significant). The ICER was €17,149.23/QALY. The CEAC showed that the probability of the intervention being cost-effective was moderate, reaching 59% at a willingness-to-pay (WTP) of €50,000/QALY. The exploratory analyses showed promising results, especially in the female subsample., Discussion: Considering aspects like the WTP and the limited time horizon, the multi-domain intervention was cost-effective compared to general health advice., Highlights: The first German randomized controlled trial (RCT) evaluating a multicomponent approach against cognitive decline.We found a favorable incremental cost-effectiveness ratio.The probability of cost-effectiveness reached 78.6%.Women could be an important target group.A longer time horizon is needed., Competing Interests: The authors confirm that there are no conflicts of interest., (© 2025 The Author(s). Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: The growing importance of collecting Broad Consent (BC) for research utilizing electronic health records in Germany has brought attention to the need for a deeper understanding of potential selection bias in the process. Since 2020, the BeoNet-Halle outpatient database has been collecting anonymous and pseudonymous patient data from primary care and specialty practices throughout Germany, with the practice being an integral part of this data collection effort. The primary objective of the pilot study is to explore potential socioeconomic discrepancies between patients who provided BC and the general practice population., Method: This is a single-center, cross-sectional study. The study was performed with patients from one Medical Care Center including eight GPs. We categorized patients with at least one interaction with a general practitioner from March 2021 to January 2023 into two sets: patients who approved BC versus a randomly chosen representative sample (RS) of non-BC inquirers. We mailed a sociodemographic survey to both groups., Results: A total of 561 patients were analyzed, with the BC group responding more actively (60.7%) than the RS group (29.7%). Age and gender were similar between the BC group and RS group. Being widowed, divorced, or unmarried and being neither open nor hostile toward research was associated with an increased likelihood of giving consent. Analysis of personality traits did not show any impact on giving consent., Conclusions: Overall, this study outlines that there is some bias between BC and RS. Possible associations in BC decisions that offer insights into complex decisions to participate in medical research are marital status, immigrant background, income, and age. Findings emphasize the potential of BC for outpatient research, warranting further investigation to optimize its application in the general practice setting., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family Medicine and Primary Care.)

Introduction: General practitioners (GPs) are mostly the first point of contact for patients with health problems in Germany. There is only a limited epidemiological overview data that describe the GP consultation hours based on other than billing data. Therefore, the aim of Saxon Epidemiological Study in General Practice-6 (SESAM-6) is to examine the frequency of reasons for encounter, prevalence of long-term diagnosed diseases and diagnostic and therapeutic decisions in general practice. This knowledge is fundamental to identify the healthcare needs and to develop strategies to improve the GP care. The results of the study will be incorporated into the undergraduate, postgraduate and continuing medical education for GP., Methods and Analysis: This cross-sectional study SESAM-6 is conducted in general practices in the state of Saxony, Germany. The study design is based on previous SESAM studies. Participating physicians are assigned to 1 week per quarter (over a survey period of 12 months) in which every fifth doctor-patient contact is recorded for one-half of the day (morning or afternoon). To facilitate valid statements, a minimum of 50 GP is required to document a total of at least 2500 doctor-patient contacts. Univariable, multivariable and subgroup analyses as well as comparisons to the previous SESAM data sets will be conducted., Ethics and Dissemination: The study was approved by the Ethics Committee of the Technical University of Dresden in March 2023 (SR-EK-7502023). Participation in the study is voluntary and will not be remunerated. The study results will be published in peer-reviewed scientific journals, preferably with open access. They will also be disseminated at scientific and public symposia, congresses and conferences. A final report will be published to summarise the central results and provided to all study participants and the public., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Many universities offer rural medical internships for medical students. The present survey was designed to show how rural medical work is perceived by students, whether these perceptions are associated with origin and previous experience, and how well medical students know rural regions in the vicinity of their university. In addition, students were asked how to support and inspire medical students to later work in a rural region., Methods: This cross-sectional study was based on an anonymous online survey of medical students at the Universities of Halle-Wittenberg and Leipzig. The evaluations included descriptive statistics, statistical group comparisons, and qualitative content analysis of free text answers., Results: A total of 882 students took part in the survey. Students who had grown up in a rural region or had lived there for a longer time (71.7% of the respondents) rated the work-life balance better (p<0.01) and the patient variety in the countryside slightly higher (p<0.05) than their fellow students from the big city. Students who had worked in a rural practice or hospital before (62.2%) rated patient diversity (p<0.001) and work variety (p<0.001), as well as workload (p<0.01), slightly higher in rural areas than students with no prior experience. On average, the specified rural model regions were still unknown to more than 60% of the students. The suggestions for attracting medical students to later work as rural physicians included financial incentives and, above all, better information about life as a rural physician and the rural regions., Conclusion: Thus, the medical faculties of the universities as well as the counties threatened by medical undersupply should further expand the transfer of knowledge and experience regarding rural physician life for the students., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023 Brütting et al.)

Expanded polymeric beads offer the advantage of being able to produce parts with complex geometries through a consolidation process. However, established polymeric beads are made of thermoplastics, deform and melt beyond their temperature services. In this manuscript, a new technique is proposed to fabricate expandable epoxy beads (EEBs), then expand and fuse them to produce epoxy particle foams (EPFs). This technique is called solid-state carbamate foaming technique. For production of EEBs, a mixture of epoxy, carbamate and hardener is prepared and poured into a 10 mL syringe. The mixture is manually extruded into 60 °C water to obtain a cylindric shape. The extrudate is then further cured to obtain an epoxy oligomer behaving rheological tan delta 3 and 2 at 60 °C. The extrudate is cut into pellets to obtain EEBs. The EEBs are then loaded into an aluminum mold and placed in an oven at 160 °C to expand, fuse to obtain EPFs of 212 kg/m 3 and 258 kg/m 3 . The obtained EPFs provide a T g of 150-154 °C. The fusion boundaries in EPFs are well formed. Thus, the produced EPFs exhibit a compressive modulus of 50-70 MPa, with a torsion storage modulus at 30 °C of 34-56 MPa.

Polylactide (PLA) is one of the most important bioplastics worldwide and thus represents a good potential substitute for bead foams made of the fossil-based Polystyrene (PS). However, foaming of PLA comes with a few challenges. One disadvantage of commercially available PLA is its low melt strength and elongation properties, which play an important role in foaming. As a polyester, PLA is also very sensitive to thermal and hydrolytic degradation. Possibilities to overcome these disadvantages can be found in literature, but improving the properties for foaming of PLA as well as the degradation behavior during foaming have not been investigated yet. In this study, reactive extrusion on a twin-screw extruder is used to modify PLA in order to increase the melt strength and to protect it against thermal degradation and hydrolysis. PLA foams are produced in an already known process from the literature and the influence of the modifiers on the properties is estimated. The results show that it is possible to enhance the foaming properties of PLA and to protect it against hydrolysis at the same time.

Homocysteine is associated with several diseases, and a series of dietary factors are known to modulate homocysteine levels. As mice are often used as model organisms to study the effects of dietary hyperhomocysteinemia, we collected data about concentrations of vitamin B 12 , vitamin B 6 , folate, methionine, cystine, and choline in mouse diets and the associated plasma/serum homocysteine levels. In addition, we more closely examined the composition of the control diet, the impact of the mouse strain, sex and age, and the duration of the dietary intervention on homocysteine levels. In total, 113 out of 1103 reviewed articles met the inclusion criteria. In the experimental and control diets, homocysteine levels varied from 0.1 to 280 µmol/l. We found negative correlations between dietary vitamin B 12 (rho = - 0.125; p < 0.05), vitamin B 6 (rho = - 0.191; p < 0.01) and folate (rho = - 0.395; p < 0.001) and circulating levels of homocysteine. In contrast, a positive correlation was observed between dietary methionine and homocysteine (methionine: rho = 0.146; p < 0.05). No significant correlations were found for cystine or choline and homocysteine levels. In addition, there was no correlation between the duration of the experimental diets and homocysteine levels. More importantly, the data showed that homocysteine levels varied widely in mice fed control diets as well. When comparing control diets with similar nutrient concentrations (AIN-based), there were significant differences in homocysteine levels caused by the strain (ANOVA, p < 0.05) and age of the mice at baseline (r = 0.47; p < 0.05). When comparing homocysteine levels and sex, female mice tended to have higher homocysteine levels than male mice (9.3 ± 5.9 µmol/l vs. 5.8 ± 4.5 µmol/l; p = 0.069). To conclude, diets low in vitamin B 12 , vitamin B 6 , or folate and rich in methionine are similarly effective in increasing homocysteine levels. AIN recommendations for control diets are adequate with respect to the amounts of homocysteine-modulating dietary parameters. In addition, the mouse strain and the age of mice can affect the homocysteine level.

The pathogenesis of multiple sclerosis (MS) remains poorly understood. Presumably, MS is caused by multiple environmental, epigenetic, and genetic factors. Among them, human endogenous retroviruses (HERVs), Epstein-Barr virus (EBV) and vitamin D have been suggested to play a role in the pathogenesis and course of MS. Because vitamin D can affect the immune system and infections, it can be hypothesized that there is a close interplay between vitamins, EBV and ERV in the pathogenesis of MS. Here, we summarize the important data on vitamin D, including polymorphisms in genes related to vitamin D metabolism, EBV and ERV, in the pathogenesis of MS and create hypotheses regarding their interactions. Data indicate that vitamin D has a strong impact on viral infections and interferes with EBV infection, while EBV is capable of activating silent ERVs. We believe that EBV could be the missing link between vitamin D and ERV in MS pathogenesis., Competing Interests: The authors have declared no conflict of interest., (© 2021 The Authors. Published by IMR Press.)

Propionate has antimicrobial activity and is suggested to influence lipid metabolism. Here, we investigated the effect of propionate on lipid metabolism and the gut microbiome in fructose-fed mice as a model of diet-induced steatosis and gut dysbiosis. Therefore, 48 male wild-type mice were fed isoenergetic diets with either 0% fructose (F-) or 40% fructose (F+) that contained 0% propionate (P-) or 1% propionate (P+) for 7 weeks. Mice that received the F+ diets developed fatty livers, had fewer small intestinal proteobacteria and colonic actinobacteria and were characterised by changes in bacterial genera (e.g., Allobaculum , Lachnospiraceae , and Escherichia ). Interestingly, mice fed the F+ diets had higher levels of propionate and butyrate in the circulation than mice fed the F- diets ( p  < 0.05). Treatment with propionate influenced neither hepatic or plasma lipids nor levels of circulating SCFAs. With the exception of Verrucomicrobia , other bacterial phyla were not affected by propionate.

In this comprehensive study, the influence of (i) material specific properties (e.g., molecular weight, zero shear viscosity, D-content) and (ii) process parameters (e.g., saturation temperature, -time, -pressure, and pressure drop rate) on the expansion behavior during the autoclave foaming process were investigated on linear Polylactide (PLA) grades, to identify and evaluate the foam relevant parameters. Its poor rheological behavior is often stated as a drawback of PLA, that limits its foamability. Therefore, nine PLA grades with different melt strength and zero shear viscosity were systematically chosen to identify whether these are the main factors governing the foam expansion and whether there is a critical value for these rheological parameters to be exceeded, to achieve low density foams with fine cells. With pressure drop induced batch foaming experiments, it could be shown that all of the investigated PLA grades could be foamed without the often used chemical modifications, although with different degrees of expansion. Interestingly, PLAs foaming behavior is rather complex and can be influenced by many other factors due to its special nature. A low molecular weight combined with a high ability to crystallize only lead to intermediate density reduction. In contrast, a higher molecular weight (i.e., increased zero shear viscosity) leads to significant increased expandability independent from the D-content. However, the D-content plays a crucial role in terms of foaming temperature and crystallization. Furthermore, the applied process parameters govern foam expansion, cell size and crystallization.

Background: Because antibiotic use in livestock is assumed to contribute to the emerging public health crisis of antibiotic resistance, alternatives are required. Phytogenic additives are extensively studied due to their antibiotic properties. Components of Agrimonia species have been reported as candidate antimicrobials that possess antioxidative and anti-inflammatory properties. We studied the impact of Agrimonia procera (AP) on the growth of selected strains of gut bacteria, the effect of AP on the mRNA abundance of genes involved in inflammation and bacterial defense in a colon carcinoma cell line, the effect of AP in piglets challenged with lipopolysaccharides, and the effect of AP on the growth performance of healthy piglets., Results: The in vitro growth rate of different bacteria strains was negatively affected by AP, especially in Pediococcus pentosaceus and all tested E. coli strains. Stimulation of Caco-2 cells with TNFα resulted in elevated mRNA expression of CXCL1, IL-8 and GPX2. After pretreatment of cells with AP, stimulation of Caco-2 cells with TNFα still resulted in elevated mRNA expression of CXCL1 and IL-8 at all measured points in time. However, mRNA expression in AP-pretreated cells was lower after 6 h and 24 h. In addition, expression of DEFB1 and GPX2 was significantly elevated after TNFα stimulation. In vivo, application of lipopolysaccharides induced significantly increased animal body temperatures. Piglets pretreated with AP prior to lipopolysaccharide application showed a faster and larger increase in body temperature than controls. In addition, piglets pretreated with AP appeared to release more TNFα than controls. In healthy piglets, AP treatment had no impact on growth performance parameters. Fecal dry matter and total plasma antioxidant capacity tended to be higher in piglets treated with AP than in control piglets (P = 0.055 and P = 0.087, respectively)., Conclusions: AP has antimicrobial effects in vitro and stimulated the expression of proinflammatory cytokines in Caco-2 cells. The additive had no effect on growth in healthy piglets but increased the immune response in LPS-treated animals. In addition, AP appeared to have antioxidative effects in vivo. Therefore, AP merits testing as a future alternative to antibiotics in animal husbandry.

Endophytic insects provide the textbook examples of herbivores that manipulate their host plant's physiology, putatively altering source/sink relationships by transferring cytokinins (CK) to create 'green islands' that increase the nutritional value of infested tissues. However, unambiguous demonstrations of CK transfer are lacking. Here we show that feeding by the free-living herbivore Tupiocoris notatus on Nicotiana attenuata is characterized by stable nutrient levels, increased CK levels and alterations in CK-related transcript levels in attacked leaves, in striking similarity to endophytic insects. Using 15 N-isotope labeling, we demonstrate that the CK N 6 -isopentenyladenine (IP) is transferred from insects to plants via their oral secretions. In the field, T. notatus preferentially attacks leaves with transgenically increased CK levels; plants with abrogated CK-perception are less tolerant of T. notatus feeding damage. We infer that this free-living insect uses CKs to manipulate source/sink relationships to increase food quality and minimize the fitness consequences of its feeding., Competing Interests: CB, CC, MS, MS, SM, NA No competing interests declared, IB Senior editor, eLife, (© 2018, Brütting et al.)

The pathogenesis of multiple sclerosis (MS) has not been clarified. In addition to environmental factors; genetic determinants have been implicated in the pathogenesis of MS. Furthermore, endogenous retroviruses (ERV) might play a role in MS. The presence of oligoclonal immunoglobulin in cerebrospinal fluid (CSF) is a typical feature of MS. Recently, genetic polymorphisms in loci on human chromosomes 6, 14 and 18 have been identified as major determinants of CSF antibody levels in MS. The functional relevance of these single nucleotide polymorphisms (SNPs) remains unclear and none of them is located in an open reading frame. In previous studies, we identified ERV sequences in the vicinity of MS associated SNPs. Here, we describe the identification of ERV sequences in the neighborhood of SNPs associated with CSF antibody levels. All of the identified SNPs are located in the vicinity of ERV sequences. One of these sequences has very high homology to a sequence derived from the so-called MS-associated retrovirus (MSRV). Another cluster of three ERV sequences from the immunoglobulin heavy chain locus has retained the typical organization of retroviral genomes. These observations might shed new light on a possible association between ERVs and MS pathogenesis., Competing Interests: The authors declare no conflicts of interest.

Human endogenous retroviruses (ERVs) have been found to be associated with different diseases, e.g., multiple sclerosis (MS). Most human ERVs integrated in our genome are not competent to replicate and these sequences are presumably silent. However, transcription of human ERVs can be reactivated, e.g., by hypoxia. Interestingly, MS has been linked to hypoxia since decades. As some patterns of demyelination are similar to white matter ischemia, hypoxic damage is discussed. Therefore, we are interested in the association between hypoxia and ERVs. As a model, we used human SH-SY5Y neuroblastoma cells after treatment with the hypoxia-mimetic cobalt chloride and analyzed differences in the gene expression profiles in comparison to untreated cells. The vicinity of up-regulated genes was scanned for endogenous retrovirus-derived sequences. Five genes were found to be strongly up-regulated in SH-SY5Y cells after treatment with cobalt chloride: clusterin, glutathione peroxidase 3, insulin-like growth factor 2, solute carrier family 7 member 11, and neural precursor cell expressed developmentally down-regulated protein 9. In the vicinity of these genes we identified large (>1,000 bp) open reading frames (ORFs). Most of these ORFs showed only low similarities to proteins from retro-transcribing viruses. However, we found very high similarity between retrovirus envelope sequences and a sequence in the vicinity of neural precursor cell expressed developmentally down-regulated protein 9. This sequence encodes the human endogenous retrovirus group FRD member 1, the encoded protein product is called syncytin 2. Transfection of syncytin 2 into the well-characterized Ewing sarcoma cell line A673 was not able to modulate the low immunostimulatory activity of this cell line. Future research is needed to determine whether the identified genes and the human endogenous retrovirus group FRD member 1 might play a role in the etiology of MS.

Endogenous viral elements (EVE) seem to be present in all eukaryotic genomes. The composition of EVE varies between different species. The endogenous retrovirus 3 (ERV3) is one of these elements that is present only in humans and other Catarrhini. Conservation of ERV3 in most of the investigated Catarrhini and the expression pattern in normal tissues suggest a putative physiological role of ERV3. On the other hand, ERV3 has been implicated in the pathogenesis of auto-immunity and cancer. In the present review we summarize knowledge about this interesting EVE. We propose the model that expression of ERV3 (and probably other EVE loci) under pathological conditions might be part of a metazoan SOS response.

We describe the synthesis of 1,1'- and 2,2'-bicarbazoles by oxidative homocoupling of 2- and 1-hydroxycarbazoles. The oxidative coupling using catalytic amounts of F 16 PcFe can be applied to both groups of substrates. Although F 16 PcFe generally provides the best yields for the synthesis of 1,1'-bicarbazoles, di-tert-butyl peroxide affords better results for the 2,2'-bicarbazoles. In our study, we have achieved the first syntheses of the biscarbalexines A-C, bisglybomine B, 2,2'-dihydroxy-7,7'-dimethoxy-3,3'-dimethyl-1,1'-bicarbazole, bispyrayafoline C, and bisisomahanine. The iron-catalyzed coupling of koenigine led to an improved synthesis of 8,8''-biskoenigine and afforded an unprecedented decacylic product. Oxidative coupling of 1-hydroxycarbazoles led to bisclausenol, and to the first total syntheses of bismurrayafoline B and D., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A series of 49 oxygenated tricyclic carbazole derivatives has been tested for inhibition of the growth of Mycobacterium tuberculosis and a mammalian cell line (vero cells). From this series, twelve carbazoles showed a significant anti-TB activity. The four most active compounds were the naturally occurring carbazole alkaloids clauszoline-M (45), murrayaline-C (41), carbalexin-C (27), and the synthetic carbazole derivative 22 with MIC 90 values ranging from 1.5 to 3.7μM. The active compounds were virtually nontoxic for the mammalian cell line in the concentration range up to 50μM., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The pathogenesis of rheumatoid arthritis (RA) is incompletely understood. Human endogenous retroviruses (HERVs) and their superantigenic envelope protein (env) have been implicated in the pathogenesis of RA. In the present investigation, the arthritogenic potential of the superantigen staphylococcal enterotoxin A (SEA) has been investigated. In the present investigation, the bacterial superantigen staphylococcal enterotoxin A (SEA) was injected into the right knee joint of 15 Lewis rats. Further nine animals received saline. Animals were sacrificed one, five and 10 days after the injection, respectively. The antigens CD3, CD4, CD8, MHC class I, MHC class II, Pax5 and CD138 were investigated by immunohistochemistry on cryo-sections. After intra-articular SEA injection, the inflammation was initially dominated by CD8+ T cells. In the course of the investigation, the numbers of CD4+, Pax5+, CD138+ and MHC class II+ cells increased. CD3 was expressed in low numbers as compared to CD8. After saline injection, no similar inflammatory response has been detected. The arthritis induced by the superantigen SEA may be a novel model for inflammatory joint diseases, that is rheumatoid arthritis or juvenile idiopathic arthritis., (© 2017 The Foundation for the Scandinavian Journal of Immunology.)

Plant defense metabolites are well known to be regulated developmentally. The optimal defense (OD) theory posits that a tssue's fitness values and probability of attack should determine defense metabolite allocations. Young leaves are expected to provide a larger fitness value to the plant, and therefore their defense allocations should be higher when compared with older leaves. The mechanisms that coordinate development with defense remain unknown and frequently confound tests of the OD theory predictions. Here we demonstrate that cytokinins (CKs) modulate ontogeny-dependent defenses in Nicotiana attenuata. We found that leaf CK levels highly correlate with inducible defense expressions with high levels in young and low levels in older leaves. We genetically manipulated the developmental patterns of two different CK classes by using senescence- and chemically inducible expression of CK biosynthesis genes. Genetically modifying the levels of different CKs in leaves was sufficient to alter ontogenic patterns of defense metabolites. We conclude that the developmental regulation of growth hormones that include CKs plays central roles in connecting development with defense and therefore in establishing optimal patterns of defense allocation in plants., (© 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.)

At least 8% of the human genome is composed of endogenous retrovirus (ERV) sequences. ERVs play a role in placental morphogenesis and can sometimes protect the host against exogenous viruses. On the other hand, ERV reactivation has been found to be associated with different diseases, for example, multiple sclerosis (MS), schizophrenia, type 1 diabetes mellitus (T1D), or amyotrophic lateral sclerosis (ALS). Little is known about the cooccurrence of these diseases. If all these diseases are caused by ERV, antiretroviral therapy should perhaps also show some effects in the other diseases. Here, we summarize literature demonstrating that some ERV-associated diseases seem to appear together more often than expected, for example, MS and ALS, MS and T1D, MS and schizophrenia, or ALS and T1D. In contrast, some ERV-associated diseases seem to appear together less frequently than expected, for example, schizophrenia and T1D. Besides, some reports demonstrate amelioration of MS, ALS, or schizophrenia under antiretroviral therapy in human immunodeficiency virus-infected patients. If such results could be confirmed in larger studies, alternative therapy strategies for ERV-associated diseases like MS and schizophrenia might be possible., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Background: The evolutionary arms race between plants and insects has driven the co-evolution of sophisticated defense mechanisms used by plants to deter herbivores and equally sophisticated strategies that enable phytophagous insects to rapidly detoxify the plant's defense metabolites. In this study, we identify the genetic determinants that enable the mirid, Tupiocoris notatus, to feed on its well-defended host plant, Nicotiana attenuata, an outstanding model for plant-insect interaction studies., Results: We used an RNAseq approach to evaluate the global gene expression of T. notatus after feeding on a transgenic N. attenuata line which does not accumulate jasmonic acid (JA) after herbivory, and consequently accumulates very low levels of defense metabolites. Using Illumina sequencing, we generated a de novo assembled transcriptome which resulted in 63,062 contigs (putative transcript isoforms) contained in 42,610 isotigs (putative identified genes). Differential expression analysis based on RSEM-estimated transcript abundances identified 82 differentially expressed (DE) transcripts between T. notatus fed on wild-type and the defenseless plants. The same analysis conducted with Corset-estimated transcript abundances identified 59 DE clusters containing 85 transcripts. In both analyses, a larger number of DE transcripts were found down-regulated in mirids feeding on JA-silenced plants (around 70%). Among these down-regulated transcripts we identified seven transcripts possibly involved in the detoxification of N. attenuata defense metabolite, specifically, one glutathione-S-transferase (GST), one UDP-glucosyltransferase (UGT), five cytochrome P450 (P450s), and six serine proteases. Real-time quantitative PCR confirmed the down-regulation for six transcripts (encoding GST, UGT and four P450s) and revealed that their expression was only slightly decreased in mirids feeding on another N. attenuata transgenic line specifically silenced in the accumulation of diterpene glycosides, one of the many classes of JA-mediated defenses in N. attenuata., Conclusions: The results provide a transcriptional overview of the changes in a specialist hemimetabolous insect associated with feeding on host plants depleted in chemical defenses. Overall, the analysis reveals that T. notatus responses to host plant defenses are narrow and engages P450 detoxification pathways. It further identifies candidate genes which can be tested in future experiments to understand their role in shaping the T. notatus-N. attenuata interaction.

We describe a regioselective synthesis of 4- or 5-substituted carbazoles by oxidative cyclisation of meta-oxygen-substituted N-phenylanilines. Using the regiodirecting effect of a pivaloyloxy group, we prepared 4-hydroxycarbazole, a precursor for the enantiospecific synthesis of the β-adrenoreceptor antagonists (-)-(S)-carazolol (5) and (-)-(S)-carvedilol (6). Regioselective palladium(II)-catalysed cyclisation of different diarylamines led to total synthesis of glycoborine (7) and the first total syntheses of the phytoalexin carbalexin A (8), glybomine A (9) and glybomine B (10). For glybomine B (10), a 5-hydroxycarbazole was converted into the corresponding triflate and utilized for introduction of a prenyl substituent., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Although multiple sclerosis (MS) is one of the most common central nervous system diseases in young adults, little is known about its etiology. Several human endogenous retroviruses (ERVs) are considered to play a role in MS. We are interested in which ERVs can be identified in the vicinity of MS associated genetic marker to find potential initiators of MS. We analysed the chromosomal regions surrounding 58 single nucleotide polymorphisms (SNPs) that are associated with MS identified in one of the last major genome wide association studies. We scanned these regions for putative endogenous retrovirus sequences with large open reading frames (ORFs). We observed that more retrovirus-related putative ORFs exist in the relatively close vicinity of SNP marker indices in multiple sclerosis compared to control SNPs. We found very high homologies to HERV-K, HCML-ARV, XMRV, Galidia ERV, HERV-H/env62 and XMRV-like mouse endogenous retrovirus mERV-XL. The associated genes (CYP27B1, CD6, CD58, MPV17L2, IL12RB1, CXCR5, PTGER4, TAGAP, TYK2, ICAM3, CD86, GALC, GPR65 as well as the HLA DRB1*1501) are mainly involved in the immune system, but also in vitamin D regulation. The most frequently detected ERV sequences are related to the multiple sclerosis-associated retrovirus, the human immunodeficiency virus 1, HERV-K, and the Simian foamy virus. Our data shows that there is a relation between MS associated SNPs and the number of retroviral elements compared to control. Our data identifies new ERV sequences that have not been associated with MS, so far.

Background: Plant metabolites are commonly functionally classified, as defense- or growth-related phytohormones, primary and specialized metabolites, and so forth. Analytical procedures for the quantifications of these metabolites are challenging because the metabolites can vary over several orders of magnitude in concentrations in the same tissues and have very different chemical characteristics. Plants clearly adjust their metabolism to respond to their prevailing circumstances in very sophisticated ways that blur the boundaries among these functional or chemically defined classifications. But if plant biologists want to better understand the processes that are important for a plant's adaptation to its environment, procedures are needed that can provide simultaneous quantifications of the large range of metabolites that have the potential to play central roles in these adjustments in a cost and time effective way and with a low sample consumption., Results: Here we present a method that combines well-established methods for the targeted analysis of phytohormones, including jasmonates, salicylic acid, abscisic acid, gibberellins, auxins and cytokinins, and extends it to the analysis of inducible and constitutive defense compounds, as well as the primary metabolites involved in the biosynthesis of specialized metabolites and responsible for nutritional quality (e.g., sugars and amino acids). The method is based on a single extraction of 10-100 mg of tissue and allows a broad quantitative screening of metabolites optimized by their chemical characteristics and concentrations, thereby providing a high throughput analysis unbiased by the putative functional attributes of the metabolites. The tissues of Nicotiana attenuata which accumulate high levels of nicotine and diterpene glycosides, provide a challenging matrix that thwarts quantitative analysis; the analysis of various tissues of this plant are used to illustrate the robustness of the procedure., Conclusions: The method described has the potential to unravel various, until now overlooked interactions among different sectors of plant metabolism in a high throughput manner. Additionally, the method could be particularly beneficial as screening method in forward genetic approaches, as well as for the investigation of plants from natural populations that likely differ in metabolic traits.

Background: Person-centred care (PCC) is a fundamental principle in general practice, emphasising practices tailored to individual patient preferences, needs, and values. Despite the importance of PCC, general practitioners (GPs) face obstacles in effectively implementing it, with associated factors remaining unclear., Objectives: The PACE GP/FP study aims to explore GPs' attitudes towards PCC and the factors facilitating or hindering its implementation in daily practice across European countries. This paper outlines the PACE GP/FP study protocol., Methods: The cross-sectional design with data collection via an online survey distribution to GPs in 24 European countries. Study instruments include two validated questionnaires (Perceived Stress Scale (PSS) and Patient Physician Orientation Scale (PPOS)) and additional items covering general information about the doctor and their practice, as well as facilitators and barriers to PCC. These additional items were specifically developed for the study, translated using the forward-backward method, evaluated through cognitive debriefing, and integrated into the REDCap platform to create language and country-specific survey links. The STROBE checklist guides the reporting of the manuscript., Conclusion: The PACE GP/FP study will provide a comprehensive exploration of GPs' attitudes towards PCC and the factors shaping its practice in Europe. The findings from the PACE GP/FP study will provide evidence for designing future implementation strategies and guide targeted interventions to promote PCC in primary care across Europe.

Cytokinins (CKs) are well-established as important phytohormonal regulators of plant growth and development. An increasing number of studies have also revealed the function of these hormones in plant responses to biotic and abiotic stresses. While the function of certain CK classes, including trans-zeatin and isopentenyladenine-type CKs, have been studied in detail, the role of cis-zeatin-type CKs (cZs) in plant development and in mediating environmental interactions is less well defined. Here we provide a comprehensive summary of the current knowledge about abundance, metabolism and activities of cZs in plants. We outline the history of their analysis and the metabolic routes comprising cZ biosynthesis and degradation. Further we provide an overview of changes in the pools of cZs during plant development and environmental interactions. We summarize studies that investigate the role of cZs in regulating plant development and defence responses to pathogen and herbivore attack and highlight their potential role as 'novel' stress-response markers. Since the functional roles of cZs remain largely based on correlative data and genetic manipulations of their biosynthesis, inactivation and degradation are few, we suggest experimental approaches using transgenic plants altered in cZ levels to further uncover their roles in plant growth and environmental interactions and their potential for crop improvement., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Herbivore attack elicits changes in cytokinins (CKs), but how these changes influence defense signaling remains poorly described. We investigated the influence of the CK pathway on the well-described inducible defense pathways of Nicotiana attenuata in response to wounding with and without elicitors from the specialist herbivore Manduca sexta. CK pathway manipulation often suffers from substantial side effects on plant growth and development. We therefore used multiple manipulation tools including spray application of CKs, chemically-inducible expression of the CK biosynthesis enzyme isopentenyltransferase, and transient and constitutive RNAi-mediated gene silencing of CK receptors to resolve the function of CKs in plant defense. The results demonstrated that CK concentrations in leaves and perception through CHASE-DOMAIN CONTAINING HIS KINASE 2 (NaCHK2) and NaCHK3 were important for the accumulation of jasmonic acid (JA) and phenolamides and proteinase inhibitor activity. By contrast, the CK pathway did not promote the accumulation of the active JA-isoleucine conjugate and negatively regulated the release of specific green leaf volatile esters. Interestingly, CK signaling also promotes the systemic phenolamide accumulation. We conclude that the CK pathway is an important regulator of herbivory-inducible defense signaling and chemistry, which expands its reported participation in adjusting a plant's physiology to abiotic and biotic stress responses., (© 2015 Max-Planck-Society New Phytologist © 2015 New Phytologist Trust.)

Nearly half a century ago insect herbivores were found to induce the formation of green islands by manipulating cytokinin (CK) levels. However, the response of the CK pathway to attack by chewing insect herbivores remains unclear. Here, we characterize the CK pathway of Nicotiana attenuata (Torr. ex S. Wats.) and its response to wounding and perception of herbivore-associated molecular patterns (HAMPs). We identified 44 genes involved in CK biosynthesis, inactivation, degradation, and signaling. Leaf wounding rapidly induced transcriptional changes in multiple genes throughout the pathway, as well as in the levels of CKs, including isopentenyladenosine and cis-zeatin riboside; perception of HAMPs present in the oral secretions (OS) of the specialist herbivore Manduca sexta amplified these responses. The jasmonate pathway, which triggers many herbivore-induced processes, was not required for these HAMP-triggered changes, but rather suppressed the CK responses. Interestingly CK pathway changes were observed also in systemic leaves in response to wounding and OS application indicating a role of CKs in mediating long distance systemic processes in response to herbivory. Since wounding and grasshopper OS elicited similar accumulations of CKs in Arabidopsis thaliana L., we propose that CKs are integral components of wounding and HAMP-triggered responses in many plant species., (© 2014 The Authors. Journal of Integrative Plant Biology published by Wiley Publishing Asia Pty Ltd on behalf of Institute of Botany, The Chinese Academy of Sciences.)

Field experiments with transgenic plants often reveal the functional significance of genetic traits that are important for the performance of the plants in their natural environments. Until now, only constitutive overexpression, ectopic expression and gene silencing methods have been used to analyze gene-related phenotypes in natural habitats. These methods do not allow sufficient control over gene expression for the study of ecological interactions in real time, of genetic traits that play essential roles in development, or of dose-dependent effects. We applied the sensitive dexamethasone (DEX)-inducible pOp6/LhGR expression system to the ecological model plant Nicotiana attenuata and established a lanolin-based DEX application method to facilitate ectopic gene expression and RNA interference-mediated gene silencing in the field and under challenging conditions (e.g. high temperature, wind and UV radiation). Fully established field-grown plants were used to silence phytoene desaturase and thereby cause photobleaching only in specific plant sectors, and to activate expression of the cytokinin (CK) biosynthesis gene isopentenyl transferase (ipt). We used ipt expression to analyze the role of CKs in both the glasshouse and the field to understand resistance to the native herbivore Tupiocoris notatus, which attacks plants at small spatial scales. By spatially restricting ipt expression and elevating CK levels in single leaves, damage by T. notatus increased, demonstrating the role of CKs in this plant-herbivore interaction at a small scale. As the arena of most ecological interactions is highly constrained in time and space, these tools will advance the genetic analysis of dynamic traits that matter for plant performance in nature., (© 2013 The Authors The Plant Journal © 2013 John Wiley & Sons Ltd.)