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Supersaturating formulations are widely used to improve the oral bioavailability of poorly soluble drugs. However, supersaturated solutions are thermodynamically unstable and such formulations often must include a precipitation inhibitor (PI) to sustain the increased concentrations to ensure that sufficient absorption will take place from the gastrointestinal tract. Recent advances in understanding the importance of drug-polymer interaction for successful precipitation inhibition have been encouraging. However, there still exists a gap in how this newfound understanding can be applied to improve the efficiency of PI screening and selection, which is still largely carried out with trial and error-based approaches. The aim of this study was to demonstrate how drug-polymer mixing enthalpy, calculated with the Conductor like Screening Model for Real Solvents (COSMO-RS), can be used as a parameter to select the most efficient precipitation inhibitors, and thus realise the most successful supersaturating formulations. This approach was tested for three different Biopharmaceutical Classification System (BCS) II compounds: dipyridamole, fenofibrate and glibenclamide, formulated with the supersaturating formulation, mesoporous silica. For all three compounds, precipitation was evident in mesoporous silica formulations without a precipitation inhibitor. Of the nine precipitation inhibitors studied, there was a strong positive correlation between the drug-polymer mixing enthalpy and the overall formulation performance, as measured by the area under the concentration-time curve in in vitro dissolution experiments. The data suggest that a rank-order based approach using calculated drug-polymer mixing enthalpy can be reliably used to select precipitation inhibitors for a more focused screening. Such an approach improves efficiency of precipitation inhibitor selection, whilst also improving the likelihood that the most optimal formulation will be realised.
Objectives Supersaturating formulations hold great promise for delivery of poorly soluble active pharmaceutical ingredients (APIs). To profit from supersaturating formulations, precipitation is hindered with precipitation inhibitors (PIs), maintaining drug concentrations for as long as possible. This review provides a brief overview of supersaturation and precipitation, focusing on precipitation inhibition. Trial-and-error PI selection will be examined alongside established PI screening techniques. Primarily, however, this review will focus on recent advances that utilise advanced analytical techniques to increase mechanistic understanding of PI action and systematic PI selection.
Key Findings. Advances in mechanistic understanding have been made possible by the use of analytical tools such as spectroscopy, microscopy and mathematical and molecular modelling, which have been reviewed herein. Using these techniques, PI selection can instead be guided by molecular rationale. However, more work is required to see wide-spread application of such an approach for PI selection.
Conclusions PIs are becoming increasingly important in enabling formulations. Trial-and-error approaches have seen success thus far. However, it is essential to learn more about the mode of action of PIs if the most optimal formulations are to be realised. Robust analytical tools, and the knowledge of where and how they can be applied, will be essential in this endeavour.
In New South Wales, the Threatened Species Conservation Act 1995 makes provision for the listing of Threatened Ecological Communities (assemblages of species occupying a particular area) as a means to conserving the variety of ecosystems present in the State. Hunter Valley Weeping Myall Woodland is listed as an Endangered Ecological Community under the New South Wales Threatened Species Conservation (TSC) Act 1995 and as a Critically Endangered Ecological Community under the Commonwealth Environment Protection and Biodiversity Conservation (EPBC) Act 1999.
The provenance of populations of Weeping Myall (Acacia pendula, family Fabaceae) in the Hunter Valley has recently been questioned. In this paper we consider the implications of its hypothesized European introduction for listing Hunter Valley Weeping Myall Woodland under the TSC and EPBS Acts. The recognition of any community is contingent on the identification of both a particular assemblage of species and the critical environmental factors that determine their co-occurrence (the area the community occupies in environmental space). Acacia pendula is one of a range of semiarid species which are primarily distributed west of the Great Dividing Range but also occur on Permian sediments in areas receiving the lowest rainfall of the Hunter Valley floor. On this basis we argue there is sufficient evidence to support the listing of Hunter Valley Weeping Myall Woodland under both Acts.
Background: Chronic hepatitis C virus (HCV) infections are causally linked with metabolic comorbidities such as insulin resistance, hepatic steatosis, and dyslipidemia. However, the clinical impact of HCV eradication achieved by direct-acting antivirals (DAAs) on glucose and lipid homeostasis is still controversial. The study aimed to prospectively investigate whether antiviral therapy of HCV with DAAs alters glucose and lipid parameters. Methods: 50 patients with chronic HCV who were treated with DAAs were screened, and 49 were enrolled in the study. Biochemical and virological data, as well as noninvasive liver fibrosis parameters, were prospectively collected at baseline, at the end of treatment (EOT) and 12 and 24 weeks post-treatment. Results: 45 of 46 patients achieved sustained virologic response (SVR). The prevalence of insulin resistance (HOMA-IR) after HCV clearance was significantly lower, compared to baseline (5.3 ± 6.1 to 2.5 ± 1.9, p < 0.001), which is primarily attributable to a significant decrease of fasting insulin levels (18.9 ± 17.3 to 11.7 ± 8.7; p = 0.002). In contrast to that, HCV eradication resulted in a significant increase in cholesterol levels (total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL-C) levels) and Controlled Attenuated Score (CAP), although BMI did not significantly change over time (p = 0.95). Moreover, HOMA-IR correlated significantly with noninvasive liver fibrosis measurements at baseline und during follow-up (TE: r = 0.45; p = 0.003, pSWE: r = 0.35; p = 0.02, APRI: r = 0.44; p = 0.003, FIB-4: r = 0.41; p < 0.001). Conclusion: Viral eradication following DAA therapy may have beneficial effects on glucose homeostasis, whereas lipid profile seems to be worsened.
Wolves (Canis lupus) are currently showing a remarkable comeback in the highly frag-mented cultural landscapes of Germany. We here show that wolf numbers increasedexponentially between 2000 and 2015 with an annual increase of about 36%. Wedemonstrate that the first territories in each newly colonized region were establishedover long distances from the nearest known reproducing pack on active militarytraining areas (MTAs). We show that MTAs, rather than protected areas, served asstepping-stones for the recolonization of Germany facilitating subsequent spreadingof wolf territories in the surrounding landscape. We did not find any significant differ-ence between MTAs and protected areas with regard to habitat. One possible reasonfor the importance of MTAs may be their lower anthropogenic mortality rates com-pared to protected and other areas. To our knowledge, this is the first documented casewhere MTAs facilitate the recolonization of an endangered species across large areas.
The haloarchaeon Haloferax volcanii was shown to contain 145 intergenic and 45 antisense sRNAs. In a comprehensive approach to unravel various biological roles of haloarchaeal sRNAs in vivo, 27 sRNA genes were selected and deletion mutants were generated. The phenotypes of these mutants were compared to that of the parent strain under ten different conditions, i.e. growth on four different carbon sources, growth at three different salt concentrations, and application of four different stress conditions. In addition, cell morphologies in exponential and stationary phase were observed. Furthermore, swarming of 17 mutants was analyzed. 24 of the 27 mutants exhibited a difference from the parent strain under at least one condition, revealing that haloarchaeal sRNAs are involved in metabolic regulation, growth under extreme conditions, regulation of morphology and behavior, and stress adaptation. Notably, 7 deletion mutants showed a gain of function phenotype, which has not yet been described for any other prokaryotic sRNA gene deletion mutant. Comparison of the transcriptomes of one sRNA gene deletion mutant and the parent strain led to the identification of differentially expressed genes. Genes for flagellins and chemotaxis were up-regulated in the mutant, in accordance with its gain of function swarming phenotype. While the deletion mutant analysis underscored that haloarchaeal sRNAs are involved in many biological functions, the degree of conservation is extremely low. Only 3 of the 27 genes are conserved in more than 10 haloarchaeal species. 22 of the 27 genes are confined to H. volcanii, indicating a fast evolution of haloarchaeal sRNA genes.
Shikonin reduces growth of docetaxel-resistant prostate cancer cells mainly through necroptosis
(2021)
Simple Summary: Prostate carcinoma (PCa) is the most common tumor in men with an increasing age-associated risk. Several therapy strategies, one of which is docetaxel (DX) chemotherapy, have been established. However, due to the development of therapy resistance, in which chemotherapy no longer effectively combats the cancer, advanced, metastasized PCa with a poor prognosis may become manifested and therapy inevitably fails. Thus, new treatment options are urgently needed. Shikonin (SHI), from Traditional Chinese Medicine, has revealed promising antitumor activity in several tumor entities. In the current study, the impact of SHI on four therapy-sensitive and four respective DX-resistant PCa cell lines was determined. SHI induced growth inhibition mainly by necroptosis, a type of cell death, in all the tested therapy-sensitive, but more importantly, DX-resistant PCa cell lines. Corresponding molecular alterations contributing to growth inhibition after SHI exposure were found. SHI could, therefore, be a promising additive in treating advanced PCa.
Abstract: The prognosis for advanced prostate carcinoma (PCa) remains poor due to development of therapy resistance, and new treatment options are needed. Shikonin (SHI) from Traditional Chinese Medicine has induced antitumor effects in diverse tumor entities, but data related to PCa are scarce. Therefore, the parental (=sensitive) and docetaxel (DX)-resistant PCa cell lines, PC3, DU145, LNCaP, and 22Rv1 were exposed to SHI [0.1–1.5 μM], and tumor cell growth, proliferation, cell cycling, cell death (apoptosis, necrosis, and necroptosis), and metabolic activity were evaluated. Correspondingly, the expression of regulating proteins was assessed. Exposure to SHI time- and dose-dependently inhibited tumor cell growth and proliferation in parental and DX-resistant PCa cells, accompanied by cell cycle arrest in the G2/M or S phase and modulation of cell cycle regulating proteins. SHI induced apoptosis and more dominantly necroptosis in both parental and DX-resistant PCa cells. This was shown by enhanced pRIP1 and pRIP3 expression and returned growth if applying the necroptosis inhibitor necrostatin-1. No SHI-induced alteration in metabolic activity of the PCa cells was detected. The significant antitumor effects induced by SHI to parental and DX-resistant PCa cells make the addition of SHI to standard therapy a promising treatment strategy for patients with advanced PCa.
Members of the Sm protein family are important for the cellular RNA metabolism in all three domains of life. The family includes archaeal and eukaryotic Lsm proteins, eukaryotic Sm proteins and archaeal and bacterial Hfq proteins. While several studies concerning the bacterial and eukaryotic family members have been published, little is known about the archaeal Lsm proteins. Although structures for several archaeal Lsm proteins have been solved already more than ten years ago, we still do not know much about their biological function, however one can confidently propose that the archaeal Lsm proteins will also be involved in RNA metabolism. Therefore, we investigated this protein in the halophilic archaeon Haloferax volcanii. The Haloferax genome encodes a single Lsm protein, the lsm gene overlaps and is co-transcribed with the gene for the ribosomal L37.eR protein. Here, we show that the reading frame of the lsm gene contains a promoter which regulates expression of the overlapping rpl37R gene. This rpl37R specific promoter ensures high expression of the rpl37R gene in exponential growth phase. To investigate the biological function of the Lsm protein we generated a lsm deletion mutant that had the coding sequence for the Sm1 motif removed but still contained the internal promoter for the downstream rpl37R gene. The transcriptome of this deletion mutant was compared to the wild type transcriptome, revealing that several genes are down-regulated and many genes are up-regulated in the deletion strain. Northern blot analyses confirmed down-regulation of two genes. In addition, the deletion strain showed a gain of function in swarming, in congruence with the up-regulation of transcripts encoding proteins required for motility.
The recent recolonisation of the Central European lowland (CEL) by the grey wolf (Canis lupus) provides an excellent opportunity to study the effect of founder events on endoparasite diversity. Which role do prey and predator populations play in the re-establishment of endoparasite life cycles? Which intrinsic and extrinsic factors control individual endoparasite diversity in an expanding host population? In 53 individually known CEL wolves sampled in Germany, we revealed a community of four cestode, eight nematode, one trematode and 12 potential Sarcocystis species through molecular genetic techniques. Infections with zoonotic Echinococcus multilocularis, Trichinella britovi and T. spiralis occurred as single cases. Per capita endoparasite species richness and diversity significantly increased with population size and changed with age, whereas sex, microsatellite heterozygosity, and geographic origin had no effect. Tapeworm abundance (Taenia spp.) was significantly higher in immigrants than natives. Metacestode prevalence was slightly higher in ungulates from wolf territories than from control areas elsewhere. Even though alternative canid definitive hosts might also play a role within the investigated parasite life cycles, our findings indicate that (1) immigrated wolves increase parasite diversity in German packs, and (2) prevalence of wolf-associated parasites had declined during wolf absence and has now risen during recolonisation.
Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses.
The assembly of a specific polymeric ubiquitin chain on a target protein is a key event in the regulation of numerous cellular processes. Yet, the mechanisms that govern the selective synthesis of particular polyubiquitin signals remain enigmatic. The homologous ubiquitin-conjugating (E2) enzymes Ubc1 (budding yeast) and Ube2K (mammals) exclusively generate polyubiquitin linked through lysine 48 (K48). Uniquely among E2 enzymes, Ubc1 and Ube2K harbor a ubiquitin-binding UBA domain with unknown function. We found that this UBA domain preferentially interacts with ubiquitin chains linked through lysine 63 (K63). Based on structural modeling, in vitro ubiquitination experiments, and NMR studies, we propose that the UBA domain aligns Ubc1 with K63-linked polyubiquitin and facilitates the selective assembly of K48/K63-branched ubiquitin conjugates. Genetic and proteomics experiments link the activity of the UBA domain, and hence the formation of this unusual ubiquitin chain topology, to the maintenance of cellular proteostasis.
Severe acute graft versus host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. Human mesenchymal stromal cells (MSCs) play an important role in endogenous tissue repair and possess strong immune-modulatory properties making them a promising tool for the treatment of steroid-refractory GvHD. To date, a few reports exist on the use of MSCs in treatment of GvHD in children indicating that children tend to respond better than adults, albeit with heterogeneous results. We here present a review of the literature and the clinical course of two instructive pediatric patients with acute steroid-refractory GvHD after haploidentical stem cell transplantation, which exemplify the beneficial effects of third-party transplanted MSCs in treatment of acute steroid-refractory GvHD. Moreover, we provide a meta-analysis of clinical studies addressing the outcome of patients with steroid-refractory GvHD and treatment with MSCs in adults and in children (n = 183; 122 adults, 61 children). Our meta-analysis demonstrates that the overall response-rate is high (73.8%) and confirms, for the first time, that children indeed respond better to treatment of GvHD with MSCs than adults (complete response 57.4% vs. 45.1%, respectively). These data emphasize the significance of this therapeutic approach especially in children and indicate that future prospective studies are needed to assess the reasons for the observed differential response-rates in pediatric and adult patients. Additional file 1: MSCs expansion and release criteria.his file contains a detailed description of the MSCs expansion and release criteria for Case A and Case B.
Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis.
Proteins encoded by small open reading frames (sORFs) have a widespread occurrence in diverse microorganisms and can be of high functional importance. However, due to annotation biases and their technically challenging direct detection, these small proteins have been overlooked for a long time and were only recently rediscovered. The currently rapidly growing number of such proteins requires efficient methods to investigate their structure–function relationship. Herein, a method is presented for fast determination of the conformational properties of small proteins. Their small size makes them perfectly amenable for solution-state NMR spectroscopy. NMR spectroscopy can provide detailed information about their conformational states (folded, partially folded, and unstructured). In the context of the priority program on small proteins funded by the German research foundation (SPP2002), 27 small proteins from 9 different bacterial and archaeal organisms have been investigated. It is found that most of these small proteins are unstructured or partially folded. Bioinformatics tools predict that some of these unstructured proteins can potentially fold upon complex formation. A protocol for fast NMR spectroscopy structure elucidation is described for the small proteins that adopt a persistently folded structure by implementation of new NMR technologies, including automated resonance assignment and nonuniform sampling in combination with targeted acquisition.
Despite recent advances in the treatment of metastatic prostate cancer (PCa), resistance development after taxane treatments is inevitable, necessitating effective options to combat drug resistance. Previous studies indicated antitumoral properties of the natural compound amygdalin. However, whether amygdalin acts on drug-resistant tumor cells remains questionable. An in vitro study was performed to investigate the influence of amygdalin (10 mg/mL) on the growth of a panel of therapy-naïve and docetaxel- or cabazitaxel-resistant PCa cell lines (PC3, DU145, and LNCaP cells). Tumor growth, proliferation, clonal growth, and cell cycle progression were investigated. The cell cycle regulating proteins (phospho)cdk1, (phospho)cdk2, cyclin A, cyclin B, p21, and p27 and the mammalian target of rapamycin (mTOR) pathway proteins (phospho)Akt, (phospho)Raptor, and (phospho)Rictor as well as integrin β1 and the cytoskeletal proteins vimentin, ezrin, talin, and cytokeratin 8/18 were assessed. Furthermore, chemotactic activity and adhesion to extracellular matrix components were analyzed. Amygdalin dose-dependently inhibited tumor growth and reduced tumor clones in all (parental and resistant) PCa cell lines, accompanied by a G0/G1 phase accumulation. Cell cycle regulating proteins were significantly altered by amygdalin. A moderate influence of amygdalin on tumor cell adhesion and chemotaxis was observed as well, paralleled by modifications of cytoskeletal proteins and the integrin β1 expression level. Amygdalin may, therefore, block tumor growth and disseminative characteristics of taxane-resistant PCa cells. Further studies are warranted to determine amygdalin’s value as an antitumor drug.
Background: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. Methods: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. Results: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. Conclusions: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.
Background: Differential RNA-Seq (dRNA-Seq) is a recently developed method of performing primary transcriptome analyses that allows for the genome-wide mapping of transcriptional start sites (TSSs) and the identification of novel transcripts. Although the transcriptomes of diverse bacterial species have been characterized by dRNA-Seq, the transcriptome analysis of archaeal species is still rather limited. Therefore, we used dRNA-Seq to characterize the primary transcriptome of the model archaeon Haloferax volcanii.
Results: Three independent cultures of Hfx. volcanii grown under optimal conditions to the mid-exponential growth phase were used to determine the primary transcriptome and map the 5′-ends of the transcripts. In total, 4749 potential TSSs were detected. A position weight matrix (PWM) was derived for the promoter predictions, and the results showed that 64 % of the TSSs were preceded by stringent or relaxed basal promoters. Of the identified TSSs, 1851 belonged to protein-coding genes. Thus, fewer than half (46 %) of the 4040 protein-coding genes were expressed under optimal growth conditions. Seventy-two percent of all protein-coding transcripts were leaderless, which emphasized that this pathway is the major pathway for translation initiation in haloarchaea. A total of 2898 of the TSSs belonged to potential non-coding RNAs, which accounted for an unexpectedly high fraction (61 %) of all transcripts. Most of the non-coding TSSs had not been previously described (2792) and represented novel sequences (59 % of all TSSs). A large fraction of the potential novel non-coding transcripts were cis-antisense RNAs (1244 aTSSs). A strong negative correlation between the levels of antisense transcripts and cognate sense mRNAs was found, which suggested that the negative regulation of gene expression via antisense RNAs may play an important role in haloarchaea. The other types of novel non-coding transcripts corresponded to internal transcripts overlapping with mRNAs (1153 iTSSs) and intergenic small RNA (sRNA) candidates (395 TSSs).
Conclusion: This study provides a comprehensive map of the primary transcriptome of Hfx. volcanii grown under optimal conditions. Fewer than half of all protein-coding genes have been transcribed under these conditions. Unexpectedly, more than half of the detected TSSs belonged to several classes of non-coding RNAs. Thus, RNA-based regulation appears to play a more important role in haloarchaea than previously anticipated.
Polazeći od teorije paralelne arhitekture koja sve jezične razine smatra generativnima, u radu se iznose rezultati istraživanja suodnosa između reda riječi, tj. reda rečeničnih sastavnica na sintaktičkoj i na fonološkoj razini, i informacijske strukture kao sastavnice rečenične gramatike. Analiza u kojoj je informacijska struktura ravnopravna razina, a ne izvanjska, pragmatički uvjetovana sastavnica, omogućuje semantički informirano tumačenje varijacija u redu riječi u hrvatskom jeziku. Istraživanje rezultati kojega se iznose metodološki predstavlja premošćivanje jaza između formalnih i funkcionalnih pristupa. Kao primjer se uzima hrvatski, koji se tradicionalno smatra jezikom u kojem je red sintaktičkih komponenata (relativno) slobodan, dok se za položaj klitika u njemu smatra da je (relativno) ograničen. Na brojnim primjerima u radu pokazuje se kako klitike i grozdovi klitika svojim smještajem unutar linearnog rečeničnog ustrojstva ne predstavljaju nepravilnost sustava, nego oblik dinamiziranja rečeničnoga sadržaja koji izvorni govornici prihvaćaju kao otvorenu mogućnost. U dosadašnjim su se istraživanjima takvoj analizi postavljale dvije ključne prepreke. Prva se tiče bavljenja isključivo tzv. „neutralnim”, kontekstualno neuvjetovanim tipovima rečenica, dakle onima koje uglavnom odgovaraju na pitanje O čemu se radi? Druga se tiče nedostatka empirijskih istraživanja, kako korpusnih, tako i psiholingvističkih, kojima se otvara potpuno nov uvid u jezičnu strukturu i istančane mogućnosti njezine izražajnosti na informacijskoj razini. U radu se bavim obama uočenim problemima.
HIV ist heutzutage eine gut behandelbare, chronische Erkrankung. Insbesondere bei chronischen Erkrankungen ist es entscheidend, auch die psychischen und physischen Auswirkungen auf die Lebenssituation zu untersuchen und dabei auch geschlechtsspezifische Aspekte in der gesundheitsbezogenen Lebensqualität von PLWH mit einzuschließen.
Ziel dieser monozentrischen Beobachtungsstudie ist es, die gesundheitsbezogene Lebensqualität von Patientinnen und Patienten des HIVCENTERs Frankfurt darzustellen und diesbezügliche Einflussfaktoren zu identifizieren. Im Zuge dessen wurden zusätzlich geschlechtsspezifische Unterschiede ausgewertet. Der Mental Component Score stellte die primäre Zielgröße der Studie dar, der Physical Component Score die sekundäre.
Zur Erhebung der gesundheitsbezogenen Lebensqualität wurde der SF-12v2 Fragebogen verwendet, der insgesamt zwölf Fragen beinhaltet. Inhaltlich gliedert sich der Bogen in acht Skalen und zwölf Items, die den Mental- und Physical Component Score bilden. Zur näheren Erfassung der aktuellen Lebenssituation der Patientinnen und Patientinnen des HIVCENTERs Frankfurt, wurde ein eigens für die Studie entwickelter Fragebogen verwendet. Dieser erfasste mit 19 Fragen unter anderem soziodemographische Daten, sowie Parameter zu Religiosität oder Sexualität. Retrospektive Daten aus der Epidem-Datenbank des HIVCENTERs und aus den Patientinnen- und Patientenakten wurden ebenfalls in die Auswertung einbezogen.
Die statistische Auswertung beinhaltete neben deskriptiven Methoden, einfache Varianzanalysen für geschlechtsunabhängige Zusammenhänge und Varianzanalysen mit Interaktion für das Geschlecht zur Ermittlung von geschlechtsspezifischen Einflussgrößen. Des Weiteren wurden Spearmankorrelationen berechnet und zur Identifikation von potenziellen Prädiktoren Regressionen mit Rückwärtsausschluss durchgeführt. Für beide Zielgrößen wurde identisch verfahren. Alle statistischen Tests waren zweiseitig und nutzen ein Signifikanzniveau von alpha=5%.
Im Zeitraum von September 2016 bis Mai 2017 wurden insgesamt 275 Patientinnen und Patienten in die Studie eingeschlossen, darunter 123 Frauen, 150 Männer und 2 transgender Personen. Letztere wurden aufgrund der geringen Fallzahl nicht über die deskriptive Statistik hinaus in den Berechnungen berücksichtigt. Das durchschnittliche Alter in der Studienpopulation betrug 46 Jahre. Frauen hatten ein Durchschnittsalter von 44, Männer von 48 Jahren. 97% der Patientinnen und Patienten waren zum Erhebungszeitpunkt unter antiretroviraler Therapie. Im Durchschnitt erzielten die Teilnehmerinnen und Teilnehmer im Vergleich mit der Referenzpopulation einen unterdurchschnittlichen Mental Component Score von 46. Die Frauen der Studie erzielten einen signifikant schlechteren MCS als die Männer (45 vs. 48; p=0,02). Im Kontext mit den übrigen Prädiktoren des Regressionsmodells erreichten Frauen einen um durchschnittlich 13 Punkte schlechteren MCS als Männer (B=-13; p=<0,001). Als geschlechtsunabhängige negative Prädiktoren auf den MCS stellten sich unter anderem regelmäßiger Alkohol- und Drogenkonsum heraus, sowie das Unterlassen von regelmäßigem Sport oder eine negative Zukunftsaussicht. Als geschlechtsabhängiger negativer Prädiktor erwies sich bei den Frauen eine afrikanische versus westeuropäische Herkunft (B=-5; p=0,028). Arbeitslosigkeit stellte sich bei Männern als geschlechtsabhängiger negativer Prädiktor heraus (B=-5; p=0,033).
Vorliegende Dissertation macht deutlich, dass PLWH auch heute noch eine unterdurchschnittliche gesundheitsbezogene Lebensqualität aufweisen und darüber hinaus deutliche geschlechtsabhängige Unterschiede existieren. HIV-positive Frauen erreichten in dieser Studie signifikant schlechtere Werte für den Mental Component Score als Männer und waren hinsichtlich negativer Einflussgrößen überrepräsentiert. Anhand der hier verwendeten Fragebögen wird es behandelnden Ärztinnen und Ärzten innerhalb der Routinesprechstunde ermöglicht, ein regelmäßiges Monitoring der HRQoL durchzuführen und auch ihren Verlauf zu beurteilen. Zudem wäre ein Screening nach den in dieser Arbeit ermittelten negativen Prädiktoren der HRQoL möglich, wodurch entsprechenden Patientinnen und Patienten ein zielgruppenspezifisches Angebot erhalten könnten.
Verschiedene sprachwissenschaftliche Denkansätze und Ausgangspunkte bringen von denselben Forschungsansätzen ausgehend unterschiedliche Methoden und theoretische Auffassungen hervor. Als Produkte verschiedener Forschungsverfahren ergeben sich in demselben Teilbereich manchmal auch kontroverse Definitionen. Die Problematik der Kollokationen ist auch eine umstrittene Frage der Linguistik. Die Umstrittenheit betrifft sowohl die Fragen der Deskription des Charakters dieser sprachlichen Erscheinungen als auch deren Abgrenzung, sprachwissenschaftliche Einreihung und Klassifikation.
In dieser Studie befassen wir uns mit der Darstellung der Heterogenität von Kollokationsauffassungen sowohl in der einheimischen als auch in der internationalen Linguistik...
Background: Natural history museums receive a rapidly growing number of requests for tissue samples from preserved specimens for DNA-based studies. Traditionally, dried vertebrate specimens were treated with arsenic because of its toxicity and insect-repellent effect. Arsenic has negative effects on in vivo DNA repair enzymes and consequently may inhibit PCR performance. In bird collections, foot pad samples are often requested since the feet were not regularly treated with arsenic and because they are assumed to provide substantial amounts of DNA. However, the actual influence of arsenic on DNA analyses has never been tested. Findings: PCR success of both foot pad and body skin samples was significantly lower in arsenic-treated samples. In general, foot pads performed better than body skin samples. Moreover, PCR success depends on collection date in which younger samples yielded better results. While the addition of arsenic solution to the PCR mixture had a clear negative effect on PCR performance after the threshold of 5.4 μg/μl, such high doses of arsenic are highly unlikely to occur in dried zoological specimens. Conclusions: While lower PCR success in older samples might be due to age effects and/or DNA damage through arsenic treatment, our results show no inhibiting effect on DNA polymerase. We assume that DNA degradation proceeds more rapidly in thin tissue layers with low cell numbers that are susceptible to external abiotic influences. In contrast, in thicker parts of a specimen, such as foot pads, the outermost horny skin may act as an additional barrier. Since foot pads often performed better than body skin samples, the intention to preserve morphologically important structures of a specimen still conflicts with the aim to obtain optimal PCR success. Thus, body skin samples from recently collected specimens should be considered as alternative sources of DNA.
In zahlreichen, in der Einleitung bereits näher beschriebenen Studien konnte anxiolytische Wirksamkeit des patentierten ätherischen Öls Silexan sowohl im Tiermodell, als auch am Menschen zur Therapie subsyndromaler und generalisierter Angsterkrankungen demonstriert werden.
Das Ziel der vorliegenden Dissertation war es, den zugrunde liegenden pharmakologischen Wirkmechanismus zu untersuchen. Nach eingehender Analyse der Targets klassischer Anxiolytika, richtete sich der Fokus auf spannungsabhängige Calciumkanäle, die die Bindungsstelle des Gabapentinoids Pregabalin enthalten. Die mögliche Modulation der Kanäle wurde an PC-Zellen, einem Modell neuronaler Vorläuferzellen, murinen Synaptosomen, aber auch in primären Neuronen der für die Genese der Angsterkrankungen relevanten Hirnareale Hippocampus und Cortex untersucht. Die Kanalexpression, sowie - distribution in den unterschiedlichen Geweben wurde charakterisiert und die Frage erörtert, ob Silexan spezifische Modulation eines bestimmten Kanalsubtyps vermittelt oder unspezifisch alle Kanäle dieser Gattung inhibiert. Um dies näher zu beleuchten wurden elektrophysiologische Messungen an transfizierten Zellen durchgeführt, die jeweils nur einen Subtyp der Familie spannungsabhängiger Calciumkanäle exprimieren. Zur weiteren Aufklärung des Wirkmechanismus wurde auch die mögliche Involvierung G-Protein gekoppelter Rezeptoren ermittelt.
Der zweite Teil der vorliegenden Untersuchung widmet sich der Klärung potentieller antidepressiver Wirkungen durch mögliche neurotrophe Effekte. Primäre hippocampale Neurone und PC12-Zellen wurden hierzu u.a. auf prä- und postsynaptische Marker, Ausdifferenzierungsmarker, sowie Neuritenwachstum hin analysiert.
Recent clinical data support the clinical use of oral lavender oil in patients suffering from subsyndromal anxiety. We identified the molecular mechanism of action that will alter the perception of lavender oil as a nonspecific ingredient of aromatherapy to a potent anxiolytic inhibiting voltage dependent calcium channels (VOCCs) as highly selective drug target. In contrast to previous publications where exorbitant high concentrations were used, the effects of lavender oil in behavioral, biochemical, and electrophysiological experiments were investigated in physiological concentrations in the nanomolar range, which correlate to a single dosage of 80 mg/d in humans that was used in clinical trials. We show for the first time that lavender oil bears some similarities with the established anxiolytic pregabalin. Lavender oil inhibits VOCCs in synaptosomes, primary hippocampal neurons and stably overexpressing cell lines in the same range such as pregabalin. Interestingly, Silexan does not primarily bind to P/Q type calcium channels such as pregabalin and does not interact with the binding site of pregabalin, the α2δ subunit of VOCCs. Lavender oil reduces non-selectively the calcium influx through several different types of VOCCs such as the N-type, P/Q-type and T-type VOCCs. In the hippocampus, one brain region important for anxiety disorders, we show that inhibition by lavender oil is mainly mediated via N-type and P/Q-type VOCCs. Taken together, we provide a pharmacological and molecular rationale for the clinical use of the oral application of lavender oil in patients suffering from anxiety.
Gloydius is a widespread pitviper group occurring from Eastern Europe to Korea and Siberia, with only one known species, G. himalayanus (Günther, 1864), found south of the Himalayas. We provide combined genetic and morphological data for G. himalayanus from specimens collected from Himachal Pradesh, India. Bayesian Inference and Maximum Likelihood phylogenetic analysis were performed on four concatenated mitochondrial genes, along with a multi-locus coalescent analysis of these and five additional nuclear genes. Our results indicate that G. himalayanus from the Chamba Valley, in western Himachal Pradesh, are highly distinct from the remaining studied populations. Haplotype networks of each nuclear locus showed that G. himalayanus contains high haplotype diversity with low haplotype sharing between the Chamba Valley population and populations from further west. Principal component analysis and canonical variate analysis conducted on morphological data of live and museum specimens also highlight the morphological distinctiveness of the Chamba population and we herein describe this population as a new species, Gloydius chambensis sp. nov. Recent descriptions of other new species of snakes from this valley underscores its isolation and suggests that further herpetological investigation of the highly dissected landscapes of the western Himalayas is needed to assess the true diversity of the region.
CD8+ T cells are key players in immunity against intracellular infections and tumors. The main cytokine associated with these protective responses is interferon-γ (IFN-γ), whose production is known to be regulated at the transcriptional level during CD8+ T cell differentiation. Here we found that microRNAs constitute a posttranscriptional brake to IFN-γ expression by CD8+ T cells, since the genetic interference with the Dicer processing machinery resulted in the overproduction of IFN-γ by both thymic and peripheral CD8+ T cells. Using a gene reporter mouse for IFN-γ locus activity, we compared the microRNA repertoires associated with the presence or absence of IFN-γ expression. This allowed us to identify a set of candidates, including miR-181a and miR-451, which were functionally tested in overexpression experiments using synthetic mimics in peripheral CD8+ T cell cultures. We found that miR-181a limits IFN-γ production by suppressing the expression of the transcription factor Id2, which in turn promotes the Ifng expression program. Importantly, upon MuHV-4 challenge, miR-181a-deficient mice showed a more vigorous IFN-γ+ CD8+ T cell response and were able to control viral infection significantly more efficiently than control mice. These data collectively establish a novel role for miR-181a in regulating IFN-γ–mediated effector CD8+ T cell responses in vitro and in vivo.
Die Herzinsuffizienz im hohen Lebensalter spielt wegen der demografischen Entwicklung in Deutschland eine zunehmende Rolle im perioperativen Setting der Herzchirurgie. Auch nehmen strukturelle Schäden und Dysfunktionen am Herzen aufgrund von chronischen kardiovaskulären Erkrankungen zu. Diese bedürfen oftmals einer operativen Intervention als Therapie. Zum perioperativen Monitoring werden verschiedene Laborwerte herangezogen, um mögliche Komplikationen frühzeitig zu erkennen. In der vorliegenden Studie wurde das Augenmerk auf Hochrisikopatienten mit Herzinsuffizienz gelegt. Die Fragestellung behandelt, ob sich gewisse Entzündungsmarker bei Hochrisikopatienten, vor allem im hohen Lebensalter, bei verschiedenen Risikogruppen unterscheiden. Es handelt sich um eine prospektive Beobachtungsstudie, in der 94 Patienten perioperativ untersucht wurden. Diese wurden in zwei Gruppen mit jeweils 47 Patienten unterteilt. Die eine enthielt Patienten unter 75 Jahren mit einer linksventrikulären Ejektionsfraktion <35%, einer operationsbedürftigen Mehrklappen-Erkrankung oder einer Herzklappendysfunktion, kombiniert mit einer operationswürdigen koronaren Herzkrankheit. In der zweiten Gruppe wählte man Patienten in einem Alter ab 75 Jahren mit einer operationsbedürftigen Herzkrankheit. Bestimmt wurden die Entzündungsparameter CRP, Procalcitonin, Interleukin 6 und Interleukin 8. Zusätzlich wurde NT-pro-BNP als Marker für Herzinsuffizienz bestimmt. Die Blutentnahmen erfolgten präoperativ, unmittelbar postoperativ, am 1.,2. und 5. Tag postoperativ. Die präoperativen Werte wurden mit dem Risikoprofil der Patienten in Korrelation gesetzt. Dabei stach heraus, dass bei Patienten mit stattgehabter kardialer Dekompensation die Werte von CRP, NT-proBNP, IL6 und IL8 signifikant erhöht waren. Postoperativ erlitten diese Patienten häufiger eine Rethorakotomie. Außerdem ergab sich ein signifikanter Zusammenhang zwischen der Höhe der postoperativen Entzündungsparameter und dem Auftreten einer postoperativen Sepsis oder Infektion. Hier zeigte sich, dass CRP erst ab dem 5. Tag postoperativ als Indikator für eine solche gewertet werden kann, während Procalcitonin, IL6 und IL8 schon unmittelbar postoperativ als Parameter für das Auftreten einer Sepsis oder Infektion herangezogen werden können. In der vorliegenden Studie wurden jedoch nicht die Zeitpunkte der postoperativen Komplikationen bestimmt, was eine Prüfung auf Unterschied mit den postoperativen Etnzündungswerten erschwert. Zwischen den perioperativen Verläufen der bestimmten Parameter gab es zwischen den beiden Gruppen keinen signifikanten Unterschied. Dies impliziert, dass eine Ejektionsfraktion <35%/eine Mehrklappen-Erkrankung und ein Alter über 75 Jahren bei gröstenteils normwertiger EF als ebenbürtige Risikofaktoren angesehen werden können.
Mesoporous silica has emerged as an enabling formulation for poorly soluble active pharmaceutical ingredients (APIs). Unlike other formulations, mesoporous silica typically does not inhibit precipitation of supersaturated API therefore, a suitable precipitation inhibitor (PI) should be added to increase absorption from the gastrointestinal (GI) tract. However, there is limited research about optimal processes for combining PIs with silica formulations. Typically, the PI is added by simply blending the API-loaded silica mechanically with the selected PI. This has the drawback of an additional blending step and may also not be optimal with regard to release of drug and PI. By contrast, loading PI simultaneously with the API onto mesoporous silica, i.e. co-incorporation, is attractive from both a performance and practical perspective. The aim of this study was to demonstrate the utility of a co-incorporation approach for combining PIs with silica formulations, and to develop a mechanistic rationale for improvement of the performance of silica formulations using the co-incorporation approach. The results indicate that co-incorporating HPMCAS with glibenclamide onto silica significantly improved the extent and duration of drug supersaturation in single-medium and transfer dissolution experiments. Extensive spectroscopic characterization of the formulation revealed that the improved performance was related to the formation of drug-polymer interactions already in the solid state; the immobilization of API-loaded silica on HPMCAS plates, which prevents premature release and precipitation of API; and drug-polymer proximity on disintegration of the formulation, allowing for rapid onset of precipitation inhibition. The data suggests that co-incorporating the PI with the API is appealing for silica formulations from both a practical and formulation performance perspective.
Amorphous formulation technologies to improve oral absorption of poorly soluble active pharmaceutical ingredients (APIs) have become increasingly prevalent. Currently, polymer-based amorphous formulations manufactured by spray drying, hot melt extrusion (HME), or co-precipitation are most common. However, these technologies have challenges in terms of the successful stabilization of poor glass former compounds in the amorphous form. An alternative approach is mesoporous silica, which stabilizes APIs in non-crystalline form via molecular adsorption inside nano-scale pores. In line with these considerations, two poor glass formers, haloperidol and carbamazepine, were formulated as polymer-based solid dispersion via HME and with mesoporous silica, and their stability was compared under accelerated conditions. Changes were monitored over three months with respect to solid-state form and dissolution. The results were supported by solid-state nuclear magnetic resonance spectroscopy (SS-NMR) and scanning electron microscopy (SEM). It was demonstrated that mesoporous silica was more successful than HME in the stabilization of the selected poor glass formers. While both drugs remained non-crystalline during the study using mesoporous silica, polymer-based HME formulations showed recrystallization after one week. Thus, mesoporous silica represents an attractive technology to extend the formulation toolbox to poorly soluble poor glass formers.
The ubiquitin (Ub) code denotes the complex Ub architectures, including Ub chains of different length, linkage-type and linkage combinations, which enable ubiquitination to control a wide range of protein fates. Although many linkage-specific interactors have been described, how interactors are able to decode more complex architectures is not fully understood. We conducted a Ub interactor screen, in humans and yeast, using Ub chains of varying length, as well as, homotypic and heterotypic branched chains of the two most abundant linkage types – K48- and K63-linked Ub. We identified some of the first K48/K63 branch-specific Ub interactors, including histone ADP-ribosyltransferase PARP10/ARTD10, E3 ligase UBR4 and huntingtin-interacting protein HIP1. Furthermore, we revealed the importance of chain length by identifying interactors with a preference for Ub3 over Ub2 chains, including Ub-directed endoprotease DDI2, autophagy receptor CCDC50 and p97-adaptor FAF1. Crucially, we compared datasets collected using two common DUB inhibitors – Chloroacetamide and N-ethylmaleimide. This revealed inhibitor-dependent interactors, highlighting the importance of inhibitor consideration during pulldown studies. This dataset is a key resource for understanding how the Ub code is read.
Ergebnisse einer modifizierten Velopharynxplastik bei gaumenspaltbedingter Velopharynxinsuffizienz
(2005)
Physiologische Nasalität basiert auf einer normalen Funktion des velopharyngealen Sphinkters. Der velopharyngeale Mechanismus trägt wesentlich zur Entstehung des Sprechklanges und der Verständlichkeit bei. Die Kinder mit operierter Lippen-Kiefer-Gaumenspalte, die bei gaumenspaltbedingter Velo-Pharynx-Insuffizienz keine artikulatorische Unauffälligkeit erreichen, erhalten eine sprechverbessernde Operation (Inzidenz in Frankfurt 2,7%). In dieser Studie werden eine Modifikation der Velopharynxplastik nach Sanvenero-Rosselli sowie die damit erreichten Untersuchungsergebnisse vorgestellt. Die Ergebnisse von drei Gruppen werden gegenübergestellt; eine Gruppe mit primären Patienten (die von Geburt an betreut wurden), eine Gruppe von „Quereinsteigern“ (jene sekundäre Patienten, die andernorts voroperiert wurden und bei denen die Velopharynxplastik in Frankfurt durchgeführt wurde) und eine sprachgesunde Kontrollgruppe. Neben einer anamnestischen Befragung anhand eines Fragebogens, der die Inhalte Selbsteinschätzung der Artikulation, Behinderung der Nasenatmung, Schnarchen, Hörfähigkeit, Notwendigkeit einer logopädischen Übungsbehandlung umfasste, fand eine globale linguistische Befunderhebung und die Einstufung in eine mehrstufige Skala statt. Es erfolgte eine objektiv-instrumentelle Messung der Nasalanz mit Hilfe des NasalView-Gerätes (Shaheen Awan, Tiger Elektronics) anhand einer modifizierten Version des Heidelberger Rhinophoniebogens. Es wurden rhinomanometrische Kenngrößen, die eine eindeutige Objektivierung der momentanen Durchgängigkeit der Nase erlauben, mit Einsatz des Rhinotest 2000 (Allergopharma) erhoben. Bei der linguistischen Befunderhebung zeigen 67% der primären und 59% der sekundären Patienten eine unauffällige Artikulationsqualität. Keine bzw. eine minimale Rhinolalie aperta weisen 72% der primären Patienten auf. Nasalität selbst ist ein schwer zu operationalisierender Parameter. Das NasalView ist ein Messgerät, welches die Nasalanz - ein akustisches Maß für den nasalen Anteil im Sprechklang - misst. Ein signifikanter Unterschied in den untersuchten Gruppen bezüglich der Nasalanzwerte ausgewählter Items besteht nicht. Bei der Rhinomanometrie zeigt sich, dass das Eigenstromverhalten der Nase bei der primären Gruppe dem der nichtoperierten gesunden Vergleichsgruppe ähnelt. Es wird eine regelrechte nasale Luftdurchgängigkeit gewährleistet, was auf optimale Bedingungen vor Ort schließen lässt. Bei der Resistenzmessung ist der gemessene Strömungswiderstand in der primären Gruppe gleich niedrig dem der in der Gruppe der gesunden Probanten. Neben dem Erreichen einer unbehinderten Nasenatmung steht die Hörfähigkeit, einschließlich einer ungestörten Funktion der Tuba auditiva im Zentrum des Interesses. Kinder mit Gaumenspalte haben häufig eine Tubenfehlfunktion, die zu einer chronischen Minderbelüftung des Mittelohres und zu einer Schallleitungsstörung und Schwerhörigkeit führen kann. Zur Vermeidung schwerwiegender Folgen sieht die Behandlung von Mittelohrerkrankungen in der Frühtherapie die Parazentese mit Paukenröhrcheneinlage vor. Patienten mit Gaumenspalte profitieren bezüglich ihres Hörvermögens im Erwachsenenalter von der Paukendrainage im Kindesalter. 84,6% der untersuchten Patienten zeigen keinen pathologischen Befund. Lediglich 11,4% der sekundären Patienten bemerken mitunter Otitiden und 15,4% der primären Patienten berichten über geringfügige Schwerhörigkeit. Die aus der Lippen-Kiefer-Gaumenspalte resultierenden Störungen essentieller Funktionen machen eine optimale Therapie und Rehabilitation notwendig und den Einfluss des operativen Konzeptes auf das Sprechen und die Sprache deutlich. Die Frage, warum bei so niedriger Inzidenz der Velopharynxplastik, diese überhaupt noch nötig ist, wird umfassend diskutiert. Geht man den Ursachen auf den Grund, so müssen lokale und allgemeine, sich häufig überschneidende und potenzierende Faktoren berücksichtigt werden. Gehen chirurgische Interventionen mit einwandfreier Technik von korrekter Anatomie aus, liegen Gründe in der Struktur der Muskulatur oder ihrem Timing? Bei stimmigem psychosozialem Umfeld, bei Berücksichtigung des heilpädagogischen Ansatzes, und wenn Störungen im Bereich der Psychomotorik und Sprachentwicklung ausgeschlossen werden, sind Gründe vielleicht in der Psycholinguistik zu suchen.
Basierend auf dem kognitiv-motivationalen Prozessmodell von Vollmeyer und Rheinberg (1998) werden zwei Studien vorgestellt, die sich mit dem selbst regulierten Lernen mit Multimedia im Physikunterricht beschäftigen. Das kognitiv-motivationale Prozessmodell beschreibt, wie die Eingangsmotivation über Mediatorvariablen auf die Leistung, in diesem Fall den Wissenserwerb, wirkt. Wie in früheren Studien gezeigt werden konnte, besteht die Eingangsmotivation aus vier voneinander unabhängigen Faktoren: Herausforderung, Interesse, Erfolgswahrscheinlichkeit und Misserfolgsbefürchtung. Als Mediatorvariablen wurden in beiden Studien die von Schülern verwendeten Strategien, der motivationale Zustand während des Lernens und der funktionale Zustand während des Lernens angenommen. Bei den Strategien handelt es sich genauer gesagt um das beobachtbare Verhalten der Schülers während des Lernens. Mit Motivationalem Zustand sind die gleichen Faktoren wie bei der Eingangsmotivation gemeint, nur dass jetzt die Lerner schon Erfahrung mit der Aufgabe haben. Der funktionale Zustand gibt an, wie sehr ein Lerner auf die Aufgabe konzentriert ist. Ein Konstrukt, das diesen Zustand gut beschreibt, ist Csikszentmihalyis Flow. Ziel der Pilotstudie war es, das Lernen im Schulalltag mit einem Physikprogramm am Computer zu untersuchen. Dazu wurden folgende Hypothesen aufgestellt: 1) Die Eingangsmotivation wirkt auf die Mediatoren. 2) Die Mediatoren wirken auf die Leistung. 3) Die Eingangsmotivation wirkt auf die Mediatoren und diese wiederum auf die Leistung (Prüfung des Prozessmodells). 4) Es gibt Geschlechtsunterschiede bei den Variablen: Eingangsmotivation, hier insbesonders beim Interesse, den Mediatoren und der Leistung. Schüler sollten bei allen Variablen besser abschneiden. In der Pilotstudie hatten 32 SchülerInnen einer 11. Klasse 30 Minuten Zeit, sich ein Physiklernprogramm zum Thema Drehmomente (Wünscher & Ehmke, IPN Kiel, 2002) selbständig zu erarbeiten. Neben der Eingangsmotivation vor Beginn des Lernens (FAM, Rheinberg, Vollmeyer & Burns, 2001) wurde die Motivation und Flow während des Lernens gemessen (FKS; Rheinberg, Vollmeyer & Engeser, 2003; 8 Items aus dem FAM). Die Vorgehensweise am PC wurde mit Hilfe eines Videoüberwachungsprogramms (ScreenVirtuoso) und eines Monitoringprogramms (StatWin) aufgezeichnet. Indikatoren für das Lernen waren die im Anschluss an die Bearbeitung des Lernprogramms in einem Lernfragebogen zu der Lerneinheit erzielte Punktzahl. Als Kontrollvariable wurde zu Beginn das Vorwissen erfasst. Indikatoren für die Strategien waren a) die Schnelligkeit der Bearbeitung (Anzahl der bearbeiteten Abschnitte und Bearbeitungszeit der einzelnen Abschnitte), b) die Aktivität (Mausklicks) und c) die Verwendung der Animationen (Schnelligkeit des Auffindens, Anzahl, Länge und Art und Weise der Nutzung). Die Hypothesen konnten bestätigt werden. Das kognitiv-motivationale Prozessmodell konnte in den meisten Teilen bestätigt werden: Die Eingangsmotivation, vor allem das Interesse, wirkt über Mediatoren, hier besonders über die verwendeten Strategien, auf die Leistung. Die Geschlechtsunterschiede beim Lernen mit einem Physikprogramm am PC (in der Eingangsmotivation, den Vorgehensweisen, und der gezeigten Leistung) waren stärker als erwartet zu Gunsten der Schüler. Die Geschlechtsunterschiede waren bei allen Variablen signifikant. Damit Schülerinnen in dem untersuchten Bereich zukünftig bessere Ergebnisse erzielen, könnte es hilfreich sein, ihr situationales Interesse und die Erfolgszuversicht zu erhöhen. In der Hauptstudie wurde daher der Versuch gemacht, durch eine Veränderung der Instruktion die Motivation, besonders die der Schülerinnen, beim Arbeiten mit einem Physiklernprogramm zu steigern. Hier sollten besonders zwei Faktoren der Eingangsmotivation wichtig sein. Wenn es eine Rolle spielt, für wie fähig sich ein Schüler hält, dann müsste es möglich sein, durch entsprechende Instruktionen die Erfolgswahrscheinlichkeit zu stärken und damit das Lernergebnis zu verbessern. Dies erschien im Hinblick auf die schlechte Erfolgswahrscheinlichkeit der Schülerinnen in der Pilotstudie geboten. Weiterhin wurde der Einfluss, den das Interesse auf die Leistung hat, diskutiert und entsprechend in der Hauptstudie versucht, das Interesse der Schüler zu steigern. Die Hypothesen lauteten: 1) Bei den Experimentalgruppen wird durch die Instruktion die Eingangsmotivation verändert. 2) Da der Einfluss von Vorwissen nicht auszuschließen ist, wird es kontrolliert. Es wird erwartet, dass das Vorwissen mit der Leistung signifikant korreliert. Bei den Experimentalgruppen wird mehr Vorwissen aktiviert als bei der Kontrollgruppe. 3) Durch die Manipulation sollen sich auch die Mediatoren des Lernprozesses verändern. 4) Die Leistung soll sich in Abhängigkeit von der Instruktion in den Experimentalgruppen verbessern. Der Versuchsablauf blieb im Wesentlichen unverändert. In einem 3 x 2 Design wurden 60 Schüler (30 weiblich, 30 männlich) aus der Klassenstufe 11 getestet. Es gab eine Instruktion, worin die Schülerinnen über die Bedrohung durch Geschlechtsrollenstereotype informiert wurden und gebeten wurden, dagegen an zu arbeiten. In einer zweiten Experimentalgruppe sollte das Interesse aller Probanden erhöht werden. Die Ergebnisse waren weitgehend hypothesenkonform. Es konnte gezeigt werden, dass sich mittels der Instruktion die Eingangsmotivation verbesserte und sich dadurch auch Flow-Erleben und Motivation während des Lernens erhöhten, wodurch eine bessere Leistung zustande kommen konnte. Dies ist ein Ergebnis, das für den Schulalltag von Schülern und Lehrern berücksichtigt und umgesetzt werden sollte. Lehrer sollten Schülerinnen in mathematisch-naturwissenschaftlichen Fächern auf das Geschlechtsrollenstereotyp aufmerksam machen, da dies zu besseren Strategien und Leistungen bei deren Lernen führt. Sie sollten überdies das Interesse der Schülerinnen wecken, durch Betonung der persönlichen Relevanz des Themas ebenso wie durch noch zu untersuchende andere, Interesse besser weckende Instruktionen. Allerdings war in der Hauptstudie das Interesse in der Interessegruppe nicht wie erwartet gestiegen, dagegen veränderten sich andere Faktoren der Eingangsmotivation. Die Schüler hielten einen Erfolg für wahrscheinlicher, die Schülerinnen waren ängstlicher. Dennoch verhielten sich die Schülerinnen dieser Gruppe strategisch besser und erzielten auch bessere Leistungen. Die Schüler hatten ein höheres Flow-Erleben, erzielten aber keine besseren Leistungen. In der Stereotypgruppe gab es ebenfalls signifikante Verbesserungen bei allen Prozessvariablen bei den Schülerinnen. Sie hatten erwartungsgemäß eine höhere Erfolgswahrscheinlichkeit, zeigten bessere Lernstrategien und erzielten bessere Leistungen als die Schülerinnen der Kontrollgruppe. Während in der Kontrollgruppe fast alle Geschlechtsunterschiede der Pilotstudie repliziert wurden, gab es in den Experimentalgruppen keine Geschlechtsunterschiede mehr. Insbesondere die Schülerinnen hatten von der Manipulation profitiert. Die Gründe für die Veränderungen in den Experimentalgruppen wurden diskutiert und weitere Forschungsansätze aufgeführt. Erfreulich ist, dass im Schulalltag beim Lernen mit einem Computerprogramm Flow-Erleben erzeugt werden konnte. Ebenfalls erfreulich ist, dass der Benachteiligung von Schülerinnen beim Lernen mit Physikprogrammen wirksam begegnet werden konnte. Der Lernprozess konnte ein weiteres Stück im Schulalltag erforscht werden und mit Hilfe von Monitoringprogrammen konnten objektive Indikatoren für das Vorgehen bzw. die Strategien von Schülern beim Lernen am Computer bestimmt werden. Als günstiger Strategieindikator erwies sich vor allem die Länge und Güte der Nutzung von Animationen. Das kognitiv-motivationale Prozessmodell konnte erneut bestätigt werden und sollte in weiteren Forschungen als theoretischer Hintergrund herangezogen werden.
Objectives: The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively.
Methods: When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7–21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)).
Results: Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up.
Conclusion: DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.
Whereas the lack of biomarkers in penile cancer (PeCa) impedes the development of efficacious treatment protocols, preliminary evidence suggests that c-MET and associated signaling elements may be dysregulated in this disorder. In the following study, we investigated whether c-MET and associated key molecular elements may have prognostic and therapeutic utility in PeCa. Formalin-fixed, paraffin-embedded tumor tissue from therapy-naïve patients with invasive PeCa was used for tissue microarray (TMA) analysis. Immunohistochemical staining was performed to determine the expression of the proteins c-MET, PPARg, β-catenin, snail, survivin, and n-MYC. In total, 94 PeCa patients with available tumor tissue were included. The median age was 64.9 years. High-grade tumors were present in 23.4%, and high-risk HPV was detected in 25.5%. The median follow-up was 32.5 months. High expression of snail was associated with HPV-positive tumors. Expression of β-catenin was inversely associated with grading. In both univariate COX regression analysis and the log-rank test, an increased expression of PPARg and c-MET was predictive of inferior disease-specific survival (DSS). Moreover, in multivariate analysis, a higher expression of c-MET was independently associated with worse DSS. Blocking c-MET with cabozantinib and tivantinib induced a significant decrease in viability in the primary PeCa cell line UKF-PeC3 isolated from the tumor tissue as well as in cisplatin- and osimertinib-resistant sublines. Strikingly, a higher sensitivity to tivantinib could be detected in the latter, pointing to the promising option of utilizing this agent in the second-line treatment setting.
Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
Resilience has been defined as the maintenance or quick recovery of mental health during and after times of adversity. How to operationalize resilience and to determine the factors and processes that lead to good long-term mental health outcomes in stressor-exposed individuals is a matter of ongoing debate and of critical importance for the advancement of the field. One of the biggest challenges for implementing an outcome-based definition of resilience in longitudinal observational study designs lies in the fact that real-life adversity is usually unpredictable and that its substantial qualitative as well as temporal variability between subjects often precludes defining circumscribed time windows of inter-individually comparable stressor exposure relative to which the maintenance or recovery of mental health can be determined. To address this pertinent issue, we propose to frequently and regularly monitor stressor exposure (E) and mental health problems (P) throughout a study's observation period [Frequent Stressor and Mental Health Monitoring (FRESHMO)-paradigm]. On this basis, a subject's deviation at any single monitoring time point from the study sample's normative E–P relationship (the regression residual) can be used to calculate that subject's current mental health reactivity to stressor exposure (“stressor reactivity,” SR). The SR score takes into account the individual extent of experienced adversity and is comparable between and within subjects. Individual SR time courses across monitoring time points reflect intra-individual temporal variability in SR, where periods of under-reactivity (negative SR score) are associated with accumulation of fewer mental health problems than is normal for the sample. If FRESHMO is accompanied by regular measurement of potential resilience factors, temporal changes in resilience factors can be used to predict SR time courses. An increase in a resilience factor measurement explaining a lagged decrease in SR can then be considered to index a process of adaptation to stressor exposure that promotes a resilient outcome (an allostatic resilience process). This design principle allows resilience research to move beyond merely determining baseline predictors of resilience outcomes, which cannot inform about how individuals successfully adjust and adapt when confronted with adversity. Hence, FRESHMO plus regular resilience factor monitoring incorporates a dynamic-systems perspective into resilience research.
Leukämien sind eine heterogene Gruppe von malignen Erkrankungen der hämatopoetischen Zellen. Die Pathogenese der akuten myeloischen Leukämie (AML) ist durch einen Differenzierungsblock charakterisiert [Gelmetti V MCB 1998, Ruthardt M MCB 1997, Grignani F Cell 1993, Testa U Leukemia 1998]. Die akute Promyelozyten Leukämie (APL) ist eine gut charakterisierte Unterform der AML, die in 95% der Fälle die t(15;17) und in 2% die t(11;17) beinhaltet. Die resultierenden Fusionsproteine PML/RARalpha und PLZF/RARalpha (X-RARalpha) geben in verschiedenen Modellen den leukämischen Phänotyp wieder und induzieren einen Differenzierungsblock. Im Tiermodell induziert die Expression von PML/RARalpha und PLZF/RARalpha eine Leukämie. Die Behandlung mit all-trans-Retinolsäure (t-RA) ist in der Lage den Differenzierungsblock in PML/RARalpha, aber nicht in PLZF/RARalpha positiven Blasten zu überwinden. Diese beiden Fusionsproteine blockieren die Differenzierung durch verschiedene Mechanismen, so z.B. durch die aberrante Rekrutierung von Histon-Deazetylase-Korepressor-Komplexen (HD-NCR) und die Deregulierung differenzierungsspezifischer Transkriptionsfaktoren wie VDR oder c/EBPa [Puccetti E Blood 2004]. Der Vitamin D3 Rezeptor (VDR) ist ein Mitglied der hormoninduzierbaren Transkriptionsfaktoren und bindet direkt an PML/RARalpha, was zur funktionellen Inaktivierung von VDR und Blockierung der VitD3-induzierten Differenzierung führt [Puccetti 2002]. Das Ziel dieser Arbeit war es zunächst, zu untersuchen, ob XRARalpha in der Lage sind andere differenzierungsrelevante Transkriptionsfaktoren, wie PU.1 und GATA-1, zu binden und dadurch funktional zu inaktivieren. GATA-1 und PU.1 sind Schlüsselfaktoren der myeloischen Differenzierung. Kürzlich wurde gezeigt, dass der Knockout dieser beiden Transkriptionsfaktoren zur Leukämogenese beiträgt [Rosenbauer F 2005, Stachura 2005]. In dieser Arbeit konnte gezeigt werden, dass X-RARalpha sowohl GATA-1, als auch PU.1 direkt binden, ohne ihre Expressionsniveaus zu beeinflussen. Die DNA-Bindungskapazität dieser beiden Transkriptionsfaktoren auf ihre Zielpromotoren war durch X-RARalpha deutlich reduziert. Die Behandlung mit t-RA restorierte die Bindung von GATA-1, aber nicht von PU.1, was darauf schließen lässt, dass die funktionale Inaktivierung von GATA-1 ligandenabhängig, die von PU.1 -unabhängig ist. Die transkriptionelle Aktivität auf künstliche Zielpromotoren war in Gegenwart von X-RARalpha bei PU.1 stark reduziert, auf GATA-1 hatten X-RARalpha in diesem Zusammenhang keinen Einfluss. Die Überexpression dieser Transkriptionsfaktoren in X-RARalpha-positiven hämatopoetischen Stammzellen hat die aberrante Selbsterneuerung leukämischer Stammzellen (LSZ) reprimiert. Während PU.1 Differenzierung erzeugte, tat GATA-1 dies nicht. Die Vermutung liegt nahe, dass die Inhibition von Dissertation von Anita Seshire 2 GATA-1 über seinen Azetylierungsstatus in Gegenwart von X-RARalpha stattfindet, durch die Sequestrierung eines weiteren Proteins der Histon-Azetyltransferase (HAT) CBP/p300, die für die Azetylierung von GATA-1 verantwortlich ist. Zusammengenommen lassen diese Daten darauf schliessen, dass PU.1 durch die Interaktion mit PML/RARalpha seinem Wirkungsort entzogen wird (sequestriert) und das die Inhibition von GATA-1 ein Zusammenspiel aus Sequestrierung und Chromatin-Modellierung durch X-RARalpha ist. Die Fähigkeit von X-RARalpha, den leukämischen Phänotyp zu induzieren ist an ihre Fähigkeit zur Oligomerisierung und zur Formierung sog. Makrokomplexe gekoppelt [Grignani 1996, Minucci 2000, Puccetti 2005]. Um die Zusammensetzung dieser Makrokomplexe zu entschlüsseln, wurde ein Mockkontrollierter TAP-Proteomics-Screen mit PLZF/RARalpha in KG-1 Zellen durchgeführt. Es konnten verschiedene Proteine identifiziert werden, die spezifisch an PLZF/RARalpha binden und vermutlich eine Rolle für die Leukämogenese spielen. Die identifizierten Proteine spielen eine Rolle bei der Migration, den kleinen GTPasen, epigenetischer Regulation und Stammzellselbsterneuerung. Das „adenomatous poliposis coli“ Protein (APC) wurde als spezifischer Interaktionspartner für PLZF/RARalpha identifiziert und ist ein Hauptinhibitor des Wnt-Signalwegs. Die Deregulierung des Wnt-Signalwegs spielt eine bedeutende Rolle in der Leukämogenese durch die aberrante Induktion der Selbsterneuerung leukämischer Stammzellen [Zheng 2004]. In dieser Arbeit konnte gezeigt werden, dass APC direkt an PLZF/RARalpha, aber nicht PML/RARalpha bindet ß-catenin/TCF vermittelte Transkriptionssignale, die zur Leukämogenese beitragen können, aktiviert. Die Bindung an APC ist abhängig von der Oligomerisierungsfähigkeit des PLZF/RARalpha und daher von der korrekten Konformation der Proteininteraktionsdomäne BTB/POZ, was durch POZ-Punktmutanten nachgewiesen wurde, die auch nicht mehr in der Lage waren ß-catenin/TCF-vermittelte Transkription in derselben Stärke wie PLZF/RARalpha zu aktivieren. Die Überexpression von APC in PLZF/RARalpha-positiven LSZ hat ihre aberrante Selbsterneuerung vollkommen reprimiert. Zusammengenommen zeigen diese Daten, dass die Interaktion von APC, GATA-1 oder PU.1 mit XRARalpha und der konsequente Sequester einen wichtigen Mechanismus zur Leukämogenese stellen. Weiterhin hat sich gezeigt, dass die Überexpression dieser Proteine, die aberrante Selbsterneuerung überwinden kann und teilweise Differenzierung erzeugt. Es konnten der Wnt-Signalweg als valides Ziel für neue Therapieansätze identifiziert werden und die molekularen Mechanismen der Pathogenese der APL weiter aufgeklärt werden.
Simple Summary: Penile cancer is a rare but aggressive malignancy characterized by rapid tumor growth as well as prompt metastasis in groin lymphatics. While localized diseases can be successfully cured by surgery in most cases, no truly effective treatment options have been established for metastatic diseases as of yet. In the current investigation, we assessed the value of selected members of the PI3K/mTOR/AKT pathway to serve as tumor markers or therapeutic targets for this disease. Higher expression of AKT was significantly more prevalent in high-grade tumors and independently predictive of the worse survival parameters, while increased expression of pmTOR was associated with an inferior prognosis as well. Treatment with the pan-AKT inhibitor capivasertib in PeCa cell lines induced significant reduction of cell viability and movement capacity. These findings might aid in the understanding of the molecular tumor background as well as development of novel treatment options for advanced penile cancer.
Abstract: The PI3K/mTOR/AKT pathway might represent an intriguing option for treatment of penile cancer (PeCa). We aimed to assess whether members of this pathway might serve as biomarkers and targets for systemic therapy. Tissue of primary cancer from treatment-naïve PeCa patients was used for tissue microarray analysis. Immunohistochemical staining was performed with antibodies against AKT, pAKT, mTOR, pmTOR, pS6, pPRAS, p4EBP1, S6K1 and pp70S6K. Protein expression was correlated with clinicopathological characteristics as well as overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and metastasis-free survival (MFS). AKT inhibition was tested in two primarily established, treatment-naïve PeCa cell lines by treatment with capivasertib and analysis of cell viability and chemotaxis. A total of 76 patients surgically treated for invasive PeCa were included. Higher expression of AKT was significantly more prevalent in high-grade tumors and predictive of DSS and OS in the Kaplan–Meier analysis, and an independent predictor of worse OS and DSS in the multivariate regression analysis. Treatment with pan-AKT inhibitor capivasertib in PeCa cell lines induced a significant downregulation of both total AKT and pAKT as well as decreased cell viability and chemotaxis. Selected protein candidates of the mTOR/AKT signaling pathway demonstrate association with histological and survival parameters of PeCa patients, whereas AKT appears to be the most promising one.
Background: Nitric oxide synthase 1 adaptor protein (NOS1AP; previously named CAPON) is linked to the glutamatergic postsynaptic density through interaction with neuronal nitric oxide synthase (nNOS). NOS1AP and its interaction with nNOS have been associated with several mental disorders. Despite the high levels of NOS1AP expression in the hippocampus and the relevance of this brain region in glutamatergic signalling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet.
Methods: To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress murine full-length NOS1AP or the NOS1AP carboxyterminus in the hippocampus of mice. We investigated these mice for changes in gene expression, neuronal morphology, and relevant behavioural phenotypes.
Findings: We found that hippocampal overexpression of NOS1AP markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density, and changed dendritic spine morphology at CA1 synapses. At the behavioural level, we observed an impairment in social memory and decreased spatial working memory capacity.
Interpretation: Our data provide a mechanistic explanation for a highly selective and specific contribution of hippocampal NOS1AP and its interaction with the glutamatergic postsynaptic density to cross-disorder pathophysiology. Our findings allude to therapeutic relevance due to the druggability of this molecule.
We report a measurement of the observed cross sections of e+ e− → J/ψX based on 3.21 fb − 1 of data accumulated at energies from 3.645 to 3.891 GeV with the BESIII detector operated at the BEPCII collider. In analysis of the cross sections, we measured the decay branching fractions of B(ψ(3686) → J/ψX) = (64.4 ± 0.6 ± 1.6)% and B(ψ(3770) → J/ψX) = (0.5 ± 0.2 ± 0.1)% for the first time. The energy-dependent line shape of these cross sections cannot be well described by two Breit-Wigner (BW) amplitudes of the expected decays ψ (3686) → J/ψX and ψ(3770) → J/ψX. Instead, it can be better described with one more BW amplitude of the decay R(3760)→ J/ψX. Under this assumption, we extracted the R (3760) mass M R (3760 ) = 3766.2 ± 3.8 ± 0.4 MeV/c2, total width Γ tot R ( 3760 ) = 22.2 ± 5.9 ± 1.4 MeV, and product of leptonic width and decay branching fraction
ΓeeR(3760) B[R(3760) → J/ψX] = (79.4 ± 85.5 ± 11.7) eV. The significance of the R(3760) is 5.3σ. The first uncertainties of these measured quantities are from fits to the cross sections and second systematic.
We measure the inclusive semielectronic decay branching fraction of the D+s meson. A double-tag technique is applied to e+e− annihilation data collected by the BESIII experiment at the BEPCII collider, operating in the center-of-mass energy range 4.178–4.230 GeV. We select positrons fromD+s→Xe+νe with momenta greater than 200 MeV/c and determine the laboratory momentum spectrum, accounting for the effects of detector efficiency and resolution. The total positron yield and semielectronic branching fraction are determined by extrapolating this spectrum below the momentum cutoff. We measure the D+s semielectronic branching fraction to be(6.30±0.13(stat.)±0.09(syst.)±0.04(ext.))%, showing no evidence for unobserved exclusive semielectronic modes. We combine this result with external data taken from literature to determine the ratio of the D+s and D0 semielectronic widths, Γ(D+s→Xe+νe)Γ(D0→Xe+νe)=0.790±0.016(stat.)±0.011(syst.)±0.016(ext.). Our results are consistent with and more precise than previous measurements.
The Born cross sections of the e+e− → D*+D*− and e+e− → D*+D− processes are measured using e+e− collision data collected with the BESIII experiment at center-of-mass energies from 4.085 to 4.600 GeV, corresponding to an integrated luminosity of 15.7 fb−1. The results are consistent with and more precise than the previous measurements by the Belle, Babar and CLEO collaborations. The measurements are essential for understanding the nature of vector charmonium and charmonium-like states.
The electromagnetic process is studied with the initial-state-radiation technique using 7.5 fb−1 of data collected by the BESIII experiment at seven energy points from 3.773 to 4.600 GeV. The Born cross section and the effective form factor of the proton are measured from the production threshold to 3.0 GeV/ using the invariant-mass spectrum. The ratio of electric and magnetic form factors of the proton is determined from the analysis of the proton-helicity angular distribution.
Using data samples collected with the BESIII detector operating at the BEPCII storage ring at center-of-mass energies from 4.178 to 4.600 GeV, we study the process eþe− → π0Xð3872Þγ and search for Zcð4020Þ0 → Xð3872Þγ. We find no significant signal and set upper limits on σðeþe− → π0Xð3872ÞγÞ · BðXð3872Þ → πþπ−J=ψÞ and σðeþe− → π0Zcð4020Þ0Þ · BðZcð4020Þ0 → Xð3872ÞγÞ · BðXð3872Þ → πþπ−J=ψÞ for each energy point at 90% confidence level, which is of the order of several tenths pb.
The Born cross sections and effective form factors for process 𝑒+𝑒−→Ξ−¯Ξ+ are measured at eight center-of-mass energies between 2.644 and 3.080 GeV, using a total integrated luminosity of 363.9 pb−1 𝑒+𝑒− collision data collected with the BESIII detector at BEPCII. After performing a fit to the Born cross section of 𝑒+𝑒−→Ξ−¯Ξ+, no significant threshold effect is observed.
Relative fractions and phases of the intermediate decays are determined. With the detection efficiency estimated by the results of the amplitude analysis, the branching fraction of Dþ s → K−Kþπþπ0 decay is measured to be ð5.42 0.10stat 0.17systÞ%.