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Besides external characteristics and reading a piece of DNA (barcode), the DNA weight per nucleus (genome size) via flow cytometry is a key value to detect species and hybrids and determine ploidy. In addition, the DNA weight appears to be related to various properties, such as the size of the cell and the nucleus, the duration of mitosis and meiosis and the generation time. Sometimes it is even possible to distinguish between groups or sections, which can lead to new classification of the genera. The variation in DNA weight is also useful to analyze biodiversity, genome evolution and relationships between related taxa. Moreover, it is important to know how large a genome is before one determines the base sequence of the DNA of a plant. Flow cytometry is also important for understanding fundamental processes in plants such as growth and development and recognizing chimeras. In the literature, DNA weight measurements are usually limited to one genus and often only locally (Siljak et al. 2010; Bai et al. 2012). In this study, however, it was decided to investigate all vascular plants from one country. This can also contribute to the protection of rare plants. This study is the first flora in the world whose weight of DNA per nucleus and peak patterns has been determined. More than 6400 plants, representing more than 2350 (sub)species (more than 90%) have been collected, thanks to the help of almost 100 volunteers of Floristisch Onderzoek Nederland (Floron). Multiple specimens of many species have therefore been measured, preferably from different populations, in some cases more than fifty. For 1370 species, these values were not previously published. Moreover, a good number of the remaining 45% are new for The Netherlands. In principle, each species has a fixed weight of DNA per nucleus. It has also been found that, especially between the genera, there are strong differences in the number of peaks that determine the DNA weight, from one to five peaks. This indicates that in a plant or organ there are sometimes nuclei with multiples of its standard DNA weight (multiple ploidy levels). It is impossible to show graphs of more than 2350 species. Therefore, we have chosen to show the peak pattern in a new way in a short formula. Within most genera there are clear differences in the DNA weights per nucleus between the species, in some other genera the DNA weight is hardly variable. Based on about twenty genera that were previously measured completely in most cases (‘t Hart et al. 2003: Veldkamp and Zonneveld 2011; Soes et al. 2012; Dirkse et al. 2014, 2015; Verloove et al. 2017; Zonneveld [et al.] 2000−2018), it can be noted that even if all species of a genus have the same number of chromosomes, there can still be a difference of up to three times in the weight of the DNA. Therefore, a twice larger DNA weight does not have to indicate four sets of chromosomes. Finally, this research has also found clues to examine further the current taxonomy of a number of species or genera.
Upon approval of a drug, the stability of the API and the FPP has to be studied intensively because it determines the shelf-life. If a drug is found to be stable, the expiry date is arbitrary set to five years at the maximum, if a drug tends to undergo degradation, the expiry date is set shorter. The drug product must comply with predefined specifications in accordance with the ICH guidelines Q6A and Q6B during its entire market life. The content of the active substance is required to be within a specification of 95–105% of its labeled claim until expiry corresponding to the ICH guideline Q1A(R2). However, there is little or scattered literature information addressing the stability of drug products beyond their expiry dates. The objective of this thesis was to study and assess the long-term stability of a collection involving numerous pure drug substances and ampoules manufactured in the 20th century. The content and the impurity profile were examined by means of appropriate analytical methods, mainly using liquid chromatography. The results were compared to data being available in the literature. Assessing the stability regarding the dosage form and the affiliation of the drug class was conducted.
The experimental studies comprise the examination of 50 drug substances manufactured 20–30 years ago and 14 long expired ampoules which were older than 40 years in the time of analysis, exceeding many times the maximum shelf life of five years.
For investigation of the solid drug substances, pharmacopoeial methods were applied as far as possible. Indeed, results of the study showed that 44 tested substances still complied with the specification of the Ph. Eur. with regard to the content and impurity profile, even after more than two decades of storage.
For analysis of the injection solutions, HPLC-UV and HPLC-ESI/MS techniques were applied, commonly based on liquid chromatography methods of the Ph. Eur. for determination of related substances. Each method was further validated for its application to ensure accurate API quantification corresponding to ICH Q2(R1). Quite a few ampoules were identified to show surprisingly high stability. In spite of their age of 53–72 years, APIs such as caffeine, etilefrine, synephrine, metamizole sodium, furosemide, and sodium salicylate complied with the specified content that is valid nowadays, respectively. Nevertheless, typical degradation reaction, e.g. hydrolysis, oxidation, or isomerization, was observed in all remaining ampoules. Various degrees of hydrolysis were revealed for scopolamine, procaine, and adenosine triphosphate, the contents were decreased to 71%, 70%, and 15% of the declared concentrations, respectively. In the epinephrine and dipyridamole ampoules, oxidative degradation has been occurred, finding respective API contents of more or less 70%. For dihydroergotamine, excessive decomposition by epimerization was observed, resulting in an API content of 21% and degradation by isomerization was found in lobeline, still containing 64% of the labeled claim.
In conclusion, supported by the data of the present studies and the literature, defining and authorizing a longer shelf-life may be applicable to numerous pharmaceuticals which should be considered by pharmaceutical manufacturers and regulatory authorities, if justified based on stability studies. A general extension of the shelf-lives of drug products and the abolishment or extension of the maximum shelf-life limit of five years would prevent disposing of still potent medications and save a lot of money to the entire health care system.
Background
Causality between hepatitis B virus (HBV) infection and diffuse large B-cell lymphoma (DLBCL) was reported in various studies. However, the implication of different virological serum markers of HBV infection in patients with both HBV infection and DLBCL is not fully understood. The aim of this study was to investigate the impact of HBV markers on overall survival (OS) and progression-free survival (PFS) in patients with both HBV infection and DLBCL.
Methods
In this study, patients (n = 40) diagnosed with both HBV infection and DLBCL were identified between 2000 and 2017. Six patients with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) co-infection were excluded from this study. We retrospectively analyzed patients’ demographic characteristics, treatment, and the prognostic impact of different HBV markers at first diagnosis of DLBCL (HBsAg, anti-HBs, HBeAg, anti-HBe, and HBV-DNA) on OS and PFS.
Results
The majority of patients (n = 21, 62%) had advanced disease stage (III/IV) at diagnosis. In the first-line therapy, 24 patients (70%) were treated with R-CHOP regimen (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone). HBeAg positive patients had a trend toward inferior OS and PFS compared with HBeAg negative patients. Anti-HBe positive patients had a statistically significant better OS and PFS compared with anti-HBe negative group (both P < .0001). Viremia with HBV-DNA ≥ 2 × 107 IU/L had a significant negative impact on OS and PFS (both P < .0001).
Conclusion
High activity of viral replication is associated with a poor survival outcome of patients with both HBV infection and DLBCL.
Polygonum cuspidatum (Japanese knotweed, also known as Huzhang in Chinese), a plant that produces bioactive components such as stilbenes and quinones, has long been recognized as important in traditional Chinese herbal medicine. To better understand the biological features of this plant and to gain genetic insight into the biosynthesis of its natural products, we assembled a draft genome of P. cuspidatum using Illumina sequencing technology. The draft genome is ca. 2.56 Gb long, with 71.54% of the genome annotated as transposable elements. Integrated gene prediction suggested that the P. cuspidatum genome encodes 55,075 functional genes, including 6,776 gene families that are conserved in the five eudicot species examined and 2,386 that are unique to P. cuspidatum. Among the functional genes identified, 4,753 are predicted to encode transcription factors. We traced the gene duplication history of P. cuspidatum and determined that it has undergone two whole-genome duplication events about 65 and 6.6 million years ago. Roots are considered the primary medicinal tissue, and transcriptome analysis identified 2,173 genes that were expressed at higher levels in roots compared to aboveground tissues. Detailed phylogenetic analysis demonstrated expansion of the gene family encoding stilbene synthase and chalcone synthase enzymes in the phenylpropanoid metabolic pathway, which is associated with the biosynthesis of resveratrol, a pharmacologically important stilbene. Analysis of the draft genome identified 7 abscisic acid and water deficit stress-induced protein-coding genes and 14 cysteine-rich transmembrane module genes predicted to be involved in stress responses. The draft de novo genome assembly produced in this study represents a valuable resource for the molecular characterization of medicinal compounds in P. cuspidatum, the improvement of this important medicinal plant, and the exploration of its abiotic stress resistance.
Stereospecific Synthesis and Photophysical Properties of Propeller-Shaped C\(_{90}\)H\(_{48}\) PAH
(2019)
Herein, we have synthesized an enantiomerically pure propeller‐shaped PAH, C\(_{90}\)H\(_{48}\), possessing three [7]helicene and three [5]helicene subunits. This compound can be obtained in gram quantities in a straightforward manner. The photophysical and chiroptical properties were investigated using UV/Vis absorption and emission, optical rotation and circular dichroism spectroscopy, supported by DFT calculations. The nonlinear optical properties were investigated by two‐photon absorption measurements using linearly and circularly polarized light. The extremely twisted structure and packing of the homochiral compound were investigated by single‐crystal X‐ray diffraction analysis.
Background
Almost 90% of cancer patients suffer from symptoms of fatigue during treatment. Supporting treatments are increasingly used to alleviate the burden of fatigue. This study examines the short-term and long-term effects of yoga on fatigue and the effect of weekly reminder e-mails on exercise frequency and fatigue symptoms.
Methods
The aim of the first part of the study will evaluate the effectiveness of yoga for cancer patients with mixed diagnoses reporting fatigue. We will randomly allocate 128 patients to an intervention group (N = 64) receiving yoga and a wait-list control group (N = 64) receiving yoga 9 weeks later. The yoga therapy will be performed in weekly sessions of 60 min each for 8 weeks. The primary outcome will be self-reported fatigue symptoms. In the second part of the study, the effectiveness of reminder e-mails with regard to the exercise frequency and self-reported fatigue symptoms will be evaluated. A randomized allocated group of the participants (“email”) receives weekly reminder e-mails, the other group does not. Data will be assessed using questionnaires the beginning and after yoga therapy as well as after 6 months.
Discussion
Support of patients suffering from fatigue is an important goal in cancer patients care. If yoga therapy will reduce fatigue, this type of therapy may be introduced into routine practice. If the reminder e-mails prove to be helpful, new offers for patients may also develop from this.
Perovskite oxides are a very versatile material class with a large variety of outstanding physical properties.
A subgroup of these compounds particularly tempting to investigate are oxides involving high-\(Z\) elements, where spin-orbit coupling is expected to give rise to new intriguing phases and potential application-relevant functionalities. This thesis deals with the preparation and characterization of two representatives of high-\(Z\) oxide sample systems based on KTaO\(_3\) and BaBiO\(_3\).
KTaO\(_3\) is a band insulator with an electronic valence configuration of Ta 5\(d\)\(^0\) . It is shown that by pulsed laser deposition of a disordered LaAlO\(_3\) film on the KTaO\(_3\)(001) surface, through the creation of oxygen vacancies, a Ta 5\(d\)\(^{0+\(\delta\)}\) state is obtained in the upmost crystal layers of the substrate. In consequence a quasi two dimensional electron system (q2DES) with large spin-orbit coupling emerges at the heterointerface. Measurements of the Hall effect establish sheet carrier densities in the range of 0.1-1.2 10\(^{14}\) cm\(^2\), which can be controlled by the applied oxygen background pressure during deposition and the LaAlO\(_3\) film thickness. When compared to the prototypical oxide q2DESs based on SrTiO\(_3\) crystals, the investigated system exhibits exceptionally large carrier mobilities of up to 30 cm\(^2\)/Vs (7000 cm\(^2\)/Vs) at room temperature (below 10 K). Through a depth profiling by photoemission spectra of the Ta 4\(f\) core level it is shown that the majority of the Ta 5\(d\)\(^0\) charge carriers, consisting of mobile and localized electrons, is situated within 4 nm from the interface at low temperatures. Furthermore, the momentum-resolved electronic structure of the q2DES \(buried\) underneath the LaAlO\(_3\) film is probed by means of hard X-ray angle-resolved photoelectron spectroscopy. It is inferred that, due to a strong confinement potential of the electrons, the band structure of the system is altered compared to \(n\)-doped bulk KTO. Despite the constraint of the electron movement along one direction, the Fermi surface exhibits a clear three dimensional momentum dependence, which is related to a depth extension of the conduction channels of at least 1 nm.
The second material, BaBiO\(_3\), is a charge-ordered insulator, which has recently been predicted to emerge as a large-gap topological insulator upon \(n\)-doping. This study reports on the thin film growth of pristine BaBiO\(_3\) on Nb:SrTiO\(_3\)(001) substrates by means of pulsed laser deposition. The mechanism is identified that facilitates the development of epitaxial order in the heterostructure despite the presence of an extraordinary large lattice mismatch of 12 %. At the heterointerface, a structurally modified layer of about 1.7 nm thickness is formed that gradually relieves the in-plane strain and serves as the foundation of a relaxed BBO film. The thereupon formed lattice orders laterally in registry with the substrate with the orientation BaBiO\(_3\)(001)||SrTiO\(_3\)(001) by so-called domain matching, where 8 to 9 BaBiO\(_3\) unit cells align with 9 to 10 unit cells of the substrate. Through the optimization of the deposition conditions in regard to the cation stoichiometry and the structural lattice quality, BaBiO\(_3\) thin films with bulk-like electronic properties are obtained, as is inferred from a comparison of valence band spectra with density functional theory calculations. Finally, a spectroscopic survey of BaBiO\(_3\) samples of various thicknesses resolves that a recently discovered film thickness-controlled phase transition in BaBiO\(_3\) thin films can be traced back to the structural and concurrent stoichiometric modifications occuring in the initially formed lattice on top of the SrTiO\(_3\) substrate rather than being purely driven by the smaller spatial extent of the BBO lattice.
Development and application of computational tools for RNA-Seq based transcriptome annotations
(2019)
In order to understand the regulation of gene expression in organisms, precise genome annotation is essential. In recent years, RNA-Seq has become a potent method for generating and improving genome annotations. However, this Approach is time consuming and often inconsistently performed when done manually. In particular, the discovery of non-coding RNAs benefits strongly from the application of RNA-Seq data but requires significant amounts of expert knowledge and is labor-intensive. As a part of my doctoral study, I developed a modular tool called ANNOgesic that can detect numerous transcribed genomic features, including non-coding RNAs, based on RNA-Seq data in a precise and automatic fashion with a focus on bacterial and achaeal species. The software performs numerous analyses and generates several visualizations. It can generate annotations of high-Resolution that are hard to produce using traditional annotation tools that are based only on genome sequences. ANNOgesic can detect numerous novel genomic Features like UTR-derived small non-coding RNAs for which no other tool has been developed before. ANNOgesic is available under an open source license (ISCL) at https://github.com/Sung-Huan/ANNOgesic.
My doctoral work not only includes the development of ANNOgesic but also its application to annotate the transcriptome of Staphylococcus aureus HG003 - a strain which has been a insightful model in infection biology. Despite its potential as a model, a complete genome sequence and annotations have been lacking for HG003. In order to fill this gap, the annotations of this strain, including sRNAs and their functions, were generated using ANNOgesic by analyzing differential RNA-Seq data from 14 different samples (two media conditions with seven time points), as well as RNA-Seq data generated after transcript fragmentation. ANNOgesic was
also applied to annotate several bacterial and archaeal genomes, and as part of this its high performance was demonstrated. In summary, ANNOgesic is a powerful computational tool for RNA-Seq based annotations and has been successfully applied to several species.
The green synthesis of silver nanoparticles (SNPs) using plant extracts is an eco-friendly method. It is a single step and offers several advantages such as time reducing, cost-effective and environmental non-toxic. Silver nanoparticles are a type of Noble metal nanoparticles and it has tremendous applications in the field of diagnostics, therapeutics, antimicrobial activity, anticancer and neurodegenerative diseases. In the present work, the aqueous extracts of aerial parts of Lampranthus coccineus and Malephora lutea F. Aizoaceae were successfully used for the synthesis of silver nanoparticles. The formation of silver nanoparticles was early detected by a color change from pale yellow to reddish-brown color and was further confirmed by transmission electron microscope (TEM), UV–visible spectroscopy, Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), X-ray diffraction (XRD), and energy-dispersive X-ray diffraction (EDX). The TEM analysis of showed spherical nanoparticles with a mean size between 12.86 nm and 28.19 nm and the UV- visible spectroscopy showed λ\(_{max}\) of 417 nm, which confirms the presence of nanoparticles. The neuroprotective potential of SNPs was evaluated by assessing the antioxidant and cholinesterase inhibitory activity. Metabolomic profiling was performed on methanolic extracts of L. coccineus and M. lutea and resulted in the identification of 12 compounds, then docking was performed to investigate the possible interaction between the identified compounds and human acetylcholinesterase, butyrylcholinesterase, and glutathione transferase receptor, which are associated with the progress of Alzheimer’s disease. Overall our SNPs highlighted its promising potential in terms of anticholinesterase and antioxidant activity as plant-based anti-Alzheimer drug and against oxidative stress.
Metabolic adaptation to the host cell is important for obligate intracellular pathogens such as Chlamydia trachomatis (Ct). Here we infer the flux differences for Ct from proteome and qRT-PCR data by comprehensive pathway modeling. We compare the comparatively inert infectious elementary body (EB) and the active replicative reticulate body (RB) systematically using a genome-scale metabolic model with 321 metabolites and 277 reactions. This did yield 84 extreme pathways based on a published proteomics dataset at three different time points of infection. Validation of predictions was done by quantitative RT-PCR of enzyme mRNA expression at three time points. Ct’s major active pathways are glycolysis, gluconeogenesis, glycerol-phospholipid (GPL) biosynthesis (support from host acetyl-CoA) and pentose phosphate pathway (PPP), while its incomplete TCA and fatty acid biosynthesis are less active. The modeled metabolic pathways are much more active in RB than in EB. Our in silico model suggests that EB and RB utilize folate to generate NAD(P)H using independent pathways. The only low metabolic flux inferred for EB involves mainly carbohydrate metabolism. RB utilizes energy -rich compounds to generate ATP in nucleic acid metabolism. Validation data for the modeling include proteomics experiments (model basis) as well as qRT-PCR confirmation of selected metabolic enzyme mRNA expression differences. The metabolic modeling is made fully available here. Its detailed insights and models on Ct metabolic adaptations during infection are a useful modeling basis for future studies.