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- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
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- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
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The proliferative darkening syndrome (PDS) is a lethal disease of brown trout (Salmo trutta fario) which occurs in several alpine Bavarian limestone rivers. Because mortality can reach 100%, PDS is a serious threat for affected fish populations. Recently, Kuehn and colleagues reported that a high throughput RNA sequencing approach identified a piscine orthoreovirus (PRV) as a causative agent of PDS. We investigated samples from PDS-affected fish obtained from two exposure experiments performed at the river Iller in 2008 and 2009. Using a RT-qPCR and a well-established next-generation RNA sequencing pipeline for pathogen detection, PRV-specific RNA was not detectable in PDS fish from 2009. In contrast, PRV RNA was readily detectable in several organs from diseased fish in 2008. However, similar virus loads were detectable in the control fish which were not exposed to Iller water and did not show any signs of the disease. Therefore, we conclude that PRV is not the causative agent of PDS of brown trout in the rhithral region of alpine Bavarian limestone rivers. The abovementioned study by Kuehn used only samples from the exposure experiment from 2008 and detected a subclinical PRV bystander infection. Work is ongoing to identify the causative agent of PDS.
The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50% in male and estimated as 54.5% in female healthy volunteers as well as 56.3% in male and 74.4% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding.
In forecasting count processes, practitioners often ignore the discreteness of counts and compute forecasts based on Gaussian approximations instead. For both central and non-central point forecasts, and for various types of count processes, the performance of such approximate point forecasts is analyzed. The considered data-generating processes include different autoregressive schemes with varying model orders, count models with overdispersion or zero inflation, counts with a bounded range, and counts exhibiting trend or seasonality. We conclude that Gaussian forecast approximations should be avoided.
Studying how cambial age and axial height affects wood anatomical traits may improve our understanding of xylem hydraulics, heartwood formation and axial growth. Radial strips were collected from six different heights (0–11.3 m) along the main trunk of three Manchurian catalpa (Catalpa bungei) trees, yielding 88 samples. In total, thirteen wood anatomical vessel and fiber traits were observed usinglight microscopy (LM) and scanning electron microscopy (SEM), and linear models were used to analyse the combined effect of axial height, cambial age and their interaction. Vessel diameter differed by about one order of magnitude between early- and latewood, and increased significantly with both cambial age and axial height in latewood, while it was positively affected by cambial age and independent of height in earlywood. Vertical position further had a positive effect on earlywood vessel density, and negative effects on fibre wall thickness, wall thickness to diameter ratio and length. Cambial age had positive effects on the pit membrane diameter and vessel element length, while the annual diameter growth decreased with both cambial age and axial position. In contrast, early- and latewood fiber diameter were unaffected by both cambial age and axial height. We further observed an increasing amount of tyloses from sapwood to heartwood, accompanied by an increase of warty layers and amorphous deposits on cell walls, bordered pit membranes and pit apertures. This study highlights the significant effects of cambial age and vertical position on xylem anatomical traits, and confirms earlier work that cautions to take into account xylem spatial position when interpreting wood anatomical structures, and thus, xylem hydraulic functioning.
With the technological advances of the last decade, it is now feasible to analyze microbiome samples, such as human stool specimens, using multi-omic techniques. Given the inherent sample complexity, there exists a need for sample methods which preserve as much information as possible about the biological system at the time of sampling. Here, we analyzed human stool samples preserved and stored using different methods, applying metagenomics as well as metaproteomics. Our results demonstrate that sample preservation and storage have a significant effect on the taxonomic composition of identified proteins. The overall identification rates, as well as the proportion of proteins from Actinobacteria were much higher when samples were flash frozen. Preservation in RNAlater overall led to fewer protein identifications and a considerable increase in the share of Bacteroidetes, as well as Proteobacteria. Additionally, a decrease in the share of metabolism-related proteins and an increase of the relative amount of proteins involved in the processing of genetic information was observed for RNAlater-stored samples. This suggests that great care should be taken in choosing methods for the preservation and storage of microbiome samples, as well as in comparing the results of analyses using different sampling and storage methods. Flash freezing and subsequent storage at −80 °C should be chosen wherever possible.
Background: Accurate assessment of hepatic fibrosis in patients with chronic HBeAg-negative Hepatitis B is of crucial importance not only to predict the long-term clinical course, but also to evaluate antiviral therapy indication. The aim of this study was to prospectively assess the utility of point shear wave elastography (pSWE) for longitudinal non-invasive fibrosis assessment in a large cohort of untreated patients with chronic HBeAg-negative hepatitis B virus (HBV) infection. Methods: 407 consecutive patients with HBeAg-negative HBV infection who underwent pSWE, transient elastography (TE) as well as laboratory fibrosis markers, including fibrosis index based on four factors (FIB-4), aspartate to platelet ratio index (APRI) and FibroTest, on the same day were prospectively followed up for six years. Patients were classified into one of the three groups: inactive carriers (IC; HBV-DNA <2000 IU/mL and ALT <40 U/L); grey zone group 1 (GZ-1; HBV DNA <2000 IU/mL and ALT >40 U/L); grey zone group 2 (GZ-2; HBV-DNA >2000 IU/mL and ALT <40 U/L). Results: pSWE results were significantly correlated with TE (r = 0.29, p < 0.001) and APRI (r = 0.17; p = 0.005). Median pSWE values did not differ between IC, GZ-1 and GZ-2 patients (p = 0.82, p = 0.17, p = 0.34). During six years of follow-up, median pSWE and TE values did not differ significantly over time (TE: p = 0.27; pSWE: p = 0.05). Conclusion: Our data indicate that pSWE could be useful for non-invasive fibrosis assessment and follow-up in patients with HBeAg-negative chronic HBV infection.
The helical distribution of the electronic density in chiral molecules, such as DNA and bacteriorhodopsin, has been suggested to induce a spin–orbit coupling interaction that may lead to the so-called chirality-induced spin selectivity (CISS) effect. Key ingredients for the theoretical modelling are, in this context, the helically shaped potential of the molecule and, concomitantly, a Rashba-like spin–orbit coupling due to the appearance of a magnetic field in the electron reference frame. Symmetries of these models clearly play a crucial role in explaining the observed effect, but a thorough analysis has been largely ignored in the literature. In this work, we present a study of these symmetries and how they can be exploited to enhance chiral-induced spin selectivity in helical molecular systems.
Oligodendrocytes provide metabolic and functional support to neuronal cells, rendering them key players in the functioning of the central nervous system. Oligodendrocytes need to be newly formed from a pool of oligodendrocyte precursor cells (OPCs). The differentiation of OPCs into mature and myelinating cells is a multistep process, tightly controlled by spatiotemporal activation and repression of specific growth and transcription factors. While oligodendrocyte turnover is rather slow under physiological conditions, a disruption in this balanced differentiation process, for example in case of a differentiation block, could have devastating consequences during ageing and in pathological conditions, such as multiple sclerosis. Over the recent years, increasing evidence has shown that epigenetic mechanisms, such as DNA methylation, histone modifications, and microRNAs, are major contributors to OPC differentiation. In this review, we discuss how these epigenetic mechanisms orchestrate and influence oligodendrocyte maturation. These insights are a crucial starting point for studies that aim to identify the contribution of epigenetics in demyelinating diseases and may thus provide new therapeutic targets to induce myelin repair in the long run.
Projected climate changes for the 21st century may cause great uncertainties on the hydrology of a river basin. This study explored the impacts of climate change on the water balance and hydrological regime of the Jhelum River Basin using the Soil and Water Assessment Tool (SWAT). Two downscaling methods (SDSM, Statistical Downscaling Model and LARS-WG, Long Ashton Research Station Weather Generator), three Global Circulation Models (GCMs), and two representative concentration pathways (RCP4.5 and RCP8.5) for three future periods (2030s, 2050s, and 2090s) were used to assess the climate change impacts on flow regimes. The results exhibited that both downscaling methods suggested an increase in annual streamflow over the river basin. There is generally an increasing trend of winter and autumn discharge, whereas it is complicated for summer and spring to conclude if the trend is increasing or decreasing depending on the downscaling methods. Therefore, the uncertainty associated with the downscaling of climate simulation needs to consider, for the best estimate, the impact of climate change, with its uncertainty, on a particular basin. The study also resulted that water yield and evapotranspiration in the eastern part of the basin (sub-basins at high elevation) would be most affected by climate change. The outcomes of this study would be useful for providing guidance in water management and planning for the river basin under climate change.
Defeat of the antibiotic resistance of pathogenic bacteria is one great challenge today and for the future. In the last century many classes of effective antibacterials have been developed, so that upcoming resistances could be met with novel drugs of various compound classes. Meanwhile, there is a certain lack of research of the pharmaceutical companies, and thus there are missing developments of novel antibiotics. Gram-positive bacteria are the most important cause of clinical infections. The number of novel antibacterials in clinical trials is strongly restricted. There is an urgent need to find novel antibacterials. We used synthetic chemistry to build completely novel hybrid molecules of substituted indoles and benzothiophene. In a simple one-pot reaction, two novel types of thienocarbazoles were yielded. Both indole substituted compound classes have been evaluated as completely novel antibacterials against the Staphylococcus and Enterococcus species. The evaluated partly promising activities depend on the indole substituent type. First lead compounds have been evaluated within in vivo studies. They confirmed the in vitro results for the new classes of small-molecule antibacterials.
Background: Cancer patients are increasingly treated with alpha-particle-emitting radiopharmaceuticals. At the subcellular level, alpha particles induce densely spaced ionizations and molecular damage. Induction of DNA lesions, especially clustered DNA double-strand breaks (DSBs), threatens a cell's survival. Currently, it is under debate to what extent the spatial topology of the damaged chromatin regions and the repair protein arrangements are contributing. Methods: Super-resolution light microscopy (SMLM) in combination with cluster analysis of single molecule signal-point density regions of DSB repair markers was applied to investigate the nano-structure of DNA damage foci tracks of Ra-223 in-solution irradiated leukocytes. Results: Alpha-damaged chromatin tracks were efficiently outlined by γ-H2AX that formed large (super) foci composed of numerous 60–80 nm-sized nano-foci. Alpha damage tracks contained 60–70% of all γ-H2AX point signals in a nucleus, while less than 30% of 53BP1, MRE11 or p-ATM signals were located inside γ-H2AX damage tracks. MRE11 and p-ATM protein fluorescent tags formed focal nano-clusters of about 20 nm peak size. There were, on average, 12 (±9) MRE11 nanoclusters in a typical γ-H2AX-marked alpha track, suggesting a minimal number of MRE11-processed DSBs per track. Our SMLM data suggest regularly arranged nano-structures during DNA repair in the damaged chromatin domain.
Approaches to mimic the complexity of the skeletal mesenchymal stem/stromal cell niche in vitro
(2019)
Mesenchymal stem/stromal cells (MSCs) are an essential element of most modern tissue engineering and regenerative medicine approaches due to their multipotency and immunoregulatory functions. Despite the prospective value of MSCs for the clinics, the stem cells community is questioning their developmental origin, in vivo localization, identification, and regenerative potential after several years of far-reaching research in the field. Although several major progresses have been made in mimicking the complexity of the MSC niche in vitro, there is need for comprehensive studies of fundamental mechanisms triggered by microenvironmental cues before moving to regenerative medicine cell therapy applications. The present comprehensive review extensively discusses the microenvironmental cues that influence MSC phenotype and function in health and disease – including cellular, chemical and physical interactions. The most recent and relevant illustrative examples of novel bioengineering approaches to mimic biological, chemical, and mechanical microenvironmental signals present in the native MSC niche are summarized, with special emphasis on the forefront techniques to achieve bio-chemical complexity and dynamic cultures. In particular, the skeletal MSC niche and applications focusing on the bone regenerative potential of MSC are addressed. The aim of the review was to recognize the limitations of the current MSC niche in vitro models and to identify potential opportunities to fill the bridge between fundamental science and clinical application of MSCs.
Background
Limited data is available to guide the choice of the conditioning regimen for patients with acute myeloid leukemia (AML) undergoing transplant with persistent disease.
Methods
We retrospectively compared outcome of fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF), and sequential fludarabine, intermediate dose Ara-C, amsacrine, total body irradiation/busulfan, cyclophosphamide (FLAMSA) conditioning in patients with refractory or relapsed AML.
Results
Complete remission rates at day 100 were 92%, 80%, and 88% for FT, TBF, and FLAMSA, respectively (p=0.13). Non-relapse mortality, incidence of relapse, acute (a) and chronic (c) graft-versus-host disease (GVHD) rates did not differ between the three groups. Overall survival at 2years was 37% for FT, 24% for TBF, and 34% for FLAMSA (p=0.10). Independent prognostic factors for survival were Karnofsky performance score and patient CMV serology (p=0.01; p=0.02), while survival was not affected by age at transplant. The use of anti-thymocyte globulin (ATG) was associated with reduced risk of grade III-IV aGVHD (p=0.02) and cGVHD (p=0.006), with no influence on relapse.
Conclusions
In conclusion, FT, TBF, and FLAMSA regimens provided similar outcome in patients undergoing transplant with active AML. Survival was determined by patient characteristics as Karnofsky performance score and CMV serology, however was not affected by age at transplant. ATG appears able to reduce the incidence of acute and chronic GVHD without influencing relapse risk.
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.
The identification of biomarker signatures is important for cancer diagnosis and prognosis. However, the detection of clinical reliable signatures is influenced by limited data availability, which may restrict statistical power. Moreover, methods for integration of large sample cohorts and signature identification are limited. We present a step-by-step computational protocol for functional gene expression analysis and the identification of diagnostic and prognostic signatures by combining meta-analysis with machine learning and survival analysis. The novelty of the toolbox lies in its all-in-one functionality, generic design, and modularity. It is exemplified for lung cancer, including a comprehensive evaluation using different validation strategies. However, the protocol is not restricted to specific disease types and can therefore be used by a broad community. The accompanying R package vignette runs in ~1 h and describes the workflow in detail for use by researchers with limited bioinformatics training.
The gastrointestinal tract is abundantly colonized by microbes, yet the translocation of oral species to the intestine is considered a rare aberrant event, and a hallmark of disease. By studying salivary and fecal microbial strain populations of 310 species in 470 individuals from five countries, we found that transmission to, and subsequent colonization of, the large intestine by oral microbes is common and extensive among healthy individuals. We found evidence for a vast majority of oral species to be transferable, with increased levels of transmission in colorectal cancer and rheumatoid arthritis patients and, more generally, for species described as opportunistic pathogens. This establishes the oral cavity as an endogenous reservoir for gut microbial strains, and oral-fecal transmission as an important process that shapes the gastrointestinal microbiome in health and disease.
Biofabrication aims to fabricate biologically functional products through bioprinting or bioassembly (Groll et al 2016 Biofabrication 8 013001). In biofabrication processes, cells are positioned at defined coordinates in three-dimensional space using automated and computer controlled techniques (Moroni et al 2018 Trends Biotechnol. 36 384–402), usually with the aid of biomaterials that are either (i) directly processed with the cells as suspensions/dispersions, (ii) deposited simultaneously in a separate printing process, or (iii) used as a transient support material. Materials that are suited for biofabrication are often referred to as bioinks and have become an important area of research within the field. In view of this special issue on bioinks, we aim herein to briefly summarize the historic evolution of this term within the field of biofabrication. Furthermore, we propose a simple but general definition of bioinks, and clarify its distinction from biomaterial inks.
Two different chromophores, namely a dipolar and an octupolar system, were prepared and their linear and nonlinear optical properties as well as their bioimaging capabilities were compared. Both contain triphenylamine as the donor and a triarylborane as the acceptor, the latter modified with cationic trimethylammonio groups to provide solubility in aqueous media. The octupolar system exhibits a much higher two‐photon brightness, and also better cell viability and enhanced selectivity for lysosomes compared with the dipolar chromophore. Furthermore, both dyes were applied in two‐photon excited fluorescence (TPEF) live‐cell imaging.
Cyclic (amino)(aryl)carbenes (cAArCs) based on the isoindoline core were successfully generated in situ by α‐elimination of 3‐alkoxyisoindolines at high temperatures or by deprotonation of isoindol‐2‐ium chlorides with sodium or copper(I) acetates at low temperatures. 3‐Alkoxy‐isoindolines 2 a,b‐OR (R=Me, Et, iPr) have been prepared in high yields by the addition of a solution of 2‐aryl‐1,1‐diphenylisoindol‐2‐ium triflate (1 a,b‐OTf; a: aryl=Dipp=2,6‐diisopropylphenyl; b: Mesityl‐, Mes=2,4,6‐trimethylphenyl) to the corresponding alcohol (ROH) with NEt3 at room temperature. Furthermore, the reaction of 2 a,b‐OMe in diethyl ether with a tenfold excess of hydrochloric acid led to the isolation of the isoindol‐2‐ium chlorides 1 a,b‐Cl in high yields. The thermally generated cAArC reacts with sulfur to form the thioamide 3 a. Without any additional trapping reagent, in situ generation of 1,1‐diphenylisoidolin‐3‐ylidenes does not lead to the isolation of these compounds, but to the reaction products of the insertion of the carbene carbon atom into an ortho C−H bond of a phenyl substituent, followed by ring‐expansion reaction; namely, anthracene derivatives 9‐N(H)aryl‐10‐Ph‐C14H8 4 a,b (a: Dipp; b: Mes). These compounds are conveniently synthesized by deprotonation of the isoindol‐2‐ium chlorides with sodium acetate in high yields. Deprotonation of 1 a‐Cl with copper(I) acetate at low temperatures afforded a mixture of 4 a and the corresponding cAArC copper(I) chloride 5 a, and allowed the isolation and structural characterization of the first example of a cAArC copper complex of general formula [(cAArC)CuCl].
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first‐line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse.