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Molecular Mechanisms of Bortezomib Action: Novel Evidence for the miRNA−mRNA Interaction Involvement
(2020)
Bortezomib is an anti-tumor agent, which inhibits 26S proteasome degrading ubiquitinated
proteins. While apoptotic transcription-associated activation in response to bortezomib has been
suggested, mechanisms related to its influence on post-transcriptional gene silencing mediated
regulation by non-coding RNAs remain not fully elucidated. In the present study, we examined
changes in global gene and miRNA expression and analyzed the identified miRNA–mRNA interactions
after bortezomib exposure in human neuroblastoma cells to define pathways affected by this agent in
this type of cells. Cell viability assays were performed to assess cytotoxicity of bortezomib. Global gene
and miRNA expression profiles of neuroblastoma cells after 24-h incubation with bortezomib were
determined using genome-wide RNA and miRNA microarray technology. Obtained results were
then confirmed by qRT-PCR and Western blot. Further bioinformatical analysis was performed
to identify affected biological processes and pathways. In total, 719 genes and 28 miRNAs were
downregulated, and 319 genes and 61 miRNAs were upregulated in neuroblastoma cells treated with
bortezomib. Possible interactions between dysregulated miRNA/mRNA, which could be linked to
bortezomib-induced neurotoxicity, affect neurogenesis, cellular calcium transport, and neuron death.
Bortezomib might exert toxic effects on neuroblastoma cells and regulate miRNA–mRNA interactions
influencing vital cellular functions. Further studies on the role of specific miRNA–mRNA interactions
are needed to elucidate mechanisms of bortezomib action.
Oral mucositis is the most common and severe non-hematological complication associated with cancer radiotherapy, chemotherapy, or their combination. Treatment of oral mucositis focuses on pain management and the use of natural anti-inflammatory, sometimes weakly antiseptic mouth rinses in combination with optimal oral cavity hygiene. To prevent negative effects of rinsing, accurate testing of oral care products is necessary. Due to their ability to mimic realistic in-vivo conditions, 3D models may be an appropriate option in compatibility testing of anti-inflammatory and antiseptically effective mouth rinses. We present a 3D model of oral mucosa based on the cell line TR-146 with a physical barrier, characterized by high transepithelial electrical resistance (TEER) and confirmed cell integrity. Histological characterization of the 3D mucosa model showed a stratified, non-keratinized multilayer of epithelial cells similar to that of human oral mucosa. By means of immuno-staining, tissue-specific expression of cytokeratin 13 and 14 was shown. Incubation of the 3D mucosa model with the rinses had no effects on cell viability, but TEER decreased 24h after incubation in all solutions except ProntOral®. Analogous to skin models, the established 3D model meets the quality control criteria of OECD guidelines and may therefore be suitable for comparing the cytocompatibility of oral rinses.
Unlike the native surface of the implant material (Ti6Al4V), oxidation with H2O2 leads to increased binding of the effective antimicrobial agent poly(hexamethylene) biguanide [PHMB]. However, treating with NaOH instead results in an even higher PHMB mass coverage. After oxidation with H2O2, strong differences in the PHMB adsorption capability between polished and corundum-blasted surfaces appear, indicating a roughness dependence. After NaOH treatment, no such effect was observed. The wetting properties of specimens treated with either H2O2 or NaOH prior to PHMB exposure clearly varied. To unravel the nature of this interaction, widespread in silico and in vitro experiments were performed. Methods: By X-ray photoelectron spectroscopy, scanning electron microscopy, water contact angle measurements and MD simulations, we characterized the interplay between the polycationic antimicrobial agent and the implant surface. A theoretical model for PHMB micelles is tested for its wetting properties and compared to carbon contaminated TiO2. In addition, quantitation of anionic functional group equivalents, the binding properties of PHMB with blocked amino end-group, and the ability to bind chlorhexidine digluconate (CHG) were investigated. Ultimately, the capability of osteoblasts to build calcium apatite, and the activity of alkaline phosphatase on PHMB coated specimens, were determined. Results: Simulated water contact angles on carbon contaminated TiO2 surfaces and PHMB micelle models reveal little influence of PHMB on the wetting properties and point out the major influence of remaining and recovering contamination from ambient air. Testing PHMB adsorption beyond the critical micelle concentration and subsequent staining reveals an island-like pattern with H2O2 as compared to an evenly modified surface with NaOH. Both CHG and PHMB, with blocked amino end groups, were adsorbed on the treated surfaces, thus negating the significant influence of PHMB’s terminal groups. The ability of osteoblasts to produce calcium apatite and alkaline phosphatase is not negatively impaired for PHMB mass coverages up to 8 μg/specimen. Conclusion: Differences in PHMB adsorption are triggered by the number of anionic groups and carbon contaminants, both of which depend on the specimen pre-treatment. With more PHMB covering, the implant surface is protected against the capture of new contamination from the ambient air, thus building a robust antimicrobial and biocompatible surface coating.
Purpose: To (1) describe the prevalence of abnormal sleep quality in patients with hip abductor tears (HAT), to (2) determine whether sleep quality improves after open HAT repair, and to (3) to report clinical short-term outcomes in patients undergoing open HAT repair. Methods: The data of 28 patients (29 hips) who underwant open HAT repair were prospectively analyzed at midterm follow-up. The Pittsburgh Sleep Quality Index (PSQI), modified Harris Hip Score (mHHS), the University of California, Los Angeles activity scale (UCLA), and Visual Analog Scale (VAS) for pain were determined via questionnaire. Paired t-tests were applied to compare preoperative and post-operative Patient-reported Outcome Measures (PROMs). Logistic regression was performed to determine the association between PSQI improvement achievement and demographic variables (laterality, sex, age, body-mass-index (BMI), and preoperative mHHS). The minimal clinically important difference (MCID) was calculated for the mHHS. Results: A total of 28 patients were included. Four patients (14.3%) suffered post-operative complications after open HAT repair. The predominance of patients was female (77.4%), with a mean age of 60 ± 13 years. The average follow-up was 30.35 ± 16.62 months. Preoperatively, 27 (96.4%) patients experienced poor sleep quality (PSQI > 5); at follow-up, 7 (25%) patients experienced poor sleep quality. Univariate logistical regression analysis demonstrated no significant association between preoperative demographic data and achieving postoperative PSQI < 5. The MCID of mHHS was calculated to be 12.5. Overall, 90% of patients achieved MCID for mHHS. Conclusion: Preoperative sleep quality was impaired in 96.4% of HAT patients (PSQI > 5). However, these patients showed an improvement in sleep disturbances after open HAT repair in the early postoperative period. Ninety percent of patients showed significant improvements in mHHS and achieved the corresponding MCID. Level of Evidence: Case series; Level IV.
Target Mechanisms of the Cyanotoxin Cylindrospermopsin in Immortalized Human Airway Epithelial Cells
(2022)
Cylindrospermopsin (CYN) is a cyanobacterial toxin that occurs in aquatic environments worldwide. It is known for its delayed effects in animals and humans such as inhibition of protein synthesis or genotoxicity. The molecular targets and the cell physiological mechanisms of CYN, however, are not well studied. As inhalation of CYN-containing aerosols has been identified as a relevant route of CYN uptake, we analyzed the effects of CYN on protein expression in cultures of immortalized human bronchial epithelial cells (16HBE14o−) using a proteomic approach. Proteins whose expression levels were affected by CYN belonged to several functional clusters, mainly regulation of protein stability, cellular adhesion and integration in the extracellular matrix, cell proliferation, cell cycle regulation, and completion of cytokinesis. With a few exceptions of upregulated proteins (e.g., ITI inhibitor of serine endopeptidases and mRNA stabilizer PABPC1), CYN mediated the downregulation of many proteins. Among these, centrosomal protein 55 (CEP55) and osteonectin (SPARC) were significantly reduced in their abundance. Results of the detailed semi-quantitative Western blot analyses of SPARC, claudin-6, and CEP55 supported the findings from the proteomic study that epithelial cell adhesion, attenuation of cell proliferation, delayed completion of mitosis, as well as induction of genomic instability are major effects of CYN in eukaryotic cells.
The pore forming alpha-toxin (hemolysin A, Hla) of Staphylococcus aureus (S. aureus) is a major virulence factor with relevance for the pathogenicity of this bacterium, which is involved in many cases of pneumonia and sepsis in humans. Until now, the presence of Hla in the body fluids of potentially infected humans could only be shown indirectly, e.g., by the presence of antibodies against Hla in serum samples or by hemolysis testing on blood agar plates of bacterial culture supernatants of the clinical isolates. In addition, nothing was known about the concentrations of Hla actually reached in the body fluids of the infected hosts. Western blot analyses on 36 samples of deep tracheal aspirates (DTA) isolated from 22 hospitalized sepsis patients using primary antibodies against different epitopes of the Hla molecule resulted in the identification of six samples from five patients containing monomeric Hla (approx. 33 kDa). Two of these samples showed also signals at the molecular mass of heptameric Hla (232 kDa). Semiquantitative analyses of the samples revealed that the concentrations of monomeric Hla ranged from 16 to 3200 ng/mL. This is, to our knowledge, the first study directly showing the presence of S. aureus Hla in samples of airway surface liquid in human patients.
Planning Modes for Major Transportation Infrastructure Projects (MTIPs): Comparing China and Germany
(2018)
Endothelial dysfunction (ED) comes with age, even without overt vessel damage such as that which occurs in atherosclerosis and diabetic vasculopathy. We hypothesized that aging would affect the downstream signalling of the endothelial nitric oxide (NO) system in the vascular smooth muscle (VSM). With this in mind, resistance mesenteric arteries were isolated from 13-week (juvenile) and 40-week-old (aged) mice and tested under isometric conditions using wire myography. Acetylcholine (ACh)-induced relaxation was reduced in aged as compared to juvenile vessels. Pretreatment with L-NAME, which inhibits nitrix oxide synthases (NOS), decreased ACh-mediated vasorelaxation, whereby differences in vasorelaxation between groups disappeared. Endothelium-independent vasorelaxation by the NO donor sodium nitroprusside (SNP) was similar in both groups; however, SNP bolus application (10−6 mol L−1) as well as soluble guanylyl cyclase (sGC) activation by runcaciguat (10−6 mol L−1) caused faster responses in juvenile vessels. This was accompanied by higher cGMP concentrations and a stronger response to the PDE5 inhibitor sildenafil in juvenile vessels. Mesenteric arteries and aortas did not reveal apparent histological differences between groups (van Gieson staining). The mRNA expression of the α1 and α2 subunits of sGC was lower in aged animals, as was PDE5 mRNA expression. In conclusion, vasorelaxation is compromised at an early age in mice even in the absence of histopathological alterations. Vascular smooth muscle sGC is a key element in aged vessel dysfunction.
Metabolic syndrome is a significant worldwide public health challenge and is inextricably linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of pro-fibrotic markers (Col1α1, Col3α1, Col4α1, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) in UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of intercellular adhesion molecule 1 (ICAM-1) and α-smooth muscle actin (α-SMA) were diminished in SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+ and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome.
Genetic variants in α-actinin-2 (ACTN2) are associated with several forms of (cardio)myopathy. We previously reported a heterozygous missense (c.740C>T) ACTN2 gene variant, associated with hypertrophic cardiomyopathy, and characterized by an electro-mechanical phenotype in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Here, we created with CRISPR/Cas9 genetic tools two heterozygous functional knock-out hiPSC lines with a second wild-type (ACTN2wt) and missense ACTN2 (ACTN2mut) allele, respectively. We evaluated their impact on cardiomyocyte structure and function, using a combination of different technologies, including immunofluorescence and live cell imaging, RNA-seq, and mass spectrometry. This study showed that ACTN2mut presents a higher percentage of multinucleation, protein aggregation, hypertrophy, myofibrillar disarray, and activation of both the ubiquitin-proteasome system and the autophagy-lysosomal pathway as compared to ACTN2wt in 2D-cultured hiPSC-CMs. Furthermore, the expression of ACTN2mut was associated with a marked reduction of sarcomere-associated protein levels in 2D-cultured hiPSC-CMs and force impairment in engineered heart tissues. In conclusion, our study highlights the activation of proteolytic systems in ACTN2mut hiPSC-CMs likely to cope with ACTN2 aggregation and therefore directs towards proteopathy as an additional cellular pathology caused by this ACTN2 variant, which may contribute to human ACTN2-associated cardiomyopathies.
Proteasomes comprise a family of proteasomal complexes essential for maintaining protein homeostasis. Accordingly, proteasomes represent promising therapeutic targets in multiple human diseases. Several proteasome inhibitors are approved for treating hematological cancers. However, their side effects impede their efficacy and broader therapeutic applications. Therefore, understanding the biology of the different proteasome complexes present in the cell is crucial for developing tailor-made inhibitors against specific proteasome complexes. Here, we will discuss the structure, biology, and function of the alternative Proteasome Activator 200 (PA200), also known as PSME4, and summarize the current evidence for its dysregulation in different human diseases. We hereby aim to stimulate research on this enigmatic proteasome regulator that has the potential to serve as a therapeutic target in cancer.
The utilization of fluorescein-guided biopsies has recently been discussed to improve and expedite operative techniques in the detection of tumor-positive tissue, as well as to avoid making sampling errors. In this study, we aimed to report our experience with fluorescein-guided biopsies and elucidate distribution patterns in different histopathological diagnoses in order to develop strategies to increase the efficiency and accuracy of this technique. We report on 45 fluorescence-guided stereotactic biopsies in 44 patients (15 female, 29 male) at our institution from March 2016 to March 2021, including 25 frame-based stereotactic biopsies and 20 frameless image-guided biopsies using VarioGuide®. A total number of 347 biopsy samples with a median of 8 samples (range: 4–18) per patient were evaluated for intraoperative fluorescein uptake and correlated to definitive histopathology. The median age at surgery was 63 years (range: 18–87). Of the acquired specimens, 63% were fluorescein positive. Final histopathology included glioblastoma (n = 16), B-cell non-Hodgkin lymphoma (n = 10), astrocytoma, IDH-mutant WHO grade III (n = 6), astrocytoma, IDH-mutant WHO grade II (n = 1), oligodendroglioma, IDH-mutant and 1p/19q-codeleted WHO grade II (n = 2), reactive CNS tissue/inflammation (n = 4), post-transplantation lymphoproliferative disorder (PTLD; n = 2), ependymoma (n = 1), infection (toxoplasmosis; n = 1), multiple sclerosis (n = 1), and metastasis (n = 1). The sensitivity for high-grade gliomas was 85%, and the specificity was 70%. For contrast-enhancing lesions, the specificity of fluorescein was 84%. The number needed to sample for contrast-enhancing lesions was three, and the overall number needed to sample for final histopathological diagnosis was five. Interestingly, in the astrocytoma, IDH-mutant WHO grade III group, 22/46 (48%) demonstrated fluorescein uptake despite no evidence for gadolinium uptake, and 73% of these were tumor-positive. In our patient series, fluorescein-guided stereotactic biopsy increases the likelihood of definitive neuropathological diagnosis, and the number needed to sample can be reduced by 50% in contrast-enhancing lesions.
Amine transaminases (ATAs) are powerful biocatalysts for the stereoselective synthesis of chiral amines. However, wild-type ATAs usually show pH optima at slightly alkaline values and exhibit low catalytic activity under physiological conditions. For efficient asymmetric synthesis ATAs are commonly used in combination with lactate dehydrogenase (LDH, optimal pH: 7.5) and glucose dehydrogenase (GDH, optimal pH: 7.75) to shift the equilibrium towards the synthesis of the target chiral amine and hence their pH optima should fit to each other. Based on a protein structure alignment, variants of (R)-selective transaminases were rationally designed, produced in E. coli, purified and subjected to biochemical characterization. This resulted in the discovery of the variant E49Q of the ATA from Aspergillus fumigatus, for which the pH optimum was successfully shifted from pH 8.5 to 7.5 and this variant furthermore had a two times higher specific activity than the wild-type protein at pH 7.5. A possible mechanism for this shift of the optimal pH is proposed. Asymmetric synthesis of (R)-1-phenylethylamine from acetophenone in combination with LDH and GDH confirmed that the variant E49Q shows superior performance at pH 7.5 compared to the wild-type enzyme.
The transcription factor EB (TFEB) promotes protein degradation by the autophagy and lysosomal pathway (ALP) and overexpression of TFEB was suggested for the treatment of ALP-related diseases that often affect the heart. However, TFEB-mediated ALP induction may perturb cardiac stress response. We used adeno-associated viral vectors type 9 (AAV9) to overexpress TFEB (AAV9-Tfeb) or Luciferase-control (AAV9-Luc) in cardiomyocytes of 12-week-old male mice. Mice were subjected to transverse aortic constriction (TAC, 27G; AAV9-Luc: n = 9; AAV9-Tfeb: n = 14) or sham (AAV9-Luc: n = 9; AAV9-Tfeb: n = 9) surgery for 28 days. Heart morphology, echocardiography, gene expression, and protein levels were monitored. AAV9-Tfeb had no effect on cardiac structure and function in sham animals. TAC resulted in compensated left ventricular hypertrophy in AAV9-Luc mice. AAV9-Tfeb TAC mice showed a reduced LV ejection fraction and increased left ventricular diameters. Morphological, histological, and real-time PCR analyses showed increased heart weights, exaggerated fibrosis, and higher expression of stress markers and remodeling genes in AAV9-Tfeb TAC compared to AAV9-Luc TAC. RNA-sequencing, real-time PCR and Western Blot revealed a stronger ALP activation in the hearts of AAV9-Tfeb TAC mice. Cardiomyocyte-specific TFEB-overexpression promoted ALP gene expression during TAC, which was associated with heart failure. Treatment of ALP-related diseases by overexpression of TFEB warrants careful consideration.
Background: Gastrointestinal hormones (GIHs) are crucial for the regulation of a variety of physiological functions and have been linked to hunger, satiety, and appetite control. Thus, they might constitute meaningful biomarkers in longitudinal and interventional studies on eating behavior and body weight control. However, little is known about the physiological levels of GIHs, their intra-individual stability over time, and their interaction with other metabolic and lifestyle-related parameters. Therefore, the aim of this pilot study is to investigate the intra-individual stability of GIHs in normal-weight adults over time. Methods: Plasma concentrations of ghrelin, leptin, GLP-1 (glucagon-like-peptide), and PP (pancreatic polypeptide) were assessed by enzyme-linked immunosorbent assay (ELISA) in 17 normal-weight, healthy adults in a longitudinal design at baseline and at follow-up six months later. The reliability of the measurements was estimated using intra-class correlation (ICC). In a second step, we considered the stability of GIH levels after controlling for changes in blood glucose and hemoglobin A1 (HbA1c) as well as self-reported physical activity and dietary habits. Results: We found excellent reliability for ghrelin, good reliability for GLP1 and PP, and moderate reliability for leptin. After considering glucose, HbA1c, physical activity, and dietary habits as co-variates, the reliability of ghrelin, GLP1, and PP did not change significantly; the reliability of leptin changed to poor reliability. Conclusions: The GIHs ghrelin, GLP1, and PP demonstrated good to excellent test–retest reliability in healthy individuals, a finding that was not modified after adjusting for glucose control, physical activity, or dietary habits. Leptin showed only moderate to poor reliability, which might be linked to weight fluctuations, albeit small, between baseline and follow-up assessment in our study sample. Together, these findings support that ghrelin, GLP1, and PP might be further examined as biomarkers in studies on weight control, with GLP1 and PP serving as anorexic markers and ghrelin as an orexigenic marker. Additional reliability studies in obese individuals are necessary to verify or refute our findings for this cohort.
Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines. In this study, six novel pentathiepins were synthesized to suit particular requirements such as fluorescent properties or improved water solubility. Structural elucidation by X-ray crystallography was successful for three derivatives. All six underwent extensive biological evaluation in 14 human cancer cell lines. These studies included investigating the inhibition of GPx1 and cell proliferation, cytotoxicity, and the induction of ROS and DNA strand breaks. Furthermore, selected hallmarks of apoptosis and the impact on cell cycle progression were studied. All six pentathiepins exerted high cytotoxic and antiproliferative activity, while five also strongly inhibited GPx1. There is a clear connection between the potential to provoke oxidative stress and damage to DNA in the form of single- and double-strand breaks. Additionally, these studies support apoptosis but not ferroptosis as the mechanism of cell death in some of the cell lines. As the various pentathiepins give rise to different biological responses, modulation of the biological effects depends on the distinct chemical structures fused to the sulfur ring. This may allow for an optimization of the anticancer activity of pentathiepins in the future.
Simple Summary
This German multicenter study investigated the importance of different supportive measures offered to patients with prostate cancer who undergo surgery (radical prostatectomy). A number of these supportive measures are required during the certification of a urologic hospital as prostate cancer center. However, a broad scientific basis evaluating these measures from the patient’s perspective is still lacking. In this study, patients were asked to rate the relevance of several supportive measures and to estimate the effective availability of these different supportive measures at their urologic clinic about 15 months after surgery. Our study highlights that only six of fifteen different supportive measures were rated as very relevant by patients. None of these six supportive measures were offered more intensively at the certified clinics compared to the non-certified clinics according to the patients. Our study helps to identify those supportive measures with the highest subjective impact on patients in this setting.
Abstract
Certification as a prostate cancer center requires the offer of several supportive measures to patients undergoing radical prostatectomy (RP). However, it remains unclear how patients estimate the relevance of these measures and whether the availability of these measures differs between certified prostate cancer centers (CERTs) and non-certified centers (NCERTs). In 20 German urologic centers, a survey comprising questions on the relevance of 15 supportive measures was sent to 1000 patients at a median of 15 months after RP. Additionally, patients were asked to rate the availability of these measures using a four-item Likert scale. The aim of this study was to compare these ratings between CERTs and NCERTs. The response rate was 75.0%. In total, 480 patients underwent surgery in CERTs, and 270 in NCERTs. Patients rated 6/15 supportive measures as very relevant: preoperative medical counselling concerning treatment options, a preoperative briefing answering last questions, preoperative pelvic floor exercises (PFEs), postoperative PFEs, postoperative social support, and postoperative rehabilitation addressing physical fitness recovery. These ratings showed no significant difference between CERTs and NCERTs (p = 0.133–0.676). In addition, 4/9 of the remaining criteria were rated as more detailed by patients in CERTs. IMPROVE represents the first study worldwide to evaluate a patient-reported assessment of the supportive measures accompanying RP. Pertinent offers vary marginally between CERTs and NCERTs.
Simple Summary
This multicenter study investigated the extent of patient’s decision regret (PatR) in patients with prostate cancer comparing different surgical modalities. Robot-assisted radical prostatectomy has replaced open radical prostatectomy as the surgical standard of care in many countries worldwide. However, a broad scientific basis evaluating the difference in patient-relevant outcomes between both approaches is still lacking. In this context, PatR is increasingly moving into the scientific focus. Our study shows a critical PatR in slightly more than one third of patients about 15 months after surgery. Patients who underwent robot-assisted surgery, and also patients without postoperative urinary stress incontinence, report significantly lower PatR. Likewise, this difference was also demonstrated for patients who decided together with their treating physician on the specific surgical procedure (consensual decision making). Our study helps to further establish PatR as an important endpoint in the setting of radical prostatectomy and identifies criteria which may be addressed to reduce PatR.
Abstract
Patient’s regret (PatR) concerning the choice of therapy represents a crucial endpoint for treatment evaluation after radical prostatectomy (RP) for prostate cancer (PCA). This study aims to compare PatR following robot-assisted (RARP) and open surgical approach (ORP). A survey comprising perioperative-functional criteria was sent to 1000 patients in 20 German centers at a median of 15 months after RP. Surgery-related items were collected from participating centers. To calculate PatR differences between approaches, a multivariate regressive base model (MVBM) was established incorporating surgical approach and demographic, center-specific, and tumor-specific criteria not primarily affected by surgical approach. An extended model (MVEM) was further adjusted by variables potentially affected by surgical approach. PatR was based on five validated questions ranging 0–100 (cutoff >15 defined as critical PatR). The response rate was 75.0%. After exclusion of patients with laparoscopic RP or stage M1b/c, the study cohort comprised 277/365 ORP/RARP patients. ORP/RARP patients had a median PatR of 15/10 (p < 0.001) and 46.2%/28.1% had a PatR >15, respectively (p < 0.001). Based on the MVBM, RARP patients showed PatR >15 relative 46.8% less frequently (p < 0.001). Consensual decision making regarding surgical approach independently reduced PatR. With the MVEM, the independent impact of both surgical approach and of consensual decision making was confirmed. This study involving centers of different care levels showed significantly lower PatR following RARP.
(1) Background: The aim of this study was to systematically compare TEM sections of mineralized human enamel and dentine prepared by focused ion beam (in situ lift-out) technique and ultramicrotomy through a combination of microscopic examination methods (scanning electron microscopy and transmission electron microscopy). In contrast with published studies, we compared the TEM preparation methods using the same specimen blocks as those for the ultramicrotomy and FIB technique. (2) Methods: A further evaluation of TEM sample preparation was obtained by confocal laser scanning microscopy and atomic force microscopy. In addition, ultramicrotome- and focused ion beam-induced artefacts are illustrated. (3) Results: The FIB technique exposed a major difference between non-decalcified enamel and dentine concerning the ultrastructural morphology compared to ultramicrotome-prepared sections. We found that ultramicrotomy was useful for cutting mineralized dentine, with the possibility of mechanical artefacts, but offers limited options for the preparation of mineralized enamel. FIB preparation produced high-quality TEM sections, showing the anisotropic ultrastructural morphology in detail, with minor structural artefacts. Our results show that the solution of artificial saliva and glutardialdehyde (2.5% by volume) is a very suitable fixative for human mineralized tissue. (4) Conclusions: The protocol that we developed has strong potential for the preparation of mineralized biomaterials for TEM imaging and analysis.
: An enhanced indoleamine 2,3-dioxygenase 1 (IDO1) activity is associated with an increased
mortality risk in sepsis patients. Thus, the preventive inhibition of IDO1 activity may be
a promising strategy to attenuate the severity of septic shock. 1-methyltryptophan (1-MT)
is currently in the interest of research due to its potential inhibitory effects on IDO1 and
immunomodulatory properties. The present study aims to investigate the protective and
immunomodulatory effects of 1-methyltryptophan against endotoxin-induced shock in a porcine
in vivo model. Effects of 1-MT were determined on lipopolysaccharide (LPS)-induced tryptophan
(TRP) degradation, immune response and sickness behaviour. 1-MT increased TRP and its metabolite
kynurenic acid (KYNA) in plasma and tissues, suppressed the LPS-induced maturation of neutrophils
and increased inactivity of the animals. 1-MT did not inhibit the LPS-induced degradation of TRP
to kynurenine (KYN)—a marker for IDO1 activity—although the increase in KYNA indicates that
degradation to one branch of the KYN pathway is facilitated. In conclusion, our findings provide
no evidence for IDO1 inhibition but reveal the side effects of 1-MT that may result from the proven
interference of KYNA and 1-MT with aryl hydrocarbon receptor signalling. These effects should be
considered for therapeutic applications of 1-MT.
Given the increasing prevalence of chronic kidney disease (CKD) and its impact on health care, it is important to better understand the multiple factors influencing health-related quality of life (HRQOL), particularly since they have been shown to affect CKD outcomes. Determinants of HRQOL as measured by the validated Kidney Disease Quality of Life questionnaire (KDQOL) and the Patient Health Questionnaire depression screener (PHQ-9) were assessed in a routine CKD patient sample, the Greifswald Approach to Individualized Medicine (GANI_MED) renal cohort (N = 160), including a wide range of self-reported data, sociodemographic and laboratory measures. Compared to the general population, CKD patients had lower HRQOL indices. Dialysis was associated with (1) low levels of physical functioning, (2) increased impairments by symptoms and problems, and (3) more effects and burden of kidney disease. HRQOL is seriously affected in CKD patients. However, impairments were found irrespective of eGFR decline and albuminuria. Rather, the comorbid conditions of depression and diabetes predicted a lower HRQOL (physical component score). Further studies should address whether recognizing and treating depression may not only improve HRQOL but also promote survival and lower hospitalization rates of CKD patients.
The release of DNA by cells during extracellular trap (ET) formation is a defense function of neutrophils and monocytes. Neutrophil ET (NET) formation in term infants is reduced compared to adults. Objective: The aim was to quantify NET and monocyte ET (MET) release and the respective key enzymes myeloperoxidase (MPO) and neutrophil elastase (NE) in preterm infants. In this prospective explorative study, ET induction was stimulated by N-formylmethionine-leucyl-phenylalanine (fMLP), phorbol 12-myristate 13-acetate (PMA), lipopolysaccharide (LPS), and lipoteichoic acid (LTA) in the cord blood of preterm infants (n = 55, 23–36 weeks) compared to term infants and adults. METs were quantified by microscopy, and NETs by microscopy and flow cytometry. We also determined the MPO levels within NETs and the intracellular concentrations of NE and MPO in neutrophils. The percentage of neutrophils releasing ET was significantly reduced for preterm infants compared to adults for all stimulants, and with a 68% further reduction for PMA compared to term infants (p = 0.0141). The NET area was not reduced except for when fMLP was administered. The amount of MPO in NET-producing cells was reduced in preterm infants compared to term infants. For preterm infants, but not term infants, the percentage of monocytes releasing ETs was significantly reduced compared to healthy adults for LTA and LPS stimulation. Conclusion: In preterm infants, ETs are measurable parts of the innate immune system, but are released in a reduced percentage of cells compared to adults.
The switch from working in-office to working from home in the context of the COVID-19 pandemic had a significant impact on people’s mobility behavior. In view of the need for action arising from the ongoing challenge of climate change, these changes should be seen as an opportunity to reduce emissions in the traffic sector. The aim of this study was to analyze changes in work-related mobility that occurred during the COVID-19 pandemic using the case of a multinational medium-sized retail chain situated in semi-rural Germany. The case study allowed us to examine those changes in connection with individual attitudes and perspectives of the company and its employees. Thus, we quantitatively recorded the mobility behavior of the company’s employees, followed by an expert interview to ascertain the company’s perspective. We found a reduction in the frequency of commuting and business trips made by employees, which seemed to continue beyond the COVID-19 crisis. However, according to our findings these changes were not based on individual motivation to act in a climate-aware manner but are subject to the framework conditions created by employers for the adoption of climate-friendly behavior. The results of this work could be used by companies and policymakers to create such favorable framework conditions.
Simple Summary
Neurotoxicity is an on-target side effect of GD2-directed immunotherapy due to the expression of GD2 on healthy cells. Patients with high-risk neuroblastoma who receive treatment with anti-GD2 immunotherapy, therefore, require close observation and supportive management to improve treatment tolerance and avoid the persistence of neurological symptoms. This study reports on the incidence, clinical course and management of patients who experienced neurotoxicity due to treatment with the anti-GD2 antibody dinutuximab beta, given with or without interleukin-2, in two clinical trials. The majority of severe neurotoxic events were observed in patients treated with dinutuximab beta combined with interleukin-2, with most patients recovering following supportive management. Given the increased risk of neurotoxic events and the lack of clinical benefit reported for the combination treatment in clinical trials, adding interleukin-2 to dinutuximab beta therapy is not recommended. The clinical experiences described here may aid clinicians in managing neurotoxicity associated with dinutuximab beta more effectively.
Abstract
Neurotoxicity is an off-tumour, on-target side effect of GD2-directed immunotherapy with monoclonal antibodies. Here, we report the frequency, management and outcome of patients enrolled in two prospective clinical trials who experienced severe neurotoxicity during immunotherapy with the anti-GD2 antibody dinutuximab beta (DB) administered as short-term infusion (HR-NBL1/SIOPEN study, randomisation R2, EudraCT 2006-001489-17) or as long-term infusion (HR-NBL1/SIOPEN study, randomisation R4, EudraCT 2006-001489-17 and LTI/SIOPEN study, EudraCT 2009-018077-31), either alone or with subcutaneous interleukin-2 (scIL-2). The total number of patients included in this analysis was 1102. Overall, 44/1102 patients (4.0%) experienced Grade 3/4 neurotoxicities (HR-NBL1 R2, 21/406; HR-NBL1 R4, 8/408; LTI study, 15/288), including 27 patients with severe neurotoxicities (2.5%). Events occurred predominantly in patients receiving combined treatment with DB and scIL-2. Neurotoxicity was treated using dexamethasone, prednisolone, intravenous immunoglobulins and, in two patients, plasmapheresis, which was highly effective. While neurological recovery was observed in 16 of 21 patients with severe neurotoxicities, 5/1102 (0.45%) patients experienced persistent and severe neurological deficits. In conclusion, severe neurotoxicity is most commonly observed in patients receiving DB with scIL-2. Considering the lack of clinical benefit for IL-2 in clinical trials so far, the administration of IL-2 alongside DB is not recommended.
Simple Summary
Paratuberculosis is a disease which affects ruminants worldwide. Many countries have implemented certification and monitoring systems to control the disease, particularly in dairy herds. Monitoring herds certified as paratuberculosis non-suspect is an important component of paratuberculosis herd certification programs. The challenge is to detect the introduction or reintroduction of the infectious agent as early as possible with reasonable efforts but high certainty. In our study, we evaluated different low-cost testing schemes in herds where the share of infected animals was low, resulting in a low within-herd prevalence of animals shedding the bacteria that causes paratuberculosis in their feces. The test methods used were repeated pooled milk samples and fecal samples from the barn environment. Our study showed that numerous repetitions of different samples are necessary to monitor such herds with sufficiently high certainty. In the case of herds with a very low prevalence, our study showed that a combination of different sampling approaches is required.
Abstract
An easy-to-use and affordable surveillance system is crucial for paratuberculosis control. The use of environmental samples and milk pools has been proven to be effective for the detection of Mycobacterium avium subsp. paratuberculosis (MAP)-infected herds, but not for monitoring dairy herds certified as MAP non-suspect. We aimed to evaluate methods for the repeated testing of large dairy herds with a very low prevalence of MAP shedders, using different sets of environmental samples or pooled milk samples, collected monthly over a period of one year in 36 herds with known MAP shedder prevalence. Environmental samples were analyzed by bacterial culture and fecal PCR, and pools of 25 and 50 individual milk samples were analyzed by ELISA for MAP-specific antibodies. We estimated the cumulative sensitivity and specificity for up to twelve sampling events by adapting a Bayesian latent class model and taking into account the between- and within-test correlation. Our study revealed that at least seven repeated samplings of feces from the barn environment are necessary to achieve a sensitivity of 95% in herds with a within-herd shedder prevalence of at least 2%. The detection of herds with a prevalence of less than 2% is more challenging and, in addition to numerous repetitions, requires a combination of different samples.
Background: Unwanted drug-drug interactions (DDIs), as caused by the upregulation of clinically relevant drug metabolizing enzymes and transporter proteins in intestine and liver, have the potential to threaten the therapeutic efficacy and safety of drugs. The molecular mechanism of this undesired but frequently occurring scenario of polypharmacy is based on the activation of nuclear receptors such as the pregnane X receptor (PXR) or the constitutive androstane receptor (CAR) by perpetrator agents such as rifampin, phenytoin or St. John’s wort. However, the expression pattern of nuclear receptors in human intestine and liver remains uncertain, which makes it difficult to predict the extent of potential DDIs. Thus, it was the aim of this study to characterize the gene expression and protein abundance of clinically relevant nuclear receptors, i.e., the aryl hydrocarbon receptor (AhR), CAR, farnesoid X receptor (FXR), glucocorticoid receptor (GR), hepatocyte nuclear factor 4 alpha (HNF4α), PXR and small heterodimer partner (SHP), in the aforementioned organs. Methods: Gene expression analysis was performed by quantitative real-time PCR of jejunal, ileal, colonic and liver samples from eight human subjects. In parallel, a targeted proteomic method was developed and validated in order to determine the respective protein amounts of nuclear receptors in human intestinal and liver samples. The LC-MS/MS method was validated according to the current bioanalytical guidelines and met the criteria regarding linearity (0.1–50 nmol/L), within-day and between-day accuracy and precision, as well as the stability criteria. Results: The developed method was successfully validated and applied to determine the abundance of nuclear receptors in human intestinal and liver samples. Gene expression and protein abundance data demonstrated marked differences in human intestine and liver. On the protein level, only AhR and HNF4α could be detected in gut and liver, which corresponds to their highest gene expression. In transfected cell lines, PXR and CAR could be quantified. Conclusions: The substantially different expression pattern of nuclear receptors in human intestinal and liver tissue may explain the different extent of unwanted DDIs in the dependence on the administration route of drugs.
This study aims to describe social network and social participation and to assess associations with depressive symptoms in older persons with increased risk for dementia in Germany. We conducted a cross-sectional observational study in primary care patients (aged 60–77) as part of a multicenter cluster-randomized controlled trial (AgeWell.de). We present descriptive and multivariate analyses for social networks (Lubben Social Network Scale and subscales) and social participation (item list of social activities) and analyze associations of these variables with depressive symptoms (Geriatric Depression Scale). Of 1030 included patients, 17.2% were at risk for social isolation (Lubben Social Network Scale < 12). Looking at the subscales, a reduced non-family network was found almost twice as often as a reduced family network. Patients with depressive symptoms had significantly smaller social networks than patients without depression (p < 0.001). They rather engaged in social activities of low involvement level or no weekly social activity at all (p < 0.001). The study shows associations of depressive symptoms with a decreased social network and less social participation in elderly participants. Sufficient non-family contacts and weekly social activities seem to play an important role in mental health and should be encouraged in elderly primary care patients.
Drained peatlands are significant sources of the greenhouse gas (GHG) carbon dioxide.Rewetting is a proven strategy used to protect carbon stocks; however, it can lead to increasedemissions of the potent GHG methane. The response to rewetting of soil microbiomes as drivers ofthese processes is poorly understood, as are the biotic and abiotic factors that control communitycomposition. We analyzed the pro- and eukaryotic microbiomes of three contrasting pairs ofminerotrophic fens subject to decade-long drainage and subsequent long-term rewetting. Abiotic soilproperties including moisture, dissolved organic matter, methane fluxes, and ecosystem respirationrates were also determined. The composition of the microbiomes was fen-type-specific, but allrewetted sites showed higher abundances of anaerobic taxa compared to drained sites. Based onmulti-variate statistics and network analyses, we identified soil moisture as a major driver ofcommunity composition. Furthermore, salinity drove the separation between coastal and freshwaterfen communities. Methanogens were more than 10-fold more abundant in rewetted than in drainedsites, while their abundance was lowest in the coastal fen, likely due to competition with sulfatereducers. The microbiome compositions were reflected in methane fluxes from the sites. Our resultsshed light on the factors that structure fen microbiomes via environmental filtering.
Background: Fatigue, dyspnea, and lack of energy and concentration are commonly interpreted as indicative of symptomatic anemia and may thus play a role in diagnostic and therapeutic decisions. Objective: To investigate the association between symptoms commonly attributed to anemia and the actual presence of anemia. Methods: Data from two independent cohorts of the Study of Health in Pomerania (SHIP) were analyzed. Interview data, laboratory data, and physical examination were individually linked with claims data from the Association of Statutory Health Insurance Physicians. A complete case analysis using logistic regression models was performed to evaluate the association of anemia with symptoms commonly attributed to anemia. The models were adjusted for confounders such as depression, medication, insomnia, and other medical conditions. Results: A total of 5979 participants (53% female, median age 55) were included in the analysis. Of those, 30% reported fatigue, 16% reported lack of energy, 16% reported lack of concentration, and 29% reported dyspnea and/or weakness. Anemia was prevalent in about 6% (379). The symptoms were more prevalent in participants with anemia. However, participants with anemia were older and had a poorer health status. There was no association in multivariate logistic regression models between the symptoms fatigue, lack of concentration, dyspnea, and/or weakness and anemia. Anemia was associated (OR: 1.45; 95% CI: 1.13–1.86) with lack of energy in the multivariate analysis. Other factors such as depression, insomnia, and medication were more strongly associated with the symptoms. Conclusion: The clinical symptoms commonly attributed to anemia are unspecific and highly prevalent both in non-anemic and anemic persons. Even in the presence of anemia, other diagnoses should be considered as causes such as depression, heart failure, asthma, and COPD, which are more closely associated with the symptoms. Further diagnostic research is warranted to explore the association of symptoms in different subgroups and settings in order to help clinical decision making.
The objectives of this study were to ascertain the fecal ESBL/AmpC-E. coli prevalence and to detect risk factors for their occurrence in young pre-weaned calves and their dams on large dairy farms in Germany. From 2018–2019 we investigated 2816 individual fecal samples from pre-weaned dairy calves and their dams, representing seventy-two farms (mean = 667 milking cows) from eight German federal states. To assess possible risk factors associated with ESBL/AmpC-E. coli prevalence in calves and dams, a questionnaire was performed, collecting management data. We observed an ESBL/AmpC-E. coli prevalence of 63.5% (95% CI: 57.4–69.5) among the sampled calves and 18.0% (95% CI: 12.5–23.5) among the dams. On all farms, at least one positive sample was obtained. To date, this is the highest ESBL/AmpC-E. coli prevalence observed in dairy herds in Europe. Feeding with waste milk was identified as a significant risk factor for a high prevalence of ESBL/AmpC-E. coli in calves. Many calves at large dairies in Germany are fed with waste milk due to the large amounts generated as a result of antibiotic dry-off routines and mastitis treatment with antibiotics. Other notable risk factors for high ESBL/AmpC-E. coli in calves were the general fitness/health of dams and calves, and the quality of farm hygiene. Taken together, these findings suggest that new or improved approaches to animal health management, for example, antibiotic dry cow management (selective dry cow therapy) and mastitis treatment (high self-recovery), as well as farm hygiene, should be researched and implemented.
Advancing Radiation-Detected Resonance Ionization towards Heavier Elements and More Exotic Nuclides
(2022)
RAdiation-Detected Resonance Ionization Spectroscopy (RADRIS) is a versatile method for highly sensitive laser spectroscopy studies of the heaviest actinides. Most of these nuclides need to be produced at accelerator facilities in fusion-evaporation reactions and are studied immediately after their production and separation from the primary beam due to their short half-lives and low production rates of only a few atoms per second or less. Only recently, the first laser spectroscopic investigation of nobelium (Z=102) was performed by applying the RADRIS technique in a buffer-gas-filled stopping cell at the GSI in Darmstadt, Germany. To expand this technique to other nobelium isotopes and for the search for atomic levels in the heaviest actinide element, lawrencium (Z=103), the sensitivity of the RADRIS setup needed to be further improved. Therefore, a new movable double-detector setup was developed, which enhances the overall efficiency by approximately 65% compared to the previously used single-detector setup. Further development work was performed to enable the study of longer-lived (t1/2>1 h) and shorter-lived nuclides (t1/2<1 s) with the RADRIS method. With a new rotatable multi-detector design, the long-lived isotope 254Fm (t1/2=3.2 h) becomes within reach for laser spectroscopy. Upcoming experiments will also tackle the short-lived isotope 251No (t1/2=0.8 s) by applying a newly implemented short RADRIS measurement cycle.
Periodontitis is a multifactorial disease. The aim of this explorative study was to investigate the role of Interleukin-(IL)-1, IL-4, GATA-3 and Cyclooxygenase-(COX)-2 polymorphisms after non-surgical periodontal therapy with adjunctive systemic antibiotics (amoxicillin/metronidazole) and subsequent maintenance in a Caucasian population. Analyses were performed using blood samples from periodontitis patients of a multi-center trial (ClinicalTrials.gov NCT00707369=ABPARO-study). Polymorphisms were analyzed using quantitative real-time PCR. Clinical attachment levels (CAL), percentage of sites showing further attachment loss (PSAL) ≥1.3 mm, bleeding on probing (BOP) and plaque score were assessed. Exploratory statistical analysis was performed. A total of 209 samples were genotyped. Patients carrying heterozygous genotypes and single-nucleotide-polymorphisms (SNP) on the GATA-3-IVS4 +1468 gene locus showed less CAL loss than patients carrying wild type. Heterozygous genotypes and SNPs on the IL-1A-889, IL-1B +3954, IL-4-34, IL-4-590, GATA-3-IVS4 +1468 and COX-2-1195 gene loci did not influence CAL. In multivariate analysis, CAL was lower in patients carrying GATA-3 heterozygous genotypes and SNPs than those carrying wild-types. For the first time, effects of different genotypes were analyzed in periodontitis progression after periodontal therapy and during supportive treatment using systemic antibiotics demonstrating a slight association of GATA-3 gene locus with CAL. This result suggests that GATA-3 genotypes are a contributory but non-essential risk factor for periodontal disease progression.
Streptococcus pneumoniaeinfections lead to high morbidity and mortality rates worldwide.Pneumococcal polysaccharide conjugate vaccines significantly reduce the burden of disease but havea limited range of protection, which encourages the development of a broadly protective protein-basedalternative. We and others have shown that immunization with pneumococcal lipoproteins that lackthe lipid anchor protects against colonization. Since immunity againstS. pneumoniaeis mediatedthrough Toll-like receptor 2 signaling induced by lipidated proteins, we investigated the effects ofa lipid modification on the induced immune responses in either intranasally or subcutaneouslyvaccinated mice. Here, we demonstrate that lipidation of recombinant lipoproteins DacB and PnrAstrongly improves their immunogenicity. Mice immunized with lipidated proteins showed enhancedantibody concentrations and different induction kinetics. The induced humoral immune responsewas modulated by lipidation, indicated by increased IgG2/IgG1 subclass ratios related to Th1-typeimmunity. In a mouse model of colonization, immunization with lipidated antigens led to a moderatebut consistent reduction of pneumococcal colonization as compared to the non-lipidated proteins,indicating that protein lipidation can improve the protective capacity of the coupled antigen. Thus,protein lipidation represents a promising approach for the development of a serotype-independentpneumococcal vaccine.
Simple Summary
Neuronal plasticity refers to the brain’s ability to adapt in response to activity-dependent changes. This process, among others, allows the brain to acquire memory or to compensate for a neurocognitive deficit. We analyzed adult FTSJ1-deficient mice in order to gain insight into the role of FTSJ1 in neuronal plasticity. These mice displayed alterations in the hippocampus (a brain structure that is involved in memory and learning, among other functions) e.g., in the form of changes in dendritic spines. Changes in dendritic spines are considered to represent a morphological hallmark of altered neuronal plasticity, and thus FTSJ1 deficiency might have a direct effect upon the capacity of the brain to adapt to plastic changes. Long-term potentiation (LTP) is an electrophysiological correlate of neuronal plasticity, and is related to learning and to processes attributed to memory. Here we show that LTP in FTSJ1-deficient mice is reduced, hinting at disturbed neuronal plasticity. These findings suggest that FTSJ1 deficiency has an impact on neuronal plasticity not only morphologically but also on the physiological level.
Abstract
The role of the tRNA methyltransferase FTSJ1 in the brain is largely unknown. We analyzed whether FTSJ1-deficient mice (KO) displayed altered neuronal plasticity. We explored open field behavior (10 KO mice (aged 22–25 weeks)) and 11 age-matched control littermates (WT) and examined mean layer thickness (7 KO; 6 WT) and dendritic spines (5 KO; 5 WT) in the hippocampal area CA1 and the dentate gyrus. Furthermore, long-term potentiation (LTP) within area CA1 was investigated (5 KO; 5 WT), and mass spectrometry (MS) using CA1 tissue (2 each) was performed. Compared to controls, KO mice showed a significant reduction in the mean thickness of apical CA1 layers. Dendritic spine densities were also altered in KO mice. Stable LTP could be induced in the CA1 area of KO mice and remained stable at for at least 1 h, although at a lower level as compared to WTs, while MS data indicated differential abundance of several proteins, which play a role in neuronal plasticity. FTSJ1 has an impact on neuronal plasticity in the murine hippocampal area CA1 at the morphological and physiological levels, which, in conjunction with comparable changes in other cortical areas, might accumulate in disturbed learning and memory functions.
Response of Osteoblasts to Electric Field Line Patterns Emerging from Molecule Stripe Landscapes
(2022)
Molecular surface gradients can constitute electric field landscapes and serve to control local cell adhesion and migration. Cellular responses to electric field landscapes may allow the discovery of routes to improve osseointegration of implants. Flat molecule aggregate landscapes of amine- or carboxyl-teminated dendrimers, amine-containing protein and polyelectrolytes were prepared on glass to provide lateral electric field gradients through their differing zeta potentials compared to the glass substrate. The local as well as the mesoscopic morphological responses of adhered osteoblasts (MG-63) with respect to the stripes were studied by means of Scanning Ion Conductance Microscopy (SICM) and Fluorescence Microscopy, in situ. A distinct spindle shape oriented parallel to the surface pattern as well as a preferential adhesion of the cells on the glass site have been observed at a stripe and spacing width of 20 μm. Excessive ruffling is observed at the spindle poles, where the cells extend. To explain this effect of material preference and electro-deformation, we put forward a retraction mechanism, a localized form of double-sided cathodic taxis.
Exploring Virulence Factors and Alternative Therapies against Staphylococcus aureus Pneumonia
(2020)
Tissue sections, which are widely used in research and diagnostic laboratories and have already been examined by immunohistochemistry (IHC), may subsequently provide a resource for proteomic studies, even though only small amount of protein is available. Therefore, we established a workflow for tandem mass spectrometry-based protein profiling of IHC specimens and characterized defined brain area sections. We investigated the CA1 region of the hippocampus dissected from brain slices of adult C57BL/6J mice. The workflow contains detailed information on sample preparation from brain slices, including removal of antibodies and cover matrices, dissection of region(s) of interest, protein extraction and digestion, mass spectrometry measurement, and data analysis. The Gene Ontology (GO) knowledge base was used for further annotation. Literature searches and Gene Ontology annotation of the detected proteins verify the applicability of this method for global protein profiling using formalin-fixed and embedded material and previously used IHC slides.
MicroRNAs (miRNA) are ubiquitous non-coding RNAs that have a prominent role in cellular regulation. The expression of many miRNAs is often found deregulated in prostate cancer (PCa) and castration-resistant prostate cancer (CRPC). Although their expression can be associated with PCa and CRPC, their functions and regulatory activity in cancer development are poorly understood. In this study, we used different proteomics tools to analyze the activity of hsa-miR-3687-3p (miR-3687) and hsa-miR-4417-3p (miR-4417), two miRNAs upregulated in CRPC. PCa and CRPC cell lines were transfected with miR-3687 or miR-4417 to overexpress the miRNAs. Cell lysates were analyzed using 2D gel electrophoresis and proteins were subsequently identified using mass spectrometry (Maldi-MS/MS). A whole cell lysate, without 2D-gel separation, was analyzed by ESI-MS/MS. The expression of deregulated proteins found across both methods was further investigated using Western blotting. Gene ontology and cellular process network analysis determined that miR-3687 and miR-4417 are involved in diverse regulatory mechanisms that support the CRPC phenotype, including metabolism and inflammation. Moreover, both miRNAs are associated with extracellular vesicles, which point toward a secretory mechanism. The tumor protein D52 isoform 1 (TD52-IF1), which regulates neuroendocrine trans-differentiation, was found to be substantially deregulated in androgen-insensitive cells by both miR-3687 and miR-4417. These findings show that these miRNAs potentially support the CRPC by truncating the TD52-IF1 expression after the onset of androgen resistance.
The thyroid gland is both a thyroid hormone (TH) generating as well as a TH responsive
organ. It is hence crucial that cathepsin-mediated proteolytic cleavage of the precursor thyroglobulin
is regulated and integrated with the subsequent export of TH into the blood circulation, which is
enabled by TH transporters such as monocarboxylate transporters Mct8 and Mct10. Previously, we
showed that cathepsin K-deficient mice exhibit the phenomenon of functional compensation through
cathepsin L upregulation, which is independent of the canonical hypothalamus-pituitary-thyroid axis,
thus, due to auto-regulation. Since these animals also feature enhanced Mct8 expression, we aimed
to understand if TH transporters are part of the thyroid auto-regulatory mechanisms. Therefore,
we analyzed phenotypic differences in thyroid function arising from combined cathepsin K and
TH transporter deficiencies, i.e., in Ctsk-/-/Mct10-/-
, Ctsk-/-/Mct8-/y, and Ctsk-/-/Mct8-/y/Mct10-/-
.
Despite the impaired TH export, thyroglobulin degradation was enhanced in the mice lacking Mct8,
particularly in the triple-deficient genotype, due to increased cathepsin amounts and enhanced cysteine peptidase activities, leading to ongoing thyroglobulin proteolysis for TH liberation, eventually
causing self-thyrotoxic thyroid states. The increased cathepsin amounts were a consequence of
autophagy-mediated lysosomal biogenesis that is possibly triggered due to the stress accompanying
intrathyroidal TH accumulation, in particular in the Ctsk-/-/Mct8-/y/Mct10-/- animals. Collectively,
our data points to the notion that the absence of cathepsin K and Mct8 leads to excessive thyroglobulin
degradation and TH liberation in a non-classical pathway of thyroid auto-regulation.
Seventeen bacterial strains able to suppress plant pathogens have been isolated from healthy Vietnamese crop plants and taxonomically assigned as members of the Bacillus cereus group. In order to prove their potential as biocontrol agents, we perform a comprehensive analysis that included the whole-genome sequencing of selected strains and the mining for genes and gene clusters involved in the synthesis of endo- and exotoxins and secondary metabolites, such as antimicrobial peptides (AMPs). Kurstakin, thumolycin, and other AMPs were detected and characterized by different mass spectrometric methods, such as MALDI-TOF-MS and LIFT-MALDI-TOF/TOF fragment analysis. Based on their whole-genome sequences, the plant-associated isolates were assigned to the following species and subspecies: B. cereus subsp. cereus (6), B. cereus subsp. bombysepticus (5), Bacillus tropicus (2), and Bacillus pacificus. These three isolates represent novel genomospecies. Genes encoding entomopathogenic crystal and vegetative proteins were detected in B. cereus subsp. bombysepticus TK1. The in vitro assays revealed that many plant-associated isolates enhanced plant growth and suppressed plant pathogens. Our findings indicate that the plant-associated representatives of the B. cereus group are a rich source of putative antimicrobial compounds with potential in sustainable agriculture. However, the presence of virulence genes might restrict their application as biologicals in agriculture.
Leukocyte telomere length (TL) has been suggested as a marker of biological age in healthy
individuals, but can also reflect inherited and acquired hematopoietic dysfunctions or indicate an
increased turnover of the hematopoietic stem and progenitor cell compartment. In addition, TL is able
to predict the response rate of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (CML),
indicates clinical outcomes in chronic lymphocytic leukemia (CLL), and can be used as screening tool
for genetic sequencing of selected genes in patients with inherited bone marrow failure syndromes
(BMFS). In tumor cells and clonal hematopoietic disorders, telomeres are continuously stabilized by
reactivation of telomerase, which can selectively be targeted by telomerase-specific therapy. The use of
the telomerase inhibitor Imetelstat in patients with essential thrombocythmia or myelofibrosis as well
as the use of dendritic cell-based telomerase vaccination in AML patients with complete remissions are
promising examples for anti-telomerase targeted strategies in hematologic malignancies. In contrast,
the elevation in telomerase levels through treatment with androgens has become an exciting clinical
intervention for patients with BMFS. Here, we review recent developments, which highlight the
impact of telomeres and telomerase targeted therapies in hematologic dysfunctions.
Permafrost-affected soil stores a significant amount of organic carbon. Identifying the biological constraints of soil organic matter transformation, e.g., the interaction of major soil microbial soil organic matter decomposers, is crucial for predicting carbon vulnerability in permafrost-affected soil. Fungi are important players in the decomposition of soil organic matter and often interact in various mutualistic relationships during this process. We investigated four different soil horizon types (including specific horizons of cryoturbated soil organic matter (cryoOM)) across different types of permafrost-affected soil in the Western Canadian Arctic, determined the composition of fungal communities by sequencing (Illumina MPS) the fungal internal transcribed spacer region, assigned fungal lifestyles, and by determining the co-occurrence of fungal network properties, identified the topological role of keystone fungal taxa. Compositional analysis revealed a significantly higher relative proportion of the litter saprotroph Lachnum and root-associated saprotroph Phialocephala in the topsoil and the ectomycorrhizal close-contact exploring Russula in cryoOM, whereas Sites 1 and 2 had a significantly higher mean proportion of plant pathogens and lichenized trophic modes. Co-occurrence network analysis revealed the lowest modularity and average path length, and highest clustering coefficient in cryoOM, which suggested a lower network resistance to environmental perturbation. Zi-Pi plot analysis suggested that some keystone taxa changed their role from generalist to specialist, depending on the specific horizon concerned, Cladophialophora in topsoil, saprotrophic Mortierella in cryoOM, and Penicillium in subsoil were classified as generalists for the respective horizons but specialists elsewhere. The litter saprotrophic taxon Cadophora finlandica played a role as a generalist in Site 1 and specialist in the rest of the sites. Overall, these results suggested that fungal communities within cryoOM were more susceptible to environmental change and some taxa may shift their role, which may lead to changes in carbon storage in permafrost-affected soil.
The G protein-coupled receptor proteinase-activated receptor 2 (PAR2) has been implicated
in various aspects of cellular physiology including inflammation, obesity and cancer. In cancer,
it usually acts as a driver of cancer progression in various tumor types by promoting invasion and
metastasis in response to activation by serine proteinases. Recently, we discovered another mode
through which PAR2 may enhance tumorigenesis: crosstalk with transforming growth factor-β
(TGF-β) signaling to promote TGF-β1-induced cell migration/invasion and invasion-associated gene
expression in ductal pancreatic adenocarcinoma (PDAC) cells. In this chapter, we review what is
known about the cellular TGF-β responses and signaling pathways affected by PAR2 expression,
the signaling activities of PAR2 required for promoting TGF-β signaling, and the potential molecular
mechanism(s) that underlie(s) the TGF-β signaling–promoting effect. Since PAR2 is activated through
various serine proteinases and biased agonists, it may couple TGF-β signaling to a diverse range of
other physiological processes that may or may not predispose cells to cancer development such as
local inflammation, systemic coagulation and pathogen infection.
Background: Recently, the expression of proteinase-activated receptor 2 (PAR2) has been
shown to be essential for activin receptor-like kinase 5 (ALK5)/SMAD-mediated signaling and cell
migration by transforming growth factor (TGF)-β1. However, it is not known whether activation
of non-SMAD TGF-β signaling (e.g., RAS–RAF–MEK–extracellular signal-regulated kinase (ERK)
signaling) is required for cell migration and whether it is also dependent on PAR2. Methods: RNA
interference was used to deplete cells of PAR2, followed by xCELLigence technology to measure
cell migration, phospho-immunoblotting to assess ERK1/2 activation, and co-immunoprecipitation
to detect a PAR2–ALK5 physical interaction. Results: Inhibition of ERK signaling with the MEK
inhibitor U0126 blunted the ability of TGF-β1 to induce migration in pancreatic cancer Panc1 cells.
ERK activation in response to PAR2 agonistic peptide (PAR2–AP) was strong and rapid, while it was
moderate and delayed in response to TGF-β1. Basal and TGF-β1-dependent ERK, but not SMAD
activation, was blocked by U0126 in Panc1 and other cell types indicating that ERK activation is
downstream or independent of SMAD signaling. Moreover, cellular depletion of PAR2 in HaCaT
cells strongly inhibited TGF-β1-induced ERK activation, while the biased PAR2 agonist GB88 at 10
and 100 µM potentiated TGF-β1-dependent ERK activation and cell migration. Finally, we provide
evidence for a physical interaction between PAR2 and ALK5. Our data show that both PAR2–APand TGF-β1-induced cell migration depend on ERK activation, that PAR2 expression is crucial for
TGF-β1-induced ERK activation, and that the functional cooperation of PAR2 and TGF-β1 involves a
physical interaction between PAR2 and ALK5
Extracellular vesicles (EVs) are reminiscent of their cell of origin and thus represent a
valuable source of biomarkers. However, for EVs to be used as biomarkers in clinical practice, simple,
comparable, and reproducible analytical methods must be applied. Although progress is being
made in EV separation methods for human biofluids, the implementation of EV assays for clinical
diagnosis and common guidelines are still lacking. We conducted a comprehensive analysis of
established EV separation techniques from human serum and plasma, including ultracentrifugation
and size exclusion chromatography (SEC), followed by concentration using (a) ultracentrifugation,
(b) ultrafiltration, or (c) precipitation, and immunoaffinity isolation. We analyzed the size, number,
protein, and miRNA content of the obtained EVs and assessed the functional delivery of EV cargo.
Our results demonstrate that all methods led to an adequate yield of small EVs. While no significant
difference in miRNA content was observed for the different separation methods, ultracentrifugation
was best for subsequent flow cytometry analysis. Immunoaffinity isolation is not suitable for
subsequent protein analyses. SEC + ultracentrifugation showed the best functional delivery of
EV cargo. In summary, combining SEC with ultracentrifugation gives the highest yield of pure
and functional EVs and allows reliable analysis of both protein and miRNA contents. We propose
this combination as the preferred EV isolation method for biomarker studies from human serum
or plasma.
Because of the importance of gastric emptying for pharmacokinetics, numerous methods have been developed for its determination. One of the methods is the salivary tracer technique, which utilizes an ice capsule containing caffeine as a salivary tracer. Despite the ice capsule’s advantage in labeling ingested fluids with caffeine for subsequent salivary detection, its risk of premature melting before swallowing, and its complicated storage and preparation, limit its application, particularly in special populations (e.g., older people). For this reason, here, a compression-coated tablet was developed and validated against the ice capsule in a cross-over clinical trial. The two dosage forms were administered simultaneously to 12 volunteers in an upright position under fasted and fed state conditions. To distinguish the caffeine concentrations in saliva from each dosage form, regular type of caffeine (12C) was added to the tablet, while for the ice capsule 13C3 labelled caffeine was used. The salivary caffeine concentrations showed no statistically significant differences for the pharmacokinetic parameters tmax and AUC0→60 (p > 0.05). Thus, the new formulation is a useful tool for determining gastric emptying that can also be used in special populations.
This article reports on the development, implementation and management of a German–Polish telemedicine network in the field of pediatric oncology and hematology in the Euroregion Pomerania. The achievements and challenges of joint medical case reviews involving patients and their care givers, as well as cross-border education activities for physicians, students and nursing staff, are presented. In addition to a progress report, the results of an evaluation of the participants and teachers, likewise the measurement of knowledge growth, are given.
A massive shift in agricultural practices over the past decades, to support exceptionally high yields and productivities involving intensive agriculture, have led to unsustainable agriculture practices across the globe. Sustenance of such high yields and productivities demand high use of organic and industrial fertilizers. This acts as a negative pressure on the environment. Excessive use of fertilizers leads to nutrient surplus in the fields, which, as a part of catchment runoff, flows into the water bodies as diffuse pollution. These nutrients through rivers are eventually passed into seas. High nutrients ending up into water bodies cause eutrophication. The situation is worsened when such unsustainable agricultural activities are carried out on drained peatlands. As a result, the nutrients that were not part of the nutrient cycle in the landscape for years begin to leach out due to mineralization of peatlands, thereby putting an additional load of nutrients on the environment, that was already under the negative impact of nutrient surplus. In view of the above, a small lowland catchment of the Ryck river in northeast Germany was assessed for its nitrogen losses from agricultural lands through empirical modelling. Initial empirical modelling resulted in an average annual total nitrogen loss of 14.7 kg ha−1 year−1. After a comparative analysis of these results with procured data, the empirical equation was modified to suit the catchment, yielding more accurate results. The study showed that 75.6% of peatlands in the catchment are under agricultural use. Subsequently, a proposal was made for potential wetland buffer zones in the Ryck catchment. Altogether, 13 peatland sites across 8 sub-catchments were recommended for mitigation of high nutrient runoff. In the end, nutrient efficiency of proposed WBZs in one of the sub-catchments of Ryck has been discussed. The results show that (i) the modified empirical equation can act as a key tool in application-based future strategies for nitrogen reduction in the Ryck catchment, (ii) restoration of peatlands and introduction of WBZs can help in mitigating the nutrient runoff for improved water quality of Ryck, and subsequently (ii) contribute to efficient reduction of riverine loads of nutrients into the Baltic Sea.
Acute pancreatitis (AP) is a major, globally increasing gastrointestinal disease and a biliary origin is the most common cause. However, the effects of bile acids (BAs), given systemically, on the pancreas and on disease severity remains elusive. In this study, we have investigated the roles of different circulating BAs in animal models for AP to elucidate their impact on disease severity and the underlying pathomechanisms. BAs were incubated on isolated acini and AP was induced through repetitive injections of caerulein or L-arginine; pancreatic duct ligation (PDL); or combined biliopancreatic duct ligation (BPDL). Disease severity was assessed using biochemical and histological parameters. Serum cholecystokinin (CCK) concentrations were determined via enzyme immunoassay. The binding of the CCK1 receptor was measured using fluorescence-labeled CCK. In isolated acini, hydrophobic BAs mitigated the damaging effects of CCK. The same BAs further enhanced pancreatitis in L-arginine- and PDL-based pancreatitis, whereas they ameliorated pancreatic damage in the caerulein and BPDL models. Mechanistically, the binding affinity of the CCK1 receptor was significantly reduced by hydrophobic BAs. The hydrophobicity of BAs and the involvement of CCK seem to be relevant in the course of AP. Systemic BAs may affect the severity of AP by interfering with the CCK1 receptor.
Endoscopic and Histopathological Characteristics of Gastrointestinal Lymphoma: A Multicentric Study
(2023)
Background: Extranodal non-Hodgkin lymphoma (NHL) is more prevalent in the gastrointestinal (GI) tract than in other sites. This study aimed to determine the endoscopic characteristics of primary gastrointestinal non-Hodgkin lymphomas. Methods: We investigated 140 patients from three tertiary referral hospitals with primary malignant lymphoma of the gastrointestinal tract. Characteristics of the lesions were evaluated and analyzed using image-enhanced endoscopy, endoscopic ultrasound, and histopathology. Results: The median age was 60.5 (range: 11–99), and 59 (42.1%) were female. The most frequent complaint was abdominal pain (74.3%), followed by bloody feces (10%) and diarrhea (2.9%). B symptoms were observed in 15 (10.7%) patients. GI obstruction was the most common complication (10.0%), followed by hemorrhage (7.9%) and perforation (1.5%). Regarding endoscopic findings, the identified sites were the following: the stomach (61.4%), colon (10%), small intestine (10%), ileocecum (8.6%), rectum (6.4%), and duodenum (3.6%). Diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma are most prevalent in the stomach. Helicobacter pylori was identified in 46 cases (39.0%), with MALT lymphoma being the most infected subtype. Nearly all gastrointestinal non-Hodgkin lymphomas manifested as superficial type (25–59.6%) and ulcer type (15.6–50%) under endoscopy. We found that fungating type and protruding with ulcer type were more frequent types of aggressive lymphomas (diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma) compared to the indolent types (MALT lymphoma, follicular lymphoma, duodenal-type follicular lymphoma, and small lymphocytic lymphoma) (p < 0.05). Conclusions: This study showed that most subtypes of gastrointestinal non-Hodgkin lymphomas exhibited same endoscopic features (superficial type and ulcer type). Aggressive gastrointestinal non-Hodgkin lymphomas (diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma) were highly suspected when fungating lesions and protruding with ulcer lesions were encountered under endoscopy. Endoscopists should be aware of the connection between enhanced endoscopic characteristics and histological varieties of gastrointestinal lymphoma to improve diagnosis.
Although disaster research has acknowledged the role of social media in crisis communication, the interplay of new (e.g., mobile apps) and traditional media (e.g., TV, radio) in public warnings has received less attention, particularly from the recipients’ perspective. Therefore, we examined sociodemographic and psychosocial correlates of different types of media use (i.e., traditional, new, mixed) for receiving public warning messages in a population survey (N = 613, 63% female; Mage = 31.56 years). More than two-thirds (68%) reported mixed media use, with 20% relying on new media and 12% on traditional media. Traditional media users were older and reported lower levels of education, while new media users were significantly younger and reported lower trust toward traditional media (i.e., TV). Migrants were more likely to use new but not mixed media. In sum, most participants utilized a mixture of traditional and new media for warning purposes, which has implications for crisis communication. Though, vulnerable populations (e.g., older and less educated participants) mainly rely on traditional media, stressing the need for continued support. Thus, it is paramount to increasingly use mixed methods designs and concurrently examine multiple channels to reflect real-world warning practices and generate ecologically valid results.
Sphingosine-1-phosphate (S1P) is a versatile signaling lipid involved in the regulation of numerous cellular processes. S1P regulates cellular proliferation, migration, and apoptosis as well as the function of immune cells. S1P is generated from sphingosine (Sph), which derives from the ceramide metabolism. In particular, high concentrations of S1P are present in the blood. This originates mainly from erythrocytes, endothelial cells (ECs), and platelets. While erythrocytes function as a storage pool for circulating S1P, platelets can rapidly generate S1P de novo, store it in large quantities, and release it when the platelet is activated. Platelets can thus provide S1P in a short time when needed or in the case of an injury with subsequent platelet activation and thereby regulate local cellular responses. In addition, platelet-dependently generated and released S1P may also influence long-term immune cell functions in various disease processes, such as inflammation-driven vascular diseases. In this review, the metabolism and release of platelet S1P are presented, and the autocrine versus paracrine functions of platelet-derived S1P and its relevance in various disease processes are discussed. New pharmacological approaches that target the auto- or paracrine effects of S1P may be therapeutically helpful in the future for pathological processes involving S1P.
Duckweeds comprise a distinctive clade of pleustophytic monocots that traditionally has been classified as the family Lemnaceae. However, molecular evidence has called into question their phylogenetic independence, with some authors asserting instead that duckweeds should be reclassified as subfamily Lemnoideae of an expanded family Araceae. Although a close phylogenetic relationship of duckweeds with traditional Araceae has been supported by multiple studies, the taxonomic disposition of duckweeds must be evaluated more critically to promote nomenclatural stability and utility. Subsuming duckweeds as a morphologically incongruent lineage of Araceae effectively eliminates the family category of Lemnaceae that has been widely used for many years. Instead, we suggest that Araceae subfamily Orontioideae should be restored to family status as Orontiaceae, which thereby would enable the recognition of three morphologically and phylogenetically distinct lineages: Araceae, Lemnaceae, and Orontiaceae.
Neuroinflammatory mechanisms and maladaptive neuroplasticity underlie the progression of complex regional pain syndrome (CRPS), which is prototypical of central neuropathic pain conditions. While cortical maladaptive alterations are well described, little is known about the contribution of the brainstem to the pathophysiology. This study investigates the role of pain-modulatory brainstem pathways in CRPS using the nociceptive blink reflex (nBR), which not only provides a direct read-out of brainstem excitability and habituation to painful stimuli but may also be suitable for use as a diagnostic biomarker for CRPS. Thirteen patients with CRPS and thirteen healthy controls (HCs) participated in this prospective case-control study investigating the polysynaptic trigemino-cervical (R2) nBR response. The R2 area and its habituation were assessed following repeated supraorbital electrical stimulation. Between-group comparisons included evaluations of diagnostic characteristics as a potential biomarker for the disease. Patients with CRPS showed a substantial decrease in habituation on the stimulated (Cohen’s d: 1.3; p = 0.012) and the non-stimulated side (Cohen’s d: 1.1; p = 0.04). This is the first study to reveal altered nBR habituation as a pathophysiological mechanism and potential diagnostic biomarker in CRPS. We confirmed previous findings of altered nBR excitability, but the diagnostic accuracy was inferior. Future studies should investigate the nBR as a marker of progression to central mechanisms in CRPS and as a biomarker to predict treatment response or prognosis.
Water Consumption of Agriculture and Natural Ecosystems along the Ili River in China and Kazakhstan
(2017)
Biological invasions pose global threats to biodiversity and ecosystem functions. Invasive species often display a high degree of phenotypic plasticity, enabling them to adapt to new environments. This study examines plasticity to water stress in native and invasive Opuntia ficus-indica populations, a prevalent invader in arid and semi-arid ecosystems. Through controlled greenhouse experiments, we evaluated three native and nine invasive populations. While all plants survived the dry treatment, natives exhibited lower plasticity to high water availability with only a 36% aboveground biomass increase compared to the invasives with a greater increase of 94%. In terms of belowground biomass, there was no significant response to increased water availability for native populations, but plants from the invasive populations showed a 75% increase from the dry to the wet treatment. Enhanced phenotypic plasticity observed in invasive populations of O. ficus-indica is likely a significant driver of their success and invasiveness across different regions, particularly with a clear environmental preference towards less arid conditions. Climate change is expected to amplify the invasion success due to the expansion of arid areas and desertification. Opuntia ficus-indica adapts to diverse environments, survives dry spells, and grows rapidly in times of high-water supply, making it a candidate for increased invasion potential with climate change.
Urm1: A Non-Canonical UBL
(2021)
Amine transaminases (ATAs) are pyridoxal-5′-phosphate (PLP)-dependent enzymes that catalyze the transfer of an amino group from an amino donor to an aldehyde and/or ketone. In the past decade, the enzymatic reductive amination of prochiral ketones catalyzed by ATAs has attracted the attention of researchers, and more traditional chemical routes were replaced by enzymatic ones in industrial manufacturing. In the present work, the influence of the presence of an α,β-unsaturated system in a methylketone model substrate was investigated, using a set of five wild-type ATAs, the (R)-selective from Aspergillus terreus (Atr-TA) and Mycobacterium vanbaalenii (Mva-TA), the (S)-selective from Chromobacterium violaceum (Cvi-TA), Ruegeria pomeroyi (Rpo-TA), V. fluvialis (Vfl-TA) and an engineered variant of V. fluvialis (ATA-256 from Codexis). The high conversion rate (80 to 99%) and optical purity (78 to 99% ee) of both (R)- and (S)-ATAs for the substrate 1-phenyl-3-butanone, using isopropylamine (IPA) as an amino donor, were observed. However, the double bond in the α,β-position of 4-phenylbut-3-en-2-one dramatically reduced wild-type ATA reactivity, leading to conversions of <10% (without affecting the enantioselectivity). In contrast, the commercially engineered V. fluvialis variant, ATA-256, still enabled an 87% conversion, yielding a corresponding amine with >99% ee. Computational docking simulations showed the differences in orientation and intermolecular interactions in the active sites, providing insights to rationalize the observed experimental results.
(1) Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to “only-children”, HRs for second- or later-born individuals were 0.70 (95% CI = 0.50–0.96) and 0.65 (95% CI = 0.45–0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults’ T1D risk assessment for early detection.
Free light chains kappa (FLCκ) in cerebrospinal fluid (CSF) are a part of the intrathecal immune response. This observational study was conducted to investigate the effects of different disease-modifying therapies (DMT) on the humoral intrathecal immune response in the CSF of patients with multiple sclerosis (MS). FLCκ were analyzed in CSF and serum samples from MS patients taking DMT (n = 60) and those in a control cohort of treatment-naïve MS patients (n = 90). DMT was classified as moderately effective (including INFß-1a, INFß-1b, glatiramer acetate, dimethyl fumarate, teriflunomide, triamcinolone); highly effective (including fingolimod, daclizumab) and very highly effective (alemtuzumab, natalizumab, rituximab/ocrelizumab, mitoxantrone). FLCκ were measured using a nephelometric FLCκ kit. Intrathecal FLCκ and IgG concentrations were assessed in relation to the hyperbolic reference range in quotient diagrams. Intrathecal FLCκ concentrations and IgG concentrations were significantly lower in samples from the cohort of MS patients taking very highly effective DMT than in samples from the cohort of MS patients taking highly effective DMT and in the treatment-naïve cohort (FLCκ: p = 0.004, p < 0.0001 respectively/IgG: p = 0.013; p = 0.021). The reduction in FLCκ could contribute to an anti-inflammatory effect in the CNS through this mechanism. There was no difference in the appearance of CSF-specific oligoclonal bands (p = 0.830). Longitudinal analyses are required to confirm these results.
Titin is a multifunctional filamentous protein anchored in the M-band, a hexagonally organized supramolecular lattice in the middle of the muscle sarcomere. Functionally, the M-band is a framework that cross-links myosin thick filaments, organizes associated proteins, and maintains sarcomeric symmetry via its structural and putative mechanical properties. Part of the M-band appears at the C-terminal end of isolated titin molecules in the form of a globular head, named here the “M-complex”, which also serves as the point of head-to-head attachment of titin. We used high-resolution atomic force microscopy and nanosurgical manipulation to investigate the topographical and internal structure and local mechanical properties of the M-complex and its associated titin molecules. We find that the M-complex is a stable structure that corresponds to the transverse unit of the M-band organized around the myosin thick filament. M-complexes may be interlinked into an M-complex array that reflects the local structural and mechanical status of the transversal M-band lattice. Local segments of titin and the M-complex could be nanosurgically manipulated to achieve extension and domain unfolding. Long threads could be pulled out of the M-complex, suggesting that it is a compact supramolecular reservoir of extensible filaments. Nanosurgery evoked an unexpected volume increment in the M-complex, which may be related to its function as a mechanical spacer. The M-complex thus displays both elastic and plastic properties which support the idea that the M-band may be involved in mechanical functions within the muscle sarcomere.
Klebsiella pneumoniae is a common member of the intestinal flora of vertebrates. In addition to opportunistic representatives, hypervirulent (hvKp) and antibiotic-resistant K. pneumoniae (ABR-Kp) occur. While ABR-Kp isolates often cause difficult-to-treat diseases due to limited therapeutic options, hvKp is a pathotype that can infect healthy individuals often leading to recurrent infection. Here, we investigated the clinical K. pneumoniae isolate PBIO3459 obtained from a blood sample, which showed an unusual colony morphology. By combining whole-genome and RNA sequencing with multiple in vitro and in vivo virulence-associated assays, we aimed to define the respective Klebsiella subtype and explore the unusual phenotypic appearance. We demonstrate that PBIO3459 belongs to sequence type (ST)20 and carries no acquired resistance genes, consistent with phenotypic susceptibility tests. In addition, the isolate showed low-level virulence, both at genetic and phenotypic levels. We thus suggest that PBIO3459 is an opportunistic (commensal) K. pneumoniae isolate. Genomic comparison of PBIO3459 with closely related ABR-Kp ST20 isolates revealed that they differed only in resistance genes. Finally, the unusual colony morphology was mainly associated with carbohydrate and amino acid transport and metabolism. In conclusion, our study reveals the characteristics of a Klebsiella sepsis isolate and suggests that opportunistic representatives likely acquire and accumulate antibiotic resistances that subsequently enable their emergence as ABR-Kp pathogens.
Zinc finger proteins play pivotal roles in health and disease and exert critical functions in various cellular processes. A majority of zinc finger proteins bind DNA and act as transcription factors. B-cell lymphoma/leukemia 11B (BCL11B) represents one member of the large family of zinc finger proteins. The N-terminal domain of BCL11B was shown to be crucial for BCL11B to exert its proper function by homodimerization. Here, we describe an easy and fast preparation protocol to yield the fluorescently tagged protein of the recombinant N-terminal BCL11B zinc finger domain (BCL11B42-94) for in vitro studies. First, we expressed fluorescently tagged BCL11B42-94 in E. coli and described the subsequent purification utilizing immobilized metal ion affinity chromatography to achieve very high yields of a purified fusion protein of 200 mg/L culture. We proceeded with characterizing the atypical zinc finger domain using circular dichroism and size exclusion chromatography. Validation of the functional fluorescent pair CyPet-/EYFP-BCL11B42-94 was achieved with Förster resonance energy transfer. Our protocol can be utilized to study other zinc finger domains to expand the knowledge in this field.
Pilot sites are currently used to test the performance of bentonite barriers for sealing high-level radioactive waste repositories, but the degree of mineral stability under enhanced thermal conditions remains a topic of debate. This study focuses on the SKB ABM5 experiment, which ran for 5 years (2012 to 2017) and locally reached a maximum temperature of 250 °C. Five bentonites were investigated using XRD with Rietveld refinement, SEM-EDX and by measuring pH, CEC and EC. Samples extracted from bentonite blocks at 0.1, 1, 4 and 7 cm away from the heating pipe showed various stages of alteration related to the horizontal thermal gradient. Bentonites close to the contact with lower CEC values showed smectite alterations in the form of tetrahedral substitution of Si4+ by Al3+ and some octahedral metal substitutions, probably related to ferric/ferrous iron derived from corrosion of the heater during oxidative boiling, with pyrite dissolution and acidity occurring in some bentonite layers. This alteration was furthermore associated with higher amounts of hematite and minor calcite dissolution. However, as none of the bentonites showed any smectite loss and only displayed stronger alterations at the heater–bentonite contact, the sealants are considered to have remained largely intact.
Solid Phase Assembly of Fully Protected Trinucleotide Building Blocks for Codon-Based Gene Synthesis
(2019)
Here, we provide a detailed taxonomic reassessment of a historically collected chondrichthyan dental assemblage from the lower Kimmeridgian of Czarnogłowy in north-western Poland and discuss its significance for better understanding hybodontiform diversity patterns prior to their post-Jurassic decline in fully marine environments. In spite of its low taxonomic diversity, consisting of four large-toothed taxa (viz., Strophodus udulfensis, Asteracanthus ornatissimus, Planohybodus sp. and cf. Meristodonoides sp.), this assemblage is remarkable in that there are only very few Mesozoic hybodontiform assemblages with more large-toothed genera or even species. Comparisons with other European Late Jurassic hybodontiform-bearing localities demonstrate fairly homogenous distribution patterns characterized by large-bodied epipelagic forms of high dispersal ability. This is in stark contrast to post-Jurassic hybodontiform associations, which are dominated by smaller species that were predominantly bound to marginal marine and continental waters, suggesting a major reorganization of chondrichthyan communities during the Early Cretaceous.
Background: Interstitial lung disease (ILD) is associated with high rates of comorbidities and non-infectious lung disease mortality. Against this background, we aimed to evaluate the prognostic capacity of lung function and cardiopulmonary exercise testing (CPET) in patients with ILD. Materials and Methods: A total of 183 patients with diverse ILD entities were included in this monocentric analysis. Prediction models were determined using Cox regression models with age, sex, body mass index (BMI), and all parameters from pulmonary function testing and CPET. Kaplan–Meier curves were plotted for selected variables. Results: The median follow-up period was 3.0 ± 2.5 years. Arterial hypertension (57%) and pulmonary hypertension (38%) were the leading comorbidities. The Charlson comorbidity index score was 2 ± 2 points. The 3-year and 5-year survival rates were 68% and 50%, respectively. VO2peak (mL/kg/min or %pred.) was identified as a significant prognostic parameter in patients with ILD. The cut-off value for discriminating mortality was 61%. Conclusion: The present analyses consistently revealed the high prognostic power of VO2peak %pred. and other parameters evaluating breathing efficacy (VÉ/VCO2 @AT und VÉ/VCO2 slope) in ILD patients. VO2peak %pred., in contrast to the established prognostic values FVC %pred., DLCO/KCO %pred., and GAP, showed an even higher prognostic ability in all statistical models.
The therapeutic efficacy of a cardiovascular device after implantation is highly dependent on the host-initiated complement and coagulation cascade. Both can eventually trigger thrombosis and inflammation. Therefore, understanding these initial responses of the body is of great importance for newly developed biomaterials. Subtle modulation of the associated biological processes could optimize clinical outcomes. However, our failure to produce truly blood compatible materials may reflect our inability to properly understand the mechanisms of thrombosis and inflammation associated with biomaterials. In vitro models mimicking these processes provide valuable insights into the mechanisms of biomaterial-induced complement activation and coagulation. Here, we review (i) the influence of biomaterials on complement and coagulation cascades, (ii) the significance of complement-coagulation interactions for the clinical success of cardiovascular implants, (iii) the modulation of complement activation by surface modifications, and (iv) in vitro testing strategies.
The cortical silent period (CSP), assessed with transcranial magnetic stimulation (TMS), provides insights into motor cortex excitability. Alterations in the CSP have been observed in multiple sclerosis (MS), although a comparison of the sometimes contradictory results is difficult due to methodological differences. The aim of this study is to provide a more profound neurophysiological understanding of fatigue’s pathophysiology and its relationship to the CSP. Twenty-three patients with MS, along with a matched control group, underwent comprehensive CSP measurements at four intensities (125, 150, 175, and 200% resting motor threshold), while their fatigue levels were assessed using the Fatigue Scale for Motor and Cognitive Functions (FSMC) and its motor and cognitive subscore. MS patients exhibited a significantly increased CSP duration compared to controls (p = 0.02), but CSP duration was not associated with the total FSMC, or the motor or cognitive subscore. Our data suggest a systematic difference in MS patients compared to healthy controls in the CSP but no association with fatigue when measured with the FSMC. Based on these results, and considering the heterogeneous literature in the field, our study highlights the need for a more standardized approach to neurophysiological data collection and validation. This standardization is crucial for exploring the link between TMS and clinical impairments in diseases like MS.