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Growth, ageing and atherosclerotic plaque development alter the biomechanical forces acting on the vessel wall. However, monitoring the detailed local changes in wall shear stress (WSS) at distinct sites of the murine aortic arch over time has been challenging. Here, we studied the temporal and spatial changes in flow, WSS, oscillatory shear index (OSI) and elastic properties of healthy wildtype (WT, n = 5) and atherosclerotic apolipoprotein E-deficient (Apoe−/−, n = 6) mice during ageing and atherosclerosis using high-resolution 4D flow magnetic resonance imaging (MRI). Spatially resolved 2D projection maps of WSS and OSI of the complete aortic arch were generated, allowing the pixel-wise statistical analysis of inter- and intragroup hemodynamic changes over time and local correlations between WSS, pulse wave velocity (PWV), plaque and vessel wall characteristics. The study revealed converse differences of local hemodynamic profiles in healthy WT and atherosclerotic Apoe−/− mice, and we identified the circumferential WSS as potential marker of plaque size and composition in advanced atherosclerosis and the radial strain as a potential marker for vascular elasticity. Two-dimensional (2D) projection maps of WSS and OSI, including statistical analysis provide a powerful tool to monitor local aortic hemodynamics during ageing and atherosclerosis. The correlation of spatially resolved hemodynamics and plaque characteristics could significantly improve our understanding of the impact of hemodynamics on atherosclerosis, which may be key to understand plaque progression towards vulnerability.
Over the last decades, thyroid hormone metabolites (THMs) received marked attention as it has been demonstrated that they are bioactive compounds. Their concentrations were determined by immunoassay or mass-spectrometry methods. Among those metabolites, 3,5-diiodothyronine (3,5-T2), occurs at low nanomolar concentrations in human serum, but might reach tissue concentrations similar to those of T4 and T3, at least based on data from rodent models. However, the immunoassay-based measurements in human sera revealed remarkable variations depending on antibodies used in the assays and thus need to be interpreted with caution. In clinical experimental approaches in euthyroid volunteers and hypothyroid patients using the immunoassay as the analytical tool no evidence of formation of 3,5-T2 from its putative precursors T4 or T3 was found, nor was any support found for the assumption that 3,5-T2 might represent a direct precursor for serum 3-T1-AM generated by combined deiodination and decarboxylation from 3,5-T2, as previously documented for mouse intestinal mucosa. We hypothesized that lowered endogenous production of 3,5-T2 in patients requiring T4 replacement therapy after thyroidectomy or for treatment of autoimmune thyroid disease, compared to production of 3,5-T2 in individuals with intact thyroid glands might contribute to the discontent seen in a subset of patients with this therapeutic regimen. So far, our observations do not support this assumption. However, the unexpected association between high serum 3,5-T2 and elevated urinary concentrations of metabolites related to coffee consumption requires further studies for an explanation. Elevated 3,5-T2 serum concentrations were found in several situations including impaired renal function, chronic dialysis, sepsis, non-survival in the ICU as well as post-operative atrial fibrillation (POAF) in studies using a monoclonal antibody-based chemoluminescence immunoassay. Pilot analysis of human sera using LC-linear-ion-trap-mass-spectrometry yielded 3,5-T2 concentrations below the limit of quantification in the majority of cases, thus the divergent results of both methods need to be reconciliated by further studies. Although positive anti-steatotic effects have been observed in rodent models, use of 3,5-T2 as a muscle anabolic, slimming or fitness drug, easily obtained without medical prescription, must be advised against, considering its potency in suppressing the HPT axis and causing adverse cardiac side effects. 3,5-T2 escapes regular detection by commercially available clinical routine assays used for thyroid function tests, which may be seriously disrupted in individuals self-administering 3,5-T2 obtained over-the counter or from other sources.
40-Year Longitudinal Caries Development in German Adolescents in the Light of New Caries Measures
(2019)
This study assessed the 40-year longitudinal caries development in German adolescents in the light of the sixth National Oral Health Survey in Children (NOHSC, 2016) employing initial DMFT (IDMFT), Significant Caries Index (SiC) and Specific Affected Caries Index (SaC). On the basis of the current NOHSC (randomized cluster selection using school list or regional community school surveys, 55,956 12-year-old sixth-graders examined by 482 calibrated community/study dentists) DMFT, SiC, a novel IDMFT including initial lesions (IT) and the recently introduced SaC were calculated and also recalculated for national and international surveys from the last 4 decades. In 2016, 78.8% of children were caries-free (DMFT = 0), 65.5% including IT lesions. The mean DMFT was 0.44 (single components: DT = 0.14, MT = 0.02, FT = 0.29, IT = 0.52) showing a clear association with the school type as marker for the socio-economic status. The mean number of affected teeth in children with DMFT >0 was 2.07 (SaC) in comparison to almost 9 teeth in the 1970s. The current care index on the tooth level was 66.3%, leaving only 7.7% of children with restorative treatment needs. Longitudinally, a continuous caries decline of more than 80%, including the risk groups (SiC/SaC), to an internationally extremely low level was observed. In conclusion, the National Oral Health Surveys reveal a continuous caries decline to a very low caries level in 12-year-old 6th-graders in Germany even if IT lesions are included (IDMFT). In spite of proportional reductions in the risk groups (SiC/SaC), the polarized caries distribution according to socio-economic parameters reveals the need for targeted preventive programmes.
Abstract
Amphidiploid fungal Verticillium longisporum strains Vl43 and Vl32 colonize the plant host Brassica napus but differ in their ability to cause disease symptoms. These strains represent two V. longisporum lineages derived from different hybridization events of haploid parental Verticillium strains. Vl32 and Vl43 carry same‐sex mating‐type genes derived from both parental lineages. Vl32 and Vl43 similarly colonize and penetrate plant roots, but asymptomatic Vl32 proliferation in planta is lower than virulent Vl43. The highly conserved Vl43 and Vl32 genomes include less than 1% unique genes, and the karyotypes of 15 or 16 chromosomes display changed genetic synteny due to substantial genomic reshuffling. A 20 kb Vl43 lineage‐specific (LS) region apparently originating from the Verticillium dahliae‐related ancestor is specific for symptomatic Vl43 and encodes seven genes, including two putative transcription factors. Either partial or complete deletion of this LS region in Vl43 did not reduce virulence but led to induction of even more severe disease symptoms in rapeseed. This suggests that the LS insertion in the genome of symptomatic V. longisporum Vl43 mediates virulence‐reducing functions, limits damage on the host plant, and therefore tames Vl43 from being even more virulent.
Abstract
Environmentally‐friendly processes for the manufacturing of valuable industrial compounds like ω‐hydroxy fatty acids (ω‐OHFAs) are highly desirable. Herein, we present such an approach by establishing a two‐step enzymatic cascade reaction for the production of 2,15,16‐trihydroxy hexadecanoic acid (THA). Starting with the easily accessible natural compound ustilagic acid (UA) that is secreted by the corn smut fungus Ustilago maydis, the recombinantly expressed esterase BS2 from Bacillus subtilis and the commercial β‐glucosidase from almonds were applied yielding 86 % product. Both hydrolases do not require expensive cofactors, making the process economically attractive. Additionally, no harmful solvents are required, so that the product THA can be labelled natural to be used in food and cosmetic products.
Introduction: It has been shown that Alzheimer’s disease (AD) is accompanied by marked structural brain changes that can be detected several years before clinical diagnosis via structural magnetic resonance (MR) imaging. In this study, we developed a structural MR-based biomarker for in vivo detection of AD using a supervised machine learning approach. Based on an individual’s pattern of brain atrophy a continuous AD score is assigned which measures the similarity with brain atrophy patterns seen in clinical cases of AD.
Methods: The underlying statistical model was trained with MR scans of patients and healthy controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-1 screening). Validation was performed within ADNI-1 and in an independent patient sample from the Open Access Series of Imaging Studies (OASIS-1). In addition, our analyses included data from a large general population sample of the Study of Health in Pomerania (SHIP-Trend).
Results: Based on the proposed AD score we were able to differentiate patients from healthy controls in ADNI-1 and OASIS-1 with an accuracy of 89% (AUC = 95%) and 87% (AUC = 93%), respectively. Moreover, we found the AD score to be significantly associated with cognitive functioning as assessed by the Mini-Mental State Examination in the OASIS-1 sample after correcting for diagnosis, age, sex, age·sex, and total intracranial volume (Cohen’s f2 = 0.13). Additional analyses showed that the prediction accuracy of AD status based on both the AD score and the MMSE score is significantly higher than when using just one of them. In SHIP-Trend we found the AD score to be weakly but significantly associated with a test of verbal memory consisting of an immediate and a delayed word list recall (again after correcting for age, sex, age·sex, and total intracranial volume, Cohen’s f2 = 0.009). This association was mainly driven by the immediate recall performance.
Discussion: In summary, our proposed biomarker well differentiated between patients and healthy controls in an independent test sample. It was associated with measures of cognitive functioning both in a patient sample and a general population sample. Our approach might be useful for defining robust MR-based biomarkers for other neurodegenerative diseases, too.
Our goal was to provide a comprehensive overview of the antibody response to Staphylococcus aureus antigens in the general population as a basis for defining disease-specific profiles and diagnostic signatures. We tested the specific IgG and IgA responses to 79 staphylococcal antigens in 996 individuals from the population-based Study of Health in Pomerania. Using a dilution-based multiplex suspension array, we extended the dynamic range of specific antibody detection to seven orders of magnitude, allowing the precise quantification of high and low abundant antibody specificities in the same sample. The observed IgG and IgA antibody responses were highly heterogeneous with differences between individuals as well as between bacterial antigens that spanned several orders of magnitude. Some antigens elicited significantly more IgG than IgA and vice versa. We confirmed a strong influence of colonization on the antibody response and quantified the influence of sex, smoking, age, body mass index, and serum glucose on anti-staphylococcal IgG and IgA. However, all host parameters tested explain only a small part of the extensive variability in individual response to the different antigens of S. aureus.
Dengue virus (DV) is a positive-strand RNA virus of the Flavivirus genus. It is one of the most prevalent mosquito-borne viruses, infecting globally 390 million individuals per year. The clinical spectrum of DV infection ranges from an asymptomatic course to severe complications such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), the latter because of severe plasma leakage. Given that the outcome of infection is likely determined by the kinetics of viral replication and the antiviral host cell immune response (HIR) it is of importance to understand the interaction between these two parameters. In this study, we use mathematical modeling to characterize and understand the complex interplay between intracellular DV replication and the host cells' defense mechanisms. We first measured viral RNA, viral protein, and virus particle production in Huh7 cells, which exhibit a notoriously weak intrinsic antiviral response. Based on these measurements, we developed a detailed intracellular DV replication model. We then measured replication in IFN competent A549 cells and used this data to couple the replication model with a model describing IFN activation and production of IFN stimulated genes (ISGs), as well as their interplay with DV replication. By comparing the cell line specific DV replication, we found that host factors involved in replication complex formation and virus particle production are crucial for replication efficiency. Regarding possible modes of action of the HIR, our model fits suggest that the HIR mainly affects DV RNA translation initiation, cytosolic DV RNA degradation, and naïve cell infection. We further analyzed the potential of direct acting antiviral drugs targeting different processes of the DV lifecycle in silico and found that targeting RNA synthesis and virus assembly and release are the most promising anti-DV drug targets.
We introduce PVSC-DTM (Parallel Vectorized Stencil Code for Dirac and Topological Materials), a library and code generator based on a domain-specific language tailored to implement the specific stencil-like algorithms that can describe Dirac and topological materials such as graphene and topological insulators in a matrix-free way. The generated hybrid-parallel (MPI+OpenMP) code is fully vectorized using Single Instruction Multiple Data (SIMD) extensions. It is significantly faster than matrix-based approaches on the node level and performs in accordance with the roofline model. We demonstrate the chip-level performance and distributed-memory scalability of basic building blocks such as sparse matrix-(multiple-) vector multiplication on modern multicore CPUs. As an application example, we use the PVSC-DTM scheme to (i) explore the scattering of a Dirac wave on an array of gate-defined quantum dots, to (ii) calculate a bunch of interior eigenvalues for strong topological insulators, and to (iii) discuss the photoemission spectra of a disordered Weyl semimetal.
The human brain is distinguished by its remarkable size, high energy consumption, and cognitive abilities compared to all other mammals and non-human primates. However, little is known about what has accelerated brain evolution in the human lineage. One possible explanation is that the appearance of advanced communication skills and language has been a driving force of human brain development. The phenotypic adaptations in brain structure and function which occurred on the way to modern humans may be associated with specific molecular signatures in today’s human genome and/or transcriptome. Genes that have been linked to language, reading, and/or autism spectrum disorders are prime candidates when searching for genes for human-specific communication abilities. The database and genome-wide expression analyses we present here revealed a clustering of such communication-associated genes (COAG) on human chromosomes X and 7, in particular chromosome 7q31-q36. Compared to the rest of the genome, we found a high number of COAG to be differentially expressed in the cortices of humans and non-human primates (chimpanzee, baboon, and/or marmoset). The role of X-linked genes for the development of human-specific cognitive abilities is well known. We now propose that chromosome 7q31-q36 also represents a hot spot for the evolution of human-specific communication abilities. Selective pressure on the T cell receptor beta locus on chromosome 7q34, which plays a pivotal role in the immune system, could have led to rapid dissemination of positive gene variants in hitchhiking COAG.
For the normal development of pregnancy, a balance between immune tolerance and defense is crucial. However, the mechanisms mediating such a balance are not fully understood. CD83 is a transmembrane protein whose expression has been linked to anti-inflammatory functions of T and B cells. The soluble form of CD83, released by cleavage of the membrane-bound protein, has strong anti-inflammatory properties and was successfully tested in different mouse models. It is assumed that this molecule contributes to the establishment of immune tolerance. Therefore, we postulated that the expression of CD83 is crucial for immune tolerance during pregnancy in mice. Here, we demonstrated that the membrane-bound form of CD83 was upregulated in T and B cells during allogeneic murine pregnancies. An upregulation was also evident in the main splenic B cell subtypes: marginal zone, follicular zone, and transitional B cells. We also showed that there was an augmentation in the number of CD83+ cells toward the end of pregnancy within splenic B and CD4+ T cells, while CD83+ dendritic cells were reduced in spleen and inguinal lymph nodes of pregnant mice. Additionally, B lymphocytes in late-pregnancy presented a markedly higher sensitivity to LPS in terms of CD83 expression and sCD83 release. Progesterone induced a dosis-dependent upregulation of CD83 on T cells. Our data suggest that the regulation of CD83 expression represents a novel pathway of fetal tolerance and protection against inflammatory threats during pregnancy.
Abstract
Non‐native invasive species are threatening ecosystems and biodiversity worldwide. High genetic variation is thought to be a critical factor for invasion success. Accordingly, the global invasion of a few clonal lineages of the gastropod Potamopyrgus antipodarum is thus both puzzling and has the potential to help illuminate why some invasions succeed while others fail. Here, we used SNP markers and a geographically broad sampling scheme (N = 1617) including native New Zealand populations and invasive North American and European populations to provide the first widescale population genetic assessment of the relationships between and among native and invasive P. antipodarum. We used a combination of traditional and Bayesian molecular analyses to demonstrate that New Zealand populations harbour very high diversity relative to the invasive populations and are the source of the two main European genetic lineages. One of these two European lineages was in turn the source of at least one of the two main North American genetic clusters of invasive P. antipodarum, located in Lake Ontario. The other widespread North American group had a more complex origin that included the other European lineage and two New Zealand clusters. Altogether, our analyses suggest that just a small handful of clonal lineages of P. antipodarum were responsible for invasion across continents. Our findings provide critical information for prevention of additional invasions and control of existing invasive populations and are of broader relevance towards understanding the establishment and evolution of asexual populations and the forces driving biological invasion.
Abstract
Background
Twenty five‐hydroxy vitamin D (25OHD) levels have been proposed to protect against periodontitis based on in vitro and observational studies but evidence from long‐term randomized controlled trials (RCTs) is lacking. This study tested whether genetically proxied 25OHD is associated with periodontitis using Mendelian randomization (MR).
Methods
Genetic variants strongly associated with 25OHD in a genome‐wide association study (GWAS) of 417,580 participants of European ancestry were used as instrumental variables, and linked to GWAS summary data of 17,353 periodontitis cases and 28,210 controls. In addition to the main analysis using an inverse variance weighted (IVW) model, we applied additional robust methods to control for pleiotropy. We also undertook sensitivity analyses excluding single nucleotide polymorphisms (SNPs) used as instruments with potential pleiotropic effects and used a second 25OHD GWAS for replication. We identified 288 SNPs to be genome‐wide significant for 25OHD, explaining 7.0% of the variance of 25OHD levels and providing ≥90% power to detect an odds ratio (OR) of ≤ 0.97.
Results
MR analysis suggested that a 1 standard deviation increase in natural log‐transformed 25OHD was not associated with periodontitis risk (IVW OR = 1.04; 95% confidence interval (CI): 0.97–1.12; P‐value = 0.297). The robust models, replication, and sensitivity analyses were coherent with the primary analysis.
Conclusions
Collectively, our findings suggest that 25OHD levels are unlikely to have a substantial effect on the risk of periodontitis, but large long‐term RCTs are needed to derive definitive evidence on the causal role of 25OHD in periodontitis.
Introduction
Neurofilament light (NfL) can be detected in blood of healthy individuals and at elevated levels in those with different neurological diseases. We investigated if the choice of biological matrix can affect results when using NfL as biomarker in epidemiological studies.
Method
We obtained paired serum and EDTA-plasma samples of 299 individuals aged 37–67 years (BiDirect study) and serum samples of 373 individuals aged 65–83 years (MEMO study). In BiDirect, Passing–Bablok analyses were performed to assess proportional and systematic differences between biological matrices. Associations between serum or EDTA-plasma NfL and renal function (serum creatinine, serum cystatin C, glomerular filtration rate, and kidney disease) were investigated using linear or logistic regression, respectively. All regression coefficients were estimated (1) per one ng/L increase and (2) per one standard deviation increase (standardization using z-scores). In MEMO, regression coefficients were estimated (1) per one ng/L increase of serum or calculated EDTA-plasma NfL and (2) per one standard deviation increase providing a comparison to the results from BiDirect.
Results
We found proportional and systematic differences between paired NfL measurements in BiDirect, i.e., serum NfL [ng/L] = −0.33 [ng/L] + 1.11 × EDTA-plasma NfL [ng/L]. Linear regression coefficients for the associations between NfL and renal function did not vary between the different NfL measurements. In MEMO, one standard deviation increase in serum NfL was associated with greater changes in the outcomes than in BiDirect.
Conclusion
Although there are differences between serum and EDTA-plasma NfL, results can be used interchangeably if standardized values are used.
Liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics experiments have become increasingly popular because of the wide range of metabolites that can be analyzed and the possibility to measure novel compounds. LC-MS instrumentation and analysis conditions can differ substantially among laboratories and experiments, thus resulting in non-standardized datasets demanding customized annotation workflows. We present an ecosystem of R packages, centered around the MetaboCoreUtils, MetaboAnnotation and CompoundDb packages that together provide a modular infrastructure for the annotation of untargeted metabolomics data. Initial annotation can be performed based on MS1 properties such as m/z and retention times, followed by an MS2-based annotation in which experimental fragment spectra are compared against a reference library. Such reference databases can be created and managed with the CompoundDb package. The ecosystem supports data from a variety of formats, including, but not limited to, MSP, MGF, mzML, mzXML, netCDF as well as MassBank text files and SQL databases. Through its highly customizable functionality, the presented infrastructure allows to build reproducible annotation workflows tailored for and adapted to most untargeted LC-MS-based datasets. All core functionality, which supports base R data types, is exported, also facilitating its re-use in other R packages. Finally, all packages are thoroughly unit-tested and documented and are available on GitHub and through Bioconductor.
Terrestrial surface waters and submarine ground water discharge (SGD) act as a source of dissolved substances for coastal systems. Solute fluxes of SGD depend on the ground water composition and the water-solid-microbe interactions close to the sediment-water interface. Thus, this study aims to characterize and evaluate the hydrogeochemical gradients developing in the fresh-salt water mixing zone of the Wismar Bay (WB), southern Baltic Sea, Germany. Sampling campaigns covering the WB, the fresh-salt water mixing zone at the beach of the WB shoreline, terrestrial surface and ground waters near the WB as well sediments pore water were carried out. In these different waters, the distribution of dissolved inorganic carbon, nutrients, major ions, trace elements, stable isotopes (H, O, C, S), and radium isotopes have been investigated. Enhanced concentrations of radium isotopes together with dissolved manganese, barium in the surface waters of the eastern WB indicated benthic-pelagic coupling via the exchange between pore water and the water column. Salinity, stable isotopes, and major ions in sediment pore water profiles identified the presence of fresh ground water below about 40 cmbsf in the central part of the bay. Geophysical acoustic techniques revealed the local impact of anthropogenic sediment excavation, which reduced the thickness of a sediment layer between the coastal aquifer and the bottom water, causing, therefore, a ground water upward flow close to the top sediments. The fresh impacted pore water stable isotope composition (δ18O, δ2H) plot close to the regional meteoric water line indicating a relatively modern ground water source. The calculated organic matter mineralization rates and the dissolved inorganic carbon sediment-water fluxes were much higher at the fresh impacted site when compared to other unimpacted sediments. Therefore, this study reveals that different fresh water sources contribute to the water balance of WB including a SGD source.
on-healing wounds continue to be a clinical challenge for patients and medical staff.
These wounds have a heterogeneous etiology, including diabetes and surgical trauma wounds. It is
therefore important to decipher molecular signatures that reflect the macroscopic process of wound
healing. To this end, we collected wound sponge dressings routinely used in vacuum assisted therapy
after surgical trauma to generate wound-derived protein profiles via global mass spectrometry.
We confidently identified 311 proteins in exudates. Among them were expected targets belonging to
the immunoglobulin superfamily, complement, and skin-derived proteins, such as keratins. Next to
several S100 proteins, chaperones, heat shock proteins, and immune modulators, the exudates
presented a number of redox proteins as well as a discrete neutrophil proteomic signature, including
for example cathepsin G, elastase, myeloperoxidase, CD66c, and lipocalin 2. We mapped over 200
post-translational modifications (PTMs; cysteine/methionine oxidation, tyrosine nitration, cysteine
trioxidation) to the proteomic profile, for example, in peroxiredoxin 1. Investigating manually
collected exudates, we confirmed presence of neutrophils and their products, such as microparticles
and fragments containing myeloperoxidase and DNA. These data confirmed known and identified
less known wound proteins and their PTMs, which may serve as resource for future studies on
human wound healing
For a long time the apocryphal Ladder of Jacob was accessible only in arbitrarily selected translations. Without a critical edition and a comprehensive study of the whole textual segment, scholars were unable to evaluate its significance for Early Jewish and Christian literature. Since 2015/17, with the publication of a new critical edition and German translation (accompanied by a detailed introduction, footnote commentaries and appendices with related texts), a new approach to this important but hitherto widely unknown text has been made possible. This approach verifies the different layers or strata in the text, which are: a supposed Jewish apocalypse (mid-second century), a Christian expansion of the angels speech in light of the praeparatio evangelica tradition (fourth–seventh centuries), a Jewish mystical prayer (eleventh century) and the incorporation of this narrative block into the Tolkovaja Paleja together with a series of exegetical commentaries (end of the thirteenth century). In the light of the new approach, it can be said that the Ladder of Jacob is most of all an outstanding example of mutual relations between Jewish and Christian theology.
A New Kind of Permutation Entropy Used to Classify Sleep Stages from Invisible EEG Microstructure
(2017)
The present study covers the synthesis, purification and evaluation of a novel aminomethacrylate-based copolymer in terms of its suitability for improving the solubility and in vitro release of poorly water-soluble drug compounds. The new copolymer was synthesized by solvent polymerization with radical initiation and by use of a chain transfer agent. Based on its composition, it can be considered as a modified type of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate “EUDRAGIT® E PO” (ModE). ModE was specifically developed to provide a copolymer with processing and application properties that exceed those of commercially available (co-)polymers in solubility enhancement technologies where possible. By varying the concentration of the chain transfer agent in the radical polymerization process, the molecular weight of ModE was varied in a range of 173–305 kDa. To evaluate the solubility-enhancing properties of ModE, a series of drug-loaded extrudates were prepared by hot melt extrusion using the novel—as well as several commercially available—(co-)polymers. These extrudates were then subjected to comparative tests for amorphousness, solubility-enhancing properties, storage stability, and drug release. Celecoxib, efavirenz, and fenofibrate were used as model drugs in all experiments. Of all the (co-)polymers included in the study, ModE with a molecular weight of 173 kDa showed the best performance in terms of desired properties and was shown to be particularly suitable for preparing amorphous solid dispersions (ASDs) of the three model drugs, which in a first set of dissolution experiments showed better release behavior under pH conditions of the fasting stomach than higher molecular weight ModE types, as well as a variety of commercially available (co-)polymers. Therefore, the results demonstrate the successful synthesis of a new copolymer, which in future studies will be investigated in more detail for universal application in the field of solubility enhancement.
Four aerobic bacteria with bacteriolytic capabilities were isolated from the brackish water site Strait Uzynaral of Lake Balkhash in Kazakhstan. The morphology and physiology of the bacterial isolates have subsequently been analyzed. Using matrix assisted laser desorption ionization-time of flight mass spectrum and partial 16S rRNA gene sequence analyses, three of the isolates have been identified as Pseudomonas veronii and one as Paenibacillus apiarius. We determined the capability of both species to lyse pre-grown cells of the Gram-negative strains Pseudomonas putida SBUG 24 and Escherichia coli SBUG 13 as well as the Gram-positive strains Micrococcus luteus SBUG 16 and Arthrobacter citreus SBUG 321 on solid media. The bacteriolysis process was analyzed by creating growth curves and electron micrographs of co-cultures with the bacteriolytic isolates and the lysis sensitive strain Arthrobacter citreus SBUG 321 in nutrient-poor liquid media. One metabolite of Paenibacillus apiarius was isolated and structurally characterized by various chemical structure determination methods. It is a novel antibiotic substance.
The GATA1 transcription factor is essential for normal erythropoiesis and megakaryocytic differentiation. Germline GATA1 pathogenic variants in the N-terminal zinc finger (N-ZF) are typically associated with X-linked thrombocytopenia, platelet dysfunction, and dyserythropoietic anemia. A few variants in the C-terminal ZF (C-ZF) domain are described with normal platelet count but altered platelet function as the main characteristic. Independently performed molecular genetic analysis identified a novel hemizygous variant (c.865C>T, p.H289Y) in the C-ZF region of GATA1 in a German patient and in a Spanish patient. We characterized the bleeding and platelet phenotype of these patients and compared these findings with the parameters of two German siblings carrying the likely pathogenic variant p.D218N in the GATA1 N-ZF domain. The main difference was profound thrombocytopenia in the brothers carrying the p.D218N variant compared to a normal platelet count in patients carrying the p.H289Y variant; only the Spanish patient occasionally developed mild thrombocytopenia. A functional platelet defect affecting αIIbβ3 integrin activation and α-granule secretion was present in all patients. Additionally, mild anemia, anisocytosis, and poikilocytosis were observed in the patients with the C-ZF variant. Our data support the concept that GATA1 variants located in the different ZF regions can lead to clinically diverse manifestations.
AbstractThe performance of a positively biased external ring anode in combination with a hollow cathode (HC) discharge or a magnetron sputtering (MS) discharge, both with a Ti cathode and with Ar as working gas, is investigated. Plasma and floating potential increase as function of anode voltage. Energy-resolved mass spectrometry reveals that the kinetic energy of argon and titanium ions is enhanced by a positive anode voltage allowing for an effective energy control of plasma ions.
Abstract
Individuals of the marine chelicerate lineage Pycnogonida (sea spiders) show considerable regenerative capabilities after appendage injury or loss. In their natural habitats, especially the long legs of sea spiders are commonly lost and regenerated, as is evidenced by the frequent encounter of specimens with missing or miniature legs. In contrast to this, the collection of individuals with abnormally developed appendages or trunk regions is comparably rare. Here, we studied a remarkable malformation in a postlarval instar of the species Phoxichilidium femoratum (Rathke, 1799) and describe the external morphology and internal organization of the specimen using a combination of fluorescent histochemistry and scanning electron microscopy. The individual completely lacks the last trunk segment with leg pair 4 and the normally penultimate trunk segment bears only a single aberrant appendage resembling an extension of the anteroposterior body axis. Externally, the proximal units of the articulated appendage are unpaired, but further distally a bifurcation into two equally developed leg‐like branches is found. Three‐dimensional reconstruction of the musculature reveals components of two regular leg muscle sets in several of the proximal articles. This confirms interpretation of the entire appendage as a malformed leg and reveals an externally hidden paired organization along its entire proximodistal axis. To explain the origin of this unique malformation, early pioneering studies on the regenerative potential of pycnogonids are evaluated and (a) an injury‐induced partial fusion of the developing limb buds of leg pair 3, as well as (b) irregular leg regeneration following near complete loss of trunk segments 3 and 4 are discussed. Which of the two hypotheses is more realistic remains to be tested by dedicated experimental approaches. These will have to rely on pycnogonid species with established laboratory husbandry in order to overcome the limitations of the few short‐term regeneration studies performed to date.
Structured examination and treatment are essential in medicine. For dental students, a structured approach to the assessment of oral mucosal lesions is missing thus far. To validate an approach, a structured questionnaire was compared with the habitually used free description of oral lesions (white lesions, ulcers, hyperplasia). Thirty-three dental students were divided into two groups (Group 1 (n = 17) used the free description; Group 2 (n = 16) used a guided questionnaire) to characterize mucosal lesions in patients and make a tentative diagnosis. Although no difference was found between the groups regarding the suspected diagnosis or the histopathological findings, there was a significant advantage of the structured questionnaire in all aspects of the description compared to the free description (p = 0.000018). Thus, a structured description is an important aspect in the evaluation of oral mucosal changes, and a guided questionnaire should be implemented in the study of dentistry.
We decided to develop a short-form of the CHC-SUN/YHC-SUN, a questionnaire aiming at assessing health care satisfaction of children and adolescents with chronic health conditions. Data analysis was based on samples from three different studies. Item selection involved statistical analysis and expert consensus. For independent validation purposes, we calculated descriptive statistics on single-item and composite-scale levels and applied classic test theory, confirmatory factor analyses, and correlation analysis to investigate the psychometric properties of the final short-form by different types of reliability and validity. Internal consistency (Cronbach’s Alpha) reached values of a = 0.89 (self-report) and a = 0.92 (parents report), split-half reliability values reached 0.85 (self-report) and 0.91 (parents report). Confirmatory factor analysis indicated no sufficient fit for the single factor solution, whereas the solution with three factors and one higher order factor indicated the best overall fit amongst three competing models. Validity of the short-form measure can be assumed, e.g., as indicated by its association with a single-item measure on general health care satisfaction. The short-form measures of the CHC-SUN for parents (CHC-SUN-SF) and the YHC-SUN self-report version for adolescents (YHC-SUN-SF) feature excellent psychometric performances, provide economical assessments, and are easy-to-administer questionnaires. They should be used whenever brief measures are needed for economic reasons.
The function and mode of action of small regulatory RNAs is currently still understudied in archaea. In the halophilic archaeon Haloferax volcanii, a plethora of sRNAs have been identified; however, in-depth functional analysis is missing for most of them. We selected a small RNA (s479) from Haloferax volcanii for detailed characterization. The sRNA gene is encoded between a CRISPR RNA locus and the Cas protein gene cluster, and the s479 deletion strain is viable and was characterized in detail. Transcriptome studies of wild-type Haloferax cells and the deletion mutant revealed upregulation of six genes in the deletion strain, showing that this sRNA has a clearly defined function. Three of the six upregulated genes encode potential zinc transporter proteins (ZnuA1, ZnuB1, and ZnuC1) suggesting the involvement of s479 in the regulation of zinc transport. Upregulation of these genes in the deletion strain was confirmed by northern blot and proteome analyses. Furthermore, electrophoretic mobility shift assays demonstrate a direct interaction of s479 with the target znuC1 mRNA. Proteome comparison of wild-type and deletion strains further expanded the regulon of s479 deeply rooting this sRNA within the metabolism of H. volcanii especially the regulation of transporter abundance. Interestingly, s479 is not only encoded next to CRISPR–cas genes, but the mature s479 contains a crRNA-like 5′ handle, and experiments with Cas protein deletion strains indicate maturation by Cas6 and interaction with Cas proteins. Together, this might suggest that the CRISPR–Cas system is involved in s479 function.
Subterranean estuaries the, subsurface mixing zones of terrestrial groundwater and seawater, substantially influence solute fluxes to the oceans. Solutes brought by groundwater from land and solutes brought from the sea can undergo biogeochemical reactions. These are often mediated by microbes and controlled by reactions with coastal sediments, and determine the composition of fluids discharging from STEs (i.e., submarine groundwater discharge), which may have consequences showing in coastal ecosystems. While at the local scale (meters), processes have been intensively studied, the impact of subterranean estuary processes on solute fluxes to the coastal ocean remains poorly constrained at the regional scale (kilometers). In the present communication, we review the processes that occur in STEs, focusing mainly on fluid flow and biogeochemical transformations of nitrogen, phosphorus, carbon, sulfur and trace metals. We highlight the spatio-temporal dynamics and measurable manifestations of those processes. The objective of this contribution is to provide a perspective on how tracer studies, geophysical methods, remote sensing and hydrogeological modeling could exploit such manifestations to estimate the regional-scale impact of processes in STEs on solute fluxes to the coastal ocean.
Background/Aims: To develop a clinically relevant immunocompetent murine model to study pancreatic cancer using two different syngeneic pancreatic cancer cell lines and to assess MRI for its applicability in this model. Methods: Two cell lines, 6606PDA and Panc02, were employed for the experiments. Cell proliferation and migration were monitored in vitro. Matrigel™ was tested for its role in tumor induction. Tumor cell growth was assessed after orthotopic injection of tumor cells into the pancreatic head of C57/BL6 mice by MRI and histology. Results: Proliferation and migration of Panc02 were significantly faster than those of 6606PDA. Matrigel did not affect tumor growth/migration but prevented tumor cell spread after injection thus avoiding undesired peritoneal tumor growth. MRI could reliably monitor longitudinal tumor growth in both cell lines: Panc02 had a more irregular finger-like growth, and 6606PDA grew more spherically. Both tumors showed local invasiveness. Histologically, Panc02 showed a sarcoma-like undifferentiated growth pattern, whereas 6606PDA displayed a moderately differentiated glandular tumor growth. Panc02 mice had a significantly shorter (28 days) survival than 6606PDA mice (50 days). Conclusion: This model closely mimics human pancreatic cancer. MRI was invaluable for longitudinal monitoring of tumor growth thus reducing the number of mice required. Employing two different cell lines, this model can be used for various treatment and imaging studies.
To reduce global greenhouse gas emissions in order to limit global warming to 1.5°C, individuals and households play a key role. Behavior change interventions to promote pro-environmental behavior in individuals are needed to reduce emissions globally. This systematic literature review aims to assess the a) evidence-based effectiveness of such interventions and b) the content of very successful interventions without limiting the results to specific emitting sectors or countries. Based on the “PICOS” mnemonic and PRISMA statement, a search strategy was developed, and eligibility criteria were defined. Three databases (Embase, PsycInfo, and Web of Science) were searched to retrieve and review potential literature. As a result, 54 publications from 2010 to 2021 were included in the analysis. The results show that most interventions only have small positive effects or none at all. A total of 15 very successful interventions focused on the sectors of mobility, energy, and waste and incorporated improved (infra-) structures, education, feedback, enablement or made the sustainable option the default. Six evidence-based recommendations for content, timing, and setting are deducted and given for interventions on enhancing pro-environmental behavior (PEB). In summary, although the various interventions and intervention types to promote PEB differ in their effectiveness, very successful interventions have common elements. Future research should focus on high-/low-impact and high-/low-cost behavior to develop interventions that aim at high-impact but low-cost behavior changes, or avoid low-impact but high-cost behavior.
Background: A telemedicine care concept based on telephone contacts and individualized text messages was developed for patients with mental disorders to continue treatment after therapy in a psychiatric day hospital. The primary objective of this study was to evaluate the effectiveness of the telemedicine interventions. Methods: The study had a 3-armed, randomized design with 2 intervention arms (intervention 1: telephone contacts; intervention 2: telephone contacts and short text messages; both took place over a period of 6 months and in addition to usual care), and a control group with usual care. Primary outcomes were 18-item Brief Symptom Inventory (BSI-18) scores for anxiety, depression and somatization. All participants were recruited from psychiatric day hospitals. The study was registered in the German Clinical Trials Register (DRKS00000662). Results: 113 participants were analyzed 6 months after starting the intervention. The average BSI-18 anxiety score after 6 months was -2.04 points lower in intervention group 2 than in the control group (p value: 0.042). The difference in BSI depression score between these two groups was marginally significant (p value: 0.1), with an average treatment effect of -1.73. In an exploratory sensitivity analysis restricted to the 75% of patients with the highest symptom scores at baseline, intervention group 1 yielded a significant effect for anxiety and depression compared to the control group (p = 0.036 and 0.046, respectively). Conclusions: Telemedicine provides a novel option in psychiatric ambulatory care with statistically significant effects on anxiety. A positive tendency was observed for depression, especially in cases with higher symptom load at baseline.
Abstract
Multiple G‐tracts within the promoter region of the c‐myc oncogene may fold into various G‐quadruplexes with the recruitment of different tracts and guanosine residues for the G‐core assembly. Thermodynamic profiles for the folding of wild‐type and representative truncated as well as mutated sequences were extracted by comprehensive DSC experiments. The unique G‐quadruplex involving consecutive G‐tracts II–V with formation of two one‐nucleotide and one central two‐nucleotide propeller loop, previously proposed to be the biologically most relevant species, was found to be the most stable fold in terms of its Gibbs free energy of formation at ambient temperatures. Its stability derives from its short propeller loops but also from the favorable type of loop residues. Whereas quadruplex folds with long propeller loops are significantly disfavored, a snap‐back loop structure formed by incorporating a 3’‐terminal guanosine into the empty position of a tetrad seems highly competitive based on its thermodynamic stability. However, its destabilization by extending the 3’‐terminus questions the significance of such a species under in vivo conditions.
The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are the main proteolytic systems involved in cellular homeostasis. Since cardiomyocytes, as terminally differentiated cells, lack the ability to share damaged proteins with their daughter cells, they are especially reliant on these protein degradation systems for their proper function. Alterations of the UPS and ALP have been reported in a wide range of cardiac diseases, including cardiomyopathies. In this study, we determined whether the UPS and ALP are altered in a mouse model of eccentric left ventricular (LV) hypertrophy expressing both cyclin T1 and Gαq under the control of the cardiac-specific α-myosin heavy chain promoter (double transgenic; DTG). Compared to wild-type (WT) littermates, DTG mice showed higher end-diastolic (ED) LV wall thicknesses and diameter with preserved ejection fraction (EF). The cardiomyopathic phenotype was further confirmed by an upregulation of the fetal gene program and genes associated with fibrosis as well as a downregulation of genes involved in Ca2+ handling. Likewise, higher NT-proBNP levels were detected in DTG mice. Investigation of the UPS showed elevated steady-state levels of (poly)ubiquitinated proteins without alterations of all proteasomal activities in DTG mice. Evaluation of ALP key marker revealed a mixed pattern with higher protein levels of microtubule-associated protein 1 light chain 3 beta (LC3)-I and lysosomal-associated membrane protein-2, lower protein levels of beclin-1 and FYVE and coiled-coil domain-containing protein 1 (FYCO1) and unchanged protein levels of p62/SQSTM1 in DTG mice when compared to WT. At transcriptional level, a > 1.2-fold expression was observed for Erbb2, Hdac6, Lamp2, Nrg1, and Sqstm1, while a < 0.8-fold expression was revealed for Fyco1 in DTG mice. The results related to the ALP suggested overall a repression of the ALP during the initiation process, but an induction of the ALP at the level of autophagosome-lysosome fusion and the delivery of ubiquitinated cargo to the ALP for degradation.
Abomasal emptying rate of diarrhoeic and healthy suckling calves fed with oral rehydration solutions
(2020)
Abstract
The aim of the study was to determine the abomasal emptying rate (AER) of calves suffering from naturally occurring diarrhoea compared with that of healthy calves. Furthermore, the effects of an oral rehydration solution (ORS) mixed into milk replacer on the AER were determined. Acetaminophen absorption test (APAT) was performed to estimate the AER. Sixty Holstein–Frisian calves (age < 14 days) were included in the study and divided into groups as follows: healthy calves (H; n = 16), healthy calves fed with ORS (HORS; n = 14), diarrhoeic calves (D; n = 15) and diarrhoeic calves fed with ORS (DORS; n = 15). For the APAT, the calves were fed 2 L of milk replacer containing 50 mg acetaminophen (AP)/kg body weight. Venous blood samples were collected before and after milk replacer and AP intake in 30–60 min intervals for 12 hr. During the APAT, no significant differences in median maximum acetaminophen concentration (Cmax) were observed among all groups. Time to reach maximum acetaminophen concentration (Tmax) in DORS (median 390 min, 25/75 quartiles: 300/480 min) was significantly higher compared with that in H (median: 270 min 25/75 quartiles: 210/315 min) and HORS (median: 300 min (25/75 quartiles: 240/360 min). Non‐linear regression revealed that the calculated abomasal half‐life (AP t1/2) tended to be delayed in DORS (median: 652 min, 25/75 quartiles: 445/795 min, p = .10). The area under the AP curve values (AUC) from 0 to 120 min and 0 to 240 min of the observation period were significantly higher in H than D and DORS. In conclusion, significant differences in the AER indices reflected delayed abomasal emptying in diarrhoeic calves. Furthermore, the hypertonic ORS tended to have an additive delaying impact on the AER, which needs attention for the feeding management of diarrhoeic calves.
Background: Robotic-assisted laparoscopy (RAL) is being widely accepted in the field of urology as a replacement for conventional laparoscopy (CL). Nevertheless, the process of its integration in clinical routines has been rather spontaneous. Objective: To determine the prevalence of robotic systems (RS) in urological clinics in Germany, Austria and Switzerland, the acceptance of RAL among urologists as a replacement for CL and its current use for 25 different urological indications. Materials and Methods: To elucidate the practice patterns of RAL, a survey at hospitals in Germany, Austria and Switzerland was conducted. All surgically active urology departments in Germany (303), Austria (37) and Switzerland (84) received a questionnaire with questions related to the one-year period prior to the survey. Results: The response rate was 63%. Among the participants, 43% were universities, 45% were tertiary care centres, and 8% were secondary care hospitals. A total of 60 RS (Germany 35, Austria 8, Switzerland 17) were available, and the majority (68%) were operated under public ownership. The perception of RAL and the anticipated superiority of RAL significantly differed between robotic and non-robotic surgeons. For only two urologic indications were more than 50% of the procedures performed using RAL: pyeloplasty (58%) and transperitoneal radical prostatectomy (75%). On average, 35% of robotic surgeons and only 14% of non-robotic surgeons anticipated RAL superiority in some of the 25 indications. Conclusions: This survey provides a detailed insight into RAL implementation in Germany, Austria and Switzerland. RAL is currently limited to a few urological indications with a small number of high-volume robotic centres. These results might suggest that a saturation of clinics using RS has been achieved but that the existing robotic capacities are being utilized ineffectively. The possible reasons for this finding are discussed, and certain strategies to solve these problems are offered.
Abstract
Background
Heparin induced thrombocytopenia (HIT) is likely a misdirected bacterial host defense mechanism. Platelet factor 4 (PF4) binds to polyanions on bacterial surfaces exposing neo‐epitopes to which HIT antibodies bind. Platelets are activated by the resulting immune complexes via FcγRIIA, release bactericidal substances, and kill Gram‐negative Escherichia coli.
Objectives
To assess the role of PF4, anti‐PF4/H antibodies and FcγRIIa in killing of Gram‐positive bacteria by platelets.
Methods
Binding of PF4 to protein‐A deficient Staphylococcus aureus (SA113Δspa) and non‐encapsulated Streptococcus pneumoniae (D39Δcps) and its conformational change were assessed by flow cytometry using monoclonal (KKO,5B9) and patient derived anti‐PF4/H antibodies. Killing of bacteria was quantified by counting colony forming units (cfu) after incubation with platelets or platelet releasate. Using flow cytometry, platelet activation (CD62P‐expression, PAC‐1 binding) and phosphatidylserine (PS)‐exposure were analyzed.
Results
Monoclonal and patient‐derived anti‐PF4/H antibodies bound in the presence of PF4 to both S. aureus and S. pneumoniae (1.6‐fold increased fluorescence signal for human anti‐PF4/H antibodies to 24.0‐fold increase for KKO). Staphylococcus aureus (5.5 × 104cfu/mL) was efficiently killed by platelets (2.7 × 104cfu/mL) or their releasate (2.9 × 104cfu/mL). Killing was not further enhanced by PF4 or anti‐PF4/H antibodies. Blocking FcγRIIa had no impact on killing of S. aureus by platelets. In contrast, S. pneumoniae was not killed by platelets or releasate. Instead, after incubation with pneumococci platelets were unresponsive to TRAP‐6 stimulation and exposed high levels of PS.
Conclusions
Anti‐PF4/H antibodies seem to have only a minor role for direct killing of Gram‐positive bacteria by platelets. Staphylococcus aureus is killed by platelets or platelet releasate. In contrast, S. pneumoniae affects platelet viability.
Abstract
A N‐heterocyclic olefin (NHO), a terminal alkene selectively activates aromatic C−F bonds without the need of any additional catalyst. As a result, a straightforward methodology was developed for the formation of different fluoroaryl‐substituted alkenes in which the central carbon–carbon double bond is in a twisted geometry.
Abstract
Because isoenzymes of the experimentally and therapeutically extremely relevant sirtuin family show high similarity, addressing the unique selectivity pocket of sirtuin 2 is a promising strategy towards selective inhibitors. An unrelated approach towards selective inhibition of isoenzymes with varied tissue distribution is targeted drug delivery or spatiotemporal activation by photochemical activation. Azologization of two nicotinamide‐mimicking lead structures was undertaken to combine both approaches and yielded a set of 33 azobenzenes and azopyridines that have been evaluated for their photochemical behaviour and bioactivity. For some compounds, inhibitory activity reached the sub‐micromolar range in their thermodynamically favoured E form and could be decreased by photoisomerization to the metastable Z form. Besides, derivatization with long‐chain fatty acids yielded potent sirtuin 2 inhibitors, featuring another intriguing aspect of azo‐based photoswitches. In these compounds, switching to the Z isomer increased aqueous solubility and thereby enhanced biological activity by up to a factor of 21. The biological activity of two compounds was confirmed by hyperacetylation of sirtuin specific histone proteins in a cell‐based activity assay.
Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) are the key enzymes of tryptophan (TRP) metabolism in the kynurenine pathway (KP). Both enzymes function as indicators of immunosuppression and poor survival in cancer patients. Direct or indirect targeting of either of these substances seems thus reasonable to improve therapy options for patients. In this study, glioblastoma multiforme (GBM) as well as head and neck squamous cell carcinomas (HNSCC) were examined because of their different mechanisms of spontaneous and treatment-induced immune escape. Effects on gene expression and protein levels were examined. Accompanying assessment of TRP metabolites from treated GBM cell culture supernatants was conducted. Our results show a heterogeneous and inversely correlated expression profile of TRP-metabolizing genes among GBM and HNSCC cells, with low, but inducible IDO1 expression upon IFNγ treatment. TDO2 expression was higher in GBM cells, while genes encoding kynurenine aminotransferases were mainly confined to HNSCC cells. These data indicate that the KP is active in both entities, with however different enzymes involved in TRP catabolism. Upon treatment with Temozolomide, the standard of care for GBM patients, IDO1 was upregulated. Comparable, although less pronounced effects were seen in HNSCC upon Cetuximab and conventional drugs (i.e., 5-fluorouracil, Gemcitabine). Here, IDO1 and additional genes of the KP (KYAT1, KYAT2, and KMO) were induced. Vice versa, the novel yet experimental cyclin-dependent kinase inhibitor Dinaciclib suppressed KP in both entities. Our comprehensive data imply inhibition of the TRP catabolism by Dinaciclib, while conventional chemotherapeutics tend to activate this pathway. These data point to limitations of conventional therapy and highlight the potential of targeted therapies to interfere with the cells' metabolism more than anticipated.
RationaleThe ubiquitin–proteasome system (UPS) is responsible for skeletal muscle atrophy. We showed earlier that the transcription factor EB (TFEB) plays a role by increasing E3 ubiquitin ligase muscle really interesting new gene-finger 1(MuRF1)/tripartite motif-containing 63 (TRIM63) expression. MuRF 1 ubiquitinates structural proteins and mediates their UPS-dependent degradation. We now investigated how TFEB-mediated TRIM63 expression is regulated.
ObjectiveBecause protein kinase D1 (PKD1), histone deacetylase 5 (HDAC5), and TFEB belong to respective families with close structural, regulatory, and functional properties, we hypothesized that these families comprise a network regulating TRIM63 expression.
Methods and ResultsWe found that TFEB and transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) activate TRIM63 expression. The class IIa HDACs HDAC4, HDAC5, and HDAC7 inhibited this activity. Furthermore, we could map the HDAC5 and TFE3 physical interaction. PKD1, PKD2, and PKD3 reversed the inhibitory effect of all tested class IIa HDACs toward TFEB and TFE3. PKD1 mediated nuclear export of all HDACs and lifted TFEB and TFE3 repression. We also mapped the PKD2 and HDAC5 interaction. We found that the inhibitory effect of PKD1 and PKD2 toward HDAC4, HDAC5, and HDAC7 was mediated by their phosphorylation and 14-3-3 mediated nuclear export.
ConclusionTFEB and TFE3 activate TRIM63 expression. Both transcription factors are controlled by HDAC4, HDAC5, HDAC7, and all PKD-family members. We propose that the multilevel PKD/HDAC/TFEB/TFE3 network tightly controls TRIM63 expression.
Active Middle Ear Implant Evoked Auditory Brainstem Response Intensity-Latency Characteristics
(2022)
Objective
To analyze intensity-latency functions of intraoperative auditory evoked brainstem responses (ABRs) to stimulation by the Vibrant Soundbridge (VSB) active middle ear implant with respect to coupling efficiency, VSB evoked ABR thresholds, and coupling modality [oval window (OW) placement vs. Incus placement and vs. round window (RW) placement].
Study Design
Exploratory study.
Setting
Bi-centric study at tertiary referral centers.
Patients
Twenty-four patients (10 female, 14 male, mean age: 58 years) who received a VSB.
Outcome Measures
Wave-V intensity-latency functions of intraoperative VSB evoked ABRs using a modified audio processor programmed to preoperative bone conduction thresholds for stimulation. Threshold level correction to coupling efficiency and ABR thresholds. Individual plots and exponential function fits.
Results
After ABR threshold level correction, the latency functions could be aligned. A large variance of latencies was observed at individual threshold level. Wave-V latency was longest in the Incus placement subgroup (9.73 ms, SD: 1.04) as compared to OW placement subgroup (9.47 ms, SD: 1.05), with the shortest latency in the RW placement subgroup (8.99 ms, SD: 0.68). For increasing stimulation levels, the variance decreased with intensity-latency function slopes converging toward a steady-state (saturation) latency caused by saturation of audio processor (stimulation) gain. Latency saturation was reached at a stimulation level of 50 dB nHL for the OW placement subgroup, 35 dB nHL for the Incus placement subgroup, and 30 dB nHL for the RW placement subgroup. The latency and saturation results indicated decreased dynamic range for RW placement, i.e., reverse stimulation.
Conclusions
VSB evoked ABR wave-V intensity-latency function slopes were similar to acoustic stimulation at high stimulation levels with a shift toward longer latencies caused by audio processor signal delay. Saturation of latencies occurred for higher stimulation levels due to saturation of audio processor gain. Thus, the analysis of VSB evoked intensity-latency functions appears to allow for the objective assessment of a patient's individual dynamic range. This can further improve diagnostics as well as intraoperative and postoperative quality control.