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The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the compound representatives, namely the acid with EWG = CN and with R = H proved to be a highly potent rhodesain inhibitor with nanomolar affinity. The respective benzyl ester (R = Bn) was found to be hydrolyzed by the target enzyme itself yielding the free acid. Detailed kinetic and mass spectrometry studies revealed a reversible covalent binding mode. Theoretical calculations with different density functionals (DFT) as well as wavefunction-based approaches were performed to elucidate the mode of action.
Excavation of burrows is an extremely physically demanding activity producing a large amount of metabolic heat. Dissipation of its surplus is crucial to avoid the risk of overheating, but in subterranean mammals it is complicated due to the absence of notable body extremities and high humidity in their burrows. IR-thermography in a previous study on two species of African mole-rats revealed that body heat was dissipated mainly through the ventral body part, which is notably less furred. Here, we analyzed the dorsal and ventral skin morphology, to test if dermal characteristics could contribute to higher heat dissipation through the ventral body part. The thickness of the epidermis and dermis and the presence, extent and connectivity of fat tissue in the dermis were examined using routine histological methods, while vascular density was evaluated using fluorescent dye and confocal microscopy in the giant mole-rat Fukomys mechowii. As in other hitherto studied subterranean mammals, no subcutaneous adipose tissue was found. All examined skin characteristics were very similar for both dorsal and ventral regions: relative content of adipose tissue in the dermis (14.4 ± 3.7% dorsally and 11.0 ± 4.0% ventrally), connectivity of dermal fat (98.5 ± 2.8% and 95.5 ± 6.8%), vascular density (26.5 ± 3.3% and 22.7 ± 2.3%). Absence of large differences in measured characteristics between particular body regions indicates that the thermal windows are determined mainly by the pelage characteristics.
Healthy and degenerating intervertebral discs (IVDs) are innervated by sympathetic nerves, however, adrenoceptor (AR) expression and functionality have never been investigated systematically. Therefore, AR gene expression was analyzed in both tissue and isolated cells from degenerated human IVDs. Furthermore, human IVD samples and spine sections of wildtype mice (WT) and of a mouse line that develops spontaneous IVD degeneration (IVDD, in SM/J mice) were stained for ARs and extracellular matrix (ECM) components. In IVD homogenates and cells α1a-, α1b-, α2a-, α2b-, α2c-, β1-, and β2-AR genes were expressed. In human sections, β2-AR was detectable, and its localization parallels with ECM alterations. Similarly, in IVDs of WT mice, only β2-AR was expressed, and in IVDs of SM/J mice, β2AR expression was stronger accompanied by increased collagen II, collagen XII, decorin as well as decreased cartilage oligomeric matrix protein expression. In addition, norepinephrine stimulation of isolated human IVD cells induced intracellular signaling via ERK1/2 and PKA. For the first time, the existence and functionality of ARs were demonstrated in IVD tissue samples, suggesting that the sympathicus might play a role in IVDD. Further studies will address relevant cellular mechanisms and thereby help to develop novel therapeutic options for IVDD.
The most frequently used boundary-layer turbulence parameterization in numerical weather prediction (NWP) models are turbulence kinetic energy (TKE) based-based schemes. However, these parameterizations suffer from a potential weakness, namely the strong dependence on an ad-hoc quantity, the so-called turbulence length scale. The physical interpretation of the turbulence length scale is difficult and hence it cannot be directly related to measurements or large eddy simulation (LES) data. Consequently, formulations for the turbulence length scale in basically all TKE schemes are based on simplified assumptions and are model-dependent. A good reference for the independent evaluation of the turbulence length scale expression for NWP modeling is missing. Here we propose a new turbulence length scale diagnostic which can be used in the gray zone of turbulence without modifying the underlying TKE turbulence scheme. The new diagnostic is based on the TKE budget: The core idea is to encapsulate the sum of the molecular dissipation and the cross-scale TKE transfer into an effective dissipation, and associate it with the new turbulence length scale. This effective dissipation can then be calculated as a residuum in the TKE budget equation (for horizontal sub-domains of different sizes) using LES data. Estimation of the scale dependence of the diagnosed turbulence length scale using this novel method is presented for several idealized cases.
Knee acoustic emissions provide information about joint health and loading in motion. As the reproducibility of knee acoustic emissions by vibroarthrography is yet unknown, we evaluated the intrasession and interday reliability of knee joint sounds. In 19 volunteers (25.6 ± 2.0 years, 11 female), knee joint sounds were recorded by two acoustic sensors (16,000 Hz; medial tibial plateau, patella). All participants performed four sets standing up/sitting down (five repetitions each). For measuring intrasession reliability, we used a washout phase of 30 min between the first three sets, and for interday reliability we used a washout phase of one week between sets 3 and 4. The mean amplitude (dB) and median power frequency (Hz, MPF) were analyzed for each set. Intraclass correlation coefficients (ICCs (2,1)), standard errors of measurement (SEMs), and coefficients of variability (CVs) were calculated. The intrasession ICCs ranged from 0.85 to 0.95 (tibia) and from 0.73 to 0.87 (patella). The corresponding SEMs for the amplitude were ≤1.44 dB (tibia) and ≤2.38 dB (patella); for the MPF, SEMs were ≤13.78 Hz (tibia) and ≤14.47 Hz (patella). The intrasession CVs were ≤0.06 (tibia) and ≤0.07 (patella) (p < 0.05). The interday ICCs ranged from 0.24 to 0.33 (tibia) and from 0 to 0.82 (patella) for both the MPF and amplitude. The interday SEMs were ≤4.39 dB (tibia) and ≤6.85 dB (patella) for the amplitude and ≤35.39 Hz (tibia) and ≤15.64 Hz (patella) for the MPF. The CVs were ≤0.14 (tibia) and ≤0.08 (patella). Knee joint sounds were highly repeatable within a single session but yielded inconsistent results for the interday reliability.
The purpose of this study was to examine the psychometric properties (i.e., factorial validity, measurement invariance, and reliability) of the Grit-Original scale (Grit-O) within the Netherlands. The Grit-O scale was subjected to a competing measurement modeling strategy that sequentially compared both independent cluster model confirmatory factor analytical- and exploratory structural equation modeling approaches. The results showed that both a two first order, bi-factor structure as well as a less restrictive two factor ESEM factorial structure best-fitted the data. The instrument showed to be reliable at both a lower- (Cronbach’s alpha) and upper-level (composite reliability) limit. However, measurement invariance between genders could only be established for the B-ICM-CFA model. Finally, concurrent validity was established through relating the GRIT-O to task performance. The linear use of the Grit-O scale should therefore carefully be considered.
Context information supports serial dependence of multiple visual objects across memory episodes
(2020)
Serial dependence is thought to promote perceptual stability by compensating for small changes of an object’s appearance across memory episodes. So far, it has been studied in situations that comprised only a single object. The question of how we selectively create temporal stability of several objects remains unsolved. In a memory task, objects can be differentiated by their to-be-memorized feature (content) as well as accompanying discriminative features (context). We test whether congruent context features, in addition to content similarity, support serial dependence. In four experiments, we observe a stronger serial dependence between objects that share the same context features across trials. Apparently, the binding of content and context features is not erased but rather carried over to the subsequent memory episode. As this reflects temporal dependencies in natural settings, our findings reveal a mechanism that integrates corresponding content and context features to support stable representations of individualized objects over time.
Type IV pili are flexible filaments on the surface of bacteria, consisting of a helical assembly of pilin proteins. They are involved in bacterial motility (twitching), surface adhesion, biofilm formation and DNA uptake (natural transformation). Here, we use cryo-electron microscopy and mass spectrometry to show that the bacterium Thermus thermophilus produces two forms of type IV pilus ("wide" and "narrow"), differing in structure and protein composition. Wide pili are composed of the major pilin PilA4, while narrow pili are composed of a so-far uncharacterized pilin which we name PilA5. Functional experiments indicate that PilA4 is required for natural transformation, while PilA5 is important for twitching motility.
Mesoporous silica has emerged as an enabling formulation for poorly soluble active pharmaceutical ingredients (APIs). Unlike other formulations, mesoporous silica typically does not inhibit precipitation of supersaturated API therefore, a suitable precipitation inhibitor (PI) should be added to increase absorption from the gastrointestinal (GI) tract. However, there is limited research about optimal processes for combining PIs with silica formulations. Typically, the PI is added by simply blending the API-loaded silica mechanically with the selected PI. This has the drawback of an additional blending step and may also not be optimal with regard to release of drug and PI. By contrast, loading PI simultaneously with the API onto mesoporous silica, i.e. co-incorporation, is attractive from both a performance and practical perspective. The aim of this study was to demonstrate the utility of a co-incorporation approach for combining PIs with silica formulations, and to develop a mechanistic rationale for improvement of the performance of silica formulations using the co-incorporation approach. The results indicate that co-incorporating HPMCAS with glibenclamide onto silica significantly improved the extent and duration of drug supersaturation in single-medium and transfer dissolution experiments. Extensive spectroscopic characterization of the formulation revealed that the improved performance was related to the formation of drug-polymer interactions already in the solid state; the immobilization of API-loaded silica on HPMCAS plates, which prevents premature release and precipitation of API; and drug-polymer proximity on disintegration of the formulation, allowing for rapid onset of precipitation inhibition. The data suggests that co-incorporating the PI with the API is appealing for silica formulations from both a practical and formulation performance perspective.
Im Mittelpunkt der Dissertation steht die Untersuchung der Sprachförderkompetenz von Grundschullehrkräften aus linguistischer Perspektive. Dabei geht es um Grundschullehrkräfte, die in der vorschulischen Sprachförderung, v.a. von Kindern mit Deutsch als früher Zweitsprache (DaZ), im Rahmen sogenannter Vorlaufkurse in Hessen tätig sind. Anhand von zwei zentralen Dimensionen professioneller Kompetenz, dem Wissen und dem Handeln, werden in zwei empirischen Studien anhand einer Gruppe von 10 Lehrkräften der Umfang des sprachlichen Fachwissens und verschiedene Eigenschaften des sprachlichen Handelns in der Interaktion mit DaZ-Kindern im Vorlaufkurs untersucht. Zudem werden mögliche Zusammenhänge zwischen Wissen und Handeln sowie Unterschiede und Gemeinsamkeiten hinsichtlich beider Dimensionen zu pädagogischen Fachkräften aus dem Elementarbereich geprüft.
Background: Physiologically-based population pharmacokinetic modeling (popPBPK) coupled with in vitro biopharmaceutics tools such as biorelevant dissolution testing can serve as a powerful tool to establish virtual bioequivalence and set clinically relevant specifications. One of several applications of popPBPK modeling is in the emerging field of virtual bioequivalence (VBE), where it can be used to streamline drug development by implementing model-informed formulation design and to inform regulatory decision-making e.g., with respect to evaluating the possibility of extending BCS-based biowaivers beyond BCS Class I and III compounds in certain cases.
Methods: In this study, Naproxen, a BCS class II weak acid was chosen as the model compound. In vitro biorelevant solubility and dissolution experiments were performed and the resulting data were used as an input to the PBPK model, following a stepwise workflow for the confirmation of the biopharmaceutical parameters. The naproxen PBPK model was developed by implementing a middle-out approach and verified against clinical data obtained from the literature. Once confidence in the performance of the model was achieved, several in vivo dissolution scenarios, based on model-based analysis of the in vitro data, were used to simulate clinical trials in healthy adults. Inter-occasion variability (IOV) was also added to critical physiological parameters and mechanistically propagated through the simulations. The various trials were simulated on a “worst/best case” dissolution scenario and average bioequivalence was assessed according to Cmax, AUC and tmax.
Results: VBE results demonstrated that naproxen products with in vitro dissolution reaching 85% dissolved within 90 minutes would lie comfortably within the bioequivalence limits for Cmax and AUC. Based on the establishment of VBE, a dissolution “safe space” was designed and a clinically relevant specification for naproxen products was proposed. The interplay between formulation-related and drug-specific PK parameters (e.g., t1/2) to predict the in vivo performance was also investigated.
Conclusion: Over a wide range of values, the in vitro dissolution rate is not critical for the clinical performance of naproxen products and therefore naproxen could be eligible for BCS-based biowaivers based on in vitro dissolution under intestinal conditions. This approach may also be applicable to other poorly soluble acidic compounds with long half-lives, providing an opportunity to streamline drug development and regulatory decision-making without putting the patient at a risk.
(1) Background: Oncological gastrectomy requires complex multidisciplinary management. Clinical pathways (CPs) can potentially facilitate this task, but evidence related to their use in managing oncological gastrectomy is limited. This study evaluated the effect of a CP for oncological gastrectomy on process and outcome quality. (2) Methods: Consecutive patients undergoing oncological gastrectomy before (n = 64) or after (n = 62) the introduction of a CP were evaluated. Assessed parameters included catheter and drain management, postoperative mobilization, resumption of diet and length of stay. Morbidity, mortality, reoperation and readmission rates were used as indicators of outcome quality. (3) Results: Enteral nutrition was initiated significantly earlier after CP implementation (5.0 vs. 7.0 days, p < 0.0001). Readmission was more frequent before CP implementation (7.8% vs. 0.0%, p = 0.05). Incentive spirometer usage increased following CP implementation (100% vs. 90.6%, p = 0.11). Mortality, morbidity and reoperation rates remained unchanged. (4) Conclusions: After implementation of an oncological gastrectomy CP, process quality improved, while indicators of outcome quality such as mortality and reoperation rates remained unchanged. CPs are a promising tool to standardize perioperative care for oncological gastrectomy
In Bone Tissue Engineering (BTE), autologous bone-regenerative cells are combined with a scaffold for large bone defect treatment (LBDT). Microporous, polylactic acid (PLA) scaffolds showed good healing results in small animals. However, transfer to large animal models is not easily achieved simply by upscaling the design. Increasing diffusion distances have a negative impact on cell survival and nutrition supply, leading to cell death and ultimately implant failure. Here, a novel scaffold architecture was designed to meet all requirements for an advanced bone substitute. Biofunctional, porous subunits in a load-bearing, compression-resistant frame structure characterize this approach. An open, macro- and microporous internal architecture (100 µm–2 mm pores) optimizes conditions for oxygen and nutrient supply to the implant’s inner areas by diffusion. A prototype was 3D-printed applying Fused Filament Fabrication using PLA. After incubation with Saos-2 (Sarcoma osteogenic) cells for 14 days, cell morphology, cell distribution, cell survival (fluorescence microscopy and LDH-based cytotoxicity assay), metabolic activity (MTT test), and osteogenic gene expression were determined. The adherent cells showed colonization properties, proliferation potential, and osteogenic differentiation. The innovative design, with its porous structure, is a promising matrix for cell settlement and proliferation. The modular design allows easy upscaling and offers a solution for LBDT.
Rethinking superdeterminism
(2020)
Quantum mechanics has irked physicists ever since its conception more than 100 years ago. While some of the misgivings, such as it being unintuitive, are merely aesthetic, quantum mechanics has one serious shortcoming: it lacks a physical description of the measurement process. This “measurement problem” indicates that quantum mechanics is at least an incomplete theory—good as far as it goes, but missing a piece—or, more radically, is in need of complete overhaul. Here we describe an approach which may provide this sought-for completion or replacement: Superdeterminism. A superdeterministic theory is one which violates the assumption of Statistical Independence (that distributions of hidden variables are independent of measurement settings). Intuition suggests that Statistical Independence is an essential ingredient of any theory of science (never mind physics), and for this reason Superdeterminism is typically discarded swiftly in any discussion of quantum foundations. The purpose of this paper is to explain why the existing objections to Superdeterminism are based on experience with classical physics and linear systems, but that this experience misleads us. Superdeterminism is a promising approach not only to solve the measurement problem, but also to understand the apparent non-locality of quantum physics. Most importantly, we will discuss how it may be possible to test this hypothesis in an (almost) model independent way.
Despite the popularity of the term Positive Psychological Coaching within the literature, there is no consensus as to how it should be defined (framed) or what the components of a positive coaching “model” should include. The aim of this systematic review was to define positive psychological coaching and to construct a clear demarcated positive psychological coaching model based on the literature. A systematic literature review led to the extraction of 2,252 records. All records were screened using specific inclusion/exclusion criteria, which resulted in the exclusion of records based on duplicates (n = 1,232), titles (n = 895), abstracts (n = 78), and criteria violations (n = 23). Twenty-four academic, peer-reviewed publications on positive psychological coaching were included. Data relating to conceptual definitions and coaching models/phases/frameworks were extracted and processed through thematic content analysis. Our results indicate that positive psychological coaching can be defined as a short to medium term professional, collaborative relationship between a client and coach, aimed at the identification, utilization, optimization, and development of personal strengths and resources in order to enhance positive states, traits and behaviors. Utilizing Socratic goal setting and positive psychological evidence-based approaches to facilitate personal growth, optimal functioning, enhanced wellbeing, and the actualization of people's potential. Further, eight critical components of a positive psychological coaching model were identified and discussed. The definition and coaching process identified in this study will provide coaches with a fundamental positive psychological framework for optimizing people's potential.
Tigers are indisputably in danger of extinction due to habitat loss and demand for their parts. Tigers are extirpated in the wild from every country bar one in mainland East and Southeast Asia. Although consumption of tiger products is known to be established in China, less is known about demand for tiger products in Southeast Asia. In this study, we investigate tiger product demand in Vietnam, a major illegal wildlife consumer country. There has been little research into consumption, in particular the level of use, the products being consumed, variation in use of products between areas, and the motivations of consuming tiger products. Through a quantitative survey of 1120 individuals, we show that use of tiger products could be as high as ~11% of the sample in both urban centers of Vietnam, Hanoi and Ho Chi Minh City. Tiger bone glue is the predominant product used, for medicinal purposes. In Hanoi, it is generally purchased by the individual for self-use, while in Ho Chi Minh City it is generally purchased as a gift. In both cities, individuals were generally highly satisfied with the product, indicating entrenched belief in efficacy among consumers. Ultimately, our results show that tiger product use is relatively pervasive. We suggest that conservation organizations should focus on behavior change campaigns that are informed by the results here, and that are specific to each area and to the specific use of tiger product glue for medicine. By reducing demand, beleaguered tiger populations will have a greater chance of stabilization and eventual growth.
Metasomatic evolution of coesite-bearing diamondiferous eclogite from the Udachnaya Kimberlite
(2020)
A coesite-bearing diamondiferous eclogite from the Udachnaya kimberlite (Daldyn field, Siberian craton) has been studied to trace its complex evolution recorded in rock-forming and minor mineral constituents. The eclogite sample is composed of rock-forming omphacite (60 vol%), garnet (35 vol%) and quartz/coesite (5 vol%) and contains intergranular euhedral zoned olivine crystals, up to 200 µm long, coexisting with phlogopite, orthopyroxene, clinopyroxene (secondary), K-feldspar, plagioclase, spinel, sodalite and djerfisherite. Garnet grains are zoned, with a relatively homogeneous core and a more magnesian overgrowth rim. The rim zones further differ from the core in having higher Zr/Y (6 times that in the cores), ascribed to interaction with, or precipitation from, a kimberlite-related melt. Judging by pressure-temperature estimates (~1200 °C; 6.2 GPa), the xenolith originated at depths of ~180–200 km at the base of the continental lithosphere. The spatial coexistence of olivine, orthopyroxene and coesite/quartz with K-Na-Cl minerals in the xenolith indicates that eclogite reacted with a deep-seated kimberlite melt. However, Fe-rich olivine, orthopyroxene and low-pressure minerals (sodalite and djerfisherite) likely result from metasomatic reaction at shallower depths during transport of the eclogite by the erupting kimberlite melt. Our results demonstrate that a mixed eclogitic-peridotitic paragenesis, reported previously from inclusions in diamond, can form by interaction of eclogite and a kimberlite-related melt.
Background: Re-treatment in patients with a chronic hepatitis C virus (HCV) infection and a previous failure to direct-acting antiviral (DAA) treatment remains a challenge. Therefore, we investigated the success rate of treatment and re-treatment regimens used at our center from October 2011 to March 2018.
Methods: A retrospective analysis of DAA-based HCV therapies of 1096 patients was conducted. Factors associated with a virological relapse were identified by univariable and multivariable logistic regression, treatment success of the re-treatment regimens was evaluated by an analysis of sustained virological response (SVR) rates in patients with a documented follow-up 12 weeks after the end of treatment.
Results: Of 1096 patients treated with DAA-based regimens, 91 patients (8%) were lost to follow-up, 892 of the remaining 1005 patients (89%) achieved an SVR12. Most patients (65/113, 58%) who experienced a virological relapse received an interferon-based DAA regimen. SVR rates were comparable in special cohorts like liver transplant recipients (53/61, 87%) and people with a human immunodeficiency virus (HIV) coinfection (41/45, 91%). On multivariable analysis, interferon-based DAA therapy was associated with treatment failure (odds ratio 0.111, 95%-confidence interval 0.054–0.218) among others. One hundred seventeen patients with multiple DAA treatment courses were identified, of which 97 patients (83%) experienced a single relapse, but further relapses after two (18/117, 15%) or even three (2/117, 2%) treatment courses were also observed. Eighty-two of 96 (85%) re-treatment attempts with all-oral DAA regimens were successful after an initial treatment failure.
Conclusion: Overall, DAA re-treatments were highly effective in this real-world cohort and only a minority of patients failed more than two treatment courses. Switching to–or addition of–a new drug class seem to be valid options for the re-treatment of patients especially after failure of an interferon-based regimen.
A myriad of signaling molecules in a heuristic network of the tumor microenvironment (TME) pose a challenge and an opportunity for novel therapeutic target identification in human cancers. MicroRNAs (miRs), due to their ability to affect signaling pathways at various levels, take a prominent space in the quest of novel cancer therapeutics. The role of miRs in cancer initiation, progression, as well as in chemoresistance, is being increasingly investigated. The canonical function of miRs is to target mRNAs for post-transcriptional gene silencing, which has a great implication in first-order regulation of signaling pathways. However, several reports suggest that miRs also perform non-canonical functions, partly due to their characteristic non-coding small RNA nature. Examples emerge when they act as ligands for toll-like receptors or perform second-order functions, e.g., to regulate protein translation and interactions. This review is a compendium of recent advancements in understanding the role of miRs in cancer signaling and focuses on the role of miRs as novel regulators of the signaling pathway in the TME.