Publications by authors named "Benjamin Peters"

41 Publications

Thromboembolic complications of recreational nitrous oxide (ab)use: a systematic review.

J Thromb Thrombolysis 2022 Jun 27. Epub 2022 Jun 27.

Department of Radiology, Radiologist, Thoracic Imaging, Jessa Hospital, Hasselt, Belgium.

The recreatinal use of nitrous oxide has become more common in recent years, especially in adolescents and young adults. It has been mainly associated with medical conditions like megaloblastic anemia and (myelo)neuropathy. We report on the thromboembolic complications, a less known side effect, associated with recreational inhalation of nitrous oxide. An extensive literature search was performed for publications reporting on the thromboembolic complications associated with recreational nitrous oxide abuse. Data about sex, age, location of thrombosis, laboratory findings, therapy and outcome were collected. A total of 13 case reports or case series were identified comprising a total of 14 patients. The reported thromboembolic side effects included deep venous thrombosis, pulmonary embolism, mesenterial-, portal and splenic vein thrombosis, cerebral sinus thrombosis, cortical vein thrombosis, stroke, acute myocardial infarction and peripheral artery thromboembolism. These side effects are possibly mediated by the interaction of nitrous oxide with vitamin B12, a cofactor of the methionine synthase complex, which eventually results in elevation of plasma levels of homocysteine. Despite being a known risk factor for cardiovascular disease, the exact pathophysiological mechanism remains unclear. Cessation of nitrous oxide inhalation is necessary to prevent recurrent thrombosis. Nitrous oxide abuse may thus result in a wide spectrum of thromboembolic complications. One should be aware of this etiology, especially in a young person with no obvious risk factors for cardiovascular disease. Spreading awareness is important to inform people about the potentially serious side effects associated with nitrous oxide inhalation.
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http://dx.doi.org/10.1007/s11239-022-02673-xDOI Listing
June 2022

Kinetic performance comparison of superficially porous, fully porous and monolithic reversed-phase columns by gradient kinetic plots for the separation of protein biopharmaceuticals.

J Chromatogr A 2022 Aug 14;1676:463251. Epub 2022 Jun 14.

Pharmaceutical (Bio-)Analysis, Institute of Pharmaceutical Sciences, University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. Electronic address:

To find the best performing column for the analysis of protein-based biopharmaceuticals is a significant challenge as meanwhile numerous modern columns with distinct stationary phase morphologies are available for reversed-phase liquid chromatography. Especially when besides morphology also several other column factors are different, it is hard to decide about the best performing column a priori. To cope with this problem, in the present work 13 different reversed-phase columns dedicated for protein separations were systematically tested by the gradient kinetic plot method. A comprehensive comparison of columns with different morphologies (monolithic, fully porous and superficially porous particle columns), particle sizes and pore diameters as well as column length was performed. Specific consideration was also given to various monolithic columns which recently shifted a bit out of the prime focus in the scientific literature. The test proteins ranged from small proteins starting from 12 kDa, to medium sized proteins (antibody subunits obtained after IdeS-digestion and disulphide reduction) and an intact antibody. The small proteins cytochrome c, lysozyme and β-lactoglobulin could be analysed with similar performance by the best columns of all three column morphologies while for the antibody fragments specific fully porous and superficially porous particle columns were superior. A 450 Å 3,5 µm superficially porous particle column showed the best performance for the intact antibody while a 1.7 µm fully porous particle column with 300 Å showed equivalent performance to the best superficially porous column with thin shell and 400 Å pore size for proteins between 12 and 25 kDa. While the majority of the columns had C4 bonding chemistry, the silica monolith with C18 bonding and 300 Å mesopore size approximated the best performing particle columns and outperformed a C4 300 Å wide-pore monolith. The current work can support the preferred choice for the most suitable reversed-phase column for protein separations.
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http://dx.doi.org/10.1016/j.chroma.2022.463251DOI Listing
August 2022

Monolithic Papain-Immobilized Enzyme Reactors for Automated Structural Characterization of Monoclonal Antibodies.

Front Mol Biosci 2021 9;8:765683. Epub 2021 Nov 9.

Department of Drug Sciences, University of Pavia, Pavia, Italy.

The characterization of monoclonal antibodies (mAbs) requires laborious and time-consuming sample preparation steps before the liquid chromatography-mass spectrometry (LC-MS) analysis. Middle-up approaches entailing the use of specific proteases (papain, IdeS, etc.) emerged as practical and informative methods for mAb characterization. This work reports the development of immobilized enzyme reactors (IMERs) based on papain able to support mAb analytical characterization. Two monolithic IMERs were prepared by the covalent immobilization of papain on different supports, both functionalized via epoxy groups: a Chromolith® WP 300 Epoxy silica column from Merck KGaA and a polymerized high internal phase emulsion (polyHIPE) material synthesized by our research group. The two bioreactors were included in an in-flow system and characterized in terms of immobilization yield, kinetics, activity, and stability using Nα-benzoyl-L-arginine ethyl ester (BAEE) as a standard substrate. Moreover, the two bioreactors were tested toward a standard mAb, namely, rituximab (RTX). An on-line platform for mAb sample preparation and analysis with minimal operator manipulation was developed with both IMERs, allowing to reduce enzyme consumption and to improve repeatability compared to in-batch reactions. The site-specificity of papain was maintained after its immobilization on silica and polyHIPE monolithic supports, and the two IMERs were successfully applied to RTX digestion for its structural characterization by LC-MS. The main pros and cons of the two supports for the present application were described.
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http://dx.doi.org/10.3389/fmolb.2021.765683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8630785PMC
November 2021

Interactions of Truncated Menaquinones in Lipid Monolayers and Bilayers.

Int J Mol Sci 2021 Sep 9;22(18). Epub 2021 Sep 9.

Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA.

Menaquinones (MK) are hydrophobic molecules that consist of a naphthoquinone headgroup and a repeating isoprenyl side chain and are cofactors used in bacterial electron transport systems to generate cellular energy. We have previously demonstrated that the folded conformation of truncated MK homologues, MK-1 and MK-2, in both solution and reverse micelle microemulsions depended on environment. There is little information on how MKs associate with phospholipids in a model membrane system and how MKs affect phospholipid organization. In this manuscript, we used a combination of Langmuir monolayer studies and molecular dynamics (MD) simulations to probe these questions on truncated MK homologues, MK-1 through MK-4 within a model membrane. We observed that truncated MKs reside farther away from the interfacial water than ubiquinones are are located closer to the phospholipid tails. We also observed that phospholipid packing does not change at physiological pressure in the presence of truncated MKs, though a difference in phospholipid packing has been observed in the presence of ubiquinones. We found through MD simulations that for truncated MKs, the folded conformation varied, but MKs location and association with the bilayer remained unchanged at physiological conditions regardless of side chain length. Combined, this manuscript provides fundamental information, both experimental and computational, on the location, association, and conformation of truncated MK homologues in model membrane environments relevant to bacterial energy production.
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http://dx.doi.org/10.3390/ijms22189755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470443PMC
September 2021

Capturing the objects of vision with neural networks.

Nat Hum Behav 2021 09 20;5(9):1127-1144. Epub 2021 Sep 20.

Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA.

Human visual perception carves a scene at its physical joints, decomposing the world into objects, which are selectively attended, tracked and predicted as we engage our surroundings. Object representations emancipate perception from the sensory input, enabling us to keep in mind that which is out of sight and to use perceptual content as a basis for action and symbolic cognition. Human behavioural studies have documented how object representations emerge through grouping, amodal completion, proto-objects and object files. By contrast, deep neural network models of visual object recognition remain largely tethered to sensory input, despite achieving human-level performance at labelling objects. Here, we review related work in both fields and examine how these fields can help each other. The cognitive literature provides a starting point for the development of new experimental tasks that reveal mechanisms of human object perception and serve as benchmarks driving the development of deep neural network models that will put the object into object recognition.
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http://dx.doi.org/10.1038/s41562-021-01194-6DOI Listing
September 2021

Immobilization of Chondroitin Sulfate A onto Monolithic Epoxy Silica Column as a New Chiral Stationary Phase for High-Performance Liquid Chromatographic Enantioseparation.

Pharmaceuticals (Basel) 2021 Jan 27;14(2). Epub 2021 Jan 27.

Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, 38106 Braunschweig, Germany.

Chondroitin sulfate A was covalently immobilized onto a monolithic silica epoxy column involving a Schiff base formation in the presence of ethylenediamine as a spacer and evaluated in terms of its selectivity in enantioseparation. The obtained column was utilized as a chiral stationary phase in enantioseparation of amlodipine and verapamil using a mobile phase consisting of 50 mM phosphate buffer pH 3.5 and UV detection. Sample dilution by organic solvents (preferably 25% / acetonitrile-aqueous solution) was applied to achieve baseline enantioresolution (s > 3.0) of the individual drug models within 7 min, an excellent linearity ( = 0.999) and an interday repeatability of 1.1% to 1.8% RSD. The performance of the immobilized column for quantification of racemate in commercial tablets showed a recovery of 86-98% from tablet matrices. Computational modeling by molecular docking was employed to investigate the feasible complexes between enantiomers and the chiral selector.
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http://dx.doi.org/10.3390/ph14020098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911330PMC
January 2021

Prognostic value of texture analysis from cardiac magnetic resonance imaging in patients with Takotsubo syndrome: a machine learning based proof-of-principle approach.

Sci Rep 2020 11 25;10(1):20537. Epub 2020 Nov 25.

Acute Cardiac Care, Andreas Grüntzig Heart Catheterization Laboratories, Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.

Cardiac magnetic resonance (CMR) imaging has become an important technique for non-invasive diagnosis of takotsubo syndrome (TTS). The long-term prognostic value of CMR imaging in TTS has not been fully elucidated yet. This study sought to evaluate the prognostic value of texture analysis (TA) based on CMR images in patients with TTS using machine learning. In this multicenter study (InterTAK Registry), we investigated CMR imaging data of 58 patients (56 women, mean age 68 ± 12 years) with TTS. CMR imaging was performed in the acute to subacute phase (median time after symptom onset 4 days) of TTS. TA of the left ventricle was performed using free-hand regions-of-interest in short axis late gadolinium-enhanced and on T2-weighted (T2w) images. A total of 608 TA features adding the parameters age, gender, and body mass index were included. Dimension reduction was performed removing TA features with poor intra-class correlation coefficients (ICC ≤ 0.6) and those being redundant (correlation matrix with Pearson correlation coefficient r > 0.8). Five common machine-learning classifiers (artificial neural network Multilayer Perceptron, decision tree J48, NaïveBayes, RandomForest, and Sequential Minimal Optimization) with tenfold cross-validation were applied to assess 5-year outcome including major adverse cardiac and cerebrovascular events (MACCE). Dimension reduction yielded 10 TA features carrying prognostic information, which were all based on T2w images. The NaïveBayes machine learning classifier showed overall best performance with a sensitivity of 82.9% (confidence interval (CI) 80-86.2), specificity of 83.7% (CI 75.7-92), and an area-under-the receiver operating characteristics curve of 0.88 (CI 0.83-0.92). This proof-of-principle study is the first to identify unique T2w-derived TA features that predict long-term outcome in patients with TTS. These features might serve as imaging prognostic biomarkers in TTS patients.
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http://dx.doi.org/10.1038/s41598-020-76432-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689426PMC
November 2020

Object-based attention prioritizes working memory contents at a theta rhythm.

J Exp Psychol Gen 2021 Jun 19;150(6):1250-1256. Epub 2020 Nov 19.

Institute of Medical Psychology.

Attention selects relevant information regardless of whether it is physically present or internally stored in working memory. Perceptual research has shown that attentional selection of external information is better conceived as rhythmic prioritization than as stable allocation. Here we tested this principle using information processing of internal representations held in working memory. Participants memorized 4 spatial positions that formed the end points of 2 objects. One of the positions was cued for a delayed match-nonmatch test. When uncued positions were probed, participants responded faster to uncued positions located on the same object as the cued position than to those located on the other object, revealing object-based attention in working memory. Manipulating the interval between cue and probe at a high temporal resolution revealed that reaction times oscillated at a theta rhythm of 6 Hz. Moreover, oscillations showed an antiphase relationship between memorized but uncued positions on the same versus other object as the cued position, suggesting that attentional prioritization fluctuated rhythmically in an object-based manner. Our results demonstrate the highly rhythmic nature of attentional selection in working memory. Moreover, the striking similarity between rhythmic attentional selection of mental representations and perceptual information suggests that attentional oscillations are a general mechanism of information processing in human cognition. These findings have important implications for current, attention-based models of working memory. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/xge0000994DOI Listing
June 2021

The Acid-Base Equilibrium of Pyrazinoic Acid Drives the pH Dependence of Pyrazinamide-Induced Growth Inhibition.

ACS Infect Dis 2020 11 20;6(11):3004-3014. Epub 2020 Oct 20.

Program in Cell and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523, United States.

Pyrazinamide, a first-line antibiotic used against , has been shown to act in a pH-dependent manner . Why pyrazinamide, an antitubercle prodrug discovered more than 65 years ago, exhibits this pH-dependent activity was unclear. Upon entering mycobacterial cells, pyrazinamide is deamidated to pyrazinoate by an enzymatic process and exists in an acid-base equilibrium with pyrazinoic acid. Thus, the effects of total pyrazinoic acid (pyrazinoic acid + pyrazinoate) on growth, pH homeostasis, and proton motive force over a range of pH values found in host tissues were investigated. Although was able to maintain pH homeostasis over an external pH range of 7.0 to 5.5, total pyrazinoic acid induced growth inhibition increased as culture medium pH was decreased from 7.3 to 6.4. Consistent with growth inhibition, total pyrazinoic acid increased both acidification of the bacterial cytoplasm and dissipation of membrane potential as the environmental pH decreased when added to the bacterial suspensions. The results suggest pyrazinoic acid is the active form of the drug, which acts as an uncoupler of proton motive force, likely a protonophore, providing a mechanistic explanation for the pH dependence of the drug activity.
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http://dx.doi.org/10.1021/acsinfecdis.0c00507DOI Listing
November 2020

Joining the dots: Day to day challenges for practitioners in delivering integrated dementia care.

Health Soc Care Community 2021 07 18;29(4):1061-1071. Epub 2020 Aug 18.

Ageing & Dementia, School of Health Sciences, University of Southampton, Southampton, UK.

Despite the increasing policy focus on integrated dementia care in the UK, little is known about the opportunities and challenges encountered by practitioners charged with implementing these policies on the ground. We undertook an extensive, mixed-methods analysis of how a contemporary multidisciplinary dementia pathway in the UK was experienced and negotiated by service providers. Our pragmatic mixed methods design incorporated three types of research interaction with practitioners: (a) Semi-structured interviews (n = 31) and focus group discussions (n = 4), (b) Practitioner 'shadowing' observations (n = 19), and (c) Service attendance and performance metrics reviews (n = 8). Through an abductive analysis of practitioner narratives and practice observations, we evidenced how inter-practitioner prejudices, restrictive and competitive commissioning frameworks, barriers to effective data sharing and other resource constraints, all challenged integrative dementia care and led to unintended consequences such as practice overlap and failure to identify and respond to people's needs. In order to more successfully realise integrated dementia pathways, we propose innovative commissioning frameworks which purposefully seek to diffuse power imbalances, encourage inter-provider respect and understanding, and determine clear lines of responsibility.
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http://dx.doi.org/10.1111/hsc.13140DOI Listing
July 2021

Comparison of in vitro and in vivo models for the elucidation of metabolic patterns of 7-azaindole-derived synthetic cannabinoids exemplified using cumyl-5F-P7AICA.

Drug Test Anal 2021 Jan 26;13(1):74-90. Epub 2020 Jul 26.

Institute of Legal Medicine, Saarland University, Homburg, Germany.

Due to the dynamic market involving synthetic cannabinoids (SCs), the determination of analytical targets is challenging in clinical and forensic toxicology. SCs usually undergo extensive metabolism, and therefore their main metabolites must be identified for the detection in biological matrices, particularly in urine. Controlled human studies are usually not possible for ethical reasons; thus, alternative models must be used. The aim of this work was to predict the in vitro and in vivo metabolic patterns of 7-azaindole-derived SCs using 1-(5-fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-pyrollo[2,3-b]pyridin-3-carboxamide (cumyl-5F-P7AICA) as an example. Different in vitro (pooled human liver S9 fraction, pooled human liver microsomes, and pig liver microsomes) and in vivo (rat and pig) systems were compared. Monooxygenase isoenzymes responsible for the most abundant phase I steps, namely oxidative defluorination (OF) followed by carboxylation, monohydroxylation, and ketone formation, were identified. In both in vivo models, OF/carboxylation and N-dealkylation/monohydroxylation/sulfation could be detected. Regarding pHS9 and pig urine, monohydroxylation/sulfation or glucuronidation was also abundant. Furthermore, the parent compound could still be detected in all models. Initial monooxygenase activity screening revealed the involvement of CYP2C19, CYP3A4, and CYP3A5. Therefore, in addition to the parent compound, the OF/carboxylated and monohydroxylated (and sulfated or glucuronidated) metabolites can be recommended as urinary targets. In comparison to literature, the pig model predicts best the human metabolic pattern of cumyl-5F-P7AICA. Furthermore, the pig model should be suitable to mirror the time-dependent excretion pattern of parent compounds and metabolites.
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http://dx.doi.org/10.1002/dta.2899DOI Listing
January 2021

Context information supports serial dependence of multiple visual objects across memory episodes.

Nat Commun 2020 04 22;11(1):1932. Epub 2020 Apr 22.

Institute of Medical Psychology, Goethe-University, Heinrich-Hoffmann-Strasse 10, 60528, Frankfurt am Main, Germany.

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.
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http://dx.doi.org/10.1038/s41467-020-15874-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176712PMC
April 2020

An Electrophysiological Dissociation of Encoding vs. Maintenance Failures in Visual-Spatial Working Memory.

Front Psychol 2020 24;11:522. Epub 2020 Mar 24.

Department of Psychology, Goethe University, Frankfurt, Germany.

Working memory (WM) performance varies substantially among individuals but the precise contribution of different WM component processes to these functional limits remains unclear. By analyzing different types of responses in a spatial WM task, we recently demonstrated a functional dissociation between confident and not-confident errors reflecting failures of WM encoding and maintenance, respectively. Here, we use event-related brain potentials to further explore this dissociation. Healthy participants performed a delayed orientation-discrimination task and rated their response confidence for each trial. The encoding-related N2pc component was significantly reduced for confident errors compared to confident correct responses, which is indicative of an encoding failure. In contrast, the maintenance-related contra-lateral delay activity was similar for these response types indicating that in confident error trials, WM representations - potentially the wrong ones - were maintained accurately and with stability throughout the delay interval. However, contra-lateral delay activity measured during the early part of the delay period was decreased for not-confident errors, potentially reflecting compromised maintenance processes. These electrophysiological findings contribute to a refined understanding of the encoding and maintenance processes that contribute to limitations in WM performance and capacity.
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http://dx.doi.org/10.3389/fpsyg.2020.00522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105797PMC
March 2020

Immobilized enzyme reactors based on nucleoside phosphorylases and 2'-deoxyribosyltransferase for the in-flow synthesis of pharmaceutically relevant nucleoside analogues.

Bioresour Technol 2020 Jul 26;307:123258. Epub 2020 Mar 26.

Department of Drug Sciences, Università degli Studi di Pavia, I-27100 Pavia, Italy. Electronic address:

In this work, a mono- and a bi-enzymatic analytical immobilized enzyme reactors (IMERs) were developed as prototypes for biosynthetic purposes and their performances in the in-flow synthesis of nucleoside analogues of pharmaceutical interest were evaluated. Two biocatalytic routes based on nucleoside 2'-deoxyribosyltransferase from Lactobacillus reuteri (LrNDT) and uridine phosphorylase from Clostridium perfrigens (CpUP)/purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP) were investigated in the synthesis of 2'-deoxy, 2',3'-dideoxy and arabinonucleoside derivatives. LrNDT-IMER catalyzed the synthesis of 5-fluoro-2'-deoxyuridine and 5-iodo-2'-deoxyuridine in 65-59% conversion yield, while CpUP/AhPNP-IMER provided the best results for the preparation of arabinosyladenine (60% conversion yield). Both IMERs proved to be promising alternatives to chemical routes for the synthesis of nucleoside analogues. The developed in-flow system represents a powerful tool for the fast production on analytical scale of nucleosides for preliminary biological tests.
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http://dx.doi.org/10.1016/j.biortech.2020.123258DOI Listing
July 2020

Age-related changes to the craniocervical ligaments in asymptomatic subjects: a prospective MR study.

Eur Spine J 2020 05 24;29(5):1029-1035. Epub 2020 Jan 24.

Department of Radiology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.

Purpose: The craniocervical junction (CCJ) is a complex of bony and ligamentous structure stabilizing CCJ. Nearly one-third of all traumatic injuries to the cervical spine involve the CCJ. Only little literature is available on this topic, and most of the studies are focused on anatomy, biomechanics or ligamentous injury in whiplash-associated disorders. We conducted a prospective study to investigate age-related changes in the craniocervical ligaments.

Methods: We included asymptomatic volunteers between 16 and 99 years old who had no history of whiplash or other cervical trauma. Volunteers underwent a three-dimensional turbo spin-echo proton density-weighted sequence with variable flip-angle distribution focused on the craniocervical ligaments. The six main ligaments of the craniocervical junction were evaluated for grade of degeneration on a four-point scale by two independent readers, blinded for age and sex.

Results: We included 102 volunteers. The mean age was 50.03 (16-94). Fifty-nine (58%) patients showed degeneration of at least one ligament of the CCJ. High-grade anomalous changes and multiligamentous involvement had a positive correlation with age (p < 0.001). The inter-rater agreement was fair to moderate, and the intra-rater agreement was moderate to substantial.

Conclusion: The craniocervical ligaments show a variable degree of signal intensity and thickness in asymptomatic adults. We postulate that these changes can be due to normal aging or due to repetitive microtrauma. We propose a new grading system to evaluate changes to the craniocervical ligaments in asymptomatic volunteers. These slides can be retrieved under Electronic Supplementary Material.
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http://dx.doi.org/10.1007/s00586-020-06302-0DOI Listing
May 2020

Visual objects interact differently during encoding and memory maintenance.

Atten Percept Psychophys 2020 Jun;82(3):1241-1257

Institute of Medical Psychology, Goethe University, Heinrich-Hoffmann-Strasse 10, 60528, Frankfurt am Main, Germany.

The storage mechanisms of working memory are the matter of an ongoing debate. The sensory recruitment hypothesis states that memory maintenance and perceptual encoding rely on the same neural substrate. This suggests that the same cortical mechanisms that shape object perception also apply to maintained memory content. We tested this prediction using the Direction Illusion, i.e., the mutual repulsion of two concurrently visible motion directions. Participants memorized the directions of two random dot patterns for later recall. In Experiments 1 and 2, we varied the temporal separation of spatially distinct stimuli to manipulate perceptual concurrency, while keeping concurrency within working memory constant. We observed mutual motion repulsion only under simultaneous stimulus presentation, but proactive repulsion and retroactive attraction under immediate stimulus succession. At inter-stimulus intervals of 0.5 and 2 s, however, proactive repulsion vanished, while the retroactive attraction remained. In Experiment 3, we presented both stimuli at the same spatial position and observed a reappearance of the repulsion effect. Our results indicate that the repulsive mechanisms that shape object perception across space fade during the transition from a perceptual representation to a consolidated memory content. This suggests differences in the underlying structure of perceptual and mnemonic representations. The persistence of local interactions, however, indicates different mechanisms of spatially global and local feature interactions.
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http://dx.doi.org/10.3758/s13414-019-01861-xDOI Listing
June 2020

Differential trajectories of memory quality and guessing across sequential reports from working memory.

J Vis 2019 07;19(7)

Institute of Medical Psychology, Goethe University, Frankfurt am Main, Germany.

Working memory enables the storage of few items for a short period of time. Previous research has shown that items in working memory cannot be accessed equally well, indicating that they are held in at least two different states with different capacity limitations. However, it is unclear whether differences between states are due to limitations of the number of items that can be stored, or the quality with which items are stored. We employed a sequential whole-report procedure where participants reported the remembered orientation of each of two or four encoded Gabor patches. In addition, they rated their memory confidence prior to each report. Participants performed 600 trials per condition, allowing us to obtain reliable subjective ratings and estimates of precision, guessing, and misreport using a mixture model, separately for each sequential report. Different measures of memory quality consistently showed discontinuous trajectories across reports with a steep drop from the first to the second remembered item but only slight decreases thereafter. In contrast, both reported and modeled guessing changed continuously across reports. Our results support the notion of two states in working memory and show that they are distinguished by memory quality rather than quantity.
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http://dx.doi.org/10.1167/19.7.3DOI Listing
July 2019

Investigating Substrate Analogues for Mycobacterial MenJ: Truncated and Partially Saturated Menaquinones.

Biochemistry 2019 03 6;58(12):1596-1615. Epub 2019 Mar 6.

Menaquinones (MKs) are essential for electron transport in prokaryotes, and importantly, partially saturated MKs represent a novel virulence factor. However, little is known regarding how the degree of saturation in the isoprenyl side chain influences conformation or quinone redox potential. MenJ is an enzyme that selectively reduces the second isoprene unit on MK-9 and is contextually essential for the survival of Mycobacterium tuberculosis in J774A.1 macrophage-like cells, suggesting that MenJ may be a conditional drug target for pathogenic mycobacteria. Therefore, fundamental information about the properties of this system is important, and we synthesized the simplest MKs, unsaturated MK-1 and the saturated analogue, MK-1(H). Using two-dimensional nuclear magnetic resonance spectroscopy, we established that MK-1 and MK-1(H) adopted similar folded-extended conformations (i.e., the isoprenyl side chain folds upward) in each solvent examined but the folded-extended conformations differed slightly between organic solvents. Saturation of the isoprenyl side chain slightly altered the MK-1 analogue conformation in each solvent. We used molecular mechanics to illustrate the MK-1 analogue conformations. The measured quinone redox potentials of MK-1 and MK-1(H) differed between organic solvents (presumably due to differences in dielectric constants), and remarkably, an ∼20 mV semiquinone redox potential difference was observed between MK-1 and MK-1(H) in pyridine, acetonitrile, and dimethyl sulfoxide, demonstrating that the degree of saturation in the isoprenyl side chain of MK-1 influences the quinone redox potential. Finally, MK-1 and MK-1(H) interacted with Langmuir phospholipid monolayers and Aerosol-OT reverse micelle (RM) model membrane interfaces, where MK-1 adopted a slightly different folded conformation within the RM model membrane interface.
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http://dx.doi.org/10.1021/acs.biochem.9b00007DOI Listing
March 2019

Massive femur defect after Ewing's sarcoma resection reconstructed with a free vascularised fibular graft in a four-year-old girl.

Acta Chir Belg 2020 Jun 11;120(3):193-197. Epub 2018 Nov 11.

Department of Plastic and Reconstructive Surgery, Antwerp University Hospital, Antwerp, Belgium.

Ewing's sarcoma is the second most common primary malignant bone tumour in children. Depending on localisation and extent, massive bone defects remain when curative surgery is performed. Whereas in the past, limb amputation was often unavoidable to obtain curative resection, nowadays different limb saving reconstructive options are available. We report the successful reconstruction of a massive femur defect with a free vascularised fibular graft (FVFG) after Ewing's sarcoma resection in a four-year-old girl. Both the age of the patient and the extensive graft hypertrophy makes this case exceptional. Femur reconstruction with a FVFG is a rarely performed and complex procedure in young children. It is an excellent reconstructive technique for large long bone defects, which can avoid limb amputation without compromising oncologic outcome.
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http://dx.doi.org/10.1080/00015458.2018.1534398DOI Listing
June 2020

Structure Dependence of Pyridine and Benzene Derivatives on Interactions with Model Membranes.

Langmuir 2018 07 19;34(30):8939-8951. Epub 2018 Jul 19.

Department of Chemistry , Monmouth College , Monmouth , Illinois 61462 , United States.

Pyridine-based small-molecule drugs, vitamins, and cofactors are vital for many cellular processes, but little is known about their interactions with membrane interfaces. These specific membrane interactions of these small molecules or ions can assist in diffusion across membranes or reach a membrane-bound target. This study explores how minor differences in small molecules (isoniazid, benzhydrazide, isonicotinamide, nicotinamide, picolinamide, and benzamide) can affect their interactions with model membranes. Langmuir monolayer studies of dipalmitoylphosphatidylcholine (DPPC) or dipalmitoylphosphatidylethanolamine (DPPE), in the presence of the molecules listed, show that isoniazid and isonicotinamide affect the DPPE monolayer at lower concentrations than the DPPC monolayer, demonstrating a preference for one phospholipid over the other. The Langmuir monolayer studies also suggest that nitrogen content and stereochemistry of the small molecule can affect the phospholipid monolayers differently. To determine the molecular interactions of the simple N-containing aromatic pyridines with a membrane-like interface, H one-dimensional NMR and H-H two-dimensional NMR techniques were utilized to obtain information about the position and orientation of the molecules of interest within aerosol-OT (AOT) reverse micelles. These studies show that all six of the molecules reside near the AOT sulfonate headgroups and ester linkages in similar positions, but nicotinamide and picolinamide tilt at the water-AOT interface to varying degrees. Combined, these studies demonstrate that small structural changes of small N-containing molecules can affect their specific interactions with membrane-like interfaces and specificity toward different membrane components.
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http://dx.doi.org/10.1021/acs.langmuir.8b01661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106790PMC
July 2018

Photon Counting Computed Tomography With Dedicated Sharp Convolution Kernels: Tapping the Potential of a New Technology for Stent Imaging.

Invest Radiol 2018 08;53(8):486-494

Department of Radiology, University Hospital of Cologne.

Objectives: The aims of this study were to assess the value of a dedicated sharp convolution kernel for photon counting detector (PCD) computed tomography (CT) for coronary stent imaging and to evaluate to which extent iterative reconstructions can compensate for potential increases in image noise.

Materials And Methods: For this in vitro study, a phantom simulating coronary artery stenting was prepared. Eighteen different coronary stents were expanded in plastic tubes of 3 mm diameter. Tubes were filled with diluted contrast agent, sealed, and immersed in oil calibrated to an attenuation of -100 HU simulating epicardial fat. The phantom was scanned in a modified second generation 128-slice dual-source CT scanner (SOMATOM Definition Flash, Siemens Healthcare, Erlangen, Germany) equipped with both a conventional energy integrating detector and PCD. Image data were acquired using the PCD part of the scanner with 48 × 0.25 mm slices, a tube voltage of 100 kVp, and tube current-time product of 100 mAs. Images were reconstructed using a conventional convolution kernel for stent imaging with filtered back-projection (B46) and with sinogram-affirmed iterative reconstruction (SAFIRE) at level 3 (I463). For comparison, a dedicated sharp convolution kernel with filtered back-projection (D70) and SAFIRE level 3 (Q703) and level 5 (Q705) was used. The D70 and Q70 kernels were specifically designed for coronary stent imaging with PCD CT by optimizing the image modulation transfer function and the separation of contrast edges. Two independent, blinded readers evaluated subjective image quality (Likert scale 0-3, where 3 = excellent), in-stent diameter difference, in-stent attenuation difference, mathematically defined image sharpness, and noise of each reconstruction. Interreader reliability was calculated using Goodman and Kruskal's γ and intraclass correlation coefficients (ICCs). Differences in image quality were evaluated using a Wilcoxon signed-rank test. Differences in in-stent diameter difference, in-stent attenuation difference, image sharpness, and image noise were tested using a paired-sample t test corrected for multiple comparisons.

Results: Interreader and intrareader reliability were excellent (γ = 0.953, ICCs = 0.891-0.999, and γ = 0.996, ICCs = 0.918-0.999, respectively). Reconstructions using the dedicated sharp convolution kernel yielded significantly better results regarding image quality (B46: 0.4 ± 0.5 vs D70: 2.9 ± 0.3; P < 0.001), in-stent diameter difference (1.5 ± 0.3 vs 1.0 ± 0.3 mm; P < 0.001), and image sharpness (728 ± 246 vs 2069 ± 411 CT numbers/voxel; P < 0.001). Regarding in-stent attenuation difference, no significant difference was observed between the 2 kernels (151 ± 76 vs 158 ± 92 CT numbers; P = 0.627). Noise was significantly higher in all sharp convolution kernel images but was reduced by 41% and 59% by applying SAFIRE levels 3 and 5, respectively (B46: 16 ± 1, D70: 111 ± 3, Q703: 65 ± 2, Q705: 46 ± 2 CT numbers; P < 0.001 for all comparisons).

Conclusions: A dedicated sharp convolution kernel for PCD CT imaging of coronary stents yields superior qualitative and quantitative image characteristics compared with conventional reconstruction kernels. Resulting higher noise levels in sharp kernel PCD imaging can be partially compensated with iterative image reconstruction techniques.
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http://dx.doi.org/10.1097/RLI.0000000000000485DOI Listing
August 2018

Enterokinase monolithic bioreactor as an efficient tool for biopharmaceuticals preparation: on-line cleavage of fusion proteins and analytical characterization of released products.

J Pharm Biomed Anal 2018 Aug 4;157:10-19. Epub 2018 May 4.

Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy. Electronic address:

One of the most popular enzymes used for the in vitro cleavage of fusion proteins is enterokinase (EK, E.C. 3.4.21.9). EK cleaves with high specificity after the sequence Asp-Lys (DDDDK), which allows the fusion protein to preserve its native amino acid terminus without any additional unwanted cleavage residue from the recognition sequence. However, the complete removal of EK after protein cleavage is a critical step to ensure protein identity and stability. As enzyme immobilization increases stability and reusability of the biocatalyst while reducing operating costs and sample contamination, in this work we report the covalent immobilization of recombinant EK (rEK) on monolithic chromatographic supports with different binding chemistries for the development of a rEK-chromatographic-bioreactor. An on-line assay for the determination of the activity of the immobilized rEK was set up using a synthetic substrate (Gly-Asp-Lys-β-naphthylamide, GDK-NA). The assay was used to study the improvement of the operational conditions (temperature and flow rate) on hydrolytic activity of the bioreactor. The immobilization yields, as well as the cleavage activity of immobilized rEK on GDK-NA, were highly satisfactory when the immobilized enzyme reactor was used in recirculation. The ability of the immobilized rEK to cleave fusion proteins was tested by recirculation of thioredoxin (Trx)-TB10.4 and Trx-Ag85B His-tagged proteins yielding the mature antigens TB10.4 and Ag85B, to be used in the preparation of potential novel glycovaccines against tuberculosis. The prepared rEK-based immobilized enzyme reactors proved to efficiently cleave the considered fusion proteins even if the cleavage specificity at the canonical site was not fully achieved. The immobilized rEK showed very good stability and reusability.
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http://dx.doi.org/10.1016/j.jpba.2018.05.005DOI Listing
August 2018

Cardiac manifestation of polyarteritis nodosa.

Eur Heart J 2018 07;39(27):2603

Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, University of Zurich, Raemistr. 100, CH-8091 Zurich, Switzerland.

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http://dx.doi.org/10.1093/eurheartj/ehy090DOI Listing
July 2018

A Synthetic Isoprenoid Lipoquinone, Menaquinone-2, Adopts a Folded Conformation in Solution and at a Model Membrane Interface.

J Org Chem 2018 01 12;83(1):275-288. Epub 2017 Dec 12.

Chemistry Department, ‡Cell and Molecular Biology Program, and §Microbiology, Immunology, and Pathology Department, Colorado State University , Fort Collins, Colorado 80523, United States.

Menaquinones (naphthoquinones, MK) are isoprenoids that play key roles in the respiratory electron transport system of some prokaryotes by shuttling electrons between membrane-bound protein complexes acting as electron acceptors and donors. Menaquinone-2 (MK-2), a truncated MK, was synthesized, and the studies presented herein characterize the conformational and chemical properties of the hydrophobic MK-2 molecule. Using 2D NMR spectroscopy, we established for the first time that MK-2 has a folded conformation defined by the isoprenyl side-chain folding back over the napthoquinone in a U-shape, which depends on the specific environmental conditions found in different solvents. We used molecular mechanics to illustrate conformations found by the NMR experiments. The measured redox potentials of MK-2 differed in three organic solvents, where MK-2 was most easily reduced in DMSO, which may suggest a combination of solvent effect (presumably in part because of differences in dielectric constants) and/or conformational differences of MK-2 in different organic solvents. Furthermore, MK-2 was found to associate with the interface of model membranes represented by Langmuir phospholipid monolayers and Aerosol-OT (AOT) reverse micelles. MK-2 adopts a slightly different U-shaped conformation within reverse micelles compared to within solution, which is in sharp contrast to the extended conformations illustrated in literature for MKs.
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http://dx.doi.org/10.1021/acs.joc.7b02649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759649PMC
January 2018

5-Year survival after splenectomy in a patient with recurrent cutaneous melanoma: a case report.

Acta Chir Belg 2018 Dec 8;118(6):384-387. Epub 2017 Nov 8.

a Department of Surgery , University Hospital Antwerp , Edegem , Belgium.

Objective: Splenic metastases of melanoma are uncommon and generally part of a disseminated disease with a poor prognosis. In case of solitary visceral metastasis, surgical resection often remains an effective treatment. This case describes a long-term survival after splenectomy for a recurrent melanoma.

Methods: We present a 55-year-old female with a solitary splenic metastasis. Her medical history revealed a melanoma of the foot in 2007 and an in-transit metastasis in 2011. A PET-CT revealed in 2012 the presence of a small aspecific lesion in the spleen. Close follow-up was chosen. Since PET-CT and MRI showed a progressive lesion, a laparoscopic splenectomy was performed.

Results: Histological report confirmed the diagnosis of a metastatic lesion. Sixty months after the first radiographic evidence of the splenic metastasis, follow-up revealed no signs of residual disease.

Conclusions: Although current systemic approaches demonstrate to provide clinically important benefit, patients with oligometastatic disease should be evaluated for surgical metastasectomy. A laparoscopic approach for splenic metastasis is shown to be a safe treatment. This disease-free survival of 60 months in a patient with a history of an in-transit metastasis has not been published before. A splenectomy for a solitary metastasis could prolong the survival, even in a recurrent melanoma.
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http://dx.doi.org/10.1080/00015458.2017.1399661DOI Listing
December 2018

Identification of Cis-Regulatory Modules that Function in the Male Germline of Flowering Plants.

Methods Mol Biol 2017 ;1669:275-293

Department of Biochemistry, University of Otago, Dunedin, New Zealand.

The male germline of flowering plants develops within the vegetative cell of the male gametophyte and displays a distinct transcriptional profile. Key to understanding the development of this unique cell lineage is determining how gene expression is regulated within germline cells. This knowledge impacts upon our understanding of cell specification, differentiation, and plant fertility. Here, we describe methods to identify cis-regulatory modules (CRMs) that act as key regulatory regions in the promoters of germline-expressed genes. We detail the complimentary techniques of phylogenetic footprinting and the use of fluorescent reporters in pollen for the identification and verification of CRMs.
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http://dx.doi.org/10.1007/978-1-4939-7286-9_22DOI Listing
May 2018

Sequential whole report accesses different states in visual working memory.

J Exp Psychol Learn Mem Cogn 2018 Apr 21;44(4):588-603. Epub 2017 Sep 21.

Institute of Medical Psychology, Goethe University Frankfurt.

Working memory (WM) enables a rapid access to a limited number of items that are no longer physically present. WM studies usually involve the encoding and retention of multiple items, while probing a single item only. Hence, little is known about how well multiple items can be reported from WM. Here we asked participants to successively report each of up to 8 encoded Gabor patches from WM. Recall order was externally cued, and stimulus orientations had to be reproduced on a continuous dimension. Participants were able to sequentially report items from WM with an above-chance precision even at high set sizes. It is important that we observed that precision varied systematically with report order: It dropped steeply from the first to the second report but decreased only slightly thereafter. The observed trajectory of precision decrease across reports was better captured as a discontinuous rather than an exponential function, suggesting that items were reported from different states in visual WM. The following 3 experiments replicated these findings. In particular, they showed that the observed drop could not be explained by a retro-cueing benefit of the first report, a longer delay duration for later reports or a visual interference effect of the first report. Instead, executive interference of the first report reduced precision of subsequent reports. Together, the results show that a sequential whole-report procedure allows the assessment of qualitatively different states in visual WM. (PsycINFO Database Record
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http://dx.doi.org/10.1037/xlm0000466DOI Listing
April 2018

The meiotic regulator JASON utilizes alternative translation initiation sites to produce differentially localized forms.

J Exp Bot 2017 07;68(15):4205-4217

Department of Biochemistry, University of Otago, Dunedin, New Zealand.

The JASON (JAS) protein plays an important role in maintaining an organelle band across the equator of male meiotic cells during the second division, with its loss leading to unreduced pollen in Arabidopsis. In roots cells, JAS localizes to the Golgi, tonoplast and plasma membrane. Here we explore the mechanism underlying the localization of JAS. Overall, our data show that leaky ribosom scanning and alternative translation initiation sites (TISs) likely leads to the formation of two forms of JAS: a long version with an N-terminal Golgi localization signal and a short version with a different N-terminal signal targeting the protein to the plasma membrane. The ratio of the long and short forms of JAS is developmentally regulated, with both being produced in roots but the short form being predominant and functional during meiosis. This regulation of TISs in meiocytes ensures that the short version of JAS is formed during meiosis to ensure separation of chromosome groups and the production of reduced pollen. We hypothesize that increased occurrence of unreduced pollen under stress conditions may be a consequence of altered usage of JAS TISs during stress.
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http://dx.doi.org/10.1093/jxb/erx222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853252PMC
July 2017

Pre-encoding gamma-band activity during auditory working memory.

Sci Rep 2017 02 15;7:42599. Epub 2017 Feb 15.

Institute of Medical Psychology, Medical Faculty, Goethe University, Frankfurt am Main, Germany.

Previous magnetoencephalography (MEG) studies have revealed gamma-band activity at sensors over parietal and fronto-temporal cortex during the delay phase of auditory spatial and non-spatial match-to-sample tasks, respectively. While this activity was interpreted as reflecting the memory maintenance of sound features, we noted that task-related activation differences might have been present already prior to the onset of the sample stimulus. The present study focused on the interval between a visual cue indicating which sound feature was to be memorized (lateralization or pitch) and sample sound presentation to test for task-related activation differences preceding stimulus encoding. MEG spectral activity was analyzed with cluster randomization tests (N = 15). Whereas there were no differences in frequencies below 40 Hz, gamma-band spectral amplitude (about 50-65 and 90-100 Hz) was higher for the lateralization than the pitch task. This activity was localized at right posterior and central sensors and present for several hundred ms after task cue offset. Activity at 50-65 Hz was also increased throughout the delay phase for the lateralization compared with the pitch task. Apparently cortical networks related to auditory spatial processing were activated after participants had been informed about the task.
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http://dx.doi.org/10.1038/srep42599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309745PMC
February 2017
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