Towards more Sustainable Peptide- based Antibiotics: Stable in Human Blood, Enzymatically Hydrolyzed in Wastewater?

The emergence and spread of antibiotic resistance is a major societal challenge and new antibiotics are needed to successfully fight bacterial infections. Because the release of antibiotics into wastewater and downstream environments is expected to contribute to the problem of antibiotic resistance, it would be beneficial to consider the environmental fate of antibiotics in the development of novel antibiotics. In this article, we discuss the possibility of designing peptide-based antibiotics that are stable during treatment (e.g. in human blood), but rapidly inactivated through hydrolysis by peptidases after their secretion into wastewater. In the first part, we review studies on the biotransformation of peptide-based antibiotics during biological wastewater treatment and on the specificity of dissolved extracellular peptidases derived from wastewater. In the second part, we present first results of our endeavour to identify peptide bonds that are stable in human blood plasma and susceptible to hydrolysis by the industrially produced peptidase Subtilisin A

Literaturauswahl und -bestellung leichter gemacht!

Im vorliegenden Artikel werden Mehrwertdienste und Unterstützungstools rund um die Literaturauswahl und den Bestellprozess vorgestellt, welche die Bearbeitung von elektronischen Erwerbungsunterlagen vereinfachen. Die vorgestellten Softwarewerkzeuge sind Eigenentwicklungen aus drei Bibliotheken und können durch andere Bibliotheken angepasst sowie nachgenutzt werden

Towards more Sustainable Peptide- based Antibiotics: Stable in Human Blood, Enzymatically Hydrolyzed in Wastewater?

The emergence and spread of antibiotic resistance is a major societal challenge and new antibiotics are needed to successfully fight bacterial infections. Because the release of antibiotics into wastewater and downstream environments is expected to contribute to the problem of antibiotic resistance, it would be beneficial to consider the environmental fate of antibiotics in the development of novel antibiotics. In this article, we discuss the possibility of designing peptide-based antibiotics that are stable during treatment (e.g. in human blood), but rapidly inactivated through hydrolysis by peptidases after their secretion into wastewater. In the first part, we review studies on the biotransformation of peptide-based antibiotics during biological wastewater treatment and on the specificity of dissolved extracellular peptidases derived from wastewater. In the second part, we present first results of our endeavour to identify peptide bonds that are stable in human blood plasma and susceptible to hydrolysis by the industrially produced peptidase Subtilisin A

Development of an effective outsourcing strategy for toxicological studies in the chemical industry

The chemical industry has been put under considerable time pressure by the European Community Regulation REACH (Registration, Evaluation, and Authorization of Chemicals). The work outlined here has been developed at the BASF SE’s Experimental Toxicology and Ecology Unit with the objective of promoting a faster reaction to the testing demand generated by the new legislation. A considerable increase in forecasted demand for tests has created the necessity to increase the Toxicology Unit’s outsourcing activities. The first goal was to optimize the selection and management process of Contract Research Organizations (CROs), so that toxicological studies can be performed with minimal risk while maximizing quality and cost advantage. A second objective was to develop performance measurement system in form of a balanced scorecard to evaluate contracting efficiency by monitoring major drivers in the outsourcing process to ensure the alignment between strategic objectives and actual performance.<br

Uukuniemi Virus as a Tick-Borne Virus Model.

International audienceIn the last decade, novel tick-borne pathogenic phleboviruses in the family Bunyaviridae, all closely related to Uukuniemi virus (UUKV), have emerged on different continents. To reproduce the tick-mammal switch in vitro, we first established a reverse genetics system to rescue UUKV with a genome close to that of the authentic virus isolated from the Ixodes ricinus tick reservoir. The IRE/CTVM19 and IRE/CTVM20 cell lines, both derived from I. ricinus, were susceptible to the virus rescued from plasmid DNAs and supported production of the virus over many weeks, indicating that infection was persistent. The glycoprotein GC was mainly highly mannosylated on tick cell-derived viral progeny. The second envelope viral protein, GN, carried mostly N-glycans not recognized by the classical glycosidases peptide-N-glycosidase F (PNGase F) and endoglycosidase H (Endo H). Treatment with β-mercaptoethanol did not impact the apparent molecular weight of GN On viruses originating from mammalian BHK-21 cells, GN glycosylations were exclusively sensitive to PNGase F, and the electrophoretic mobility of the protein was substantially slower after the reduction of disulfide bonds. Furthermore, the amount of viral nucleoprotein per focus forming unit differed markedly whether viruses were produced in tick or BHK-21 cells, suggesting a higher infectivity for tick cell-derived viruses. Together, our results indicate that UUKV particles derived from vector tick cells have glycosylation and structural specificities that may influence the initial infection in mammalian hosts. This study also highlights the importance of working with viruses originating from arthropod vector cells in investigations of the cell biology of arbovirus transmission and entry into mammalian hosts. Tick-borne phleboviruses represent a growing threat to humans globally. Although ticks are important vectors of infectious emerging diseases, previous studies have mainly involved virus stocks produced in mammalian cells. This limitation tends to minimize the importance of host alternation in virus transmission to humans and initial infection at the molecular level. With this study, we have developed an in vitro tick cell-based model that allows production of the tick-borne Uukuniemi virus to high titers. Using this system, we found that virions derived from tick cells have specific structural properties and N-glycans that may enhance virus infectivity for mammalian cells. By shedding light on molecular aspects of tick-derived viral particles, our data illustrate the importance of considering the host switch in studying early virus-mammalian receptor/cell interactions. The information gained here lays the basis for future research on not only tick-borne phleboviruses but also all viruses and other pathogens transmitted by ticks

Deep-Learning-Based Segmentation of the Shoulder from MRI with Inference Accuracy Prediction

Three-dimensional (3D)-image-based anatomical analysis of rotator cuff tear patients has been proposed as a way to improve repair prognosis analysis to reduce the incidence of postoperative retear. However, for application in clinics, an efficient and robust method for the segmentation of anatomy from MRI is required. We present the use of a deep learning network for automatic segmentation of the humerus, scapula, and rotator cuff muscles with integrated automatic result verification. Trained on N = 111 and tested on N = 60 diagnostic T1-weighted MRI of 76 rotator cuff tear patients acquired from 19 centers, a nnU-Net segmented the anatomy with an average Dice coefficient of 0.91 ± 0.06. For the automatic identification of inaccurate segmentations during the inference procedure, the nnU-Net framework was adapted to allow for the estimation of label-specific network uncertainty directly from its subnetworks. The average Dice coefficient of segmentation results from the subnetworks identified labels requiring segmentation correction with an average sensitivity of 1.0 and a specificity of 0.94. The presented automatic methods facilitate the use of 3D diagnosis in clinical routine by eliminating the need for time-consuming manual segmentation and slice-by-slice segmentation verification

Multitrophic diversity in a biodiverse forest is highly nonlinear across spatial scales

Date of Acceptance: 10/11/2015 Acknowledgements We thank the administration of the Gutianshan National Nature Reserve and members of the BEF-China consortium for support, the many people involved in the plant and arthropod censuses, and T. Fang, S. Chen, T. Li, M. Ohl and C.-D. Zhu for help with species identification. G. Seidler kindly calculated forest cover and T. Scholten and P. Kühn provided soil data. The study was funded by the German Research Foundation (DFG FOR 891/1, 891/2), the Sino-German Centre for Research Promotion (GZ 524, 592, 698, 699, 785 and 1020) and the National Science Foundation of China (NSFC 30710103907 and 30930005).Peer reviewedPublisher PD

New quantitative radiographic parameters for vertical and horizontal instability in acromioclavicular joint dislocations.

PURPOSE The aim of this study was to identify the most accurate and reliable quantitative radiographic parameters for assessing vertical and horizontal instability in different Rockwood grades of acromioclavicular joint (ACJ) separations. Furthermore, the effect of projectional variation on these parameters was investigated in obtaining lateral Alexander view radiographs. METHODS A Sawbone model of a scapula with clavicle was mounted on a holding device, and acromioclavicular dislocations as per the Rockwood classification system were simulated with the addition of horizontal posterior displacement. Projectional variations for each injury type were performed by tilting/rotating the Sawbone construct in the coronal, sagittal or axial plane. Radiographic imaging in the form of an anterior-posterior Zanca view and a lateral Alexander view were taken for each injury type and each projectional variation. Five newly defined radiographic parameters for assessing horizontal and vertical displacement as well as commonly used coracoclavicular distance view were measured. Reliability, validity and the effect of projectional variation were investigated for these radiographic measurements. RESULTS All radiographic parameters showed excellent intra- and interobserver reliability. The validity was excellent for the acromial centre line to dorsal clavicle (AC-DC) in vertical displacement and for the glenoid centre line to posterior clavicle (GC-PC) in horizontal displacement, whilst the remaining measurements showed moderate validity. For AC-DC and GC-PC, convergent validity expressed strong correlation to the effective distance and discriminant validity demonstrated its ability to differentiate between various grades of ACJ dislocations. The effect of projectional variation increased with the degree of deviation and was maximal (3 mm) for AC-DC in 20° anteverted malpositioning and for GC-PC in 20° retroverted malpositioning. CONCLUSIONS AC-DC and the GC-PC are two novel quantitative radiographic parameters of vertical and horizontal instability in ACJ dislocations that demonstrate excellent reliability and validity with reasonable inertness to malpositioning. The use of AC-DC for assessing vertical displacement and GC-PC for assessing horizontal displacement in a single Alexander view is recommended to guide the appropriate management of ACJ dislocations. A better appreciation of the degree of horizontal instability, especially in lower Rockwood grades (II, III) of ACJ dislocations, may improve management of these controversial injuries

Neer Award 2016: reduced muscle degeneration and decreased fatty infiltration after rotator cuff tear in a poly(ADP-ribose) polymerase 1 (PARP-1) knock-out mouse model.

BACKGROUND Disturbed muscular architecture, atrophy, and fatty infiltration remain irreversible in chronic rotator cuff tears even after repair. Poly (adenosine 5'-diphosphate-ribose) polymerase 1 (PARP-1) is a key regulator of inflammation, apoptosis, muscle atrophy, muscle regeneration, and adipocyte development. We hypothesized that the absence of PARP-1 would lead to a reduction in damage to the muscle subsequent to combined tenotomy and neurectomy in a PARP-1 knockout (KO) mouse model. METHODS PARP-1 KO and wild-type C57BL/6 (WT group) mice were analyzed at 1, 6, and 12 weeks (total n = 84). In all mice, the supraspinatus and infraspinatus muscles of the left shoulder were detached and denervated. Macroscopic analysis, magnetic resonance imaging, gene expression analysis, immunohistochemistry, and histology were used to assess the differences in PARP-1 KO and WT mice. RESULTS The muscles in the PARP-1 KO group had significantly less retraction, atrophy, and fatty infiltration after 12 weeks than in the WT group. Gene expression of inflammatory, apoptotic, adipogenic, and muscular atrophy genes was significantly decreased in PARP-1 KO mice in the first 6 weeks. DISCUSSION Absence of PARP-1 leads to a reduction in muscular architectural damage, early inflammation, apoptosis, atrophy, and fatty infiltration after combined tenotomy and neurectomy of the rotator cuff muscle. Although the macroscopic reaction to injury is similar in the first 6 weeks, the ability of the muscles to regenerate was much greater in the PARP-1 KO group, leading to a near-normalization of the muscle after 12 weeks