Rewetting does not return drained fen peatlands to their old selves.

Peatlands have been drained for land use for a long time and on a large scale, turning them from carbon and nutrient sinks into respective sources, diminishing water regulation capacity, causing surface height loss and destroying biodiversity. Over the last decades, drained peatlands have been rewetted for biodiversity restoration and, as it strongly decreases greenhouse gas emissions, also for climate protection. We quantify restoration success by comparing 320 rewetted fen peatland sites to 243 near-natural peatland sites of similar origin across temperate Europe, all set into perspective by 10k additional European fen vegetation plots. Results imply that rewetting of drained fen peatlands induces the establishment of tall, graminoid wetland plants (helophytisation) and long-lasting differences to pre-drainage biodiversity (vegetation), ecosystem functioning (geochemistry, hydrology), and land cover characteristics (spectral temporal metrics). The Paris Agreement entails the rewetting of 500,000 km2 of drained peatlands worldwide until 2050-2070. A better understanding of the resulting locally novel ecosystems is required to improve planning and implementation of peatland rewetting and subsequent management.

Pregnancy outcome in Charcot-Marie-Tooth disease: results of the CMT-NET cohort study in Germany.

BACKGROUND AND PURPOSE: Systematic research on the effect of Charcot-Marie-Tooth (CMT) disease on the outcome of pregnancy and conversely the effect of pregnancy on neuropathy is still sparse. METHODS: A clinical cohort study and cross-sectional study within the German CMT-NET was conducted between 2016 and 2019. Inclusion criteria were a confirmed diagnosis of CMT and at least one completed pregnancy after 1990. All participants agreed to fill in questionnaires and have their medical files reviewed. RESULTS: The study group comprised 54 women with a total of 98 pregnancies. The mean age at onset of CMT disease was 12.6 years (range 0-37 years). Fifty (92%) patients had autosomal dominant CMT; two patients each (4%) had X-linked and autosomal recessive CMT. Forty patients (74%) had a PMP22 gene duplication (CMT1A). Obstetric complications did not differ significantly from a German reference population, neither in the whole group nor in the CMT1A group. Overall there was no increased newborn morbidity and mortality. About one-third of patients reported exacerbation of CMT disease in or after pregnancy. No adverse effects of anaesthesia were reported. Most participants stressed a positive attitude and awareness of challenges associated with pregnancy. Important issues were assistance and support in caring for the family. DISCUSSION: In line with findings from our previous study undertaken in the 1990s, there were no increased complication rates for pregnancy and delivery. These results are reassuring for the vast majority of CMT patients and are important for family planning and clinical care.

Trabectedin Reduces Skeletal Prostate Cancer Tumor Size in Association with Effects on M2 Macrophages and Efferocytosis.

Macrophages play a dual role in regulating tumor progression. They can either reduce tumor growth by secreting antitumorigenic factors or promote tumor progression by secreting a variety of soluble factors. The purpose of this study was to define the monocyte/macrophage population prevalent in skeletal tumors, explore a mechanism employed in supporting prostate cancer (PCa) skeletal metastasis, and examine a novel therapeutic target. Phagocytic CD68+ cells were found to correlate with Gleason score in human PCa samples, and M2-like macrophages (F4/80+CD206+) were identified in PCa bone resident tumors in mice. Induced M2-like macrophages in vitro were more proficient at phagocytosis (efferocytosis) of apoptotic tumor cells than M1-like macrophages. Moreover, soluble factors released from efferocytic versus nonefferocytic macrophages increased PC-3 prostate cancer cell numbers in vitro. Trabectedin exposure reduced M2-like (F4/80+CD206+) macrophages in vivo. Trabectedin administration after PC-3 cell intracardiac inoculation reduced skeletal metastatic tumor growth. Preventative pretreatment with trabectedin 7 days prior to PC-3 cell injection resulted in reduced M2-like macrophages in the marrow and reduced skeletal tumor size. Together, these findings suggest that M2-like monocytes and macrophages promote PCa skeletal metastasis and that trabectedin represents a candidate therapeutic target.

Olfactory discrimination and memory deficits in the Flinders Sensitive Line rodent model of depression.

Major Depressive Disorder (MDD) is a heterogeneous psychiatric disorder with broad symptomatic manifestations. The current study examined, for the first time, olfactory memory and discrimination in the Flinders Sensitive Line (FSL) rodent model of depression. Male FSL rats and controls were trained on an Olfactory Discrimination (OD) and a Social Interaction (SI) test. On the OD test, the FSL and controls performed similarly at the shortest inter-trial interval (5min), however, with extended delay of 30min, the FSLs had a recall and odour discrimination deficit. At the longest delay (60min) both groups performed poorly. The FSL rats i.) had a deficit in olfactory discrimination suggesting impairment in olfactory memory and recall; ii.) were less likely to socialize with unfamiliar rats. The data suggests that FSL animals have an impaired olfactory information processing capacity.

Landau-Zener Transition in a Continuously Measured Single-Molecule Spin Transistor.

We monitor the Landau-Zener dynamics of a single-ion magnet inserted into a spin-transistor geometry. For increasing field-sweep rates, the spin reversal probability shows increasing deviations from that of a closed system. In the low-conductance limit, such deviations are shown to result from a dephasing process. In particular, the observed behaviors are successfully simulated by means of an adiabatic master equation, with time averaged dephasing (Lindblad) operators. The time average is tentatively interpreted in terms of the finite time resolution of the continuous measurement.

Rotationally symmetric formulation of the wave propagation method-application to the straylight analysis of diffractive lenses.

We introduce a modified formulation of the wave propagation method for the efficient simulation of rotationally symmetric micro-optical components. The reformulated algorithm provides an increased computational performance of approximately two orders of magnitude and strongly reduced memory requirements, in comparison to the original formulation. This enables the efficient wave optical simulation of extended micro-optical structures beyond the common thin-element approximation. As a prototypical example, we assess the modified algorithm for the evaluation of straylight induced by diffractive lenses. We find an excellent accuracy, while comparing to rigorous simulations, which justifies the ability to overcome the limitations of the thin-element approximation.

Bimodal endoscopic probe combining white-light microscopy and optical coherence tomography.

We present a novel bimodal endoscopic imaging probe that can simultaneously provide full-field white-light video microscopy and confocal optical coherence tomography (OCT) depth scans. The two modalities rely on spectrally separated optical paths that run partially in parallel through a micro-optical bench system, which has a cross-section of only 2 mm×2.76 mm and is realized via standard silicon micromachining techniques. With a numerical aperture of 0.061, the video modality has a resolution and field of view of 9.3 and 1240 µm×1080 µm, respectively. The resolution is limited by the pixel spacing of the coherent fiber bundle, which relays the acquired image from the distal to the proximal end. A custom-designed diffractive optical element placed within the video imaging path significantly improves the image contrast by up to 45% in the medium frequency range. The OCT modality is optimized for 830 nm center wavelength, and works in a confocal arrangement with an NA of 0.018. It provides single-point depth probing at the center of the video image with a lateral resolution of 20 µm. Through its compact footprint and enhanced functionality, the probe can provide depth-resolved guiding capability for existing laparoscopes and represents a major step toward a new class of multimodal endoscopic imaging probes.

p38 MAPK regulates the Wnt inhibitor Dickkopf-1 in osteotropic prostate cancer cells.

The Wnt inhibitor Dickkopf-1 (DKK-1) has been associated with the occurrence of bone metastases in osteotropic prostate cancer by inhibiting osteoblastogenesis. P38 mitogen-activated protein kinase (MAPK) activity is also dysregulated in advanced prostate cancer. However, the impact of p38 MAPK signaling on DKK-1 remains unknown. Inhibition of p38 MAPK signaling in osteolytic PC3 cells by small molecule inhibitors (doramapimod, LY2228820 and SB202190) suppressed DKK-1 expression, whereas activation of p38 MAPK by anisomycin increased DKK-1. Further dissection by targeting individual p38 MAPK isoforms with siRNA revealed a stronger role for MAPK11 than MAPK14 and MAPK12 in the regulation of DKK-1. Moreover, prostate cancer cells with a predominantly osteolytic phenotype produced sufficient amounts of DKK-1 to inhibit Wnt3a-induced osteoblastic differentiation in C2C12 cells. This inhibition was blocked directly by neutralizing DKK-1 using a specific antibody and also indirectly by blocking p38 MAPK. Furthermore, tissue expression in human prostate cancer revealed a correlation between p38 MAPK and DKK-1 expression with higher expression in tumor compared with normal tissues. These results reveal that p38 MAPK regulates DKK-1 in prostate cancer and may present a potential target in osteolytic prostate cancers.

Long-term characterization of the Flinders Sensitive Line rodent model of human depression: Behavioral and PET evidence of a dysfunctional entorhinal cortex.

The etiology of depression is unknown but has been associated with dysregulation of neuronal activity at numerous loci on the limbic-cortical circuitry. The Flinders Sensitive Line (FSL) is a validated rodent model of human depression with spontaneously emerging behavioral and physiological phenotype, however, the durability and robustness of the phenotypes have not been described. The objective of the current study was to evaluate longitudinal dynamics of the depressive-like symptoms in this animal model. FSL and control rats of both genders were assessed over 8 months, characterizing their performance at different time points on motor, sensorimotor and complex learning/memory based tasks. Changes over time in physiological parameters, such as corticosterone and blood glucose levels, were monitored. Regional glucose metabolism, used as a marker of neuronal activity, was assessed at different time points using F18-FDG Positron Emission Tomography (PET). Results show that certain deficits at 2-3 months--on tests such as the Elevated Plus Maze, Object Recognition, and the Forced Swim Test--were transitory and the phenotype was no longer present when re-testing at 6-7 months of age. However, a stable impairment was detected on a learning and memory task, particularly indicating dysfunction in retention of spatial information. Furthermore, at multiple time points, the PET scan indicated a significate bilateral, hypo-metabolism in the temporal lobes in the FSL rats compared to healthy controls. The data suggests possible alterations of entorhinal cortex metabolism concomitant with specific behavioral changes and supports the importance of understanding the dynamics and the time and gender dependence of the phenotypes present.

Lateral epicondylitis: This is still a main indication for extracorporeal shockwave therapy.

Extracorporeal shockwave therapy (ESWT) is used in a number of indications in the medical field. A number of tendinopathies show good and excellent results due to evidence based medicine. The treatment of lateral epicondylitis is known to show conflicting results. This overview of the published RCT's on ESWT for lateral epicondylitis tries to show the reasons for this conflicting data-base and point out, why we think that this is still a main indication for extracorporeal shockwave therapy.

Adult osteochondritis dissecans and focussed ESWT: A successful treatment option.

Extracorporeal shockwave therapy (ESWT) has gained acceptance in the medical field and in the treatment of non-unions and delayed bone healing. ESWT has been used effectively for many years as a noninvasive surgical procedure. The idea of treating Osteochondritis dissecans of knee and talus arose in the middle of the 1990's. OCD is known as a pre-arthritic factor in the long-term and still there is no consistent treatment. In the literature there is still only a small number of publications but international societies for shockwave treatment are convinced that ESWT on OCD shows to be an effective and safe method in the treatment of OCD in the early stages. We want to summarize the actual data on the treatment of OCD by ESWT.

Degradation of Li/S Battery Electrodes On 3D Current Collectors Studied Using X-ray Phase Contrast Tomography.

Lithium/sulphur batteries are promising candidates for future energy storage systems, mainly due to their high potential capacity. However low sulphur utilization and capacity fading hinder practical realizations. In order to improve understanding of the system, we investigate Li/S electrode morphology changes for different ageing steps, using X-ray phase contrast tomography. Thereby we find a strong decrease of sulphur loading after the first cycle, and a constant loading of about 15% of the initial loading afterwards. While cycling, the mean sulphur particle diameters decrease in a qualitatively similar fashion as the discharge capacity fades. The particles spread, migrate into the current collector and accumulate in the upper part again. Simultaneously sulphur particles lose contact area with the conducting network but regain it after ten cycles because their decreasing size results in higher surface areas. Since the capacity still decreases, this regain could be associated with effects such as surface area passivation and increasing charge transfer resistance.

Determination of the binding mode for the cyclopentapeptide CXCR4 antagonist FC131 using a dual approach of ligand modifications and receptor mutagenesis.

BACKGROUND AND PURPOSE: The cyclopentapeptide FC131 (cyclo(-L-Arg(1) -L-Arg(2) -L-2-Nal(3) -Gly(4) -D-Tyr(5) -)) is an antagonist at the CXC chemokine receptor CXCR4, which plays a role in human immunodeficiency virus infection, cancer and stem cell recruitment. Binding modes for FC131 in CXCR4 have previously been suggested based on molecular docking guided by structure-activity relationship (SAR) data; however, none of these have been verified by in vitro experiments. EXPERIMENTAL APPROACH: Heterologous (125) I-12G5-competition binding and functional assays (inhibition of CXCL12-mediated activation) of FC131 and three analogues were performed on wild-type CXCR4 and 25 receptor mutants. Computational modelling was used to rationalize the experimental data. KEY RESULTS: The Arg(2) and 2-Nal(3) side chains of FC131 interact with residues in TM-3 (His(113) , Asp(171) ) and TM-5 (hydrophobic pocket) respectively. Arg(1) forms charge-charge interactions with Asp(187) in ECL-2, while D-Tyr(5) points to the extracellular side of CXCR4. Furthermore, the backbone of FC131 interacts with the chemokine receptor-conserved Glu(288) via two water molecules. Intriguingly, Tyr(116) and Glu(288) form a H-bond in CXCR4 crystal structures and mutation of either residue to Ala abolishes CXCR4 activity. CONCLUSIONS AND IMPLICATIONS: Ligand modification, receptor mutagenesis and computational modelling approaches were used to identify the binding mode of FC131 in CXCR4, which was in agreement with binding modes suggested from previous SAR studies. Furthermore, insights into the mechanism for CXCR4 activation by CXCL12 were gained. The combined findings will facilitate future design of novel CXCR4 antagonists.

Wave-optical design of a combined refractive-diffractive varifocal lens.

A novel type of integrated refractive-diffractive varifocal membrane lens is designed and analyzed by wave-optical methods. In contrast to other hybrid devices, the diffractive microstructure is directly imprinted onto the soft deflecting membrane, allowing for a high level of integration. Elastic deformation is taken into account by mechanical simulations with the finite element method (FEM). We show, that the superimposed structure can considerably suppress chromatic and spherical aberration. Furthermore, our algorithm is successfully applied to design a confocal hyperspectral lens.

Communication architecture for AAL. Supporting patient care by health care providers in AAL-enhanced living quarters.

INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Using Data from Ambient Assisted Living and Smart Homes in Electronic Health Records". BACKGROUND: Concepts of Ambient Assisted Living (AAL) support a long-term health monitoring and further medical and other services for multi-morbid patients with chronic diseases. In Germany many AAL and telemedical applications exist. Synergy effects by common agreements for essential application components and standards are not achieved. OBJECTIVES: It is necessary to define a communication architecture which is based on common definitions of communication scenarios, application components and communication standards. METHODS: The development of a communication architecture requires different steps. To gain a reference model for the problem area different AAL and telemedicine projects were compared and relevant data elements were generalized. The derived reference model defines standardized communication links. RESULTS: As a result the authors present an approach towards a reference architecture for AAL-communication. The focus of the architecture lays on the communication layer. The necessary application components are identified and a communication based on standards and their extensions is highlighted. CONCLUSION: The exchange of patient individual events supported by an event classification model, raw and aggregated data from the personal home area over a telemedicine center to health care providers is possible.

Gating function of isoleucine-116 in TM-3 (position III:16/3.40) for the activity state of the CC-chemokine receptor 5 (CCR5).

BACKGROUND AND PURPOSE: A conserved amino acid within a protein family indicates a significance of the residue. In the centre of transmembrane helix (TM)-5, position V:13/5.47, an aromatic amino acid is conserved among class A 7TM receptors. However, in 37% of chemokine receptors - a subgroup of 7TM receptors - it is a leucine indicating an altered function. Here, we describe the significance of this position and its possible interaction with TM-3 for CCR5 activity. EXPERIMENTAL APPROACH: The effects of [L203F]-CCR5 in TM-5 (position V:13/5.47), [I116A]-CCR5 in TM-3 (III:16/3.40) and [L203F;G286F]-CCR5 (V:13/5.47;VII:09/7.42) were determined in G-protein- and ß-arrestin-coupled signalling. Computational modelling monitored changes in amino acid conformation. KEY RESULTS: [L203F]-CCR5 increased the basal level of G-protein coupling (20-70% of Emax ) and ß-arrestin recruitment (50% of Emax ) with a threefold increase in agonist potency. In silico, [I116A]-CCR5 switched χ1-angle in [L203F]-CCR5. Furthermore, [I116A]-CCR5 was constitutively active to a similar degree as [L203F]-CCR5. Tyr(244) in TM-6 (VI:09/6.44) moved towards TM-5 in silico, consistent with its previously shown function for CCR5 activation. On [L203F;G286F]-CCR5 the antagonist aplaviroc was converted to a superagonist. CONCLUSIONS AND IMPLICATIONS: The results imply that an aromatic amino acid in the centre of TM-5 controls the level of receptor activity. Furthermore, Ile(116) acts as a gate for the movement of Tyr(244) towards TM-5 in the active state, a mechanism proposed previously for the ß2 -adrenoceptor. The results provide an understanding of chemokine receptor function and thereby information for the development of biased and non-biased antagonists and inverse agonists.

Somatropin treatment of spinal muscular atrophy: a placebo-controlled, double-blind crossover pilot study.

In preclinical studies growth hormone and its primary mediator IGF-1 have shown potential to increase muscle mass and strength. A single patient with spinal muscular atrophy reported benefit after compassionate use of growth hormone. Therefore we evaluated the efficacy and safety of growth hormone treatment for spinal muscular atrophy in a multicenter, randomised, double-blind, placebo-controlled, crossover pilot trial. Patients (n = 19) with type II/III spinal muscular atrophy were randomised to receive either somatropin (0.03 mg/kg/day) or placebo subcutaneously for 3 months, followed by a 2-month wash-out phase before 3 months of treatment with the contrary remedy. Changes in upper limb muscle strength (megascore for elbow flexion and hand-grip in Newton) were assessed by hand-held myometry as the primary measure of outcome. Secondary outcome measures included lower limb muscle strength, motor function using the Hammersmith Functional Motor Scale and other functional tests for motor function and pulmonary function. Somatropin treatment did not significantly affect upper limb muscle strength (point estimate mean: 0.08 N, 95% confidence interval (CI:-3.79;3.95, p = 0.965), lower limb muscle strength (point estimate mean: 2.23 N, CI:-2.19;6.63, p = 0.302) or muscle and pulmonary function. Side effects occurring during somatropin treatment corresponded with well-known side effects of growth hormone substitution in patients with growth hormone deficiency. In this pilot study, growth hormone treatment did not improve muscle strength or function in patients with spinal muscular atrophy type II/III.

Electrical readout of individual nuclear spin trajectories in a single-molecule magnet spin transistor.

We present the electrical readout of time trajectories obtained from an isolated nuclear spin. The device, a TbPc(2) single-molecule magnet spin transistor, detects the four different nuclear spin states of the Tb(3+) ion with fidelities better than 69%, allowing us to measure individual relaxation times (T(1)) of several tens of seconds. A good agreement with quantum Monte Carlo simulations suggests that the relaxation times are limited by the current tunneling through the transistor, which opens up the possibility to tune T(1) electrically by means of bias and gate voltages.

[Multikinase inhibitors as a new approach in neovascular age-related macular degeneration (AMD) treatment: in vitro safety evaluations of axitinib, pazopanib and sorafenib for intraocular use]. / Multikinase-inhibitoren als therapeutischer ansatz bei neovaskulärer AMD: in-vitro-evaluation der sicherheit von axitinib, pazopanib und sorafenib zur intraokularen anwendung.

BACKGROUND: Multikinase inhibitors (MKI) interfere effectively at different levels of the neovascularisation cascade. Early clinical and experimental data suggest that MKIs represent a promising novel approach for the treatment of neovascular age-related macular degeneration (AMD). However, so far little is known about the biocompatibility of MKIs regarding human ocular cells. This in vitro study investigates and compares the biocompatibility of three MKIs, axitinib, pazopanib, and sorafenib regarding ocular cells of the anterior and posterior segments, as well as organ-cultured donor corneas. METHODS: Primary human optic nerve head astrocytes (ONHA), trabecular meshwork cells (TMC), and retinal pigment epithelium (RPE), human corneal endothelial and lens epithelial cells (CEC and LEC) were treated with different concentrations of axitinib, pazopanib, or sorafenib (0.1 to 100 µg/mL). To simulate oxidative stress, the cells were additionally co-incubated with 400 µM hydrogen peroxide. Induction of cell death and cellular viability were examined by live-dead assay and tetrazolium dye reduction assay (MTT). In addition, the influence of the three substances on human corneal endothelium was evaluated in seropositive donor corneas in organ culture by phase contrast microscopy. RESULTS: Up to a concentration of 7.5 mg/mL of the substances tested in any cell type examined, no toxic effects were found. Even after 10 days of incubation of organ-cultured donor corneas with 7.5 µg/mL, axitinib, pazopanib, or sorafenib, no evidence for endothelial toxicity was found. CONCLUSION: All three MKIs tested, axitinib, pazopanib, and sorafenib showed a good biocompatibility on the investigated ocular cells. Even under conditions of oxidative stress, there were no toxic effects up to a concentration of 7.5 µg/mL. Only at higher concentrations, there was a dose-dependent decrease in cellular viability and pronounced induction of cell death. These effects on cellular viability and induction of cell death appeared to be stronger with pazopanib, followed by sorafenib, than with axitinib.

Total body Na(+)-depletion without hyponatraemia can trigger overtraining-like symptoms with sleeping disorders and increasing blood pressure: explorative case and literature study.

Exhausting physical exercise and insufficient nutritional intake impairing immunological and neuro-endocrine pathways are the most discussed issues in research on overtraining syndrome (OTS). Interestingly, depletion of the total body sodium (Na(+))-content which occurs in case of various diseases with completely different aetiologies is associated with a symptom pattern strikingly comparable to overreaching (OR) and/or OTS. The transient dilution based hyponatraemia gained attention due to its impact on reduced performance and the death of various endurance athletes. But the stepwise depletion of the total body (tissue) Na(+)-content is a completely different pathophysiology and is still relatively unknown. That is because depleted tissue Na(+)-content is hard to detect. The complex, dominant mechanisms for the maintenance of plasma homeostasis are concealing the Na(+)-depletion in the tissues quite successfully in a stage when symptoms already may be prominent. Furthermore, we are all programmed to think about sedentary people who are rather at risk to have a salt (Na(+)) intake which is far too high. But either, competitive top athletes and engaged recreational athletes have high losses of electrolytes with sweat and might be prone to a stepwise Na(+)-depletion. All the more because they also try to have a balanced, health sodium reduced diet. One person of our research group who is used to a rather low sodium-nutrition repeatedly experienced OR-(short term-OTS)-symptoms when training loads of recreational sport activities were increasing. Getting aware about identical symptoms between OR and total body Na(+)-depletion in another professional context the decision for a self experiment was settled. Under a given training protocol changing symptoms under low sodium-nutrition were recorded. When OR-like symptoms became prominent the training loads were maintained but stringent Na(+)-substitution was performed instead of the usually recommended resting period. As experienced before, typical symptoms such as sleeping disorders, harassed feeling, high diuresis, thirst and increasing blood pressure developed within 2 weeks with the increased training loads and the usual low Na(+)-nutrition. This was before plasma sodium decreased below the physiological range. High Na(+)-substitution instead of a resting period enabled the recovery from OR symptoms within some days. Out of various articles we choose and report some interesting further medical phenomenon where our hypothesis of Na(+)-depletion as a trigger mechanism might give new ideas for identifying pathophysiological mechanisms. The hypothesis: Tissue Na(+)-depletion triggers OR- and OTS- development via the renin-angiotensin-aldosterone system which initiate at first a stimulation and then exhaustion of the sympathetic system.