julilili42/papers huggingface dataset:
The N -Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the Pseudomonas Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance
2017-03-29

ABSTRACT Bacterial cells are encased in and stabilized by a netlike peptidoglycan (PGN) cell wall that undergoes turnover during bacterial growth. PGN turnover fragments are frequently salvaged by the cells via a pathway referred to as PGN recycling. Two different routes for the recycling of the cell wall sugar N -acetylmuramic acid (MurNAc) have been recognized in bacteria. In Escherichia coli and related enterobacteria, as well as in most Gram-positive bacteria, MurNAc is recovered via a catabolic route requiring a MurNAc 6-phosphate etherase (MurQ in E. coli ) enzyme. However, many Gram-negative bacteria, including Pseudomonas species, lack a MurQ ortholog and use an alternative, anabolic recycling route that bypasses the de novo biosynthesis of uridyldiphosphate (UDP)-MurNAc, the first committed precursor of PGN. Bacteria featuring the latter pathway become intrinsically resistant to the antibiotic fosfomycin, which targets the de novo biosynthesis of UDP-MurNAc. We report here the identification and characterization of a phosphatase enzyme, named MupP, that had been predicted to complete the anabolic recycling pathway of Pseudomonas species but has remained unknown so far. It belongs to the large haloacid dehalogenase family of phosphatases and specifically converts MurNAc 6-phosphate to MurNAc. A Δ mupP mutant of Pseudomonas putida was highly susceptible to fosfomycin, accumulated large amounts of MurNAc 6-phosphate, and showed lower levels of UDP-MurNAc than wild-type cells, altogether consistent with a role for MupP in the anabolic PGN recycling route and as a determinant of intrinsic resistance to fosfomycin. IMPORTANCE Many Gram-negative bacteria, but not E. coli , make use of a cell wall salvage pathway that contributes to the pool of UDP-MurNAc, the first committed precursor of cell wall synthesis in bacteria. This salvage pathway is of particular interest because it confers intrinsic resistance to the antibiotic fosfomycin, which blocks de novo UDP-MurNAc biosynthesis. Here we identified and characterized a previously missing enzyme within the salvage pathway, the MurNAc 6-phosphate phosphatase MupP of P. putida . MupP, together with the other enzymes of the anabolic recycling pathway, AnmK, AmgK, and MurU, yields UDP-MurNAc, renders bacteria intrinsically resistant to fosfomycin, and thus may serve as a novel drug target for antimicrobial therapy.
Dysregulated IER3 Expression is Associated with Enhanced Apoptosis in Titin-Based Dilated Cardiomyopathy
2017-03-29

Apoptosis (type I programmed cell death) of cardiomyocytes is a major process that plays a role in the progression of heart failure. The early response gene IER3 regulates apoptosis in a wide variety of cells and organs. However, its role in heart failure is largely unknown. Here, we investigate the role of IER3 in an inducible heart failure mouse model. Heart failure was induced in a mouse model that imitates a human titin truncation mutation we found in a patient with dilated cardiomyopathy (DCM). Transferase dUTP nick end labeling (TUNEL) and ssDNA stainings showed induction of apoptosis in titin-deficient cardiomyocytes during heart failure development, while IER3 response was dysregulated. Chromatin immunoprecipitation and knock-down experiments revealed that IER3 proteins target the promotors of anti-apoptotic genes and act as an anti-apoptotic factor in cardiomyocytes. Its expression is blunted during heart failure development in a titin-deficient mouse model. Targeting the IER3 pathway to reduce cardiac apoptosis might be an effective therapeutic strategy to combat heart failure.
Structural basis for non-genuine phenolic acceptor substrate specificity of Streptomyces roseochromogenes prenyltransferase CloQ from the ABBA/PT-barrel superfamily
2017-03-29

Acceptor substrate specificity of Streptomyces roseochromogenes prenyltransferase SrCloQ was investigated using different non-genuine phenolic compounds. RP-UHPLC-UV-MSn was used for the tentative annotation and quantification of the prenylated products. Flavonoids, isoflavonoids and stilbenoids with different types of substitution were prenylated by SrCloQ, although with less efficiency than the genuine substrate 4-hydroxyphenylpyruvate. The isoflavan equol, followed by the flavone 7,4'-dihydroxyflavone, were the best non-genuine acceptor substrates. B-ring C-prenylation was in general preferred over A-ring C-prenylation (ratio 5:1). Docking studies of non-genuine acceptor substrates with the B-ring oriented towards the donor substrate dimethylallyl pyrophosphate, showed that the carbonyl group of the C-ring was able to make stabilizing interactions with the residue Arg160, which might determine the preference observed for B-ring prenylation. No reaction products were formed when the acceptor substrate had no phenolic hydroxyl groups. This preference can be explained by the essential hydrogen bond needed between a phenolic hydroxyl group and the residue Glu281. Acceptor substrates with an additional hydroxyl group at the C3' position (B-ring), were mainly O3'-prenylated (> 80% of the reaction products). This can be explained by the proximity of the C3' hydroxyl group to the donor substrate at the catalytic site. Flavones were preferred over isoflavones by SrCloQ. Docking studies suggested that the orientation of the B-ring and of the phenolic hydroxyl group at position C7 (A-ring) of flavones towards the residue Tyr233 plays an important role in this observed preference. Finally, the insights obtained on acceptor substrate specificity and regioselectivity for SrCloQ were extended to other prenyltransferases from the CloQ/NhpB family.
Bryophyte-dominated biological soil crusts mitigate soil erosion in an early successional Chinese subtropical forest
2017-03-29

Abstract. This study investigated the development of biological soil crust (biocrust) covers in an early successional subtropical forest ecosystem and their impact on soil erosion. Within a biodiversity and ecosystem functioning experiment in Southeast China (BEF China), sediment discharge and runoff measurements were conducted with micro-scale runoff plots under natural rainfall and biocrust covers were surveyed over a five-year period. Results showed that biocrusts occurred widely in our experimental forest ecosystem and developed from initial light cyanobacteria- and algae-dominated crusts to later-stage bryophyte-dominated crusts in only three years. Biocrust covers were still increasing after six years of tree growth. Within later stage crusts, 25 bryophyte species were determined. The development of biocrusts was significantly influenced by the surrounding vegetation cover and terrain attributes. Besides high crown cover and leaf area index, the development of biocrusts was favoured by low slope gradients, slope orientations towards the incident sunlight and the altitude of the research plots. Our measurements showed, that bryophyte-dominated biocrusts were importantly decreasing soil erosion and more effective in erosion reduction than abiotic soil surface covers. Hence, their significant role to mitigate sediment discharge and runoff generation in mesic forest environments and their ability to quickly colonize gaps in higher vegetation layers are of particular interest for soil erosion control in early stage forest plantations. A detailed record of different biocrust species and their functional influence on soil erosion processes as well as a thorough monitoring of biocrust covers under closing tree canopy in subtropical forests is required in further studies.
Short- and long-term effects of diving on pulmonary function
2017-03-29

The diving environment provides a challenge to the lung, including exposure to high ambient pressure, altered gas characteristics and cardiovascular effects on the pulmonary circulation. Several factors associated with diving affect pulmonary function acutely and can potentially cause prolonged effects that may accumulate gradually with repeated diving exposure. Evidence from experimental deep dives and longitudinal studies suggests long-term adverse effects of diving on the lungs in commercial deep divers, such as the development of small airways disease and accelerated loss of lung function. In addition, there is an accumulating body of evidence that diving with self-contained underwater breathing apparatus (scuba) may not be associated with deleterious effects on pulmonary function. Although changes in pulmonary function after single scuba dives have been found to be associated with immersion, ambient cold temperatures and decompression stress, changes in lung function were small and suggest a low likelihood of clinical significance. Recent evidence points to no accelerated loss of lung function in military or recreational scuba divers over time. Thus, the impact of diving on pulmonary function largely depends on factors associated with the individual diving exposure. However, in susceptible subjects clinically relevant worsening of lung function may occur even after single shallow-water scuba dives.
Scope for sympatric giant-dwarf speciation driven by cannibalism in South-American annual killifish (Austrolebias)
2017-03-29

Abstract A trophic radiation in the South-American annual killifish genus Austrolebias has led to the evolution of large specialized piscivores from small generalized carnivores. It has been proposed that this occurred in a single series of vicariant speciation events. An alternative hypothesis is denoted giant-dwarf speciation: piscivores would have evolved in sympatry by character displacement and cannibalism. We test the plausibility of both scenarios using size measures combined with distributional data and new phylogenetic trees based on mitochondrial and nuclear molecular markers. Our analysis uses historical biogeography models and Ornstein-Uehlenbeck processes describing trait evolution across the posterior distributions of phylogenetic trees. Large species most likely evolved three times from small ones. For the clade containing A. elongatus , we argue that vicariance was not involved in the origin of these large and specialized piscivores. They experience stabilizing selection with an optimum shifted towards larger bodies and longer jaws. The branch leading to this clade has the fastest evolving jaw lengths across the phylogeny, in agreement with expectations for giant-dwarf speciation. For A. wolterstorffi , the support for giant-dwarf speciation is weaker. When the species is placed at the root of Austrolebias , ancestral reconstructions are unreliable and vicariance cannot be ruled out. For the remaining large species, we can reject vicariance and giant dwarf speciation. Our results give rise to two new additional scenarios for the evolution of specialized piscivores. In the first, two successive speciation events in sympatry or parapatry produced large and piscivorous species. In the second, the immigration of a different annual killifish genus ( Cynopoecilus ) in the Patos area of endemism has contributed to in-situ diversification of Austrolebias species.
Prolonged Temozolomide Maintenance Therapy in Newly Diagnosed Glioblastoma
2017-03-30

Abstract Background The impact of prolonging temozolomide (TMZ) maintenance beyond six cycles in newly diagnosed glioblastoma (GBM) remains a topic of discussion. We investigated the effects of prolonged TMZ maintenance on progression-free survival (PFS) and overall survival (OS). Patients and Methods In this retrospective single-center cohort study, we included patients with GBM who were treated with radiation therapy with concomitant and adjuvant TMZ. For analysis, patients were considered who either completed six TMZ maintenance cycles (group B), continued with TMZ therapy beyond six cycles (group C), or stopped TMZ maintenance therapy within the first six cycles (group A). Patients with progression during the first six TMZ maintenance cycles were excluded. Results Clinical data from 107 patients were included for Kaplan-Meier analyses and 102 for Cox regressions. Median PFS times were 8.1 months (95% confidence interval [CI] 6.1–12.4) in group A, 13.7 months (95% CI 10.6–17.5) in group B, and 20.9 months (95% CI 15.2–43.5) in group C. At first progression, response rates of TMZ/lomustine rechallenge were 47% in group B and 13% in group C. Median OS times were 12.7 months (95% CI 10.3–16.8) in group A, 25.2 months (95% CI 17.7–55.5) in group B, and 28.6 months (95% CI 24.4–open) in group C. Nevertheless, multivariate Cox regression for patients in group C compared with group B that accounted for imbalances of other risk factors showed no different relative risk (RR) for OS (RR 0.77, p = .46). Conclusion Our data do not support a general extension of TMZ maintenance therapy beyond six cycles.
Extracorporeal life support prior to left ventricular assist device implantation leads to improvement of the patients INTERMACS levels and outcome
2017-03-30

LVAD implantation in ECLS patients leads to improvement of INTERMACS level to INTERMACS III TCS status. Excellent mid-term survival comparable to true INTERMACS III-IV patients could be shown. ECLS prior to LVAD as a bridge-to-bridge therapy may help to lower mortality in primarily unstable patients.
Simulation of Tracer Dose Reduction in 18F-FDG PET/MRI: Effects on Oncologic Reading, Image Quality, and Artifacts
2017-03-30

The aim of our study was to evaluate the effect of stepwise-reduced doses on objective and subjective image parameters and on oncologic readings in whole-body <sup>18</sup>F-FDG PET/MRI. <b>Methods:</b> We retrospectively simulated the stepwise reduction of <sup>18</sup>F-FDG doses of 19 patients (mean age ± SD, 50.9 ± 11.7 y; mean body mass index ± SD, 22.8 ± 3.2 kg/m<sup>2</sup>) who received a whole-body PET/MRI examination from 3 to 0.5 MBq/kg of body weight (kgBW) in intervals of 0.25. Objective imaging parameters were assessed by measuring the SUV and coefficient of variation in different regions (aorta, liver, spleen, kidney, small bowel, lumbar vertebra, psoas muscle, urinary bladder) as well as the noise-equivalent counting rates in each bed position. Subjective image quality was evaluated with a masked reading of each simulated PET compared with the dose of 2 MBq/kgBW. Oncologic reading was performed first according to PERCIST in each dose and second by defining malignant lesions in doses of 2 MBq/kgBW and the maximum dose image (gold standard). The diagnostic confidence of each lesion was measured using a Likert scale. <b>Results:</b> With decreasing doses, regions in the mid abdomen showed a stronger decrease of SUV<sub>mean</sub> and noise-equivalent counting rates than regions in the upper abdomen (SUV<sub>mean</sub>, -45% and -15% on average in the small bowel and the liver, respectively). The coefficient of variation showed a nonlinear increase, pronounced below 1.5 MBq/kgBW. Subjective image quality was stable over a range between 1.25 and 2.75 MBq/kgBW compared with 2 MBq/kgBW. However, large photopenic areas in the mid abdomen were observed in 2 patients. In the PERCIST reading, target lesions were above the liver threshold with a stable SUV<sub>peak</sub> in all cases down to 2 MBq/kgBW. Eighty-six of 90 lesions were identified correctly with a dose of 2 MBq/kgBW; Likert scores did not differ significantly. <b>Conclusion:</b> A reduction of doses in <sup>18</sup>F-FDG PET/MRI might be possible down to 2 MBq/kgBW in oncologic whole-body examinations. The image quality in the mid abdomen seems to be more affected by lower doses than in the upper abdomen, and in single cases large photopenic areas can occur. Therefore, we do not recommend reducing doses below 3 MBq/kgBW in adults at this time.
Brain–Computer Interface–Based Communication In The Completely Locked-In State
2017-03-30

Despite partial success, communication has remained impossible for persons suffering from complete motor paralysis but intact cognitive and emotional processing, a state called com- plete locked-in state (CLIS). Based on a motor learning theoretical context and on the failure of neuroelectric brain–computer interface (BCI) communication attempts in CLIS, we here report BCI communication using functional near-infrared spectroscopy (fNIRS) and an implicit attentional processing procedure. Four patients suffering from advanced amyotro- phic lateral sclerosis (ALS)—two of them in permanent CLIS and two entering the CLIS with- out reliable means of communication—learned to answer personal questions with known answers and open questions all requiring a “yes” or “no” thought using frontocentral oxygen- ation changes measured with fNIRS. Three patients completed more than 46 sessions spread over several weeks, and one patient (patient W) completed 20 sessions. Online fNIRS classification of personal questions with known answers and open questions using linear support vector machine (SVM) resulted in an above-chance-level correct response rate over 70%. Electroencephalographic oscillations and electrooculographic signals did not exceed the chance-level threshold for correct communication despite occasional differences between the physiological signals representing a “yes” or “no” response. However, electro- encephalogram (EEG) changes in the theta-frequency band correlated with inferior commu- nication performance, probably because of decreased vigilance and attention. If replicated with ALS patients in CLIS, these positive results could indicate the first step towards aboli- tion of complete locked-in states, at least for ALS.
Neurofeedback of Slow Cortical Potentials in Children with Attention-Deficit/Hyperactivity Disorder: A Multicenter Randomized Trial Controlling for Unspecific Effects
2017-03-31

<b>Background:</b> Neurofeedback (NF) in children with attention-deficit/hyperactivity disorder (ADHD) has been investigated in a series of studies over the last years. Previous studies did not unanimously support NF as a treatment in ADHD. Most studies did not control for unspecific treatment effects and did not demonstrate that self-regulation took place. The present study examined the efficacy of NF in comparison to electromyographic (EMG) feedback to control for unspecific effects of the treatment, and assessed self-regulation of slow cortical potentials (SCPs). <b>Methods:</b> A total of 150 children aged 7-9 years diagnosed with ADHD (82% male; 43% medicated) were randomized to 25 sessions of feedback of SCPs (NF) or feedback of coordination of the supraspinatus muscles (EMG). The primary endpoint was the change in parents' ratings of ADHD core symptoms 4 weeks after the end of treatment compared to pre-tests. <b>Results:</b> Children in both groups showed reduced ADHD-core symptoms (NF 0.3, 95% CI -0.42 to -0.18; EMG 0.13, 95% CI -0.26 to -0.01). NF showed a significant superiority over EMG (treatment difference 0.17, 95% CI 0.02-0.3, <i>p</i> = 0.02). This yielded an effect size (ES) of <i>d</i> = 0.57 without and 0.40 with baseline observation carried forward (BOCF). The sensitivity analysis confirmed the primary result. Successful self-regulation of brain activity was observed only in NF. As a secondary result teachers reported no superior improvement from NF compared to EMG, but within-group analysis revealed effects of NF on the global ADHD score, inattention, and impulsivity. In contrast, EMG feedback did not result in changes despite more pronounced self-regulation learning. <b>Conclusions:</b> Based on the primary parent-rated outcome NF proved to be superior to a semi-active EMG feedback treatment. The study supports the feasibility and efficacy of NF in a large sample of children with ADHD, based on both specific and unspecific effects. <b>Trial Register:</b> Current controlled trials ISRCTN76187185, registered 5 February 2009.
3D‐electron microscopic characterization of interstitial cells in the human bladder upper lamina propria
2017-03-31

Aims To explore the ultrastructure of interstitial cells in the upper lamina propria of the human bladder, to describe the spatial relationships and to investigate cell‐cell contacts. Methods Focused ion beam scanning electron microscopy (FIB‐SEM), 3‐View SEM and confocal laser scanning microscopy were used to analyze the 3D ultrastructure of the upper lamina propria in male and female human bladders. Results 3View‐SEM image stacks as large as 59 × 59 × 17 μm 3 (xyz) at a resolution of 16 × 16 × 50 nm 3 and high resolution (5 × 5 × 10 nm 3 ) FIB‐SEM stacks could be analyzed. Interstitial cells with myoid differentiation (mIC) and fibroblast like interstitial cells (fIC) were the major cell types in the upper lamina propria. The flat, sheet‐like ICs were oriented strictly parallel to the urothelium. No spindle shaped cells were present. We furthermore identified one branched cell (bIC) with several processes contacting urothelial cells by penetrating the basal membrane. This cell did not make any contacts to other ICs within the upper lamina propria. We found no evidence for the occurrence of telocytes in the upper lamina propria. Conclusions Comprehensive 3D‐ultrastructural analysis of the human bladder confirmed distinct subtypes of interstitial cells. We provide evidence for a foremost unknown direct connection between a branched interstitial cell and urothelial cells of which the functional role has still to be elucidated. 3D‐ultrastructure analyses at high resolution are needed to further define the subpopulations of lamina propria cells and cell‐cell interactions.
The 100 € lab: A 3-D printable open source platform for fluorescence microscopy, optogenetics and accurate temperature control during behaviour of zebrafish,DrosophilaandC. elegans
2017-03-31

Small, genetically tractable species such as larval zebrafish, Drosophila or C. elegans have become key model organisms in modern neuroscience.In addition to their low maintenance costs and easy sharing of strains across labs, one key appeal is the possibility to monitor single or groups of animals in a behavioural arena while controlling the activity of select neurons using optogenetic or thermogenetic tools.However, the purchase of a commercial solution for these types of experiments, including an appropriate camera system as well as a controlled behavioural arena can be costly.Here, we present a low-cost and modular open-source alternative called "FlyPi".Our design is based on a 3-D printed mainframe, a Raspberry Pi computer and highdefinition camera system as well as Arduino-based optical and thermal control circuits.Depending on the configuration, FlyPi can be assembled for well under 100 € and features optional modules for LED-based fluorescence microscopy and optogenetic stimulation as well as a Peltier-based temperature stimulator for thermogenetics.The complete version with all modules costs ~200 €, or substantially less if the user is prepared to "shop around".All functions of FlyPi can be controlled through a customwritten graphical user interface.To demonstrate FlyPi's capabilities we present its use in a series of state-of-the-art neurogenetics experiments.In addition, we demonstrate FlyPi's utility as a medical diagnostic tool as well as a teaching aid at Neurogenetics courses held at several African universities.Taken together, the low cost and modular nature as well as fully open design of FlyPi make it a highly versatile tool in a range of applications, including the classroom, diagnostic centres and research labs..