julilili42/papers huggingface dataset:
Identification of Novel α-Pyrones from Conexibacter woesei Serving as Sulfate Shuttles
2019-08-16

Pyrones comprise a structurally diverse class of compounds. Although they are widespread in nature, their specific physiological functions remain unknown in most cases. We recently described that triketide pyrones mediate the sulfotransfer in caprazamycin biosynthesis. Herein, we report the identification of conexipyrones A-C, three previously unrecognized tetra-substituted α-pyrones, from the soil actinobacterium <i>Conexibacter woesei</i>. Insights into their biosynthesis via a type III polyketide synthase were obtained by feeding studies using isotope-enriched precursors. <i>In vitro</i> assays employing the genetically associated 3'-phosphoadenosine-5'-phosphosulfate (PAPS)-dependent sulfotransferase CwoeST revealed conexipyrones as the enzymes' genuine sulfate acceptor substrates. Furthermore, conexipyrones were determined to function as sulfate shuttles in a two-enzyme assay, because their sulfated derivatives were accepted as donor molecules by the PAPS-independent arylsulfate sulfotransferase (ASST) Cpz4 to yield sulfated caprazamycin intermediates.
Synthesis of a Novel Curcumin Derivative as a Potential Imaging Probe in Alzheimer’s Disease Imaging
2019-08-16

Background: Curcumin has been of interest in the field of Alzheimer’s disease. Early studies on transgenic mice showed promising results in the reduction of amyloid plaques.However, curcumin is very poorly soluble in aqueous solutions and not easily accessible to coupling as it contains only phenolic groups as potential coupling sites. For these reasons only few imaging studies using curcumin bound as an ester were performed and curcumin is mainly used as nutritional supplement. Methods: In the present study we produced an aminoethyl ether derivative of curcumin using a nucleophilic substitution reaction. This is a small modification and should not impact the properties of curcumin while introducing an easily accessible reactive amino group. This novel compound could be used to couple curcumin to other molecules using the standard methods of peptide synthesis. We studied the aminoethyl-curcumin compound and a tripeptide carrying this aminoethyl-curcumin and the fluorescent dye fluorescein (FITC-curcumin) in vitro on cell culture using confocal laser scanning microscopy and flow cytometry. Then these two substances were tested ex vivo on brain sections prepared from transgenic mice depicting Alzheimer-like β-amyloid plaques. Results: In the in vitro CLSM microscopy and flow cytometry experiments we found dot-like unspecific uptake and only slight cytotoxicity correlating with this uptake. As these measurements were optimized for the use of fluorescein as dye we found that the curcumin at 488nm fluorescence excitation was not strong enough to use it as a fluorescence marker in these applications. In the ex vivo sections CLSM experiments both the aminoethyl-curcumin and the FITC-curcumin peptide bound specifically to β- amyloid plaques. Conclusion: In conclusion we successfully produced a novel curcumin derivative which could easily be coupled to other imaging or therapeutic molecules as a sensor for amyloid plaques.
Faculty Opinions recommendation of Genome-wide cell-free DNA fragmentation in patients with cancer.
2019-08-16

Cell-free DNA (cfDNA) in the blood provides a noninvasive diagnostic avenue for patients with cancer 1 .However, characteristics of the origins and molecular features of cfDNA are poorly understood.We developed an approach to evaluate fragmentation patterns of cfDNA across the genome and found that cfDNA profiles of healthy individuals reflected nucleosomal patterns of white blood cells, while patients with cancer had altered fragmentation profiles.We applied this method to analyze fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric, or bile duct cancer and 245 healthy individuals.A machine learning model incorporating genome-wide fragmentation features had sensitivities of detection ranging from 57% to >99% among the seven cancer types at 98% specificity, with an overall AUC of 0.94.Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases.Combining our approach with mutation based cfDNA analyses detected 91% of cancer patients.The results of these analyses highlight important properties of cfDNA and provide a proof of principle approach for screening, early detection, and monitoring of human cancer.
Thrombogenicity and Antithrombotic Strategies in Structural Heart Interventions and Nonaortic Cardiac Device Therapy—Current Evidence and Practice
2019-08-17

Abstract As the number of, and the indications for, structural heart interventions are increasing worldwide, the optimal secondary prevention to reduce device thrombosis is becoming more important. To date, most of the recommendations are empiric. The current review discusses mechanisms behind device-related thrombosis, the available evidence with regard to antithrombotic regimen after cardiac device implantation, as well as providing an algorithm for identification of risk factors for device thrombogenicity and for management of device thrombosis after implantation of patent foramen ovale and left atrial appendage occluders, MitraClips/transcatheter mitral valve replacement, pacemaker leads, and left ventricular assist devices. Of note, the topic of antithrombotic therapy and thrombogenicity of prostheses in aortic position (transcatheter aortic valve replacement, surgical, mechanical, and bioprostheses) is not part of the present article and is discussed in detail in other contemporary focused articles.
HARMFUL SIGNALS: CARTEL PROHIBITION AND OLIGOPOLY THEORY IN THE AGE OF MACHINE LEARNING
2019-08-17

Abstract The traditional legal approach for distinguishing between illicit collusion and legitimate oligopoly conduct is to rely on criteria that relate to the means and form of how rivals interact, such as elements of “practical cooperation”, or on the finding of an anticompetitive intent. These criteria ultimately refer to the inner sphere of natural persons and its emanations in communicative acts. Some authors therefore conclude that the cartel prohibition of Article 101 Treaty on the Functioning of the European Union (TFEU) or Section 1 of the U.S. Sherman Act is unable to capture collusion if it is achieved by autonomously acting computers relying on machine learning capabilities. It is instead suggested here to define collusion as parallel informational signals, which achieve a supracompetitive equilibrium, and to use the consumer welfare standard as a proxy for distinguishing between illicit collusion and legitimate oligopoly conduct. This approach is not tantamount to the idea of prohibiting tacit collusion as such. Rather, it is to check singular elements of communication, that is, “informational signals”, within an existing oligopolistic setting for their propensity to create consumer harm. This approach can help to close potential regulatory gaps currently associated with the surge of algorithmic pricing.
Do longitudinal cerebrospinal fluid profiles correspond to postmortem brain pathology in LRRK2 Parkinson's disease?
2019-08-17

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice
2019-08-18

Recent works highlight the therapeutic potential of targeting cyclic guanosine monophosphate (cGMP)-dependent pathways in the context of brain ischemia/reperfusion injury (IRI). Although cGMP-dependent protein kinase I (cGKI) has emerged as a key mediator of the protective effects of nitric oxide (NO) and cGMP, the mechanisms by which cGKI attenuates IRI remain poorly understood. We used a novel, conditional cGKI knockout mouse model to study its role in cerebral IRI. We assessed neurological deficit, infarct volume, and cerebral perfusion in tamoxifen-inducible vascular smooth muscle cell-specific cGKI knockout mice and control animals. Stroke experiments revealed greater cerebral infarct volume in smooth muscle cell specific cGKI knockout mice (males: 96 ± 16 mm 3 ; females: 93 ± 12 mm 3 , mean±SD) than in all control groups: wild type (males: 66 ± 19; females: 64 ± 14), cGKI control (males: 65 ± 18; females: 62 ± 14), cGKI control with tamoxifen (males: 70 ± 8; females: 68 ± 10). Our results identify, for the first time, a protective role of cGKI in vascular smooth muscle cells during ischemic stroke injury. Moreover, this protective effect of cGKI was found to be independent of gender and was mediated via improved reperfusion. These results suggest that cGKI in vascular smooth muscle cells should be targeted by therapies designed to protect brain tissue against ischemic stroke.
Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia
2019-08-18

Abstract Parkinson’s disease (PD) is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of PD, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA , LRRK2 , and GBA ) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA , encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as PD and Lewy body dementia (LBD). These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to &gt;10-fold. An outstanding question in the field is what other genetic factors that influence GBA -associated risk for disease, and whether these overlap with known PD risk variants. Using multiple, large case-control datasets, totalling 217,165 individuals (22,757 PD cases, 13,431 PD proxy cases, 622 LBD cases and 180,355 controls), we identified 1,772 PD cases, 711 proxy cases and 7,624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent PD-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall PD genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB . Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S neurons were shown to have decreased Cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA -associated PD risk and age at onset and demonstrate that variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have important implications for selection of GBA carriers for therapeutic interventions.
Birch tar production does not prove Neanderthal behavioral complexity
2019-08-19

Significance We found a previously unknown way to produce birch tar. Instead of creating cognitively demanding structures (underground or in containers), this method consists of simply burning bark close to cobbles in a hearth. The tar is deposited on the stones and can be scraped off for use. This approach to interpreting early tar resolves the mystery of the associated and still not understood early technical complexity and provides a “discoverable” pathway to one of the earliest pyrotechnologies. These results have implications for our interpretation of birch tar in the archaeological record: Birch tar from early archaeological contexts alone can no longer indicate the presence of modern cognition and/or cultural behaviors in Neanderthals.
Topographic Shelf Waves Control Seasonal Melting Near Antarctic Ice Shelf Grounding Lines
2019-08-19

Abstract The buttressing potential of ice shelves is modulated by changes in subshelf melting, in response to changing ocean conditions. We analyze the temporal variability in subshelf melting using an autonomous phase‐sensitive radio‐echo sounder near the grounding line of the Roi Baudouin Ice Shelf in East Antarctica. When combined with additional oceanographic evidence of seasonal variations in the stratification and the amplification of diurnal tides around the shelf break topography (Gunnerus Bank), the results suggest an intricate mechanism in which topographic waves control the seasonal melt rate variability near the grounding line. This mechanism has not been considered before and has the potential to enhance local melt rates without advecting different water masses. As topographic waves seem to strengthen in a stratified ocean, the freshening of Antarctic surface water, predicted by observations and models, is likely to increase future basal melting in this area.
Navigating Through Electronic Health Records: Survey Study on Medical Students’ Perspectives in General and With Regard to a Specific Training
2019-08-19

Background An electronic health record (EHR) is the state-of-the-art method for ensuring all data concerning a given patient are up to date for use by multidisciplinary hospital teams. Therefore, medical students need to be trained to use health information technologies within this environment from the early stages of their education. Objective As little is known about the effects of specific training within the medical curriculum, this study aimed to develop a course module and evaluate it to offer best practice teaching for today’s students. Moreover, we looked at the acceptance of new technologies such as EHRs. Methods Fifth-year medical students (N=104) at the University of Tübingen took part in a standardized two-day training procedure about the advantages and risks of EHR use. After the training, students performed their own EHR entries on hypothetical patient cases in a safe practice environment. In addition, questionnaires—standardized and with open-ended questions—were administered to assess students’ experiences with a new teaching module, a newly developed EHR simulator, the acceptance of the health technology, and their attitudes toward it before and after training. Results After the teaching, students rated the benefit of EHR training for medical knowledge significantly higher than before the session (mean 3.74, SD 1.05). However, they also had doubts about the long-term benefit of EHRs for multidisciplinary coworking after training (mean 1.96, SD 0.65). The special training with simulation software was rated as helpful for preparing students (88/102, 86.2%), but they still did not feel safe in all aspects of EHR. Conclusions A specific simulated training on using EHRs helped students improve their knowledge and become more aware of the risks and challenges of such a system. Overall, students welcomed the new training module and supported the integration of EHR teaching into the medical curriculum. Further studies are needed to optimize training modules and make use of long-term feedback opportunities a simulated system offers.
Difficulties in the description of Drell-Yan processes at low invariant mass and high transverse momentum
2019-08-19

We study the Drell-Yan cross section differential with respect to the transverse momentum of the produced lepton pair. We consider data with moderate invariant mass Q of the lepton pair, between 4.5 GeV and 13.5 GeV, and similar (although slightly smaller) values of the transverse momentum qT . We approach the problem by deriving predictions based on standard collinear factorization, which are expected to be valid toward the high-qT end of the spectrum and to which any description of the spectrum at lower qT based on transverse-momentum dependent parton distributions ultimately needs to be matched. We find that the collinear framework predicts cross sections that in most cases are significantly below available data at high qT . We discuss additional perturbative and possible non-perturbative effects that increase the predicted cross section, but not by a sufficient amount.
Comparison of catchment scale 3D and 2.5D modelling of soil organic carbon stocks in Jiangxi Province, PR China
2019-08-20

As limited resources, soils are the largest terrestrial sinks of organic carbon. In this respect, 3D modelling of soil organic carbon (SOC) offers substantial improvements in the understanding and assessment of the spatial distribution of SOC stocks. Previous three-dimensional SOC modelling approaches usually averaged each depth increment for multi-layer two-dimensional predictions. Therefore, these models are limited in their vertical resolution and thus in the interpretability of the soil as a volume as well as in the accuracy of the SOC stock predictions. So far, only few approaches used spatially modelled depth functions for SOC predictions. This study implemented and evaluated an approach that compared polynomial, logarithmic and exponential depth functions using non-linear machine learning techniques, i.e. multivariate adaptive regression splines, random forests and support vector machines to quantify SOC stocks spatially and depth-related in the context of biodiversity and ecosystem functioning research. The legacy datasets used for modelling include profile data for SOC and bulk density (BD), sampled at five depth increments (0-5, 5-10, 10-20, 20-30, 30-50 cm). The samples were taken in an experimental forest in the Chinese subtropics as part of the biodiversity and ecosystem functioning (BEF) China experiment. Here we compared the depth functions by means of the results of the different machine learning approaches obtained based on multi-layer 2D models as well as 3D models. The main findings were (i) that 3rd degree polynomials provided the best results for SOC and BD (R2 = 0.99 and R2 = 0.98; RMSE = 0.36% and 0.07 g cm-3). However, they did not adequately describe the general asymptotic trend of SOC and BD. In this respect the exponential (SOC: R2 = 0.94; RMSE = 0.56%) and logarithmic (BD: R2 = 84; RMSE = 0.21 g cm-3) functions provided more reliable estimates. (ii) random forests with the exponential function for SOC correlated better with the corresponding 2.5D predictions (R2: 0.96 to 0.75), compared to the 3rd degree polynomials (R2: 0.89 to 0.15) which support vector machines fitted best. We recommend not to use polynomial functions with sparsely sampled profiles, as they have many turning points and tend to overfit the data on a given profile. This may limit the spatial prediction capacities. Instead, less adaptive functions with a higher degree of generalisation such as exponential and logarithmic functions should be used to spatially map sparse vertical soil profile datasets. We conclude that spatial prediction of SOC using exponential depth functions, in conjunction with random forests is well suited for 3D SOC stock modelling, and provides much finer vertical resolutions compared to 2.5D approaches.
Brain State-dependent Brain Stimulation with Real-time Electroencephalography-Triggered Transcranial Magnetic Stimulation
2019-08-20

The effect of a stimulus to the brain depends not only on the parameters of the stimulus but also on the dynamics of brain activity at the time of the stimulation. The combination of electroencephalography (EEG) and transcranial magnetic stimulation (TMS) in a real-time brain state-dependent stimulation system allows the study of relations of dynamics of brain activity, cortical excitability, and plasticity induction. Here, we demonstrate a newly developed method to synchronize the timing of brain stimulation with the phase of ongoing EEG oscillations using a real-time data analysis system. This real-time EEG-triggered TMS of the human motor cortex, when TMS is synchronized with the surface EEG negative peak of the sensorimotor μ-alpha (8-14 Hz) rhythm, has shown differential corticospinal excitability and plasticity effects. The utilization of this method suggests that real-time information about the instantaneous brain state can be used for efficacious plasticity induction. Additionally, this approach enables personalized EEG-synchronized brain stimulation which may lead to the development of more effective therapeutic brain stimulation protocols.
Event-Related potentials in an associative word pair learning paradigm
2019-08-20

Abstract The study investigated the effect of unintentional learning of semantically unrelated word pairs on event-related brain potentials. Two experiments were conducted, in whose acquisition phase participants listened to five pairs of semantically unrelated words, each pair being repeated twenty times. In the test phase of Experiment 1, these “old” pairs were presented mixed with “new” pairs containing other words. In the test phase of Experiment 2, a third condition was added in which the first word in a pair was one of the words presented during acquisition but the second word was new. In both experiments, the second word in new word pairs elicited an N400 and a late (550-1000 ms) frontal positivity. The amplitude of the N400 to new second words in Experiment 2 was significantly larger when the first word in the pair was an old (previously learnt) word, as compared with the condition in which both first and second words were new. The results indicate that, in addition to a repetition effect, unintentional learning of word pairs results in building new associations between previously unrelated words.
Oral Selinexor–Dexamethasone for Triple-Class Refractory Multiple Myeloma
2019-08-21

Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).
The inner clock—Blue light sets the human rhythm
2019-08-21

Abstract Visible light synchronizes the human biological clock in the suprachiasmatic nuclei of the hypothalamus to the solar 24‐hour cycle. Short wavelengths, perceived as blue color, are the strongest synchronizing agent for the circadian system that keeps most biological and psychological rhythms internally synchronized. Circadian rhythm is important for optimum function of organisms and circadian sleep–wake disruptions or chronic misalignment often may lead to psychiatric and neurodegenerative illness. The beneficial effect on circadian synchronization, sleep quality, mood, and cognitive performance depends not only on the light spectral composition but also on the timing of exposure and its intensity. Exposure to blue light during the day is important to suppress melatonin secretion, the hormone that is produced by the pineal gland and plays crucial role in circadian rhythm entrainment. While the exposure to blue is important for keeping organism's wellbeing, alertness, and cognitive performance during the day, chronic exposure to low‐intensity blue light directly before bedtime, may have serious implications on sleep quality, circadian phase and cycle durations. This rises inevitably the need for solutions to improve wellbeing, alertness, and cognitive performance in today's modern society where exposure to blue light emitting devices is ever increasing.