julilili42/papers huggingface dataset:
Simulation‐based training improves process times in acute stroke care (STREAM)
2021-09-03

Abstract Background The objective of the STREAM Trial was to evaluate the effect of simulation training on process times in acute stroke care. Methods The multicenter prospective interventional STREAM Trial was conducted between 10/2017 and 04/2019 at seven tertiary care neurocenters in Germany with a pre‐ and post‐interventional observation phase. We recorded patient characteristics, acute stroke care process times, stroke team composition and simulation experience for consecutive direct‐to‐center patients receiving intravenous thrombolysis (IVT) and/or endovascular therapy (EVT). The intervention consisted of a composite intervention centered around stroke‐specific in situ simulation training. Primary outcome measure was the ‘door‐to‐needle’ time (DTN) for IVT. Secondary outcome measures included process times of EVT and measures taken to streamline the pre‐existing treatment algorithm. Results The effect of the STREAM intervention on the process times of all acute stroke operations was neutral. However, secondary analyses showed a DTN reduction of 5 min from 38 min pre‐intervention (interquartile range [IQR] 25–43 min) to 33 min (IQR 23–39 min, p = 0.03) post‐intervention achieved by simulation‐experienced stroke teams. Concerning EVT, we found significantly shorter door‐to‐groin times in patients who were treated by teams with simulation experience as compared to simulation‐naive teams in the post‐interventional phase (−21 min, simulation‐naive: 95 min, IQR 69–111 vs. simulation‐experienced: 74 min, IQR 51–92, p = 0.04). Conclusion An intervention combining workflow refinement and simulation‐based stroke team training has the potential to improve process times in acute stroke care.
Chemical Probes for Understudied Kinases: Challenges and Opportunities
2021-09-03

Over 20 years after the approval of the first-in-class protein kinase inhibitor imatinib, the biological function of a significant fraction of the human kinome remains poorly understood while most research continues to be focused on few well-validated targets. Given the strong genetic evidence for involvement of many kinases in health and disease, the understudied fraction of the kinome holds a large and unexplored potential for future therapies. Specific chemical probes are indispensable tools to interrogate biology enabling proper preclinical validation of novel kinase targets. In this Perspective, we highlight recent case studies illustrating the development of high-quality chemical probes for less-studied kinases and their application in target validation. We spotlight emerging techniques and approaches employed in the generation of chemical probes for protein kinases and beyond and discuss the associated challenges and opportunities.
Operando Investigation of the Aging Mechanism of Lead Sulfide Colloidal Quantum Dots in an Oxidizing Background
2021-09-03

Lead sulfide (PbS) is a p-type semiconductor that is often applied in photodetectors and solar cells. One major problem that researchers are regularly confronted with is the loss of performance when operated in air. The sensitivity to the ambient, however, makes it an interesting material for the application in gas sensors. Although a lot of research has been focused on the aging of PbS, the influencing factors and the associated material changes are still a matter of debate. Resistance measurements of differently prepared PbS samples operated as sensors for the detection of NO2 (a strongly oxidative gas) in combination with surface-sensitive methods (diffuse reflectance infrared Fourier transform spectroscopy and X-ray photoelectron spectroscopy) enabled the investigation of the changes associated with aging and their influence on the sensing mechanism. The aging mechanism was found to be predominantly influenced by the presence of residuals of the stabilizing agent oleic acid that was adsorbed at the surface of the colloidal quantum dots. Additionally, it was found that a byproduct of the consumption of oleic acid enhanced the detected sensor signal.
Parallelizable Microfluidic Platform to Model and Assess In Vitro Cellular Barriers: Technology and Application to Study the Interaction of 3D Tumor Spheroids with Cellular Barriers
2021-09-03

Endothelial and epithelial cellular barriers play a vital role in the selective transport of solutes and other molecules. The properties and function of these barriers are often affected in case of inflammation and disease. Modelling cellular barriers in vitro can greatly facilitate studies of inflammation, disease mechanisms and progression, and in addition, can be exploited for drug screening and discovery. Here, we report on a parallelizable microfluidic platform in a multiwell plate format with ten independent cell culture chambers to support the modelling of cellular barriers co-cultured with 3D tumor spheroids. The microfluidic platform was fabricated by microinjection molding. Electrodes integrated into the chip in combination with a FT-impedance measurement system enabled transepithelial/transendothelial electrical resistance (TEER) measurements to rapidly assess real-time barrier tightness. The fluidic layout supports the tubeless and parallelized operation of up to ten distinct cultures under continuous unidirectional flow/perfusion. The capabilities of the system were demonstrated with a co-culture of 3D tumor spheroids and cellular barriers showing the growth and interaction of HT29 spheroids with a cellular barrier of MDCK cells.
Real-Time Detection of Tumor Cells during Capture on a Filter Element Significantly Enhancing Detection Rate
2021-09-03

Circulating tumor cells (CTCs) that enter the bloodstream play an important role in the formation of metastases. The prognostic significance of CTCs as biomarkers obtained from liquid biopsies is intensively investigated and requires accurate methods for quantification. The purpose of this study was the capture of CTCs on an optically accessible surface for real-time quantification. A filtration device was fabricated from a transparent material so that capturing of cells could be observed microscopically. Blood samples were spiked with stained tumor cells and the sample was filtrated using a porous structure with pore sizes of 7.4 μm. The possible removal of lysed erythrocytes and the retention of CTCs were assessed. The filtration process was observed in real-time using fluorescence microscopy, whereby arriving cells were counted in order to determine the number of CTCs present in the blood. Through optimization of the microfluidic channel design, the cell retention rate could be increased by 13% (from 76% ± 7% to 89% ± 5%). Providing the possibility for real-time detection significantly improved quantification efficiency even for the smallest cells evaluated. While end-point evaluation resulted in a detection rate of 63% ± 3% of the spiked cells, real-time evaluation led to an increase of 21% to 84% ± 4%. The established protocol provides an advantageous and efficient method for integration of fully automated sample preparation and CTC quantification into a lab-on-a-chip system.
Immunological Adverse Events After Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis Patients
2021-09-03

Autologous hematopoietic stem cell transplantation (aHSCT) represents an effective treatment for systemic sclerosis (SSc), but it also can cause immunological adverse events (iAEs). Therefore, we aimed to determine the frequency of iAEs [engraftment syndrome (ES) and secondary autoimmune disorder (sAD)] and to identify potential risk factors for their development in a retrospective analysis on 22 patients similarly transplanted due to SSc. While nine patients (41%) suffered from ESs, seven sADs occurred in six patients (27%). Patients who developed ES were older in our cohort (52.45 vs. 42.58 years, p = .0433, Cohen’s d = 0.86), and cardiac involvement by SSc was associated with development of ES (OR = 40.11, p = .0017). Patients with manifestation of sAD had a higher modified Rodnan skin score (mRSS) reduction after aHSCT (90.50% vs. 60.00%, p = .0064, r = .65). Thus, IAEs are common after aHSCT for SSc and can occur in different stages during and after aHSCT with characteristic clinical manifestations. Good cutaneous response after aHSCT might be considered as a risk factor for sAD, and higher age at aHSCT and cardiac involvement might be considered as risk factors for the development of ES.
Teaching patient-centred communication skills during clinical procedural skill training - a preliminary pre-post study comparing international and local medical students
2021-09-03

Abstract Background International medical students are frequently confronted with intercultural, psychosocial, and language barriers and often receive lower marks in written, oral, and clinical-practical examinations than fellow local students. Training communication competence in procedural skills, such as blood sampling, is further challenge in this particular group of medical students. This pre-post comparative intervention study aimed to investigate the effects of training communication skills during the performance of procedural skills (taking blood samples from a silicone model) in international and local students as part of their clinical practical medical training. Methods Study participants performed blood sampling on an arm prosthesis model (part-task trainer) before and after the communication skills training, focusing on accompanying communication with a simulation patient sitting next to the arm model. The pre- and post-evaluation video was assessed by two independent evaluators using a binary checklist, the Integrated Procedural Performance Instrument (IPPI) and global assessments of clinical professionalism in terms of procedural and communication performance. Linear models with mixed effects were used. Group differences regarding global competence levels were analysed with χ 2 -tests. Results International medical students did not perform as well as their local counterparts in the pre- and post-examinations. Both groups improved their performance significantly, whereby the international students improved more than their local counterparts in terms of their communication performance, assessed via binary checklist. Clinical professionalism evaluated via global assessments of procedural and communication performance highlights the intervention’s impact insofar as no international student was assessed as clinically not competent after the training. Conclusions Our results suggest that already a low-dose intervention can lead to improved communication skills in medical students performing procedural tasks and significantly increase their confidence in patient interaction.
A high resolution single molecule sequencing-based Arabidopsis transcriptome using novel methods of Iso-seq analysis
2021-09-03

Abstract Background Accurate and comprehensive annotation of transcript sequences is essential for transcript quantification and differential gene and transcript expression analysis. Single molecule long read sequencing technologies provide improved integrity of transcript structures including alternative splicing, and transcription start and polyadenylation sites. However, accuracy is significantly affected by sequencing errors, mRNA degradation or incomplete cDNA synthesis. Results We present a new and comprehensive Arabidopsis thaliana Reference Transcript Dataset 3 (AtRTD3). AtRTD3 contains over 160k transcripts - twice that of the best current Arabidopsis transcriptome and including over 1,500 novel genes. 79% of transcripts are from Iso-seq with accurately defined splice junctions and transcription start and end sites. We developed novel methods to determine splice junctions and transcription start and end sites accurately. Mis- match profiles around splice junctions provided a powerful feature to distinguish correct splice junctions and remove false splice junctions. Stratified approaches identified high confidence transcription start/end sites and removed fragmentary transcripts due to degradation. AtRTD3 is a major improvement over existing transcriptomes as demonstrated by analysis of an Arabidopsis cold response RNA-seq time-series. AtRTD3 provided higher resolution of transcript expression profiling and identified cold- and light-induced differential transcription start and polyadenylation site usage. Conclusions AtRTD3 is the most comprehensive Arabidopsis transcriptome currently available. It improves the precision of differential gene and transcript expression, differential alternative splicing, and transcription start/end site usage from RNA-seq data. The novel methods for identifying accurate splice junctions and transcription start/end sites are widely applicable and will improve single molecule sequencing analysis from any species.
Scenario-Aware Program Specialization for Timing Predictability
2021-09-03

The successful application of static program analysis strongly depends on flow facts of a program such as loop bounds, control-flow constraints, and operating modes. This problem heavily affects the design of real-time systems, since static program analyses are a prerequisite to determine the timing behavior of a program. For example, this becomes obvious in worst-case execution time (WCET) analysis, which is often infeasible without user-annotated flow facts. Moreover, many timing simulation approaches use statically derived timings of partial program paths to reduce simulation overhead. Annotating flow facts on binary or source level is either error-prone and tedious, or requires specialized compilers that can transform source-level annotations along with the program during optimization. To overcome these obstacles, so-called scenarios can be used. Scenarios are a design-time methodology that describe a set of possible system parameters, such as image resolutions, operating modes, or application-dependent flow facts. The information described by a scenario is unknown in general but known and constant for a specific system. In this article, 1 we present a methodology for scenario-aware program specialization to improve timing predictability. Moreover, we provide an implementation of this methodology for embedded software written in C/C++. We show the effectiveness of our approach by evaluating its impact on WCET analysis using almost all of TACLeBench–achieving an average reduction of WCET of 31%. In addition, we provide a thorough qualitative and evaluation-based comparison to closely related work, as well as two case studies.
Reconsidering power functional theory
2021-09-03

The original derivation of power functional theory [M. Schmidt and J. M. Brader, J. Chem. Phys. 138, 214101 (2013)] is reworked in some detail with a view to clarifying and simplifying the logic and making explicit the various functional dependencies. We note various issues with the original development and suggest a modification that allows us to avoid them. In the process, we also suggest an alternative interpretation of our results, which bears surprising similarities to classical density functional theory.
Neural Networks for self-adjusting Mutation Rate Estimation when the Recombination Rate is unknown
2021-09-03

Estimating the mutation rate, or equivalently effective population size, is a common task in population genetics. If recombination is low or high, optimal linear estimation methods are known and well understood. For intermediate recombination rates, the calculation of optimal estimators is more challenging. As an alternative to model-based estimation, neural networks and other machine learning tools could help to develop good estimators in these involved scenarios. However, if no benchmark is available it is difficult to assess how well suited these tools are for different applications in population genetics. Here we investigate feedforward neural networks for the estimation of the mutation rate based on the site frequency spectrum and compare their performance with model-based estimators. For this we use the model-based estimators introduced by Fu, Futschik et al., and Watterson that minimize the variance or mean square error for no and free recombination. We find that neural networks reproduce these estimators if provided with the appropriate features and training sets. Remarkably, using the model-based estimators to adjust the weights of the training data, only one hidden layer is necessary to obtain a single estimator that performs almost as well as model-based estimators for low and high recombination rates, and at the same time provides a superior estimation method for intermediate recombination rates. We apply the method to simulated data based on the human chromosome 2 recombination map, highlighting its robustness in a realistic setting where local recombination rates vary and/or are unknown.
Donor cell leukemia/myelodysplastic syndrome after allogeneic stem cell transplantation: a rare phenomenon with more challenges for hematologists
2021-09-03

Donor cell leukemia (DCL) or Donor cell myelodysplastic syndrome (DC-MDS) is a rare type of leukemia or MDS and originates from the donor cells. It has very low frequency, but it seems to be steadily increasing as the physiopathology and mechanisms remain largely unknown. Here we report one case of acute lymphocytic leukemia (ALL) and one case of MDS of donor origin after allogeneic hematopoietic stem cell transplantation (HSCT). We also collated and reviewed literatures regarding DCL, and discuss the morbidity of DCL, the methods used to confirm donor origin and the etiology and pathogenesis of DCL. A new proposed theory will help us to better understand the mechanism for the oncogenesis of DCL.
Native Metabolomics Identifies the Rivulariapeptolide Family of Protease Inhibitors
2021-09-04

Abstract The identity and biological activity of most metabolites still remain unknown. A key bottleneck in the full exploration of this tremendous source of new structures and pharmaceutical activities is the compound purification needed for bioactivity assignments of individual compounds and downstream structure elucidation. To enable bioactivity-focused compound identification from complex mixtures, we developed a scalable native metabolomics approach that integrates non-targeted liquid chromatography tandem mass spectrometry, and simultaneous detection of protein binding via native mass spectrometry. While screening for new protease inhibitors from an environmental cyanobacteria community, native metabolomics revealed 30 cyclodepsipeptides as chymotrypsin binders. Mass spectrometry-guided purification then allowed for the full structure elucidation of four new specialized metabolites via tandem mass spectrometry, chemical derivatization, and nuclear magnetic resonance spectroscopy. Together with the evaluation of biological activities, our results identified the rivulariapeptolides as a family of serine protease inhibitors with nanomolar potency, highlighting native metabolomics as promising approach for drug discovery, chemical ecology, and chemical biology studies.
Hydroclimate of the Tibetan Plateau and Central Asia during the Late Cenozoic
2021-09-04

These repository data contain netcdf files for each of the four high-resolution (~0.75° per grid cell) general circulation model (GCM) ECHAM-5 experiments with boundary conditions for the mid-Pliocene (~3 Ma; ECHAM5_PLIO_1d_aprl_aprc_q_v_u_Asia.nc), the Last Glacial Maximum (LGM; ~21 ka; ECHAM5_LGM_1d_aprl_aprc_q_v_u_Asia.nc), the mid-Holocene (~6 ka; ECHAM5_MH_1d_aprl_aprc_q_v_u_Asia.nc), and the pre-industrial (ECHAM5_PI_1d_aprl_aprc_q_v_u_Asia.nc). Each file contains 3D fields of specific humidity and winds, as well as precipitation (large-scale and convective) for Asian region.
Forest wildflowers bloom earlier as Europe warms – but not everywhere equally
2021-09-05

Abstract Some of the most striking biological responses to climate change are the observed shifts in the timing of life-history events of many organisms. Plants, in particular, often flower earlier in response to climate warming, and herbarium specimens are excellent witnesses of such long-term changes. However, in large-scale analyses the magnitude of phenological shifts may vary geographically, and the data are often clustered, and it is thus necessary to account for spatial correlation to avoid geographical biases and pseudoreplication. Here, we analysed herbarium specimens of 20 spring-flowering forest understory herbs to estimate how their flowering phenology shifted across Europe during the last century. Our analyses show that on average these forest wildflowers now bloom over six days earlier than at the beginning of the last century. These changes were strongly associated with warmer spring temperatures. Plants flowered on average of 3.6 days earlier per 1°C warming. However, in some parts of Europe plants flowered earlier or later than expected. This means, there was significant residual spatial variation in flowering time across Europe, even after accounting for the effects of temperature, precipitation, elevation and year. Including this spatial autocorrelation into our statistical models significantly improved model fit and reduced bias in coefficient estimates. Our study indicates that forest wildflowers in Europe strongly advanced their phenology in response to climate change during the last century, with potential severe consequences for their associated ecological communities. It also demonstrates the power of combining herbarium data with spatial modelling when testing for long-term phenology trends across large spatial scales.
Histological confidence of transbronchial cryobiopsy in interstitial lung diseases is influenced by sample size
2021-09-05

<b>Introduction:</b> In patients with interstitial lung disease (ILD) with an uncertain noninvasive diagnosis, transbronchial lung cryobiopsy (TBLC) is a valuable technique for tissue sampling with good benefit/side effect ratio. However, it is yet unclear which procedural factors of TBLC impact histological diagnosis. <b>Aims and objectives:</b> We aimed to determine the factors that influence the confidence of TBLC histological diagnoses in a prospective multicentre trial. <b>Methods:</b> In 127 patients with suspected ILD TBLCs were performed. The number of biopsies taken was recorded. The TBLC samples were evaluated by two independent expert pathologists and histologic diagnoses divided into three groups: high confidence (HC), low confidence (LC) and non-diagnostic (ND). The total area (TA) of all histological specimens were measured planimetrically. Histopathological confidence levels were correlated with TA and biopsy numbers - above and below their means - using the likelihood chi square test. <b>Results:</b> The mean TA of all biopsies per patient was 51.2 ±29.2 mm2. The mean TA per biopsy of all biopsies per patient was 10.9 ±6.3 mm2. The mean number of biopsies per patient was 4.8 ±1.3. Both pathologists found a significant correlation of TA per patient (p=0.01 and p=0.0004) and TA per biopsy (p=0.036 and p=0.014) with the confidence level of histological diagnosis (HC, LC, ND). There was no significant correlation between diagnostic confidence and the number of biopsies per patient. <b>Conclusions:</b> The confidence of histopathologic diagnosis of TBLC in ILD seems to be influenced more by the evaluable surface area rather than by the number of biopsies taken.