julilili42/papers huggingface dataset:
Quality assurance in anti-tuberculosis drug procurement by the Stop TB Partnership—Global Drug Facility: Procedures, costs, time requirements, and comparison of assay and dissolution results by manufacturers and by external analysis
2020-12-03

Background Quality-assured medicines are a principal means of achieving health-related Sustainable Development Goals. An example of quality assurance/quality control (QA/QC) procedures in drug procurement is provided by the operation of the Global Drug Facility (GDF) of the Stop TB Partnership, the largest provider of tuberculosis (TB) medicines to the public sector worldwide. Methods Procedures and results of GDF’s quality assurance/quality control (QA/QC) over the five-year period 2013–2017 were analysed retrospectively. 13,999 batches of 51 different medicines had been procured and reviewed within this period. 1,388 of these batches had been analysed in the laboratories of GDF’s external quality control agent (QCA). Assay and dissolution results determined by the manufacturers and by the external QCA were compared using Bland-Altman analysis. Results All investigated batches of medicines were in specifications at the time of shipment. The costs for QA/QC were 0.8% of purchase costs. The median time required for chemical analysis was 10 working days. Comparison of the medicine quality analysis results showed for the poorly water-soluble compound rifampicin a bias of 4.4%, with the manufacturers reporting higher values than the external QCA, most likely due to different methods employed for the analysis. Overall 95% limits of agreement (LOAs) were -6.7 to +8.0% for assay, and -10.1 to +11.8% for dissolution. In case of kanamycin injections, 95% LOAs for assay reached -14.5 to +13.2%, largely attributable to samples from one manufacturer who had used a microbiological assay while the external QCA had used an HPLC assay. Conclusions GDF’s procedures represent a useful benchmark when evaluating QA/QC procedures of other medicine procurement operations. Inter-laboratory comparison using Bland-Altman plots allows to investigate bias and variability in medicine quality control and should be considered as a routine procedure by drug procurement agencies, to identify priorities for further improvements.
Using the SNAP-Tag technology to easily measure and demonstrate apoptotic changes in cancer and blood cells with different dyes
2020-12-03

In vitro and ex vivo development of novel therapeutic agents requires reliable and accurate analyses of the cell conditions they were preclinical tested for, such as apoptosis. The detection of apoptotic cells by annexin V (AV) coupled to fluorophores has often shown limitations in the choice of the dye due to interference with other fluorescent-labeled cell markers. The SNAP-tag technology is an easy, rapid and versatile method for functionalization of proteins and was therefore used for labeling AV with various fluorophores. We generated the fusion protein AV-SNAP and analyzed its capacity for the specific display of apoptotic cells in various assays with therapeutic agents. AV-SNAP showed an efficient coupling reaction with five different fluorescent dyes. Two selected fluorophores were tested with suspension, adherent and peripheral blood cells, treated by heat-shock or apoptosis-inducing therapeutic agents. Flow cytometry analysis of apoptotic cells revealed a strong visualization using AV-SNAP coupled to these two fluorophores exemplary, which was comparable to a commercial AV-Assay-kit. The combination of the apoptosis-specific binding protein AV with the SNAP-tag provides a novel solid method to facilitate protein labeling using several, easy to change, fluorescent dyes at once. It avoids high costs and allows an ordinary exchange of dyes and easier use of other fluorescent-labeled cell markers, which is of high interest for the preclinical testing of therapeutic agents in e.g. cancer research.
How massed practice improves visual expertise in reading panoramic radiographs in dental students: An eye tracking study
2020-12-03

The interpretation of medical images is an error-prone process that may yield severe consequences for patients. In dental medicine panoramic radiography (OPT) is a frequently used diagnostic procedure. OPTs typically contain multiple, diverse anomalies within one image making the diagnostic process very demanding, rendering students’ development of visual expertise a complex task. Radiograph interpretation is typically taught through massed practice; however, it is not known how effective this approach is nor how it changes students’ visual inspection of radiographs. Therefore, this study investigated how massed practice–an instructional method that entails massed learning of one type of material–affects processing of OPTs and the development of diagnostic performance. From 2017 to 2018, 47 dental students in their first clinical semester diagnosed 10 OPTs before and after their regular massed practice training, which is embedded in their curriculum. The OPTs contained between 3 to 26 to-be-identified anomalies. During massed practice they diagnosed 100 dental radiographs without receiving corrective feedback. The authors recorded students’ eye movements and assessed the number of correctly identified and falsely marked low- and high prevalence anomalies before and after massed practice. Massed practice had a positive effect on detecting anomalies especially with low prevalence ( p &lt; .001). After massed practice students covered a larger proportion of the OPTs ( p &lt; .001), which was positively related to the detection of low-prevalence anomalies ( p = .04). Students also focused longer, more frequently, and earlier on low-prevalence anomalies after massed practice ( p s &lt; .001). While massed practice improved visual expertise in dental students with limited prior knowledge, there is still substantial room for improvement. The results suggest integrating massed practice with more deliberate practice, where, for example, corrective feedback is provided, and support is adapted to students’ needs.
Colourfulness as a possible measure of object proximity in the larval zebrafish brain
2020-12-03

The encoding of light increments and decrements by separate On- and Off- systems is a fundamental ingredient of vision, which supports the detection of edges in space and time and makes efficient use of limited dynamic range of visual neurons [1]. Theory predicts that the neural representation of On- and Off-signals should be approximately balanced, including across an animals’ full visible spectrum. Here we find that larval zebrafish violate this textbook expectation: in the fish brain, UV-stimulation near exclusively gives On-responses, blue/green-stimulation mostly Off- responses, and red-light alone elicits approximately balanced On- and Off-responses (see also [2–4]). We link these findings to zebrafish visual ecology, and suggest that the observed spectral tuning boosts the encoding of object “colourfulness”, which correlates with object proximity in their underwater world [5].
Diagnosis of SARS-CoV-2 infections in times of material shortage
2020-12-03

Abstract The pandemic caused by SARS-CoV-2 resulted in increasing demands for diagnostic tests, leading to a shortage of recommended testing materials and reagents. This study reports on the performance of self-sampled alternative swabbing material (ordinary Q-tips tested against flocked swab and rayon swab), of reagents for classical RNA extraction (phenol/guanidine-based protocol against a commercial kit), and of intercalating dye-based one-step quantitative reverse transcription real-time PCRs (RT-qPCR) compared against the gold standard hydrolysis probe-based assays for SARS-CoV-2 detection. The study found sampling with Q-tips, RNA extraction with classical protocol and intercalating dye-based RT-qPCR as a reliable and comparably sensitive strategy for detection of SARS-CoV-2 - particularly valuable in the current period with a resurgent and dramatic increase in SARS-CoV-2 infections and growing shortage of diagnostic materials as well for regions limited in resources.
Problems in measuring the JTC-bias in patients with psychotic disorders with the fish task: A secondary analysis of a baseline assessment of a randomized controlled trial
2020-12-03

Abstract Background: The jumping to conclusions bias (JTC) is considered to be an important causal factor in theoretical models for the formation and maintenance of delusions. However, recent meta-analytic findings show a rather equivocal pattern of results regarding associations between JTC and delusions. Thus, the present study aims to investigate in a large sample whether the JTC-bias is more pronounced in patients with psychotic disorders in comparison to controls and whether the JTC bias is associated with a more severe delusional conviction, persecutory delusions, and positive symptoms in general. Methods: Patients with psychotic disorders ( n = 300) enrolled in a therapy trial and healthy controls ( n = 51) conducted a variant of the beads task (fish task) as a measure for the JTC-bias at the start of the trial. Further, clinical interviews were used to assess patients’ delusional severity and delusional conviction. Results: There were no statistically significant differences between patients with psychotic disorders (with 53% displaying the JTC-bias) and controls (41%). Furthermore, there were no statistically significant correlations between JTC measures and persecutory delusions, delusional conviction, and positive symptoms. Conclusions: We found no differences in JTC between patients with psychotic disorders and healthy controls, which is in part in line with meta-analytic findings using a wide range of JTC task variants. Interestingly, patients with psychotic disorders displayed JTC rates commonly found in the literature, while healthy control subjects showed an unexpectedly high level of JTC. The task variant we used in the present study (fish task) is discussed as a potential reason for our results, as it may induce a more deliberative reasoning style in controls as compared to the traditional beads task. Furthermore, possible implications for the measurement of the JTC-bias, in general, are discussed. Trial Registration: ISRCTN29242879 (isrctn.com), date of registration: April 12 th 2006, retrospectively registered
Teaching electric circuits with a focus on potential differences
2020-12-04

[This paper is part of the Focused Collection on Curriculum Development: Theory into Design.] Developing a solid understanding of simple electric circuits represents a major challenge to most students in middle school. In particular, students tend to reason exclusively with current and resistance when analyzing electric circuits as they view voltage as a property of the electric current and not an independent physical quantity. As a result, they often struggle to understand the important relationship between voltage and current in electric circuits. Following diSessa’s interpretation of learning as the construction and reorganization of previously loosely connected elements of knowledge (“p-prims”) into a coherent mental structure (“coordination class”), a new curriculum was developed that systematically builds on students’ everyday experiences with air pressure (e.g., with air mattresses and bicycle tires). In order to make voltage rather than current the students’ primary concept when analyzing electric circuits, voltage is introduced as an “electric pressure difference” across a resistor that is as much the cause for an electric current as air pressure differences are the cause for air flow. The objective of the curriculum is to provide a structure for students to develop a qualitative understanding of simple dc circuits that allows them to make intuitive inferences about the electric current based on voltage and resistance. With an effect size of d=0.94 the new curriculum has proven to be more effective than traditional approaches for teaching electric circuits in a quasi-experimental field study with 790 students from Frankfurt am Main, Germany.
Event‐Predictive Cognition: A Root for Conceptual Human Thought
2020-12-04

Abstract Our minds navigate a continuous stream of sensorimotor experiences, selectively compressing them into events. Event‐predictive encodings and processing abilities have evolved because they mirror interactions between agents and objects—and the pursuance or avoidance of critical interactions lies at the heart of survival and reproduction. However, it appears that these abilities have evolved not only to pursue live‐enhancing events and to avoid threatening events, but also to distinguish food sources, to produce and to use tools, to cooperate, and to communicate. They may have even set the stage for the formation of larger societies and the development of cultural identities. Research on event‐predictive cognition investigates how events and conceptualizations thereof are learned, structured, and processed dynamically. It suggests that event‐predictive encodings and processes optimally mediate between sensorimotor processes and language. On the one hand, they enable us to perceive and control physical interactions with our world in a highly adaptive, versatile, goal‐directed manner. On the other hand, they allow us to coordinate complex social interactions and, in particular, to comprehend and produce language. Event‐predictive learning segments sensorimotor experiences into event‐predictive encodings. Once first encodings are formed, the mind learns progressively higher order compositional structures, which allow reflecting on the past, reasoning, and planning on multiple levels of abstraction. We conclude that human conceptual thought may be grounded in the principles of event‐predictive cognition constituting its root.
Drivers of reef fish assemblages in an upwelling region from the Eastern Tropical Pacific Ocean
2020-12-04

Abstract Reef fish assemblages are exposed to a wide range of anthropogenic threats as well as chronic natural disturbances. In upwelling regions, for example, there is a seasonal influx of cool nutrient‐rich waters that may shape the structure and composition of reef fish assemblages. Given that climate change may disrupt the natural oceanographic processes by altering the frequency and strength of natural disturbances, understanding how fish assemblages respond to upwelling events is essential to effectively manage reef ecosystems under changing ocean conditions. This study used the baited remote underwater video stations (BRUVS) and the traditional underwater visual census (UVC) to investigate the spatiotemporal patterns of reef fish assemblages in an upwelling region in the North Pacific of Costa Rica. A total of 183 reef fish species from 60 families were recorded, of which 166 species were detected using BRUVS and 122 using UVC. Only 66% of all species were detected using both methods. This study showed that the upwelling had an important role in shaping reef fish assemblages in this region, but there was also a significant interaction between upwelling and location. In addition, other drivers such as habitat complexity and habitat composition had an effect on reef fish abundances and species. To authors’ knowledge, this is the first study in the Eastern Tropical Pacific that combines BRUVS and UVC to monitor reef fish assemblages in an upwelling region, which provides more detailed information to assess the state of reef ecosystems in response to multiple threats and changing ocean conditions.
Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK
2020-12-04

The nonreceptor tyrosine TEC kinases are key regulators of the immune system and play a crucial role in the pathogenesis of diverse hematological malignancies. In contrast to the substantial efforts in inhibitor development for Bruton’s tyrosine kinase (BTK), specific inhibitors of the other TEC kinases, including the bone marrow tyrosine kinase on chromosome X (BMX), remain sparse. Here we present a novel class of dual BMX/BTK inhibitors, which were designed from irreversible inhibitors of Janus kinase (JAK) 3 targeting a cysteine located within the solvent-exposed front region of the ATP binding pocket. Structure-guided design exploiting the differences in the gatekeeper residues enabled the achievement of high selectivity over JAK3 and certain other kinases harboring a sterically demanding residue at this position. The most active compounds inhibited BMX and BTK with apparent IC50 values in the single digit nanomolar range or below showing moderate selectivity within the TEC family and potent cellular target engagement. These compounds represent an important first step towards selective chemical probes for the protein kinase BMX.
Advances in the In Vivo Molecular Imaging of Invasive Aspergillosis
2020-12-04

Invasive pulmonary aspergillosis (IPA) is a life-threatening infection of immunocompromised patients with Aspergillus fumigatus, a ubiquitous environmental mould. While there are numerous functioning antifungal therapies, their high cost, substantial side effects and fear of overt resistance development preclude permanent prophylactic medication of risk-patients. Hence, a fast and definitive diagnosis of IPA is desirable, to quickly identify those patients that really require aggressive antimycotic treatment and to follow the course of the therapeutic intervention. However, despite decades of research into this issue, such a diagnostic procedure is still not available. Here, we discuss the array of currently available methods for IPA detection and their limits. We then show that molecular imaging using positron emission tomography (PET) combined with morphological computed tomography or magnetic imaging is highly promising to become a future non-invasive approach for IPA diagnosis and therapy monitoring, albeit still requiring thorough validation and relying on further acceptance and dissemination of the approach. Thereby, our approach using the A. fumigatus-specific humanized monoclonal antibody hJF5 labelled with 64Cu as PET-tracer has proven highly effective in pre-clinical models and hence bears high potential for human application.
When self‐prioritization crosses the senses: Crossmodal self‐prioritization demonstrated between vision and touch
2020-12-04

Abstract The investigation of self‐prioritization via a simple matching paradigm represents a new way of enhancing our knowledge about the processing of self‐relevant content and also increases our understanding of the self‐concept itself. By associating formerly neutral material with the self, and assessing the resulting prioritization of these newly formed self‐associations, conclusions can be drawn concerning the effects of self‐relevance without the burden of highly overlearned materials such as one’s own name. This approach was used to gain further insights into the structure and complexity of self‐associations: a tactile pattern was associated with the self and thereafter, the prioritization of the exact same visual pattern was assessed – enabling the investigation of crossmodal self‐associations. The results demonstrate a prioritization of self‐associated material that rapidly extends beyond the borders of a sensory modality in which it was first established.
Reactivation during sleep with incomplete reminder cues rather than complete ones stabilizes long-term memory in humans
2020-12-04

Abstract Reactivation by reminder cues labilizes memories during wakefulness, requiring reconsolidation to persist. In contrast, during sleep, cued reactivation seems to directly stabilize memories. In reconsolidation, incomplete reminders are more effective in reactivating memories than complete reminders by inducing a mismatch, i.e. a discrepancy between expected and actual events. Whether mismatch is likewise detected during sleep is unclear. Here we test whether cued reactivation during sleep is more effective for mismatch-inducing incomplete than complete reminders. We first establish that only incomplete but not complete reminders labilize memories during wakefulness. When complete or incomplete reminders are presented during 40-min sleep, both reminders are equally effective in stabilizing memories. However, when extending the retention interval for another 7 hours (following 40-min sleep), only incomplete but not complete reminders stabilize memories, regardless of the extension containing wakefulness or sleep. We propose that, during sleep, only incomplete reminders initiate long-term memory stabilization via mismatch detection.
Tissue-specific safety mechanism results in opposite protein aggregation patterns during aging
2020-12-04

Abstract During aging, proteostasis capacity declines and aggregation-prone proteins become instable, accumulating in protein aggregates both inside and outside cells. Both in disease and during aging, proteins selectively aggregate in certain tissues and not others. Yet, tissue-specific regulation of protein aggregation remains poorly understood. Surprisingly, we found that the inhibition of three core protein quality control systems, i.e. chaperones, proteasome and macroautophagy, leads to lower levels of age-dependent protein aggregation in C. elegans pharyngeal muscles, but higher levels in body-wall muscles. We describe a novel safety mechanism called SAPA that selectively targets newly synthesized aggregation-prone proteins to suppress aggregation and proteotoxicity. vha-12 and scav-3 mutants reveal that SAPA relies on macroautophagy-independent lysosomal degradation. Furthermore, SAPA involves several previously uncharacterized components of the intracellular pathogen response. We propose that SAPA represents an anti-aggregation machinery targeting aggregation-prone proteins for lysosomal degradation.