julilili42/papers huggingface dataset:
A flow bioreactor system compatible with real-time two-photon fluorescence lifetime imaging microscopy
2017-11-17

Bioreactors are essential cell and tissue culture tools that allow the introduction of biophysical signals into in vitro cultures. One major limitation is the need to interrupt experiments and sacrifice samples at certain time points for analyses. To address this issue, we designed a bioreactor that combines high-resolution contact-free imaging and continuous flow in a closed system that is compatible with various types of microscopes. The high throughput fluid flow bioreactor was combined with two-photon fluorescence lifetime imaging microscopy (2P-FLIM) and validated. The hydrodynamics of the bioreactor chamber were characterized using COMSOL. The simulation of shear stress indicated that the bioreactor system provides homogeneous and reproducible flow conditions. The designed bioreactor was used to investigate the effects of low shear stress on human umbilical vein endothelial cells (HUVECs). In a scratch assay, we observed decreased migration of HUVECs under shear stress conditions. Furthermore, metabolic activity shifts from glycolysis to oxidative phosphorylation-dependent mechanisms in HUVECs cultured under low shear stress conditions were detected using 2P-FLIM. Future applications for this bioreactor range from observing cell fate development in real-time to monitoring the environmental effects on cells or metabolic changes due to drug applications.
Interest in tanning beds and sunscreen in German‐speaking countries
2017-11-17

Summary Background The growing incidence of nearly all types of skin cancer can be attributed to increased exposure to natural or artificial ultraviolet (UV) radiation. However, there is a scarcity of statistical data on risk behavior or sunscreen use, which would be important for any prevention efforts. Methods Using the search engine Google ® , we analyzed search patterns for the terms Solarium (tanning bed), Sonnencreme (sunscreen), and Sonnenschutz (sun protection) in Germany, Austria, and Switzerland between 2004 and 2016, and compared it to search patterns worldwide. For this purpose, “normalized search volumes” (NSVs) were calculated for the various search queries. The corresponding polynomial functions were then compared with each other over the course of time. Results Since 2001, there has been a marked worldwide decrease in the search queries for tanning bed , whereas those for sunscreen have steadily increased. In German‐speaking countries, on the other hand, there have – for years – consistently been more search queries for tanning bed than for sunscreen . There is an annual periodicity of the queries, with the highest NSVs for tanning bed between March and May and those for sunscreen in the summer months around June. In Germany, the city‐states of Hamburg and Berlin have particularly high NSVs for tanning bed . Conclusions Compared to the rest of the world, German‐speaking countries show a strikingly unfavorable search pattern. There is still great need for education and prevention with respect to sunscreen use and avoidance of artificial UV exposure.
Germline Genome Editing and the Functions of Consent
2017-11-17

Recent advances in the area of genome editing with tools such as CRISPR are generating a controversial discussion whether clinical research on human germline interventions should ever be endorsed (...
Correction for Ebner et al., “Excreted Cytoplasmic Proteins Contribute to Pathogenicity in Staphylococcus aureus”
2017-11-17

Volume 84, no. 6, p. 1672–1681, 2016, [https://doi.org/10.1128/IAI.00138-16][1]. Page 1678: Figure 5C, left panel, should appear as shown below. In the original figure, an unspecified smear was removed from the background, which was inappropriate. ![Figure][2] [1]: /lookup/doi/10.1128/IAI
(E)-1-(Pyridin-4-yl)propan-1-oneO-tosyl oxime
2017-11-17

The title compound, C 15 H 16 N 2 O 3 S, was obtained by the reaction of ( E )-1-(pyridin-4-yl)propan-1-one oxime and para -toluenesulfonic acid. The pyridine ring makes a dihedral angle of 54.70 (10)° with the benzene ring. In the crystal, molecules are linked by C—H...O hydrogen bonds, forming a chain along the c -axis direction.
Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach
2017-11-19

Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel β 1 (CNGB1) cause approximately 4% of autosomal recessive RP. Gene augmentation therapy shows promise for treating inherited retinal degenerations; however, relevant animal models and biomarkers of progression in patients with RP are needed to assess therapeutic outcomes. Here, we evaluated RP patients with CNGB1 mutations for potential biomarkers of progression and compared human phenotypes with those of mouse and dog models of the disease. Additionally, we used gene augmentation therapy in a CNGβ1-deficient dog model to evaluate potential translation to patients. CNGB1-deficient RP patients and mouse and dog models had a similar phenotype characterized by early loss of rod function and slow rod photoreceptor loss with a secondary decline in cone function. Advanced imaging showed promise for evaluating RP progression in human patients, and gene augmentation using adeno-associated virus vectors robustly sustained the rescue of rod function and preserved retinal structure in the dog model. Together, our results reveal an early loss of rod function in CNGB1-deficient patients and a wide window for therapeutic intervention. Moreover, the identification of potential biomarkers of outcome measures, availability of relevant animal models, and robust functional rescue from gene augmentation therapy support future work to move CNGB1-RP therapies toward clinical trials.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update
2017-11-20

The purpose of this guideline is to provide information for the interpretation of clinical dihydropyrimidine dehydrogenase ( DPYD ) genotype tests so that the results can be used to guide dosing of fluoropyrimidines (5‐fluorouracil and capecitabine). Detailed guidelines for the use of fluoropyrimidines, their clinical pharmacology, as well as analyses of cost‐effectiveness are beyond the scope of this document. The Clinical Pharmacogenetics Implementation Consortium (CPIC ® ) guidelines consider the situation of patients for which genotype data are already available (updates available at https://cpicpgx.org/guidelines/guideline‐for‐fluoropyrimidines‐and‐dpyd/ ).
Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer’s disease
2017-11-20

Significance The clinical and pathological variability among patients with Alzheimer’s disease (AD) remains largely unexplained. Evidence is growing that this heterogeneity may be influenced by the heterogeneous molecular architecture of misfolded amyloid-β peptide (Aβ) in the brain. To test this hypothesis, we used unique fluorescent ligands to interrogate the molecular structure of Aβ in amyloid plaques from patients who had died with etiologically distinct subtypes of AD. We found that Aβ-amyloid plaques in the brain cluster as clouds of conformational variants that differ among certain subtypes of AD. The conformational features of AD plaques were partially transmissible to transgenic mice in a seeding paradigm, suggesting a mechanism whereby different molecular strains of Aβ propagate their features within the brain.
How does “not left” become “right”? Electrophysiological evidence for a dynamic conflict-bound negation processing account.
2017-11-20

Human thought and language is traditionally considered as abstract, amodal, and symbolic. However, recent theories propose that high-level human cognition is directly linked to basic, modal biological systems such as sensorimotor areas. Despite this influential representational debate very little is known regarding whether the mechanisms involved in sensorimotor control are also shared with higher-level cognitive processes, such as language comprehension. We investigated negation as a universal of human language, addressing two key questions: (a) Does negation result in a conflict-like representation? (b) Does negation trigger executive control adjustments in a similar manner as standard information processing conflicts do (e.g., Simon, Flanker)? Electrophysiological data indicated that phrases such as "not left/not right" result in initial activation of the to-be-negated information and subsequently the outcome of the negation process. More importantly, our findings also suggest that negation triggers conflict-related adjustments in information processing in line with traditional conflict tasks. Trial-by-trial conflict adaptation patterns in both behavioral and electrophysiological data indicated that negation processing dynamically changes depending on the current cognitive state. In summary, negation processing results in cognitive conflict, and dynamic influences of the cognitive state determine conflict resolution, that is, negation implementation. (PsycINFO Database Record
Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice
2017-11-20

Nonalcoholic fatty liver disease (NAFLD) contributes to the pathogenesis of type 2 diabetes and cardiovascular disease, and patients with nonalcoholic steatohepatitis (NASH) are also at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. To date, no specific therapy exists for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the twenty‐first century. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of energy homeostasis and NAFLD progression. Here, we investigated the effect of antisense oligonucleotides (ASOs) targeting Stk25 on the metabolic and molecular phenotype of mice after chronic exposure to dietary lipids. We found that Stk25 ASOs efficiently reversed high‐fat diet‐induced systemic hyperglycemia and hyperinsulinemia, improved whole‐body glucose tolerance and insulin sensitivity, and ameliorated liver steatosis, inflammatory infiltration, apoptosis, hepatic stellate cell activation, and nutritional fibrosis in obese mice. Moreover, Stk25 ASOs suppressed the abundance of liver acetyl‐coenzyme A carboxylase (ACC) protein, a key regulator of both lipid oxidation and synthesis, revealing the likely mechanism underlying repression of hepatic fat accumulation by ASO treatment. We also found that STK25 protein levels correlate significantly and positively with NASH development in human liver biopsies, and several common nonlinked single‐nucleotide polymorphisms in the human STK25 gene are associated with altered liver fat, supporting a critical role of STK25 in the pathogenesis of NAFLD in humans. Conclusion : Preclinical validation for the metabolic benefit of pharmacologically inhibiting STK25 in the context of obesity is provided. Therapeutic intervention aimed at reducing STK25 function may provide a new strategy for the treatment of patients with NAFLD, type 2 diabetes, and related complex metabolic diseases. ( Hepatology Communications 2018;2:69–83)
Akt1 Stimulates Homologous Recombination Repair of DNA Double-Strand Breaks in a Rad51-Dependent Manner
2017-11-20

Akt1 is known to promote non-homologous end-joining (NHEJ)-mediated DNA double-strand break (DSB) repair by stimulation of DNA-PKcs. In the present study, we investigated the effect of Akt1 on homologous recombination (HR)-dependent repair of radiation-induced DSBs in non-small cell lung cancer (NSCLC) cells A549 and H460. Akt1-knockdown (Akt1-KD) significantly reduced Rad51 protein level, Rad51 foci formation and its colocalization with γH2AX foci after irradiation. Moreover, Akt1-KD decreased clonogenicity after treatment with Mitomycin C and HR repair, as tested by an HR-reporter assay. Double knockdown of Akt1 and Rad51 did not lead to a further decrease in HR compared to the single knockdown of Rad51. Consequently, Akt1-KD significantly increased the number of residual DSBs after irradiation partially independent of the kinase activity of DNA-PKcs. Likewise, the number of residual BRCA1 foci, indicating unsuccessful HR events, also significantly increased in the irradiated cells after Akt1-KD. Together, the results of the study indicate that Akt1 seems to be a regulatory component in the HR repair of DSBs in a Rad51-dependent manner. Thus, based on this novel role of Akt1 in HR and the previously described role of Akt1 in NHEJ, we propose that targeting Akt1 could be an effective approach to selectively improve the killing of tumor cells by DSB-inducing cytotoxic agents, such as ionizing radiation.
Once bitten, less shy? The influence of prior misappropriation experience on R&D collaboration
2017-11-20

Firms often face the challenge of collaborating for innovation and protecting themselves from misappropriation. Given this tension, we investigate the relationship between prior misappropriation of protected and unprotected intellectual property (IP) and R&amp;D collaboration. We combine more than 600 firm observations from the German Community Innovation Survey with patent data and qualitative interview data. Our results consistently point to (1) less subsequent R&amp;D collaboration after being copied (misappropriation of unprotected IP) and (2) more subsequent R&amp;D collaboration after being infringed (misappropriation of protected IP) in the following three years. Moreover, we find indication that firms that are copied start to collaborate more during the subsequent period (four to six years later). Our study adds to a better understanding of the tension between appropriating innovation rents and remaining open to R&amp;D collaboration. Further, we provide insights on how firms strategically leverage previous misappropriation experience to create value.
Ensuring Consistent European-Wide Urological Care by the Use of Evidence-Based Clinical Practice Guidelines: Can We Do Better
2017-11-20

The European Association of Urology (EAU) annually updates 21 clinical practice guidelines in which summaries of the evidence base and best practice recommendations are made. The methodology applied to achieve this and integrate stakeholder opinion is continuously improving. However, there is evidence to suggest wide variation in clinical practice indicating that many patients receive suboptimal and heterogeneous care. Studies from certain countries suggest that 2 out of 5 patients do not receive care according to the current scientific evidence, and in 1 out of 4 cases the care provided is potentially harmful. Clearly, the harmonisation of care in alignment with evidence-based best practice recommendations is something to strive for. Development of robust methods to disseminate and implement guideline recommendations and measure their impact is an objective the EAU is committed to improving. An important strategy for achieving harmonisation in urological care across Europe is to ensure the availability of high-quality clinical practice guidelines and to actively promote their implementation by clinicians and healthcare providers.
Constrained optimization for position calibration of an NMR field camera
2017-11-20

Purpose Knowledge of the positions of field probes in an NMR field camera is necessary for monitoring the B 0 field. The typical method of estimating these positions is by switching the gradients with known strengths and calculating the positions using the phases of the FIDs. We investigated improving the accuracy of estimating the probe positions and analyzed the effect of inaccurate estimations on field monitoring. Methods The field probe positions were estimated by 1) assuming ideal gradient fields, 2) using measured gradient fields (including nonlinearities), and 3) using measured gradient fields with relative position constraints. The fields measured with the NMR field camera were compared to fields acquired using a dual‐echo gradient recalled echo B 0 mapping sequence. Comparisons were done for shim fields from second‐ to fourth‐order shim terms. Results The position estimation was the most accurate when relative position constraints were used in conjunction with measured (nonlinear) gradient fields. The effect of more accurate position estimates was seen when compared to fields measured using a B 0 mapping sequence (up to 10%–15% more accurate for some shim fields). The models acquired from the field camera are sensitive to noise due to the low number of spatial sample points. Conclusion Position estimation of field probes in an NMR camera can be improved using relative position constraints and nonlinear gradient fields. Magn Reson Med 80:380–390, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
Rods progressively escape saturation to drive visual responses in daylight conditions
2017-11-21

Abstract Rod and cone photoreceptors support vision across large light intensity ranges. Rods, active under dim illumination, are thought to saturate at higher (photopic) irradiances. The extent of rod saturation is not well defined; some studies report rod activity well into the photopic range. Using electrophysiological recordings from retina and dorsal lateral geniculate nucleus of cone-deficient and visually intact mice, we describe stimulus and physiological factors that influence photopic rod-driven responses. We find that rod contrast sensitivity is initially strongly reduced at high irradiances, but progressively recovers to allow responses to moderate contrast stimuli. Surprisingly, rods recover faster at higher light levels. A model of rod phototransduction suggests that phototransduction gain adjustments and bleaching adaptation underlie rod recovery. Consistently, exogenous chromophore reduces rod responses at bright background. Thus, bleaching adaptation renders mouse rods responsive to modest contrast at any irradiance. Paradoxically, raising irradiance across the photopic range increases the robustness of rod responses.
The prognostic value of physiological and physical characteristics in youth soccer: A systematic review
2017-11-21

Abstract Talent identification and selection in soccer is typically based on subjective evaluations of experienced coaches. Recently, there has been a trend to complement these subjective assessments with objective tests. However, there is currently no comprehensive overview of the prognostic relevance of objective measurements in youth soccer. Therefore, the primary purpose of the current study was to systematically review published empirical studies related to the prognostic relevance of physiological (e.g. endurance and speed) and physical characteristics (i.e. height and weight). Of 6876 initially identified studies, nine articles were included. In those studies, endurance (nine studies), change of direction (seven), height (seven), and weight (seven) received the most meaningful consideration within the literature. In regard to physiological predictors, between 16 and 29 effect sizes were tested for endurance, sprint, and change of direction, and about half of them were found to be significant with small to moderate effects (0.37 ≤ Mdn(d) ≤ 0.57). In addition, while only investigated in two studies all tested effect sizes for repeated sprint ability were found to be significant. Despite their frequent consideration in the literature, low numbers of significant effect sizes (≤ 26%) and magnitude (0.23 ≤ Mdn( d ) ≤ 0.29) were found for the physical predictors height and weight. Overall, results appear to be dependent on the respective study design and, in particular, moderator variables (i.e. soccer development stage, performance level T1/T2, prognostic period, and sample size). Consequently, additional research seems warranted to more comprehensively investigate the predictive relevance of the individual characteristics using more homogeneous study designs.
Competency-based teacher training: A systematic revision of a proven programme in medical didactics
2017-11-21

Objectives: Competency-based medical education (CBME) requires factual knowledge to be practically applied together with skills and attitudes. With the National Competence-Based Learning Objectives for Undergraduate Medical Education (NKLM) representing a strong official demand for competence-orientation, it is generally important to explicitly outline its characteristics and review its realisation in teacher trainings. Further requirements are given by the core competencies for medical teachers (KLM). As an example the MQ programme (“Medizindidaktische Qualifikation”) in Baden-Wuerttemberg, a long established and well-accepted training, has been critically revised on this basis, concerning its suitability for the demands of CBME, its needs for adjustment and the efforts to be undertaken for its implementation. Methods: In a systematic quality management process the MQ curriculum and its organisational framing were analysed and further developed in a step-wise comprehensive approach, using the six-step cycle by Kern. The procedures included a thorough needs assessment (e.g. literature research, programme mapping), strategic decisions on structure and content, piloting and evaluation. During the process essential elements of project and change management were considered. Results: The experiences of the MQ example revealed helpful information for key factors to be considered in the pending change process any training provider will be confronted with. Guiding questions were developed related to the process phases. Our analyses showed persistent key points of proven value as stable foundation for change, as well as components needing special consideration to foster competence-oriented aims and transfer into practice: reflection, feedback, application-oriented methods and transparent competence development. These aspects have to be consciously perceived and experienced by participants. Taking this into account, we re-designed the course evidence-based. Besides visualising competencies and their progress, the occasions for reflection and feedback as well as the number of typical, practice-oriented tasks were extended to facilitate self-directed learning, critical self-reflection and individualised solutions. It is shown at what point, in what form and with which purpose these aspects were integrated in the MQ programme. Piloting showed good acceptance by participants, trainers. Preliminary assessment of the outcome is promising. Conclusion: Respecting the high workload, most likely medical teachers will not put CBME concepts into practice without impulses and support. Therefore, in didactical trainings, medical teachers should practice in a competency-based teaching setting and reflect themselves in different professional roles to be able to transfer the experiences to their own educational approach. Trainers and training can serve as models for CBME realisation.
Circulations beyond nodes: (in)securities along the pipeline
2017-11-21

In this article, I draw attention to the way that critical security scholars have privileged governing nodes in their accounts of circulation and have consequently overlooked practices of security that are conducted between these nodal sites. As a result, the potential and actual mobilities of circulating entities (and their implications for security) have also been viewed within nodes. This has resulted in circulation being effectively reduced to lines between two or more points. I consequently call for security researchers to attend better to entities’ journeys. I use the case of natural gas’s movements within UK pipelines to demonstrate how such movements are productive of a variety of forms of (in)security and, in the process, highlight the role that the mobilities literature can play in bringing about a shift towards a broadened account of circulatory security.