关键词： Developmental toxicity   Teratogen   Dictyostelium discoideum   Nonanimal model   social amoeba   genetics   high throughput  

摘要： A critical aspect of toxicity evaluation is developmental and reproductive toxicity (DART) testing. Traditionally, DART testing has been conducted in vivo in mammalian model systems. New legislation aimed at reducing animal use and the prohibitive costs associated with DART testing, together with a need to understand the genetic pathways underlying developmental toxicity means there is a growing demand for alternative model systems for toxicity evaluation. Here we explore the potential of the eukaryotic social amoeba Dictyostelium discoideum, which is already widely used as a simple model system for cell and developmental biology, as a potential nonanimal model for DART testing. We developed assays for high-throughput screening of toxicity during D. discoideum growth and development. This allowed the toxicity of a broad range of test compounds to be characterized, which revealed that D. discoideum can broadly predict mammalian toxicity. In addition, we show that this system can be used to perform functional genomic screens to compare the molecular modes of action of different compounds. For example, genome-wide screens for mutations that affect lithium and valproic acid toxicity allowed common and unique biological targets and molecular processes mediating their toxicity to be identified. These studies illustrate that D. discoideum could represent a predictive nonanimal model for DART testing due to its amenability to high-throughput approaches and molecular genetic tractability.

摘要： The value of structured development processes has been recognized and implemented in formal physician training programs such as residencies and fellowships. Physicians are seemingly viewed as a "finished product" upon completing formal training. In recent years, a number of academic medical centers have implemented formalized early-career development programs for physicians, largely those who have a major research focus. However, beyond the early stage of physicians' careers, formalized and intentional physician career development programs are rare. The lack of a philosophy of intentional, career-long individual development at academic medical centers reflects a narrow understanding of the implicit contract between employers and employees. The resulting gap leads the vast majority of physicians to fall short of their potential, further leading to long-term loss for the academic medical centers, their physicians, and society as a whole. Based on the framework of analyze-design-develop-implement-evaluate, the authors propose a robust, iterative model for physician career development that goes beyond skills and knowledge maintenance toward leveraging a broad range of individual capabilities, needs, and contexts along the career lifespan. The model provides a means for harnessing physicians' strengths and passions in concert with the needs of their organization to create greater physician fulfillment and success, which in turn would benefit the patients they care for and the academic medical centers in which they work.

关键词： Classification   Diagnostic systems   Psychiatry   Psychosis   Schizophrenia  

摘要： Standard diagnostic systems, the predominantly categorical DSM-5 and ICD-11, have limitations in validity, utility, and predictive and descriptive power. For psychotic disorders, these issues were partly addressed in current versions, but additional modifications are thought to be needed. Changes should be evidence based. We reviewed categorical, modified-categorical, and continuum-based models versus factor-based models of psychosis. Factors are clusters of symptoms or single prominent aspects of illness. Consistent evidence from studies of the genetics, pathobiology, and clinical presentation of psychotic disorders all support an underlying structure of factors, not categories, as best characterizing psychoses. Factors are not only the best fit but also comprehensive, as they can encompass any key feature of illness, including symptoms and course, as well as determinants of risk or response. Factors are inherently dimensional, even multidimensional, as are the psychoses themselves, and they provide the detail needed for either grouping or distinguishing patients for treatment decisions. The tools for making factor-based diagnoses are available, reliable, and concordant with actual practices used for clinical assessments. If needed, factors can be employed to create categories similar to those in current use. In addition, they can be used to define unique groupings of patients relevant to specific treatments or studies of the psychoses. Lastly, factor-based classifications are concordant with other comprehensive approaches to psychiatric nosology, including personalized (precision treatment) models and hierarchical models, both of which are currently being explored. Factors might be considered as the right primary structural choice for future versions of standard diagnostic systems, both DSM and ICD. (C) 2021 S. Karger AG, Basel

关键词： Left atrial indexation   Body surface area   Obesity   Allometric indexation   Isometric indexation  

摘要： Background: Left atrial (LA) size indexed to body surface area (BSA) is a clinically important marker of cardiovascular prognosis. However, indexation using a scaling variable such as BSA has inherent flaws, particularly in an obese population. The aim of this study was to determine whether alternative indexation methods may more accurately scale for LA size. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used to execute a structured search of medical databases, to identify articles discussing alternative methods of LA indexation in echocardiography. Articles that stratified indexed LA size by obesity class were also included. Two independent reviewers identified relevant articles and extracted baseline characteristics, alternative indexation methods, scaling variables, obesity class characteristics, and correlation coefficients. Results: A total of 3,804 articles were found in the database search after removing duplicates. After abstract and full-text screening, 13 relevant articles were identified. Twelve studies used alternative methods of LA indexation, of which nine reported allometric indices. Seven of the included studies reported LA size by obesity class, of which six reported alternative indices. Correlation coefficients plotted for indexed LA size against absolute measured LA size showed that allometric indices (specifically to height) were more likely to maintain proportionality to body size compared with isometric indices such as BSA. Allometric indices were less likely to overcorrect for body size compared with isometric indices. Conclusions: Compared with isometric indexation to BSA, allometric indexation (specifically to height) improves scaling of LA volumes to maintain proportionality and avoid overcorrection for body size.

关键词： nomograms   erectile dysfunction   prostatectomy  

摘要： Purpose: Prediction of potency recovery following robot-assisted radical prostatectomy (RARP) is useful for better patient counseling and postoperative treatment strategies. In this study we propose a preoperative and postoperative nomogram to predict postoperative potency recovery following RARP. Materials and Methods: Patients from development set (6,502) were selected to develop the nomograms, and patients in validation set (2,706) were used for validation. Cox regression models were fitted on the development cohort to predict potency recovery after RARP using as prognostic factors the covariates selected. Two nomograms were drawn using the regression coefficients of the preoperative and postoperative Cox models. Results: The discrimination ability of the preoperative model was evaluated on the development cohort using the receiver operator curves estimated at 3, 6, 12 and 24 months. The AUC at these time points was 0.726, 0.734, 0.754, and 0.778, respectively. The areas under the curve of the postoperative model at 3, 6, 12 and 24 months were 0.746, 0.756 and 0.777, and 0.801, respectively. Preoperative and postoperative predictive models were validated using a separate set of 2,706 patients. The AUCs of the preoperative model at 3, 6, 12 and 24 months were 0.789, 0.772, 0.768, and 0.778, respectively. The ROC curves of the postoperative model at 3, 6, 12 and 24 months with AUCs of 0.807, 0.797, 0.793 and 0.798, respectively. Along with age and preoperative sexual function, nerve-sparing technique determines the potency outcomes justifying better AUC for postoperative model vs the preoperative model. Conclusions: The above nomograms help us to predict with good accuracy the probability of potency recovery within 3, 6, 12 and 24 months following surgery taking into consideration preoperative and postoperative factors. This is a novel tool for the care giver to predict realistic expectation of potency outcomes to the patients, while preoperative and immediate post

关键词： ASDEX Upgrade   In-vessel coil   Snow-flake divertor  

摘要： ASDEX Upgrade (AUG) is the experimental tokamak based in Germany that since many years, 1991, explores technical solutions to address physic aspects. This time, the aim is to prove that alternative divertor configurations (X-divertor or Snowflake divertor) can mitigate the power exhaust problem, in a machine with high heating power like AUG. To realize the required magnetic configurations [2], two poloidal field coils are required in the divertor region. The upgrade in AUG will be carried out in the upper divertor and the following components will be newly designed and installed in the next years: cryopump, inner and outer divertors and finally two divertor coils [4]. In the design phase, many challenges were faced: 1) Manufacturing and qualification of a conductor able to safely operate the coils [6];2) Implementation of the new components in a tight room, maintaining the plasma volume and the present plasma configurations;3) Implementation of the divertor coils close to the strike line. The design has reached a certain level of maturity and a prototyping phase has been started. The installation of the component is planned for 2022 and at that time AUG will be the first tokamak having in-situ winded coils. The components design is based on the experience gained in years of AUG operation, which allowed for the building up of an extensive database to get the input parameters for the FEM analyses. Induced and halo currents interacting with the static toroidal field are the main source of loads in the structure. Different electromagnetic models were prepared to address the problem together with their corresponding mechanical models. The design has been iteratively changing according to the results of the FEM analyses. The paper will present the design of the upper divertor components and the analyses carried out to verify their mechanical integrity.

关键词： Helicobacter pylori   antibiotic resistance   alternative therapy   nanoformulations  

摘要： The prevalence of Helicobacter pylori infection remains significant worldwide and it depends on many factors: gender, age, socio-economic status, geographic area, diet, and lifestyle. All successful infectious diseases treatments use antibiotic-susceptibility testing, but this strategy is not currently practical for H. pylori and the usual cure rates of H. pylori are lower than other bacterial infections. Actually, there is no treatment that ensures complete eradication of this pathogen. In the context of an alarming increase in resistance to antibiotics (especially to clarithromycin and metronidazole), alternative and complementary options and strategies are taken into consideration. As the success of antibacterial therapy depends not only on the susceptibility to given drugs, but also on the specific doses, formulations, use of adjuvants, treatment duration, and reinfection rates, this review discusses the current therapies for H. pylori treatment along with their advantages and limitations. As an alternative option, this work offers an extensively referenced approach on natural medicines against H. pylori, including the significance of nanotechnology in developing new strategies for treatment of H. pylori infection.

关键词： adaptive divergence   alternative splicing   convergent evolution   ecological speciation   gene expression   parallel evolution   salmonid  

摘要： Understanding the contribution of different molecular processes to evolution and development is crucial for identifying the mechanisms of adaptation. Here, we used RNA-sequencing data to test the importance of alternative splicing and differential gene expression in a case of parallel adaptive evolution, the replicated postglacial divergence of the salmonid fish Arctic charr (Salvelinus alpinus) into sympatric benthic and pelagic ecotypes across multiple independent lakes. We found that genes differentially spliced between ecotypes were mostly not differentially expressed (<6% overlap) and were involved in different biological processes. Differentially spliced genes were primarily enriched for muscle development and functioning, while differentially expressed genes were involved in metabolism, immunity and growth. Furthermore, alternative splicing and gene expression were mostly controlled by independent cis-regulatory quantitative trait loci (<3.4% overlap). Cis-regulatory regions were associated with the parallel divergence in splicing (16.5% of intron clusters) and expression (6.7%-10.1% of differentially expressed genes), indicating shared regulatory variation across ecotype pairs. Contrary to theoretical expectation, we found that differentially spliced genes tended to be highly central in regulatory networks ("hub genes") and were annotated to significantly more gene ontology terms compared to nondifferentially spliced genes, consistent with a higher level of pleiotropy. Together, our results suggest that the concerted regulation of alternative splicing and differential gene expression through different regulatory regions leads to the divergence of complementary processes important for local adaptation. This provides novel insights into the importance of contrasting but putatively complementary molecular processes in rapid parallel adaptive evolution.

关键词： Hydrogen   Solid oxide electrolysis cell   High temperature electrolysis   Electrolyte   Hydrogen electrode   Oxygen electrode   Intermediate layer   Interconnector  

摘要： Solid oxide electrolysis cell is the leading technology for production of green hydrogen by high temperature electrolysis. However, optimization of existing reference materials constituting the cell and development of innovative materials remain critical for solid oxide electrolysis cell. In particular, they are key to reach performance and durability targets compatible with a commercialization for the three main markets identified as follows: large-scale H2 production, Power-to-X and Power-to-Power. This short review summarizes the latest progress in research and development of alternative and innovative materials for solid oxide electrolysis cells, with a main focus on cathode-supported cell materials. A brief description of the layers constituting the solid oxide electrolysis cell is provided, with the associated current state-of-the-art materials. A further emphasis on the most promising alternative and innovative materials for each layer follows based on the major aspects from an industrial perspective to reach a competitive hydrogen production cost for the main targeted markets: performance, durability, scaling up/manufacturing ability and operational flexibility.

摘要： Alternative polyadenylation (APA) is a major mechanism of post-transcriptional regulation in various cellular processes including cell proliferation and differentiation, but the APA heterogeneity among single cells remains largely unknown. Single-cell RNA sequencing (scRNA-seq) has been extensively used to define cell subpopulations at the transcription level. Yet, most scRNA-seq data have not been analyzed in an "APA-aware" manner. Here, we introduce dynamic analysis of APA from single-cell RNA-seq (scDaPars), a bioinformatics algorithm to accurately quantify APA events at both single-cell and single-gene resolution using either 3 '-end (10x Chromium) or full-length (Smart-seq2) scRNA-seq data. Validations in both real and simulated data indicate that scDaPars can robustly recover missing APA events caused by the low amounts of mRNA sequenced in single cells. When applied to cancer and human endoderm differentiation data, scDaPars not only revealed cell-type-specific APA regulation but also identified cell subpopulations that are otherwise invisible to conventional gene expression analysis. Thus, scDaPars will enable us to understand cellular heterogeneity at the post-transcriptional APA level.