A Novel ENU-Induced

The fission and fusion of mitochondria are important processes for maintaining mitochondrial health. One of the proteins responsible for mediating mitochondrial fusion, mitofusin 2 (MFN2), has over 100 known mutations that cause Charcot–Marie–Tooth disease type 2A (CMT2A). This disease causes the nerves that control your muscles to degenerate, leading to muscle atrophy and weakness, problems walking, and other related symptoms. In this paper, we describe a mouse line with a recessive mutation in the Mfn2 gene (Leu643Pro) that causes a similar set of symptoms, including abnormal gait, weight loss, and decreased muscular endurance. However, further analysis of these mice revealed signs of skeletal muscle dysfunction (including smaller mitochondria) and bone abnormalities, with little evidence of axon degeneration typical of CMT2A. While this makes these mice a poor model for CMT2A, they are the first reported mouse line with a mutation in the transmembrane domain, a region critical for MFN2′s role in mitochondrial fusion. For this reason, we believe these mice will be a valuable tool for scientists interested in studying the biological functions of MFN2

ACMG clinical laboratory standards for next-generation sequencing

Next-generation sequencing technologies have been and continue to be deployed in clinical laboratories, enabling rapid transformations in genomic medicine. These technologies have reduced the cost of large-scale sequencing by several orders of magnitude, and continuous advances are being made. It is now feasible to analyze an individual's near-complete exome or genome to assist in the diagnosis of a wide array of clinical scenarios. Next-generation sequencing technologies are also facilitating further advances in therapeutic decision making and disease prediction for at-risk patients. However, with rapid advances come additional challenges involving the clinical validation and use of these constantly evolving technologies and platforms in clinical laboratories. To assist clinical laboratories with the validation of next-generation sequencing methods and platforms, the ongoing monitoring of next-generation sequencing testing to ensure quality results, and the interpretation and reporting of variants found using these technologies, the American College of Medical Genetics and Genomics has developed the following professional standards and guidelines

Double jeopardy:subordinates' worldviews and poor performance as predictors of abusive supervision

Purpose - To test a moderated mediation model where a positive relationship between subordinates’ perceptions of a dangerous world—the extent to which an individual views the world as a dangerous place—and supervisory abuse is mediated by their submission to authority figures, and that this relationship is heightened for more poorly performing employees. Design/Methodology/Approach - Data were obtained from 173 subordinates and 45 supervisors working in different private sector organizations in Pakistan. Findings - Our model was supported. It appears that subordinates’ dangerous worldviews are positively associated with their perceptions of abusive supervision and that this is because such views are likely to lead to greater submission to authority figures. But this is only for those employees who are performing more poorly. Implications - We highlight the possibility that individual differences (worldviews, attitudes to authority figures, and performance levels) may lead employees to become victims of abusive supervision. As such, our research informs organizations on how they may better support supervisors in managing effectively their subordinate relationships and, in particular, subordinate poor performance. Originality/Value - We add to recent work exploring subordinate-focused antecedents of abusive supervision, finding support for the salience of the previously untested constructs of individual worldviews, authoritarian submission, and individual job performance. In so doing we also extend research on dangerous worldviews into a new organizational setting. Finally, our research takes place within a new Pakistani context, adding to the burgeoning non-US based body of empirical work into the antecedents and consequences of abusive supervision

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution

A Novel ENU-Induced Mutation Causes Motor Deficits in Mice without Causing Peripheral Neuropathy

Mitochondrial fission and fusion are required for maintaining functional mitochondria. The mitofusins (MFN1 and MFN2) are known for their roles in mediating mitochondrial fusion. Recently, MFN2 has been implicated in other important cellular functions, such as mitophagy, mitochondrial motility, and coordinating endoplasmic reticulum-mitochondria communication. In humans, over 100 mutations are associated with a form of inherited peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Here we describe an ENU-induced mutant mouse line with a recessive neuromuscular phenotype. Behavioral screening showed progressive weight loss and rapid deterioration of motor function beginning at 8 weeks. Mapping and sequencing revealed a missense mutation in exon 18 of (T1928C; Leu643Pro), within the transmembrane domain. Compared to wild-type and heterozygous littermates, mice exhibited diminished rotarod performance and decreases in activity in the open field test, muscular endurance, mean mitochondrial diameter, sensory tests, mitochondrial DNA content, and MFN2 protein levels. However, tests of peripheral nerve physiology and histology were largely normal. Mutant leg bones had reduced cortical bone thickness and bone area fraction. Together, our data indicate that causes a recessive motor phenotype with mild bone and mitochondrial defects in mice. Lack of apparent nerve pathology notwithstanding, this is the first reported mouse model with a mutation in the transmembrane domain of the protein, which may be valuable for researchers studying MFN2 biology

Getting it right generally, but not precisely: learning the relation between multiple inputs and outputs

In real-world situations, people are often faced with the complex task of deciding which of many potential variables are affecting their own or others\u27 behavior, as well as noting which specific aspects of behavior are being affected. Although it is common for professionals who encounter such conditions to claim that they acquire accurate and specific knowledge from their experience, it is unclear that such confidence is justified. Using a managerial task, we examined participants\u27 ability to learn how various interventions affect various aspects of their employees\u27 performance. The results of three experiments reveal that although participants appear to avoid prescribing an intervention that has a positive effect on a primary performance measure and a negative side effect on a secondary measure, when asked directly about the impact of the intervention, they respond by reducing their judgments of its positive impact. This was true regardless of whether participants indicated clear knowledge of its negative side effect (Experiment 3) or did not (Experiments 1 and 2). Thus, participants appear to be automatically integrating across the effects on different outcome measures

ACMG clinical laboratory standards for next-generation sequencing

Next-generation sequencing technologies have been and continue to be deployed in clinical laboratories, enabling rapid transformations in genomic medicine. These technologies have reduced the cost of large-scale sequencing by several orders of magnitude, and continuous advances are being made. It is now feasible to analyze an individual's near-complete exome or genome to assist in the diagnosis of a wide array of clinical scenarios. Next-generation sequencing technologies are also facilitating further advances in therapeutic decision making and disease prediction for at-risk patients. However, with rapid advances come additional challenges involving the clinical validation and use of these constantly evolving technologies and platforms in clinical laboratories. To assist clinical laboratories with the validation of next-generation sequencing methods and platforms, the ongoing monitoring of next-generation sequencing testing to ensure quality results, and the interpretation and reporting of variants found using these technologies, the American College of Medical Genetics and Genomics has developed the following professional standards and guidelines