The Musashi-2 (Msi2) RNA-binding protein maintains stem cell self-renewal and promotes oncogenesis by enhancing cell proliferation in hematopoietic and gastrointestinal tissues. However, it is ...unclear how Msi2 recognizes and regulates mRNA targets in vivo and whether Msi2 primarily controls cell growth in all cell types. Here we identified Msi2 targets with HITS-CLIP and revealed that Msi2 primarily recognizes mRNA 3'UTRs at sites enriched in multiple copies of UAG motifs in epithelial progenitor cells. RNA-seq and ribosome profiling demonstrated that Msi2 promotes targeted mRNA decay without affecting translation efficiency. Unexpectedly, the most prominent Msi2 targets identified are key regulators that govern cell motility with a high enrichment in focal adhesion and extracellular matrix-receptor interaction, in addition to regulators of cell growth and survival. Loss of Msi2 stimulates epithelial cell migration, increases the number of focal adhesions and also compromises cell growth. These findings provide new insights into the molecular mechanisms of Msi2's recognition and repression of targets and uncover a key function of Msi2 in restricting epithelial cell migration.
The protein complexes of the mitochondrial electron transport chain exist in isolation and in higher order assemblies termed supercomplexes (SCs) or respirasomes (SC I+III
+IV). The association of ...complexes I, III and IV into the respirasome is regulated by unknown mechanisms. Here, we designed a nanoluciferase complementation reporter for complex III and IV proximity to determine in vivo respirasome levels. In a chemical screen, we found that inhibitors of the de novo pyrimidine synthesis enzyme dihydroorotate dehydrogenase (DHODH) potently increased respirasome assembly and activity. By-passing DHODH inhibition via uridine supplementation decreases SC assembly by altering mitochondrial phospholipid composition, specifically elevated peroxisomal-derived ether phospholipids. Cell growth rates upon DHODH inhibition depend on ether lipid synthesis and SC assembly. These data reveal that nucleotide pools signal to peroxisomes to modulate synthesis and transport of ether phospholipids to mitochondria for SC assembly, which are necessary for optimal cell growth in conditions of nucleotide limitation.
BACKGROUND:Operating rooms are identified as being one of the noisiest of clinical environments, and intraoperative noise is associated with adverse effects on staff and patient safety. ...Simulation-based experiments would offer controllable and safe venues for investigating this noise problem. However, realistic simulation of the clinical auditory environment is rare in current simulators. Therefore, we retrofitted our operating room simulator to be able to produce immersive auditory simulations with the use of typical sound sources encountered during surgeries. Then, we tested the hypothesis that anesthesia residents would perceive greater task load and fatigue while being given simulated lunch breaks in noisy environments rather than in quiet ones. As a secondary objective, we proposed and tested the plausibility of a novel psychometric instrument for the assessment of stress.
METHODS:In this simulation-based, randomized, repeated-measures, crossover study, 2 validated psychometric survey instruments, the NASA Task Load Index (NASA-TLX), composed of 6 items, and the Swedish Occupational Fatigue Inventory (SOFI), composed of 5 items, were used to assess perceived task load and fatigue, respectively, in first-year anesthesia residents. Residents completed the psychometric instruments after being given lunch breaks in quiet and noisy intraoperative environments (soundscapes). The effects of soundscape grouping on the psychometric instruments and their comprising items were analyzed with a split-plot analysis. A model for a new psychometric instrument for measuring stress that combines the NASA-TLX and SOFI instruments was proposed, and a factor analysis was performed on the collected data to determine the model’s plausibility.
RESULTS:Twenty residents participated in this study. Multivariate analysis of variance showed an effect of soundscape grouping on the combined NASA-TLX and SOFI instrument items (P = 0.003) and the comparisons of univariate item reached significance for the NASA Temporal Demand item (P = 0.0004) and the SOFI Lack of Energy item (P = 0.001). Factor analysis extracted 4 factors, which were assigned the following construct names for model developmentPsychological Task Load, Psychological Fatigue, Acute Physical Load, and Performance-Chronic Physical Load. Six of the 7 fit tests used in the partial confirmatory factor analysis were positive when we fitted the data to the proposed model, suggesting that further validation is warranted.
CONCLUSIONS:This study provides evidence that noise during surgery can increase feelings of stress, as measured by perceived task load and fatigue levels, in anesthesiologists and adds to the growing literature pointing to an overall adverse impact of clinical noise on caregivers and patient safety. The psychometric model proposed in this study for assessing perceived stress is plausible based on factor analysis and will be useful for characterizing the impact of the clinical environment on subject stress levels in future investigations.
Mitochondrial dysfunction can increase oxidative stress and extend lifespan in Caenorhabditis elegans. Homeostatic mechanisms exist to cope with disruptions to mitochondrial function that promote ...cellular health and organismal longevity. Previously, we determined that decreased expression of the cytosolic pentose phosphate pathway (PPP) enzyme transaldolase activates the mitochondrial unfolded protein response (UPRmt) and extends lifespan. Here we report that transaldolase (tald-1) deficiency impairs mitochondrial function in vivo, as evidenced by altered mitochondrial morphology, decreased respiration, and increased cellular H2O2 levels. Lifespan extension from knockdown of tald-1 is associated with an oxidative stress response involving p38 and c-Jun N-terminal kinase (JNK) MAPKs and a starvation-like response regulated by the transcription factor EB (TFEB) homolog HLH-30. The latter response promotes autophagy and increases expression of the flavin-containing monooxygenase 2 (fmo-2). We conclude that cytosolic redox established through the PPP is a key regulator of mitochondrial function and defines a new mechanism for mitochondrial regulation of longevity.
Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these ...changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis. Mice overexpressing hepatic MIC19 show resistance to diet-induced obesity and improved glucose homeostasis. Interestingly, MIC19 overexpressing mice exhibit elevated energy expenditure and increased pedestrian locomotion. Metabolite profiling revealed that uracil accumulates in the livers of these mice due to increased uridine phosphorylase UPP2 activity. Furthermore, uracil-supplemented diet increases locomotion in wild-type mice. Thus, MIC19-induced mitochondrial cristae formation in the liver increases uracil as a signal to promote locomotion, with protective effects against diet-induced obesity.
•Cerebral visual impairment (CVI) is the most common individual cause of pediatric visual impairment and blindness in developed countries.•Large gaps remain in our understanding of brain ...reorganization in CVI compared to the case of ocular based blindness.•Paradigms utilizing virtual reality may characterize visual deficits in an ecologically valid and clinically meaningful manner.•Advanced structural and functional neuroimaging approaches highlight key differences in the neural correlates associated CVI compared to ocular blindness.
Cerebral visual impairment (CVI) results from perinatal injury to visual processing structures and pathways and is the most common individual cause of pediatric visual impairment and blindness in developed countries. While there is mounting evidence demonstrating extensive neuroplastic reorganization in early onset, profound ocular blindness, how the brain reorganizes in the setting of congenital damage to cerebral (i.e. retro-geniculate) visual pathways remains comparatively poorly understood. Individuals with CVI exhibit a wide range of visual deficits and, in particular, present with impairments of higher order visual spatial processing (referred to as “dorsal stream dysfunction”) as well as object recognition (associated with processing along the ventral stream). In this review, we discuss the need for ongoing work to develop novel, neuroscience-inspired approaches to investigate functional visual deficits in this population. We also outline the role played by advanced structural and functional neuroimaging in helping to elucidate the underlying neurophysiology of CVI, and highlight key differences with regard to patterns of neural reorganization previously described in ocular blindness.
Background
The purpose of this study was to complete a comprehensive analysis of gender differences in faculty rank among U.S. emergency physicians that reflected all academic emergency physicians.
...Methods
We assembled a comprehensive list of academic emergency medicine (EM) physicians with U.S. medical school faculty appointments from Doximity.com linked to detailed information on physician gender, age, years since residency completion, scientific authorship, National Institutes of Health (NIH) research funding, and participation in clinical trials. To estimate gender differences in faculty rank, multivariable logistic regression models were used that adjusted for these factors.
Results
Our study included 3,600 academic physicians (28%, or 1,016, female). Female emergency physicians were younger than their male colleagues (mean ±SD age was 43.8 ±8.7 years for females and 47.4 ±9.9 years for males p < 0.001), had fewer years since residency completion (12.4 years vs. 15.6 years, p < 0.001), had fewer total and first/last author publications (4.7 vs. 8.6 total publications, p < 0.001; 4.3 vs. 7.1 first or last author publications, p < 0.001), and were less likely to be principal investigators on NIH grants (1.2% vs. 2.9%, p = 0.002) or clinical trials (1.8% vs. 4.4%, p < 0.001). In unadjusted analysis, male physicians were more likely than female physicians to hold the rank of associate or full professor versus assistant professor (13.7 percentage point difference, p < 0.001), a relationship that persisted after multivariable adjustment (5.5 percentage point difference, p = 0.001).
Conclusions
Female academic EM physicians are less likely to hold the rank of associate or full professor compared to male physicians even after detailed adjustment for other factors that may influence faculty rank.
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•A monitoring system for the in-process study of the welding conditions is presented.•A methodology to extract the physical phenomena occurring during a weld is proposed.•The runout ...during the weld shows spikes 6 times larger the one before parts contact.•Parts interaction causes uneven pressure gradient around the workpiece circumference.•An equivalent radial stiffness of 4e+8 N/m for the machine spindle has been obtained.
Inertia Friction Welding (IFW) is commonly approached by considering ideal conditions in which the two workpieces are in perfect contact, subjected to the nominal loads and the machine reacts ideally to the process loads. These conditions, however, are not representative of a real weld, where fixturing issues, non-ideal interaction between the workpieces and compliance of the system under the process loads could significantly affect the quality and the repeatability of the weld. To fill this research gap, a novel monitoring system able to collect in-process data and a methodology for their analysis was developed. A set of rundown tests and steel w elds were performed on an industrial inertia welder to validate the rig. Then, the data extracted were used to study the interaction conditions between the spindle and fixture side of the machine and build dynamics models to understand the physical implication of specific events connected to the impact at part contact and the flywheel deceleration. The results showed a significant influence of the machine in the alignment of the workpieces, with the runout between spindle and fixture that became larger and irregular during welding when the workpieces interact in non-ideal conditions. The quantitative comparison between the runout magnitude of rundown tests and welds showed an increase of more than four times that can be justified with the compliance of the machine, in which the spindle bearings representing the weakest element. The comparison of the outputs of the different sensors installed allowed to obtain, for the first time, a holistic view of the macroscopic phenomena occurring during the welding phase and observe how these could affect the final weld geometry and the dynamically evolving thermo-mechanical conditions of the weld.
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