The displacement of the mitotic spindle to one side of a cell is important for many cells to divide unequally. While recent progress has begun to unveil some of the molecular mechanisms of mitotic ...spindle displacement, far less is known about how spindle displacement is precisely timed. A conserved mitotic progression mechanism is known to time events in dividing cells, although this has never been linked to spindle displacement. This mechanism involves the anaphase-promoting complex (APC), its activator Cdc20/Fizzy, its degradation target cyclin, and cyclin-dependent kinase (CDK). Here we show that these components comprise a previously unrecognized timer for spindle displacement. In the Caenorhabditis elegans zygote, mitotic spindle displacement begins at a precise time, soon after chromosomes congress to the metaphase plate. We found that reducing the function of the proteasome, the APC, or Cdc20/Fizzy delayed spindle displacement. Conversely, inactivating CDK in prometaphase caused the spindle to displace early. The consequence of experimentally unlinking spindle displacement from this timing mechanism was the premature displacement of incompletely assembled components of the mitotic spindle. We conclude that in this system, asymmetric positioning of the mitotic spindle is normally delayed for a short time until the APC inactivates CDK, and that this delay ensures that the spindle does not begin to move until it is fully assembled. To our knowledge, this is the first demonstration that mitotic progression times spindle displacement in the asymmetric division of an animal cell. We speculate that this link between the cell cycle and asymmetric cell division might be evolutionarily conserved, because the mitotic spindle is displaced at a similar stage of mitosis during asymmetric cell divisions in diverse systems.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diets rich in minimally processed plant-based foods are recommended to breast cancer patients, and some may have an interest in whole-food, plant-based (WFPB) diets that avoid animal-based foods, ...added fats, and refined sugars. Within WFPB diets, the intakes of isoflavones, omega-6 polyunsaturated fatty acids (n-6 PUFAs), and omega-3 polyunsaturated FAs (n-3 PUFAs), which have been discussed in reference to breast cancer outcomes, have not been well characterized.
Women with stage IV breast cancer on stable therapy were randomized 2:1 into (1) a WFPB intervention (
= 21) or (2) usual care (
= 11) for 8 weeks. Three meals per day were provided. Outcomes presented here include dietary intake of isoflavones, n-3 and n-6- PUFAs, which were assessed using three-day food records at baseline and 8 weeks. Baseline and 8-week mean intake within groups were compared using the Wilcoxon signed-rank test and between control and intervention groups by a two-sample
-test.
The WFPB intervention participants increased their daily consumption of total isoflavones from a mean of 0.8 mg/day to 14.5 mg/day (
< 0.0001) and decreased the n-6:n-3 ratio of their diet from a mean of 9.3 to 3.7 (
< 0.0001). Within the WFPB group, linoleic acid (n-6 PUFA) consumption decreased by a mean of 3.8 g (
= 0.0095), from 12.8 g/day to 9.0 g/day; total n-3 PUFA consumption increased by a mean of 1.1 g (
= 0.0005), from 1.6 g/day to 2.7 g/day.
Transitioning to a WFPB diet resulted in significantly increased isoflavone intake and decreased n-6:n-3 ratio in women with breast cancer.
During decades‐long infections in the cystic fibrosis (CF) airway, Pseudomonas aeruginosa undergoes selection. One bacterial genetic adaptation often observed in CF isolates is mucA mutations. MucA ...inhibits the sigma factor AlgU. Mutations in mucA lead to AlgU misregulation, resulting in a mucoid phenotype that is associated with poor CF disease outcomes. Due to its ability to be mutated, mucA is assumed to be dispensable for bacterial viability. Here we show that, paradoxically, a portion of mucA is essential in P. aeruginosa. We demonstrate that mucA is no longer required in a strain lacking algU, that mucA alleles encoding for proteins that do not bind to AlgU are insufficient for viability, and that mucA is no longer essential in mutant strains containing AlgU variants with reduced sigma factor activity. Furthermore, we found that overexpression of algU prevents cell growth in the absence of MucA, and that this phenotype can be rescued by the overproduction of RpoD, the housekeeping sigma factor. Together, these results suggest that in the absence of MucA, the inability to regulate AlgU activity results in the loss of bacterial viability. Finally, we speculate that the essentiality of anti‐sigma factors that regulate envelope function may be a widespread phenomenon in bacteria.
The opportunistic pathogen Pseudomonas aeruginosa forms chronic infections in the lungs of cystic fibrosis (CF) patients. In clinical settings, mutations often arise in the gene mucA of P. aeruginosa, which result in mucoid cells and are associated with poor disease outcomes in these patients. Our study explores the paradox of mucA essentiality, which we show is due to the required regulation of AlgU, its cognate sigma factor that activates the envelope stress response.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Young children (ages 3 to 5) are using mobile touchscreen technology, including tablet computers, yet little is known on the potential musculoskeletal and physical activity implications of its use. ...This within-subject laboratory study (n = 10) examined head, trunk and arm postures, upper trapezius muscle activity, and total body and upper limb physical activity during playing with tablets compared to during TV watching and playing with non-screen toys. Overall, this study found that during tablet play children had greater mean head, trunk and upper arm angles compared to both TV watching and toy play. Conversely, compared to toy play, children playing with tablets had lesser trunk, upper arm and elbow postural variation, lesser trapezius activity, more time sitting and lesser physical activity. Thus, to minimize potential musculoskeletal and sedentary risks, non-screen toy play should be encouraged and education and guidelines provided for parents and caretakers to support wise use of tablets.
•Compared to TV, children using tablet computers had poorer neck postures and increased posture variation and activity.•Compared to toy play, children using tablets had poorer neck postures, less posture variation, more sitting and less physical activity.•Increased tablet use may increase musculoskeletal risk and increased sedentary activity compared to non-screen play.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Despite the availability of various dietary assessment tools, there is a need for a tool aligned with the needs of lifestyle medicine (LM) physicians. Such a tool would be brief, aimed at use in a ...clinical setting, and focused on a "food as medicine" approach consistent with recommendations for a diet based predominately on whole plant foods. The objective of this study is to describe the development and initial pilot testing of a brief, dietary screener to assess the proportion of whole, unrefined plant foods and water relative to total food and beverage intake.
A multidisciplinary study team led the screener development, providing input on the design and food/beverage items included, and existing published dietary assessment tools were reviewed for relevance. Feedback was solicited from LM practitioners in the form of a cross-sectional survey that captured information on medical practice, barriers, and needs in assessing patients' diets, in addition to an opportunity to complete the screener and provide feedback on its utility. The study team assessed feedback and revised the screener accordingly, which included seeking and incorporating feedback on additional food items to be included from subject matter experts in specific cultural and ethnic groups in the United States. The final screener was submitted for professional design, and scoring was developed.
Of 539 total participants, the majority reported assessing diet either informally (62%) or formally (26%) during patient encounters, and 73% reported discussing diet with all or most of their patients. Participants also reported facing barriers (80%) to assessing diet. Eighty-eight percent believed the screener was quick enough to use in a clinical setting, and 68% reported they would use it.
The ACLM Diet Screener was developed through iterative review and pilot testing. The screener is a brief, 27-item diet assessment tool that can be successfully used in clinical settings to track patient dietary intakes, guide clinical conversations, and support nutrition prescriptions. Pilot testing of the screener found strong alignment with clinician needs for assessing a patient's intake of whole plant food and water relative to the overall diet. Future research will involve pilot testing the screener in clinical interventions and conducting a validation study to establish construct validity.
•Children had a high adherence to the prescribed active video game use during the study.•Several factors including game selection and efficiency of play may have impacted the quality of play ...influencing outcomes.•The ineffectiveness of the current intervention to improve motor skill and physical activity was likely due to the quality of play.
Active video games (AVGs) have been identified as a novel strategy to improve motor skill and physical activity in clinical populations. A recent cross-over randomized trial found AVGs to be ineffective at improving motor skill and physical activity in the home-environment for children with or at-risk for developmental coordination disorder (DCD).
The study purpose was to better understand why the intervention had been ineffective by examining the quantity and quality of AVG play during an AVG intervention for children with or at-risk for DCD.
Participants (n=21, ages 9–12) completed the 16 week AVG intervention. Detailed quantitative and qualitative data were systematically triangulated to obtain the quantity of exposure (AVG exposure over time, patterns of exposure) and quality of use (game selection, facilitators and barriers to play).
The median AVG dose (range 30–35min/day) remained relatively stable across the intervention and met the prescribed dose. Play quality was impacted by game selection, difficulty playing games, lack of time, illness, technical difficulties and boredom.
The ineffectiveness of a home-based AVG intervention may be due to quality of play. Strategies to improve the quality of game play may help realize the potential benefits of AVGs as a clinical tool for children with DCD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The accurate interpretation of genetic variants is critical for characterizing genotype-phenotype associations. Because the effects of genetic variants can depend strongly on their local genomic ...context, accurate genome annotations are essential. Furthermore, as some variants have the potential to disrupt or alter gene structure, variant interpretation efforts stand to gain from the use of individualized annotations that account for differences in gene structure between individuals or strains.
We describe a suite of software tools for identifying possible functional changes in gene structure that may result from sequence variants. ACE ('Assessing Changes to Exons') converts phased genotype calls to a collection of explicit haplotype sequences, maps transcript annotations onto them, detects gene-structure changes and their possible repercussions, and identifies several classes of possible loss of function. Novel transcripts predicted by ACE are commonly supported by spliced RNA-seq reads, and can be used to improve read alignment and transcript quantification when an individual-specific genome sequence is available. Using publicly available RNA-seq data, we show that ACE predictions confirm earlier results regarding the quantitative effects of nonsense-mediated decay, and we show that predicted loss-of-function events are highly concordant with patterns of intolerance to mutations across the human population. ACE can be readily applied to diverse species including animals and plants, making it a broadly useful tool for use in eukaryotic population-based resequencing projects, particularly for assessing the joint impact of all variants at a locus.
ACE is written in open-source C ++ and Perl and is available from geneprediction.org/ACE.
myandell@genetics.utah.edu or tim.reddy@duke.edu.
Supplementary information is available at Bioinformatics online.
Maternal tobacco smoke (MTS) predisposes human and rat offspring to visceral obesity in early adulthood. Glucocorticoid excess also causes visceral obesity. We hypothesized that in utero MTS would ...increase visceral adiposity and alter the glucocorticoid pathway in young adult rats.
We developed a novel model of in utero MTS exposure in pregnant rats by exposing them to cigarette smoke from E11.5 to term. Neonatal rats were cross-fostered to control dams and weaned to standard rat chow through young adulthood (postnatal day 60).
We demonstrated increased visceral adiposity (193%)*, increased visceral adipose 11-β hydroxysteroid dehydrogenase 1 mRNA (204%)*, increased serum corticosterone (147%)*, and no change in glucocorticoid receptor protein in adult male MTS rat offspring. Female rats exposed to MTS in utero demonstrated no change in visceral or subcutaneous adiposity, decreased serum corticosterone (60%)*, and decreased adipose glucocorticoid receptor protein (66%)*. *P < 0.05.
We conclude that in utero MTS exposure increased visceral adiposity and altered in the glucocorticoid pathway in a sex-specific manner. We speculate that in utero MTS exposure programs adipose dysfunction in adult male rat offspring via alteration in the glucocorticoid pathway.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Background Conduction system disease and beta-blocker therapy are both common among heart failure (HF) patients and contribute to increasing reliance on paced rhythms. We hypothesized that ...many HF patients dependent on pacing have suboptimal heart rate responses and associated limitations in exercise capacity. Methods and Results We studied 122 HF patients (left ventricular ejection fractions ≤40%) referred for cardiopulmonary exercise testing, comparing those with pacing at baseline with those with native rhythms. The paced group (PG) had lower resting (71 ± 9 vs 75 ± 15 beats/min; P = .048) and peak heart rates (103 ± 22 vs 127 ± 27 beats/min; P < .0001). Although beta-blockers were prescribed with similar frequency in both groups (90% vs 85%), average dose was higher in the PG. Inotropic reserve (oxygen pulse) was similar in both groups (11.1 ± 3.3 vs 11.1 ± 3.4 mL/beat; P = .94), consistent with equivalent stroke volumes, but chronotropic incompetence was higher (95% vs 71%, P = .001) and peak VO2 was lower (12.2 ± 3.4 vs 14.2 ± 4.1 mL/kg/min; P = .004) in the PG. Conclusions Chronotropic incompetence and exercise capacity are worse in HF patients depending on paced heart rate responses. This has implications for quality of life as well as advanced therapy choices based on exercise capacity. Reevaluating beta-blocker dosing and optimizing pacemaker programming may therefore benefit the growing population of HF patients with device-dependent rhythms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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