Muscle satellite cell proliferation and association: new insights from myofiber time-lapse imaging

<p>Abstract</p> <p>Background</p> <p>As the resident stem cells of skeletal muscle, satellite cells are activated by extracellular cues associated with local damage. Once activated, satellite cells will re-enter the cell cycle to proliferate and supply a population of myoblasts, which will repair or replace damaged myofibers by differentiating and fusing either with an existing myofiber or with each other. There is also evidence that the orientation of cell division with respect to the myofiber may indicate or convey asymmetry in the two daughter cells. Our recent studies with time-lapse imaging of myofiber-associated satellite cells <it>in vitro </it>have yielded new data on the timing and orientation of satellite cell divisions, and revealed persistent differences in the behavior of daughter cells from planar versus vertical divisions.</p> <p>Results</p> <p>We analyzed 244 individual fiber-associated satellite cells in time-lapse video from 24 to 48 hours after myofiber harvest. We found that initial cell division in fiber culture is not synchronous, although presumably all cells were activated by the initial trauma of harvest; that cell cycling time is significantly shorter than previously thought (as short as 4.8 hours, averaging 10 hours between the first and second divisions and eight hours between the second and third); and that timing of subsequent divisions is not strongly correlated with timing of the initial division. Approximately 65% of first and 80% of second cell divisions occur parallel to the axis of the myofiber, whereas the remainder occur outside the plane of the fiber surface (vertical division). We previously demonstrated that daughter cells frequently remain associated with each other after division or reassociate after a brief separation, and that unrelated cells may also associate for significant periods of time. We show in this paper that daughter cells resulting from a vertical division remain associated with one another several times longer than do daughters from a horizontal division. However, the total average time of association between sister cells is not significantly different from the total average time of association between unrelated cells.</p> <p>Conclusions</p> <p>These longitudinal characterizations of satellite cell behavior shortly after activation provide new insights into cell proliferation and association as a function of relatedness, and indicate significant and consistent heterogeneity within the population based on these metrics.</p

Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction.

The neurochemical changes underlying human emotions and social behaviour are largely unknown. Here we report on the changes in the levels of two hypothalamic neuropeptides, hypocretin-1 and melanin-concentrating hormone, measured in the human amygdala. We show that hypocretin-1 levels are maximal during positive emotion, social interaction and anger, behaviours that induce cataplexy in human narcoleptics. In contrast, melanin-concentrating hormone levels are minimal during social interaction, but are increased after eating. Both peptides are at minimal levels during periods of postoperative pain despite high levels of arousal. Melanin-concentrating hormone levels increase at sleep onset, consistent with a role in sleep induction, whereas hypocretin-1 levels increase at wake onset, consistent with a role in wake induction. Levels of these two peptides in humans are not simply linked to arousal, but rather to specific emotions and state transitions. Other arousal systems may be similarly emotionally specialized

Neural Tube Defects and Folate Pathway Genes: Family-Based Association Tests of Gene–Gene and Gene–Environment Interactions

BACKGROUND: Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect. Most studies addressed these genes individually, often with different populations providing conflicting results. OBJECTIVES: Our study evaluates several folate pathway genes for association with human NTDs, incorporating an environmental cofactor: maternal folate supplementation. METHODS: In 304 Caucasian American NTD families with myelomeningocele or anencephaly, we examined 28 polymorphisms in 11 genes: folate receptor 1, folate receptor 2, solute carrier family 19 member 1, transcobalamin II, methylenetetrahydrofolate dehydrogenase 1, serine hydroxymethyl-transferase 1, 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homo-cysteine methyltransferase, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, betaine-homocysteine methyltransferase (BHMT), and cystathionine-beta-synthase. RESULTS: Only single nucleotide polymorphisms (SNPs) in BHMT were significantly associated in the overall data set; this significance was strongest when mothers took folate-containing nutritional supplements before conception. The BHMT SNP rs3733890 was more significant when the data were stratified by preferential transmission of the MTHFR rs1801133 thermolabile T allele from parent to offspring. Other SNPs in folate pathway genes were marginally significant in some analyses when stratified by maternal supplementation, MTHFR, or BHMT allele transmission. CONCLUSIONS: BHMT rs3733890 is significantly associated in our data set, whereas MTHFR rs1801133 is not a major risk factor. Further investigation of folate and methionine cycle genes will require extensive SNP genotyping and/or resequencing to identify novel variants, inclusion of environmental factors, and investigation of gene–gene interactions in large data sets

Pre-HEAT: submillimeter site testing and astronomical spectra from Dome A, Antarctica

Pre-HEAT is a 20 cm aperture submillimeter-wave telescope with a 660 GHz (450 micron) Schottky diode heterodyne receiver and digital FFT spectrometer for the Plateau Observatory (PLATO) developed by the University of New South Wales. In January 2008 it was deployed to Dome A, the summit of the Antarctic plateau, as part of a scientific traverse led by the Polar Research Institute of China and the Chinese Academy of Sciences. Dome A may be one of the best sites in the world for ground based Terahertz astronomy, based on the exceptionally cold, dry and stable conditions which prevail there. Pre-HEAT is measuring the 450 micron sky opacity at Dome A and mapping the Galactic Plane in the ^(13)CO J=6-5 line, constituting the first submillimeter measurements from Dome A. It is field-testing many of the key technologies for its namesake -- a successor mission called HEAT: the High Elevation Antarctic Terahertz telescope. Exciting prospects for submillimeter astronomy from Dome A and the status of Pre-HEAT will be presented

“Top-Down-Bottom-Up” Methodology as a Common Approach to Defining Bespoke Sets of Sustainability Assessment Criteria for the Built Environment

YesThe top-down-bottom-up (TDBU) methodology for defining bespoke sets of sustainability criteria for specific civil engineering project types is introduced and discussed. The need to define sustainability criteria for specific civil engineering project types occurs mainly in one or both of the following cases: (1) when a more comprehensive and indicative assessment of the sustainability of the project type in question is required; and/or (2) there is no readily available bespoke sustainability assessment tool, or set of criteria, for assessing the sustainability of the project type. The construction of roads, buildings, airports, tunnels, dams, flood banks, bridges, water supply, and sewage systems and their supporting systems are considered to be unique civil engineering/infrastructure project types. The normative definition of sustainable civil engineering/infrastructure projects and the framework for assessing its sustainability is defined and provided by the authors. An example of the TDBU methodology being applied to define sustainability criteria for transport noise reducing devices is presented and discussed. The end result of applying the methodology is a systematically researched and industry validated set of criteria that denotes assessing the sustainability of the civil engineering/infrastructure project type. The paper concludes that the top-down-bottom-up will support stakeholders and managers involved in assessing sustainability to consider all major research methods to define general and unique sustainability criteria to assess and so maximize sustainability

Multi-Messenger Astronomy with Extremely Large Telescopes

The field of time-domain astrophysics has entered the era of Multi-messenger Astronomy (MMA). One key science goal for the next decade (and beyond) will be to characterize gravitational wave (GW) and neutrino sources using the next generation of Extremely Large Telescopes (ELTs). These studies will have a broad impact across astrophysics, informing our knowledge of the production and enrichment history of the heaviest chemical elements, constrain the dense matter equation of state, provide independent constraints on cosmology, increase our understanding of particle acceleration in shocks and jets, and study the lives of black holes in the universe. Future GW detectors will greatly improve their sensitivity during the coming decade, as will near-infrared telescopes capable of independently finding kilonovae from neutron star mergers. However, the electromagnetic counterparts to high-frequency (LIGO/Virgo band) GW sources will be distant and faint and thus demand ELT capabilities for characterization. ELTs will be important and necessary contributors to an advanced and complete multi-messenger network.Comment: White paper submitted to the Astro2020 Decadal Surve

Evaluating a Measure of Social Health Derived from Two Mental Health Recovery Measures: The California Quality of Life (CA-QOL) and Mental Health Statistics Improvement Program Consumer Survey (MHSIP)

Social health is important to measure when assessing outcomes in community mental health. Our objective was to validate social health scales using items from two broader commonly used measures that assess mental health outcomes. Participants were 609 adults receiving psychological treatment services. Items were identified from the California Quality of Life (CA-QOL) and Mental Health Statistics Improvement Program (MHSIP) outcome measures by their conceptual correspondence with social health and compared to the Social Functioning Questionnaire (SFQ) using correlational analyses. Pearson correlations for the identified CA-QOL and MSHIP items with the SFQ ranged from .42 to .62, and the identified scale scores produced Pearson correlation coefficients of .56, .70, and, .70 with the SFQ. Concurrent validity with social health was supported for the identified scales. The current inclusion of these assessment tools allows community mental health programs to include social health in their assessments

A Chemical Genetic Screen for Modulators of Asymmetrical 2,2′-Dimeric Naphthoquinones Cytotoxicity in Yeast

BACKGROUND: Dimeric naphthoquinones (BiQ) were originally synthesized as a new class of HIV integrase inhibitors but have shown integrase-independent cytotoxicity in acute lymphoblastic leukemia cell lines suggesting their use as potential anti-neoplastic agents. The mechanism of this cytotoxicity is unknown. In order to gain insight into the mode of action of binaphthoquinones we performed a systematic high-throughput screen in a yeast isogenic deletion mutant array for enhanced or suppressed growth in the presence of binaphthoquinones. METHODOLOGY/PRINCIPAL FINDINGS: Exposure of wild type yeast strains to various BiQs demonstrated inhibition of yeast growth with IC(50)s in the microM range. Drug sensitivity and resistance screens were performed by exposing arrays of a haploid yeast deletion mutant library to BiQs at concentrations near their IC(50). Sensitivity screens identified yeast with deletions affecting mitochondrial function and cellular respiration as having increased sensitivity to BiQs. Corresponding to this, wild type yeast grown in the absence of a fermentable carbon source were particularly sensitive to BiQs, and treatment with BiQs was shown to disrupt the mitochondrial membrane potential and lead to the generation of reactive oxygen species (ROS). Furthermore, baseline ROS production in BiQ sensitive mutant strains was increased compared to wild type and could be further augmented by the presence of BiQ. Screens for resistance to BiQ action identified the mitochondrial external NAD(P)H dehydrogenase, NDE1, as critical to BiQ toxicity and over-expression of this gene resulted in increased ROS production and increased sensitivity of wild type yeast to BiQ. CONCLUSIONS/SIGNIFICANCE: In yeast, binaphthoquinone cytotoxicity is likely mediated through NAD(P)H:quonine oxidoreductases leading to ROS production and dysfunctional mitochondria. Further studies are required to validate this mechanism in mammalian cells

Enhanced metastatic risk assessment in cutaneous squamous cell carcinoma with the 40-gene expression profile test

Aim: To clinically validate the 40-gene expression profile (40-GEP) test for cutaneous squamous cell carcinoma patients and evaluate coupling the test with individual clinicopathologic risk factor-based assessment methods. Patients & methods: In a 33-site study, primary tumors with known patient outcomes were assessed under clinical testing conditions (n = 420). The 40-GEP results were integrated with clinicopathologic risk factors. Kaplan–Meier and Cox regression analyses were performed for metastasis. Results: The 40-GEP test demonstrated significant prognostic value. Risk classification was improved via integration of 40-GEP results with clinicopathologic risk factor-based assessment, with metastasis rates near the general cutaneous squamous cell carcinoma population for Class 1 and ≥50% for Class 2B. Conclusion: Combining molecular profiling with clinicopathologic risk factor assessment enhances stratification of cutaneous squamous cell carcinoma patients and may inform decision-making for risk-appropriate management strategies

Pre-HEAT: submillimeter site testing and astronomical spectra from Dome A, Antarctica

Pre-HEAT is a 20 cm aperture submillimeter-wave telescope with a 660 GHz (450 micron) Schottky diode heterodyne receiver and digital FFT spectrometer for the Plateau Observatory (PLATO) developed by the University of New South Wales. In January 2008 it was deployed to Dome A, the summit of the Antarctic plateau, as part of a scientific traverse led by the Polar Research Institute of China and the Chinese Academy of Sciences. Dome A may be one of the best sites in the world for ground based Terahertz astronomy, based on the exceptionally cold, dry and stable conditions which prevail there. Pre-HEAT is measuring the 450 micron sky opacity at Dome A and mapping the Galactic Plane in the ^(13)CO J=6-5 line, constituting the first submillimeter measurements from Dome A. It is field-testing many of the key technologies for its namesake -- a successor mission called HEAT: the High Elevation Antarctic Terahertz telescope. Exciting prospects for submillimeter astronomy from Dome A and the status of Pre-HEAT will be presented