Obesity is associated with increased recurrence and reduced survival of breast cancer. Adipocytes constitute a significant component of breast tissue, yet their role in provisioning metabolic ...substrates to support breast cancer progression is poorly understood.
Here, we show that co-culture of breast cancer cells with adipocytes revealed cancer cell-stimulated depletion of adipocyte triacylglycerol. Adipocyte-derived free fatty acids were transferred to breast cancer cells, driving fatty acid metabolism via increased CPT1A and electron transport chain complex protein levels, resulting in increased proliferation and migration. Notably, fatty acid transfer to breast cancer cells was enhanced from "obese" adipocytes, concomitant with increased stimulation of cancer cell proliferation and migration. This adipocyte-stimulated breast cancer cell proliferation was dependent on lipolytic processes since HSL/ATGL knockdown attenuated cancer cell responses.
These findings highlight a novel and potentially important role for adipocyte lipolysis in the provision of metabolic substrates to breast cancer cells, thereby supporting cancer progression.
The ability to obtain accurate and reproducible data using quantitative real-time Polymerase Chain Reaction (RT-qPCR) is limited by the process of data normalization. The use of 'housekeeping' or ...'reference' genes is the most common technique used to normalize RT-qPCR data. However, commonly used reference genes are often poorly validated and may change as a result of genetic background, environment and experimental intervention. Here we present an analysis of 10 reference genes in mouse skeletal muscle (Actb, Aldoa, Gapdh, Hprt1, Ppia, Rer1, Rn18s, Rpl27, Rpl41 and Rpl7L1), which were identified as stable either by microarray or in the literature. Using the MIQE guidelines we compared wild-type (WT) mice across three genetic backgrounds (R129, C57BL/6j and C57BL/10) as well as analyzing the α-actinin-3 knockout (Actn3 KO) mouse, which is a model of the common null polymorphism (R577X) in human ACTN3. Comparing WT mice across three genetic backgrounds, we found that different genes were more tightly regulated in each strain. We have developed a ranked profile of the top performing reference genes in skeletal muscle across these common mouse strains. Interestingly the commonly used reference genes; Gapdh, Rn18s, Hprt1 and Actb were not the most stable. Analysis of our experimental variant (Actn3 KO) also resulted in an altered ranking of reference gene suitability. Furthermore we demonstrate that a poor reference gene results in increased variability in the normalized expression of a gene of interest, and can result in loss of significance. Our data demonstrate that reference genes need to be validated prior to use. For the most accurate normalization, it is important to test several genes and use the geometric mean of at least three of the most stably expressed genes. In the analysis of mouse skeletal muscle, strain and intervention played an important role in selecting the most stable reference genes.
Birds exhibit a remarkable array of seasonal migrations. Despite much research describing migratory behaviour, the underlying forces driving how a species’ breeding and wintering populations ...redistribute each year, that is, migratory connectivity, remain largely unknown. Here, we test the hypothesis that birds migrate in a way that minimises energy expenditure while considering intraspecific competition for energy acquisition, by developing a modelling framework that simulates an optimal redistribution of individuals between breeding and wintering areas. Using 25 species across the Americas, we find that the model accurately predicts empirical migration patterns, and thus offers a general explanation for migratory connectivity based on first ecological and energetic principles. Our model provides a strong basis for exploring additional processes underlying the ecology and evolution of migration, but also a framework for predicting how migration impacts local adaptation across seasons and how environmental change may affect population dynamics in migratory species.
Despite much research describing migratory behaviour, the underlying forces driving how a species’ breeding and wintering populations redistribute each year, that is, migratory connectivity, remain largely unknown. Here, we test the hypothesis that birds migrate in a way that minimises energy expenditure while considering intraspecific competition for energy acquisition, by developing a modelling framework that simulates an optimal redistribution of individuals between breeding and wintering areas. Using empirical data for 7145 individuals from 25 species across the Americas, we find that the model accurately predicts empirical migration patterns, and thus offers a general explanation for migratory connectivity based on first ecological and energetic principles.
The little greenbul, a common rainforest passerine from sub‐Saharan Africa, has been the subject of long‐term evolutionary studies to understand the mechanisms leading to rainforest speciation. ...Previous research found morphological and behavioural divergence across rainforest–savannah transition zones (ecotones), and a pattern of divergence with gene flow suggesting divergent natural selection has contributed to adaptive divergence and ecotones could be important areas for rainforests speciation. Recent advances in genomics and environmental modelling make it possible to examine patterns of genetic divergence in a more comprehensive fashion. To assess the extent to which natural selection may drive patterns of differentiation, here we investigate patterns of genomic differentiation among populations across environmental gradients and regions. We find compelling evidence that individuals form discrete genetic clusters corresponding to distinctive environmental characteristics and habitat types. Pairwise FST between populations in different habitats is significantly higher than within habitats, and this differentiation is greater than what is expected from geographic distance alone. Moreover, we identified 140 SNPs that showed extreme differentiation among populations through a genomewide selection scan. These outliers were significantly enriched in exonic and coding regions, suggesting their functional importance. Environmental association analysis of SNP variation indicates that several environmental variables, including temperature and elevation, play important roles in driving the pattern of genomic diversification. Results lend important new genomic evidence for environmental gradients being important in population differentiation.
Mitochondrial oxidative stress, mitochondrial dysfunction, or both have been implicated in insulin resistance. However, disentangling the individual roles of these processes in insulin resistance has ...been difficult because they often occur in tandem, and tools that selectively increase oxidant production without impairing mitochondrial respiration have been lacking. Using the dimer/monomer status of peroxiredoxin isoforms as an indicator of compartmental hydrogen peroxide burden, we provide evidence that oxidative stress is localized to mitochondria in insulin-resistant 3T3-L1 adipocytes and adipose tissue from mice. To dissociate oxidative stress from impaired oxidative phosphorylation and study whether mitochondrial oxidative stress per se can cause insulin resistance, we used mitochondria-targeted paraquat (MitoPQ) to generate superoxide within mitochondria without directly disrupting the respiratory chain. At ≤10 μm, MitoPQ specifically increased mitochondrial superoxide and hydrogen peroxide without altering mitochondrial respiration in intact cells. Under these conditions, MitoPQ impaired insulin-stimulated glucose uptake and glucose transporter 4 (GLUT4) translocation to the plasma membrane in both adipocytes and myotubes. MitoPQ recapitulated many features of insulin resistance found in other experimental models, including increased oxidants in mitochondria but not cytosol; a more profound effect on glucose transport than on other insulin-regulated processes, such as protein synthesis and lipolysis; an absence of overt defects in insulin signaling; and defective insulin- but not AMP-activated protein kinase (AMPK)-regulated GLUT4 translocation. We conclude that elevated mitochondrial oxidants rapidly impair insulin-regulated GLUT4 translocation and significantly contribute to insulin resistance and that MitoPQ is an ideal tool for studying the link between mitochondrial oxidative stress and regulated GLUT4 trafficking.
ABSTRACT
RZ2109 is the first of several extragalactic globular clusters shown to host an ultraluminous X-ray source. RZ2109 is particularly notable because optical spectroscopy shows it has broad, ...luminous O iii λλ4959,5007 emission, while also having no detectable hydrogen emission. The X-ray and optical characteristics of the source in RZ2109 make it a good candidate for being a stellar mass black hole accreting from a white dwarf donor (i.e. an ultracompact black hole X-ray binary). In this paper we present optical spectroscopic monitoring of the O iii5007 emission line from 2007 to 2018. We find that the flux of the emission line is significantly lower in recent observations from 2016 to 2018 than it was in earlier observations in 2007–2011. We also explore the behaviour of the emission line shape over time. Both the core and the wings of the emission line decline over time, with some evidence that the core declines more rapidly than the wings. However, the most recent observations (in 2019) unexpectedly show the emission line core rebrightening
Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram ...in patients with advanced solid tumors and liver involvement.
Disulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. Protein S-glutathionylation was evaluated as a pharmacodynamic marker.
Twenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28-124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. Increased S-glutathionylation of serum proteins was observed with treatment.
Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function.
NCT00742911 , first posted 28/08/2008.
Neotropic migratory birds are declining across the Western Hemisphere, but conservation efforts have been hampered by the inability to assess where migrants are most limited—the breeding grounds, ...migratory stopover sites or wintering areas. A major challenge has been the lack of an efficient, reliable and broadly applicable method for measuring the strength of migratory connections between populations across the annual cycle. Here, we show how high‐resolution genetic markers can be used to identify genetically distinct groups of a migratory bird, the Wilson's warbler (Cardellina pusilla), at fine enough spatial scales to facilitate assessing regional drivers of demographic trends. By screening 1626 samples using 96 highly divergent single nucleotide polymorphisms selected from a large pool of candidates (~450 000), we identify novel region‐specific migratory routes and timetables of migration along the Pacific Flyway. Our results illustrate that high‐resolution genetic markers are more reliable, precise and amenable to high throughput screening than previously described intrinsic marking techniques, making them broadly applicable to large‐scale monitoring and conservation of migratory organisms.
ABSTRACT
Ultraluminous X-ray sources (ULXs) in globular clusters (GCs) are low-mass X-ray binaries that achieve high X-ray luminosities through a currently uncertain accretion mechanism. Using ...archival Chandra and Hubble Space Telescope observations, we perform a volume-limited search (≲70 Mpc) of 21 of the most massive ($\gt 10^{11.5} \, \mathrm{M}_\odot$) early-type galaxies to identify ULXs hosted by GC candidates. We find a total of 34 ULX candidates above the expected background within five times the effective radius of each galaxy, with 10 of these ($\sim 29.4{{\ \rm per\ cent}}$) potentially hosted by a GC. A comparison of the spatial and luminosity distributions of these new candidate GC ULXs with previously identified GC ULXs shows that they are similar: both samples peak at LX ∼ a few × 1039 erg s−1 and are typically located within a few effective radii of their host galaxies.
ABSTRACT
We have identified seven ultraluminous X-ray sources (ULXs) that are coincident with globular cluster candidates (GC) associated with M87. ULXs in the old GC environment represent a new ...population of ULXs, and ones likely to be black holes. In this study, we perform detailed X-ray spectroscopic follow-up to seven GC ULXs across a wealth of archival Chandra observations and long time baseline of 16 yr. This study brings the total known sample of GC ULXs to 17. Two of these sources show variability in their X-ray luminosity of an order of magnitude over many years, and one of these sources shows intra-observational variability on the scale of hours. While the X-ray spectra of the majority of GC ULXs are best fit by single-component models, one of the sources studied in this paper is the second GC ULX to be best fit by a two-component model. We compare this new sample of GC ULXs to the previously studied sample, and compare the X-ray and optical properties counterparts across the samples. We find that the clusters that host ULXs in M87 have metallicities from g − z = 1.01 to g − z = 1.70. The best-fitting power-law indices of the X-ray spectra range from Γ = 1.37 to 2.21, and the best-fitting inner blackbody disc temperatures range from kT = 0.56 to 1.90 keV.
PDF
