Evolution of species trait through resource competition

To understand the evolution of diverse species, theoretical studies using a Lotka–Volterra type direct competition model had shown that concentrated distributions of species in continuous trait space often occurs. However, a more mechanistic approach is preferred because the competitive interaction of species usually occurs not directly but through competition for resource. We consider a chemostat-type model where species consume resource that are constantly supplied. Continuous traits in both consumer species and resource are incorporated. Consumers utilize resource whose trait values are similar with their own. We show that, even when resource-supply has a continuous distribution in trait space, a positive continuous distribution of consumer trait is impossible. Self-organized generation of distinct species occurs. We also prove global convergence to the evolutionarily stable distribution.     

Skeletal muscle respiratory capacity is enhanced in rats consuming an obesogenic Western diet

Obesity-induced lipid oversupply promotes skeletal muscle mitochondrial biogenesis. Previous investigations have utilized extreme high-fat diets (HFD) to induce such mitochondrial perturbations despite their disparity from human obesogenic diets. Here, we evaluate the effects of Western diet (WD)-induced obesity on skeletal muscle mitochondrial function. Long-Evans rats were given ad libitum access to either a WD [40% energy (E) from fat, 17% protein, and 43% carbohydrate (30% sucrose); n = 12] or a control diet (CON; 16% of E from fat, 21% protein, and 63% carbohydrate; n = 12) for 12 wk. Rats fed the WD consumed 23% more E than CON (P = 0.0001), which was associated with greater increases in body mass (23%, P = 0.0002) and adiposity (17%, P = 0.03). There were no differences in fasting blood glucose concentration or glucose tolerance between diets, although fasting insulin was increased by 40% (P = 0.007). Fasting serum triglycerides were also elevated in WD (86%, P = 0.001). The maximal capacity of the electron transfer system was greater following WD (37%, P = 0.02), as were the maximal activities of several mitochondrial enzymes (citrate synthase, β-hydroxyacyl-CoA dehydrogenase, carnitine palmitoyltransferase). Protein expression of citrate synthase, UCP3, and individual respiratory complexes was greater after WD (P < 0.05) despite no differences in the expression of peroxisome proliferator-activated receptor (PPAR)α, PPARδ, or PPARγ coactivator-1 mRNA or protein abundance. We conclude that the respiratory capacity of skeletal muscle is enhanced in response to the excess energy supplied by a WD. This is likely due to an increase in mitochondrial density, which at least in the short term, and in the absence of increased energy demand, may protect the tissue from lipid-induced impairments in glycemic control.     

Population structure and migration pattern of a conifer pathogen, Grosmannia clavigera, as influenced by its symbiont, the mountain pine beetle

We investigated the population structure of Grosmannia clavigera (Gc), a fungal symbiont of the mountain pine beetle (MPB) that plays a crucial role in the establishment and reproductive success of this pathogen. This insect-fungal complex has destroyed over 16 million ha of lodgepole pine forests in Canada, the largest MPB epidemic in recorded history. During this current epidemic, MPB has expanded its range beyond historically recorded boundaries, both northward and eastward, and has now reached the jack pine of Alberta, potentially threatening the Canadian boreal forest. To better understand the dynamics between the beetle and its fungal symbiont, we sampled 19 populations in western North America and genotyped individuals from these populations with eight microsatellite markers. The fungus displayed high haplotype diversity, with over 250 unique haplotypes observed in 335 single spore isolates. Linkage equilibria in 13 of the 19 populations suggested that the fungus reproduces sexually. Bayesian clustering and distance analyses identified four genetic clusters that corresponded to four major geographical regions, which suggested that the epidemic arose from multiple geographical sources. A genetic cluster north of the Rocky Mountains, where the MPB has recently become established, experienced a population bottleneck, probably as a result of the recent range expansion. The two genetic clusters located north and west of the Rocky Mountains contained many fungal isolates admixed from all populations, possibly due to the massive movement of MPB during the epidemic. The general agreement in north-south differentiation of MPB and G. clavigera populations points to the fungal pathogen's dependence on the movement of its insect vector. In addition, the patterns of diversity and the individual assignment tests of the fungal associate suggest that migration across the Rocky Mountains occurred via a northeastern corridor, in accordance with meteorological patterns and observation of MPB movement data. Our results highlight the potential of this pathogen for both expansion and sexual reproduction, and also identify some possible barriers to gene flow. Understanding the ecological and evolutionary dynamics of this fungus-beetle association is important for the modelling and prediction of MPB epidemics.     

Network analysis and the impact of Aflibercept on specific mediators of angiogenesis in HUVEC cells

Angiogenesis, inflammation and endothelial cells’ migration and proliferation exert fundamental roles in different diseases. However, more studies are needed to identify key proteins and pathways involved in these processes. Aflibercept has received the approval of the US Food and Drug Administration (FDA) for the treatment of wet AMD and colorectal cancer. Moreover, the effect of Aflibercept on VEGFR2 downstream signalling pathways has not been investigated yet. Here, we integrated text mining data, protein-protein interaction networks and multi-experiment microarray data to specify candidate genes that are involved in VEGFA/VEGFR2 signalling pathways. Network analysis of candidate genes determined the importance of the nominated genes via different centrality parameters. Thereupon, several genes—with the highest centrality indexes—were recruited to investigate the impact of Aflibercept on their expression pattern in HUVEC cells. Real-time PCR was performed, and relative expression of the specific genes revealed that Aflibercept modulated angiogenic process by VEGF/PI3KA/AKT/mTOR axis, invasion by MMP14/MMP9 axis and inflammation-related angiogenesis by IL-6-STAT3 axis. Data showed Aflibercept simultaneously affected these processes and determined the nominated axes that had been affected by the drug. Furthermore, integrating the results of Aflibercept on expression of candidate genes with the current network analysis suggested that resistance against the Aflibercept effect is a plausible process in HUVEC cells.     

Direct competition results from strong competition for limited resource

We study a model of competition for resource through a chemostat-type model where species consume the common resource that is constantly supplied. We assume that the species and resources are characterized by a continuous trait. As already proved, this model, although more complicated than the usual Lotka–Volterra direct competition model, describes competitive interactions leading to concentrated distributions of species in continuous trait space. Here we assume a very fast dynamics for the supply of the resource and a fast dynamics for death and uptake rates. In this regime we show that factors that are independent of the resource competition become as important as the competition efficiency and that the direct competition model is a good approximation of the chemostat. Assuming these two timescales allows us to establish a mathematically rigorous proof showing that our resource-competition model with continuous traits converges to a direct competition model. We also show that the two timescales assumption is required to mathematically justify the corresponding classic result on a model consisting of only finite number of species and resources (MacArthur in, Theor Popul Biol 1:1–11, 1970). This is performed through asymptotic analysis, introducing different scales for the resource renewal rate and the uptake rate. The mathematical difficulty relies in a possible initial layer for the resource dynamics. The chemostat model comes with a global convex Lyapunov functional. We show that the particular form of the competition kernel derived from the uptake kernel, satisfies a positivity property which is known to be necessary for the direct competition model to enjoy the related Lyapunov functional.     

Delay in Apoptosome Formation Attenuates Apoptosis in Mouse Embryonic Stem Cell Differentiation

Differentiation is an inseparable process of development in multicellular organisms. Mouse embryonic stem cells (mESCs) represent a valuable research tool to conduct in vitro studies of cell differentiation. Apoptosis as a well known cell death mechanism shows some common features with cell differentiation, which has caused a number of ambiguities in the field. The research question here is how cells could differentiate these two processes from each other. We have investigated the role of the mitochondrial apoptotic pathway and cell energy level during differentiation of mESCs into the cardiomyocytes and their apoptosis. p53 expression, cytochrome c release, apoptosome formation, and caspase-3/7 activation are observed upon induction of both apoptosis and differentiation. However, remarkable differences are detected in time of cytochrome c appearance, apoptosome formation, and caspase activity upon induction of both processes. In apoptosis, apoptosome formation and caspase activity were observed rapidly following the cytochrome c release. Unlike apoptosis, the release of cytochrome c upon differentiation took more time, and the maximum caspase activity was also postponed for 24 h. This delay suggests that there is a regulatory mechanism during differentiation of mESCs into cardiomyocytes. The highest ATP content of cells was observed immediately after cytochrome c release 6 h after apoptosis induction and then decreased, but it was gradually increased up to 48 h after differentiation. These observations suggest that a delay in the release of cytochrome c or delay in ATP increase attenuate apoptosome formation, and caspase activation thereby discriminates apoptosis from differentiation in mESCs.     

Structure of a mutant human purine nucleoside phosphorylase with the prodrug, 2‐fluoro‐2′‐deoxyadenosine and the cytotoxic drug, 2‐fluoroadenine

A double mutant of human purine nucleoside phosphorylase (hDM) with the amino acid mutations Glu201Gln:Asn243Asp cleaves adenosine‐based prodrugs to their corresponding cytotoxic drugs. When fused to an anti‐tumor targeting component, hDM is targeted to tumor cells, where it effectively catalyzes phosphorolysis of the prodrug, 2‐fluoro‐2′‐deoxyadenosine (F‐dAdo) to the cytotoxic drug, 2‐fluoroadenine (F‐Ade). This cytotoxicity should be restricted only to the tumor microenvironment, because the endogenously expressed wild type enzyme cannot use adenosine‐based prodrugs as substrates. To gain insight into the interaction of hDM with F‐dAdo, we have determined the crystal structures of hDM with F‐dAdo and F‐Ade. The structures reveal that despite the two mutations, the overall fold of hDM is nearly identical to the wild type enzyme. Importantly, the residues Gln201 and Asp243 introduced by the mutation form hydrogen bond contacts with F‐dAdo that result in its binding and catalysis. Comparison of substrate and product complexes suggest that the side chains of Gln201 and Asp243 as well as the purine base rotate during catalysis possibly facilitating cleavage of the glycosidic bond. The two structures suggest why hDM, unlike the wild‐type enzyme, can utilize F‐dAdo as substrate. More importantly, they provide a critical foundation for further optimization of cleavage of adenosine‐based prodrugs, such as F‐dAdo by mutants of human purine nucleoside phosphorylase.     

Synthesis, characterization and structural studies of new palladium(II) complexes including non-symmetric phosphorus ylides

The reaction of the non-symmetric phosphorus ylides, Ph₂P(CH₂)_nPPh₂C(H)C(O)PhR [Y₁-Y₄: n = 1, R = Cl, Br, NO₂, OCH₃ and Y₅-Y₈: n = 2, R = Cl, Br, NO, OCH₃] with dichloro(1,5-cyclooctadiene)palladium(II) in dichloromethane under mild conditions afford the monomeric P-C chelated complexes, [(Y)PdCl₂] (Y = Y₁-Y₈). These complexes were fully characterized by elemental analysis and spectroscopic techniques such as IR, ¹H, ³¹P, and ¹³C NMR. In addition, the identity of complexes [(Y₅)PdCl₂] (1b) and [(Y₈)PdCl₂] (4b) was unequivocally determined by single crystal X-diffraction techniques, both structures consisting of six-membered rings formed by coordination of the ligands through the phosphine group and the ylidic carbon atom to the metal center. The coordination geometry around the Pd atoms in both these complexes be defined as slightly distorted square planar. Furthermore, their electrochemical behavior was also investigated by cyclic voltammeters, thus the cyclic voltammetry of complex [(Y₁)PdCl₂], in dichloromethane solution with Pt electrode, shows that the redox reaction of the pair Pd(II)/Pd(0) is irreversible with the cathodic peak potential at −1.08 V versus Ag wire.