Akt Activation Emulates Chk1 Inhibition and Bcl2 Overexpression and Abrogates G2 Cell Cycle Checkpoint by Inhibiting BRCA1 Foci

Akt is perhaps the most frequently activated oncoprotein in human cancers. Overriding cell cycle checkpoint in combination with the inhibition of apoptosis are two principal requirements for predisposition to cancer. Here we show that the activation of Akt is sufficient to promote these two principal processes, by inhibiting Chk1 activation with concomitant inhibition of apoptosis. These activities of Akt cannot be recapitulated by the knockdown of Chk1 alone or by overexpression of Bcl2. Rather the combination of Chk1 knockdown and Bcl2 overexpression is required to recapitulate Akt activities. Akt was shown to directly phosphorylate Chk1. However, we found that Chk1 mutants in the Akt phosphorylation sites behave like wild-type Chk1 in mediating G2 arrest, suggesting that the phosphorylation of Chk1 by Akt is either dispensable for Chk1 activity or insufficient by itself to exert an effect on Chk1 activity. Here we report a new mechanism by which Akt affects G2 cell cycle arrest. We show that Akt inhibits BRCA1 function that induces G2 cell cycle arrest. Akt prevents the translocation of BRCA1 to DNA damage foci and, thereby, inhibiting the activation of Chk1 following DNA damage.     

Multiomic Metabolic Enrichment Network Analysis Reveals Metabolite–Protein Physical Interaction Subnetworks Altered in Cancer

Metabolism is recognized as an important driver of cancer progression and other complex diseases, but global metabolite profiling remains a challenge. Protein expression profiling is often a poor proxy since existing pathway enrichment models provide an incomplete mapping between the proteome and metabolism. To overcome these gaps, we introduce multiomic metabolic enrichment network analysis (MOMENTA), an integrative multiomic data analysis framework for more accurately deducing metabolic pathway changes from proteomics data alone in a gene set analysis context by leveraging protein interaction networks to extend annotated metabolic models. We apply MOMENTA to proteomic data from diverse cancer cell lines and human tumors to demonstrate its utility at revealing variation in metabolic pathway activity across cancer types, which we verify using independent metabolomics measurements. The novel metabolic networks we uncover in breast cancer and other tumors are linked to clinical outcomes, underscoring the pathophysiological relevance of the findings.     

Autumnal moth – why autumnal?

1. As for some other spring‐feeding moths, adult flight of Epirrita autumnata (Lepidoptera: Geometridae) occurs in late autumn. Late‐season flight is a result of a prolonged pupal period. Potential evolutionary explanations for this phenological pattern are evaluated. 2. In a laboratory rearing, there was a weak correlation between pupation date and the time of adult emergence. A substantial genetic difference in pupal period was found between two geographic populations. Adaptive evolution of eclosion time can thus be expected. 3. Metabolic costs of a prolonged pupal period were found to be moderate but still of some ecological significance. Pupal mortality is likely to form the main cost of the prolonged pupal period. 4. Mortality rates of adults, exposed in the field, showed a declining temporal trend from late summer to normal eclosion time in autumn. Lower predation pressure on adults may constitute the decisive selective advantage of late‐season flight. It is suggested that ants, not birds, were the main predators responsible for the temporal trend. 5. Egg mortality was estimated to be low; it is thus unlikely that the late adult period is selected for to reduce the time during which eggs are exposed to predators. 6. In a laboratory experiment, oviposition success was maximal at the time of actual flight peak of E. autumnata, however penalties resulting from sub‐optimal timing of oviposition remained limited.     

Expression level of enzymes related to in situ estrogen synthesis and clinicopathological parameters in breast cancer patients

In order to evaluate the importance of estrogen production in tumor and surrounding tissues, we measured mRNA expression levels of 5 enzymes participating to estrogen synthesis in situ and 4 breast cancer-related proteins in 27 pairs of tumor and non-malignant tissues. Steroid sulfatase (STS) mRNA was more frequently detected in tumor tissues rather than in their non-malignant counterparts. Estrogen sulfotransferase (EST) was constantly expressed with high level not only in tumor tissues but also in their surrounding non-malignant counterparts. In contrast, mRNA expression levels of aromatase, and 17β-hydroxysteroid dehydrogenase type I and II were relatively low and detected only in small proportion of the patients. We also measured the mRNA expression levels of the same nine genes in tumor tissues of 197 breast cancer patients, and analyzed relationship between the mRNA expression level and the clinicopathological parameters. The mRNA expression levels of STS, aromatase and erbB2 in tumor tissues increased as breast cancer progressed. The tumoral mRNA expression levels of STS, estrogen receptor β, and erbB2 in patients with recurrence were higher than those in patients without recurrence. Upregulation of STS expression plays an important role in tumor progression of human breast cancer and is considered to be responsible for estrogen production in tumor and surrounding tissues.     

Spatial and temporal factors associated with nest survival of Gray Flycatchers in managed ponderosa pine forests

Gray Flycatchers (Empidonax wrightii) breed in a variety of habitats in the arid and semi‐arid regions of the western United States, but little is known about their breeding biology, especially in the northern portion of their range where they nest in ponderosa pine (Pinus ponderosa) forests. From May to July 2014 and 2015, we conducted surveys for singing male Gray Flycatchers along the eastern slope of the Cascade Range in Washington, U.S.A, monitored flycatcher nests, and quantified nest‐site vegetation. We used a logistic‐exposure model fit within a Bayesian framework to model the daily survival probability of flycatcher nests. During the 2 yr of our study, we monitored 141 nests, with 93% in ponderosa pines. Mean clutch size was 3.6 eggs and the mean number of young fledged per nest was 3.2. Predation accounted for 90% of failed nests. We found a positive association between daily nest survival and both nest height and distance of nest substrates from the nearest tree. Flycatchers that locate their nests higher above the ground and further from adjacent trees may be choosing the safest alternative because higher nests may be less exposed to terrestrial predators and nests in trees that are farther from other trees may be less exposed to arboreal predators such as jays (Corvidae) that may forage in patches with connected canopies. Nests in trees farther from other trees may also allow earlier detection of approaching predators and thus aid in nest defense.     

Normal vision can compensate for the loss of the circadian clock

Circadian clocks are thought to be essential for timing the daily activity of animals, and consequently increase fitness. This view was recently challenged for clock-less fruit flies and mice that exhibited astonishingly normal activity rhythms under outdoor conditions. Compensatory mechanisms appear to enable even clock mutants to live a normal life in nature. Here, we show that gradual daily increases/decreases of light in the laboratory suffice to provoke normally timed sharp morning (M) and evening (E) activity peaks in clock-less flies. We also show that the compound eyes, but not Cryptochrome (CRY), mediate the precise timing of M and E peaks under natural-like conditions, as CRY-less flies do and eyeless flies do not show these sharp peaks independently of a functional clock. Nevertheless, the circadian clock appears critical for anticipating dusk, as well as for inhibiting sharp activity peaks during midnight. Clock-less flies only increase E activity after dusk and not before the beginning of dusk, and respond strongly to twilight exposure in the middle of the night. Furthermore, the circadian clock responds to natural-like light cycles, by slightly broadening Timeless (TIM) abundance in the clock neurons, and this effect is mediated by CRY.     

The critical weed-free period in organically-grown winter wheat

Two experiments were conducted in central southern England between September 1994 and August 1996 to identify the critical weed-free period in organically grown winter wheat (Triticum aestivum, cv. Mercia). In competition with a mixed weed infestation of predominately Alopecurus myosuroides and Tripleurospermum inodorum it was found that wheat yield decreased as the duration of the weed-infested period increased and that the crop needed to be kept free of weeds from sowing in order to completely avoid any yield loss. Also, weeds emerging in the wheat crop (predominately T. inodorum) during the growing season had a significant and detrimental effect on yield. The existence of the critical period, therefore, depends on the imposition of an acceptable yield loss. If a 5% yield loss gives a marginal benefit compared with the cost of weed control, the critical period will begin at 506°C days after sowing (November) and end at 1023°C days after sowing (February). This information could be used by farmers to target mechanical weeding operations to control weeds at a time that will have maximum benefit to the crop.     

The Administration of an α-MSH Analogue Reduces the Serum Release of IL-1α and TNFα Induced by the Injection of a Sublethal Dose of Lipopolysaccharides in the BALB/c Mouse

The injection of α-MSH or of one of its analogues ([Nle₄-D.Phe₇] α-MSH_4–10) reduced, in vivo, the release of two cytokines (IL-1α and TNFα) involved in inflammation. The inflammatory state was induced in BALB/c mice by intraperitoneal injection of a sublethal dose of lipopolysaccharides (LPS). The assay of these cytokines by ELISA showed a reduction of 20% with α-MSH and between 30 and 60% with the α-MSH analogue. The α-MSH or the analogue was administered in one of two ways: intravenously or subcutaneously. The most efficient method seemed to be the subcutaneous one because it improved the activity 10,000 times more than the intravenous method. Moreover, the analogue induced a regression of mortality in the animals treated by the intravenous method. Our results show that α-MSH and one of its analogues inhibit IL-1α and TNFα, and can be used as anti-inflammatory molecules.     

Influence of latitude, water depth, day v. night and wet v. dry periods on the species composition of reef fish communities in tropical Western Australia

Trap sampling over reefs in deep (mean = 20 m) and shallow (mean = 10 m) waters along c. 1500 km of coastline in tropical north‐western Australia during both day and night and in wet and dry periods yielded 23 377 fishes, representing 32 families, 58 genera and 119 species. Individuals of the Serranidae, Lutjanidae, Lethrinidae and Carangidae contributed 88·9% to the total catch. The ichthyofaunal compositions of the Kimberley, Canning and Pilbara bioregions were relatively discrete. Species composition was influenced far more by location (latitude) than by water depth, period and time of day, and underwent a gradational change southwards. The latter change reflected differences in the trends exhibited by the relative abundances of certain species with increasing latitude and the confinement of other species largely to particular regions. The three most abundant species, i.e. Lethrinus sp. 3, Lutjanus carponotatus and Lethrinus laticaudis contributed 34·8, 20·8 and 11·6% to the total catch, respectively. The first species was rarely recorded in the two most northern locations and was abundant in the four most southern locations, whereas the last two species were relatively more abundant in northern than in southern locations. Lutjanus bitaeniatus and Lutjanus johnii were found exclusively at the two locations in the Kimberley region, whereas Abalistes stellatus, Pentapodus emeryii and Lethrinus nebulosus were not caught in this region but were found in both locations of the Canning and Pilbara regions. The species composition in deep and shallow waters at each location almost invariably differed significantly between day and night and between dry and wet periods, with species such as L. bitaeniatus, L. johnii, Lutjanus sebae and A. stellatus being more abundant over deep reefs, whereas L. carponotatus, L. laticaudis, Siganus fuscescens and Lethrinus lentjan were more numerous over shallow reefs. Species such as L. johnii and Lethrinus atkinsoni were relatively more important in night‐time than daytime catches, whereas the reverse applied to Lethrinus lentjan, L. laticaudis and Choerodon cyanodus. Lethrinus sp. 3 and L. laticaudis were relatively more important in catches during the dry than wet period.     

Interleukin-1-β and Tumor Necrosis Factor-α Increase Peripheral-Type Benzodiazepine Binding Sites in Cultured Polygonal Astrocytes

Peripheral-type benzodiazepine binding sites (PTBBS) are markedly increased in the injured CNS. Astrocytes appear to be the primary cell type which express increased PTBBS. Because certain cytokines within the injured CNS are potent mitogens for astrocytes, we examined the effects of two such cytokines, interleukin (IL)-1 beta and tumor necrosis factor (TNF), on PTBBS in cultured astrocytes using [3H]Ro 5-4864 as the specific ligand. Purified cultures of either polygonal or process-bearing astrocytes were prepared from neonatal rat cerebral hemispheres. At a concentration of 1.8 nM, specific binding of the radioactive ligand to polygonal astrocytes reached equilibrium within 60 min and was half-maximal by 5-10 min. By contrast, specific binding to process-bearing astrocytes barely exceeded background levels. IL-1 and TNF increased PTBBS within polygonal astrocytes in both dose- and time-dependent manners. At 10-50 ng/ml, IL-1 beta and TNF-alpha elevated [3H]Ro 5-4864 binding in polygonal astrocyte cultures 65 and 87%, respectively, above the level in control cultures. However, no changes in PTBBS were seen within polygonal astrocytes after IL-2 treatment. Scatchard analysis of saturation binding experiments suggested that the increase in PTBBS promoted by TNF was due to an increased number of binding sites present in polygonal astrocytes and not due to an increase in receptor affinity. Binding data suggested that PTBBS within cultures of process-bearing astrocytes were virtually absent irrespective of the treatment. These in vitro data suggest that certain cytokines found in the injured brain may be involved in up-regulating PTBBS within a particular subtype of astrocyte.