Cell cycle regulators cyclin D1 and CDK4/6 have estrogen receptor-dependent divergent functions in breast cancer migration and stem cell-like activity

Cyclin D1 and its binding partners CDK4/6 are essential regulators of cell cycle progression and are implicated in cancer progression. Our aim was to investigate a potential regulatory role of these proteins in other essential tumor biological characteristics. Using a panel of breast cancer cell lines and primary human breast cancer samples, we have demonstrated the importance of these cell cycle regulators in both migration and stem-like cell activity. siRNA was used to target cyclin D1 and CDK4/6 expression, having opposing effects on both migration and stem-like cell activity dependent upon estrogen receptor (ER) expression. Inhibition of cyclin D1 or CDK4/6 increases or decreases migration and stem-like cell activity in ER−ve (ER-negative) and ER+ve (ER-positive) breast cancer, respectively. Furthermore, overexpressed cyclin D1 caused decreased migration and stem-like cell activity in ER−ve cells while increasing activity in ER+ve breast cancer cells. Treatment of breast cancer cells with inhibitors of cyclin D1 and CDK4/6 (Flavopiridol/PD0332991), currently in clinical trials, mimicked the effects observed with siRNA treatment. Re-expression of ER in two ER−ve cell lines was sufficient to overcome the effects of either siRNA or clinical inhibitors of cyclin D1 and CDK4/6.   In conclusion, cyclin D1 and CDK4/6 have alternate roles in regulation of migration and stem-like cell activity. Furthermore, these effects are highly dependent upon expression of ER. The significance of these results adds to our general understanding of cancer biology but, most importantly, could be used diagnostically to predict treatment response to cell cycle inhibition in breast cancer.     

Age-Specific Mortality During the 1918 Influenza Pandemic: Unravelling the Mystery of High Young Adult Mortality

The worldwide spread of a novel influenza A (H1N1) virus in 2009 showed that influenza remains a significant health threat, even for individuals in the prime of life. This paper focuses on the unusually high young adult mortality observed during the Spanish flu pandemic of 1918. Using historical records from Canada and the U.S., we report a peak of mortality at the exact age of 28 during the pandemic and argue that this increased mortality resulted from an early life exposure to influenza during the previous Russian flu pandemic of 1889–90. We posit that in specific instances, development of immunological memory to an influenza virus strain in early life may lead to a dysregulated immune response to antigenically novel strains encountered in later life, thereby increasing the risk of death. Exposure during critical periods of development could also create holes in the T cell repertoire and impair fetal maturation in general, thereby increasing mortality from infectious diseases later in life. Knowledge of the age-pattern of susceptibility to mortality from influenza could improve crisis management during future influenza pandemics.

“The war is over – and I must go” Egon Schiele, 1890–1918.

     

Serum lipoproteins promote efficient presentation of the malaria virulence protein PfEMP1 at the erythrocyte surface

The virulence of the malaria parasite Plasmodium falciparum is related to its ability to express a family of adhesive proteins known as P. falciparum erythrocyte membrane protein 1 (PfEMP1) at the infected red blood cell surface. The mechanism for the transport and delivery of these adhesins to the erythrocyte membrane is only poorly understood. In this work, we have used specific immune reagents in a flow cytometric assay to monitor the effects of serum components on the surface presentation of PfEMP1. We show that efficient presentation of the A4 and VAR2CSA variants of PfEMP1 is dependent on the presence of serum in the bathing medium during parasite maturation. Lipid-loaded albumin supports parasite growth but allows much less efficient presentation of PfEMP1 at the red blood cell surface. Analysis of the serum components reveals that lipoproteins, especially those of the low-density lipoprotein fraction, promote PfEMP1 presentation. Cytoadhesion of infected erythrocytes to the host cell receptors CD36 and ICAM-1 is also decreased in infected erythrocytes cultured in the absence of serum. The defect appears to be in the transfer of PfEMP1 from parasite-derived structures known as the Maurer's clefts to the erythrocyte membrane or in surface conformation rather than a down-regulation or switching of particular PfEMP1 variants.     

Land use and dispersal influence mortality in white-tailed deer

Restoring male age structure in white-tailed deer populations has become an important objective for many state agencies aimed at improving herd dynamics. Limiting mortality in the yearling (1–2 yr old) age class is a primary consideration, and regional differences in climate, habitat characteristics, hunting regulations, and hunter behavior complicate the understanding of how specific factors influence the risk of mortality. We used Cox proportional hazard modeling to determine the effects of body size, mean distance to road, dispersal behaviors, use of forested land, and use of land open to public hunting on the risk of mortality for a population of radio-collared, yearling males (n = 76) in Sussex County, Delaware, USA. Annual survival averaged 0.55 (95% CI = 0.45–0.68), with harvest accounting for 79% (26/33) of all mortalities. Measurements of body size (chest girth, shoulder height, and total length; cm) influenced dispersal probability but not dispersal distance. The best approximating model for mortality risk included a covariate for landownership, whereby mortality risk increased on public land. Among males who dispersed, longer-distance dispersal was associated with reduced mortality, which contradicts previous research describing dispersal as a high-risk behavior. The effect of landownership on mortality risk has not been previously identified, especially when regulations regarding harvest of yearling males are similar between landownership types. We observed annual survival rates of 0.69 (95% CI = 0.57–0.82) for deer apparently using private land exclusively during the hunting season, and 0.20 (95% CI = 0.11–0.48) for deer that used public land during the hunting season. Survival rates on private land were comparable to those of other regions actively managing male age structure. These results suggest survival of yearling males in the region is influenced by hunter harvest and the risks associated with dispersal may be minimal in areas where harvest pressure is low, although hunter harvest on public land may limit male age structure on a localized scale. © The Wildlife Society, 2019     

Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem

Hereditary degeneration of photoreceptors has been linked to over-activation of Ca²⁺-permeable channels, excessive Ca²⁺-influx, and downstream activation of Ca²⁺-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca²⁺-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca²⁺-influx, most probably by blocking the pore of Ca²⁺-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca²⁺ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca²⁺-independent degenerative mechanisms.Subject terms: Cell death in the nervous system, Ion channels in the nervous system, Molecular neuroscience     

The cover of living and dead corals from airborne remote sensing

Trends in coral cover are widely used to indicate the health of coral reefs but are costly to obtain from field survey over large areas. In situ studies of reflected spectra at the coral surface show that living and recently dead colonies can be distinguished. Here, we investigate whether such spectral differences can be detected using an airborne remote sensing instrument. The Compact Airborne Spectrographic Imager (Itres Research Ltd, Canada) was flown in two configurations: 10 spectral bands with 1-m² pixels and 6 spectral bands with 0.25-m² pixels. First, we show that an instrument with 10 spectral bands possesses adequate spectral resolution to distinguish living Porites, living Pocillopora spp., partially dead Porites, recently dead Porites (total colony mortality within 6 months), old dead (>6 months) Porites, Halimeda spp., and coralline red algae when there is no water column to confuse spectra. All substrata were distinguished using fourth-order spectral derivatives around 538 nm and 562 nm. Then, at a shallow site (Tivaru) at Rangiroa Atoll, Tuamotu Archipelago (French Polynesia), we show that live and dead coral can be distinguished from the air to a depth of at least 4 m using first- and fourth-order spectral derivatives between 562–580 nm. However, partially dead and recently dead Porites colonies could not be distinguished from an airborne platform. Spectral differences among substrata are then exploited to predict the cover of reef substrata in ten 25-m² plots at nearby Motu Nuhi (max depth 8 m). The actual cover in these plots was determined in situ using quadrats with a 0.01-m² grid. Considerable disparity occurred between field and image-based measures of substrate cover within individual 25-m² quadrats. At this small scale, disparity, measured as the absolute difference in cover between field and remote-sensing methods, reached 25% in some substrata but was always less than 10% for living coral (99% of which consisted of Porites spp.). At the scale of the reef (all ten 25-m² quadrats), however, disparities in percent cover between imagery and field data were less than 10% for all substrata and extremely low for some classes (e.g. <3% for living Porites, recently dead Porites and Halimeda). The least accurately estimated substrata were sand and coralline red algae, which were overestimated by absolute values 7.9% and 6.6%, respectively. The precision of sampling was similar for field and remote-sensing methods: field methods required 19 plots to detect a 10% difference in coral cover among three reefs with a statistical power of 95%. Remote-sensing methods required 21 plots. However, it took 1 h to acquire imagery over 92,500 m² of reef, which represents 3,700 plots of 25 m² each, compared with 3 days to survey 10 such plots underwater. There were no significant differences in accuracy between 1-m² and 0.25-m² image resolutions, suggesting that the advantage of using smaller pixels is offset by reduced spectral information and an increase in noise (noise was observed to be 1.6–1.8 times greater in 0.25-m² pixels). We show that airborne remote sensing can be used to monitor coral and algal cover over large areas, providing that water is shallow and clear, and that brown fleshy macroalgae are scarce, that depth is known independently (e.g. from sonar survey).     

Malaria in pregnancy and the endemicity spectrum: what can we learn?

The increased susceptibility of pregnant women to malaria infection has long been recognized, but the magnitude of the disease burden in this particular group, together with the pathophysiology of maternal malaria and the specific difficulties in treatment, have only recently been the focus of research. Most research on maternal malaria has derived from sub-Saharan Africa where transmission is high, whereas most of the studies on the treatment of malaria and the effect of non-falciparum species has been conducted in low-transmission areas of Asia. In this paper, we attempt to improve our understanding of the disease and its mechanisms from observed differences and similarities between contrasting areas of transmission, and to identify priorities for future research.     

Platyamoeba pseudovannellida n. sp., a naked amoeba with wide salt tolerance isolated from the Salton Sea, California

A new species of naked amoeba, Platyamoeba pseudovannellida n.sp., is described on the basis of light microscopic and fine structural features. The amoeba was isolated from the Salton Sea, California, from water at a salinity of ca. 44%. Locomotive amoebae occasionally had a spatulate outline and floating cells had radiating pseudopodia, sometimes with pointed tips. Both these features are reminiscent of the genus Vannella. However, the surface coat (glycocalyx) as revealed by TEM indicates that this is a species of Platyamoeba. Although salinity was not used as a diagnostic feature, this species was found to have remarkable tolerance to fluctuating salinity levels, even when changes were rapid. Amoebae survived over the range 0 per thousand to 150 per thousand salt and grew within the range 0 per thousand to 138 per thousand salt. The generation time of cells averaged 29 h and was not markedly affected by salt concentration. This is longer than expected for an amoeba of this size and suggests a high energetic cost of coping with salinity changes. The morphology of cells changed with increasing salinity: at 0 per thousand cells were flattened and active and at the other extreme (138 per thousand) amoebae were wrinkled and domed and cell movement was very slow. At the ultrastructural level, the cytoplasm of cells grown at high salinity (98 per thousand was considerably denser than that of cells reared at 0 per thousand.     

The effect of five weeks of Tribulus terrestris supplementation on muscle strength and body composition during preseason training in elite rugby league players

Tribulus terrestris is an herbal nutritional supplement that is promoted to produce large gains in strength and lean muscle mass in 5-28 days (15, 18). Although some manufacturers claim T. terrestris will not lead to a positive drug test, others have suggested that T. terrestris may increase the urinary testosterone/epitestosterone (T/E) ratio, which may place athletes at risk of a positive drug test. The purpose of the study was to determine the effect of T. terrestris on strength, fat free mass, and the urinary T/E ratio during 5 weeks of preseason training in elite rugby league players. Twenty-two Australian elite male rugby league players (mean +/- SD; age = 19.8 +/- 2.9 years; weight = 88.0 +/- 9.5 kg) were match-paired and randomly assigned in a double-blind manner to either a T. terrestris (n = 11) or placebo (n = 11) group. All subjects performed structured heavy resistance training as part of the club's preseason preparations. A T. terrestris extract (450 mg.d(-1)) or placebo capsules were consumed once daily for 5 weeks. Muscular strength, body composition, and the urinary T/E ratio were monitored prior to and after supplementation. After 5 weeks of training, strength and fat free mass increased significantly without any between-group differences. No between-group differences were noted in the urinary T/E ratio. It was concluded that T. terrestris did not produce the large gains in strength or lean muscle mass that many manufacturers claim can be experienced within 5-28 days. Furthermore, T. terrestris did not alter the urinary T/E ratio and would not place an athlete at risk of testing positive based on the World Anti-Doping Agency's urinary T/E ratio limit of 4:1.