Oestrogen and Antioestrogen Induced Gene Expression

The aim of this project was to study the effect of oestrogen and the antioestrogen tamoxifen on the expression of specific genes in the immature rat uterus and MCF-7 human breast cancer cells in order to try and further understand the mechanism of action of these two compounds. In order to do this a cDNA library was constructed using mRNA from 4 hour oestrogen-stimulated rat uteri. This was then screened with cDNA to mRNA from oestrogen stimulated and unstimulated rat uteri in order to isolate clones of oestrogen-regulated mRNAs. Twelve such clones were isolated and the expression of three of these, F4, B11 and E10, together with clones to a number of oncogenes, v-myc, v-Ha-ras, v-Ki-ras and c-sis, the oestrogen-regulated pS2 clone from MCF-7 cells, and an actin clone, p749, were studied in the immature rat uterus and MCF-7 cells in response to oestrogen and tamoxifen. In the immature rat uterus oestrogen caused a biphasic stimulation of expression of total mRNA with peaks at 4 and 16-20 hours after administration and, although the extent of induction was variable, it had a similar effect on all the clones studied, except actin which showed a continual increase from 0-20 hours after administration. Taking into account the slower uptake of tamoxifen, when compared to oestrogen, by uterine cells, and its metabolism to a more active derivative, this compound was found to be agonistic with respect to the induction of all the genes studied except the oestrogen-regulated clone from the rat uterine cDNA library, F4, which showed only one early peak of induction in response to tamoxifen. In MCF-7 human breast cancer cells oestrogen caused a 2-2.5 fold increase in mRNA. levels over control cells between 3 and 36 hours after administration, whereas tamoxifen treatment resulted in no increase in mRNA levels over the first 8 hours, and a decrease to half control level by 36 hours. Oestrogen also stimulated the expression of all the clones studied in this system, except the uterine library clone E10 which did not cross-react with MCF-7 cell RNA, though not to the same extent as in the immature rat uterus. However, the effect of tamoxifen on the amount of total mRNA available from MCF-7 cells meant that only two of the clones, pS2 and p-myc-2, could be studied in full. Of these the level of myc specific RNA was not increased at all but decreased steadily over the 36 hours studied, and although the level of pS2 specific RNA was increased within 1 hour of tamoxifen administration, this increase was only a fraction of that caused by oestrogen at 24 hours, and had fallen to control levels by 36 hours

Trunk muscle activity during drop jump performance in adolescent athletes with back pain

It was with great interest we read the recently published article “Trunk Muscle Activity during Drop Jump Performance in Adolescent Athletes with Back Pain.” Investigating back pain (BP) in adolescents is commendable as there is growing evidence that for many, an experience of BP as early as 14 years of age may relate to ongoing pain in adulthood (Coenen et al., 2017). Indeed, the conventional narrative is changing as individual physical factors such as posture, use of schoolbags, and hypermobility are only weakly associated with adolescent BP. Rather, factors which predict BP at a young age are considered to be multi-dimensional and include gender, negative BP beliefs and poor mental health (O\u27Sullivan et al., 2017; Smith et al., 2017). Mueller et al. (2017) have focused on a single physical factor (trunk muscle activation patterns) drawing inferences regarding BP prevention and treatment. This article prompts consideration of three essential aspects regarding research design and interpretation of findings: 1. Interpreting results from cross-sectional designs 2. Interpreting pain-related differences in motor behavior 3. Translating and conveying scientific results to the end-user (patients, healthcare professionals and policy makers)

Diet-induced obesity impairs mammary development and lactogenesis in murine mammary gland

We have developed a mouse model of diet-induced obesity that shows numerous abnormalities relating to mammary gland function. Animals ate 40% more calories when offered a high-fat diet and gained weight at three times the rate of controls. They exhibited reduced conception rates, increased peripartum pup mortality, and impaired lactogenesis. The impairment of lactogenesis involved lipid accumulation in the secretory epithelial cells indicative of an absence of copius milk secretion. Expression of mRNAs for -casein, whey acid protein, and -lactalbumin were all decreased immediately postpartum but recovered as lactation was established over 2–3 days. Expression of acetyl-CoA carboxylase (ACC)- mRNA was also decreased at parturition as was the total enzyme activity, although there was a compensatory increase in the proportion in the active state. By day 10 of lactation, the proportion of ACC in the active state was also decreased in obese animals, indicative of suppression of de novo fatty acid synthesis resulting from the supply of preformed fatty acids in the diet. Although obese animals consumed more calories in the nonpregnant and early pregnant states, they showed a marked depression in fat intake around day 9 of pregnancy before food intake recovered in later pregnancy. Food intake increased dramatically in both lean and obese animals during lactation although total calories consumed were identical in both groups. Thus, despite access to high-energy diets, the obese animals mobilized even more adipose tissue during lactation than their lean counterparts. Obese animals also exhibited marked abnormalities in alveolar development of the mammary gland, which may partially explain the delay in differentiation evident during lactogenesis

Time walkers and spatial dynamics of ageing information

The distribution of information is essential for living system's ability to coordinate and adapt. Random walkers are often used to model this distribution process and, in doing so, one effectively assumes that information maintains its relevance over time. But the value of information in social and biological systems often decay and must continuously be updated. To capture the spatial dynamics of ageing information, we introduce time walkers. A time walker moves like a random walker, but interacts with traces left by other walkers, some representing older information, some newer. The traces forms a navigable information landscape. We quantify the dynamical properties of time walkers moving on a two-dimensional lattice and the quality of the information landscape generated by their movements. We visualise the self-similar landscape as a river network, and show that searching in this landscape is superior to random searching and scales as the length of loop-erased random walks

Confidence is higher in touch than in vision in cases of perceptual ambiguity

The inclination to touch objects that we can see is a surprising behaviour, given that vision often supplies relevant and sufficiently accurate sensory evidence. Here we suggest that this 'fact-checking' phenomenon could be explained if touch provides a higher level of perceptual certainty than vision. Testing this hypothesis, observers explored inverted T-shaped stimuli eliciting the Vertical-horizontal illusion in vision and touch, which included clear-cut and ambiguous cases. In separate blocks, observers judged whether the vertical bar was shorter or longer than the horizontal bar and rated the confidence in their judgments. Decisions reached by vision were objectively more accurate than those reached by touch with higher overall confidence ratings. However, while confidence was higher for vision rather than for touch in clear-cut cases, observers were more confident in touch when the stimuli were ambiguous. This relative bias as a function of ambiguity qualifies the view that confidence tracks objective accuracy and uses a comparable mapping across sensory modalities. Employing a perceptual illusion, our method disentangles objective and subjective accuracy showing how the latter is tracked by confidence and point towards possible origins for 'fact checking' by touch

At Physiological Temperatures the ATPase Rates of Shortening Soleus and Psoas Myofibrils Are Similar

AbstractWe obtained the temperature dependences of the adenosine triphosphatase (ATPase) activities (calcium-activated and relaxed) of myofibrils from a slow muscle, which we compared with those from a fast muscle. We chose rabbit soleus and psoas because their myosin heavy chains are almost pure: isoforms I and IIX, respectively. The Arrhenius plots of the ATPases are linear (4–35°C) with energies of activation for soleus myofibrils 155kJmol−1 (activated) and 78kJmol−1 (relaxed). With psoas myofibrils, the energies of activation were 71kJmol−1 (activated) and 60kJmol−1 (relaxed). When extrapolated to 42°C the ATPase rates of the two types of myofibril were identical: 50s−1 (activated) and 0.23s−1 (relaxed). Whereas with psoas myofibrils the Km for adenosine triphosphate (activated ATPase) is relatively insensitive to temperature, that for soleus myofibrils increased from 0.3μM at 4°C to 66.5μM at 35°C. Our results illustrate the importance of temperature when comparing the mechanochemical coupling in different types of muscle. We discuss the problem of how to reconcile the similarity of the myofibrillar ATPase rates at physiological temperatures with their different mechanical properties

Stress transmission in granular matter

The transmission of forces through a disordered granular system is studied by means of a geometrical-topological approach that reduces the granular packing into a set of layers. This layered structure constitutes the skeleton through which the force chains set up. Given the granular packing, and the region where the force is applied, such a skeleton is uniquely defined. Within this framework, we write an equation for the transmission of the vertical forces that can be solved recursively layer by layer. We find that a special class of analytical solutions for this equation are L\'evi-stable distributions. We discuss the link between criticality and fragility and we show how the disordered packing naturally induces the formation of force-chains and arches. We point out that critical regimes, with power law distributions, are associated with the roughness of the topological layers. Whereas, fragility is associated with local changes in the force network induced by local granular rearrangements or by changes in the applied force. The results are compared with recent experimental observations in particulate matter and with computer simulations.Comment: 14 pages, Latex, 5 EPS figure

Force Distribution in a Granular Medium

We report on systematic measurements of the distribution of normal forces exerted by granular material under uniaxial compression onto the interior surfaces of a confining vessel. Our experiments on three-dimensional, random packings of monodisperse glass beads show that this distribution is nearly uniform for forces below the mean force and decays exponentially for forces greater than the mean. The shape of the distribution and the value of the exponential decay constant are unaffected by changes in the system preparation history or in the boundary conditions. An empirical functional form for the distribution is proposed that provides an excellent fit over the whole force range measured and is also consistent with recent computer simulation data.Comment: 6 pages. For more information, see http://mrsec.uchicago.edu/granula