Is the mechanical activity of epithelial cells controlled by deformations or forces?

The traction forces developed by cells depend strongly on the substrate rigidity. In this letter, we characterize quantitatively this effect on MDCK epithelial cells by using a microfabricated force sensor consisting in a high-density array of soft pillars whose stiffness can be tailored by changing their height and radius to obtain a rigidity range from 2 nN/microm up to 130 nN/microm. We find that the forces exerted by the cells are proportional to the spring constant of the pillars meaning that, on average, the cells deform the pillars by the same amount whatever their rigidity. The relevant parameter may thus be a deformation rather than a force. These dynamic observations are correlated with the reinforcement of focal adhesions that increases with the substrate rigidity.     

p53 Mutations: Gains or losses?

Although the case for p53 as a tumor suppressor gene appears very strong, one should still keep an open eye for the possibility that mutations in p53 do not necessarily imply a mere loss of "suppressor" activity. It is still possible that the presence of a p53 mutation in a tumor contributes, in a dominant positive manner, to tumorigenesis. In other words, certain p53 mutants may well be oncogenic in their own right, and carry distinct activities that promote growth deregulation and malignant progression. Elucidating this issue also has practical implications, since the nature of the resident mutations may greatly dictate the consequences of attempts to reintroduce wild-type (wt) p53 into particular types of tumor cells. There are two major obstacles along the road to meaningful answers: the limitations of the experimental systems used for evaluating the biological activities of wt and mutant p53 and a fundamental lack of knowledge about the relevant biochemistry of the p53 protein. These two aspects constitute primary experimental challenges for investigators in the field.     

Akt Inhibits DNA damage by Suppressing p73, p53, Forkhead or all Three?

No abstract available.     

To aggregate or not? Capturing the spatio-temporal complexity of the thermal regime

Freshwater stream systems are under immense pressure from various anthropogenic impacts, including climate change. Stream systems are increasingly being altered by changes to the magnitude, timing, frequency, and duration of their thermal regimes, which will have profound impacts on the life-history dynamics of resident biota within their home range. Although temperature regimes have a significant influence on the biology of instream fauna, large spatio-temporal temperature datasets are often reduced to a single metric at discrete locations and used to describe the thermal regime of a system; potentially leading to a significant loss of information crucial to stream management. Models are often used to extrapolate these metrics to unsampled locations, but it is unclear whether predicting actual daily temperatures or an aggregated metric of the temperature regime best describes the complexity of the thermal regime. We fit spatial statistical stream-network models (SSNMs), random forest and non-spatial linear models to stream temperature data from the Upper Condamine River in QLD, Australia and used them to semi-continuously predict metrics describing the magnitude, duration, and frequency of the thermal regime through space and time. We compared both daily and aggregated temperature metrics and found that SSNMs always had more predictive ability than the random forest models, but both models outperformed the non-spatial linear model. For metrics describing thermal magnitude and duration, aggregated predictions were most accurate, while metrics describing the frequency of heating events were better represented by metrics based on daily predictions generated using a SSNM. A more comprehensive representation of the spatio-temporal thermal regime allows researchers to explore new spatio-temporally explicit questions about the thermal regime. It also provides the information needed to generate a suite of ecologically meaningful metrics capturing multiple aspects of the thermal regime, which will increase our scientific understanding of how organisms respond to thermal cues and provide much-needed information for more effective management actions.     

Tumor suppression by p53: fall of the triumvirate?

p53 is a key tumor suppressor protein that has numerous functions. Its primary mode of action has generally been ascribed to the induction of cell-cycle arrest, apoptosis, or senescence upon stress. Li et al. challenge this dogma with evidence that all three of these programs are dispensable for p53's tumor suppressive role.     

Brushing cytology of the upper gastrointestinal tract. Obsolete or not?

The merit of brushing cytology of the upper gastrointestinal tract has been questioned since it appears to duplicate biopsy. To determine its value, the reports on all endoscopic biopsy and cytology specimens from a one-year period were reviewed. The 683 procedures included 481 in which only a histologic biopsy sample was obtained, 47 in which only a cytologic brushing sample was obtained and 155 in which both types of samples were obtained ("combined specimens"). Among the 155 combined specimens, 4 of the confirmed malignancies were detected by histology only while 2 were detected by cytology only. A diagnosis of suspicious or positive for malignancy was made for 20% of the combined specimens as compared to less than 5% of the biopsy-only or brushing-only specimens. While 15% of the specimens that included a brushing sample (either alone or with biopsy) showed fungal infections, only 1.2% of the biopsy-only specimens did. It appears that the clinicians at this hospital tend to use brushing in combination with biopsy when either a malignancy or a fungal infection is suspected. Other empiric advantages of endoscopic brushing cytology include its rapid turn-around time, minimal invasiveness and good recognition of lymphoid cells. The selective use of brushing cytology should increase the probability of detecting malignancies and fungal infections without any increased risk or discomfort to the patients.     

Dissecting the pathways that destabilize mutant p53: The proteasome or autophagy?

One fundamental feature of mutant forms of p53 consists in their accumulation at high levels in tumors. At least in the case of neomorphic p53 mutations, which acquire oncogenic activity, stabilization is a driving force for tumor progression. It is well documented that p53 mutants are resistant to proteasome-dependent degradation compared with wild-type p53, but the exact identity of the pathways that affect mutant p53 stability is still debated. We have recently shown that macroautophagy (autophagy) provides a route for p53 mutant degradation during restriction of glucose. Here we further show that in basal conditions of growth, inhibition of autophagy with chemical inhibitors or by downregulation of the essential autophagic genes ATG1/Ulk1, Beclin-1 or ATG5, results in p53 mutant stabilization. Conversely, overexpression of Beclin-1 or ATG1/Ulk1 leads to p53 mutant depletion. Furthermore, we found that in many cell lines, prolonged inhibition of the proteasome does not stabilize mutant p53 but leads to its autophagic-mediated degradation. Therefore, we conclude that autophagy is a key mechanism for regulating the stability of several p53 mutants. We discuss plausible mechanisms involved in this newly identified degradation pathway as well as the possible role played by autophagy during tumor evolution driven by mutant p53.     

p53 Mutants: the Achilles’ Heel of Human Cancers?

Recent scientific discoveries have thrust mutants of the tumor suppressor protein p53 into the forefront of the war on cancer, and hold out eventual hope for a small molecule drug that will be useful in treating human cancers with mutant p53 protein.     

p53: The Janus of autophagy?

The autophagy pathway functions in adaptation to nutrient stress and tumour suppression. The p53 tumour suppressor, previously thought to positively regulate autophagy, may also inhibit it. This dual interplay between p53 and autophagy regulation is enigmatic, but may underlie key aspects of metabolism and cancer biology.