Heat shock proteins Hsp90 and Hsp70 facilitate protein folding but can also direct proteins for ubiquitin-mediated degradation. The mechanisms regulating these opposite activities involve Hsp binding ...to co-chaperones including CHIP and HOP at their C-termini. We demonstrated that the extreme C-termini of Hsp70 and Hsp90 contain phosphorylation sites targeted by kinases including CK1, CK2 and GSK3-β in vitro. The phosphorylation of Hsp90 and Hsp70 prevents binding to CHIP and thus enhances binding to HOP. Highly proliferative cells contain phosphorylated chaperones in complex with HOP and phospho-mimetic and non-phosphorylable Hsp mutant proteins show that phosphorylation is directly associated with increased proliferation rate. We also demonstrate that primary human cancers contain high levels of phosphorylated chaperones and show increased levels of HOP protein and mRNA. These data identify C-terminal phosphorylation of Hsp70 and Hsp90 as a switch for regulating co-chaperone binding and indicate that cancer cells possess an elevated protein folding environment by the concerted action of co-chaperone expression and chaperone modifications. In addition to identifying the pathway responsible for regulating chaperone-mediated protein folding/degradation balances in normal cells, the data provide novel mechanisms to account for the aberrant chaperone activities observed in human cancer cells and have implications for the application of anti-chaperone therapies in cancer treatment.
The RNA helicase p68 (DDX5) is an established co-activator of the p53 tumour suppressor that itself has a pivotal role in orchestrating the cellular response to DNA damage. Although several factors ...influence the biological outcome of p53 activation, the mechanisms governing the choice between cell-cycle arrest and apoptosis remain to be elucidated. In the present study, we show that, while p68 is critical for p53-mediated transactivation of the cell-cycle arrest gene p21(WAF1/CIP1), it is dispensable for induction of several pro-apoptotic genes in response to DNA damage. Moreover, p68 depletion results in a striking inhibition of recruitment of p53 and RNA Pol II to the p21 promoter but not to the Bax or PUMA promoters, providing an explanation for the selective effect on p21 induction. Importantly, these findings are mirrored in a novel inducible p68 knockout mouse model in which p68 depletion results in a selective inhibition of p21 induction in several tissues. Moreover, in the bone marrow, p68 depletion results in an increased sensitivity to γ-irradiation, consistent with an increased level of apoptosis. These data highlight a novel function of p68 as a modulator of the decision between p53-mediated growth arrest and apoptosis in vitro and in vivo.
Hand, foot, and mouth disease (HFMD) is an enterovirus‐mediated condition that predominantly affects children under 5 years of age. The tendency for outbreaks to peak in warmer summer months suggests ...a relationship between HFMD and weather patterns. We reviewed the English‐language literature for articles describing a relationship between meteorological variables and HFMD. Seventy‐two studies meeting criteria were identified. A positive, statistically significant relationship was identified between HFMD cases and both temperature (61 of 67 studies, or 91.0%, reported a positive relationship) CI 81.8–95.8%, P = 0.0001 and relative humidity (41 of 54 studies, or 75.9%) CI 63.1–85.4%, P = 0.0001. No significant relationship was identified between HFMD and precipitation, wind speed, and/or sunshine. Most countries reported a single peak of disease each year (most commonly early Summer), but subtropical and tropical climate zones were significantly more likely to experience a bimodal distribution of cases throughout the year (two peaks a year; most commonly late spring/early summer, with a smaller peak in autumn). The rising global incidence of HFMD, particularly in Pacific Asia, may be related to climate change. Weather forecasting might be used effectively in the future to indicate the risk of HFMD outbreaks and the need for targeted public health interventions.
•First simulation of the hierarchical multi-mode molecular stress function model.•The model is compared to experiment for a 3D contraction flow of Lupolen LDPE.•Striking agreement shown for vortex ...opening angles over a large range of flow rates.•Simulated and experimental birefringence show very good correspondence.•Variation of apparent stress optical coefficient with flow rate shown to be low.
A recent development of the Molecular Stress Function constitutive model, the Hierarchical Multi-Mode Molecular Stress Function (HMMSF) model has been shown to fit a large range of rheometrical data with accuracy, for a large range of polymer melts. We develop a 3D simulation of the HMMSF model and compare it to experimental data for the flow of Lupolen 1840H LDPE through an abrupt 3D contraction flow. We believe this to be the first finite element implementation of the HMMSF model. It is shown that the model gives a striking agreement with experimental vortex opening angles, with very good agreement to full-field birefringence measurements, over a wide range of flow rates. A method to give fully-developed inlet boundary conditions is implemented (in place of using parabolic inlet boundary conditions), which gives a significantly improved match to birefringence measurements in the inlet area, and in low stress areas downstream from the inlet. Alternative constitutive model parameters are assessed following the principle that extensional rheometer data actually provides a ‘lower bound’ for peak extensional viscosity. It is shown that the model robustly maintains an accurate fit to vortex opening angle and full-field birefringence data, provided that both adjustable parameters are kept such that both shear and extensional data are well fitted.
BACKGROUND: Juvenile‐onset spinocerebellar ataxia has been recognized in Jack Russell Terriers and related Russell group terriers (RGTs) for over 40 years. Ataxia occurs with varying combinations of ...myokymia, seizures, and other signs of neurologic disease. More than 1 form of the disease has been suspected. HYPOTHESIS/OBJECTIVES: The objective was to identify the mutation causing the spinocerebellar ataxia associated with myokymia, seizures, or both and distinguish the phenotype from other ataxias in the RGTs. ANIMALS: DNA samples from 16 RGTs with spinocerebellar ataxia beginning from 2 to 12 months of age, 640 control RGTs, and 383 dogs from 144 other breeds along with the medical records of affected dogs were studied. METHODS: This case‐control study compared the frequencies of a KCNJ10 allele in RGTs with spinocerebellar ataxia versus control RGTs. This allele was identified in a whole‐genome sequence of a single RGT with spinocerebellar ataxia and myokymia by comparison to whole‐genome sequences from 81 other canids that were normal or had other diseases. RESULTS: A missense mutation in the gene coding for the inwardly rectifying potassium channel Kir4.1 (KCNJ10:c.627C>G) was significantly (P < .001) associated with the disease. Dogs homozygous for the mutant allele all had spinocerebellar ataxia with varying combinations of myokymia and seizures. CONCLUSIONS AND CLINICAL IMPORTANCE: Identification of the KCNJ10 mutation in dogs with spinocerebellar ataxia with myokymia, seizures, or both clarifies the multiple forms of ataxia seen in these breeds and provides a DNA test to identify carriers.
Flows of complex fluids need to be understood at both macroscopic and molecular scales, because it is the macroscopic response that controls the fluid behavior, but the molecular scale that ...ultimately gives rise to rheological and solid-state properties. Here the flow field of an entangled polymer melt through an extended contraction, typical of many polymer processes, is imaged optically and by small-angle neutron scattering. The dual-probe technique samples both the macroscopic stress field in the flow and the microscopic configuration of the polymer molecules at selected points. The results are compared with a recent "tube model" molecular theory of entangled melt flow that is able to calculate both the stress and the single-chain structure factor from first principles. The combined action of the three fundamental entangled processes of reptation, contour length fluctuation, and convective constraint release is essential to account quantitatively for the rich rheological behavior. The multiscale approach unearths a new feature: Orientation at the length scale of the entire chain decays considerably more slowly than at the smaller entanglement length.
Throughout much of the African continent, healthcare systems are already strained in their efforts to meet the needs of a growing population using limited resources. Climate change threatens to ...undermine many of the public health gains that have been made in this region in the last several decades via multiple mechanisms, including malnutrition secondary to drought‐induced food insecurity, mass human displacement from newly uninhabitable areas, exacerbation of environmentally sensitive chronic diseases, and enhanced viability of pathogenic microbes and their vectors. We reviewed the literature describing the various direct and indirect effects of climate change on diseases with cutaneous manifestations in Africa. We included non‐communicable diseases such as malignancies (non‐melanoma skin cancers), inflammatory dermatoses (i.e. photosensitive dermatoses, atopic dermatitis), and trauma (skin injury), as well as communicable diseases and neglected tropical diseases. Physicians should be aware of the ways in which climate change threatens human health in low‐ and middle‐income countries in general, and particularly in countries throughout Africa, the world's lowest‐income and second most populous continent.
PDF
