Structure and Chemical Inhibition of the Ret Tyrosine Kinase Domain.

The RET proto-oncogene encodes a receptor tyrosine kinase for the glial cell line-derived neurotrophic factor family of ligands. Loss-of-function mutations in RET are implicated in Hirschsprung disease, whereas activating mutations in RET are found in human cancers, including familial medullar thyroid carcinoma and multiple endocrine neoplasias 2A and 2B. We report here the biochemical characterization of the human RET tyrosine kinase domain and the structure determination of the non-phosphorylated and phosphorylated forms. Both structures adopt the same active kinase conformation competent to bind ATP and substrate and have a pre-organized activation loop conformation that is independent of phosphorylation status. In agreement with the structural data, enzyme kinetic data show that autophosphorylation produces only a modest increase in activity. Longer forms of RET containing the juxtamembrane domain and C-terminal tail exhibited similar kinetic behavior, implying that there is no cis-inhibitory mechanism within the RET intracellular domain. Our results suggest the existence of alternative inhibitory mechanisms, possibly in trans, for the autoregulation of RET kinase activity. We also present the structures of the RET tyrosine kinase domain bound to two inhibitors, the pyrazolopyrimidine PP1 and the clinically relevant 4-anilinoquinazoline ZD6474. These structures explain why certain multiple endocrine neoplasia 2-associated RET mutants found in patients are resistant to inhibition and form the basis for design of more effective inhibitors

A Second Large Subglacial Impact Crater in Northwest Greenland?

Following the discovery of the Hiawatha impact crater beneath the northwest margin of the Greenland Ice Sheet, we explored satellite and aerogeophysical data in search of additional such craters. Here we report the discovery of a possible second subglacial impact crater that is 36.5 km wide and 183 km southeast of the Hiawatha impact crater. Although buried by 2 km of ice, the structure's rim induces a conspicuously circular surface expression, it possesses a central uplift and it causes a negative gravity anomaly. The existence of two closely-spaced and similarlysized complex craters raises the possibility that they formed during related impact events. However, the second structure's morphology is shallower, its overlying ice is conformal and older, and such an event can be explained by chance. We conclude that the identified structure is very likely an impact crater, but it is unlikely to be a twin of the Hiawatha impact crater

Solving 1d plasmas and 2d boundary problems using Jack polynomials and functional relations

The general one-dimensional ``log-sine'' gas is defined by restricting the positive and negative charges of a two-dimensional Coulomb gas to live on a circle. Depending on charge constraints, this problem is equivalent to different boundary field theories. We study the electrically neutral case, which is equivalent to a two-dimensional free boson with an impurity cosine potential. We use two different methods: a perturbative one based on Jack symmetric functions, and a non-perturbative one based on the thermodynamic Bethe ansatz and functional relations. The first method allows us to compute explicitly all coefficients in the virial expansion of the free energy and the experimentally-measurable conductance. Some results for correlation functions are also presented. The second method provides in particular a surprising fluctuation-dissipation relation between the free energy and the conductance.Comment: 19 page

Prevalence and tracking of back pain from childhood to adolescence

<p>Abstract</p> <p>Background</p> <p>It is generally acknowledged that back pain (BP) is a common condition already in childhood. However, the development until early adulthood is not well understood and, in particular, not the individual tracking pattern. The objectives of this paper are to show the prevalence estimates of BP, low back pain (LBP), mid back pain (MBP), neck pain (NP), and care-seeking because of BP at three different ages (9, 13 and15 years) and how the BP reporting tracks over these age groups over three consecutive surveys.</p> <p>Methods</p> <p>A longitudinal cohort study was carried out from the years of 1997 till 2005, collecting interview data from children who were sampled to be representative of Danish schoolchildren. BP was defined overall and specifically in the three spinal regions as having reported pain within the past month. The prevalence estimates and the various patterns of BP reporting over time are presented as percentages.</p> <p>Results</p> <p>Of the 771 children sampled, 62%, 57%, and 58% participated in the three back surveys and 34% participated in all three. The prevalence estimates for children at the ages of 9, 13, and 15, respectively, were for BP 33%, 28%, and 48%; for LBP 4%, 22%, and 36%; for MBP 20%, 13%, and 35%; and for NP 10%, 7%, and 15%. Seeking care for BP increased from 6% and 8% at the two youngest ages to 34% at the oldest. Only 7% of the children who participated in all three surveys reported BP each time and 30% of these always reported no pain. The patterns of development differed for the three spinal regions and between genders. Status at the previous survey predicted status at the next survey, so that those who had pain before were more likely to report pain again and vice versa. This was most pronounced for care-seeking.</p> <p>Conclusion</p> <p>It was confirmed that BP starts early in life, but the patterns of onset and development over time vary for different parts of the spine and between genders. Because of these differences, it is recommended to report on BP in youngsters separately for the three spinal regions, and to differentiate in the analyses between the genders and age groups. Although only a small minority reported BP at two or all three surveys, tracking of BP (particularly NP) and care seeking was noted from one survey to the other. On the positive side, individuals without BP at a previous survey were likely to remain pain free at the subsequent survey.</p

Determinants of Acceptance of Cervical Cancer Screening in Dar es Salaam, Tanzania.

To describe how demographic characteristics and knowledge of cervical cancer influence screening acceptance among women living in Dar es Salaam, Tanzania. Multistage cluster sampling was carried out in 45 randomly selected streets in Dar es Salaam. Women between the ages of 25-59 who lived in the sampled streets were invited to a cervical cancer screening; 804 women accepted and 313 rejected the invitation. Information on demographic characteristics and knowledge of cervical cancer were obtained through structured questionnaire interviews. Women aged 35-44 and women aged 45-59 had increased ORs of 3.52 and 7.09, respectively, for accepting screening. Increased accepting rates were also found among single women (OR 2.43) and among women who had attended primary or secondary school (ORs of 1.81 and 1.94). Women who had 0-2 children were also more prone to accept screening in comparison with women who had five or more children (OR 3.21). Finally, knowledge of cervical cancer and awareness of the existing screening program were also associated with increased acceptance rates (ORs of 5.90 and 4.20). There are identifiable subgroups where cervical cancer screening can be increased in Dar es Salaam. Special attention should be paid to women of low education and women of high parity. In addition, knowledge and awareness raising campaigns that goes hand in hand with culturally acceptable screening services will likely lead to an increased uptake of cervical cancer screening

Textiles and environment in the showcase containing Saint Canute the Holy († AD 1086): Radiocarbon dating and chemical interactions

The cathedral in Odense, Denmark, has for nine centuries held the relics of the Danish King St Canute the Holy and his brother Benedikt. They were both murdered in the predecessor church at the site in AD 1086, and Canute was sanctified in already in AD 1100. The history of the relics has been that of turmoil at times, varying from initial worship of the Catholic believers, to being walled up and hidden away after the protestant reformation in AD 1536, and since the 19th Century on display as important heritage objects of national importance. In the present work we have characterised some of the textiles and analysed the air inside the glass showcases exhibiting the 11th Century wooden coffins holding the remains of St King Canute the Holy and his brother together with some precious textiles. Contrary to previous belief, we now prove that all the textiles analysed have the same age, which is consistent with the time of the enshrinement of the King and his brother in AD 1100. It is also shown that some of the textiles were treated with paraffin wax, most likely during attempts at conservation at the National Museum in the nineteenth century. The results of the air chemistry analyses show the problematic side of simultaneously storing of slowly decaying wood, fine textiles, and human bones in rather airtight environments. The wood continuously releases organic acids, the soaring concentrations of which are potentially harmful to the 11th Century textiles and probably also to the bones

Ice core evidence for a 20th century increase in surface mass balance in coastal Dronning Maud Land, East Antarctica

Ice cores provide temporal records of surface mass balance (SMB). Coastal areas of Antarctica have relatively high and variable SMB, but are under-represented in records spanning more than 100 years. Here we present SMB reconstruction from a 120 m-long ice core drilled in 2012 on the Derwael Ice Rise, coastal Dronning Maud Land, East Antarctica. Water stable isotope (δ18O and δD) stratigraphy is supplemented by discontinuous major ion profiles and continuous electrical conductivity measurements. The base of the ice core is dated to AD 1759 ± 16, providing a climate proxy for the past  ∼ 250 years. The core's annual layer thickness history is combined with its gravimetric density profile to reconstruct the site's SMB history, corrected for the influence of ice deformation. The mean SMB for the core's entire history is 0.47 ± 0.02 m water equivalent (w.e.) a−1. The time series of reconstructed annual SMB shows high variability, but a general increase beginning in the 20th century. This increase is particularly marked during the last 50 years (1962–2011), which yields mean SMB of 0.61 ± 0.01 m w.e. a−1. This trend is compared with other reported SMB data in Antarctica, generally showing a high spatial variability. Output of the fully coupled Community Earth System Model (CESM) suggests that, although atmospheric circulation is the main factor influencing SMB, variability in sea surface temperatures and sea ice cover in the precipitation source region also explain part of the variability in SMB. Local snow redistribution can also influence interannual variability but is unlikely to influence long-term trends significantly. This is the first record from a coastal ice core in East Antarctica to show an increase in SMB beginning in the early 20th century and particularly marked during the last 50 years

A Possible Second Large Subglacial Impact Crater in Northwest Greenland

Following the discovery of the Hiawatha impact crater beneath the northwest margin of the Greenland Ice Sheet, we explored satellite and aerogeophysical data in search of additional such craters. Here we report the discovery of a possible second subglacial impact crater that is 36.5 km wide and 183 km southeast of the Hiawatha impact crater. Although buried by 2 km of ice, the structure's rim induces a conspicuously circular surface expression, it possesses a central uplift and it causes a negative gravity anomaly. The existence of two closely-spaced and similarlysized complex craters raises the possibility that they formed during related impact events. However, the second structure's morphology is shallower, its overlying ice is conformal and older, and such an event can be explained by chance. We conclude that the identified structure is very likely an impact crater, but it is unlikely to be a twin of the Hiawatha impact crater