Molecular dynamics studies of the STAT3 homodimer:DNA complex: relationships between STAT3 mutations and protein-DNA recognition.

Signal Transducers and Activators of Transcription (STAT) proteins are a group of latent cytoplasmic transcription factors involved in cytokine signaling. STAT3 is a member of the STAT family and is expressed at elevated levels in a large number of diverse human cancers and is now a validated target for anticancer drug discovery.. Understanding the dynamics of the STAT3 dimer interface, accounting for both protein-DNA and protein-protein interactions, with respect to the dynamics of the latent unphosphorylated STAT3 monomer, is important for designing potential small-molecule inhibitors of the activated dimer. Molecular dynamics (MD) simulations have been used to study the activated STAT3 homodimer:DNA complex and the latent unphosphorylated STAT3 monomer in an explicit water environment. Analysis of the data obtained from MD simulations over a 50 ns time frame has suggested how the transcription factor interacts with DNA, the nature of the conformational changes, and ways in which function may be affected. Examination of the dimer interface, focusing on the protein-DNA interactions, including involvement of water molecules, has revealed the key residues contributing to the recognition events involved in STAT3 protein-DNA interactions. This has shown that the majority of mutations in the DNA-binding domain are found at the protein-DNA interface. These mutations have been mapped in detail and related to specific protein-DNA contacts. Their structural stability is described, together with an analysis of the model as a starting-point for the discovery of novel small-molecule STAT3 inhibitors.

Relationships between lameness and feeding behaviour in cubicle-housed Holstein-Friesian dairy cows

The relationship between lameness and feeding behaviour in dairy cows is not yet fully understood. This study examined the effect of lameness on feeding behaviour at two points during lactation. Forty-five Holstein–Friesian dairy cows (average parity 3.3) were housed in cubicle accommodation after calving and fed a total mixed ration (TMR). At approximately 60 and 120 days post partum, 48 h of information on feeding behaviour (including number of meals eaten, meal duration, meal size and feeding rate) was collected for each animal using feed boxes fitted to a data recording system. At the same time points, locomotion scores were recorded for each cow as a measure of lameness (1.0-sound to 4.5-severely lame). Relationships between feeding behaviour and locomotion score were analysed using Residual Maximum Likelihood (REML) analysis. At both time points, cows with higher locomotion scores ate fewer (P < 0.001), larger meals (P < 0.001) and had a shorter total feeding time (P < 0.001). At day 60 post partum, an increase in locomotion score was associated with a decrease in dry matter intake (P < 0.05), but at day 120 post partum no relationship was found between locomotion score and DMI. No relationship was found at either time point between locomotion score and mean meal duration or rate of feeding. The results of this study suggest that the effect of lameness on feeding behaviour in dairy cows does not remain constant across lactation.

The Family of Love in English Society, 1550-1630

A detailed investigation of an outlawed mystical religious fellowship in early modern England.

Severity staging by early features of age-related maculopathy exhibits weak relationships with functional deficits on SWS grating acuity

To examine the relationship between short-wavelength-sensitive (SWS) resolution acuity and epidemiologically defined stages of early age-related maculopathy (ARM).

Structural basis for understanding structure-activity relationships for the glutamate binding site of the NMDA receptor

We present new homology-based models of the glutamate binding site (in closed and open forms) of the NMDA receptor NR2B subunit derived from X-ray structures of the water soluble AMPA sensitive glutamate receptor. The models were used for revealing binding modes of agonists and competitive antagonists, as well as for rationalizing known experimental facts concerning structure-activity relationships: (i) the switching between the agonist and the antagonist modes of action upon lengthening the chain between the distal acidic group and the amino acid moiety, (ii) the preference for the methyl group attached to the a-amino group of ligands, (iii) the preference for the D-configuration of agonists and antagonists, and (iv) the existence of "superacidic" agonists.

The UNCRC and social workers' relationships with young children

In the UK, The Munro Review of Child Protection (2010, 2011a, 2011b) has recently highlighted that among the failings in safeguarding children known to social services is the lack of meaningful relationships between social workers and children. In her final report, Munro (2011b) has made recommendations for a more child-centred system anchored on two themes – the child's journey and the United Nations Convention on the Rights of the Child (UNCRC). This article illustrates by way of practical examples how the UNCRC, together with the detailed advice and guidance contained in the UNCRC general comments numbers 5, 7 and 12, provides the best framework for developing effective social work relationships with, and safeguarding, young children.

Cube, cylinder, core and pull-off strength relationships

This limited experimental investigation examined the relationships between the compressive strengths of cubes, cylinders, cores and the estimated compressive strengths derived from pull-off tests for a relatively low-strength structural-grade concrete (<35 N/mm2). Test specimens were cast and tested at 7, 14, 28, 56 and 84 days. The relationships of the trends of the test results to the trends of results of standard cube specimens and standard cylinder specimens were compared. It was found that the mean strength of each type of specimen tended to increase as a function of the natural logarithm of the specimen age. The mean strength of cylinders of length/diameter ratio 2.0 was found to be slightly greater (by about 7.5%) than the generally accepted value of 80% of the mean cube strength. Core results were corrected using correction factors defined in BS 6089 and the UK national annex to BS EN 12504-1. The mean corrected cube strength of cores taken from cubes was approximately 12% greater than the mean companion cube strength. The mean corrected cylinder strength of cores taken from cubes was approximately 5% greater than the mean companion cylinder strength. The potential cube and cylinder strengths of cores taken from slabs cured under different environmental conditions correlated well with companion cube and cylinder strengths respectively at 28 days. The pull-off test results gave a variable but, on average, slightly conservative estimate of the cube compressive strength of the relatively low-strength structural-grade concrete, using a simple general linear estimated compressive cube strength to tensile strength correlation factor of 10.