The Irish fossil Polyplacophora

Three species of fossil polyplacophoran molluscs are known from Ireland. Two species were originally described in the nineteenth century: Helminthochiton griffithi Salter in M‘Coy, 1846 and Pterochiton thomondiensis (Baily, 1859), and an articulated specimen representing a third indeterminate species, described here for the first time. Previous work on the evolutionary context of these species has relied on published illustrations and descriptions without examination of the type material. as chitons are considered rare in the fossil record, these specimens represent an interesting and important aspect of Irish palaeobiology.

The Ectocarpus genome and the independent evolution of multicellularity in brown algae

Brown algae (Phaeophyceae) are complex photosynthetic organisms with a very different evolutionary history to green plants, to which they are only distantly related(1). These seaweeds are the dominant species in rocky coastal ecosystems and they exhibit many interesting adaptations to these, often harsh, environments. Brown algae are also one of only a small number of eukaryotic lineages that have evolved complex multicellularity (Fig. 1). We report the 214 million base pair (Mbp) genome sequence of the filamentous seaweed Ectocarpus siliculosus (Dillwyn) Lyngbye, a model organism for brown algae(2-5), closely related to the kelps(6,7) (Fig. 1). Genome features such as the presence of an extended set of light-harvesting and pigment biosynthesis genes and new metabolic processes such as halide metabolism help explain the ability of this organism to cope with the highly variable tidal environment. The evolution of multicellularity in this lineage is correlated with the presence of a rich array of signal transduction genes. Of particular interest is the presence of a family of receptor kinases, as the independent evolution of related molecules has been linked with the emergence of multicellularity in both the animal and green plant lineages. The Ectocarpus genome sequence represents an important step towards developing this organism as a model species, providing the possibility to combine genomic and genetic(2) approaches to explore these and other(4,5) aspects of brown algal biology further.

BRD7, a subunit of SWI/SNF complexes, binds directly to BRCA1 and regulates BRCA1-dependent transcription

We carried out a yeast two-hybrid screen using a BRCA1 bait composed of amino acids 1 to 1142 and identified BRD7 as a novel binding partner of BRCA1. This interaction was confirmed by coimmunoprecipitation of endogenous BRCA1 and BRD7 in T47D and HEK-293 cells. BRD7 is a bromodomain containing protein, which is a subunit of PBAF-specific Swi/Snf chromatin remodeling complexes. To determine the functional consequences of the BRCA1-BRD7 interaction, we investigated the role of BRD7 in BRCA1-dependent transcription using microarray-based expression profiling. We found that a variety of targets were coordinately regulated by BRCA1 and BRD7, such as estrogen receptor alpha (ERalpha). Depletion of BRD7 or BRCA1 in either T47D or MCF7 cells resulted in loss of expression of ERalpha at both the mRNA and protein level, and this loss of ERalpha was reflected in resistance to the antiestrogen drug fulvestrant. We show that BRD7 is present, along with BRCA1 and Oct-1, on the ESR1 promoter (the gene which encodes ERalpha). Depletion of BRD7 prevented the recruitment of BRCA1 and Oct-1 to the ESR1 promoter; however, it had no effect on the recruitment of the other Swi/Snf subunits BRG1, BAF155, and BAF57 or on RNA polymerase II recruitment. These results support a model whereby the regulation of ERalpha transcription by BRD7 is mediated by its recruitment of BRCA1 and Oct-1 to the ESR1 promoter.

Gamma Knife Radiosurgery as a Therapeutic Strategy for Intracranial Sarcomatous Metastases

Purpose: To determine the indication and outcomes for Gamma Knife stereotactic radiosurgery (GKSRS) in the care of patients with intracranial sarcomatous metastases. Methods and Materials: Data from 21 patients who underwent radiosurgery for 60 sarcomatous intracranial metastases (54 parenchymal and 6 dural-based) were studied. Nine patients had radiosurgery for solitary tumors and 12 for multiple tumors. The primary pathology was metastatic leiomyosarcoma (4 patients), osteosarcoma (3 patients), soft-tissue sarcoma (5 patients), chondrosarcoma (2 patients), alveolar soft part sarcoma (2 patients), and rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, neurofibrosarcoma, and synovial sarcoma (1 patient each). Twenty patients received multimodality management for their primary tumor, and 1 patient had no evidence of systemic disease. The mean tumor volume was 6.2 cm 3 (range, 0.07-40.9 cm 3), and a median margin dose of 16 Gy was administered. Three patients had progressive intracranial disease despite fractionated whole-brain radiotherapy before SRS. Results: A local tumor control rate of 88% was achieved (including patients receiving boost, up-front, and salvage SRS). New remote brain metastases developed in 7 patients (33%). The median survival after diagnosis of intracranial metastasis was 16 months, and the 1-year survival rate was 61%. Conclusions: Gamma Knife radiosurgery was a well-tolerated and initially effective therapy in the management of patients with sarcomatous intracranial metastases. However, many patients, including those who also received fractionated whole-brain radiotherapy, developed progressive new brain disease. © 2010 Elsevier Inc. All rights reserved.

Evolution in the deep sea: a combined analysis of the earliest diverging living chitons (Mollusca : Polyplacophora : Lepidopleurida)

Lepidopleurida is the earliest diverged group of living polyplacophoran molluscs. They are found predominantly in the deep sea, including sunken wood, cold seeps, other abyssal habitats, and a few species are found in shallow water. The group is morphologically identified by anatomical features of their gills, sensory aesthetes, and gametes. Their shell features closely resemble the oldest fossils that can be identified as modern polyplacophorans. We present the first molecular phylogenetic study of this group, and also the first combined phylogenetic analysis for any chiton, including three gene regions and 69 morphological characters. The results show that Lepidopleurida is unambiguously monophyletic, and the nine genera fall into five distinct clades, which partly support the current view of polyplacophoran taxonomy. The genus Hanleyella Sirenko, 1973 is included in the family Protochitonidae, and Ferreiraellidae constitutes another distinct clade. The large cosmopolitan genus Leptochiton Gray, 1847 is not monophyletic; Leptochiton and Leptochitonidae sensu stricto are restricted to North Atlantic and Mediterranean taxa. Leptochitonidae s. str. is sister to Protochitonidae. The results also suggest two separate clades independently inhabiting sunken wood substrates in the south-west Pacific. Antarctic and other chemosynthetic-dwelling species may be derived from wood-living species. Substantial taxonomic revision remains to be done to resolve lepidopleuran classification, but the phylogeny presented here is a dramatic step forward in clarifying the relationships within this interesting group.

Potentially inappropriate prescribing in an Irish elderly population in primary care.

AIMS Screening tools have been formulated to identify potentially inappropriate prescribing (IP) in older people. Beers’ criteria are the most widely used but have disadvantages when used in Europe. New
IP screening tools called Screening Tool of Older Person’s Prescriptions (STOPP) and Screening Tool to Alert doctors to Right Treatment (START) have been developed to identify potential IP and potential prescribing omissions (PPOs). The aim was to measure the prevalence rates of potential IP and PPOs in primary care using Beers’ criteria, STOPP and START.

METHODS
Case records of 1329 patients 65 years old from three general practices in one region of southern Ireland were studied. The mean age SD of the patients was 74.9 6.4 years, 60.9% were female. Patients’current diagnoses and prescription medicines were reviewed and the Beers’ criteria, STOPP and START tools applied.

RESULTS
The total number of medicines prescribed was 6684; median number of medicines per patient was ?ve (range 1–19). Overall, Beers’ criteria identi?ed 286 potentially inappropriate prescriptions in 18.3% (243) of patients, whilst the corresponding IP rate identi?ed by STOPP was 21.4% (284), in respect of 346 potentially inappropriate prescriptions. A total of 333 PPOs were identi?ed in 22.7% (302) of patients using the START tool.

CONCLUSION
Potentially inappropriate drug prescribing and errors of drug omission are highly prevalent among older people living in the community. Prevention strategies should involve primary care doctors and community pharmacists.

Replication of EPHA1 and CD33 associations with late-onset Alzheimer’s disease: a multi-centre case-control study

A recently published genome-wide association study (GWAS) of late-onset Alzheimer's disease (LOAD) revealed genome-wide significant association of variants in or near MS4A4A, CD2AP, EPHA1 and CD33. Meta-analyses of this and a previously published GWAS revealed significant association at ABCA7 and MS4A, independent evidence for association of CD2AP, CD33 and EPHA1 and an opposing yet significant association of a variant near ARID5B. In this study, we genotyped five variants (in or near CD2AP, EPHA1, ARID5B, and CD33) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE e4 dosage.

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

In this study we describe a novel interaction between the breast/ovarian tumor suppressor gene BRCA1 and the transcription factor GATA3, an interaction, which is important for normal breast differentiation. We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that FOXC1 is an essential survival factor maintaining the proliferation of BLBCs cell lines. We define the mechanistic basis of this corepression and identify the GATA3-binding site within the FOXC1 distal promoter region. We show that BRCA1 and GATA3 interact on the FOXC1 promoter and that BRCA1 requires GATA3 for recruitment to this region. This interaction requires fully functional BRCA1 as a mutant BRCA1 protein is unable to localize to the FOXC1 promoter or repress FOXC1 expression. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. Finally, we demonstrate the importance of our findings by showing that loss of GATA3 expression or aberrant FOXC1 expression contributes to the drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs. Oncogene (2012) 31, 3667-3678; doi:10.1038/onc.2011.531; published online 28 November 2011

A virtual surgery in general practice: evaluation of a novel undergraduate virtual patient learning package

Background: A suite of 10 online virtual patients developed using the IVIMEDS ‘Riverside’ authoring tool has been introduced into our undergraduate general practice clerkship. These cases provide a multimedia-rich experience to students. Their interactive nature promotes the development of clinical reasoning skills such as discriminating key clinical features, integrating information from a variety of sources and forming diagnoses and management plans.

Aims: To evaluate the usefulness and usability of a set of online virtual patients in an undergraduate general practice clerkship.
Method: Online questionnaire completed by students after their general practice placement incorporating the System Usability Scale questionnaire.

Results: There was a 57% response rate. Ninety-five per cent of students agreed that the online package was a useful learning tool and ranked virtual patients third out of six learning modalities. Questions and answers and the use of images and videos were all rated highly by students as useful learning methods. The package was perceived to have a high level of usability among respondents.

Conclusion: Feedback from students suggest that this implementation of virtual patients, set in primary care, is user friendly and rated as a valuable adjunct to their learning. The cost of production of such learning resources demands close attention to design.

Deep-sea chitons from sunken wood in the West Pacific (Mollusca: Polyplacophora: Lepidopleurida): taxonomy, distribution, and seven new species

Natural deposits of sunken wood provide an important habitat for deep-sea invertebrates. Deep-sea chitons in the primitive order Lepidopleurida are typically collected rarely and as single specimens. However, these animals have been recovered in large densities associated with sunken wood in the tropical West Pacific, in groups of up to 50 individuals. Four deep- sea expeditions in the West Pacific, to the Philippines, Solomon Islands, and Vanuatu, recovered a large number of poly- placophorans. We have examined the morphology as well as the range and distribution of these species, based on the larg- est collection ever examined (more than 1300 individuals). These species show potentially adapted characters associated with exploitation of sunken wood as habitat, such as protruding caps on sensory shell pores (aesthetes) and large interseg- mental bristles with potential sensory function. In this study we investigated the twenty-two species recovered, including seven newly described here (Leptochiton consimilis n. sp., L. angustidens n. sp., L. dykei n. sp., L. samadiae n. sp., L. longisetosus n. sp., L. clarki n. sp., L. schwabei n. sp.), and provide the first identification key to the 34 lepidopleuran chitons known from sunken wood worldwide.

A chiton without a foot

The palaeoloricate ‘polyplacophorans’ are an extinct paraphyletic group of basal chiton-like organisms known primarily from their fossilized valves. Their phylo- genetic placement remains contentious, but they are likely to include both stem-group Polyplacophora and stem- group Aplacophora. Candidates for the latter position include ‘Helminthochiton’ thraivensis from the Ordovician of Scotland, which we redescribe here through a combined optical and micro-CT (XMT) restudy of the type material. The 11 specimens in the type series are all articulated, presenting partial or complete valve series as well as moul- dic preservation of the girdle armature; they demonstrate a vermiform body plan. The valves are typically palaeolori- cate in aspect, but differ in detail from all existing palaeol- oricate genera; we hence erect Phthipodochiton gen. nov. to contain the species. The most notable feature of the fossils is the spicular girdle; this is impersistently preserved, but demonstrably wraps entirely around the ventral surface of the animal, implying that a ‘true’ (i.e. polyplacophoran like) foot was absent, although we do not exclude the pos- sibility of a narrow solenogastre-like median pedal groove having been present. Phthipodochiton thraivensis presents an apparent mosaic of aplacophoran and polyplacophoran features and as such will inform our understanding of the relationship between these groups of extant molluscs. An inference may also be drawn that at least some other pal- aeoloricates possessed an ‘armoured aplacophoran’ body plan, in contrast to the ‘limpet-like’ body plan of extant Polyplacophora.