Human parietal and primary motor cortical interactions are selectively modulated during the transport and grip formation of goal-directed hand actions

Posterior parietal cortex (PPC) constitutes a critical cortical node in the sensorimotor system in which goal-directed actions are computed. This information then must be transferred into commands suitable for hand movements to the primary motor cortex (M1). Complexity arises because reach-to-grasp actions not only require directing the hand towards the object (transport component), but also preshaping the hand according to the features of the object (grip component). Yet, the functional influence that specific PPC regions exert over ipsilateral M1 during the planning of different hand movements remains unclear in humans. Here we manipulated transport and grip components of goal-directed hand movements and exploited paired-pulse transcranial magnetic stimulation (ppTMS) to probe the functional interactions between M1 and two different PPC regions, namely superior parieto-occipital cortex (SPOC) and the anterior region of the intraparietal sulcus (aIPS), in the left hemisphere. We show that when the extension of the arm is required to contact a target object, SPOC selectively facilitates motor evoked potentials, suggesting that SPOC-M1 interactions are functionally specific to arm transport. In contrast, a different pathway, linking the aIPS and ipsilateral M1, shows enhanced functional connections during the sensorimotor planning of grip. These results support recent human neuroimaging findings arguing for specialized human parietal regions for the planning of arm transport and hand grip during goal-directed actions. Importantly, they provide new insight into the causal influences these different parietal regions exert over ipsilateral motor cortex for specific types of planned hand movements

Calcification and ossification of the convexity of the falx cerebri and related subdural space in human cadavers

OBJECTIVE: The present work was planned to report the incidence of calcification and ossification of an isolated cranial dural fold. The form, degree of severity and range of extension of such changes will be described. Involvement of the neighboring brain tissue and blood vessels, whether meningeal or cerebral, will also be determined. The results of this study might highlight the occasional incidence of intracranial calcification and ossification in images of the head and their interpretation, by radiologists and neurologists, to be of dural or vascular origin.

METHODS: Two human formalin-fixed cadavers, one middle-aged female another older male, were investigated at the Anatomy Laboratory, College of Medicine, King Faisal University, Dammam, Kingdom of Saudi Arabia during the period from 2000 to 2003. In each cadaver, the skullcap was removed and the convexity of the cranial dura mater, as well as the individual dural folds, were carefully examined for any calcification or ossification. The meningeal and cerebral blood vessels together with the underlying brain were grossly inspected for such structural changes. Calcified or ossified tissues, when identified, were subjected to histological examination to confirm their construction.

RESULTS: The female cadaver showed a calcified parietal emissary vein piercing the skullcap and projecting into the scalp. The latter looked paler and deficient in hair on its right side. The base of the stump was surrounded by a granular patch of calcification. The upper convex border of the falx cerebri was hardened and it presented granules, plaques and a cauliflower mass, which all proved to be osseous in structure. The meningeal and right cerebral vessels were mottled with calcium granules. The underlying temporal and parietal lobes of the right cerebral hemisphere were degenerated. The male cadaver also revealed a calcified upper border of the falx cerebri and superior sagittal sinus. Osseous granules and plaques, similar to those of the first specimen, were also identified but without gross changes in the underlying brain.

CONCLUSION: Calcification or ossification of an isolated site of the cranial dura mater and the intracranial blood vessels might occur. These changes should be kept in mind while interpreting images of the skull and brain. Clinical assessment and laboratory investigations are required to determine whether these changes are idiopathic, traumatic, or as a manifestation of a generalized disease such as hyperparathyroidism, vitamin D-intoxication, or chronic renal failure.

Tephrochronology and the extended intimate (integration of ice‐core, marine and terrestrial records) event stratigraphy 8-128kab2k

The comparison of palaeoclimate records on their own independent timescales is central to the work of the INTIMATE (INTegrating Ice core, MArine and TErrestrial records) network. For the North Atlantic region, an event stratigraphy has been established from the high-precision Greenland ice-core records and the integrated GICC05 chronology. This stratotype provides a palaeoclimate signal to which the timing and nature of palaeoenvironmental change recorded in marine and terrestrial archives can be compared. To facilitate this wider comparison, without assuming synchroneity of climatic change/proxy response, INTIMATE has also focussed on the development of tools to achieve this. In particular the use of time-parallel marker horizons e.g. tephra layers (volcanic ash). Coupled with the recent temporal extension of the Greenland stratotype, as part of this special issue, we present an updated INTIMATE event stratigraphy highlighting key tephra horizons used for correlation across Europe and the North Atlantic. We discuss the advantages of such an approach, and the key challenges for the further integration of terrestrial palaeoenvironmental records with those from ice cores and the marine realm.

Development of Novel Activity-Based Probes for the Detection of Serine Proteases

Cystic Fibrosis (CF) is a genetic disease featuring a chronic cycle of inflammation and infection in the airways of sufferers. Mutations lead to altered ion transport, which in turn causes dehydrated airways and reduced mucociliary clearance which predisposes the patient to infection, resulting in a severe immune response and tissue destruction (1). Airway dehydration is primarily caused by the hyperabsorption of sodium by the epithelial sodium channel (ENaC) (2). ENaC is activated by the action of a number of predominantly trypsin-like Channel Activating Proteases (CAPs) including prostasin, matriptase and furin (3). Additional proteases known to activate ENaC include human airway trypsin (3), plasmin, neutrophil elastase and chymotrypsin (4).

Activity profiling is a valuable technique which involves the use of small inhibitory molecules called Activity-Based Probes (ABPs) which can be used to covalently label the active site of proteases and provide a range of information regarding its structure, catalytic mechanism, location and function within biological systems. The development of novel ABPs for CAPs, would enhance understanding of the role of these proteases in CF airways disease and in particular their role in ENaC activation and airway dehydration. This project investigates the application of a range of novel broad-spectrum ABPs targeting the various subclasses of serine proteases, to include those proteases involved in ENaC activation. Additionally, the application of more selective ABPs in detecting specific serine proteases is investigated.

Compounds were synthesised by Solid-Phase Peptide Synthesis (SPPS) using a standard Fmoc/tBu strategy. Kinetic evaluation of synthesised ABPs against various serine proteases was determined by fluorogenic steady-state enzyme assays. Furthermore, application of ABPs and confirmation of irreversible nature of the compounds was carried out through SDS-PAGE and electroblotting techniques.

Synthesised compounds showed potent irreversible inhibition of serine proteases within their respective targeting class (NAP855 vs Trypsin k3/Ki = 2.60 x 106 M-1 min-1, NFP849 vs Chymotrypsin k3/Ki = 1.28 x 106 M-1 min-1 and NVP800 vs Neutrophil Elastase k3/Ki = 6.41 x 104 M-1 min-1). Furthermore ABPs showed little to no cross-reactivity between classes and so display selectivity between classes. The irreversible nature of compounds was further demonstrated through labelling of proteases, followed by separation and detection via SDS-PAGE and electroblotting techniques. Targeted labelling of active proteases only, was demonstrated by failure of ABPs to detect previously inactivated proteases. Extension of the substrate recognition site within probes resulted in an increased potency and selectivity in the detection of the target proteases. Successful detection of neutrophil elastase from CF sputum samples by NVP800, demonstrated the application of compounds within biological samples and their potential use in identifying further proteases involved in ENaC activation and airway dehydration in CF patients.

Estimation of the small strain stiffness of glacial till using geophysical methods and barometric loading response

Stiffness values in geotechnical structures can range over many orders of magnitude for relatively small operational strains. The typical strain levels where soil stiffness changes most dramatically is in the range 0.01-0.1%, however soils do not exhibit linear stress-strain behaviour at small strains. Knowledge of the in situ stiffness at small strain is important in geotechnical numerical modelling and design. The stress-strain regime of cut slopes is complex, as we have different principle stress directions at different positions along the potential failure plane. For example, loading may be primarily in extension near the toe of the slope, while compressive loading is predominant at the crest of a slope. Cuttings in heavily overconsolidated clays are known to be susceptible to progressive failure and subsequent strain softening, in which progressive yielding propagates from the toe towards the crest of the slope over time. In order to gain a better understanding of the rate of softening it would be advantageous to measure changes in small strain stiffness in the field.

Of no fixed form: The Irish Pavilion at Venice 2014 and beyond

This paper explores the theme of exhibiting architectural research through a particular example, the development of the Irish pavilion for the 14th architectural biennale, Venice 2014. Responding to Rem Koolhaas’s call to investigate the international absorption of modernity, the Irish pavilion became a research project that engaged with the development of the architectures of infrastructure in Ireland in the twentieth and twenty-first centuries. Central to this proposition was that infrastructure is simultaneously a technological and cultural construct, one that for Ireland occupied a critical position in the building of a new, independent post-colonial nation state, after 1921.

Presupposing infrastructure as consisting of both visible and invisible networks, the idea of a matrix become a central conceptual and visual tool in the curatorial and design process for the exhibition and pavilion. To begin with this was a two-dimensional grid used to identify and order what became described as a series of ten ‘infrastructural episodes’. These were determined chronologically across the decades between 1914 and 2014 and their spatial manifestations articulated in terms of scale: micro, meso and macro. At this point ten academics were approached as researchers. Their purpose was twofold, to establish the broader narratives around which the infrastructures developed and to scrutinise relevant archives for compelling visual material. Defining the meso scale as that of the building, the media unearthed was further filtered and edited according to a range of categories – filmic/image, territory, building detail, and model – which sought to communicate the relationship between the pieces of architecture and the larger systems to which they connect. New drawings realised by the design team further iterated these relationships, filling in gaps in the narrative by providing composite, strategic or detailed drawings.

Conceived as an open-ended and extendable matrix, the pavilion was influenced by a series of academic writings, curatorial practices, artworks and other installations including: Frederick Kiesler’s City of Space (1925), Eduardo Persico and Marcello Nizzoli’s Medaglio d’Oro room (1934), Sol Le Witt’s Incomplete Open Cubes (1974) and Rosalind Krauss’s seminal text ‘Grids’ (1979). A modular frame whose structural bays would each hold and present an ‘episode’, the pavilion became both a visual analogue of the unseen networks embodying infrastructural systems and a reflection on the predominance of framed structures within the buildings exhibited. Sharing the aspiration of adaptability of many of these schemes, its white-painted timber components are connected by easily-dismantled steel fixings. These and its modularity allow the structure to be both taken down and re-erected subsequently in different iterations. The pavilion itself is, therefore, imagined as essentially provisional and – as with infrastructure – as having no fixed form. Presenting archives and other material over time, the transparent nature of the space allowed these to overlap visually conveying the nested nature of infrastructural production. Pursuing a means to evoke the qualities of infrastructural space while conveying a historical narrative, the exhibition’s termination in the present is designed to provoke in the visitor, a perceptual extension of the matrix to engage with the future.

The neoliberalisation of the Cathedral Quarter and its contestations

Over time Belfast has been well researched as a site of ethnosectarian conflict, segregation and fear see (Boal et al 1976) and (Gaffiken and Morrisey 2011). The study of socio-spatial patterns of ‘ethnocracy’ is useful, but this article will argue how it is equally important to understand local forms of urban restructuring in terms of global processes that are linked to neoliberalism. To better understand the neoliberal urbanisation of Belfast this article is organised into two parts. The first part will demonstrate how the Northern Ireland State has sought legitimacy in the free market as ‘therapy’ for the production of neutral socio-spatial formations such as the Cathedral Quarter. Secondly it will examine this performance of neoliberal urbanism, as it ‘actually exists’ and demonstrate how market-led renewal has been extended through the clustering and non-sectarian interests, ‘soft’ arrangements of urban governance, cultural re-branding strategies, economic development incentives, and the development of various flagship projects. Critically this place-based grounding of neoliberalism is useful, as it also allows for the contestations of neoliberal urbanism to become real rather than just theoretical. The second part of the article will draw attention to the responses of local, and sometimes marginal, interests that have looked to challenge, adapt and, at times, divert the extension of market-led renewal. To be clear, this article does not want to overstate the performance of such interests. Nor does it want to claim that they significantly impact or obstruct the wider neoliberal urbanisation of Belfast. Instead it is interested in their behaviours and their different methods of working to explore what may be constituted as ‘alternative’, at least in the locality of the Cathedral Quarter. By studying how and why these interests have responded to the extension of neoliberal urbanism over time, it may just be possible to provide a better platform to articulate what more progressive forms of urban resistance might look like.

A Reappraisal of the Safety and Cost-Effectiveness of Statin Therapy in Primary Prevention

Statins are among the most investigated drugs of all time. There is now a wealth of evidence supporting their use in the primary and secondary prevention arenas. The reduction in event recurrence has since been demonstrated across all levels of risk and in elderly patients. As a result, it is now accepted practice for statins to be prescribed universally in secondary prevention unless contraindicated. The extension of this policy into the primary prevention setting is more problematic, with moral and financial issues arising from the long-term treatment of many young apparently healthy individuals. For these reasons it is necessary to prove not only the financial sustainability of such a strategy but also the long-term safety of statins and the degree of benefit that might be expected.