Daylighting: appraisal at the early design stages

For a building design team concerned with the quality of the internal environment of buildings the percentage area of glazing on a building facade is one of the most useful criteria for judging the building envelope as a modifier of climate at early design stages since it is at the window that the various environmental parameters (heat, light and sound) remain only minimally modified. The percentage area of glazing can be used to relate the numerous and often conflicting functions of the window such as the provision of daylight, summer time teperatures, sound insulation, energy efficiency and view satisfaction

Strain analysis of a seismically imaged mass‐transport complex, offshore Uruguay

Strain style, magnitude and distribution within mass‐transport complexes (MTCs) are important for understanding the process evolution of submarine mass flows and for estimating their runout distances. Structural restoration and quantification of strain in gravitationally driven passive margins have been shown to approximately balance between updip extensional and downdip contractional domains; such an exercise has not yet been attempted for MTCs. We here interpret and structurally restore a shallowly buried (c. 1,500 mbsf) and well‐imaged MTC, offshore Uruguay using a high‐resolution (12.5 m vertical and 15 × 12.5 m horizontal resolution) three‐dimensional seismic‐reflection survey. This allows us to characterise and quantify vertical and lateral strain distribution within the deposit. Detailed seismic mapping and attribute analysis shows that the MTC is characterised by a complicated array of kinematic indicators, which vary spatially in style and concentration. Seismic‐attribute extractions reveal several previously undocumented fabrics preserved in the MTC, including internal shearing in the form of sub‐orthogonal shear zones, and fold‐thrust systems within the basal shear zone beneath rafted‐blocks. These features suggest multiple transport directions and phases of flow during emplacement. The MTC is characterised by a broadly tripartite strain distribution, with extensional (e.g. normal faults), translational and contractional (e.g. folds and thrusts) domains, along with a radial frontally emergent zone. We also show how strain is preferentially concentrated around intra‐MTC rafted‐blocks due to their kinematic interactions with the underlying basal shear zone. Overall, and even when volume loss within the frontally emergent zone is included, a strain deficit between the extensional and contractional domains (c. 3%–14%) is calculated. We attribute this to a combination of distributed, sub‐seismic, ‘cryptic’ strain, likely related to de‐watering, grain‐scale deformation and related changes in bulk sediment volume. This work has implications for assessing MTCs strain distribution and provides a practical approach for evaluating structural interpretations within such deposits

Holistic Dwelling Energy Assessment Protocol for Mine-water District Heat Network

UK buildings and energy infrastructures are heavily dependent on natural gas, and a large proportion is used for domestic space heating; but 50% is imported. Improving energy security and reducing carbon emissions are major government drivers for reducing gas dependency. So, there needs to be a wholesale shift in the energy provision to householders without impacting on thermal comfort levels, convenience or cost of supply. Electrical powered heat pumps are seen as a potential alternative system for heating new dwellings, but will they work in dwellings built prior to 1919? This paper investigates the energy demand of pre-1919 dwellings in Wales, UK as part of a feasibility study to extract water from disused coal mines to supply a district heat network. A holistic surveying protocol providing a more accurate/realistic assessment of total household heat demand is considered. The protocol’s techniques include condition surveys, air permeability and thermography tests, and heat loss calculations are discussed. The results were used to predict future (beyond 2019) heat demand after potential retrofit improvements, thereby informing the size of heat pumps required. The findings show estimated heat demand to be in close correlation to household energy bills, and that the use of heat pumps in pre-1919 dwellings is viable, provided sufficient improvement to thermal performance is possible

Extended haplotype association study in Crohn’s disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3

The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn’s disease compared to non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to Crohn’s disease etiology in this population, most notably at NOD2, in which three causal, uncommon, and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes which showed significantly greater association to Crohn’s disease in the Ashkenazi Jewish population compared to a non-Jewish population (145 haplotypes and no haplotypes with P-value < 10−3, respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established Crohn’s disease loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare Crohn’s disease-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association

C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons.

Intronic hexanucleotide expansions in C9ORF72 are common in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but it is unknown whether loss of function, toxicity by the expanded RNA or dipeptides from non-ATG-initiated translation are responsible for the pathophysiology. We determined the interactome of C9ORF72 in motor neurons and found that C9ORF72 was present in a complex with cofilin and other actin binding proteins. Phosphorylation of cofilin was enhanced in C9ORF72-depleted motor neurons, in patient-derived lymphoblastoid cells, induced pluripotent stem cell-derived motor neurons and post-mortem brain samples from ALS patients. C9ORF72 modulates the activity of the small GTPases Arf6 and Rac1, resulting in enhanced activity of LIM-kinases 1 and 2 (LIMK1/2). This results in reduced axonal actin dynamics in C9ORF72-depleted motor neurons. Dominant negative Arf6 rescues this defect, suggesting that C9ORF72 acts as a modulator of small GTPases in a pathway that regulates axonal actin dynamics

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

C9orf72-mediated ALS and FTD: multiple pathways to disease

The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression