Interrogating the technical, economic and cultural challenges of delivering the PassivHaus standard in the UK.

A peer-reviewed eBook, which is based on a collaborative research project coordinated by Dr. Henrik Schoenefeldt at the Centre for Architecture and Sustainable Environment at the University of Kent between May 2013 and June 2014. This project investigated how architectural practice and the building industry are adapting in order to successfully deliver Passivhaus standard buildings in the UK. Through detailed case studies the project explored the learning process underlying the delivery of fourteen buildings, certified between 2009 and 2013. Largely founded on the study of the original project correspondence and semi-structured interviews with clients, architects, town planners, contractors and manufacturers, these case studies have illuminated the more immediate technical as well as the broader cultural challenges. The peer-reviewers of this book stressed that the findings included in the book are valuable to students, practitioners and academic researchers in the field of low-energy design. It was launched during the PassivHaus Project Conference, held at the Bulb Innovation Centre on the 27th June 2014

The histone deacetylase inhibitor sodium valproate causes limited transcriptional change in mouse embryonic stem cells but selectively overrides Polycomb-mediated Hoxb silencing.

BACKGROUND: Histone deacetylase inhibitors (HDACi) cause histone hyperacetylation and H3K4 hypermethylation in various cell types. They find clinical application as anti-epileptics and chemotherapeutic agents, but the pathways through which they operate remain unclear. Surprisingly, changes in gene expression caused by HDACi are often limited in extent and can be positive or negative. Here we have explored the ability of the clinically important HDACi valproic acid (VPA) to alter histone modification and gene expression, both globally and at specific genes, in mouse embryonic stem (ES) cells. RESULTS: Microarray expression analysis of ES cells exposed to VPA (1 mM, 8 h), showed that only 2.4% of genes showed a significant, >1.5-fold transcriptional change. Of these, 33% were down-regulated. There was no correlation between gene expression and VPA-induced changes in histone acetylation or H3K4 methylation at gene promoters, which were usually minimal. In contrast, all Hoxb genes showed increased levels of H3K9ac after exposure to VPA, but much less change in other modifications showing bulk increases. VPA-induced changes were lost within 24 h of inhibitor removal. VPA significantly increased the low transcription of Hoxb4 and Hoxb7, but not other Hoxb genes. Expression of Hoxb genes increased in ES cells lacking functional Polycomb silencing complexes PRC1 and PRC2. Surprisingly, VPA caused no further increase in Hoxb transcription in these cells, except for Hoxb1, whose expression increased several fold. Retinoic acid (RA) increased transcription of all Hoxb genes in differentiating ES cells within 24 h, but thereafter transcription remained the same, increased progressively or fell progressively in a locus-specific manner. CONCLUSIONS: Hoxb genes in ES cells are unusual in being sensitive to VPA, with effects on both cluster-wide and locus-specific processes. VPA increases H3K9ac at all Hoxb loci but significantly overrides PRC-mediated silencing only at Hoxb4 and Hoxb7. Hoxb1 is the only Hoxb gene that is further up-regulated by VPA in PRC-deficient cells. Our results demonstrate that VPA can exert both cluster-wide and locus-specific effects on Hoxb regulation.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Acetylation increases access of remodelling complexes to their nucleosome targets to enhance initiation of V(D)J recombination

Targeted chromatin remodelling is essential for many nuclear processes, including the regulation of V(D)J recombination. ATP-dependent nucleosome remodelling complexes are important players in this process whose activity must be tightly regulated. We show here that histone acetylation regulates nucleosome remodelling complex activity to boost RAG cutting during the initiation of V(D)J recombination. RAG cutting requires nucleosome mobilization from recombination signal sequences. Histone acetylation does not stimulate nucleosome mobilization per se by CHRAC, ACF or their catalytic subunit, ISWI. Instead, we find the more open structure of acetylated chromatin regulates the ability of nucleosome remodelling complexes to access their nucleosome templates. We also find that bromodomain/acetylated histone tail interactions can contribute to this targeting at limited concentrations of remodelling complex. We therefore propose that the changes in higher order chromatin structure associated with histone acetylation contribute to the correct targeting of nucleosome remodelling complexes and this is a novel way in which histone acetylation can modulate remodelling complex activity

A Glimpse of the Stellar Populations and Elemental Abundances of Gravitationally Lensed, Quiescent Galaxies at z≳1z\gtrsim 1 with Keck Deep Spectroscopy

Gravitational lenses can magnify distant galaxies, allowing us to discover and characterize the stellar populations of intrinsically faint, quiescent galaxies that are otherwise extremely difficult to directly observe at high redshift from ground-based telescopes. Here, we present the spectral analysis of two lensed, quiescent galaxies at $z\gtrsim 1$ discovered by the ASTRO 3D Galaxy Evolution with Lenses survey: AGEL1323 ($M_*\sim 10^{11.1}M_{\odot}$, $z=1.016$, $\mu \sim 14.6$) and AGEL0014 ($M_*\sim 10^{11.3}M_{\odot}$, $z=1.374$, $\mu \sim 4.3$). We measured the age, [Fe/H], and [Mg/Fe] of the two lensed galaxies using deep, rest-frame-optical spectra (S/N $\gtrsim$ 40\AA$^{-1}$) obtained on the Keck I telescope. The ages of AGEL1323 and AGEL0014 are $5.6^{+0.8}_{-0.8}$ Gyr and $3.1^{+0.8}_{-0.3}$ Gyr, respectively, indicating that most of the stars in the galaxies were formed less than 2 Gyr after the Big Bang. Compared to nearby quiescent galaxies of similar masses, the lensed galaxies have lower [Fe/H] and [Mg/H]. Surprisingly, the two galaxies have comparable [Mg/Fe] to similar-mass galaxies at lower redshifts, despite their old ages. Using a simple analytic chemical evolution model connecting the instantaneously recycled element Mg with the mass-loading factors of outflows averaged over the entire star formation history, we found that the lensed galaxies may have experienced enhanced outflows during their star formation compared to lower-redshift galaxies, which may explain why they quenched early.Comment: 18 pages, 11 figures, submitted to ApJ; comments welcom

Genes Are Often Sheltered from the Global Histone Hyperacetylation Induced by HDAC Inhibitors

Histone deacetylase inhibitors (HDACi) are increasingly used as therapeutic agents, but the mechanisms by which they alter cell behaviour remain unclear. Here we use microarray expression analysis to show that only a small proportion of genes (∼9%) have altered transcript levels after treating HL60 cells with different HDACi (valproic acid, Trichostatin A, suberoylanilide hydroxamic acid). Different gene populations respond to each inhibitor, with as many genes down- as up-regulated. Surprisingly, HDACi rarely induced increased histone acetylation at gene promoters, with most genes examined showing minimal change, irrespective of whether genes were up- or down-regulated. Many genes seem to be sheltered from the global histone hyperacetyation induced by HDACi

Evaluating triple oxygen isotope estimates of gross primary production at the Hawaii Ocean Time-series and Bermuda Atlantic Time-series Study sites

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 117 (2012): C05012, doi:10.1029/2010JC006856.The triple oxygen isotopic composition of dissolved oxygen (17Δ) is a promising tracer of gross oxygen productivity (P) in the ocean. Recent studies have inferred a high and variable ratio of P to 14C net primary productivity (12–24 h incubations) (e.g., P:NPP(14C) of 5–10) using the 17Δ tracer method, which implies a very low efficiency of phytoplankton growth rates relative to gross photosynthetic rates. We added oxygen isotopes to a one-dimensional mixed layer model to assess the role of physical dynamics in potentially biasing estimates of P using the 17Δ tracer method at the Bermuda Atlantic Time-series Study (BATS) and Hawaii Ocean Time-series (HOT). Model results were compared to multiyear observations at each site. Entrainment of high 17Δ thermocline water into the mixed layer was the largest source of error in estimating P from mixed layer 17Δ. At both BATS and HOT, entrainment bias was significant throughout the year and resulted in an annually averaged overestimate of mixed layer P of 60 to 80%. When the entrainment bias is corrected for, P calculated from observed 17Δ and 14C productivity incubations results in a gross:net productivity ratio of 2.6 (+0.9 −0.8) at BATS. At HOT a gross:net ratio decreasing linearly from 3.0 (+1.0 −0.8) at the surface to 1.4 (+0.6 −0.6) at depth best reproduced observations. In the seasonal thermocline at BATS, however, a significantly higher gross:net ratio or large lateral fluxes of 17Δ must be invoked to explain 17Δ field observations.We acknowledge support from Center for Microbial Oceanography Research and Education (CMORE) (NSF EF-0424599) and NOAA Global Carbon Program (NA 100AR4310093). BL thanks the USA-Israel Binational Science Foundation for supporting his project at BATS.2012-11-0

The SOLAS air-sea gas exchange experiment (SAGE) 2004

Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Deep Sea Research Part II: Topical Studies in Oceanography 58 (2011): 753-763, doi:10.1016/j.dsr2.2010.10.015.The SOLAS air-sea gas exchange experiment (SAGE) was a multiple-objective study investigating gas-transfer processes and the influence of iron fertilisation on biologically driven gas exchange in high-nitrate low-silicic acid low-chlorophyll (HNLSiLC) Sub-Antarctic waters characteristic of the expansive Subpolar Zone of the southern oceans. This paper provides a general introduction and summary of the main experimental findings. The release site was selected from a pre-voyage desktop study of environmental parameters to be in the south-west Bounty Trough (46.5°S 172.5°E) to the south-east of New Zealand and the experiment conducted between mid-March and mid-April 2004. In common with other mesoscale iron addition experiments (FeAX’s), SAGE was designed as a Lagrangian study quantifying key biological and physical drivers influencing the air-sea gas exchange processes of CO2, DMS and other biogenic gases associated with an iron-induced phytoplankton bloom. A dual tracer SF6/3He release enabled quantification of both the lateral evolution of a labelled volume (patch) of ocean and the air-sea tracer exchange at the 10’s of km’s scale, in conjunction with the iron fertilisation. Estimates from the dual-tracer experiment found a quadratic dependency of the gas exchange coefficient on windspeed that is widely applicable and describes air-sea gas exchange in strong wind regimes. Within the patch, local and micrometeorological gas exchange process studies (100 m scale) and physical variables such as near-surface turbulence, temperature microstructure at the interface, wave properties, and wind speed were quantified to further assist the development of gas exchange models for high-wind environments. There was a significant increase in the photosynthetic competence (Fv/Fm) of resident phytoplankton within the first day following iron addition, but in contrast to other FeAX’s, rates of net primary production and column-integrated chlorophyll a concentrations had only doubled relative to the unfertilised surrounding waters by the end of the experiment. After 15 days and four iron additions totalling 1.1 tonne Fe2+, this was a very modest response compared to the other mesoscale iron enrichment experiments. An investigation of the factors limiting bloom development considered co- limitation by light and other nutrients, the phytoplankton seed-stock and grazing regulation. Whilst incident light levels and the initial Si:N ratio were the lowest recorded in all FeAX’s to date, there was only a small seed-stock of diatoms (less than 1% of biomass) and the main response to iron addition was by the picophytoplankton. A high rate of dilution of the fertilised patch relative to phytoplankton growth rate, the greater than expected depth of the surface mixed layer and microzooplankton grazing were all considered as factors that prevented significant biomass accumulation. In line with the limited response, the enhanced biological draw-down of pCO2 was small and masked by a general increase in pCO2 due to mixing with higher pCO2 waters. The DMS precursor DMSP was kept in check through grazing activity and in contrast to most FeAX’s dissolved dimethylsulfide (DMS) concentration declined through the experiment. SAGE is an important low-end member in the range of responses to iron addition in FeAX’s. In the context of iron fertilisation as a geoengineering tool for atmospheric CO2 removal, SAGE has clearly demonstrated that a significant proportion of the low iron ocean may not produce a phytoplankton bloom in response to iron addition.SAGE was jointly funded through the New Zealand Foundation for Research, Science and Technology (FRST) programs (C01X0204) "Drivers and Mitigation of Global Change" and (C01X0223) "Ocean Ecosystems: Their Contribution to NZ Marine Productivity." Funding was also provided for specific collaborations by the US National Science Foundation from grants OCE-0326814 (Ward), OCE-0327779 (Ho), and OCE 0327188 OCE-0326814 (Minnett) and the UK Natural Environment Research Council NER/B/S/2003/00282 (Archer). The New Zealand International Science and Technology (ISAT) linkages fund provided additional funding (Archer and Ziolkowski), and the many collaborator institutions also provided valuable support

Prophylactic Cefazolin Dosing and Surgical Site Infections: Does the Dose Matter in Obese Patients?

Background Most surgical prophylaxis guidelines recommend a 3-g cefazolin intravenous dose in patients weighing ≥ 120 kg. However, this recommendation is primarily based on pharmacokinetic studies rather than robust clinical evidence. This study aimed to compare the prevalence of surgical site infections (SSIs) in obese and non-obese patients (body mass index ≥ 30 kg/m2 and < 30 kg/m2), and those weighing ≥ 120 kg and < 120 kg, who received 2- g cefazolin preoperatively. Methods A retrospective case-control study was conducted in adult elective surgical patients. Patients receiving 2- g cefazolin were grouped as obese and non-obese, and by weight (≥ 120 kg or < 120 kg). The 90-day prevalence of SSI and potential contributing factors were investigated. Results We identified 152 obese (median 134 kg) and 152 non-obese control (median 73 kg) patients. Baseline characteristics were similar between groups, except for an increased prevalence in the obese group of diabetes (35.5% vs 13.2%; p < 0.001) and an American Society of Anaesthesiologists Score of 3 (61.8% vs 17.1%; p < 0.001). While not statistically significant, the prevalence of SSI in the obese group was almost double that in the non-obese group (8.6% vs 4.6%; p = 0.25) and in patients weighing ≥ 120 kg (n = 102) compared to those weighing < 120 kg (n = 202) (9.8% vs 5.0%; p = 0.17). Conclusion The prevalence of SSI was not significantly increased in obese patients, or those weighing ≥ 120 kg, who received cefazolin 2- g prophylactically; however, trends toward an increase were evident. Large-scale randomised trials are needed to examine whether a 2-g or 3-g cefazolin is adequate to prevent SSI in obese (and ≥ 120 kg) individuals

Perspectives and Integration in SOLAS Science

Why a chapter on Perspectives and Integration in SOLAS Science in this book? SOLAS science by its nature deals with interactions that occur: across a wide spectrum of time and space scales, involve gases and particles, between the ocean and the atmosphere, across many disciplines including chemistry, biology, optics, physics, mathematics, computing, socio-economics and consequently interactions between many different scientists and across scientific generations. This chapter provides a guide through the remarkable diversity of cross-cutting approaches and tools in the gigantic puzzle of the SOLAS realm. Here we overview the existing prime components of atmospheric and oceanic observing systems, with the acquisition of ocean–atmosphere observables either from in situ or from satellites, the rich hierarchy of models to test our knowledge of Earth System functioning, and the tremendous efforts accomplished over the last decade within the COST Action 735 and SOLAS Integration project frameworks to understand, as best we can, the current physical and biogeochemical state of the atmosphere and ocean commons. A few SOLAS integrative studies illustrate the full meaning of interactions, paving the way for even tighter connections between thematic fields. Ultimately, SOLAS research will also develop with an enhanced consideration of societal demand while preserving fundamental research coherency. The exchange of energy, gases and particles across the air-sea interface is controlled by a variety of biological, chemical and physical processes that operate across broad spatial and temporal scales. These processes influence the composition, biogeochemical and chemical properties of both the oceanic and atmospheric boundary layers and ultimately shape the Earth system response to climate and environmental change, as detailed in the previous four chapters. In this cross-cutting chapter we present some of the SOLAS achievements over the last decade in terms of integration, upscaling observational information from process-oriented studies and expeditionary research with key tools such as remote sensing and modelling. Here we do not pretend to encompass the entire legacy of SOLAS efforts but rather offer a selective view of some of the major integrative SOLAS studies that combined available pieces of the immense jigsaw puzzle. These include, for instance, COST efforts to build up global climatologies of SOLAS relevant parameters such as dimethyl sulphide, interconnection between volcanic ash and ecosystem response in the eastern subarctic North Pacific, optimal strategy to derive basin-scale CO2 uptake with good precision, or significant reduction of the uncertainties in sea-salt aerosol source functions. Predicting the future trajectory of Earth’s climate and habitability is the main task ahead. Some possible routes for the SOLAS scientific community to reach this overarching goal conclude the chapter

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes