Cell biology:Collagen secretion explained

Cells package proteins into vesicles for secretion to the extracellular milieu. A study shows that an enzyme modifies the packaging machinery to encapsulate unusually large proteins such as collagen

A synthesis of the environmental response of the North and South Atlantic Sub-Tropical Gyres during two decades of AMT

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Anthropogenically-induced global warming is expected to decrease primary productivity in the subtropical oceans by strengthening stratification of the water column and reducing the flux of nutrients from deep-waters to the sunlit surface layers. Identification of such changes is hindered by a paucity of long-term, spatially-resolved, biological time-series data at the basin scale. This paper exploits Atlantic Meridional Transect (AMT) data on physical and biogeochemical properties (1995–2014) in synergy with a wide range of remote-sensing (RS) observations from ocean colour, Sea Surface Temperature (SST), Sea Surface Salinity (SSS) and altimetry (surface currents), combined with different modelling approaches (both empirical and a coupled 1-D Ecosystem model), to produce a synthesis of the seasonal functioning of the North and South Atlantic Sub-Tropical Gyres (STGs), and assess their response to longer-term changes in climate. We explore definitive characteristics of the STGs using data of physical (SST, SSS and peripheral current systems) and biogeochemical variables (chlorophyll and nitrate), with inherent criteria (permanent thermal stratification and oligotrophy), and define the gyre boundary from a sharp gradient in these physical and biogeochemical properties. From RS data, the seasonal cycles for the period 1998–2012 show significant relationships between physical properties (SST and PAR) and gyre area. In contrast to expectations, the surface layer chlorophyll concentration from RS data (CHL) shows an upward trend for the mean values in both subtropical gyres. Furthermore, trends in physical properties (SST, PAR, gyre area) differ between the North and South STGs, suggesting the processes responsible for an upward trend in CHL may vary between gyres. There are significant anomalies in CHL and SST that are associated with El Niño events. These conclusions are drawn cautiously considering the short length of the time-series (1998–2012), emphasising the need to sustain spatially-extensive surveys such as AMT and integrate such observations with models, autonomous observations and RS data, to help address fundamental questions about how our planet is responding to climate change. A small number of dedicated AMT cruises in the keystone months of January and July would complement our understanding of seasonal cycles in the STGs.Natural Environment Research Council National CapabilityUK National Centre for Earth Observatio

Proportional/non-proportional constant/variable amplitude multiaxial notch fatigue: cyclic plasticity, non-zero mean stresses, and critical distance/plane

This paper deals with the formulation and experimental validation of a novel fatigue lifetime estimation technique suitable for assessing the extent of damage in notched metallic materials subjected to in‐service proportional/nonproportional constant/variable amplitude multiaxial load histories. The methodology being formulated makes use of the Modified Manson‐Coffin Curve Method, the Shear Strain–Maximum Variance Method, and the elasto‐plastic Theory of Critical Distances, with the latter theory being applied in the form of the Point Method. The accuracy and reliability of our novel fatigue lifetime estimation technique were checked against a large number of experimental results we generated by testing, under proportional/nonproportional constant/variable amplitude axial‐torsional loading, V‐notched cylindrical specimens made of unalloyed medium‐carbon steel En8 (080M40). Specific experimental trials were run to investigate also the effect of non‐zero mean stresses as well as of different frequencies between the axial and torsional stress/strain components. This systematic validation exercise allowed us to demonstrate that our novel multiaxial fatigue assessment methodology is remarkably accurate, with the estimates falling within an error factor of 2. By modelling the cyclic elasto‐plastic behaviour of metals explicitly, the design methodology being formulated and validated in the present paper offers a complete solution to the problem of estimating multiaxial fatigue lifetime of notched metallic materials, with this holding true independently of sharpness of the stress/strain raiser and complexity of the load history

Exposure and impact of a mass media campaign targeting sexual health amongst Scottish men who have sex with men: an outcome evaluation

Background: This paper explores the exposure and impact of a Scottish mass media campaign: Make Your Position Clear. It ran from October 2009 to July 2010, targeted gay men and other men who have sex with men (MSM), and had two key aims: to promote regular sexual health and HIV testing every 6 months, and to promote the use of appropriate condoms and water-based lubricant with each episode of anal intercourse. Methods: A cross-sectional survey (anonymous and self-report) was conducted 10 months after the campaign was launched (July 2010). Men were recruited from commercial venues. Outcome measures included use of lubricant, testing for sexually transmitted infections and HIV, and intentions to seek HIV testing within the following six months. Linear-by-linear chi-square analysis and binary logistic regressions were conducted to explore the associations between the outcome measures and campaign exposure. Results: The total sample was 822 men (62.6% response rate). Men self-identifying as HIV positive were excluded from the analysis (n = 38). Binary logistic analysis indicated that those with mid or high campaign exposure were more likely to have been tested for HIV in the previous six months when adjusted for age, area of residence and use of the “gay scene” (AOR = 1.96, 95% CI = 1.26 to 3.06, p = .003), but were not more likely to be tested for STIs (AOR = 1.37, 95% CI = 0.88 to 2.16, p = .167). When adjusted for previous HIV testing, those with mid or high campaign exposure were not more likely to indicate intention to be tested for HIV in the following six months (AOR = 1.30, 95% CI = 0.73 to 2.32, p = .367). Those with no campaign exposure were less likely than those with low exposure to have used appropriate lubricant with anal sex partners in the previous year (AOR = 0.42, 95% CI = 0.23 to 0.77, p = .005). Conclusions: The campaign had demonstrable reach. The analysis showed partial support for the role of mass media campaigns in improving sexual health outcomes. This suggests that a role for mass media campaigns remains within combination HIV prevention

Biopsy confirmation of metastatic sites in breast cancer patients:clinical impact and future perspectives

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue

Massively Parallel Sequencing Reveals the Complex Structure of an Irradiated Human Chromosome on a Mouse Background in the Tc1 Model of Down Syndrome

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype – phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439

Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer

AZD3409 is an orally active double prodrug that was developed as a novel dual prenyltransferase inhibitor. The formation of the active metabolite AZD3409 acid is mediated by esterases in plasma and cells. The aim of this phase I study was to determine the maximum tolerated dose, toxicities, pharmacokinetics and pharmacodynamics of AZD3409. AZD3409 was administered orally to patients with advanced solid malignancies using an interpatient dose-escalation scheme starting at 500 mg AZD3409 once daily. Twenty-nine patients were treated at seven dose levels. The MTD of part A was defined as 750 mg b.i.d. in the fasted state. Adverse events were mainly gastrointestinal and the severity was on average mild to moderate and reversible. The dose-limiting toxicities were vomiting, diarrhoea and uncontrolled nausea. Pharmacokinetic studies of the prodrug and the active metabolite indicated dose proportionality. Pharmacodynamic studies showed that farnesyltransferase (FTase) was inhibited at all dose levels. In conclusion, chronic oral dosing with AZD3409 is feasible and results in significant inhibition of FTase activity. Pharmacodynamic studies revealed that the maximal FTase inhibition, estimated at 49±11%, appeared to be reached at AZD3409 acid plasma concentrations at which the occurrence of drug-related toxicity was low. This study supports the rationale to implement biological effect studies in clinical trials with biologically active anticancer drugs to define optimal dosing regimens

Observational constraints on atmospheric and oceanic cross-equatorial heat transports: revisiting the precipitation asymmetry problem in climate models

Satellite based top-of-atmosphere (TOA) and surface radiation budget observations are combined with mass corrected vertically integrated atmospheric energy divergence and tendency from reanalysis to infer the regional distribution of the TOA, atmospheric and surface energy budget terms over the globe. Hemispheric contrasts in the energy budget terms are used to determine the radiative and combined sensible and latent heat contributions to the cross-equatorial heat transports in the atmosphere (AHT_EQ) and ocean (OHT_EQ). The contrast in net atmospheric radiation implies an AHT_EQ from the northern hemisphere (NH) to the southern hemisphere (SH) (0.75 PW), while the hemispheric difference in sensible and latent heat implies an AHT_EQ in the opposite direction (0.51 PW), resulting in a net NH to SH AHT_EQ (0.24 PW). At the surface, the hemispheric contrast in the radiative component (0.95 PW) dominates, implying a 0.44 PW SH to NH OHT_EQ. Coupled model intercomparison project phase 5 (CMIP5) models with excessive net downward surface radiation and surface-to-atmosphere sensible and latent heat transport in the SH relative to the NH exhibit anomalous northward AHT_EQ and overestimate SH tropical precipitation. The hemispheric bias in net surface radiative flux is due to too much longwave surface radiative cooling in the NH tropics in both clear and all-sky conditions and excessive shortwave surface radiation in the SH subtropics and extratropics due to an underestimation in reflection by clouds

Type II Secretory Phospholipase A2 and Prognosis in Patients with Stable Coronary Heart Disease: Mendelian Randomization Study

Serum type II secretory phospholipase A(2) (sPLA(2)-IIa) has been found to be predictive of adverse outcomes in patients with stable coronary heart disease. Compounds targeting sPLA(2)-IIa are already under development. This study investigated if an association of sPLA(2)-IIa with secondary cardiovascular disease (CVD) events may be of causal nature or mainly a matter of confounding by correlated cardiovascular risk markers.Eight-year follow-up data of a prospective cohort study (KAROLA) of patients who underwent in-patient rehabilitation after an acute cardiovascular event were analysed. Associations of polymorphisms (SNP) in the sPLA(2)-IIa-coding gene PLA2G2A with serum sPLA(2)-IIa and secondary fatal or non-fatal CVD events were examined by multiple regression. Hazard ratios (HR) were compared with those expected if the association between sPLA(2)-IIa and CVD were causal. The strongest determinants of sPLA(2)-IIa (rs4744 and rs10732279) were associated with an increase of serum concentrations by 81% and 73% per variant allele. HRs (95% confidence intervals) estimating the associations of the SNPs with secondary CVD events were increased, but not statistically significant (1.16 [0.89-1.51] and 1.18 [0.91-1.52] per variant allele, respectively). However, these estimates were very similar to those expected when assuming causality (1.18 and 1.17), based on an association of natural log-transformed sPLA(2)-IIa concentration with secondary events with HR = 1.33 per unit.The present findings regarding genetic polymorphisms, determination of serum sPLA(2)-IIa, and prognosis in CVD patients are consistent with a genuine causal relationship and thus might point to a valid drug target for prevention of secondary CVD events

Glycine propionyl-L-carnitine increases plasma nitrate/nitrite in resistance trained men

We have recently demonstrated that oral intake of glycine propionyl-L-carnitine (GPLC) increases plasma nitrate/nitrite (NOx), a surrogate measure of nitric oxide production. However, these findings were observed at rest, and in previously sedentary subjects