Overexpression of Key Sterol Pathway Enzymes in Two Model Marine Diatoms Alters Sterol Profiles in <i>Phaeodactylum tricornutum</i>.

Sterols are a class of triterpenoid molecules with diverse functional roles in eukaryotic cells, including intracellular signaling and regulation of cell membrane fluidity. Diatoms are a dominant eukaryotic phytoplankton group that produce a wide diversity of sterol compounds. The enzymes 3-hydroxy-3-methyl glutaryl CoA reductase (HMGR) and squalene epoxidase (SQE) have been reported to be rate-limiting steps in sterol biosynthesis in other model eukaryotes; however, the extent to which these enzymes regulate triterpenoid production in diatoms is not known. To probe the role of these two metabolic nodes in the regulation of sterol metabolic flux in diatoms, we independently over-expressed two versions of the native HMGR and a conventional, heterologous SQE gene in the diatoms Thalassiosira pseudonana and Phaeodactylum tricornutum. Overexpression of these key enzymes resulted in significant differential accumulation of downstream sterol pathway intermediates in P. tricornutum. HMGR-mVenus overexpression resulted in the accumulation of squalene, cycloartenol, and obtusifoliol, while cycloartenol and obtusifoliol accumulated in response to heterologous NoSQE-mVenus overexpression. In addition, accumulation of the end-point sterol 24-methylenecholesta-5,24(24')-dien-3β-ol was observed in all P. tricornutum overexpression lines, and campesterol increased three-fold in P. tricornutum lines expressing NoSQE-mVenus. Minor differences in end-point sterol composition were also found in T. pseudonana, but no accumulation of sterol pathway intermediates was observed. Despite the successful manipulation of pathway intermediates and individual sterols in P. tricornutum, total sterol levels did not change significantly in transformed lines, suggesting the existence of tight pathway regulation to maintain total sterol content

A comparison of A-level performance in economics and business studies: how much more difficult is economics?

This paper uses ALIS data to compare academic performance in two subjects often viewed as relatively close substitutes for one another at A-level. The important role of GCSE achievement is confirmed for both subjects. There is evidence of strong gender effects and variation in outcomes across Examination Boards. A counterfactual exercise suggests that if the sample of Business Studies candidates had studied Economics nearly 40% of those who obtained a grade C or better in the former subject would not have done so in the latter. The opposite exercise uggests that 12% more Economics candidates would have achieved a grade C or better if they had taken Business Studies. In order to render a Business Studies A-level grade comparable to an Economics one in terms of relative difficulty, we estimate that a downward adjustment of 1.5 UCAS points should be applied to the former subject. This adjustment is lower than that suggested by correction factors based on conventional subject pair analysis for these two subjects

Descriptors of Sepsis Using the Sepsis-3 Criteria: A Cohort Study in Critical Care Units Within the U.K. National Institute for Health Research Critical Care Health Informatics Collaborative

OBJECTIVES: To describe the epidemiology of sepsis in critical care by applying the Sepsis-3 criteria to electronic health records. DESIGN: Retrospective cohort study using electronic health records. SETTING: Ten ICUs from four U.K. National Health Service hospital trusts contributing to the National Institute for Health Research Critical Care Health Informatics Collaborative. PATIENTS: A total of 28,456 critical care admissions (14,332 emergency medical, 4,585 emergency surgical, and 9,539 elective surgical). MEASUREMENTS AND MAIN RESULTS: Twenty-nine thousand three hundred forty-three episodes of clinical deterioration were identified with a rise in Sequential Organ Failure Assessment score of at least 2 points, of which 14,869 (50.7%) were associated with antibiotic escalation and thereby met the Sepsis-3 criteria for sepsis. A total of 4,100 episodes of sepsis (27.6%) were associated with vasopressor use and lactate greater than 2.0 mmol/L, and therefore met the Sepsis-3 criteria for septic shock. ICU mortality by source of sepsis was highest for ICU-acquired sepsis (23.7%; 95% CI, 21.9-25.6%), followed by hospital-acquired sepsis (18.6%; 95% CI, 17.5-19.9%), and community-acquired sepsis (12.9%; 95% CI, 12.1-13.6%) (p for comparison less than 0.0001). CONCLUSIONS: We successfully operationalized the Sepsis-3 criteria to an electronic health record dataset to describe the characteristics of critical care patients with sepsis. This may facilitate sepsis research using electronic health record data at scale without relying on human coding

Children who are both wasted and stunted are also underweight and have a high risk of death: a descriptive epidemiology of multiple anthropometric deficits using data from 51 countries.

BACKGROUND: Wasting and stunting are common. They are implicated in the deaths of almost two million children each year and account for over 12% of disability-adjusted life years lost in young children. Wasting and stunting tend to be addressed as separate issues despite evidence of common causality and the fact that children may suffer simultaneously from both conditions (WaSt). Questions remain regarding the risks associated with WaSt, which children are most affected, and how best to reach them. METHODS: A database of cross-sectional survey datasets containing data for almost 1.8 million children was compiled. This was analysed to determine the intersection between sets of wasted, stunted, and underweight children; the association between being wasted and being stunted; the severity of wasting and stunting in WaSt children; the prevalence of WaSt by age and sex, and to identify weight-for-age z-score and mid-upper arm circumference thresholds for detecting cases of WaSt. An additional analysis of the WHO Growth Standards sought the maximum possible weight-for-age z-score for WaSt children. RESULTS: All children who were simultaneously wasted and stunted were also underweight. The maximum possible weight-for-age z-score in these children was below - 2.35. Low WHZ and low HAZ have a joint effect on WAZ which varies with age and sex. WaSt and "multiple anthropometric deficits" (i.e. being simultaneously wasted, stunted, and underweight) are identical conditions. The conditions of being wasted and being stunted are positively associated with each other. WaSt cases have more severe wasting than wasted only cases. WaSt cases have more severe stunting than stunted only cases. WaSt is largely a disease of younger children and of males. Cases of WaSt can be detected with excellent sensitivity and good specificity using weight-for-age. CONCLUSIONS: The category "multiple anthropometric deficits" can be abandoned in favour of WaSt. Therapeutic feeding programs should cover WaSt cases given the high mortality risk associated with this condition. Work on treatment effectiveness, duration of treatment, and relapse after cure for WaSt cases should be undertaken. Routine reporting of the prevalence of WaSt should be encouraged. Further work on the aetiology, prevention, case-finding, and treatment of WaSt cases as well as the extent to which current interventions are reaching WaSt cases is required

Prognostic factors for response to treatment by corticosteroid injection or surgery in carpal tunnel syndrome (PaLMS study): a prospective multi‐centre cohort study

Introduction: Studies of prognosis for surgery and corticosteroid injection for carpal tunnel syndrome have considered only a limited range of explanatory variables for outcome. Methods: Data were prospectively collected on patient‐reported symptoms, physical and psychological functioning, comorbidity and quality of life at baseline and 6 monthly for up to 2 years. Outcomes were patient‐rated change over a 6‐month period and symptom‐severity score at 18 months. Results: 754 patients with CTS completed baseline questionnaires and 626 (83%) completed follow‐up to 18 months. Multivariable modelling identified, independent of symptom severity at outset, higher health utility, fewer comorbidities and lower anxiety as significant predictors of better outcome from surgery. In patients treated by steroid injection, independent of symptom severity at outset, shorter duration of symptoms and having no prior injection were significant predictors of better outcome. Discussion: These multivariable models of outcome may inform shared decision‐making about treatment for CTS

Two <em>Dictyostelium</em> Tyrosine Kinase-Like kinases function in parallel, stress-induced STAT activation pathways

When Dictyostelium cells are hyperosmotically stressed, STATc is activated by tyrosine phosphorylation. Unusually, activation is regulated by serine phosphorylation and consequent inhibition of a tyrosine phosphatase: PTP3. The identity of the cognate tyrosine kinase is unknown, and we show that two tyrosine kinase–like (TKL) enzymes, Pyk2 and Pyk3, share this function; thus, for stress-induced STATc activation, single null mutants are only marginally impaired, but the double mutant is nonactivatable. When cells are stressed, Pyk2 and Pyk3 undergo increased autocatalytic tyrosine phosphorylation. The site(s) that are generated bind the SH2 domain of STATc, and then STATc becomes the target of further kinase action. The signaling pathways that activate Pyk2 and Pyk3 are only partially overlapping, and there may be a structural basis for this difference because Pyk3 contains both a TKL domain and a pseudokinase domain. The latter functions, like the JH2 domain of metazoan JAKs, as a negative regulator of the kinase domain. The fact that two differently regulated kinases catalyze the same phosphorylation event may facilitate specific targeting because under stress, Pyk3 and Pyk2 accumulate in different parts of the cell; Pyk3 moves from the cytosol to the cortex, whereas Pyk2 accumulates in cytosolic granules that colocalize with PTP3

Comprehensive Genomic Analysis of a BRCA2 Deficient Human Pancreatic Cancer

Capan-1 is a well-characterised BRCA2-deficient human cell line isolated from a liver metastasis of a pancreatic adenocarcinoma. Here we report a genome-wide assessment of structural variations and high-depth exome characterization of single nucleotide variants and small insertion/deletions in Capan-1. To identify potential somatic and tumour-associated variations in the absence of a matched-normal cell line, we devised a novel method based on the analysis of HapMap samples. We demonstrate that Capan-1 has one of the most rearranged genomes sequenced to date. Furthermore, small insertions and deletions are detected more frequently in the context of short sequence repeats than in other genomes. We also identify a number of novel mutations that may represent genetic changes that have contributed to tumour progression. These data provide insight into the genomic effects of loss of BRCA2 function

The relevance of nanoscale biological fragments for ice nucleation in clouds

Most studies of the role of biological entities as atmospheric ice-nucleating particles have focused on relatively rare supermicron particles such as bacterial cells, fungal spores and pollen grains. However, it is not clear that there are sufficient numbers of these particles in the atmosphere to strongly influence clouds. Here we show that the ice-nucleating activity of a fungus from the ubiquitous genus Fusarium is related to the presence of nanometre-scale particles which are far more numerous, and therefore potentially far more important for cloud glaciation than whole intact spores or hyphae. In addition, we quantify the ice-nucleating activity of nano-ice nucleating particles (nano-INPs) washed off pollen and also show that nano-INPs are present in a soil sample. Based on these results, we suggest that there is a reservoir of biological nano-INPs present in the environment which may, for example, become aerosolised in association with fertile soil dust particles