The Relationship Between Leaf Area Index and Photosynthetic Temperature Response in Wheat (\u3cem\u3eTriticum aestivum\u3c/em\u3e L.) Canopies

The objective of this study was to determine the effect of increasing leaf area index on the photosynthetic temperature response of a wheat canopy. Hard red spring wheat (Triticum aestivum L. cv. Veery-10) was grown hydroponically in a growth chamber, which also served as the gas-exchange chamber. Gas-exchange parameters were measured on single leaves and on wheat canopies at various leaf area indices. The temperature response curves of the canopy shifted from being steeper with a high temperature optimum to being flatter with a lower temperature optimum as leaf area index increased from 0 to 20.0 m2m-2. Single-leaf and canopy measurements show that this shift was primarily a result of increasing respiration from accumulating stems and reproductive structures and, to a lesser extent, from lower temperature optimums associated with lower light levels within the canopy

Likelihood of ‘falling through the net’ relates to contemporary prevalence of gestational diabetes. Reply to Ikomi A, Mannan S, Anthony R, Kiss S

This project was not supported by any specific funding. Claire Meek receives salary funding from the European Union Seventh Framework Programme (FP7/2007-2013; grant agreement n° 266408) and from the Wellcome Trust Translational Medicine and Therapeutics Programme which is funded by the Wellcome Trust in association with Glaxo SmithKline.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00125-015-3737-

Test–retest reliability of multidimensional dyspnea profile recall ratings in the emergency department: a prospective, longitudinal study

BACKGROUND: Dyspnea is among the most common reasons for emergency department (ED) visits by patients with cardiopulmonary disease who are commonly asked to recall the symptoms that prompted them to come to the ED. The reliability of recalled dyspnea has not been systematically investigated in ED patients. METHODS: Patients with chronic or acute cardiopulmonary conditions who came to the ED with dyspnea (N = 154) completed the Multidimensional Dyspnea Profile (MDP) several times during the visit and in a follow-up visit 4 to 6 weeks later (n = 68). The MDP has 12 items with numerical ratings of intensity, unpleasantness, sensory qualities, and emotions associated with how breathing felt when participants decided to come to the ED (recall MDP) or at the time of administration (“now” MDP). The recall MDP was administered twice in the ED and once during the follow-up visit. Principal components analysis (PCA) with varimax rotation was used to assess domain structure of the recall MDP. Internal consistency reliability was assessed with Cronbach’s alpha. Test–retest reliability was assessed with intraclass correlation coefficients (ICCs) for absolute agreement for individual items and domains. RESULTS: PCA of the recall MDP was consistent with two domains (Immediate Perception, 7 items, Cronbach’s alpha = .89 to .94; Emotional Response, 5 items; Cronbach’s alpha = .81 to .85). Test–retest ICCs for the recall MDP during the ED visit ranged from .70 to .87 for individual items and were .93 and .94 for the Immediate Perception and Emotional Response domains. ICCs were much lower for the interval between the ED visit and follow-up, both for individual items (.28 to .66) and for the Immediate Perception and Emotional Response domains (.72 and .78, respectively). CONCLUSIONS: During an ED visit, recall MDP ratings of dyspnea at the time participants decided to seek care in the ED are reliable and sufficiently stable, both for individual items and the two domains, that a time lag between arrival and questionnaire administration does not critically affect recall of perceptual and emotional characteristics immediately prior to the visit. However, test–retest reliability of recall over a 4- to 6-week interval is poor for individual items and significantly attenuated for the two domains

Likelihood of 'falling through the net' relates to contemporary prevalence of gestational diabetes. Reply to Ikomi A, Mannan S, Anthony R, Kiss S [letter].

This project was not supported by any specific funding. Claire Meek receives salary funding from the European Union Seventh Framework Programme (FP7/2007-2013; grant agreement n° 266408) and from the Wellcome Trust Translational Medicine and Therapeutics Programme which is funded by the Wellcome Trust in association with Glaxo SmithKline.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00125-015-3737-

The primary familial brain calcification associated protein MYORG is an α-galactosidase with restricted substrate specificity

Primary familial brain calcification (PFBC) is characterised by abnormal deposits of calcium phosphate within various regions of the brain that are associated with severe cognitive impairments, psychiatric conditions, and movement disorders. Recent studies in diverse populations have shown a link between mutations in myogenesis-regulating glycosidase (MYORG) and the development of this disease. MYORG is a member of glycoside hydrolase (GH) family 31 (GH31) and, like the other mammalian GH31 enzyme α-glucosidase II, this enzyme is found in the lumen of the endoplasmic reticulum (ER). Though presumed to act as an α-glucosidase due to its localization and sequence relatedness to α-glucosidase II, MYORG has never been shown to exhibit catalytic activity. Here, we show that MYORG is an α-galactosidase and present the high-resolution crystal structure of MYORG in complex with substrate and inhibitor. Using these structures, we map detrimental mutations that are associated with MYORG-associated brain calcification and define how these mutations may drive disease progression through loss of enzymatic activity. Finally, we also detail the thermal stabilisation of MYORG afforded by a clinically approved small molecule ligand, opening the possibility of using pharmacological chaperones to enhance the activity of mutant forms of MYORG

LRH-1 drives colon cancer cell growth by repressing the expression of the <i>CDKN1A</i> gene in a p53-dependent manner

Liver receptor homologue 1 (LRH-1) is an orphan nuclear receptor that has been implicated in the progression of breast, pancreatic and colorectal cancer (CRC). To determine mechanisms underlying growth promotion by LRH-1 in CRC, we undertook global expression profiling following siRNA-mediated LRH-1 knockdown in HCT116 cells, which require LRH-1 for growth and in HT29 cells, in which LRH-1 does not regulate growth. Interestingly, expression of the cell cycle inhibitor p21 (CDKN1A) was regulated by LRH-1 in HCT116 cells. p21 regulation was not observed in HT29 cells, where p53 is mutated. p53 dependence for the regulation of p21 by LRH-1 was confirmed by p53 knockdown with siRNA, while LRH-1-regulation of p21 was not evident in HCT116 cells where p53 had been deleted. We demonstrate that LRH-1-mediated p21 regulation in HCT116 cells does not involve altered p53 protein or phosphorylation, and we show that LRH-1 inhibits p53 recruitment to the p21 promoter, likely through a mechanism involving chromatin remodelling. Our study suggests an important role for LRH-1 in the growth of CRC cells that retain wild-type p53

MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically

Epidemiology, prehospital care and outcomes of patients arriving by ambulance with dyspnoea: An observational study

Background: This study aimed to determine epidemiology and outcome for patients presenting to emergency departments (ED) with shortness of breath who were transported by ambulance. Methods: This was a planned sub-study of a prospective, interrupted time series cohort study conducted at three time points in 2014 and which included consecutive adult patients presenting to the ED with dyspnoea as a main symptom. For this sub-study, additional inclusion criteria were presentation to an ED in Australia or New Zealand and transport by ambulance. The primary outcomes of interest are the epidemiology and outcome of these patients. Analysis was by descriptive statistics and comparisons of proportions. Results: One thousand seven patients met inclusion criteria. Median age was 74 years (IQR 61-68) and 46.1 % were male. There was a high rate of co-morbidity and chronic medication use. The most common ED diagnoses were lower respiratory tract infection (including pneumonia, 22.7 %), cardiac failure (20.5%) and exacerbation of chronic obstructive pulmonary disease (19.7 %). ED disposition was hospital admission (including ICU) for 76.4 %, ICU admission for 5.6 % and death in ED in 0.9 %. Overall in-hospital mortality among admitted patients was 6.5 %. Discussion: Patients transported by ambulance with shortness of breath make up a significant proportion of ambulance caseload and have high comorbidity and high hospital admission rate. In this study, >60 % were accounted for by patients with heart failure, lower respiratory tract infection or COPD, but there were a wide range of diagnoses. This has implications for service planning, models of care and paramedic training. Conclusion: This study shows that patients transported to hospital by ambulance with shortness of breath are a complex and seriously ill group with a broad range of diagnoses. Understanding the characteristics of these patients, the range of diagnoses and their outcome can help inform training and planning of services