Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44.

Sulfatase modifying factor 1 (SUMF1) encodes for the formylglicine generating enzyme, which activates sulfatases by modifying a key cysteine residue within their catalytic domains. SUMF1 is mutated in patients affected by multiple sulfatase deficiency, a rare recessive disorder in which all sulfatase activities are impaired. Despite the absence of canonical retention/retrieval signals, SUMF1 is largely retained in the endoplasmic reticulum (ER), where it exerts its enzymatic activity on nascent sulfatases. Part of SUMF1 is secreted and paracrinally taken up by distant cells. Here we show that SUMF1 interacts with protein disulfide isomerase (PDI) and ERp44, two thioredoxin family members residing in the early secretory pathway, and with ERGIC-53, a lectin that shuttles between the ER and the Golgi. Functional assays reveal that these interactions are crucial for controlling SUMF1 traffic and function. PDI couples SUMF1 retention and activation in the ER. ERGIC-53 and ERp44 act downstream, favoring SUMF1 export from and retrieval to the ER, respectively. Silencing ERGIC-53 causes proteasomal degradation of SUMF1, while down-regulating ERp44 promotes its secretion. When over-expressed, each of three interactors favors intracellular accumulation. Our results reveal a multistep control of SUMF1 trafficking, with sequential interactions dynamically determining ER localization, activity and secretion

PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer

BRCA and poly-ADP ribose polymerase (PARP) regulate pathways of DNA repair. Due to the accumulation of mutations introduced by error-prone DNA repair, breast and ovarian cancers develop in the setting of BRCA deficiency. A series of recent clinical trials has tested the use of PARP inhibition as a therapeutic strategy to target BRCA-deficient tumors

Food waste as a consequence of an inefficient consumer’s choices: a microeconomic approach

This study frames the household food waste challenge in the microeconomic theory context by proposing a model that considers food waste a consequence of inefficient consumer choices. A data envelopment analysis (DEA) methodology was applied to factor consumer’s efficiency level dimension, starting from data collected through a web survey conducted in Italy with a sample of 530 individuals responsible for their households’ food-shopping. The findings confirm that food waste is a complex issue, affected by both behavioural and psychological factors, synthesized in three indices constructed with fuzzy analysis. The results show that the shopping behaviour index generates a higher average efficiency score for food waste minimization than the food waste concerns and moral attitudes indices. Furthermore, those drivers have different efficiency levels in reducing food waste with reference to gender, age, family composition, and educational level. The results have several implications for policymakers: they highlight the need to implement tailored educational and information campaigns that consider the most important targets identified, such as large families with children, young people, and me

Organocatalytic alpha-trifluoromethylthiolation of silylenol ethers : Batch vs continuous flow reactions

This work describes the organocatalytic \uce\ub1-trifluoromethylthiolation of silylenol ethers using N-(trifluoromethylthio)saccharin as trifluoromethylthiolating reagent that is activated by the presence of catalytic amounts of a Lewis base. Tetrahydrothiophene was identified as the best organocatalyst and it was successfully employed to promote the synthesis of different \uce\ub1-trifluoromethylketones; the reaction has been performed under a traditional batch methodology and under continuous flow conditions. In general, yields obtained using the traditional batch process were higher than those observed when the reaction was performed under flow conditions. However, short reaction times, higher productivity and higher space time yields were observed when a flow system process was employed. Preliminary DFT calculations were also performed in order to elucidate the mechanism of the reaction

Myocardial hypothermia increases autophagic flux, mitochondrial mass and myocardial function after ischemia-reperfusion injury.

Animal studies have demonstrated beneficial effects of therapeutic hypothermia on myocardial function, yet exact mechanisms remain unclear. Impaired autophagy leads to heart failure and mitophagy is important for mitigating ischemia/reperfusion injury. This study aims to investigate whether the beneficial effects of therapeutic hypothermia are due to preserved autophagy and mitophagy. Under general anesthesia, the left anterior descending coronary artery of 19 female farm pigs was occluded for 90 minutes with consecutive reperfusion. 30 minutes after reperfusion, we performed pericardial irrigation with warm or cold saline for 60 minutes. Myocardial tissue analysis was performed one and four weeks after infarction. Therapeutic hypothermia induced a significant increase in autophagic flux, mitophagy, mitochondrial mass and function in the myocardium after infarction. Cell stress, apoptosis, inflammation as well as fibrosis were reduced, with significant preservation of systolic and diastolic function four weeks post infarction. We found similar biochemical changes in human samples undergoing open chest surgery under hypothermic conditions when compared to the warm. These results suggest that autophagic flux and mitophagy are important mechanisms implicated in cardiomyocyte recovery after myocardial infarction under hypothermic conditions. New therapeutic strategies targeting these pathways directly could lead to improvements in prevention of heart failure

Random Graph-Homomorphisms and Logarithmic Degree

A graph homomorphism between two graphs is a map from the vertex set of one graph to the vertex set of the other graph, that maps edges to edges. In this note we study the range of a uniformly chosen homomorphism from a graph G to the infinite line Z. It is shown that if the maximal degree of G is `sub-logarithmic', then the range of such a homomorphism is super-constant. Furthermore, some examples are provided, suggesting that perhaps for graphs with super-logarithmic degree, the range of a typical homomorphism is bounded. In particular, a sharp transition is shown for a specific family of graphs C_{n,k} (which is the tensor product of the n-cycle and a complete graph, with self-loops, of size k). That is, given any function psi(n) tending to infinity, the range of a typical homomorphism of C_{n,k} is super-constant for k = 2 log(n) - psi(n), and is 3 for k = 2 log(n) + psi(n)