Characterization of the monocyte-specific esterase (MSE) gene

Carboxylic esterases are widely distributed in hematopoietic cells. Monocytes express the esterase isoenzyme (termed 'monocyte-specific esterase', MSE) that can be inhibited by NaF in the alpha-naphthyl acetate cytochemical staining. We examined the expression of MSE in normal cells and primary and cultured leukemia-lymphoma cells. The MSE protein was demonstrated by isoelectric focusing (IEF); MSE mRNA expression was investigated by Northern blotting and reverse transcriptase-polymerase chain reaction (RT-PCR). The following samples were positive for MSE protein and Northern mRNA expression: 20/24 monocytic, 4/32 myeloid, and 1/20 erythroid-megakaryocytic leukemia cell lines, but none of the 112 lymphoid leukemia or lymphoma cell lines; of the normal purified cell populations only the monocytes were positive whereas, T, B cells, and granulocytes were negative; of primary acute (myelo) monocytic leukemia cells (CD14-positive, FAB M4/M5 morphology) 14/20 were Northern mRNA and 11/14 IEF protein positive. RT-PCR revealed MSE expression in 29/49 Northern-negative lymphoid leukemia-lymphoma cell lines. The RT-PCR signals in monocytic cell lines were on average 50-fold stronger than the mostly weak trace expression in lymphoid specimens. On treatment with various biomodulators, only all-trans retinoic acid significantly upregulated MSE message and protein levels but could not induce new MSE expression in several leukemia cell lines; lipopolysaccharide and interferon-gamma increased MSE expression in normal monocytes. Analysis of DNA methylation with sensitive restriction enzymes showed no apparent regulation of gene expression by differential methylation; the MSE gene is evolutionarily conserved among mammalian species; the half-life of the human MSE transcripts was about 5-6 h. The extent of MSE expression varied greatly among different monocytic leukemia samples. However, the MSE overexpression in a significant number of specimens was not associated with gene amplification, gross structural rearrangements or point mutations within the cDNA region. Taken together, the results suggest that MSE expression is not absolutely specific for, but strongly associated with cells of the monocytic lineage; MSE is either not expressed at all or expressed at much lower levels in cells from other lineages. The biological significance, if any, of rare MSE messages in lymphoid cells detectable only by the hypersensitive RT-PCR remains unclear. Further studies on the regulation of this gene and on the physiological function of the enzyme will no doubt be informative with respect to its striking overexpression in some malignant cells and to a possible role in the pathobiology of monocytic leukemias

Perturbed cholesterol and vesicular trafficking associated with dengue blocking in Wolbachia-infected Aedes aegypti cells

Wolbachia are intracellular maternally inherited bacteria that can spread through insect populations and block virus transmission by mosquitoes, providing an important approach to dengue control. To better understand the mechanisms of virus inhibition, we here perform proteomic quantification of the effects of Wolbachia in Aedes aegypti mosquito cells and midgut. Perturbations are observed in vesicular trafficking, lipid metabolism and in the endoplasmic reticulum that could impact viral entry and replication. Wolbachia-infected cells display a differential cholesterol profile, including elevated levels of esterified cholesterol, that is consistent with perturbed intracellular cholesterol trafficking. Cyclodextrins have been shown to reverse lipid accumulation defects in cells with disrupted cholesterol homeostasis. Treatment of Wolbachia-infected Ae. aegypti cells with 2-hydroxypropyl-β-cyclodextrin restores dengue replication in Wolbachia-carrying cells, suggesting dengue is inhibited in Wolbachia-infected cells by localised cholesterol accumulation. These results demonstrate parallels between the cellular Wolbachia viral inhibition phenotype and lipid storage genetic disorders

Improving coding and primary care management for people with Chronic Kidney Disease: an observational controlled study in east London

Background: The UK national chronic kidney disease (CKD) audit in primary care shows diagnostic coding in the electronic health record for CKD averages 70%, with wide practice variation. Coding is associated with improvements to risk factor management; CKD cases coded in primary care have lower rates of unplanned hospital admission. Aim: To increase diagnostic coding of CKD (stages 3–5) and primary care management, including blood pressure to target and prescription of statins to reduce cardiovascular disease risk. Design and setting: Controlled, cross-sectional study in four East London clinical commissioning groups (CCGs). Method: Interventions to improve coding formed part of a larger system change to the delivery of renal services in both primary and secondary care in East London. Quarterly anonymised data on CKD coding, blood pressure values, and statin prescriptions were extracted from practice computer systems for 1-year pre- and post-initiation of the intervention. Results: Three intervention CCGs showed significant coding improvement over a 1 year period following the intervention (regression for post-intervention trend P<0.001). The CCG with highest coding rates increased from 76–90% of CKD cases coded; the lowest coding CCG increased from 52–81%. The comparison CCG showed no change in coding rates. Combined data from all practices in the intervention CCGs showed a significant increase in the proportion of cases with blood pressure achieving target levels (difference in proportion P<0.001) over the 2-year study period. Differences in statin prescribing were not significant. Conclusion: Clinically important improvements to coding and management of CKD in primary care can be achieved by quality improvement interventions that use shared data to track and monitor change supported by practice-based facilitation. Alignment of clinical and CCG priorities and the provision of clinical targets, financial incentives, and educational resource were additional important elements of the intervention

Exact and semiclassical approach to a class of singular integral operators arising in fluid mechanics and quantum field theory

A class of singular integral operators, encompassing two physically relevant cases arising in perturbative QCD and in classical fluid dynamics, is presented and analyzed. It is shown that three special values of the parameters allow for an exact eigenfunction expansion; these can be associated to Riemannian symmetric spaces of rank one with positive, negative or vanishing curvature. For all other cases an accurate semiclassical approximation is derived, based on the identification of the operators with a peculiar Schroedinger-like operator.Comment: 12 pages, 1 figure, amslatex, bibtex (added missing label eq.11

Shareholder Activism on Climate Change: Evolution, Determinants, and Consequences

We study 944 shareholder proposals submitted to 343 U.S. firms on climate change issues during 2009–2022. We use logistic and two-stage regression to estimate the propensity for a firm to be targeted or subjected to a vote at the annual general meeting and, for voted proposals, the determinants of that vote. We also examine whether climate-related proposals affect investor returns and how they relate to firms’ future environmental performance and greenhouse gas emissions. Compared to a matched sample, we first find that activists target larger, more carbon-intensive, and less R&D-active firms. Second, voting likelihood is higher for firms with repeated and operations-related proposals and lower pre-proposal environmental ratings. By contrast, disclosure-related proposals are likelier to be negotiated and withdrawn. Third, repeated and operations-related proposals receive higher votes in favor, whereas votes on carbon-intensive firms do not. Fourth, building on the theory that investors act as if they distinguish among the different shareholder proposals based on the expected cost to the firm, we find evidence to support this idea. We find that investors respond negatively to ex-ante costlier proposals, such as those that relate to emissions reduction and target carbon-intensive firms. Fifth, targets’ future environmental performance rating is almost twenty percent higher after a proposal than before compared to the matched sample, whereas emissions do not budge appreciably

Intense physical activity is associated with cognitive performance in the elderly

Numerous studies have reported positive impacts of physical activity on cognitive function. However, the majority of these studies have utilised physical activity questionnaires or surveys, thus results may have been influenced by reporting biases. Through the objective measurement of routine levels of physical activity via actigraphy, we report a significant association between intensity, but not volume, of physical activity and cognitive functioning. A cohort of 217 participants (aged 60–89 years) wore an actigraphy unit for 7 consecutive days and underwent comprehensive neuropsychological assessment. The cohort was stratified into tertiles based on physical activity intensity. Compared with individuals in the lowest tertile of physical activity intensity, those in the highest tertile scored 9%, 9%, 6% and 21% higher on the digit span, digit symbol, Rey Complex Figure Test (RCFT) copy and Rey Figure Test 30-min recall test, respectively. Statistically, participants in the highest tertile of physical activity intensity performed significantly better on the following cognitive tasks: digit symbol, RCFT copy and verbal fluency test (all P<0.05). The results indicate that intensity rather than quantity of physical activity may be more important in the association between physical activity and cognitive function

The Large-scale J=3-2 and J=2-1 CO Emission from M17 and its Implications for Extragalactic CO Observations

We observed a 10x20 pc region of the molecular cloud M17 in the 12CO and 13CO J=3-2 and J=2-1 transitions to determine their global behavior and to assess the reliability of using ratios of CO line intensities integrated over an entire cloud to determine the physical conditions within the cloud. Both the 12CO/13CO J=2-1 and J=3-2 line ratios correlate with the 13CO integrated intensity, with smaller line ratios observed at locations with large integrated intensities. This correlation is likely due to variations in the column density from one position to another within M17. The 12CO and 13CO (J=3-2/J=2-1) line ratios show no significant variation from place to place within M17, even on the peak of the photon-dominated region. A Large Velocity Gradient analysis of globally averaged line ratios gives results in reasonable agreement with the results obtained for individual lines-of-sight through the cloud, which suggests that the typical physical conditions in a molecular cloud can be determined using CO line ratios integrated over the entire cloud. There appears to be a clear trend of increasing 12CO/13CO J=2-1 and J=3-2 line ratios as one moves from Galactic molecular cloud cores to entire Galactic molecular clouds to normal galaxies. The most likely explanation of the high line ratios for normal galaxies is a significant contribution to the CO emission by low column density material, such as diffuse molecular clouds or the outer envelopes of giant molecular clouds.Comment: 26 pages, 6 figures, 2 tables. Accepted for publication in Ap