Inhibition of fungal and mammalian sterol biosynthesis by 2-aza-2,3-dihydrosqualene

Abstract2-Aza-2,3-dihydrosqualene (I) and a quaternary ammonium derivative (II) inhibited ergosterol biosynthesis in cells and cell-free extracts of the pathogenic yeast Candida albicans as measured by incorporation of radiolabelled precursors. The compounds inhibited squalene epoxidase and 2,3-oxidosqualene cyclase to varying degrees in microsomes from C. albicans and from rat liver. The rat liver epoxidase was 50% inhibited by I at 2.4 μM. In C. albicans cells, but not in cell-free extracts, I also inhibited lanosterol demethylation and led to accumulation of an unidentified polar product

CO2 induced seawater acidification impacts sea urchin larval development I: Elevated metabolic rates decrease scope for growth and induce developmental delay

Anthropogenic CO(2) emissions are acidifying the world's oceans. A growing body of evidence is showing that ocean acidification impacts growth and developmental rates of marine invertebrates. Here we test the impact of elevated seawater pCO(2) (129Pa, 1271 atm) on early development, larval metabolic and feeding rates in a marine model organism, the sea urchin Strongylocentrotus purpuratus. Growth and development was assessed by measuring total body length, body rod length, postoral rod length and posterolateral rod length. Comparing these parameters between treatments suggests that larvae suffer from a developmental delay (by ca. 8%) rather than from the previously postulated reductions in size at comparable developmental stages. Further, we found maximum increases in respiration rates of +100% under elevated pCO(2), while body length corrected feeding rates did not differ between larvae from both treatments. Calculating scope for growth illustrates that larvae raised under high pCO(2) spent an average of 39 to 45% of the available energy for somatic growth, while control larvae could allocate between 78 and 80% of the available energy into growth processes. Our results highlight the importance of defining a standard frame of reference when comparing a given parameter between treatments, as observed differences can be easily due to comparison of different larval ages with their specific set of biological characters

Partner Choices in Long Established Migrant Communities in Belgium

This paper aims to shed light on the partner choices of Moroccan, Turkish, Congolese, and Algerian migrants in Belgium. Three partner choices are distinguished: marrying a partner from the country of origin (partner migration), marrying a local co-ethnic partner, and establishing a mixed marriage. We focused on the role of migration history and transnational links, culture (religion, language), skin colour and structural characteristics of the district migrants live in (mainly community size) to gain further insight into the partner choices of migrants in Belgium. Our data comprise an extraction of the Belgian national register (2001-2008) and focus on first marriages among first, 1.5, and second generation migrants of Moroccan, Turkish, Algerian, and Congolese origin (N=52,142). We apply a multinomial logistic multilevel design to simultaneously incorporate individual and contextual effects at the district level. The main conclusion from this paper is that the partner selection pattern in early 21st century Belgian society still bears the traces of the starting conditions that migrant groups experienced when they first entered the country. While this continuity is important to understand the situation citizens with a migrant origin have to deal with today, it does not make change impossible. In fact, for the Turkish and Moroccan group, research recently showed a quite strong decline in transnational marriages and a modest increase in mixed marriages. These are indications that after 50 years of migration a transition towards full inclusion in Belgian society is not beyond reach. The conditions analysed in this paper, namely the strength of transnational networks, the cultural boundaries and the ethnic community size, may help to understand why this inclusion takes such a long period of time

Developmental expression of 4-repeat-Tau induces neuronal aneuploidy in Drosophila tauopathy models

Tau-mediated neurodegeneration in Alzheimer's disease and tauopathies is generally assumed to start in a normally developed brain. However, several lines of evidence suggest that impaired Tau isoform expression during development could affect mitosis and ploidy in post-mitotic differentiated tissue. Interestingly, the relative expression levels of Tau isoforms containing either 3 (3R-Tau) or 4 repeats (4R-Tau) play an important role both during brain development and neurodegeneration. Here, we used genetic and cellular tools to study the link between 3R and 4R-Tau isoform expression, mitotic progression in neuronal progenitors and post-mitotic neuronal survival. Our results illustrated that the severity of Tau-induced adult phenotypes depends on 4R-Tau isoform expression during development. As recently described, we observed a mitotic delay in 4R-Tau expressing cells of larval eye discs and brains. Live imaging revealed that the spindle undergoes a cycle of collapse and recovery before proceeding to anaphase. Furthermore, we found a high level of aneuploidy in post-mitotic differentiated tissue. Finally, we showed that overexpression of wild type and mutant 4R-Tau isoform in neuroblastoma SH-SY5Y cell lines is sufficient to induce monopolar spindles. Taken together, our results suggested that neurodegeneration could be in part linked to neuronal aneuploidy caused by 4R-Tau expression during brain development

Prevalence of Enteric Pathogens among International Travelers with Diarrhea Acquired in Kenya (Mombasa), India (Goa), or Jamaica (Montego Bay)

Stools from tourists from Europe and North America who acquired diarrhea in Mombasa (Kenya), Goa (India), or Montego Bay (Jamaica) were examined for enteric pathogens. Enterotoxigenic Escherichia coli (ETEC) was the most common pathogen (25%) identified in the 3 locations. Isolation of Shigella species was more frequent in Goa and Mombasa than in Montego Bay (10%, 9%, and 0.3%, respectively; P < .005). Viruses (rotaviruses and enteric adenoviruses) were found in 9% of travelers to the 3 areas. Of 275 ETEC isolates in this study, 158 (57%) produced a defined colonization factor antigen (CFA). Coli surface 6 (CS6) was the most frequent and was found in 41%-52% of CFA/CS-positive ETEC isolates. The frequency of resistance among bacterial enteropathogens to traditional antimicrobial agents was particularly high throughout the study period in all 3 regions. Quinolones were active against the bacterial enteropathogens in the 3 site

Transcription factor 7-like 2 (TCF7L2) variant is associated with familial breast cancer risk: a case-control study

BACKGROUND: The transcription factor 7-like 2 (TCF7L2) is a critical component of the Wnt/β-catenin pathway. Aberrant TCF7L2 expression modifies Wnt signaling and mediates oncogenic effects through the upregulation of c-MYC and cyclin D. Genetic alterations in TCF7L2 may therefore affect cancer risk. Recently, TCF7L2 variants, including the microsatellite marker DG10S478 and the nearly perfectly linked SNP rs12233372, were identified to associate with type 2 diabetes. METHODS: We investigated the effect of the TCF7L2 rs12255372 variant on familial breast cancer (BC) risk by means of TaqMan allelic discrimination, analyzing BRCA1/2 mutation-negative index patients of 592 German BC families and 735 control individuals. RESULTS: The T allele of rs12255372 showed an association with borderline significance (OR = 1.19, 95% C.I. = 1.01-1.42, P = 0.04), and the Cochran-Armitage test for trend revealed an allele dose-dependent association of rs12255372 with BC risk (P(trend )= 0.04). CONCLUSION: Our results suggest a possible influence of TCF7L2 rs12255372 on the risk of familial BC

Sodium and potassium changes during decongestion with acetazolamide:A pre-specified analysis from the ADVOR trial

AIMS: Acetazolamide, an inhibitor of proximal tubular sodium reabsorption, leads to more effective decongestion in acute heart failure (AHF). It is unknown whether acetazolamide alters serum sodium and potassium levels on top of loop diuretics and if baseline values modify the treatment effect of acetazolamide.METHODS AND RESULTS: This is a pre-specified sub-analysis of the ADVOR trial that randomized 519 patients with AHF and volume overload in a 1:1 ratio to intravenous acetazolamide or matching placebo on top of standardized intravenous loop diuretics. Mean potassium and sodium levels at randomization were 4.2 ± 0.6 and 139 ± 4 mmol/L in the acetazolamide arm versus 4.2 ± 0.6 and 140 ± 4 mmol/L in the placebo arm. Hypokalaemia (&lt;3.5 mmol/L) on admission was present in 44 (9%) patients and hyponatraemia (≤135 mmol/L) in 82 (16%) patients. After 3 days of treatment, 44 (17%) patients in the acetazolamide arm and 35 (14%) patients in the placebo arm developed hyponatraemia (p = 0.255). Patients randomized to acetazolamide demonstrated a slight decrease in mean potassium levels during decongestion, which was non-significant over time (p = 0.053) and had no significant impact on hypokalaemia incidence (p = 0.061). Severe hypokalaemia (&lt;3.0 mmol/L) occurred in only 7 (1%) patients, similarly distributed between the two treatment arms (p = 0.676). Randomization towards acetazolamide improved decongestive response irrespective of baseline serum sodium and potassium levels.CONCLUSIONS: Acetazolamide on top of standardized loop diuretic therapy does not lead to clinically important hypokalaemia or hyponatraemia and improves decongestion over the entire range of baseline serum potassium and sodium levels.</p