Rare APOA5 promoter variants associated with paradoxical HDL cholesterol decrease in response to fenofibric acid therapy

Individuals with mixed dyslipidemia, including high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C), have increased risk for coronary events. We examined the effect of rare genetic variants in the APOA5 gene region on plasma HDL-C, apolipoprotein A-I (apoA-I), and TG response to fenofibric acid monotherapy and in combination with statins. The APOA5 gene region was sequenced in 1,612 individuals with mixed dyslipidemia in a randomized trial of fenofibric acid alone and in combination with statins. Student''s t-test and rare variant burden tests were used to examine plasma HDL-C, apoA-I, and TG response. Rare APOA5 promoter region variants were associated with decreased HDL-C and apoA-I levels in response to fenofibric acid therapy; rare missense variants were associated with increased TG response to combination therapy. Further study is needed to examine the effect of these rare variants on coronary outcomes in this population in response to fenofibric acid monotherapy or combined with statins     

Characterization of type III TGF-β receptor expression in invasive breast carcinomas: a potential new marker and target for triple negative breast cancer

Invasive breast carcinomas are heterogeneous and exhibit distinct molecular features and biological behavior. Understanding the underlying molecular events that promote breast cancer progression is necessary to improve treatment and prognostication. TGF-β receptor III (TBR3) is a member of the TGF-β signaling pathway, with functions in cell proliferation and migration in malignancies, including breast cancer. Recent studies propose that TBR3 may function as a tumor suppressor and that its loss may correlate with disease progression. However, there are limited data on the expression of TBR3 in breast cancer in relationship to tumor type, hormonal receptor status and HER-2/neu, and patient outcome. In this study, we investigated the expression of TBR3 in a cohort of 205 primary invasive breast carcinomas in tissue microarrays (TMAs), with comprehensive clinical, pathological and follow- up information. Sections were stained for TBR3 and evaluated for intensity of reactivity based on a 4-tiered scoring system (1 to 4; TBR3 low = scores 1–2; TBR3 high = scores 3–4). Of the 205 invasive carcinomas, 123 were luminal type (95 type A, 28 type B), 8 were HER-2 type, and 62 were triple negative (TN). TBR3 was high in 112 (55 %) and low in 93 (45 %) cases. Low TBR3 was associated with higher histological grade and worse disease free and overall survival, all features of biologically aggressive breast carcinomas. TBR3 was significantly associated with the subtype of breast cancer, as low TBR3 was detected in 95 % of TN compared to 22 % of luminal tumors (p < 0.0001). We discovered a significant association between low TBR3 protein expression, TN breast cancer phenotype, and disease progression. These data suggest that TBR3 loss might be linked to the development of TN breast cancers and pave the way to investigating whether restoring TBR3 function may be a therapeutic strategy against TN breast carcinomas.     

Population fluctuations and their causes in the African Fish Eagle, (Haliaeetus vocifer (Daudin)) at Lake Naivasha,Kenya

Soft water lakes possess a highly characteristic vegetation adapted to limitation of carbon. Based upon hydrology, vegetation and geographic distribution, boreal and Atlantic lake types can be distinguished. Reducing the input of nutrients or liming, or both, the stream or its catchment is generally sufficient to restore typical soft water vegetation of boreal soft water lakes. The vegetation of Atlantic soft water lakes is subject to many anthropogenic degradation processes. Therefore, spontaneous recovery in the near future is not expected and restoration is urgently required. Removal of nutrient-rich, anoxic, organic sediments is a prerequisite for restoration of these lakes. In acidified or acid-sensitive lakes, additional measures against acidification are required. Controlled supply of calcareous, nutrient-poor water is much better than direct liming. The effects of these restoration measures strongly depend on the detrimental effects of processes such as atmospheric deposition, drainage, catchment acidification, eutrophication and reduced colonisation rates.     

Oxygen consumption, blood lactate and inter-individual variation in the gulf killifish, Fundulus grandis, during hypoxia and recovery

Rates of oxygen consumption (M(O(2))) for Fundulus grandis, the gulf killifish, were measured in air-saturated water, at four progressively lower levels of oxygen and upon normoxic recovery. The pattern of M(O(2)) versus oxygen partial pressure (P(w)O(2)) was that of an oxygen regulator, with a critical oxygen pressure (P(c)) of 34 torr (1 torr=133.3 Pa). Below this value, M(O(2)) decreased and the concentration of blood lactate increased, indicating anaerobic metabolism during hypoxia. Recovery was characterized by elevated M(O(2)) compared to the initial normoxic exposure, coupled with the rapid clearance of blood lactate. Variation in M(O(2)) among the individual fish was appreciable and, in general, it was greater at higher levels of P(w)O(2). This inter-individual variation was significantly larger than the variation between replicate measures of M(O(2)) for a given individual, i.e. it cannot be attributed solely to random error. Furthermore, values for M(O(2)) during normoxia were found to be repeatable when the same fish were used in multiple experimental trials. The observation of significant, repeatable inter-individual variation in M(O(2)) suggests that such variation is a real and potentially important feature of fish metabolism.     

Homing Receptor Expression Is Deviated on CD56+ Blood Lymphocytes during Pregnancy in Type 1 Diabetic Women

Type 1 Diabetes Mellitus (T1DM) is characterized by an augmented pro-inflammatory immune state. This contributes to the increased risk for gestational complications observed in T1DM mothers. In normal pregnancies, critical immunological changes occur, including the massive recruitment of lymphocytes, particularly CD56^bright NK cells, into early decidua basalis and a 2^nd trimester shift towards Type 2 immunity. Decidual CD56^bright NK cells arise at least partly from circulating progenitors expressing adhesion molecules SELL and ITGA4 and the chemokine receptors CXCR3 and CXCR4. In vitro studies show that T1DM reduces interactions between blood CD56⁺ NK cells and decidual endothelial cells by reducing SELL and ITGA4-based interactions. To address the mechanisms by which specific lymphocyte subsets may be recruited from the circulation during pregnancy and whether these mechanisms are altered in T1DM, flow cytometry was used to examine eight peripheral blood lymphocyte subsets (Type 1 (IL18R1⁺) and Type 2 (IL1RL1⁺) CD56^bright NK, CD56^dim NK, NKT and T cells) from control and T1DM women. Blood was collected serially over pregnancy and postpartum, and lymphocytes were compared for expression of homing receptors SELL, ITGA4, CXCR3, and CXCR4. The decline of Type 1/Type 2 immune cells in normal pregnancy was driven by an increase in Type 2 cells that did not occur in T1DM. CD56^bright NK cells from control women had the highest expression of all four receptors with greatest expression in 2^nd trimester. At this time, these receptors were expressed at very low levels by CD56^bright NK cells from TIDM patients. Type 1/Type 2 NKT cell ratios were not influenced by either pregnancy or TIDM. Our results suggest that T1DM alters immunological balances during pregnancy with its greatest impact on CD56^bright NK cells. This implicates CD56^bright NK cells in diabetic pregnancy complications.     

Synthesis and evaluation of 2,5-diamino and 2,5-dianilinomethyl pyridine analogues as potential CXCR4 antagonists

CXCR4 and its cognate ligand CXCL12 has been linked to various pathways such as cancer metastasis, inflammation, HIV-1 proliferation, and auto-immune diseases. Small molecules have shown potential as CXCR4 inhibitors and modulators, and therefore can mitigate diseases related to the CXCR4-CXCL12 pathway. We have designed and synthesized a series of 2,5-diamino and 2,5-dianilinomethyl pyridine derivatives as potential CXCR4 antagonists. Thirteen compounds have an effective concentration (EC) of 100?nM or less in a binding affinity assay and nine of these have at least 75% inhibition of invasion in Matrigel binding assay. Compounds 3l, 7f, 7j, and 7p show a minimal reduction in inflammation when carrageenan paw edema test is conducted. Overall, these compounds show potential as CXCR4 antagonist.     

Molecular imaging of c-Met tyrosine kinase activity

Fluorescent flow cytometry has become the method of choice for interrogation of bacterial populations at the single-cell level. However, limitations of this technique include issues of dynamic range, spectral overlap, photobleaching, and overall low signal intensity due to the small size of bacteria. The recent development of mass cytometry allows single-cell analysis with the resolution of inductively coupled plasma mass spectrometry, facilitating multiparametric analysis. Using a combination of a metal-based membrane stain and lectins conjugated to lanthanide-chelating polymers, we demonstrate that individual Escherichia coli cells can be differentiated based on their cell surface polysaccharides using mass cytometry. The model E. coli system involves evaluation of three different surface polysaccharides using element-tagged concanavalin A and wheat germ agglutinin lectins. Finally, this technique enabled experiments designed to follow the export of O-antigen substituted lipopolysaccharide in a conditional mutant. These studies revealed that the culture responds as a uniform population and that lipopolysaccharide export is approximately 10 times faster than the logarithmic bacterial doubling time.     

African Vultures Don’t Follow Migratory Herds: Scavenger Habitat Use Is Not Mediated by Prey Abundance

The ongoing global decline in vulture populations raises major conservation concerns, but little is known about the factors that mediate scavenger habitat use, in particular the importance of abundance of live prey versus prey mortality. We test this using data from the Serengeti-Mara ecosystem in East Africa. The two hypotheses that prey abundance or prey mortality are the main drivers of vulture habitat use provide alternative predictions. If vultures select areas based only on prey abundance, we expect tracked vultures to remain close to herds of migratory wildebeest regardless of season. However, if vultures select areas where mortality rates are greatest then we expect vultures to select the driest regions, where animals are more likely to die of starvation, and to be attracted to migratory wildebeest only during the dry season when wildebeest mortality is greatest. We used data from GSM-GPS transmitters to assess the relationship between three vulture species and migratory wildebeest in the Mara-Serengeti ecosystem. Results indicate that vultures preferentially cluster around migratory herds only during the dry season, when herds experience their highest mortality. Additionally during the wet season, Ruppell’s and Lappet-faced vultures select relatively dry areas, based on Normalized Difference Vegetation Index, whereas White-backed vultures preferred wetter areas during the wet season. Differences in habitat use among species may mediate coexistence in this scavenger guild. In general, our results suggest that prey abundance is not the primary driver of avian scavenger habitat use. The apparent reliance of vultures on non-migratory ungulates during the wet season has important conservation implications for vultures in light of on-going declines in non-migratory ungulate species and use of poisons in unprotected areas.     

Habitat associations of birds at Mara Naboisho Conservancy,Kenya

Habitat associations of birds were quantified through fixed-radius timed bird counts at Mara Naboisho Conservancy within the Greater Mara Region, Kenya. We conducted 73 timed counts in four distinct habitats (riparian, woodland, rocky outcrop and plains) in both dry and wet seasons. During this survey, we observed 188 species of birds of which 140 were recorded during the timed counts. The riparian zone had the highest species richness, more than three times that of the plains. The woodlands and rocky outcrops had similar species richness. The mean number of species seen per count was higher in the riparian zone compared with the other three habitats. Bird species composition in the riparian zone and the plains were distinct from each other and from the woodlands and rocky outcrops, although they overlapped significantly in the last two mentioned habitats. The possible conservation implication of an increasing and/or immigrant elephant population and its likely effect on the vegetation is discussed in relation to bird community composition.     

Vulture distribution and people perception of vultures in Pokhara Valley,Nepal

Due to an abundance and diversity of vultures, Nepal is one of the most important countries for vulture conservation. Within Nepal, the Pokhara Valley is especially significant. We examine the distribution of vultures within the Pokhara Valley by conducting counts at 11 potential feeding or roosting sites using point count method. We further surveyed people of the valley regarding their perception of vulture ecology and conservation, knowledge of diclofenac use within the valley, and burial of livestock carcasses. We detected eight species of vultures, four of which are currently threatened with extinction. White‐rumped vulture Gyps bengalensis, Egyptian vulture Nephron percnopterus, and Himalayan vulture G. himalayensis were the most abundant. Almost all respondents (98%) had sighted the vultures in the wild. Formally educated respondents reported seeing vultures’ slightly more than nonformally educated respondents. Fifty‐eight percent respondents suspected habitat loss was the major threat for the vulture population decline in Pokhara Valley, and 97% respondents were not aware of any diclofenac use. The knowledge of vultures in people with different age groups suggests a more awareness programs are needed for local people, especially those who carry out animal husbandry and provide livestock to the vulture restaurant.