Novel nicotinic acetylcholine receptor agonists containing carbonyl moiety as a hydrogen bond acceptor

A novel series of α4β2 nAChR agonists lacking common pyridine or its bioisosteric heterocycle have been disclosed. Essential pharmacophoric elements of the series are exocyclic carbonyl moiety as a hydrogen bond acceptor and secondary amino group within diaza- or azabicyclic scaffold. Computer modeling studies suggested that molecular shape of the ligand also contributes to promotion of agonism. Proof of concept for improving working memory performance in a novel object recognition task has been demonstrated on a representative of the series, 3-propionyl-3,7-diazabicyclo[3.3.0]octane (34).     

Foraging niche shift maintains breeding parameters of a colonial waterbird during range expansion

Relating the effects of foraging niche variation to reproductive dynamics is critical to understand species response to environmental change. We examined foraging niche variations of the slender‐billed gull (Chroicocephalus genei), a nomadic colonial waterbird species during its range expansion along the French Mediterranean coast over a 16‐year period (1998–2013). We investigated whether range expansion was associated with a change in chick diet, breeding success, and chicks body condition. We also examined whether breeding success and chicks body condition were explained by diet and colonial characteristics (number of pairs, laying phenology, habitat, and locality). Diet was characterized using dual‐stable isotopic proxies (δ¹³C and δ¹⁵N) of feather keratin from 331 individuals subsampled from a total of 4,154 chicks ringed and measured at 18 different colonies. δ¹³C decreased and δ¹⁵N increased significantly during range expansion suggesting that chicks were fed from preys of increasing trophic level found in the less salty habitat colonized by the end of the study period. Niche shift occurred without significant change of niche width which did not vary among periods, habitats, or localities either. Breeding success and chick body condition showed no consistent trends over years. Breeding success tended to increase with decreasing δ¹³C at the colony level while there was no relationship between stable isotope signatures and chick body condition. Overall, our results suggest that even if range expansion is associated with foraging niche shift toward the colonization of less salty and more brackish habitats, the shift had marginal effect on the breeding parameters of the Slender‐billed gull. Niche width appears as an asset of this species, which likely explains its ability to rapidly colonize new locations.     

Discovery of triazine-benzimidazoles as selective inhibitors of mTOR

mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kα. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC₅₀ of 0.41 μM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model.     

Analysis of genetic diversity of Guizotia abyssinica from Ethiopia using inter simple sequence repeat markers

Within and among population genetic diversity of 37 Guizotia abyssinica populations from Ethiopia were analyzed using inter simple sequence repeats (ISSRs). Five primers amplified a total of 118 genomic DNA fragments across a total of 370 individuals of which 106 were polymorphic (89.83%). The average number of polymorphic bands per primer was 21.2. More bands were generated by primer UBC 888 (BDB(CA)(7.) The total genetic diversity (Ht) and the coefficient of genetic differentiation (Gst) were 0.4115 and 0.0918 respectively, while the within population genetic diversity (Hs) and the among population genetic diversity(Dst) were 0.3738 and 0.03776 respectively suggesting more variability within the populations than among them. The standard genetic distances between the G. abyssinica populations of the eight regions ranged from 0.0281 (between Wollo and Gojam) to 0.1148 (between Jimma and Hararghe). Generally, the standard genetic distances are smaller between populations of neighboring regions and highest between those of Jimma and the other regions, ranging from 0.0696 (between Jimma and Shewa) to 0.1148 (between Jimma and Hararghe). The ISSR based UPGMA clustering using the standardized genetic distances matrix also placed populations from neighboring regions closer than those from farther apart areas, while the UPGMA clustering by regions based on the standard genetic distances produced three clusters following the proximity and the contiguity of the regions. The mean Shannon Weaver diversity indices for the populations of the eight regions ranged from 0.8197 (Jimma) to 0.9176 (Hararghe), with a mean of 0.8841 for the whole material.     

The role of maternal Activin-like signals in zebrafish embryos

Maternal Activin-like proteins, a subgroup of the TGF-beta superfamily, play a key role in establishing the body axes in many vertebrates, but their role in teleosts is unclear. At least two maternal Activin-like proteins are expressed in zebrafish, including the Vg1 orthologue, zDVR-1, and the nodal-related gene, Squint. Our analysis of embryos lacking both maternal and zygotic squint function revealed that maternal squint is required in some genetic backgrounds for the formation of dorsal and anterior tissues. Conditional inactivation of the ALK4, 5 and 7 receptors by SB-505124 treatment during the cleavage stages ruled out a role for maternal Squint, zDVR-1, or other Activin-like ligands before the mid-blastula transition, when the dorsal axis is established. Furthermore, we show that maternal Squint and zDVR-1 are not required during the cleavage stages to induce zygotic nodal-related gene expression. nodal-related gene expression decreases when receptor inhibition continues past the mid-blastula transition, resulting in a progressive loss of mesoderm and endoderm. We conclude that maternally expressed Activin-like signals do not act before the mid-blastula transition in zebrafish, but do have a variably penetrant role in the later stages of axis formation. This contrasts with the early role for these signals during Xenopus development.     

Causes of Death among Adults in Northern Ethiopia: Evidence from Verbal Autopsy Data in Health and Demographic Surveillance System

Background

In countries where registration of vital events is lacking and the proportion of people who die at home without medical care is high, verbal autopsy is used to determine and estimate causes of death.

Methods

We conducted 723 verbal autopsy interviews of adult (15 years of age and above) deaths from September 2009 to January 2013. Trained physicians interpreted the collected verbal autopsy data, and assigned causes of death according to the international classification of diseases (ICD-10). We did analysis of specific as well as broad causes of death (i.e. non-communicable diseases, communicable diseases and external causes of death) by sex and age using Stata version 11.1. We performed logistic regression to identify socio-demographic predictors using odds ratio with 95% confidence interval and a p-value of 0.05.

Findings

Tuberculosis, cerebrovascular diseases and accidental falls were leading specific causes of death accounting for 15.9%, 7.3% and 3.9% of all deaths. Two hundred sixty three (36.4% [95% CI: 32.9, 39.9]), 252 (34.9% [95% CI: 31.4, 38.4]) and 89 (12.3% [95% CI: 10.1, 14.9]) deaths were due to non-communicable, communicable diseases, and external causes, respectively. Females had 1.5 times (AOR = 1.53 [95% CI: 1.10, 2.15]) higher odds of dying due to communicable diseases than males. The odds of dying due to external causes were 4 times higher among 15–49 years of age (AOR = 4.02 [95% CI: 2.25, 7.18]) compared to older ages. Males also had 1.7 times (AOR = 1.70 [95% CI: 1.01, 2.85]) higher odds of dying due to external causes than females.

Conclusion

Tuberculosis, cerebrovascular diseases and accidental falls were the top three causes of death among adults. Efforts to prevent tuberculosis and cerebrovascular diseases related deaths should be improved and safety efforts to reduce accidents should also receive attention.     

Active Sulforhodamine 101 Uptake into Hippocampal Astrocytes

Sulforhodamine 101 (SR101) is widely used as a marker of astrocytes. In this study we investigated labeling of astrocytes by SR101 in acute slices from the ventrolateral medulla and the hippocampus of transgenic mice expressing EGFP under the control of the astrocyte-specific human GFAP promoter. While SR101 efficiently and specifically labeled EGFP-expressing astrocytes in hippocampus, we found that the same staining procedure failed to label astrocytes efficiently in the ventrolateral medulla. Although carbenoxolone is able to decrease the SR101-labeling of astrocytes in the hippocampus, it is unlikely that SR101 is taken up via gap-junction hemichannels because mefloquine, a blocker for pannexin and connexin hemichannels, was unable to prevent SR101-labeling of hippocampal astrocytes. However, SR101-labeling of the hippocampal astrocytes was significantly reduced by substrates of organic anion transport polypeptides, including estron-3-sulfate and dehydroepiandrosterone sulfate, suggesting that SR101 is actively transported into hippocampal astrocytes.     

The statistics of calcium-mediated focal excitations on a one-dimensional cable

It is well known that various cardiac arrhythmias are initiated by an ill-timed excitation that originates from a focal region of the heart. However, up to now, it is not known what governs the timing, location, and morphology of these focal excitations. Recent studies have shown that these excitations can be caused by abnormalities in the calcium (Ca) cycling system. However, the cause-and-effect relationships linking subcellular Ca dynamics and focal activity in cardiac tissue is not completely understood. In this article, we present a minimal model of Ca-mediated focal excitations in cardiac tissue. This model accounts for the stochastic nature of spontaneous Ca release on a one-dimensional cable of cardiac cells. Using this model, we show that the timing of focal excitations is equivalent to a first passage time problem in a spatially extended system. In particular, we find that for a short cable the mean first passage time increases exponentially with the number of cells in tissue, and is critically dependent on the ratio of inward to outward currents near the threshold for an action potential. For long cables excitations occurs due to ectopic foci that occur on a length scale determined by the minimum length of tissue that can induce an action potential. Furthermore, we find that for long cables the mean first passage time decreases as a power law in the number cells. These results provide precise criteria for the occurrence of focal excitations in cardiac tissue, and will serve as a guide to determine the propensity of Ca-mediated triggered arrhythmias in the heart.