Effects of habitat and land use on breeding season density of male Asian Houbara Chlamydotis macqueenii

Landscape-scale habitat and land-use influences on Asian Houbara Chlamydotis macqueenii (IUCN Vulnerable) remain unstudied, while estimating numbers of this cryptic, low-density, over-hunted species is challenging. In spring 2013, male houbara were recorded at 231 point counts, conducted twice, across a gradient of sheep density and shrub assemblages within 14,300 km² of the Kyzylkum Desert, Uzbekistan. Four sets of models related male abundance to: (1) vegetation structure (shrub height and substrate); (2) shrub assemblage; (3) shrub species composition (multidimensional scaling); (4) remote-sensed derived land-cover (GLOBCOVER, 4 variables). Each set also incorporated measures of landscape rugosity and sheep density. For each set, multi-model inference was applied to generalised linear mixed models of visit-specific counts that included important detectability covariates and point ID as a random effect. Vegetation structure received strongest support, followed by shrub species composition and shrub assemblage, with weakest support for the GLOBCOVER model set. Male houbara numbers were greater with lower mean shrub height, more gravel and flatter surfaces, but were unaffected by sheep density. Male density (mean 0.14 km-2, 95% CI, 0.12‒0.15) estimated by distance analysis differed substantially among shrub assemblages, being highest in vegetation dominated by Salsola rigida (0.22 [CI, 0.20‒0.25]), high in areas of S. arbuscula and Astragalus (0.14 [CI, 0.13‒0.16] and 0.15 [CI, 0.14‒0.17] respectively), lower (0.09 [CI, 0.08‒0.10]) in Artemisia and lowest (0.04 [CI, 0.04‒0.05]) in Calligonum. The study area was estimated to hold 1,824 males (CI: 1,645‒2,030). The spatial distribution of relative male houbara abundance, predicted from vegetation structure models, had the strongest correspondence with observed numbers in both model-calibration and the subsequent year’s data. We found no effect of pastoralism on male distribution but potential effects on nesting females are unknown. Density differences among shrub communities suggest extrapolation to estimate country- or range-wide population size must take account of vegetation composition

7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis.

Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate

Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis.

6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead

Effects of habitat and livestock on nest productivity of the Asian houbara Chlamydotis macqueenii in Bukhara Province, Uzbekistan

To inform population support measures for the unsustainably hunted Asian houbara Chlamydotis macqueenii (IUCN Vulnerable) we examined potential habitat and land-use effects on nest productivity in the Kyzylkum Desert, Uzbekistan. We monitored 177 nests across different semi-arid shrub assemblages (clay-sand and salinity gradients) and a range of livestock densities (0–80 km-2). Nest success (mean 51.4%, 95% CI 42.4–60.4%) was similar across four years; predation caused 85% of those failures for which the cause was known, and only three nests were trampled by livestock. Nesting begins within a few weeks of arrival when food appears scarce, but later nests were more likely to fail owing to the emergence of a key predator, suggesting foraging conditions on wintering and passage sites may be important for nest productivity. Nest success was similar across three shrub assemblages and was unrelated to landscape rugosity, shrub frequency or livestock density, but was greater with taller mean shrub height (range 13–67 cm) within 50 m. Clutch size (mean = 3.2 eggs) and per-egg hatchability in successful nests (87.5%) did not differ with laying date, shrub assemblage or livestock density. We therefore found no evidence that livestock density reduced nest productivity across the range examined, while differing shrub assemblages appeared to offer similar habitat quality. Asian houbara appear well-adapted to a range of semi-desert habitats and tolerate moderate disturbance by pastoralism. No obvious in situ mitigation measures arise from these findings, leaving regulation and control as the key requirement to render hunting sustainable

Development of (6 R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H-imidazo[2,1- b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis.

Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1- b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1- b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1- b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6 R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads ( R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds ( R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate

Modelling stereotyping in cooperation systems

Cooperation is a sophisticated example of collective intelligence. This is particularly the case for indirect reciprocity, where benefit is provided to others without a guarantee of a future return. This is becoming increasingly relevant to future technology, where autonomous machines face cooperative dilemmas. This paper addresses the problem of stereotyping, where traits belonging to an individual are used as proxy when assessing their reputation. This is a cognitive heuristic that humans frequently use to avoid deliberation, but can lead to negative societal implications such as discrimination. It is feasible that machines could be equally susceptible. Our contribution concerns a new and general framework to examine how stereotyping affects the reputation of agents engaging in indirect reciprocity. The framework is flexible and focuses on how reputations are shared. This offers the opportunity to assess the interplay between the sharing of traits and the cost, in terms of reduced cooperation, through opportunities for shirkers to benefit. This is demonstrated using a number of key scenarios. In particular, the results show that cooperation is sensitive to the structure of reputation sharing between individuals

Serca1 Truncated Proteins Unable to Pump Calcium Reduce the Endoplasmic Reticulum Calcium Concentration and Induce Apoptosis

By pumping calcium from the cytosol to the ER, sarco/endoplasmic reticulum calcium ATPases (SERCAs) play a major role in the control of calcium signaling. We describe two SERCA1 splice variants (S1Ts) characterized by exon 4 and/or exon 11 splicing, encoding COOH terminally truncated proteins, having only one of the seven calcium-binding residues, and thus unable to pump calcium. As shown by semiquantitative RT-PCR, S1T transcripts are differentially expressed in several adult and fetal human tissues, but not in skeletal muscle and heart. S1T proteins expression was detected by Western blot in nontransfected cell lines. In transiently transfected cells, S1T homodimers were revealed by Western blot using mildly denaturing conditions. S1T proteins were shown, by confocal scanning microscopy, to colocalize with endogenous SERCA2b into the ER membrane. Using ER-targeted aequorin (erAEQ), we have found that S1T proteins reduce ER calcium and reverse elevation of ER calcium loading induced by SERCA1 and SERCA2b. Our results also show that SERCA1 variants increase ER calcium leakage and are consistent with the hypothesis of a cation channel formed by S1T homodimers. Finally, when overexpressed in liver-derived cells, S1T proteins significantly induce apoptosis. These data reveal a further mechanism modulating Ca2+ accumulation into the ER of nonmuscle cells and highlight the relevance of S1T proteins to the control of apoptosis

Seroprevalence of Bordetella pertussis antibodies in adults in Hungary: results of an epidemiological cross-sectional study.

BACKGROUND: Pertussis (whooping cough) is well known to be underreported, particularly among adults, who can act as an infectious reservoir, potentially putting susceptible newborns at risk of serious illness. The purpose of this study was to estimate the seroprevalence of pertussis in adults in Hungary. METHODS: This epidemiological, cross-sectional study was conducted in adults in five general practitioners' practices in Hungary. Serum anti-pertussis toxin immunoglobulin G (anti-PT IgG) antibody levels were analyzed using enzyme-linked immunosorbent assay. Sera were classified following manufacturer's instructions as: strongly indicative of current/recent infection (>/=1.5 optical density [OD] units); indicative of current/recent infection (>/=1.0 OD units); seropositive (>0.3 OD units); or seronegative (/=60 years (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.39-2.80; p = .0002) or 18-29 years (OR, 1.67; 95% CI, 1.13-2.46; p = .0094) vs. 45-59 years; former smoker (OR, 1.46; 95% CI, 1.08-1.97; p = .014) or current smoker (OR, 1.38; 95% CI, 1.01-1.89; p = .045) vs. never smoker; and male (OR, 1.30; 95% CI, 1.01-1.68; p = .041) vs. female. Also, between increased rates of probable current/recent infection and current smoker (OR, 7.50; 95% CI, 2.32-24.31; p = .0008) or former smoker (OR, 4.07; 95% CI, 1.21-13.64; p = .023) vs. never smoker. CONCLUSIONS: Approximately 85% of the adults studied were seronegative and therefore susceptible to pertussis infection. Approximately 1% had anti-PT IgG levels indicative of current/recent pertussis infection, which could potentially be transmitted to susceptible young infants. Vaccination of adults is a key way to indirectly protect infants. TRIAL REGISTRATION: Clinical Trials.gov NCT02014519 . Prospectively registered 12 December 2013

Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumours

Doxorubicin pharmacokinetics were determined in 33 patients with solid tumours who received intravenous doses of 20–320 mg m−2 HPMA copolymer bound doxorubicin (PK1) in a phase I study. Since assay constraints limited the data at lower doses, conventional analysis was not feasible and a ‘population approach’ was used. Bound concentrations were best described by a biexponential model and further analyses revealed a small influence of dose or weight on V1 but no identifiable effects of age, body surface area, renal or hepatic function. The final model was: clearance (Q) 0.194 l h−1; central compartment volume (V1) 4.48 × (1+0.00074 × dose (mg)) l; peripheral compartment volume (V2) 7.94 l; intercompartmental clearance 0.685 l h−1. Distribution and elimination half-lives had median estimates of 2.7 h and 49 h respectively. Free doxorubicin was present at most sampling times with concentrations around 1000 times lower than bound doxorubicin values. Data were best described using a biexponential model and the following parameters were estimated: apparent clearance 180 l h−1; apparent V1 (l) 1450 × (1+0.0013 × dose (mg)), apparent V2 (l) 21 300 × (1–0.0013 × dose (mg)) × (1+2.95 × height (m)) and apparent Q 6950 l h−1. Distribution and elimination half-lives were 0.13 h and 85 h respectively. © 1999 Cancer Research Campaig