Investigation of an F-18 oxytocin receptor selective ligand via PET imaging

The compound 1-(1-(2-(2-(2-fluoroethoxy)-4-(piperidin-4-yloxy)phenyl)acetyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (1) was synthesized and positively evaluated in vitro for high potency and selectivity with human oxytocin receptors. The positron emitting analogue, [F-18]1, was synthesized and investigated in vivo via PET imaging using rat and cynomolgus monkey models. PET imaging studies in female Sprague–Dawley rats suggested [F-18]1 reached the brain and accumulated in various regions of the brain, but washed out too rapidly for adequate quantification and localization. In vivo PET imaging studies in a male cynomolgus monkey suggested [F-18]1 had limited brain penetration while specific uptake of radioactivity significantly accumulated within the vasculature of the cerebral ventricles in areas representative of the choroid plexus.     

Downregulation of multiple CDK inhibitor ICK/KRP genes upregulates the E2F pathway and increases cell proliferation,and organ and seed sizes in Arabidopsis

The ICK/KRP cyclin‐dependent kinase (CDK) inhibitors are important plant cell cycle factors sharing only limited similarity with the metazoan CIP/KIP family of CDK inhibitors. Little is known about the specific functions of different ICK/KRP genes in planta. In this study, we created double and multiple mutants from five single Arabidopsis ICK/KRP T‐DNA mutants, and used a set of 20 lines for the functional investigation of the important gene family. There were gradual increases in CDK activity from single to multiple mutants, indicating that ICK/KRPs act as CDK inhibitors under normal physiological conditions in plants. Whereas lower‐order mutants showed no morphological phenotypes, the ick1 ick2 ick6 ick7 and ick1 ick2 ick5 ick6 ick7 mutants had a slightly altered leaf shape. The quintuple mutant had larger cotyledons, leaves, petals and seeds than the wild‐type control. At the cellular level, the ICK/KRP mutants had more but smaller cells in all the organs examined. These phenotypic effects became more apparent as more ICK/KRPs were downregulated, suggesting that to a large extent ICK/KRPs function in plants redundantly in a dosage‐dependent manner. Analyses also revealed increased expression of E2F‐dependent genes, and elevated RBR1 as well as an increased level of phospho‐RBB1 protein in the quintuple mutant. Thus, downregulation of multiple ICK/KRP genes increases CDK activity, upregulates the E2F pathway and stimulates cell proliferation, resulting in increased cell numbers, and larger organs and seeds.     

Genome-wide interval mapping using SNPs identifies new QTL for growth,body composition and several physiological variables in an F2 intercross between fat and lean chicken lines

Background

For decades, genetic improvement based on measuring growth and body composition traits has been successfully applied in the production of meat-type chickens. However, this conventional approach is hindered by antagonistic genetic correlations between some traits and the high cost of measuring body composition traits. Marker-assisted selection should overcome these problems by selecting loci that have effects on either one trait only or on more than one trait but with a favorable genetic correlation. In the present study, identification of such loci was done by genotyping an F₂ intercross between fat and lean lines divergently selected for abdominal fatness genotyped with a medium-density genetic map (120 microsatellites and 1302 single nucleotide polymorphisms). Genome scan linkage analyses were performed for growth (body weight at 1, 3, 5, and 7 weeks, and shank length and diameter at 9 weeks), body composition at 9 weeks (abdominal fat weight and percentage, breast muscle weight and percentage, and thigh weight and percentage), and for several physiological measurements at 7 weeks in the fasting state, i.e. body temperature and plasma levels of IGF-I, NEFA and glucose. Interval mapping analyses were performed with the QTLMap software, including single-trait analyses with single and multiple QTL on the same chromosome.

Results

Sixty-seven QTL were detected, most of which had never been described before. Of these 67 QTL, 47 were detected by single-QTL analyses and 20 by multiple-QTL analyses, which underlines the importance of using different statistical models. Close analysis of the genes located in the defined intervals identified several relevant functional candidates, such as ACACA for abdominal fatness, GHSR and GAS1 for breast muscle weight, DCRX and ASPSCR1 for plasma glucose content, and ChEBP for shank diameter.

Conclusions

The medium-density genetic map enabled us to genotype new regions of the chicken genome (including micro-chromosomes) that influenced the traits investigated. With this marker density, confidence intervals were sufficiently small (14 cM on average) to search for candidate genes. Altogether, this new information provides a valuable starting point for the identification of causative genes responsible for important QTL controlling growth, body composition and metabolic traits in the broiler chicken.     

Which New Health Technologies Do We Need to Achieve an End to HIV/AIDS?

In the last 15 years, antiretroviral therapy (ART) has been the most globally impactful life-saving development of medical research. Antiretrovirals (ARVs) are used with great success for both the treatment and prevention of HIV infection. Despite these remarkable advances, this epidemic grows relentlessly worldwide. Over 2.1 million new infections occur each year, two-thirds in women and 240,000 in children. The widespread elimination of HIV will require the development of new, more potent prevention tools. Such efforts are imperative on a global scale. However, it must also be recognised that true containment of the epidemic requires the development and widespread implementation of a scientific advancement that has eluded us to date—a highly effective vaccine. Striving for such medical advances is what is required to achieve the end of AIDS.In the last 15 years, antiretroviral therapy (ART) has been the most globally impactful life-saving development of medical research. Antiretrovirals (ARVs) are used with great success for both the treatment and prevention of HIV infection. In the United States, the widespread implementation of combination ARVs led to the virtual eradication of mother-to-child transmission of HIV from 1,650 cases in 1991 to 110 cases in 2011, and a turnaround in AIDS deaths from an almost 100% five-year mortality rate to a five-year survival rate of 91% in HIV-infected adults [1]. Currently, the estimated average lifespan of an HIV-infected adult in the developed world is well over 40 years post-diagnosis. Survival rates in the developing world, although lower, are improving: in sub-Saharan Africa, AIDS deaths fell by 39% between 2005 and 2013, and the biggest decline, 51%, was seen in South Africa [2].Furthermore, the association between ART, viremia, and transmission has led to the concept of “test and treat,” with the hope of reducing community viral load by testing early and initiating treatment as soon as a diagnosis of HIV is made [3]. Indeed, selected regions of the world have begun to actualize the public health value of ARVs, from gains in life expectancy to impact on onward transmission, with a potential 1% decline in new infections for every 10% increase in treatment coverage [2]. In September 2015, WHO released new guidelines removing all limitations on eligibility for ART among people living with HIV and recommending pre-exposure prophylaxis (PrEP) to population groups at significant HIV risk, paving the way for a global onslaught on HIV [4].Despite these remarkable advances, this epidemic grows relentlessly worldwide. Over 2.1 million new infections occur each year, two-thirds in women and 240,000 in children [2]. In heavily affected countries, HIV infection rates have only stabilized at best: the annualized acquisition rates in persons in their first decade of sexual activity average 3%–5% yearly in southern Africa [5–7]. These figures are hardly compatible with the international health community’s stated goal of an “AIDS-free generation” [8,9]. In highly resourced settings, microepidemics of HIV still occur, particularly among gays, bisexuals, and men who have sex with men (MSM) [10]. HIV epidemics are expanding in two geographic regions in 2015—the Middle East/North Africa and Eastern Europe/Central Asia—largely due to challenges in implementing evidence-based HIV policies and programmes [2]. Even for the past decade in the US, almost 50,000 new cases recorded annually, two-thirds among MSM, has been a stable figure for years and shows no evidence of declining [1].While treatment scale-up, medical male circumcision [11], and the implementation of strategies to prevent mother-to-child transmission [12] have received global traction, systemic or topical ARV-based biomedical advances to prevent sexual acquisition of HIV have, as yet, made limited impressions on a population basis, despite their reported efficacy. Factors such as their adherence requirements, cost, potential for drug resistance, and long-term feasibility have restricted the appetite for implementation, even though these approaches may reduce HIV incidence in select populations.Already, several trials have shown that daily oral administration of the ARV tenofovir disoproxil fumarate (TDF), taken singly or in combination with emtricitabine, as PrEP by HIV-uninfected individuals, reduces HIV acquisition among serodiscordant couples (where one partner is HIV-positive and the other is HIV-negative) [13], MSM [14], at-risk men and women [15], and people who inject drugs [16,17] by between 44% and 75%. Long-acting injectable antiretroviral agents such as rilpivirine and cabotegravir, administered every two and three months, respectively, are also being developed for PrEP. All of these PrEP approaches are dependent on repeated HIV testing and adherence to drug regimens, which may challenge effectiveness in some populations and contexts.The widespread elimination of HIV will require the development of new, more potent prevention tools. Because HIV acquisition occurs subclinically, the elimination of HIV on a population basis will require a highly effective vaccine. Alternatively, if vaccine development is delayed, supplementary strategies may include long-acting pre-exposure antiretroviral cocktails and/or the administration of neutralizing antibodies through long-lasting parenteral preparations or the development of a “genetic immunization” delivery system, as well as scaling up delivery of highly effective regimens to eliminate mother-to-child HIV transmission (Fig 1).Open in a separate windowFig 1Medical interventions required to end the epidemic of HIV.Image credit: Glenda Gray.     

Correlates of Performance of Healthcare Workers in Emergency,Triage, Assessment and Treatment plus Admission Care (ETAT+) Course in Rwanda: Context Matters

Background

The Emergency, Triage, Assessment and Treatment plus Admission care (ETAT+) course, a comprehensive advanced pediatric life support course, was introduced in Rwanda in 2010 to facilitate the achievement of the fourth Millennium Development Goal. The impact of the course on improving healthcare workers (HCWs) knowledge and practical skills related to providing emergency care to severely ill newborns and children in Rwanda has not been studied.

Objective

To evaluate the impact of the ETAT+ course on HCWs knowledge and practical skills, and to identify factors associated with greater improvement in knowledge and skills.

Methods

We used a one group, pre-post test study using data collected during ETAT+ course implementation from 2010 to 2013. The paired t-test was used to assess the effect of ETAT+ course on knowledge improvement in participating HCWs. Mixed effects linear and logistic regression models were fitted to explore factors associated with HCWs performance in ETAT+ course knowledge and practical skills assessments, while accounting for clustering of HCWs in hospitals.

Results

374 HCWs were included in the analysis. On average, knowledge scores improved by 22.8/100 (95% confidence interval (CI) 20.5, 25.1). In adjusted models, bilingual (French & English) participants had a greater improvement in knowledge 7.3 (95% CI 4.3, 10.2) and higher odds of passing the practical skills assessment (adjusted odds ratio (aOR) = 2.60; 95% CI 1.25, 5.40) than those who were solely proficient in French. Participants who attended a course outside of their health facility had higher odds of passing the skills assessment (aOR = 2.11; 95% CI 1.01, 4.44) than those who attended one within their health facility.

Conclusions

The current study shows a positive impact of ETAT+ course on improving participants’ knowledge and skills related to managing emergency pediatric and neonatal care conditions. The findings regarding key factors influencing ETAT+ course outcomes demonstrate the importance of considering key contextual factors (e.g., language barriers) that might affect HCWs performance in this type of continuous medical education.     

Use of GPS tags to describe the home ranges,migration routes,stop-over locations and breeding area of Taiga Bean Geese Anser fabalis fabalis wintering in central Scotland

Capsule: Taiga Bean Geese Anser fabalis fabalis wintering near Falkirk, Scotland staged in Denmark, Norway and Sweden and summered in central Sweden.

Aims: To determine the migration routes, timing of movements, breeding area and home ranges of Taiga Bean Geese wintering near Falkirk, Scotland.

Methods: Ten Taiga Bean Geese, caught on the wintering grounds in Scotland, were marked with neck collars carrying global positioning system (GPS) tags. A further 21 geese were fitted with individually marked plastic neck collars. GPS location data were collected and field counts and searches for individually marked geese were undertaken to provide detailed information on their location throughout the year.

Results: Seven GPS tags provided information away from Scotland, indicating that two migration routes were used en route to the breeding grounds in Dalarna, Sweden. During the non-breeding season, the total home range of the geese was approximately 466?km², although the total area within agricultural fields used by the geese may have been as small as 13?km².

Conclusions: The timing of movements, migration routes, breeding area and identification of important stop-over sites for this wintering population are described for the first time.     

Taxon-specific prey handling by the loggerhead shrike (<Emphasis Type="Italic">Lanius ludovicianus</Emphasis>)

True Shrikes (Laniidae) are sit-and-wait predators that hunt prey from elevated perches and frequently impale them on sharp objects in conspicuous places. During the 2014 breeding season, we followed a pair of Loggerhead Shrike (Lanius ludovicianus) through their reproductive cycle and documented over 100 h of their behavior on video. On three occasions, the shrikes were observed hunting grasshoppers and in a sequence of very quick stereotypic behaviors, they eviscerated their prey. The shrike held the grasshopper in its feet and with its sharp beak, penetrated the body between the head and the shield-like pronotum, removed the digestive tract in one pull, and then ingested the prey. The removal of the alimentary tract appears to target the anterior portion, specifically the foregut or crop, along with its associated contents. This particular behavior was observed only when grasshoppers were caught but not with other invertebrates. The whole process lasted ca. 5 (±2.6 SD) s.     

Ontogeny and Sexual Dimorphism of <Emphasis Type="Italic">Glyptotherium texanum</Emphasis> (Xenarthra,Cingulata) from the Pliocene and Pleistocene (Blancan and Irvingtonian NALMA) of Arizona,New Mexico,and Mexico

North American glyptodonts originated from South American ancestors during the Great American Biotic Interchange no later than early Blancan North American Land Mammal Age (NALMA). A substantial expansion in population samples from the late Blancan 111 Ranch fauna of southeastern Arizona, several late Blancan faunas in New Mexico, and the early Blancan–Irvingtonian faunas of Guanajuato, Mexico, permit, analysis of sexual dimorphism and ontogeny of Glyptotherium texanum Osborn, 1903. Growth of carapacial osteoderms was allometric, including changes of the external sculpturing. Overall anatomy of the carapace changed with growth, with development of distinctive pre-iliac and post-iliac regions in lateral profile of adults. Skulls of adults possess a unique boss on the anterior surface of the descending process of the zygomatic arch that is not present in juveniles. Sexual dimorphism involves differences in anatomy of lateral and posterior osteoderms. Glyptotherium arizonae Gidley, 1926, is a junior synonym of G. texanum. The temporal distribution of G. texanum extends from early Blancan NALMA to Irvingtonian NALMA, with geographical distribution from Central America and Mexico to southern United States.