Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.

Background The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies

TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors.

The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas

"I should live and finish it": A qualitative inquiry into Turkish women's menopause experience

<p>Abstract</p> <p>Background</p> <p>While bio-medically, menopause could be treated as an illness, from a psychosocial and cultural perspective it could be seen as a "natural" process without requiring medication unless severe symptoms are present.</p> <p>Our objective is to explore the perceptions of Turkish women regarding menopause and Hormone Therapy (HT) to provide health care workers with an insight into the needs and expectations of postmenopausal women.</p> <p>Methods</p> <p>A qualitative inquiry through semi-structured, in-depth interviews was used to explore the study questions. We used a purposive sampling and included an equal number of participants who complained about the climacteric symptoms and those who visited the outpatient department for a problem other than climacteric symptoms but when asked declared that they had been experiencing climacteric symptoms. The interview questions focused on two areas; 1) knowledge, experiences, attitudes and beliefs about menopause and; 2) menopause-related experiences and ways to cope with menopause and perception of HT.</p> <p>Results</p> <p>Most of the participants defined menopause as a natural transition process that one should go through. Cleanliness, maturity, comfort of not having a period and positive changes in health behaviour were the concepts positively attributed to menopause, whereas hot flushes, getting old and difficulties in relationships were the negatives. Osteoporosis was an important concern for most of the participants. To deal with the symptoms, the non-pharmacological options were mostly favoured.</p> <p>Conclusion</p> <p>To our knowledge, this is the first qualitative study which focuses on Turkish women's menopausal experiences. Menopause was thought to be a natural process which was characterised by positive and negative features. Understanding these features and their implications in these women's lives may assist healthcare workers in helping their clients with menopause.</p

Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis

Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow. In addition, the approach is effective against drug-resistant clinical isolates of Escherichiacoli and Acinetobacterbaumannii, reducing bacterial load in a murine bladder infection model. Our results indicate that redundant APRs are weak points of bacterial protein homeostasis and that targeting these may be an attractive antibacterial strategy

Glaciation Effects on the Phylogeographic Structure of Oligoryzomys longicaudatus (Rodentia: Sigmodontinae) in the Southern Andes

The long-tailed pygmy rice rat Oligoryzomys longicaudatus (Sigmodontinae), the major reservoir of Hantavirus in Chile and Patagonian Argentina, is widely distributed in the Mediterranean, Temperate and Patagonian Forests of Chile, as well as in adjacent areas in southern Argentina. We used molecular data to evaluate the effects of the last glacial event on the phylogeographic structure of this species. We examined if historical Pleistocene events had affected genetic variation and spatial distribution of this species along its distributional range. We sampled 223 individuals representing 47 localities along the species range, and sequenced the hypervariable domain I of the mtDNA control region. Aligned sequences were analyzed using haplotype network, Bayesian population structure and demographic analyses. Analysis of population structure and the haplotype network inferred three genetic clusters along the distribution of O. longicaudatus that mostly agreed with the three major ecogeographic regions in Chile: Mediterranean, Temperate Forests and Patagonian Forests. Bayesian Skyline Plots showed constant population sizes through time in all three clusters followed by an increase after and during the Last Glacial Maximum (LGM; between 26,000–13,000 years ago). Neutrality tests and the “g” parameter also suggest that populations of O. longicaudatus experienced demographic expansion across the species entire range. Past climate shifts have influenced population structure and lineage variation of O. longicaudatus. This species remained in refugia areas during Pleistocene times in southern Temperate Forests (and adjacent areas in Patagonia). From these refugia, O. longicaudatus experienced demographic expansions into Patagonian Forests and central Mediterranean Chile using glacial retreats

A Serological Survey of Infectious Disease in Yellowstone National Park’s Canid Community

BACKGROUND:Gray wolves (Canis lupus) were reintroduced into Yellowstone National Park (YNP) after a >70 year absence, and as part of recovery efforts, the population has been closely monitored. In 1999 and 2005, pup survival was significantly reduced, suggestive of disease outbreaks. METHODOLOGY/PRINCIPAL FINDINGS:We analyzed sympatric wolf, coyote (Canis latrans), and red fox (Vulpes vulpes) serologic data from YNP, spanning 1991-2007, to identify long-term patterns of pathogen exposure, identify associated risk factors, and examine evidence for disease-induced mortality among wolves for which there were survival data. We found high, constant exposure to canine parvovirus (wolf seroprevalence: 100%; coyote: 94%), canine adenovirus-1 (wolf pups [0.5-0.9 yr]: 91%, adults [>or=1 yr]: 96%; coyote juveniles [0.5-1.5 yrs]: 18%, adults [>or=1.6 yrs]: 83%), and canine herpesvirus (wolf: 87%; coyote juveniles: 23%, young adults [1.6-4.9 yrs]: 51%, old adults [>or=5 yrs]: 87%) suggesting that these pathogens were enzootic within YNP wolves and coyotes. An average of 50% of wolves exhibited exposure to the protozoan parasite, Neospora caninum, although individuals' odds of exposure tended to increase with age and was temporally variable. Wolf, coyote, and fox exposure to canine distemper virus (CDV) was temporally variable, with evidence for distinct multi-host outbreaks in 1999 and 2005, and perhaps a smaller, isolated outbreak among wolves in the interior of YNP in 2002. The years of high wolf-pup mortality in 1999 and 2005 in the northern region of the park were correlated with peaks in CDV seroprevalence, suggesting that CDV contributed to the observed mortality. CONCLUSIONS/SIGNIFICANCE:Of the pathogens we examined, none appear to jeopardize the long-term population of canids in YNP. However, CDV appears capable of causing short-term population declines. Additional information on how and where CDV is maintained and the frequency with which future epizootics might be expected might be useful for future management of the Northern Rocky Mountain wolf population