Comparison of the CNS effects induced by TRH and bicuculline after microinjection into medial septum, substantia nigra and inferior colliculus: Absence of support for a GABA antagonist action for TRH

Antagonism of ethanol-induced depression of locomotion was observed after intracisternal injection of thyrotropin releasing hormone (TRH) and bicuculline methiodide (BICM), as well as after microinjection of these drugs into the medial septum. The present investigation compared the behavioral and physiological consequence of administering TRH and BICM into the medial septum, inferior colliculus and substantia nigra to quantitate the similarities between these compounds. BICM produced a major increase in locomotor activity when injected into the medial septum and stereotypies when injected into the substantia nigra, suggesting that GABA-containing neurons have widespread influences on motor function. The wild running and seizure activity observed after BICM injection into the inferior colliculus was also consistent with this latter view. The marked increase in rectal temperature observed when BICM was injected into the medial septum may also implicate GABAergic mechanisms in temperature control at this brain site. TRH produced no such behavioral or physiological changes when administered into these three sites. Thus, this work strongly suggests that TRH does not exert a widespread action as a GABA antagonist because TRH did not produce the same changes induced by BICM. The actions of BICM and TRH to antagonize ethanol-induced depression when microinjected into the medial septum suggests that this brain area may be a critical site for the depressant action of ethanol

Behavioral Differences between Neonatal and Adult 6-Hydroxydopamine-Treated Rats to Dopamine Agonists: Relevance to Neurological Symptoms in Clinical Syndromes with Reduced Brain Dopamine

Administration of L-dopa or apomorphine to neonatal and adult 6-hydroxydopamine (6-OHDA)-treated rats resulted in different behavioral responses depending on the age at which dopaminergic fibers were destroyed. When neonatal 6-OHDA-treated rats were tested as adults, they exhibited marked stereotypies, self-biting and self-mutilation behavior (SMB) when given these dopamine agonists. Self-biting as well as the incidence of SMB in neonatal 6-OHDA-treated rats showed dose-related changes between 10 and 100 mg/kg of L-dopa. This SMB and self-biting after L-dopa was observed as early as 22 to 24 days of age. Adult 6-OHDA-treated rats did not exhibit SMB or self-biting to L-dopa (100 mg/kg) or apomorphine (10 mg/kg), but did display paw treading and head nodding—behaviors not observed in neonatal 6-OHDA-treated rats. In addition, the locomotor response to apomorphine (1 mg/kg) was significantly greater in adult 6-OHDA-treated rats than in neonatal 6-OHDA-treated rats. Brain dopamine was reduced markedly in striatum, nucleus accumbens and olfactory tubercles in both 6-OHDA treatment groups with the reduction being slightly greater in rats treated with 6-OHDA neonatally. Serotonin content was elevated in striatum of rats treated neonatally with 6-OHDA, but not in adult 6-OHDA-treated rats. SMB and behaviors observed after L-dopa in rats treated neonatally with 6-OHDA were not apparent after L-dopa in rats with brain serotonin or norepinephrine reduced. Rats with brain dopaminergic fibers destroyed neonatally exhibited self-biting and SMB after L-dopa, suggesting that neonatal reduction of this amine is responsible for the SMB and self-biting in neonatal 6-OHDA-treated rats. 5-Hydroxytryptophan administration to neonatal 6-OHDA-treated rats did not induce SMB, indicating that release of serotonin by L-dopa is not responsible for this behavior. Because inhibition of dopamine-β-hydroxylase did not alter the SMB response to L-dopa observed in neonatal 6-OHDA-treated rats, norepinephrine synthesized from L-dopa does not appear to contribute to the response. High closes of a decarboxylase inhibitor sufficient to inhibit conversion of dopa to dopamine in brain did not reduce the incidence of SMB. Administration of haloperidol (1 mg/kg) reduced the incidence of SMB, but did not antagonize the self-biting or the taffy pulling exhibited by L-dopa. In contrast, cisflupentixol completely blocked the SMB and self-biting induced by L-dopa. The latter findings suggest that these behaviors in neonatal 6-OHDA-treated rats are more associated with D-1 than D-2 receptor function. The age-dependent effects of dopamine agonists observed in these studies provide an explanation for the different symptomatology observed in Lesch-Nyhan patients and Parkinson’s disease—neurological disorders with reduced brain dopamine

Farmers, advisers and researchers learning together better management of crops and croplands

Summary. Farmers in the northeastern sub-tropics of Australia must cope with very high climatic variability in order to succeed in crop production. Their capacity for innovation was tapped by means of an on-farm research project that brought farmers, advisers and researchers together on the Darling Downs and in central Queensland. The researchers added value to the farmers' own experiments on fertility and water use efficiency by soil and weather monitoring at specific sites and then using a simulation model of cropping systems to extend findings to a wider context of climate and soil. The advisers extended knowledge aquired from this experience via local farmer networks and have undertaken training in the use of simulation to support farmers' management decisions. The experience described opens up possibilities for developing new, cost-effective ways for devising and testing improved farm management

Free will and mental disorder: Exploring the relationship

A link between mental disorder and freedom is clearly present in the introduction of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). It mentions “an important loss of freedom” as one of the possible defining features of mental disorder. Meanwhile, it remains unclear how “an important loss of freedom” should be understood. In order to get a clearer view on the relationship between mental disorder and (a loss of) freedom, in this article, I will explore the link between mental disorder and free will. I examine two domains in which a connection between mental disorder and free will is present: the philosophy of free will and forensic psychiatry. As it turns out, philosophers of free will frequently refer to mental disorders as conditions that compromise free will and reduce moral responsibility. In addition, in forensic psychiatry, the rationale for the assessment of criminal responsibility is often explained by referring to the fact that mental disorders can compromise free will. Yet, in both domains, it remains unclear in what way free will is compromised by mental disorders. Based on the philosophical debate, I discuss three senses of free will and explore their relevance to mental disorders. I conclude that in order to further clarify the relationship between free will and mental disorder, the accounts of people who have actually experienced the impact of a mental disorder should be included in future research

Generation of a Cell Culture-Adapted Hepatitis C Virus with Longer Half Life at Physiological Temperature

BACKGROUND: We previously reported infectious HCV clones that contain the convenient reporters, green fluorescent protein (GFP) and Renilla luciferase (Rluc), in the NS5a-coding sequence. Although these viruses were useful in monitoring viral proliferation and screening of anti-HCV drugs, the infectivity and yield of the viruses were low. METHODOLOGY/PRINCIPAL FINDINGS: In order to obtain a highly efficient HCV cultivation system, we transfected Huh7.5.1 cells [1] with JFH 5a-GFP RNA and then cultivated cells for 20 days. We found a highly infectious HCV clone containing two cell culture-adapted mutations. Two cell culture-adapted mutations which were responsible for the increased viral infectivity were located in E2 and p7 protein coding regions. The viral titer of the variant was ∼100-fold higher than that of the parental virus. The mutation in the E2 protein increased the viability of virus at 37°C by acquiring prolonged interaction capability with a HCV receptor CD81. The wild-type and p7-mutated virus had a half-life of ∼2.5 to 3 hours at 37°C. In contrast, the half-life of viruses, which contained E2 mutation singly and combination with the p7 mutation, was 5 to 6 hours at 37°C. The mutation in the p7 protein, either singly or in combination with the E2 mutation, enhanced infectious virus production about 10-50-fold by facilitating an early step of virion production. CONCLUSION/SIGNIFICANCE: The mutation in the E2 protein generated by the culture system increases virion viability at 37°C. The adaptive mutation in the p7 protein facilitates an earlier stage of virus production, such as virus assembly and/or morphogenesis. These reporter-containing HCV viruses harboring adaptive mutations are useful in investigations of the viral life cycle and for developing anti-viral agents against HCV

The contribution of metacognitions and attentional control to decisional procrastination

Earlier research has implicated metacognitions and attentional control in procrastination and self-regulatory failure. This study tested several hypotheses: (1) that metacognitions would be positively correlated with decisional procrastination; (2) that attentional control would be negatively correlated with decisional procrastination; (3) that metacognitions would be negatively correlated with attentional control; and (4) that metacognitions and attentional control would predict decisional procrastination when controlling for negative affect. One hundred and twenty-nine participants completed the Depression Anxiety Stress Scale 21, the Meta-Cognitions Questionnaire 30, the Attentional Control Scale, and the Decisional Procrastination Scale. Significant relationships were found between all three attentional control factors (focusing, shifting, and flexible control of thought) and two metacognitions factors (negative beliefs concerning thoughts about uncontrollability and danger, and cognitive confidence). Results also revealed that decisional procrastination was significantly associated with negative affect, all measured metacognitions factors, and all attentional control factors. In the final step of a hierarchical regression analysis only stress, cognitive confidence, and attention shifting were independent predictors of decisional procrastination. Overall these findings support the hypotheses and are consistent with the Self-Regulatory Executive Function model of psychological dysfunction. The implications of these findings are discussed

Elevated 17β-Estradiol Protects Females from Influenza A Virus Pathogenesis by Suppressing Inflammatory Responses

Studies of the 1918 H1N1 influenza pandemic, the H5N1 avian influenza outbreak, and the 2009 H1N1 pandemic illustrate that sex and pregnancy contribute to severe outcome from infection, suggesting a role for sex steroids. To test the hypothesis that the sexes respond differently to influenza, the pathogenesis of influenza A virus infection was investigated in adult male and female C57BL/6 mice. Influenza infection reduced reproductive function in females and resulted in greater body mass loss, hypothermia, and mortality in females than males. Whereas lung virus titers were similar between the sexes, females had higher induction of proinflammatory cytokines and chemokines, including TNF-α, IFN-γ, IL-6, and CCL2, in their lungs than males. Removal of the gonads in both sexes eliminated the sex difference in influenza pathogenesis. Manipulation of testosterone or dihydrotestosterone concentrations in males did not significantly impact virus pathogenesis. Conversely, females administered high doses of estradiol had a ≥10-fold lower induction of TNF-α and CCL2 in the lungs and increased rates of survival as compared with females that had either low or no estradiol. The protective effects of estradiol on proinflammatory cytokines and chemokines, morbidity, and mortality were primarily mediated by signaling through estrogen receptor α (ERα). In summary, females suffer a worse outcome from influenza A virus infection than males, which can be reversed by administration of high doses of estradiol to females and reflects differences in the induction of proinflammatory responses and not in virus load

Farmers’ perceptions of climate change : identifying types

Ambitious targets to reduce greenhouse gas (GHG) emissions from agriculture have been set by both national governments and their respective livestock sectors. We hypothesize that farmer self-identity influences their assessment of climate change and their willingness to im- plement measures which address the issue. Perceptions of climate change were determined from 286 beef/sheep farmers and evaluated using principal component analysis (PCA). The analysis elicits two components which evaluate identity (productivism and environmental responsibility), and two components which evaluate behavioral capacity to adopt mitigation and adaptation measures (awareness and risk perception). Subsequent Cluster Analyses reveal four farmer types based on the PCA scores. ‘The Productivist’ and ‘The Countryside Steward’ portray low levels of awareness of climate change, but differ in their motivation to adopt pro-environmental behavior. Conversely, both ‘The Environmentalist’ and ‘The Dejected’ score higher in their awareness of the issue. In addition, ‘The Dejected’ holds a high sense of perceived risk; however, their awareness is not conflated with an explicit understanding of agricultural GHG sources. With the exception of ‘The Environmentalist’, there is an evident disconnect between perceptions of agricultural emission sources and their contribution towards GHG emissions amongst all types. If such linkages are not con- ceptualized, it is unlikely that behavioral capacities will be realized. Effective communication channels which encour- age action should target farmers based on the groupings depicted. Therefore, understanding farmer types through the constructs used in this study can facilitate effective and tai- lored policy development and implementation

The lived experiences of experienced Vipassana Mahasi meditators: an interpretative phenomenological analysis.

Research into the effects and mechanisms of mindfulness training draws predominantly on quantitative research. There is a lack of understanding about the subjective experiences of experienced mindfulness meditators, which may provide additional insights into the effects, processes and context of mindfulness training. This qualitative study explored the lived experiences of a novel group of experienced mindfulness meditators who practise Vipassana Mahasi (VM) meditation. The study aimed to understand how experienced VM practitioners make sense of the effects of practice and what processes they ascribe to it. Participants attended semistructured interviews, and their responses were analysed using interpretative phenomenological analysis. Results yielded overarching themes including (a) improvements in hedonic and eudaimonic well-being; (b) insights into self, others and perception of reality; (c) attaining equanimity; and (d) physical and interpersonal difficulties. Participants perceived VM as a ‘cleansing’ process whereby maladaptive responses were eliminated through mindfulness, other supportive mental qualities, decentering and nonattachment. The findings revealed a complex and dynamic set of interdependent outcomes and processes, which are reinforced by Buddhist teachings and ethical practices. This study highlights the need for additional interdisciplinary research into topics such as insight generation and supportive mental qualities cultivated during VM, novel states of well-being informed by Buddhist constructs and interpersonal difficulties related to long-term practice. Findings also suggest that incorporating Buddhist teachings and ethics into mindfulness-based interventions may enhance practitioner understanding and implementation of meditation techniques.N/

Designer Gene Delivery Vectors: Molecular Engineering and Evolution of Adeno-Associated Viral Vectors for Enhanced Gene Transfer

Gene delivery vectors based on adeno-associated virus (AAV) are highly promising due to several desirable features of this parent virus, including a lack of pathogenicity, efficient infection of dividing and non-dividing cells, and sustained maintenance of the viral genome. However, several problems should be addressed to enhance the utility of AAV vectors, particularly those based on AAV2, the best characterized AAV serotype. First, altering viral tropism would be advantageous for broadening its utility in various tissue or cell types. In response to this need, vector pseudotyping, mosaic capsids, and targeting ligand insertion into the capsid have shown promise for altering AAV specificity. In addition, library selection and directed evolution have recently emerged as promising approaches to modulate AAV tropism despite limited knowledge of viral structure–function relationships. Second, pre-existing immunity to AAV must be addressed for successful clinical application of AAV vectors. “Shielding” polymers, site-directed mutagenesis, and alternative AAV serotypes have shown success in avoiding immune neutralization. Furthermore, directed evolution of the AAV capsid is a high throughput approach that has yielded vectors with substantial resistance to neutralizing antibodies. Molecular engineering and directed evolution of AAV vectors therefore offer promise for generating ‘designer’ gene delivery vectors with enhanced properties