The use of happiness research for public policy

Research on happiness tends to follow a "benevolent dictator" approach where politicians pursue people's happiness. This paper takes an antithetic approach based on the insights of public choice theory. First, we inquire how the results of happiness research may be used to improve the choice of institutions. Second, we show that the policy approach matters for the choice of research questions and the kind of knowledge happiness research aims to provide. Third, we emphasize that there is no shortcut to an optimal policy maximizing some happiness indicator or social welfare function since governments have an incentive to manipulate this indicator

Glutamate Induces the Elongation of Early Dendritic Protrusions via mGluRs in Wild Type Mice, but Not in Fragile X Mice

Fragile X syndrome (FXS), the most common inherited from of autism and mental impairment, is caused by transcriptional silencing of the Fmr1 gene, resulting in the loss of the RNA-binding protein FMRP. Dendritic spines of cortical pyramidal neurons in affected individuals are abnormally immature and in Fmr1 knockout (KO) mice they are also abnormally unstable. This could result in defects in synaptogenesis, because spine dynamics are critical for synapse formation. We have previously shown that the earliest dendritic protrusions, which are highly dynamic and might serve an exploratory role to reach out for axons, elongate in response to glutamate. Here, we tested the hypothesis that this process is mediated by metabotropic glutamate receptors (mGluRs) and that it is defective in Fmr1 KO mice. Using time-lapse imaging with two-photon microscopy in acute brain slices from early postnatal mice, we find that early dendritic protrusions in layer 2/3 neurons become longer in response to application of glutamate or DHPG, a Group 1 mGluR agonist. Blockade of mGluR5 signaling, which reverses some adult phenotypes of KO mice, prevented the glutamate-mediated elongation of early protrusions. In contrast, dendritic protrusions from KO mice failed to respond to glutamate. Thus, absence of FMRP may impair the ability of cortical pyramidal neurons to respond to glutamate released from nearby pre-synaptic terminals, which may be a critical step to initiate synaptogenesis and stabilize spines

Mutual Inhibition between Kaposi's Sarcoma-Associated Herpesvirus and Epstein-Barr Virus Lytic Replication Initiators in Dually-Infected Primary Effusion Lymphoma

Background: Both Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are members of the human gamma herpesvirus family: each is associated with various human cancers. The majority of AIDS-associated primary effusion lymphoma (PEL) are co-infected with both KSHV and EBV. Dually-infected PELs selectively switch from latency to lytic replication of either KSHV or EBV in response to chemical stimuli. KSHV replication and transcription activator (K-RTA) is necessary and sufficient for the switch from KSHV latency to lytic replication, while EBV BZLF1 gene product (EBV-Z) is a critical initiator for induction of EBV lytic replication. Methodology/Principal Findings: We show K-RTA and EBV-Z are co-localized and physically interact with each other in dually-infected PELs. K-RTA inhibits the EBV lytic replication by nullifying EBV-Z-mediated EBV lytic gene activation. EBV-Z inhibits KSHV lytic gene expression by blocking K-RTA-mediated transactivations. The physical interaction between K-RTA and EBV-Z are required for the mutual inhibition of the two molecules. The leucine heptapeptide repeat (LR) region in K-RTA and leucine zipper region in EBV-Z are involved in the physical interactions of the two molecules. Finally, initiation of KSHV lytic gene expression is correlated with the reduction of EBV lytic gene expression in the same PEL cells. Conclusions/Significance: In this report, how the two viruses interact with each other in dually infected PELs is addressed. Our data may provide a possible mechanism for maintaining viral latency and for selective lytic replication in dually infected PELs, i.e., through mutual inhibition of two critical lytic replication initiators. Our data about putative interactions between EBV and KSHV would be applicable to the majority of AIDS-associated PELs and may be relevant to the pathogenesis of PELs

Physiological changes to the swallowing mechanism following (Chemo)radiotherapy for head and neck cancer: a systematic review

Emerging research suggests that preventative swallowing rehabilitation, undertaken before or during (chemo)radiotherapy ([C]RT), can significantly improve early swallowing outcomes for head and neck cancer (HNC) patients. However, these treatment protocols are highly variable. Determining specific physiological swallowing parameters that are most likely to be impacted post-(C)RT would assist in refining clear targets for preventative rehabilitation. Therefore, this systematic review (1) examined the frequency and prevalence of physiological swallowing deficits observed post-(C)RT for HNC, and (2) determined the patterns of prevalence of these key physiological deficits over time post-treatment. Online databases were searched for relevant papers published between January 1998 and March 2013. A total of 153 papers were identified and appraised for methodological quality and suitability based on exclusionary criteria. Ultimately, 19 publications met the study’s inclusion criteria. Collation of reported prevalence of physiological swallowing deficits revealed reduced laryngeal excursion, base-of-tongue (BOT) dysfunction, reduced pharyngeal contraction, and impaired epiglottic movement as most frequently reported. BOT dysfunction and impaired epiglottic movement showed a collective prevalence of over 75 % in the majority of patient cohorts, whilst reduced laryngeal elevation and pharyngeal contraction had a prevalence of over 50 %. Subanalysis suggested a trend that the prevalence of these key deficits is dynamic although persistent over time. These findings can be used by clinicians to inform preventative intervention and support the use of specific, evidence-based therapy tasks explicitly selected to target the highly prevalent deficits post-(C)RT for HNC

Phosphorylation of Kif26b Promotes Its Polyubiquitination and Subsequent Proteasomal Degradation during Kidney Development

Kif26b, a member of the kinesin superfamily proteins (KIFs), is essential for kidney development. Kif26b expression is restricted to the metanephric mesenchyme, and its transcription is regulated by a zinc finger transcriptional regulator Sall1. However, the mechanism(s) by which Kif26b protein is regulated remain unknown. Here, we demonstrate phosphorylation and subsequent polyubiquitination of Kif26b in the developing kidney. We find that Kif26b interacts with an E3 ubiquitin ligase, neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4) in developing kidney. Phosphorylation of Kif26b at Thr-1859 and Ser-1962 by the cyclin-dependent kinases (CDKs) enhances the interaction of Kif26b with Nedd4. Nedd4 polyubiquitinates Kif26b and thereby promotes degradation of Kif26b via the ubiquitin-proteasome pathway. Furthermore, Kif26b lacks ATPase activity but does associate with microtubules. Nocodazole treatment not only disrupts the localization of Kif26b to microtubules but also promotes phosphorylation and polyubiquitination of Kif26b. These results suggest that the function of Kif26b is microtubule-based and that Kif26b degradation in the metanephric mesenchyme via the ubiquitin-proteasome pathway may be important for proper kidney development

Expression of RNA interference triggers from an oncolytic herpes simplex virus results in specific silencing in tumour cells in vitro and tumours in vivo

<p>Abstract</p> <p>Background</p> <p>Delivery of small interfering RNA (siRNA) to tumours remains a major obstacle for the development of RNA interference (RNAi)-based therapeutics. Following the promising pre-clinical and clinical results with the oncolytic herpes simplex virus (HSV) OncoVEX^GM-CSF, we aimed to express RNAi triggers from oncolytic HSV, which although has the potential to improve treatment by silencing tumour-related genes, was not considered possible due to the highly oncolytic properties of HSV.</p> <p>Methods</p> <p>To evaluate RNAi-mediated silencing from an oncolytic HSV backbone, we developed novel replicating HSV vectors expressing short-hairpin RNA (shRNA) or artificial microRNA (miRNA) against the reporter genes green fluorescent protein (eGFP) and β-galactosidase (lacZ). These vectors were tested in non-tumour cell lines <it>in vitro </it>and tumour cells that are moderately susceptible to HSV infection both <it>in vitro </it>and in mice xenografts <it>in vivo</it>. Silencing was assessed at the protein level by fluorescent microscopy, x-gal staining, enzyme activity assay, and western blotting.</p> <p>Results</p> <p>Our results demonstrate that it is possible to express shRNA and artificial miRNA from an oncolytic HSV backbone, which had not been previously investigated. Furthermore, oncolytic HSV-mediated delivery of RNAi triggers resulted in effective and specific silencing of targeted genes in tumour cells <it>in vitro </it>and tumours <it>in vivo</it>, with the viruses expressing artificial miRNA being comprehensibly more effective.</p> <p>Conclusions</p> <p>This preliminary data provide the first demonstration of oncolytic HSV-mediated expression of shRNA or artificial miRNA and silencing of targeted genes in tumour cells <it>in vitro </it>and <it>in vivo</it>. The vectors developed in this study are being adapted to silence tumour-related genes in an ongoing study that aims to improve the effectiveness of oncolytic HSV treatment in tumours that are moderately susceptible to HSV infection and thus, potentially improve response rates seen in human clinical trials.</p

Genomic view of the evolution of the complement system

The recent accumulation of genomic information of many representative animals has made it possible to trace the evolution of the complement system based on the presence or absence of each complement gene in the analyzed genomes. Genome information from a few mammals, chicken, clawed frog, a few bony fish, sea squirt, fruit fly, nematoda and sea anemone indicate that bony fish and higher vertebrates share practically the same set of complement genes. This suggests that most of the gene duplications that played an essential role in establishing the mammalian complement system had occurred by the time of the teleost/mammalian divergence around 500 million years ago (MYA). Members of most complement gene families are also present in ascidians, although they do not show a one-to-one correspondence to their counterparts in higher vertebrates, indicating that the gene duplications of each gene family occurred independently in vertebrates and ascidians. The C3 and factor B genes, but probably not the other complement genes, are present in the genome of the cnidaria and some protostomes, indicating that the origin of the central part of the complement system was established more than 1,000 MYA

Computing Highly Correlated Positions Using Mutual Information and Graph Theory for G Protein-Coupled Receptors

G protein-coupled receptors (GPCRs) are a superfamily of seven transmembrane-spanning proteins involved in a wide array of physiological functions and are the most common targets of pharmaceuticals. This study aims to identify a cohort or clique of positions that share high mutual information. Using a multiple sequence alignment of the transmembrane (TM) domains, we calculated the mutual information between all inter-TM pairs of aligned positions and ranked the pairs by mutual information. A mutual information graph was constructed with vertices that corresponded to TM positions and edges between vertices were drawn if the mutual information exceeded a threshold of statistical significance. Positions with high degree (i.e. had significant mutual information with a large number of other positions) were found to line a well defined inter-TM ligand binding cavity for class A as well as class C GPCRs. Although the natural ligands of class C receptors bind to their extracellular N-terminal domains, the possibility of modulating their activity through ligands that bind to their helical bundle has been reported. Such positions were not found for class B GPCRs, in agreement with the observation that there are not known ligands that bind within their TM helical bundle. All identified key positions formed a clique within the MI graph of interest. For a subset of class A receptors we also considered the alignment of a portion of the second extracellular loop, and found that the two positions adjacent to the conserved Cys that bridges the loop with the TM3 qualified as key positions. Our algorithm may be useful for localizing topologically conserved regions in other protein families

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700