A Recombination Hotspot in a Schizophrenia-Associated Region of GABRB2

Background: Schizophrenia is a major disorder with complex genetic mechanisms. Earlier, population genetic studies revealed the occurrence of strong positive selection in the GABRB2 gene encoding the β2 subunit of GABAA receptors, within a segment of 3,551 bp harboring twenty-nine single nucleotide polymorphisms (SNPs) and containing schizophrenia-associated SNPs and haplotypes. Methodology/Principal Findings:In the present study, the possible occurrence of recombination in this 'S1-S29' segment was assessed. The occurrence of hotspot recombination was indicated by high resolution recombination rate estimation, haplotype diversity, abundance of rare haplotypes, recurrent mutations and torsos in haplotype networks, and experimental haplotyping of somatic and sperm DNA. The sub-segment distribution of relative recombination strength, measured by the ratio of haplotype diversity (Hd) over mutation rate (θ), was indicative of a human specific Alu-Yi6 insertion serving as a central recombining sequence facilitating homologous recombination. Local anomalous DNA conformation attributable to the Alu-Yi6 element, as suggested by enhanced DNase I sensitivity and obstruction to DNA sequencing, could be a contributing factor of the increased sequence diversity. Linkage disequilibrium (LD) analysis yielded prominent low LD points that supported ongoing recombination. LD contrast revealed significant dissimilarity between control and schizophrenic cohorts. Among the large array of inferred haplotypes, H26 and H73 were identified to be protective, and H19 and H81 risk-conferring, toward the development of schizophrenia. Conclusions/Significance: The co-occurrence of hotspot recombination and positive selection in the S1-S29 segment of GABRB2 has provided a plausible contribution to the molecular genetics mechanisms for schizophrenia. The present findings therefore suggest that genome regions characterized by the co-occurrence of positive selection and hotspot recombination, two interacting factors both affecting genetic diversity, merit close scrutiny with respect to the etiology of common complex disorders. © 2010 Ng et al

Alternative-Splicing in the Exon-10 Region of GABAA Receptor β2 Subunit Gene: Relationships between Novel Isoforms and Psychotic Disorders

BACKGROUND: Non-coding single nucleotide polymorphisms (SNPs) in GABRB2, the gene for beta(2)-subunit of gamma-aminobutyric acid type A (GABA(A)) receptor, have been associated with schizophrenia (SCZ) and quantitatively correlated to mRNA expression and alternative splicing. METHODS AND FINDINGS: Expression of the Exon 10 region of GABRB2 from minigene constructs revealed this region to be an "alternative splicing hotspot" that readily gave rise to differently spliced isoforms depending on intron sequences. This led to a search in human brain cDNA libraries, and the discovery of two novel isoforms, beta(2S1) and beta(2S2), bearing variations in the neighborhood of Exon-10. Quantitative real-time PCR analysis of postmortem brain samples showed increased beta(2S1) expression and decreased beta(2S2) expression in both SCZ and bipolar disorder (BPD) compared to controls. Disease-control differences were significantly correlated with SNP rs187269 in BPD males for both beta(2S1) and beta(2S2) expressions, and significantly correlated with SNPs rs2546620 and rs187269 in SCZ males for beta(2S2) expression. Moreover, site-directed mutagenesis indicated that Thr(365), a potential phosphorylation site in Exon-10, played a key role in determining the time profile of the ATP-dependent electrophysiological current run-down. CONCLUSION: This study therefore provided experimental evidence for the importance of non-coding sequences in the Exon-10 region in GABRB2 with respect to beta(2)-subunit splicing diversity and the etiologies of SCZ and BPD

Online peer assessment in higher education: a systematic review of literature in educational practices

Neste artigo procedemos a uma revisão sistemática da literatura sobre Online Peer Assessment (OPA) no Ensino Superior, mediadas por Tecnologias Digitais de Informação e Comunicação (TIC). Identificamos suas características, centrais e opcionais e mapeamos exemplos práticos (procedimentos e TIC) de OPA que poderão ser transversais, adaptáveis e aplicáveis em diversas unidades curriculares e regimes educacionais. Os resultados apontam para a utilização da OPA como uma estratégia que potencia a “avaliação para a aprendizagem”. Os referenciais teóricos subjacentes, os métodos de avaliação e os tipos de TIC utilizadas indicam seu direcionamento para um maior envolvimento e responsabilidade do aluno na sua aprendizagem. Evidenciamos na literatura que se busca desenvolver essas competências, dando ao aluno oportunidades com alguma regularidade para autoavaliar-se e avaliar seus pares por meio de feedback construtivo. Há também evidências de que dar ou produzir feedback é mais benéfico para a aprendizagem do que apenas recebê-lo, como também é cognitivamente mais exigente e envolve os alunos de forma mais ativa e os direciona ao pensamento crítico e a processos metacognitivos. A partir dos resultados alcançados, consideramos que a OPA, enquanto ferramenta cognitiva, contribui para a construção do conhecimento e para a reflexão sobre a aprendizagem. Um desafio que se coloca diz respeito ao desenvolvimento criativo com foco na diversificação e na inovação das práticas de avaliação no sentido de potenciar aprendizagens e resultados acadêmicos, em atenção às necessidades de aprendizagem que se manifestam frente às expectativas da educação atual e futura e às exigências da sociedade.In this research a systematic review of literature about Online Peer Assessment (OPA) in higher education, mediated by Information and Communication Technology (ICT), was carried out. Optional and central characteristics and its practices (procedures and ICT) were identified and mapping. These procedures and practices may be transversal, adaptable and applied in several curriculum units and educational regimes. The results point to the use of OPA as a strategy that enhances “assessment for learning”. The theoretical framework, the methods of assessment and the kinds of ICT used indicate directions for greater involvement and responsibility from the part of the student in his/her learning. Theoretical framework identifies the need to develop students’ skills, providing them with opportunities for self-assessment and peer assessment on a regular basis through constructive feedback. There is also evidence that to give or receive feedback is more beneficial for learning than just receiving it. It is also cognitively more demanding and directs the students to critical thinking and metacognitive processes. From the results obtained, OPA is seen as a cognitive tool, contributing to the building of knowledge and to reflection about learning. Issues for further reflection are also identified such as the creative development of assessment methods with a focus on diversity and innovation in order to enhance students’ learning and academic results, taking into account their learning needs in face of the expectations of current and future education and the demands of society.CIEC - Centro de Investigação em Estudos da Criança, IE, UMinho (UI 317 da FCT), PortugalFundos Nacionais através da FCT (Fundação para a Ciência e a Tecnologia) e cofinanciado pelo Fundo Europeu de Desenvolvimento Regional (FEDER) através do COMPETE 2020 – Programa Operacional Competitividade e Internacionalização (POCI) com a referência POCI-01-0145-FEDER-007562info:eu-repo/semantics/publishedVersio

Positive Selection within the Schizophrenia-Associated GABA(A) Receptor β(2) Gene

The gamma-aminobutyric acid type-A (GABA(A)) receptor plays a major role in inhibitory neurotransmissions. Intronic SNPs and haplotypes in GABRB2, the gene for GABA(A) receptor β(2) subunit, are associated with schizophrenia and correlated with the expression of two alternatively spliced β(2) isoforms. In the present study, using chimpanzee as an ancestral reference, high frequencies were observed for the derived (D) alleles of the four SNPs rs6556547, rs187269, rs1816071 and rs1816072 in GABRB2, suggesting the occurrence of positive selection for these derived alleles. Coalescence-based simulation showed that the population frequency spectra and the frequencies of H56, the haplotype having all four D alleles, significantly deviated from neutral-evolution expectation in various demographic models. Haplotypes containing the derived allele of rs1816072 displayed significantly less diversity compared to haplotypes containing its ancestral allele, further supporting positive selection. The variations in DD-genotype frequencies in five human populations provided a snapshot of the evolutionary history, which suggested that the positive selections of the D alleles are recent and likely ongoing. The divergence between the DD-genotype profiles of schizophrenic and control samples pointed to the schizophrenia-relevance of positive selections, with the schizophrenic samples showing weakened selections compared to the controls. These DD-genotypes were previously found to increase the expression of β(2), especially its long isoform. Electrophysiological analysis showed that this long β(2) isoform favored by the positive selections is more sensitive than the short isoform to the inhibition of GABA(A) receptor function by energy depletion. These findings represent the first demonstration of positive selection in a schizophrenia-associated gene

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Asymptotic tradeoff between cross-layer goodput gain and outage diversity in OFDMA systems with slow fading and delayed CSIT

There are two important aspects of cross-layer gains in multiuser OFDMA systems with slow fading channels. They are the system goodput gain as well as the packet diversity gain. The former aspect of cross-layer designs has been well-studied under perfect CSIT conditions and is known as the multi-user diversity gain (MuDiv). In cross-layer OFDMA systems with perfect CSIT, it is well known that the system throughput (ergodic capacity) scales in the order of O(log log K) due to the MuDiv gain, where K is the number users. However, in slow fading channels with delayed CSIT, there will always be potential packet errors (due to channel outage if the scheduled data rate exceeds the instantaneous mutual information) even if very strong channel coding is applied at the base station. In this case, the cross-layer packet outage diversity is important to protect the packet errors due to channel outage and there is a natural tradeoff between the goodput gain and packet diversity. In this paper, we shall focus on the asymptotic tradeoff analysis between the system goodput gain and the packet outage diversity gain in cross-layer OFDMA systems with delayed CSIT

Cross-layer optimization for OFDMA system with imperfect CSIT in quasi static channel

Asymptotic performance analysis of orthogonal frequency division multiple access (OFDMA) is conducted in this work. We take a cross-layer approach and analyze how the system performance scale with some important parameters such as number of user, CSIT quality and order of diversity. It is well studied that system goodput scale with number of user K in the order of script O (log log K) due to multiuser diversity (system goodput gain) under perfect CSIT assumption. However, in quasi static fading channels with imperfect CSIT, channel outage happens even if capacity achieving coding is applied at the base station. In this case, cross-layer scheduler can protect the packet by increasing the order of diversity (packet outage diversity) . So, there is a trade-off between system goodput gain and packet outage diversity

Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA(A) receptor beta(2) subunit

Schizophrenia is a complex genetic disorder, the inheritance pattern of which is likely complicated by epigenetic factors yet to be elucidated. In this study, transmission disequilibrium tests with family trios yielded significant differences between paternal and maternal transmissions of the disease-associated single-nucleotide polymorphism (SNP) rs6556547 and its haplotypes. The minor allele (T) of rs6556547 was paternally undertransmitted to male schizophrenic offsprings, and this parent-of-origin effect strongly suggested that GABRB2 is imprinted. 'Flipping' of allelic expression in heterozygotes of SNP rs2229944 (C/T) in GABRB2 or rs2290732 (G/A) in the neighboring GABRA1 was compatible with imprinting effects on gene expression. Clustering analysis of GABRB2 mRNA expressions suggested that imprinting brought about the observed two-tiered distribution of expression levels in controls with heterozygous genotype at the disease-associated SNP rs1816071 (A/G). The deficit of upper-tiered expressions accounted for the lowered expression levels in the schizophrenic heterozygotes. The occurrence of a two-tiered distribution furnished support for imprinting, and also pointed to the necessity of differentiating between two kinds of heterozygotes of different parental origins in disease association studies on GABRB2. Bisulfite sequencing revealed hypermethylation in the neighborhood of SNP rs1816071, and methylation differences between controls and schizophrenia patients. Notably, the two schizophrenia-associated SNPs rs6556547 and rs1816071 overlapped with a CpG dinucleotide, thereby opening the possibility that CpG methylation status of these sites could have an impact on the risk of schizophrenia. Thus multiple lines of evidence pointed to the occurrence of imprinting in the GABRB2 gene and its possible role in the development of schizophrenia. Molecular Psychiatry (2011) 16, 557-568; doi: 10.1038/mp.2010.47; published online 20 April 201