LINKING CRIME AND MORALITY: Reviewing the Moral Regeneration Movement

Politicians, religious leaders and social commentators have all spoken about a breakdown in morality in South Africa, with crime as the most commonly cited evidence. The moral regeneration initiative is one response to this crisis, emerging in parallel to countless other initiatives aimed at reducing crime, some of which have themselves contained explicit appeals to morals, values or ethics. A review of its origins and development shows that the moral regeneration initiative has suffered from a lack of clarity about both its mission and its strategy. The movement’s attempts to build meaningful civil society participation in the campaign have also been a key challenge

E-Learning Is Not Inferior to On-Site Teaching in a Psychiatric Examination Course

Background: Implementing e-learning into medical education is a growing field of research. Researchers have had positive experiences so far, and evidence suggests it to be no less effective than offline teaching. However, there are a few findings concerning psychiatric education and the use of simulated patients online. Methods: We developed an online workshop for medical students at our psychiatric clinic, including group work exercises, lectures, and interviews with simulated patients. To compare the learning outcome, a cohort of students learning online was compared with a previous cohort that learned on-site. The same objective structured clinical examination (OSCE) was used in both cases. Evaluation questionnaires were gathered from students and lecturers and were compared with the former semesters along with the exam results. Results: The exam grades did not significantly differ between on-site and online teaching, even though students rated their own communication skills better with online teaching. We also found that the connection experienced between students and teachers was impaired without on-site contact. Discussion: We conclude that an online course may be an effective alternative to on-site teaching but requires further improvement to maintain a dependable student–teacher relationship

Mapping of southern security and justice civil society organisations and networks

The purpose of this mapping study is to provide the UK Department for International Development (DFID) with a quantitative and qualitative snapshot of security and justice civil society organisations (CSOs) and networks working in and across the countries investigated. CSO engagement on issues of security and justice is inherently difficult in many countries due to the nature of their governing regimes (such as where the state has authoritarian tendencies or where military regimes preside). In some cases the political space for CSOs to engage in issues of security and justice is being increasingly suppressed. Consequently, the success of donor support for security and justice CSOs often depends to a great extent on the political will of respective governments to enable CSOs to work freely. Furthermore, donors who wish to support security and justice CSOs need to take account of the extent to which donor interactions with government security and justice structures may influence the extent and quality of donor interaction with CSOs. In many countries, an understanding of security and justice as conceptualised and defined by donors is lacking amongst civil society – and an understanding of these issues as conceptualised by civil society is often lacking among donors and governments. This scenario even holds true in those countries where civil society as a whole is otherwise vibrant. Consequently, there is a need to increase the basic level of understanding on security and justice matters (both within CSOs and governments), to broaden the strategic community (those working in think tanks or engaged in policy analysis), and to support the development of research capacity and expertise in security and justice areas. Joined up approaches to security and justice work are rare in almost all contexts and common/collaborative/networking fora do not exist. Recommendations were made in almost all sub-regions stating that donor approaches should encourage collaboration at the outset between security and justice CSOs and devise schemes that reward or encourage joined up working

Parvovirus 4 Infection and Clinical Outcome in High-Risk Populations

Parvovirus 4 (PARV4) is a DNA virus frequently associated with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, but its clinical significance is unknown. We studied the prevalence of PARV4 antibodies in 2 cohorts of HIV- and HCV-infected individuals (n=469) and the correlations with disease status. We found that PARV4 infection frequently occurred in individuals exposed to bloodborne viruses (95% in HCV-HIV coinfected intravenous drug users [IDUs]). There were no correlations between PARV4 serostatus and HCV outcomes. There was, however, a significant association with early HIV-related symptoms, although because this was tightly linked to both HCV status and clinical group (IDU), the specific role of PARV4 is not yet clea

Parvovirus 4 Infection and Clinical Outcome in High-Risk Populations

Parvovirus 4 (PARV4) is a DNA virus frequently associated with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, but its clinical significance is unknown. We studied the prevalence of PARV4 antibodies in 2 cohorts of HIV- and HCV-infected individuals (n = 469) and the correlations with disease status. We found that PARV4 infection frequently occurred in individuals exposed to bloodborne viruses (95% in HCV-HIV coinfected intravenous drug users [IDUs]). There were no correlations between PARV4 serostatus and HCV outcomes. There was, however, a significant association with early HIV-related symptoms, although because this was tightly linked to both HCV status and clinical group (IDU), the specific role of PARV4 is not yet clear

Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability

DNA double-strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can give rise to genomic instability. Non-homologous end-joining (NHEJ), a well-orchestrated, multistep process involving numerous proteins essential for cell viability, represents one major pathway to repair DSBs in mammalian cells, and mutations in different NHEJ components have been described in microcephalic syndromes associated, e.g. with short stature, facial dysmorphism and immune dysfunction. By using whole-exome sequencing, we now identified in three affected brothers of a consanguineous Turkish family a homozygous mutation, c.482G>A, in the XRCC4 gene encoding a crucial component of the NHEJ pathway. Moreover, we found one additional patient of Swiss origin carrying the compound heterozygous mutations c.25delG (p.His9Thrfs*8) and c.823C>T (p.Arg275*) in XRCC4. The clinical phenotype presented in these patients was characterized by severe microcephaly, facial dysmorphism and short stature, but they did not show a recognizable immunological phenotype. We showed that the XRCC4 c.482G>A mutation, which affects the last nucleotide of exon 4, induces defective splicing of XRCC4 pre-mRNA mainly resulting in premature protein truncation and most likely loss of XRCC4 function. Moreover, we observed on cellular level that XRCC4 deficiency leads to hypersensitivity to DSB-inducing agents and defective DSB repair, which results in increased cell death after exposure to genotoxic agents. Taken together, our data provide evidence that autosomal recessive mutations in XRCC4 induce increased genomic instability and cause a NHEJ-related syndrome defined by facial dysmorphism, primary microcephaly and short statur

A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling

Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. De novo dominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategie

Possible Existence of Lysosome-Like Organella within Mitochondria and Its Role in Mitochondrial Quality Control

The accumulation of unhealthy mitochondria results in mitochondrial dysfunction, which has been implicated in aging, cancer, and a variety of degenerative diseases. However, the mechanism by which mitochondrial quality is regulated remains unclear. Here, we show that Mieap, a novel p53-inducible protein, induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control. Mieap expression is directly regulated by p53 and is frequently lost in human cancer as result of DNA methylation. Mieap dramatically induces the accumulation of lysosomal proteins within mitochondria and mitochondrial acidic condition without destroying the mitochondrial structure (designated MALM, for Mieap-induced accumulation of lysosome-like organelles within mitochondria) in response to mitochondrial damage. MALM was not related to canonical autophagy. MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation. These results suggest that Mieap induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control by eliminating oxidized mitochondrial proteins. Cancer cells might accumulate unhealthy mitochondria due to p53 mutations and/or Mieap methylation, representing a potential cause of the Warburg effect

TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.This work was supported by funding from the Medical Research Council and the European Research Council (ERC, 281847) (A.P.J.), the Lister Institute for Preventative Medicine (A.P.J. and G.S.S.), Medical Research Scotland (L.S.B.), German Federal Ministry of Education and Research (BMBF, 01GM1404) and E-RARE network EuroMicro (B.W), Wellcome Trust (M. Hurles), CMMC (P.N.), Cancer Research UK (C17183/A13030) (G.S.S. and M.R.H), Swiss National Science Foundation (P2ZHP3_158709) (O.M.), AIRC (12710) and ERC/EU FP7 (CIG_303806) (S.S.), Cancer Research UK (C6/A11224) and ERC/EU FP7 (HEALTH-F2- 2010-259893) (A.N.B. and S.P.J.).This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.345

The recent breakthroughs in the understanding of host genomics in hepatitis C.

BACKGROUND: Hepatitis C Virus (HCV) infection is spontaneously resolved in about 30% of acutely infected individuals. In those who progress to chronic hepatitis C, HCV therapy permanently eradicates infection in about 40% of cases. It has long been suspected that host genetic factors are key determinants for the control of HCV infection. DESIGN: We will review in this study four genome-wide association studies (GWAS) and two large candidate gene studies that assessed the role of host genetic variation for the natural and treatment-induced control of HCV infection. RESULTS: The studies consistently identified genetic variation in interleukin 28B (IL28B) as the strongest predictor for the control of HCV infection. Importantly, single nucleotide polymorphisms (SNPs) in IL28B strongly predicted both spontaneous and treatment-induced HCV recovery. IL28B is located on chromosome 19 and encodes interferon-λ, a type III interferon with antiviral activity, which is mediated through the JAK-STAT pathway by inducing interferon-stimulated genes. The SNPs identified in the GWAS are in high linkage disequilibrium with coding or functional non-coding SNPs that might modulate function and/or expression of IL28B. The role of the different IL28B alleles on gene expression and cytokine function has not yet been established. CONCLUSIONS: These findings provide strong genetic evidence for the influence of interferon-λ for both the natural and treatment-induced control of HCV infection, and support the further investigation of interferon-λ for the treatment of chronic hepatitis C. Furthermore, genetic testing before HCV therapy could provide important information towards an individualized HCV treatment