TRIM32 regulates skeletal muscle stem cell differentiation and is necessary for normal adult muscle regeneration

Limb girdle muscular dystrophy type 2H (LGMD2H) is an inherited autosomal recessive disease of skeletal muscle caused by a mutation in the TRIM32 gene. Currently its pathogenesis is entirely unclear. Typically the regeneration process of adult skeletal muscle during growth or following injury is controlled by a tissue specific stem cell population termed satellite cells. Given that TRIM32 regulates the fate of mammalian neural progenitor cells through controlling their differentiation, we asked whether TRIM32 could also be essential for the regulation of myogenic stem cells. Here we demonstrate for the first time that TRIM32 is expressed in the skeletal muscle stem cell lineage of adult mice, and that in the absence of TRIM32, myogenic differentiation is disrupted. Moreover, we show that the ubiquitin ligase TRIM32 controls this process through the regulation of c-Myc, a similar mechanism to that previously observed in neural progenitors. Importantly we show that loss of TRIM32 function induces a LGMD2H-like phenotype and strongly affects muscle regeneration in vivo. Our studies implicate that the loss of TRIM32 results in dysfunctional muscle stem cells which could contribute to the development of LGMD2H.

The music instinct: the evolutionary basis of musicality

Why does music pervade our lives and those of all known human beings living today and in the recent past? Why do we feel compelled to engage in musical activity, or at least simply enjoy listening to music even if we choose not to actively participate? I argue that this is because musicality—communication using variations in pitch, rhythm, dynamics and timbre, by a combination of the voice, body (as in dance), and material culture—was essential to the lives of our pre-linguistic hominin ancestors. As a consequence we have inherited a desire to engage with music, even if this has no adaptive benefit for us today as a species whose communication system is dominated by spoken language. In this article I provide a summary of the arguments to support this view.

Colorectal cancer and the relationship between genes and the environment

Colorectal cancer (CRC) is a significant cause of morbidity and mortality in developed countries, with both genetic and environmental factors contributing to the etiology and progression of the disease. Several risk factors have been identified, including positive family history, red meat intake, smoking, and alcohol intake. Protective factors include vegetables, calcium, hormone replacement therapy, folate, nonsteroidal anti-inflammatory drugs, and physical activity. The interaction between these environmental factors, in particular diet and genes, is an area of growing interest. Currently, oncogenes, tumor suppressor genes, and mismatch repair genes are believed to play an essential role in colorectal carcinogenesis. When considering the genetics of CRC, only 10% of cases are inherited and only 2-6% can be ascribed to the highly penetrant genes, such as APC, hMLH and hMSH2. Lower penetrance genes combined with a Western-style diet contribute to the majority of sporadic CRCs. The purpose of this article is to give a brief overview of the epidemiologic studies that have been conducted and present the major findings. Here, we examine the molecular events in CRC, with particular focus on the interaction between genes and environment, and review the most current research in this area.

Wolbachia infection and dramatic intraspecific mitochondrial dna divergence in a fig wasp

Mitochondria and Wolbachia are maternally inherited genomes that exhibit strong linkage disequilibrium in many organisms. We surveyed Wolbachia infections in 187 specimens of the fig wasp species, Ceratosolen solmsi, and found an infection prevalence of 89.3%. DNA sequencing of 20 individuals each from Wolbachia-infected and -uninfected subpopulations revealed extreme mtDNA divergence (up to 9.2% and 15.3% in CO1 and cytochrome b, respectively) between infected and uninfected wasps. Further, mtDNA diversity was significantly reduced within the infected group. Our sequencing of a large part of the mitochondrial genome from both Wolbachia-infected and -uninfected individuals revealed that high sequence divergence is common throughout the mitochondrial genome. These patterns suggest a partial selective sweep of mitochondria subsequent to the introduction of Wolbachia into C. solsmi, by hybrid introgression from a related species.

Safeguarding inheritance and enhancing the resilience of orphaned young people living in child- and youth-headed households in Tanzania and Uganda

This paper explores the resilience of orphaned young people in safeguarding the physical assets (land and property) that they inherited from their parents and in sustaining their households without a co-resident adult relative. Drawing on the concept of resilience and the sustainable livelihoods framework, this paper analyses the findings of an exploratory study conducted with 15 orphaned young people heading households,18 of their siblings and 39 NGO workers and community members in Tanzania and Uganda. The research suggests that inherited land and property represent key determining factors in the formation and viability of child- and youth-headed households in both rural and urban areas. Despite experiences of stigma and marginalisation in the community, social networks were crucial in enabling young people to protect themselves and their property, in providing access to material and emotional resources and in enhancing their skills and capabilities to develop sustainable livelihoods. Support for child- and youth-headed households needs to recognise young people's agency and adopt a holistic approach to their lives that analyses the physical assets, material resources, human and social capital available to the household, as well as individual young people's wellbeing, outlook and aspirations. Alongside cash transfers and material support, youth-led collective mobilisation that is sustained over time may also help to build resilience and foster more supportive social environments that challenge property grabbing and the stigmatisation of child- and youth-headed households.

Transfers, contracts and regulation: a new institutional economics perspective on the changing provision of social housing in Britain

Social housing policy in the UK mirrors wider processes Associated with shifts in broad welfare regimes. Social housing has moved from dominance by state housing provision to the funding of new investment through voluntary sector housing associations to what is now a greater focus on the regulation and private financing of these not-for-profit bodies. If these trends run their course, we are likely to see a range of not-for-profit bodies providing non-market housing in a highly regulated quasi-market. This paper examines these issues through the lens of new institutional economics, which it is believed can provide important insights into the fundamental contractual and regulatory relationships that are coming to dominate social housing from the perspective of the key actors in the sector (not-for-profit housing organisations, their tenants, private lenders and the regulatory state). The paper draws on evidence recently collected from a study evaluating more than 100 stock transfer organisations that inherited ex-public housing in Scotland, including 12 detailed case studies. The paper concludes that social housing stakeholders need to be aware of the risks (and their management) faced across the sector and that the state needs to have clear objectives for social housing and coherent policy instruments to achieve those ends.

Evolution of discrimination in populations at equilibrium between selfishness and altruism

Where there is genetically based variation in selfishness and altruism, as in man, altruists with an innate ability to recognise and thereby only help their altruistic relatives may evolve. Here we use diploid population genetic models to chart the evolution of genetically-based discrimination in populations initially in stable equilibrium between altruism and selfishness. The initial stable equilibria occur because help is assumed subject to diminishing returns. Similar results were obtained whether we used a model with two independently inherited loci, one controlling altruism the other discrimination, or a one locus model with three alleles. The latter is the opposite extreme to the first model, and can be thought of as involving complete linkage between two loci on the same chromosome. The introduction of discrimination reduced the benefits obtained by selfish individuals, more so as the number of discriminators increased, and selfishness was eventually eliminated in some cases. In others selfishness persisted and the evolutionary outcome was a stable equilibrium involving selfish individuals and both discriminating and non-discriminating altruists. Heritable variation in selfishness, altruism and discrimination is predicted to be particularly evident among full sibs. The suggested coexistence of these three genetic dispositions could explain widespread interest within human social groups as to who will and who will not help others. These predictions merit experimental and observational investigation by primatologists, anthropologists and psychologists. Keywords: Population genetics, Diploid, Heritability, Prosocial, Behaviour genetics

Environmental oestrogens and breast cancer: long-term low-dose effects of mixtures of various chemical combinations

The incidence of breast cancer has risen worldwide to unprecedented levels in recent decades, making it now the major cancer of women in many parts of the world.1 Although diet, alcohol, radiation and inherited loss of BRCA1/2 genes have all been associated with increased incidence, the main identified risk factors are life exposure to hormones including physiological variations associated with puberty/pregnancy/menopause,1 personal choice of use of hormonal contraceptives2 and/or hormone replacement therapy.3–6 On this basis, exposure of the human breast to the many environmental pollutant chemicals capable of mimicking or interfering with oestrogen action7 should also be of concern.8 Hundreds of such environmental chemicals have now been measured in human breast tissue from a range of dietary and domestic exposure sources7 ,9 including persistent organochlorine pollutants (POPs),10 polybrominated diphenylethers and polybromobiphenyls,11 polychlorinated biphenyls,12 dioxins,13 alkyl phenols,14 bisphenol-A and chlorinated derivatives,15 as well as other less lipophilic compounds such as parabens (alkyl esters of p-hydroxybenzoic acid),16 but studies investigating any association between raised levels of such compounds and the development of breast cancer remain inconclusive.7–16 However, the functionality of these chemicals has continued to be assessed on the basis of individual chemicals rather than the environmental reality of long-term low-dose exposure to complex mixtures. This misses the potential for individuals to have high concentrations of different compounds but with a common mechanism of action. It also misses the complex interactions between chemicals and physiological hormones which together may act to alter the internal homeostasis of the oestrogenic environment of mammary tissue.

Delivery of AAV2/9-microdystrophin genes incorporating helix 1 of the coiled-coil motif in the C-terminal domain of dystrophin improves muscle pathology and restores the level of α1-syntrophin and α-dystrobrevin in skeletal muscles of mdx mice. Level of α1-Syntrophin and α-Dystrobrevin in Skeletal Muscles of mdx Mice

Duchenne muscular dystrophy is a severe X-linked inherited muscle wasting disorder caused by mutations in the dystrophin gene. Adeno-associated virus (AAV) vectors have been extensively used to deliver genes efficiently for dystrophin expression in skeletal muscles. To overcome limited packaging capacity of AAV vectors (<5 kb), truncated recombinant microdystrophin genes with deletions of most of rod and carboxyl-terminal (CT) domains of dystrophin have been developed. We have previously shown the efficiency of mRNA sequence–optimized microdystrophin (ΔR4-23/ΔCT, called MD1) with deletion of spectrin-like repeat domain 4 to 23 and CT domain in ameliorating the pathology of dystrophic mdx mice. However, the CT domain of dystrophin is thought to recruit part of the dystrophin-associated protein complex, which acts as a mediator of signalling between extracellular matrix and cytoskeleton in muscle fibers. In this study, we extended the ΔR4-23/ΔCT microdystrophin by incorporating helix 1 of the coiled-coil motif in the CT domain of dystrophin (MD2), which contains the α1-syntrophin and α-dystrobrevin binding sites. Intramuscular injection of AAV2/9 expressing CT domain–extended microdystrophin showed efficient dystrophin expression in tibialis anterior muscles of mdx mice. The presence of the CT domain of dystrophin in MD2 increased the recruitment of α1-syntrophin and α-dystrobrevin at the sarcolemma and significantly improved the muscle resistance to lengthening contraction–induced muscle damage in the mdx mice compared with MD1. These results suggest that the incorporation of helix 1 of the coiled-coil motif in the CT domain of dystrophin to the microdystrophins will substantially improve their efficiency in restoring muscle function in patients with Duchenne muscular dystrophy.

The genetics of diabetes mellitus

Genes play an important role in the development of diabetes mellitus. Putative susceptibility genes could be the key to the development of diabetes. Type 1 diabetes mellitus is one of the most common chronic diseases of childhood. A combination of genetic and environmental factors is most likely the cause of Type 1 diabetes. The pathogenetic sequence leading to the selective autoimmune destruction of islet beta-cells and development of Type 1 diabetes involves genetic factors, environmental factors, immune regulation and chemical mediators. Unlike Type 1 diabetes mellitus, Type 2 diabetes is often considered a polygenic disorder with multiple genes located on different chromosomes being associated with this condition. This is further complicated by numerous environmental factors which also contribute to the clinical manifestation of the disorder in genetically predisposed persons. Only a minority of cases of type 2 diabetes are caused by single gene defects such as maturity onset diabetes of the young (MODY), syndrome of insulin resistance (insulin receptor defect) and maternally inherited diabetes and deafness (mitochondrial gene defect). Although Type 2 diabetes mellitus appears in almost epidemic proportions our knowledge of the mechanism of this disease is limited. More information about insulin secretion and action and the genetic variability of the various factors involved will contribute to better understanding and classification of this group of diseases. This article discusses the results of various genetic studies on diabetes with special reference to Indian population.

Do IMF and World Bank programs induce government crises? an empirical analysis

We examine whether and under what circumstances World Bank and International Monetary Fund (IMF) programs affect the likelihood of major government crises. We find that crises are, on average, more likely as a consequence of World Bank programs. We also find that governments face an increasing risk of entering a crisis when they remain under an IMF or World Bank arrangement once the economy's performance improves. The international financial institution's (IFI) scapegoat function thus seems to lose its value when the need for financial support is less urgent. While the probability of a crisis increases when a government turns to the IFIs, programs inherited by preceding governments do not affect the probability of a crisis. This is in line with two interpretations. First, the conclusion of IFI programs can signal the government's incompetence, and second, governments that inherit programs might be less likely to implement program conditions agreed to by their predecessors.

Chaos of Wolbachia Sequences Inside the Compact Fig Syconia of Ficus benjamina (Ficus: Moraceae)

Figs and fig wasps form a peculiar closed community in which the Ficus tree provides a compact syconium (inflorescence) habitat for the lives of a complex assemblage of Chalcidoid insects. These diverse fig wasp species have intimate ecological relationships within the closed world of the fig syconia. Previous surveys of Wolbachia, maternally inherited endosymbiotic bacteria that infect vast numbers of arthropod hosts, showed that fig wasps have some of the highest known incidences of Wolbachia amongst all insects. We ask whether the evolutionary patterns of Wolbachia sequences in this closed syconium community are different from those in the outside world. In the present study, we sampled all 17 fig wasp species living on Ficus benjamina, covering 4 families, 6 subfamilies, and 8 genera of wasps. We made a thorough survey of Wolbachia infection patterns and studied evolutionary patterns in wsp (Wolbachia Surface Protein) sequences. We find evidence for high infection incidences, frequent recombination between Wolbachia strains, and considerable horizontal transfer, suggesting rapid evolution of Wolbachia sequences within the syconium community. Though the fig wasps have relatively limited contact with outside world, Wolbachia may be introduced to the syconium community via horizontal transmission by fig wasps species that have winged males and visit the syconia earlier.

Holocene alluvial environments at Barking, Lower Thames Valley (London, UK)

Deposit modelling based on archived borehole logs supplemented by a small number of dedicated boreholes is used to reconstruct the main boundary surfaces and the thickness of the main sediment units within the succession of Holocene alluvial deposits underlying the floodplain in the Barking Reach of the Lower Thames Valley. The basis of the modelling exercise is discussed and the models are used to assess the significance of floodplain relief in determining patterns of sedimentation. This evidence is combined with the results of biostratigraphical and geochronological investigations to reconstruct the environmental conditions associated with each successive stage of floodplain aggradation. The two main factors affecting the history and spatial pattern of Holocene sedimentation are shown to be the regional behaviour of relative sea level and the pattern of relief on the surface of the sub-alluvial, Late Devensian Shepperton Gravel. As is generally the case in the Lower Thames Valley, three main stratigraphic units are recognised, the Lower Alluvium, a peat bed broadly equivalent to the Tilbury III peat of Devoy (1979) and an Upper Alluvium. There is no evidence to suggest that the floodplain was substantially re-shaped by erosion during the Holocene. Instead, the relief inherited from the Shepperton Gravel surface was gradually buried either by the accumulation of peat or by deposition of fine-grained sediment from suspension in standing or slow-moving water. The palaeoenvironmental record from Barking confirms important details of the Holocene record observed elsewhere in the Lower Thames Valley, including the presence of Taxus in the valley-floor fen carr woodland between about 5000 and 4000 cal BP, and the subsequent growth of Ulmus on the peat surface.

Parental death as a vital conjuncture? Intergenerational care and responsibility following bereavement in Senegal

This article explores the ways that parental death represents a 'vital conjuncture' for Serer young people that reconfigures and potentially transforms intergenerational caring responsibilities in different spatial and temporal contexts. Drawing on semi-structured interviews with young people (aged 15-27), family members, religious and community leaders and professionals in rural and urban Senegal, I explore young people's responses to parental death. 'Continuing bonds' with the deceased were expressed through memories evoked in homespace, shared family practices and gendered responsibilities to 'take care of' bereaved family members, to cultivate inherited farmland and to fulfil the wishes of the deceased. Parental death could reconfigure intergenerational care and lead to shifts in power dynamics, as eldest sons asserted their position of authority. While care-giving roles were associated with agency, the low social status accorded to young women's paid and unpaid domestic work undermined their efforts. The research contributes to understandings of gendered nuances in the experience of bereavement and continuing bonds and provides insight into intra-household decision-making processes, ownership and control of assets. Analysis of the culturally specific meanings of relationships and a young person's social location within hierarchies of gender, age, sibling birth order and wider socio-cultural norms and practices is needed.

Arable crop rotations under abiotic stress: a dynamic economic model

Break crops and multi-crop rotations are common in arable farm management, and the soil quality inherited from a previous crop is one of the parameters that determine the gross margin that is achieved with a given crop from a given parcel of land. In previous work we developed a dynamic economic model to calculate the potential yield and gross margin of a set of crops grown in a selection of typical rotation scenarios, and we reported use of the model to calculate coexistence costs for GM maize grown in a crop rotation. The model predicts economic effects of pest and weed pressures in monthly time steps. Validation of the model in respect of specific traits is proceeding as data from trials with novel crop varieties is published. Alongside this aspect of the validation process, we are able to incorporate data representing the economic impact of abiotic stresses on conventional crops, and then use the model to predict the cumulative gross margin achievable from a sequence of conventional crops grown at varying levels of abiotic stress. We report new progress with this aspect of model validation. In this paper, we report the further development of the model to take account of abiotic stress arising from drought, flood, heat or frost; such stresses being introduced in addition to variable pest and weed pressure. The main purpose is to assess the economic incentive for arable farmers to adopt novel crop varieties having multiple ‘stacked’ traits introduced by means of various biotechnological tools available to crop breeders.