SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging.

Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in the desilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizes to DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the aging mouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability and suppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin-modifying proteins may be a conserved mechanism of aging in eukaryotes.

Who is responsible for postpartum contraception advice and provision? The perspective of hospital-based maternity clinicians in New South Wales, Australia.

Access to postpartum contraception is critical for the health of the mother and subsequent pregnancies. However, the differential roles and responsibilities of maternity care providers in contraception discussions and provision are often unclear. Our study, part of a larger study on midwifery provision of contraceptive implants, presents the perspectives of hospital-based maternity clinicians. Participants suggested that contraception discussions and provision are a shared responsibility of maternity care providers but identified inconsistencies and issues with current approaches. Access to contraception could be improved through more routine discussions antenatally and postnatally and greater collaboration between maternity care providers in hospital, community and primary care settings.

Nuclear positioning, higher-order folding, and gene expression of Mmu15 sequences are refractory to chromosomal translocation.

Nuclear localization influences the expression of certain genes. Chromosomal rearrangements can reposition genes in the nucleus and thus could impact the expression of genes far from chromosomal breakpoints. However, the extent to which chromosomal rearrangements influence nuclear organization and gene expression is poorly understood. We examined mouse progenitor B cell lymphomas with a common translocation, der(12)t(12;15), which fuses a gene-rich region of mouse chromosome 12 (Mmu 12) with a gene-poor region of mouse chromosome 15 (Mmu 15). We found that sequences 2.3 Mb proximal and 2.7 Mb distal to the der(12)t(12;15) breakpoint had different nuclear positions measured relative to the nuclear radius. However, their positions were similar on unrearranged chromosomes in the same tumor cells and normal progenitor B cells. In addition, higher-order chromatin folding marked by three-dimensional gene clustering was not significantly altered for the 7 Mb of Mmu 15 sequence distal to this translocation breakpoint. Translocation also did not correspond to significant changes in gene expression in this region. Thus, any changes to Mmu 15 structure and function imposed by the der(12)t(12;15) translocation are constrained to sequences near (<2.5 Mb) the translocation junction. These data contrast with those of certain other chromosomal rearrangements and suggest that significant changes to Mmu 15 sequence are structurally and functionally tolerated in the tumor cells examined.

Feasibility, acceptability and sustainability of postpartum contraceptive implant provision by midwives in NSW public hospitals.

BACKGROUND: Repeat pregnancy in the first year after a birth is common. Many of these conceptions are unintended and may be prevented by providing access to contraception in the immediate postpartum period. Midwives in the hospital setting could potentially play a greater role in improving postnatal contraception information and provision. AIM: We sought to implement and examine the success of a program training hospital-based midwives in immediate postpartum implant insertion. METHODS: This mixed methods study in two hospitals in New South Wales sought to explore the feasibility, acceptability and sustainability of a program that provided competency-based implant insertion training for midwives. The study documented training completion, implant insertion numbers and experience, and conducted end of study interviews with midwives and stakeholders. FINDINGS: Twenty-seven midwives undertook training and inserted 265 implants during the study period. Interviews with 13 midwives and 11 stakeholders concluded the program to be feasible and acceptable with midwives reporting high satisfaction from their involvement. All interviewees felt that midwives were well placed to insert implants, and reported that challenges around workload and opportunities for practice were generally manageable. It was recognised that sustainability of the program would require supportive policy and regular insertion opportunities. CONCLUSIONS: Midwives successfully upskilled in implant insertions and there was widespread support for the program with expectations it would be sustained. Provision of contraceptive information and implant insertion by midwives in the immediate postpartum period is likely to increase contraceptive choice and access for women and contribute to reducing rapid repeat pregnancies.

Contraception provision in the postpartum period: Knowledge, views and practices of midwives.

BACKGROUND: Women are susceptible to unintended pregnancies in the first year after giving birth, particularly as consideration of contraception may be a low priority during this time. Discussing and providing contraception before women leave hospital after giving birth may prevent rapid repeat pregnancy and its associated risks. Midwives are well placed to assist with contraceptive decision-making and provision; however, this is not routinely undertaken by midwives in the Australian hospital setting and little is known regarding their views and experiences in relation to contraception. METHODS: An anonymous survey was conducted with midwives at two urban hospitals in New South Wales to better understand their contraceptive knowledge, views and practices regarding midwifery-led contraception provision in the postpartum period. FINDINGS: The survey was completed by 128 midwives. Most agreed that information about contraception provided in the postpartum period is valuable to women, although their knowledge about different methods was variable. The majority (88%) believed that midwives have a role in providing contraceptive information, and 79% reported currently providing contraceptive counselling. However, only 14% had received formal training in this area. CONCLUSION: Findings demonstrate that most midwives provide some contraception information and believe this is an important part of a midwife's role. Yet most have not undertaken formal training in contraception. Additional research is needed to explore the content and quality of midwives' contraception discussions with women. Training midwives in contraceptive counselling would ensure women receive accurate information about available options. Upskilling midwives in contraception provision may increase postpartum uptake and reduce rapid repeat pregnancies.

Uncovering the Mechanisms Responsible for Why Language Learning May Promote Healthy Cognitive Aging.

One of the great challenges facing humankind in the 21st century is preserving healthy brain function in our aging population. Individuals over 60 are the fastest growing age group in the world, and by 2050, it is estimated that the number of people over the age of 60 will triple. The typical aging process involves cognitive decline related to brain atrophy, especially in frontal brain areas and regions that subserve declarative memory, loss of synaptic connections, and the emergence of neuropathological symptoms associated with dementia. The disease-state of this age-related cognitive decline is Alzheimer's disease and other dementias, which may cause older adults to lose their independence and rely on others to live safely, burdening family members and health care systems in the process. However, there are two lines of research that offer hope to those seeking to promote healthy cognitive aging. First, it has been observed that lifestyle variables such as cognitive leisure activities can moderate the risk of Alzheimer's disease, which has led to the development of plasticity-based interventions for older adults designed to protect against the adverse effects of cognitive decline. Second, there is evidence that lifelong bilingualism acts as a safeguard in preserving healthy brain function, possibly delaying the incidence of dementia by several years. In previous work, we have suggested that foreign language learning programs aimed at older populations are an optimal solution for building cognitive reserve because language learning engages an extensive brain network that is known to overlap with the regions negatively affected by the aging process. Here, we will outline potential future lines of research that may uncover the mechanism responsible for the emergence of language learning related brain advantages, such as language typology, bi- vs. multi-lingualism, age of acquisition, and the elements that are likely to result in the largest gains.

Evolution of virulence in Photorhabdus spp., entomopathogenic nematode symbionts.

Photorhabdus is a genus of Gram-negative bacteria belonging to the Enterobacteriaceae family. In addition to forming a mutualistic relationship with the Heterorhabditidae family of nematodes, these bacteria are the causal agent of insect mortality during nematode infection, and are commonly used as biocontrol agents against pest insects in managed ecosystems. There are three described species of Photorhabdus; Photorhabdus luminescens and Photorhabdus temperata, which are strictly entomopathogens, and Photorhabdus asymbiotica, which has been isolated from wound infections in humans. While there has been extensive research on its virulence mechanisms, the evolution of virulence in Photorhabdus has not previously been investigated within a phylogenetic context. To investigate how virulence has evolved in this genus, we first reconstructed the phylogenetic relationships among 18 strains representing each of the main taxonomic lineages in the genus. Bacterial cells were injected into Galleria mellonella and Tenebrio molitor larvae, and the LT50 was calculated for each strain. These values were mapped onto the phylogeny using ancestral character reconstruction methods. With few exceptions, we found that the general trend of Photorhabdus evolution is one of increasing virulence. We also explored the relationship between virulence and Photorhabdus cell types and growth rates. Although we found no correlation between cell type and virulence, there was a strong correlation between virulence and growth rates in T. molitor. A better understanding of the origin and maintenance of virulence in this bacterium will aid in unraveling the mechanisms of the Heterorhabditis-Photorhabdus complex, resulting in the selection of more effective nematode-bacterium complexes for biocontrol.

Global changes in processing of mRNA 3' untranslated regions characterize clinically distinct cancer subtypes.

Molecular cancer diagnostics are an important clinical advance in cancer management, but new methods are still needed. In this context, gene expression signatures obtained by microarray represent a useful molecular diagnostic. Here, we describe novel probe-level microarray analyses that reveal connections between mRNA processing and neoplasia in multiple tumor types, with diagnostic potential. We now show that characteristic differences in mRNA processing, primarily in the 3'-untranslated region, define molecular signatures that can distinguish similar tumor subtypes with different survival characteristics, with at least 74% accuracy. Using a mouse model of B-cell leukemia/lymphoma, we find that differences in transcript isoform abundance are likely due to both alternative polyadenylation (APA) and differential degradation. While truncation of the 3'-UTR is the most common observed pattern, genes with elongated transcripts were also observed, and distinct groups of affected genes are found in related but distinct tumor types. Genes with elongated transcripts are overrepresented in ontology categories related to cell-cell adhesion and morphology. Analysis of microarray data from human primary tumor samples revealed similar phenomena. Western blot analysis of selected proteins confirms that changes in the 3'-UTR can correlate with changes in protein expression. Our work suggests that alternative mRNA processing, particularly APA, can be a powerful molecular biomarker with prognostic potential. Finally, these findings provide insights into the molecular mechanisms of gene deregulation in tumorigenesis.

Complex oncogenic translocations with gene amplification are initiated by specific DNA breaks in lymphocytes.

Chromosomal instability is a hallmark of many tumor types. Complex chromosomal rearrangements with associated gene amplification, known as complicons, characterize many hematologic and solid cancers. Whereas chromosomal aberrations, including complicons, are useful diagnostic and prognostic cancer markers, their molecular origins are not known. Although accumulating evidence has implicated DNA double-strand break repair in suppression of oncogenic genome instability, the genomic elements required for chromosome rearrangements, especially complex lesions, have not been elucidated. Using a mouse model of B-lineage lymphoma, characterized by complicon formation involving the immunoglobulin heavy chain (Igh) locus and the c-myc oncogene, we have now investigated the requirement for specific genomic segments as donors for complex rearrangements. We now show that specific DNA double-strand breaks, occurring within a narrow segment of Igh, are necessary to initiate complicon formation. By contrast, neither specific DNA breaks nor the powerful intronic enhancer Emu are required for complicon-independent oncogenesis. This study is the first to delineate mechanisms of complex versus simple instability and the first to identify specific chromosomal elements required for complex chromosomal aberrations. These findings will illuminate genomic cancer susceptibility and risk factors.