Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis

Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of γ-secretase, cause familial Alzheimer’s disease (fAD). We hypothesized that mutations in PSEN1 reduce Notch signaling and alter neurogenesis. Expression data from developmental and adult neurogenesis show relative enrichment of Notch and γ-secretase expression in stem cells, whereas expression of APP and β-secretase is enriched in neurons. We observe premature neurogenesis in fAD iPSCs harboring PSEN1 mutations using two orthogonal systems: cortical differentiation in 2D and cerebral organoid generation in 3D. This is partly driven by reduced Notch signaling. We extend these studies to adult hippocampal neurogenesis in mutation-confirmed postmortem tissue. fAD cases show mutation-specific effects and a trend toward reduced abundance of newborn neurons, supporting a premature aging phenotype. Altogether, these results support altered neurogenesis as a result of fAD mutations and suggest that neural stem cell biology is affected in aging and disease

A highly obscured and strongly clustered galaxy population discovered with the Spitzer Space Telescope

The ~800 optically unseen (R>25.5) 24mum-selected sources in the complete Spitzer First Look Survey sample (Fadda et al. 2006) with F[24mum]>0.35 mJy are found to be very strongly clustered. If, as indicated by several lines of circumstantial evidence, they are ultraluminous far-IR galaxies at z ~ [1.6-2.7], the amplitude of their spatial correlation function is very high. The associated comoving clustering length is estimated to be r_0=14.0_{-2.4}^{+2.1} Mpc, value which puts these sources amongst the most strongly clustered populations of our known universe. Their 8mum-24mum colours suggest that the AGN contribution dominates above F[24mum] ~ 0.8 mJy, consistent with earlier analyses. The properties of these objects (number counts, redshift distribution, clustering amplitude) are fully consistent with those of proto-spheroidal galaxies in the process of forming most of their stars and of growing their active nucleus, as described by the Granato et al. (2004) model. In particular, the inferred space density of such galaxies at z ~ 2 is much higher than what expected from most semi-analytic models. Matches of the observed projected correlation function w(\theta) with models derived within the so-called Halo Occupation Scenario show that these sources have to be hosted by haloes more massive than ~10^{13.4} M_\odot. This value is significantly higher than that for the typical galactic haloes hosting massive elliptical galaxies, suggesting a duration of the starburst phase of massive high-redshift dusty galaxies of T_B ~ 0.5 Gyr.Comment: 14 pages, 10 figures, minor revisions, to appear on MNRA

Minimising barriers to dental care in older people

<p>Abstract</p> <p>Background</p> <p>Older people are increasingly retaining their natural teeth but at higher risk of oral disease with resultant impact on their quality of life. Socially deprived people are more at risk of oral disease and yet less likely to take up care. Health organisations in England and Wales are exploring new ways to commission and provide dental care services in general and for vulnerable groups in particular. This study was undertaken to investigate barriers to dental care perceived by older people in socially deprived inner city area where uptake of care was low and identify methods for minimising barriers in older people in support of oral health.</p> <p>Methods</p> <p>A qualitative dual-methodological approach, utilising both focus groups and individual interviews, was used in this research. Participants, older people and carers of older people, were recruited using purposive sampling through day centres and community groups in the inner city boroughs of Lambeth, Southwark and Lewisham in South London. A topic guide was utilised to guide qualitative data collection. Informants' views were recorded on tape and in field notes. The data were transcribed and analysed using Framework Methodology.</p> <p>Results</p> <p>Thirty-nine older people and/or their carers participated in focus groups. Active barriers to dental care in older people fell into five main categories: cost, fear, availability, accessibility and characteristics of the dentist. Lack of perception of a need for dental care was a common 'passive barrier' amongst denture wearers in particular. The cost of dental treatment, fear of care and perceived availability of dental services emerged to influence significantly dental attendance. Minimising barriers involves three levels of action to be taken: individual actions (such as persistence in finding available care following identification of need), system changes (including reducing costs, improving information, ensuring appropriate timing and location of care, and good patient management) and societal issues (such as reducing isolation and loneliness). Older people appeared to place greater significance on system and societal change than personal action.</p> <p>Conclusion</p> <p>Older people living within the community in an inner city area where NHS dental care is available face barriers to dental care. Improving access to care involves actions at individual, societal and system level. The latter includes appropriate management of older people by clinicians, policy change to address NHS charges; consideration of when, where and how dental care is provided; and clear information for older people and their carers on available local dental services, dental charges and care pathways.</p

The PEP survey: clustering of infrared-selected galaxies and structure formation at z~2 in the GOODS South

ABRIDGED-This paper presents the first direct estimate of the 3D clustering properties of far-infrared sources up to z~3. This has been possible thanks to the Pacs Evolutionary Probe (PEP) survey of the GOODS South field performed with the PACS instrument onboard the Herschel Satellite. An analysis of the two-point correlation function over the whole redshift range spanned by the data reports for the correlation length, r_0~6.3 Mpc and r_0~6.7 Mpc, respectively at 100um and 160um, corresponding to dark matter halo masses M>~10^{12.4} M_sun. Objects at z~2 instead seem to be more strongly clustered, with r_0~19 Mpc and r_0~17 Mpc in the two considered PACS channels. This dramatic increase of the correlation length between z~1 and z~2 is connected with the presence of a wide, M>~10^{14} M_sun, filamentary structure which includes more than 50% of the sources detected at z~2. An investigation of the properties of such sources indicates the possibility for boosted star-forming activity in those which reside within the overdense environment with respect of more isolated galaxies found in the same redshift range. Lastly, we also present our results on the evolution of the relationship between luminous and dark matter in star-forming galaxies between z~1 and z~2. We find that the increase of (average) stellar mass in galaxies between z~1 and z~2 is about a factor 10 lower than that of the dark matter haloes hosting such objects ([z~1]/[z~2] ~ 0.4 vs M_{halo}[z~1]/M_{halo}[z~2] ~ 0.04). Our findings agree with the evolutionary picture of downsizing whereby massive galaxies at z~2 were more actively forming stars than their z~1 counterparts, while at the same time contained a lower fraction of their mass in the form of luminous matter.Comment: 14 pages, 8 figures, MNRAS accepte

Cell-free (RNA) and cell-associated (DNA) HIV-1 and postnatal transmission through breastfeeding

&lt;p&gt;Introduction - Transmission through breastfeeding remains important for mother-to-child transmission (MTCT) in resource-limited settings. We quantify the relationship between cell-free (RNA) and cell-associated (DNA) shedding of HIV-1 virus in breastmilk and the risk of postnatal HIV-1 transmission in the first 6 months postpartum.&lt;/p&gt; &lt;p&gt;Materials and Methods - Thirty-six HIV-positive mothers who transmitted HIV-1 by breastfeeding were matched to 36 non-transmitting HIV-1 infected mothers in a case-control study nested in a cohort of HIV-infected women. RNA and DNA were quantified in the same breastmilk sample taken at 6 weeks and 6 months. Cox regression analysis assessed the association between cell-free and cell-associated virus levels and risk of postnatal HIV-1 transmission.&lt;/p&gt; &lt;p&gt;Results - There were higher median levels of cell-free than cell-associated HIV-1 virus (per ml) in breastmilk at 6 weeks and 6 months. Multivariably, adjusting for antenatal CD4 count and maternal plasma viral load, at 6 weeks, each 10-fold increase in cell-free or cell-associated levels (per ml) was significantly associated with HIV-1 transmission but stronger for cell-associated than cell-free levels [2.47 (95% CI 1.33–4.59) vs. aHR 1.52 (95% CI, 1.17–1.96), respectively]. At 6 months, cell-free and cell-associated levels (per ml) in breastmilk remained significantly associated with HIV-1 transmission but was stronger for cell-free than cell-associated levels [aHR 2.53 (95% CI 1.64–3.92) vs. 1.73 (95% CI 0.94–3.19), respectively].&lt;/p&gt; &lt;p&gt;Conclusions - The findings suggest that cell-associated virus level (per ml) is more important for early postpartum HIV-1 transmission (at 6 weeks) than cell-free virus. As cell-associated virus levels have been consistently detected in breastmilk despite antiretroviral therapy, this highlights a potential challenge for resource-limited settings to achieve the UNAIDS goal for 2015 of eliminating vertical transmission. More studies would further knowledge on mechanisms of HIV-1 transmission and help develop more effective drugs during lactation.&lt;/p&gt

Plasma amyloid-β ratios in autosomal dominant Alzheimer's disease: the influence of genotype.

In-vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-beta peptides in disease pathogenesis, however less is known about the behaviour of these mutations in-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at-risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-beta42:38, 42:40 and 38:40 ratios between presenilin1 and amyloid precursor protein carriers. We examined the relationship between plasma and in-vitro models of amyloid-beta processing and tested for associations with parental age at onset. 39 participants were mutation carriers (28 presenilin1 and 11 amyloid precursor protein). Age- and sex-adjusted models showed marked differences in plasma amyloid-beta between genotypes: higher amyloid-beta42:38 in presenilin1 versus amyloid precursor protein (p < 0.001) and non-carriers (p < 0.001); higher amyloid-beta38:40 in amyloid precursor protein versus presenilin1 (p < 0.001) and non-carriers (p < 0.001); while amyloid-beta42:40 was higher in both mutation groups compared to non-carriers (both p < 0.001). Amyloid-beta profiles were reasonably consistent in plasma and cell lines. Within presenilin1, models demonstrated associations between amyloid-beta42:38, 42:40 and 38:40 ratios and parental age at onset. In-vivo differences in amyloid-beta processing between presenilin1 and amyloid precursor protein carriers provide insights into disease pathophysiology, which can inform therapy development

University teachers’ views of interprofessional learning and their role in achieving outcomes - a qualitative study

Over the past decade, there has been a rapid increase in higher education institutions offering opportunities for interprofessional learning (IPL) to their students. The literature presents a number of factors that contribute to effective IPL, including having trained facilitators that help optimise the learning process. Many of these IPL facilitators are university teachers and the literature provides us with some insight into their views of IPL. However, little is known about university teachers’ views about IPL and their role in supporting students in achieving outcomes linked to IPL during their own teaching; this paper explores these areas. University teachers, working with students in Norway and England who contribute to patients’ care pathway were purposively invited to join focus groups. Data collected from the teachers’ conversations during these focus groups were analysed to elicit the main themes. Findings show that university teachers have a wide range of views about IPL, its potential to enhance collaborative practice and care, and their role in helping students achieve outcomes linked to IPL. A key challenge appears to be whether IPL is “worth the struggle,” which emphasises the need for strong leadership in order to align pedagogical approaches in education and practice that strive to achieve agreed outcomes

The Magnitude and Kinetics of the Mucosal HIV-Specific CD8+ T Lymphocyte Response and Virus RNA Load in Breast Milk

BACKGROUND: The risk of postnatal HIV transmission is associated with the magnitude of the milk virus load. While HIV-specific cellular immune responses control systemic virus load and are detectable in milk, the contribution of these responses to the control of virus load in milk is unknown. METHODS: We assessed the magnitude of the immunodominant GagRY11 and subdominant EnvKY9-specific CD8+ T lymphocyte response in blood and milk of 10 A*3002+, HIV-infected Malawian women throughout the period of lactation and correlated this response to milk virus RNA load and markers of breast inflammation. RESULTS: The magnitude and kinetics of the HIV-specific CD8+ T lymphocyte responses were discordant in blood and milk of the right and left breast, indicating independent regulation of these responses in each breast. However, there was no correlation between the magnitude of the HIV-specific CD8+ T lymphocyte response and the milk virus RNA load. Further, there was no correlation between the magnitude of this response and markers of breast inflammation. CONCLUSIONS: The magnitude of the HIV-specific CD8+ T lymphocyte response in milk does not appear to be solely determined by the milk virus RNA load and is likely only one of the factors contributing to maintenance of low virus load in milk