Evidence for frequent incest in a cooperatively breeding mammal.

As breeding between relatives often results in inbreeding depression, inbreeding avoidance is widespread in the animal kingdom. However, inbreeding avoidance may entail fitness costs. For example, dispersal away from relatives may reduce survival. How these conflicting selection pressures are resolved is challenging to investigate, but theoretical models predict that inbreeding should occur frequently in some systems. Despite this, few studies have found evidence of regular incest in mammals, even in social species where relatives are spatio-temporally clustered and opportunities for inbreeding frequently arise. We used genetic parentage assignments together with relatedness data to quantify inbreeding rates in a wild population of banded mongooses, a cooperatively breeding carnivore. We show that females regularly conceive to close relatives, including fathers and brothers. We suggest that the costs of inbreeding avoidance may sometimes outweigh the benefits, even in cooperatively breeding species where strong within-group incest avoidance is considered to be the norm

A longitudinal, qualitative study exploring sustained adherence to a hand exercise programme for rheumatoid arthritis evaluated in the SARAH trial

This study explores the experience of participants taking part in a hand exercise programme for people with rheumatoid arthritis with a focus on adherence. The exercise programme was tested in a randomised controlled trial. This parallel qualitative study will inform future implementation into clinical practice.Twenty-seven semi-structured interviews from 14 participants were undertaken at two time points (4 and 12 months after randomisation). We collected data of participants' experiences over time. This was guided by an interview schedule. Interview data were analysed using interpretative phenomenological analysis which is informed by phenomenological and hermeneutic theory. We recruited participants from National Health Service rheumatology and therapy departments.At 4 months, 11/14 participants reported continuing with the exercises. By 12 months, 7/13 participants still reported exercising. The ability to establish a routine determined whether participants adhered to the exercise programme. This was sometimes influenced by practical issues. We also identified facilitators and barriers to regular exercise in the themes of the following: the therapeutic encounter, perceived benefit of exercises, attitude of mind, confidence, and unpredictability.Establishing a routine was an important step towards participants being able to exercise independently. Therapists provided participants with skills to continue to exercise while dealing with changes in symptoms and schedules. Potential barriers to long-term exercise adherence need to be taken into account and addressed for successful implementation of this programme. Implications for Rehabilitation Behavioural change components such as the use of an exercise planner (stating intentions of where, when and how), daily diary sheets, and joint goal setting enhance adherence to a hand exercise programme for RA by helping to establish routines. Exercise routines need to be flexible enough to fit in with life and symptom changes whilst delivering a sufficient dosage. Therapists facilitate this process by using behavioural components alongside more commonly used aspects of care (assessment, education, advice, and encouragement) to enable people with RA to become independent exercisers

Reproductive competition triggers mass eviction in cooperative banded mongooses

In many vertebrate societies, forced eviction of group members is an important determinant of population structure, but little is known about what triggers eviction. Three main explanations are (1) the reproductive competition hypothesis; (2) the coercion of cooperation hypothesis; and (3) the adaptive forced dispersal hypothesis. The last hypothesis proposes that dominant individuals use eviction as an adaptive strategy to propagate copies of their alleles through a highly structured population. We tested these hypotheses as explanations for eviction in cooperatively breeding banded mongooses (Mungos mungo), using a 16-year dataset on life history, behaviour and relatedness. In this species, groups of females, or mixed-sex groups, are periodically evicted en masse. Our evidence suggests that reproductive competition is the main ultimate trigger for eviction for both sexes. We find little evidence that mass eviction is used to coerce helping, or as a mechanism to force dispersal of relatives into the population. Eviction of females changes the landscape of reproductive competition for remaining males, which may explain why males are evicted alongside females. Our results show that the consequences of resolving within-group conflict resonate through groups and populations to affect population structure, with important implications for social evolution

Autopsy as an outcome and performance measure: three years of hospital autopsy as an instrument of clinical audit

An extensive literature documents a high prevalence of errors in clinical diagnosis discovered at autopsy. Multiple studies have suggested no significant decrease in these errors over time. Despite these findings, autopsies have dramatically decreased in frequency in the United States and many other countries. In 1994, the last year for which national U.S. data exist, the autopsy rate for all non-forensic deaths fell below 6%. The marked decline in autopsy rates from previous rates of 40\u201350% undoubtedly reflects various factors, including reimbursement issues, the attitudes of clinicians regarding the utility of autopsies in the setting of other diagnostic advances, and general unfamiliarity with the autopsy and techniques for requesting it, especially among physicians-in-training. The autopsy is valuable for its role in undergraduate and graduate medical education, the identification and characterization of new diseases, and contributions to the understanding of disease pathogenesis. Although extensive, these benefits are difficult to quantify. This review of the last three years of hospital autopsy in Lucca studied the more easily quantifiable benefits of the autopsy as a tool in performance measurement and improvement. Such benefits largely relate to the role of the autopsy in detecting errors in clinical diagnosis and unsuspected complications of treatment. It is hoped that characterizing the extent to which the autopsy provides data relevant to clinical performance measurement and improvement will help inform strategies for preserving the benefits of routinely obtained autopsies and for considering its wider use as an instrument for quality improvement

Phosphorylated Dihydroceramides from Common Human Bacteria Are Recovered in Human Tissues

Novel phosphorylated dihydroceramide (PDHC) lipids produced by the periodontal pathogen Porphyromonas gingivalis include phosphoethanolamine (PE DHC) and phosphoglycerol dihydroceramides (PG DHC) lipids. These PDHC lipids mediate cellular effects through Toll-like receptor 2 (TLR2) including promotion of IL-6 secretion from dendritic cells and inhibition of osteoblast differentiation and function in vitro and in vivo. The PE DHC lipids also enhance (TLR2)-dependent murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. The unique non-mammalian structures of these lipids allows for their specific quantification in bacteria and human tissues using multiple reaction monitoring (MRM)-mass spectrometry (MS). Synthesis of these lipids by other common human bacteria and the presence of these lipids in human tissues have not yet been determined. We now report that synthesis of these lipids can be attributed to a small number of intestinal and oral organisms within the Bacteroides, Parabacteroides, Prevotella, Tannerella and Porphyromonas genera. Additionally, the PDHCs are not only present in gingival tissues, but are also present in human blood, vasculature tissues and brain. Finally, the distribution of these TLR2-activating lipids in human tissues varies with both the tissue site and disease status of the tissue suggesting a role for PDHCs in human disease

Female reproductive competition explains variation in prenatal investment in wild banded mongooses

Female intrasexual competition is intense in cooperatively breeding species where offspring compete locally for resources and helpers. In mammals, females have been proposed to adjust prenatal investment according to the intensity of competition in the postnatal environment (a form of ‘predictive adaptive response’; PAR). We carried out a test of this hypothesis using ultrasound scanning of wild female banded mongooses in Uganda. In this species multiple females give birth together to a communal litter, and all females breed regularly from one year old. Total prenatal investment (size times the number of fetuses) increased with the number of potential female breeders in the group. This relationship was driven by fetus size rather than number. The response to competition was particularly strong in low weight females and when ecological conditions were poor. Increased prenatal investment did not trade off against maternal survival. In fact we found the opposite relationship: females with greater levels of prenatal investment had elevated postnatal maternal survival. Our results support the hypothesis that mammalian prenatal development is responsive to the intensity of postnatal competition. Understanding whether these responses are adaptive requires information on the long-term consequences of prenatal investment for offspring fitness

Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are pathogenic for familial Parkinson's disease. However, it is unknown whether levels of LRRK2 protein in the brain are altered in patients with LRRK2-associated Parkinson's disease. Because LRRK2 mutations are relatively rare, accounting for approximately 1% of all Parkinson's disease, we accessioned cases from five international brain banks to investigate levels of the LRRK2 protein, and other genetically associated Parkinson's disease proteins. Brain tissue was obtained from 17 LRRK2 mutation carriers (12 with the G2019S mutation and five with the I2020T mutation) and assayed by immunoblot. Compared to matched controls and idiopathic Parkinson's disease cases, we found levels of LRRK2 protein were reduced in the LRRK2 mutation cases. We also measured a decrease in two other proteins genetically implicated in Parkinson's disease, the core retromer component, vacuolar protein sorting associated protein 35 (VPS35), and the lysosomal hydrolase, glucocerebrosidase (GBA). Moreover, the classical retromer cargo protein, cation-independent mannose-6-phosphate receptor (MPR300, encoded by IGF2R), was also reduced in the LRRK2 mutation cohort and protein levels of the receptor were correlated to levels of LRRK2. These results provide new data on LRRK2 protein expression in brain tissue from LRRK2 mutation carriers and support a relationship between LRRK2 and retromer dysfunction in LRRK2-associated Parkinson's disease brain

Cerebellar Integrity in the Amyotrophic Lateral Sclerosis - Frontotemporal Dementia Continuum

Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology

The Explication Defence of Arguments from Reference

In a number of influential papers, Machery, Mallon, Nichols and Stich have presented a powerful critique of so-called arguments from reference, arguments that assume that a particular theory of reference is correct in order to establish a substantive conclusion. The critique is that, due to cross-cultural variation in semantic intuitions supposedly undermining the standard methodology for theorising about reference, the assumption that a theory of reference is correct is unjustified. I argue that the many extant responses to Machery et al.’s critique do little for the proponent of an argument from reference, as they do not show how to justify the problematic assumption. I then argue that it can in principle be justified by an appeal to Carnapian explication. I show how to apply the explication defence to arguments from reference given by Andreasen (for the biological reality of race) and by Churchland (against the existence of beliefs and desires)

pH control of conductance in a pyrazolyl Langmuir–Blodgett monolayer

In this contribution pyrazole is identified as an excellent anchor group that forms high quality films under pH controlled conditions, allowing the modulation of the electrical properties with a more efficient electronic coupling in basic conditions.</p