Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism

N-terminal acetylation of proteins is a widespread and highly conserved process. Aminoacylase 1 (ACY1; EC 3.5.14) is the most abundant of the aminoacylases, a class of enzymes involved in hydrolysis of N-acetylated proteins. Here, we present four children with genetic deficiency of ACY1. They were identified through organic acid analyses using gas chromatography-mass spectrometry, revealing increased urinary excretion of several N-acetylated amino acids, including the derivatives of methionine, glutamic acid, alanine, leucine, glycine, valine, and isoleucine. Nuclear magnetic resonance spectroscopy analysis of urine samples detected a distinct pattern of N-acetylated metabolites, consistent with ACY1 dysfunction. Functional analyses of patients' lymphoblasts demonstrated ACY1 deficiency. Mutation analysis uncovered recessive loss-of-function or missense ACY1 mutations in all four individuals affected. We conclude that ACY1 mutations in these children led to functional ACY1 deficiency and excretion of N-acetylated amino acids. Questions remain, however, as to the clinical significance of ACY1 deficiency. The ACY1-deficient individuals were ascertained through urine metabolic screening because of unspecific psychomotor delay (one subject), psychomotor delay with atrophy of the vermis and syringomyelia (one subject), marked muscular hypotonia (one subject), and follow-up for early treated biotinidase deficiency and normal clinical findings (one subject). Because ACY1 is evolutionarily conserved in fish, frog, mouse, and human and is expressed in the central nervous system (CNS) in human, a role in CNS function or development is conceivable but has yet to be demonstrated. Thus, at this point, we cannot state whether ACY1 deficiency has pathogenic significance with pleiotropic clinical expression or is simply a biochemical variant. Awareness of this new genetic entity may help both in delineating its clinical significance and in avoiding erroneous diagnoses.     

Wealth transmission and inequality among hunter-gatherers

We report quantitative estimates of intergenerational transmission and population-wide inequality for wealth measures in a set of hunter-gatherer populations. Wealth is defined broadly as factors that contribute to individual or household well-being, ranging from embodied forms such as weight and hunting success to material forms such household goods, as well as relational wealth in exchange partners. Intergenerational wealth transmission is low to moderate in these populations, but is still expected to have measurable influence on an individual's life chances. Wealth inequality (measured with Gini coefficients) is moderate for most wealth types, matching what qualitative ethnographic research has generally indicated (if not the stereotype of hunter-gatherers as extreme egalitarians). We discuss some plausible mechanisms for these patterns, and suggest ways in which future research could resolve questions about the role of wealth in hunter-gatherer social and economic life.     

GEOGRAPHIC VARIATION IN THE SONGS OF NEOTROPICAL SINGING MICE: TESTING THE RELATIVE IMPORTANCE OF DRIFT AND LOCAL ADAPTATION

Patterns of geographic variation in communication systems can provide insight into the processes that drive phenotypic evolution. Although work in birds, anurans, and insects demonstrates that acoustic signals are sensitive to diverse selective and stochastic forces, processes that shape variation in mammalian vocalizations are poorly understood. We quantified geographic variation in the advertisement songs of sister species of singing mice, montane rodents with a unique mode of vocal communication. We tested three hypotheses to explain spatial variation in the song of the lower altitude species, Scotinomys teguina: selection for species recognition in sympatry with congener, S. xerampelinus, acoustic adaptation to different environments, and stochastic divergence. Mice were sampled at seven sites in Costa Rica and Panamá; genetic distances were estimated from mitochondrial control region sequences, between‐site differences in acoustic environment were estimated from climatic data. Acoustic, genetic and geographic distances were all highly correlated in S. teguina, suggesting that population differentiation in song is largely shaped by genetic drift. Contrasts between interspecific genetic‐acoustic distances were significantly greater than expectations derived from intraspecific contrasts, indicating accelerated evolution of species‐specific song. We propose that, although much intraspecific acoustic variation is effectively neutral, selection has been important in shaping species differences in song.     

Cytokine-mediated β-cell damage in PARP-1-deficient islets

Poly(ADP)-ribose polymerase (PARP) is an abundant nuclear protein that is activated by DNA damage; once active, it modifies nuclear proteins through attachment of poly(ADP)-ribose units derived from β-nicotinamide adenine dinucleotide (NAD(+)). In mice, the deletion of PARP-1 attenuates tissue injury in a number of animal models of human disease, including streptozotocin-induced diabetes. Also, inflammatory cell signaling and inflammatory gene expression are attenuated in macrophages isolated from endotoxin-treated PARP-1-deficient mice. In this study, the effects of PARP-1 deletion on cytokine-mediated β-cell damage and macrophage activation were evaluated. There are no defects in inflammatory mediator signaling or inflammatory gene expression in macrophages and islets isolated from PARP-1-deficient mice. While PARP-1 deficiency protects islets against cytokine-induced islet cell death as measured by biochemical assays of membrane polarization, the genetic absence of PARP-1 does not effect cytokine-induced inhibition of insulin secretion or cytokine-induced DNA damage in islets. While PARP-1 deficiency appears to provide protection from cell death, it fails to provide protection against the inhibitory actions of cytokines on insulin secretion or the damaging actions on islet DNA integrity.     

Organizational Determinants of Interprofessional Collaboration in Integrative Health Care: Systematic Review of Qualitative Studies

Context

Inteprofessional collaboration (IPC) between biomedically trained doctors (BMD) and traditional, complementary and alternative medicine practitioners (TCAMP) is an essential element in the development of successful integrative healthcare (IHC) services. This systematic review aims to identify organizational strategies that would facilitate this process.

Methods

We searched 4 international databases for qualitative studies on the theme of BMD-TCAMP IPC, supplemented with a purposive search of 31 health services and TCAM journals. Methodological quality of included studies was assessed using published checklist. Results of each included study were synthesized using a framework approach, with reference to the Structuration Model of Collaboration.

Findings

Thirty-seven studies of acceptable quality were included. The main driver for developing integrative healthcare was the demand for holistic care from patients. Integration can best be led by those trained in both paradigms. Bridge-building activities, positive promotion of partnership and co-location of practices are also beneficial for creating bonding between team members. In order to empower the participation of TCAMP, the perceived power differentials need to be reduced. Also, resources should be committed to supporting team building, collaborative initiatives and greater patient access. Leadership and funding from central authorities are needed to promote the use of condition-specific referral protocols and shared electronic health records. More mature IHC programs usually formalize their evaluation process around outcomes that are recognized both by BMD and TCAMP.

Conclusions

The major themes emerging from our review suggest that successful collaborative relationships between BMD and TCAMP are similar to those between other health professionals, and interventions which improve the effectiveness of joint working in other healthcare teams with may well be transferable to promote better partnership between the paradigms. However, striking a balance between the different practices and preserving the epistemological stance of TCAM will remain the greatest challenge in successful integration.     

Intensity of the vaccine-elicited immune response determines tumor clearance.

Tumor Ag-specific vaccines used for cancer immunotherapy can generate specific CD8 responses detectable in PBMCs and in tumor-infiltrating lymphocytes. However, human studies have shown that detection of a systemic vaccine-induced response does not necessarily correlate with the occasional instances of tumor rejection. Because this discrepancy might partially be attributable to the genetic heterogeneity of human cancers, as well as to the immunosuppressive effects of previous treatments, we turned to a mouse model in which these variables could be controlled to determine whether a relationship exists between the strength of vaccine-induced immune responses and tumor rejection. We challenged mice with the beta-galactosidase (beta-gal)-expressing tumor cells, C25.F6, vaccinated them with beta-gal-carrying viral vectors, and used quantitative RT-PCR to measure the vaccine-induced immune response of splenocytes directly ex vivo. We found that the strength of the response increased with increasing doses of beta-gal-carrying vector and/or upon boosting with a heterologous beta-gal-carrying virus. Most importantly, we found that the strength of the detected immune response against this foreign Ag strongly correlated with reduction in the number of lung metastases. The results from this mouse model have major implications for the implementation of tumor vaccines in humans.     

The invertebrate communities associated with a Chrysanthemum coronarium-invaded coastal sage scrub area in Southern California

The escape of ornamental plants is a main pathway of invasion into many ecosystems. Non-native plants can alter basal resources and abiotic factors leading to effects that ripple throughout an ecosystem. Invertebrates mediate these effects—responding quickly to abiotic and primary producer changes and, in turn, influencing other species. Invasions are of particular concern in the coastal sage scrub ecosystems of Southern California, where habitat loss and urban encroachment increase invasive species propagule sources and decrease native community resistance. The introduced annual Chrysanthemum coronarium (crown daisy) is a common invader with largely undocumented community-level effects. Our study tested the relationships between the invasive Chrysanthemum and a coastal scrub invertebrate community using a field study at the Tijuana River Estuary. We found similar or lower abundances and diversity of canopy fauna in the presence of Chrysanthemum. Community composition dramatically differed, however, in the presence Chrysanthemum, which was associated with higher abundances of dipterans, wasps and flower beetles, and lower abundances of hemipterans and thysanopterans than native shrubs. Differences in communities were consistent at the species- and order-levels, and were associated with the generally greater plant biomass and shadier conditions afforded by the natives. This study reveals that even a proportionally small amount of Chrysanthemum may shift the invertebrate community through alterations of abiotic properties and plant biomass. We recommend that Chrysanthemum be removed at the first sign of invasion or that spread is prevented since effects on the invertebrate community are dramatic and occur quickly.