Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum.

Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a common and clinically distinct form of familial spastic paraplegia that is linked to the SPG11 locus on chromosome 15 in most affected families. We analyzed 12 ARHSP-TCC families, refined the SPG11 candidate interval and identified ten mutations in a previously unidentified gene expressed ubiquitously in the nervous system but most prominently in the cerebellum, cerebral cortex, hippocampus and pineal gland. The mutations were either nonsense or insertions and deletions leading to a frameshift, suggesting a loss-of-function mechanism. The identification of the function of the gene will provide insight into the mechanisms leading to the degeneration of the corticospinal tract and other brain structures in this frequent form of ARHSP

Visual classification of feral cat Felis silvestris catus vocalizations

Cat vocal behavior, in particular, the vocal and social behavior of feral cats, is poorly understood, as are the differences between feral and fully domestic cats. The relationship between feral cat social and vocal behavior is important because of the markedly different ecology of feral and domestic cats, and enhanced comprehension of the repertoire and potential information content of feral cat calls can provide both better understanding of the domestication and socialization process, and improved welfare for feral cats undergoing adoption. Previous studies have used conflicting classification schemes for cat vocalizations, often relying on onomatopoeic or popular descriptions of call types (e.g., “miow”). We studied the vocalizations of 13 unaltered domestic cats that complied with our behavioral definition used to distinguish feral cats from domestic. A total of 71 acoustic units were extracted and visually analyzed for the construction of a hierarchical classification of vocal sounds, based on acoustic properties. We identified 3 major categories (tonal, pulse, and broadband) that further breakdown into 8 subcategories, and show a high degree of reliability when sounds are classified blindly by independent observers (Fleiss’ Kappa $K$ = 0.863). Due to the limited behavioral contexts in this study, additional subcategories of cat vocalizations may be identified in the future, but our hierarchical classification system allows for the addition of new categories and new subcategories as they are described. This study shows that cat vocalizations are diverse and complex, and provides an objective and reliable classification system that can be used in future studies

Magnetic Field Evolution in Accreting White Dwarfs

We discuss the evolution of the magnetic field of an accreting white dwarf. We first show that the timescale for ohmic decay in the liquid interior is 8 to 12 billion years for a dipole field, and 4 to 6 billion years for a quadrupole field. We then compare the timescales for ohmic diffusion and accretion at different depths in the star, and for a simplified field structure and spherical accretion, calculate the time-dependent evolution of the global magnetic field at different accretion rates. In this paper, we neglect mass loss by classical nova explosions and assume the white dwarf mass increases with time. In this case, the field structure in the outer layers of the white dwarf is significantly modified for accretion rates above the critical rate (1-5) x 10^(-10) solar masses per year. We consider the implications of our results for observed systems. We propose that accretion-induced magnetic field changes are the missing evolutionary link between AM Her systems and intermediate polars. The shorter ohmic decay time for accreting white dwarfs provides a partial explanation of the lack of accreting systems with 10^9 G fields. In rapidly accreting systems such as supersoft X-ray sources, amplification of internal fields by compression may be important for Type Ia supernova ignition and explosion. Finally, spreading matter in the polar cap may induce complexity in the surface magnetic field, and explain why the more strongly accreting pole in AM Her systems has a weaker field. We conclude with speculations about the field evolution when classical nova explosions cause the white dwarf mass to decrease with time.Comment: To appear in MNRAS (15 pages, 10 figures); minor revision

Structural and biochemical characterization of the exopolysaccharide deacetylase Agd3 required for Aspergillus fumigatus biofilm formation

The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Deletion of a gene encoding a putative deacetylase, Agd3, leads to defects in GAG deacetylation, biofilm formation, and virulence. Here, we show that Agd3 deacetylates GAG in a metal-dependent manner, and is the founding member of carbohydrate esterase family CE18. The active site is formed by four catalytic motifs that are essential for activity. The structure of Agd3 includes an elongated substrate-binding cleft formed by a carbohydrate binding module (CBM) that is the founding member of CBM family 87. Agd3 homologues are encoded in previously unidentified putative bacterial exopolysaccharide biosynthetic operons and in other fungal genomes. The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Here, the authors study an A. fumigatus enzyme that deacetylates GAG in a metal-dependent manner and constitutes a founding member of a new carbohydrate esterase family.Bio-organic Synthesi

Death-associated protein 3 is overexpressed in human thyroid oncocytic tumours

Background: The human death-associated protein 3 (hDAP3) is a GTP-binding constituent of the small subunit of the mitochondrial ribosome with a pro-apoptotic function.Methods: A search through publicly available microarray data sets showed 337 genes potentially coregulated with the DAP3 gene. The promoter sequences of these 337 genes and 70 out of 85 mitochondrial ribosome genes were analysed in silico with the DAP3 gene promoter sequence. The mitochondrial role of DAP3 was also investigated in the thyroid tumours presenting various mitochondrial contents. Results: The study revealed nine transcription factors presenting enriched motifs for these gene promoters, five of which are implicated in cellular growth (ELK1, ELK4, RUNX1, HOX11-CTF1, TAL1-ternary complex factor 3) and four in mitochondrial biogenesis (nuclear respiratory factor-1 (NRF-1), GABPA, PPARG-RXRA and estrogen-related receptor alpha (ESRRA)). An independent microarray data set showed the overexpression of ELK1, RUNX1 and ESRRA in the thyroid oncocytic tumours. Exploring the thyroid tumours, we found that DAP3 mRNA and protein expression is upregulated in tumours presenting a mitochondrial biogenesis compared with the normal tissue. ELK1 and ESRRA were also showed upregulated with DAP3. Conclusion: ELK1 and ESRRA may be considered as potential regulators of the DAP3 gene expression. DAP3 may participate in mitochondrial maintenance and play a role in the balance between mitochondrial homoeostasis and tumourigenesis

Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease

Missing Data in Randomized Clinical Trials for Weight Loss: Scope of the Problem, State of the Field, and Performance of Statistical Methods

BACKGROUND: Dropouts and missing data are nearly-ubiquitous in obesity randomized controlled trails, threatening validity and generalizability of conclusions. Herein, we meta-analytically evaluate the extent of missing data, the frequency with which various analytic methods are employed to accommodate dropouts, and the performance of multiple statistical methods. METHODOLOGY/PRINCIPAL FINDINGS: We searched PubMed and Cochrane databases (2000-2006) for articles published in English and manually searched bibliographic references. Articles of pharmaceutical randomized controlled trials with weight loss or weight gain prevention as major endpoints were included. Two authors independently reviewed each publication for inclusion. 121 articles met the inclusion criteria. Two authors independently extracted treatment, sample size, drop-out rates, study duration, and statistical method used to handle missing data from all articles and resolved disagreements by consensus. In the meta-analysis, drop-out rates were substantial with the survival (non-dropout) rates being approximated by an exponential decay curve (e(-lambdat)) where lambda was estimated to be .0088 (95% bootstrap confidence interval: .0076 to .0100) and t represents time in weeks. The estimated drop-out rate at 1 year was 37%. Most studies used last observation carried forward as the primary analytic method to handle missing data. We also obtained 12 raw obesity randomized controlled trial datasets for empirical analyses. Analyses of raw randomized controlled trial data suggested that both mixed models and multiple imputation performed well, but that multiple imputation may be more robust when missing data are extensive. CONCLUSION/SIGNIFICANCE: Our analysis offers an equation for predictions of dropout rates useful for future study planning. Our raw data analyses suggests that multiple imputation is better than other methods for handling missing data in obesity randomized controlled trials, followed closely by mixed models. We suggest these methods supplant last observation carried forward as the primary method of analysis

Periodic trends and easy estimation of relative stabilities in 11-vertex nido-p-block-heteroboranes and -borates

Density functional theory computations were carried out for 11-vertex nido-p-block-hetero(carba)boranes and -borates containing silicon, germanium, tin, arsenic, antimony, sulfur, selenium and tellurium heteroatoms. A set of quantitative values called “estimated energy penalties” was derived by comparing the energies of two reference structures that differ with respect to one structural feature only. These energy penalties behave additively, i.e., they allow us to reproduce the DFT-computed relative stabilities of 11-vertex nido-heteroboranes in general with good accuracy and to predict the thermodynamic stabilities of unknown structures easily. Energy penalties for neighboring heteroatoms (HetHet and HetHet′) decrease down the group and increase along the period (indirectly proportional to covalent radii). Energy penalties for a five- rather than four-coordinate heteroatom, [Het5k(1) and Het5k(2)], generally, increase down group 14 but decrease down group 16, while there are mixed trends for group 15 heteroatoms. The sum of HetHet′ energy penalties results in different but easily predictable open-face heteroatom positions in the thermodynamically most stable mixed heterocarbaboranes and -borates with more than two heteroatoms

Discovery of a black smoker vent field and vent fauna at the Arctic Mid-Ocean Ridge

The Arctic Mid-Ocean Ridge (AMOR) represents one of the most slow-spreading ridge systems on Earth. Previous attempts to locate hydrothermal vent fields and unravel the nature of venting, as well as the provenance of vent fauna at this northern and insular termination of the global ridge system, have been unsuccessful. Here, we report the first discovery of a black smoker vent field at the AMOR. The field is located on the crest of an axial volcanic ridge (AVR) and is associated with an unusually large hydrothermal deposit, which documents that extensive venting and long-lived hydrothermal systems exist at ultraslow-spreading ridges, despite their strongly reduced volcanic activity. The vent field hosts a distinct vent fauna that differs from the fauna to the south along the Mid-Atlantic Ridge. The novel vent fauna seems to have developed by local specialization and by migration of fauna from cold seeps and the Pacific

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation