Some discussions of D. Fearnhead and D. Prangle's Read Paper "Constructing summary statistics for approximate Bayesian computation: semi-automatic approximate Bayesian computation"

This report is a collection of comments on the Read Paper of Fearnhead and Prangle (2011), to appear in the Journal of the Royal Statistical Society Series B, along with a reply from the authors

Evaluation of a joint Bioinformatics and Medical Informatics international course in Peru

Background: New technologies that emerge at the interface of computational and biomedical science could drive new advances in global health, therefore more training in technology is needed among health care workers. To assess the potential for informatics training using an approach designed to foster interaction at this interface, the University of Washington and the Universidad Peruana Cayetano Heredia developed and assessed a one-week course that included a new Bioinformatics (BIO) track along with an established Medical/Public Health Informatics track (MI) for participants in Peru. Methods: We assessed the background of the participants, and measured the knowledge gained by track-specific (MI or BIO) 30-minute pre- and post-tests. Participants' attitudes were evaluated both by daily evaluations and by an end-course evaluation. Results: Forty-three participants enrolled in the course - 20 in the MI track and 23 in the BIO track. Of 20 questions, the mean % score for the MI track increased from 49.7 pre-test (standard deviation or SD = 17.0) to 59.7 (SD = 15.2) for the post-test (P = 0.002, n = 18). The BIO track mean score increased from 33.6 pre-test to 51.2 post-test (P less than 0.001, n = 21). Most comments (76%) about any aspect of the course were positive. The main perceived strength of the course was the quality of the speakers, and the main perceived weakness was the short duration of the course. Overall, the course acceptability was very good to excellent with a rating of 4.1 (scale 1-5), and the usefulness of the course was rated as very good. Most participants (62.9%) expressed a positive opinion about having had the BIO and MI tracks come together for some of the lectures. Conclusion: Pre- and post-test results and the positive evaluations by the participants indicate that this first joint Bioinformatics and Medical/Public Health Informatics (MI and BIO) course was a success.The University of Washington AMAUTA Global Training in Health Informatics, a Fogarty International Center/NIH funded grant (5D43TW007551), and the AMAUTA Research Practica Program, a Puget Sound Partners for Global Health-funded grant

The Second Transmembrane Domain of P2X7 Contributes to Dilated Pore Formation

Activation of the purinergic receptor P2X7 leads to the cellular permeability of low molecular weight cations. To determine which domains of P2X7 are necessary for this permeability, we exchanged either the C-terminus or portions of the second transmembrane domain (TM2) with those in P2X1 or P2X4. Replacement of the C-terminus of P2X7 with either P2X1 or P2X4 prevented surface expression of the chimeric receptor. Similarly, chimeric P2X7 containing TM2 from P2X1 or P2X4 had reduced surface expression and no permeability to cationic dyes. Exchanging the N-terminal 10 residues or C-terminal 14 residues of the P2X7 TM2 with the corresponding region of P2X1 TM2 partially restored surface expression and limited pore permeability. To further probe TM2 structure, we replaced single residues in P2X7 TM2 with those in P2X1 or P2X4. We identified multiple substitutions that drastically changed pore permeability without altering surface expression. Three substitutions (Q332P, Y336T, and Y343L) individually reduced pore formation as indicated by decreased dye uptake and also reduced membrane blebbing in response to ATP exposure. Three others substitutions, V335T, S342G, and S342A each enhanced dye uptake, membrane blebbing and cell death. Our results demonstrate a critical role for the TM2 domain of P2X7 in receptor function, and provide a structural basis for differences between purinergic receptors. © 2013 Sun et al

Stroke in urban and rural populations in north-east Bulgaria: incidence and case fatality findings from a 'hot pursuit' study

BACKGROUND: Bulgaria's official stroke mortality rates are higher for rural than urban areas. Official mortality data has indicated that these rates are amongst the highest in Europe. There has been a lack of studies measuring stroke incidence in urban and rural populations. METHODS: We established intensive notification networks covering 37791 residents in Varna city and 18656 residents (55% of them village-dwellers), all aged 45 to 84, in 2 rural districts. From May 1, 2000 to April 30, 2001 frequent contact was maintained with notifiers and death registrations were scanned regularly. Suspected incident strokes were assessed by study neurologists within a median of 8 days from onset. RESULTS: 742 events were referred for neurological assessment and 351 of these, which met the WHO criteria for stroke, were in persons aged 45 to 84 and were first ever in a lifetime. Incidence rates, standardised using the world standard weights for ages 45 to 84, were 909 (/100000/year) (95% CI 712–1105) and 597 (482–712) for rural and urban males and 667 (515–818) and 322 (248–395) for rural and urban females. Less than half were admitted to hospital (15% among rural females over 65). Twenty-eight day case fatality was 35% (123/351) overall and 48% (46/96) in village residents. The excess case fatality in the villages could not be explained by age or severity. CONCLUSIONS: Rural incidence rates were over twice those reported for western populations but the rate for urban females was similar to other western rates. The high level and marked heterogeneity in both stroke incidence and case fatality merit further investigation

Sensitivity to musical emotion is influenced by tonal structure in congenital amusia

Emotional communication in music depends on multiple attributes including psychoacoustic features and tonal system information, the latter of which is unique to music. The present study investigated whether congenital amusia, a lifelong disorder of musical processing, impacts sensitivity to musical emotion elicited by timbre and tonal system information. Twenty-six amusics and 26 matched controls made tension judgments on Western (familiar) and Indian (unfamiliar) melodies played on piano and sitar. Like controls, amusics used timbre cues to judge musical tension in Western and Indian melodies. While controls assigned significantly lower tension ratings to Western melodies compared to Indian melodies, thus showing a tonal familiarity effect on tension ratings, amusics provided comparable tension ratings for Western and Indian melodies on both timbres. Furthermore, amusics rated Western melodies as more tense compared to controls, as they relied less on tonality cues than controls in rating tension for Western melodies. The implications of these findings in terms of emotional responses to music are discussed

Aβ Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer

Anomalous self-assembly of the Aβ peptide into fibrillar amyloid deposits is strongly correlated with the development of Alzheimer's disease. Aβ fibril extension follows a template guided “dock and lock” mechanism where polymerisation is catalysed by the fibrillar ends. Using surface plasmon resonance (SPR) and quenched hydrogen-deuterium exchange NMR (H/D-exchange NMR), we have analysed the fibrillar structure and polymerisation properties of both the highly aggregation prone Aβ1–40 Glu22Gly (Aβ40Arc) and wild type Aβ1–40 (Aβ40WT). The solvent protection patterns from H/D exchange experiments suggest very similar structures of the fibrillar forms. However, through cross-seeding experiments monitored by SPR, we found that the monomeric form of Aβ40WT is significantly impaired to acquire the fibrillar architecture of Aβ40Arc. A detailed characterisation demonstrated that Aβ40WT has a restricted ability to dock and isomerise with high binding affinity onto Aβ40Arc fibrils. These results have general implications for the process of fibril assembly, where the rate of polymerisation, and consequently the architecture of the formed fibrils, is restricted by conformational constraints of the monomers. Interestingly, we also found that the kinetic rate of fibril formation rather than the thermodynamically lowest energy state determines the overall fibrillar structure

Hexokinase II Detachment from Mitochondria Triggers Apoptosis through the Permeability Transition Pore Independent of Voltage-Dependent Anion Channels

Type II hexokinase is overexpressed in most neoplastic cells, and it mainly localizes on the outer mitochondrial membrane. Hexokinase II dissociation from mitochondria triggers apoptosis. The prevailing model postulates that hexokinase II release from its mitochondrial interactor, the voltage-dependent anion channel, prompts outer mitochondrial membrane permeabilization and the ensuing release of apoptogenic proteins, and that these events are inhibited by growth factor signalling. Here we show that a hexokinase II N-terminal peptide selectively detaches hexokinase II from mitochondria and activates apoptosis. These events are abrogated by inhibiting two established permeability transition pore modulators, the adenine nucleotide translocator or cyclophilin D, or in cyclophilin D knock-out cells. Conversely, insulin stimulation or genetic ablation of the voltage-dependent anion channel do not affect cell death induction by the hexokinase II peptide. Therefore, hexokinase II detachment from mitochondria transduces a permeability transition pore opening signal that results in cell death and does not require the voltage-dependent anion channel. These findings have profound implications for our understanding of the pathways of outer mitochondrial membrane permeabilization and their inactivation in tumors

Predicting complexity perception of real world images

The aim of this work is to predict the complexity perception of real world images.We propose a new complexity measure where different image features, based on spatial, frequency and color properties are linearly combined. In order to find the optimal set of weighting coefficients we have applied a Particle Swarm Optimization. The optimal linear combination is the one that best fits the subjective data obtained in an experiment where observers evaluate the complexity of real world scenes on a web-based interface. To test the proposed complexity measure we have performed a second experiment on a different database of real world scenes, where the linear combination previously obtained is correlated with the new subjective data. Our complexity measure outperforms not only each single visual feature but also two visual clutter measures frequently used in the literature to predict image complexity. To analyze the usefulness of our proposal, we have also considered two different sets of stimuli composed of real texture images. Tuning the parameters of our measure for this kind of stimuli, we have obtained a linear combination that still outperforms the single measures. In conclusion our measure, properly tuned, can predict complexity perception of different kind of images

Intrinsically determined cell death of developing cortical interneurons

Cortical inhibitory circuits are formed by GABAergic interneurons, a cell population that originates far from the cerebral cortex in the embryonic ventral forebrain. Given their distant developmental origins, it is intriguing how the number of cortical interneurons is ultimately determined. One possibility, suggested by the neurotrophic hypothesis1-5, is that cortical interneurons are overproduced, and then following their migration into cortex, excess interneurons are eliminated through a competition for extrinsically derived trophic signals. Here we have characterized the developmental cell death of mouse cortical interneurons in vivo, in vitro, and following transplantation. We found that 40% of developing cortical interneurons were eliminated through Bax- (Bcl-2 associated X-) dependent apoptosis during postnatal life. When cultured in vitro or transplanted into the cortex, interneuron precursors died at a cellular age similar to that at which endogenous interneurons died during normal development. Remarkably, over transplant sizes that varied 200-fold, a constant fraction of the transplanted population underwent cell death. The death of transplanted neurons was not affected by the cell-autonomous disruption of TrkB (tropomyosin kinase receptor B), the main neurotrophin receptor expressed by central nervous system (CNS) neurons6-8. Transplantation expanded the cortical interneuron population by up to 35%, but the frequency of inhibitory synaptic events did not scale with the number of transplanted interneurons. Together, our findings indicate that interneuron cell death is intrinsically determined, either cell-autonomously, or through a population-autonomous competition for survival signals derived from other interneurons