Gut immune dysfunction through impaired innate pattern recognition receptor expression and gut microbiota dysbiosis in chronic SIV infection.

HIV targets the gut mucosa early in infection, causing immune and epithelial barrier dysfunction and disease progression. However, gut mucosal sensing and innate immune signaling through mucosal pattern recognition receptors (PRRs) during HIV infection and disease progression are not well defined. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model of AIDS, we found a robust increase in PRRs and inflammatory cytokine gene expression during the acute SIV infection in both peripheral blood and gut mucosa, coinciding with viral replication. PRR expression remained elevated in peripheral blood following the transition to chronic SIV infection. In contrast, massive dampening of PRR expression was detected in the gut mucosa, despite the presence of detectable viral loads. Exceptionally, expression of Toll-like receptor 4 (TLR4) and TLR8 was downmodulated and diverged from expression patterns for most other TLRs in the gut. Decreased mucosal PRR expression was associated with increased abundance of several pathogenic bacterial taxa, including Pasteurellaceae members, Aggregatibacter and Actinobacillus, and Mycoplasmataceae family. Early antiretroviral therapy led to viral suppression but only partial maintenance of gut PRRs and cytokine gene expression. In summary, SIV infection dampens mucosal innate immunity through PRR dysregulation and may promote immune activation, gut microbiota changes, and ineffective viral clearance

GUT theories from Calabi-Yau 4-folds with SO(10) Singularities

We consider an SO(10) GUT model from F-theory compactified on an elliptically fibered Calabi-Yau with a D5 singularity. To obtain the matter curves and the Yukawa couplings, we use a global description to resolve the singularity. We identify the vector and spinor matter representations and their Yukawa couplings and we explicitly build the G-fluxes in the global model and check the agreement with the semi-local results. As our bundle is of type SU(2k), some extra conditions need to be applied to match the fluxes.Comment: 27 page

Genetic relationships and evolution in Cucurbita pepo (pumpkin, squash, gourd) as revealed by simple sequence repeat polymorphisms

Genetic relationships among 104 accessions of Cucurbita pepo were assessed from polymorphisms in 134 SSR (microsatellite) and four SCAR loci, yielding a total of 418 alleles, distributed among all 20 linkage groups. Genetic distance values were calculated, a dendrogram constructed, and principal coordinate analyses conducted. The results showed 100 of the accessions as distributed among three clusters representing each of the recognized subspecies, pepo, texana, and fraterna. The remaining four accessions, all having very small, round, striped fruits, assumed central positions between the two cultivated subspecies, pepo and texana, suggesting that they are relicts of undescribed wild ancestors of the two domesticated subspecies. In both, subsp. texana and subsp. pepo, accessions belonging to the same cultivar-group (fruit shape) associated with one another. Within subsp. pepo, accessions grown for their seeds or that are generalists, used for both seed and fruit consumption, assumed central positions. Specialized accessions, grown exclusively for consumption of their young fruits, or their mature fruit flesh, or seed oil extraction, tended to assume outlying positions, and the different specializations radiated outward from the center in different directions. Accessions of the longest-fruited cultivar-group, Cocozelle, radiated bidirectionally, indicating independent selection events for long fruits in subsp. pepo probably driven by a common desire to consume the young fruits. Among the accessions tested, there was no evidence for crossing between subspecies after domestication

Overexpression of human kynurenine-3-monooxygenase protects against 3-hydroxykynurenine-mediated apoptosis through bidirectional non-linear feedback

Kynurenine 3-monooxygenase (KMO) is a critical regulator of inflammation. The preferred KMO substrate, kynurenine, is converted to 3-hydroxykynurenine (3HK), and this product exhibits cytotoxicity through mechanisms that culminate in apoptosis. Here, we report that overexpression of human KMO with orthotopic localisation to mitochondria creates a metabolic environment during which the cell exhibits increased tolerance for exogenous 3HK-mediated cellular injury. Using the selective KMO inhibitor Ro61-8048, we show that KMO enzyme function is essential for cellular protection. Pan-caspase inhibition with Z-VAD-FMK confirmed apoptosis as the mode of cell death. By defining expression of pathway components upstream and downstream of KMO, we observed alterations in other key kynurenine pathway components, particularly tryptophan-2,3-dioxygenase upregulation, through bidirectional nonlinear feedback. KMO overexpression also increased expression of inducible nitric oxide synthase (iNOS). These changes in gene expression are functionally relevant, because siRNA knockdown of the pathway components kynureninase and quinolinate phosphoribosyl transferase caused cells to revert to a state of susceptibility to 3HK-mediated apoptosis. In summary, KMO overexpression, and importantly KMO activity, have metabolic repercussions that fundamentally affect resistance to cell stress

Generalised Player Modelling : Why Artificial Intelligence in Games Should Incorporate Meaning, with a Formalism for so Doing

General game-playing artificial intelligence (AI) has recently seen important advances due to the various techniques known as ‘deep learning’. However, in terms of human-computer interaction, the advances conceal a major limitation: these algorithms do not incorporate any sense of what human players find meaningful in games. I argue that adaptive game AI will be enhanced by a generalised player model, because games are inherently human artefacts which require some encoding of the human perspective in order to respond naturally to individual players. The player model provides constraints on the adaptive AI, which allow it to encode aspects of what human players find meaningful. I propose that a general player model requires parameters for the subjective experience of play, including: player psychology, game structure, and actions of play. I argue that such a player model would enhance efficiency of per-game solutions, and also support study of game-playing by allowing (within-player) comparison between games, or (within-game) comparison between players (human and AI). Here we detail requirements for functional adaptive AI, arguing from first-principles drawn from games research literature, and propose a formal specification for a generalised player model based on our ‘Behavlets’ method for psychologically-derived player modelling.Peer reviewe

Partial sequencing of the bottle gourd genome reveals markers useful for phylogenetic analysis and breeding

<p>Abstract</p> <p>Background</p> <p>Bottle gourd [<it>Lagenaria siceraria </it>(Mol.) Standl.] is an important cucurbit crop worldwide. Archaeological research indicates that bottle gourd was domesticated more than 10,000 years ago, making it one of the earliest plants cultivated by man. In spite of its widespread importance and long history of cultivation almost nothing has been known about the genome of this species thus far.</p> <p>Results</p> <p>We report here the partial sequencing of bottle gourd genome using the 454 GS-FLX Titanium sequencing platform. A total of 150,253 sequence reads, which were assembled into 3,994 contigs and 82,522 singletons were generated. The total length of the non-redundant singletons/assemblies is 32 Mb, theoretically covering ~ 10% of the bottle gourd genome. Functional annotation of the sequences revealed a broad range of functional types, covering all the three top-level ontologies. Comparison of the gene sequences between bottle gourd and the model cucurbit cucumber (<it>Cucumis sativus</it>) revealed a 90% sequence similarity on average. Using the sequence information, 4395 microsatellite-containing sequences were identified and 400 SSR markers were developed, of which 94% amplified bands of anticipated sizes. Transferability of these markers to four other cucurbit species showed obvious decline with increasing phylogenetic distance. From analyzing polymorphisms of a subset of 14 SSR markers assayed on 44 representative China bottle gourd varieties/landraces, a principal coordinates (PCo) analysis output and a UPGMA-based dendrogram were constructed. Bottle gourd accessions tended to group by fruit shape rather than geographic origin, although in certain subclades the lines from the same or close origin did tend to cluster.</p> <p>Conclusions</p> <p>This work provides an initial basis for genome characterization, gene isolation and comparative genomics analysis in bottle gourd. The SSR markers developed would facilitate marker assisted breeding schemes for efficient introduction of desired traits.</p

The Latent Structure of Autistic Traits:A Taxometric, Latent Class and Latent Profile Analysis of the Adult Autism Spectrum Quotient

Autistic traits are widely thought to operate along a continuum. A taxometric analysis of Adult Autism Spectrum Quotient data was conducted to test this assumption, finding little support but identifying a high severity taxon. To understand this further, latent class and latent profile models were estimated that indicated the presence of six distinct subtypes: one with little probability of endorsing any autistic traits, one engaging in ‘systemising’ behaviours, three groups endorsing multiple components of Wing and Gould’s autistic triad, and a group similar in size and profile to the taxon previously identified. These analyses suggest the AQ (and potentially by extension autistic traits) have a categorical structure. These findings have important implications for the analysis and interpretation of AQ data

Is health-related quality of life associated with the risk of low-energy wrist fracture: a case-control study

<p>Abstract</p> <p>Background</p> <p>Some risk factors for low-energy wrist fracture have been identified. However, self-reported measures such as health-related quality of life (HRQOL) have not been examined as potential risk factors for wrist fracture. The aims of this study were to compare HRQOL prior to a low-energy wrist fracture in elderly patients (≥ 50 years) with HRQOL in age- and sex-matched controls, and to explore the association between HRQOL and wrist fracture after adjusting for known risk factors for fracture such as age, weight, osteoporosis and falls.</p> <p>Methods</p> <p>Patients with a low-energy wrist fracture (n = 181) and age- and sex-matched controls (n = 181) were studied. Shortly after fracture (median 10 days), patients assessed their HRQOL before fracture using the Short Form 36 (SF-36). Statistical tests included <it>t </it>tests and multivariate logistic regression analysis.</p> <p>Results</p> <p>Several dimensions of HRQOL were significantly associated with wrist fracture. The direction of the associations with wrist fracture varied between the different sub-dimensions of the SF-36. After controlling for demographic and clinical variables, higher scores on <it>general health </it>(odds ratio (OR) = 1.31, 95% confidence interval (CI) = 1.10–1.56), <it>bodily pain </it>(OR = 1.18, 95% CI = 1.03–1.34) and <it>mental health </it>(OR = 1.39, 95% CI = 1.09–1.79) were related to an increased chance of being a wrist fracture patient rather than a control. In contrast, higher scores on <it>physical role limitation </it>(OR = 0.87, 95% CI = 0.79–0.95) and <it>social function </it>(OR = 0.65, 95% CI 0.53–0.80) decreased this chance. Significant associations with wrist fracture were also found for living alone (OR = 1.91, 95% CI 1.07–3.4), low body mass index (BMI) (OR = 0.92, 95% CI 0.86–0.98), osteoporosis (OR = 3.30, 95% CI 1.67–6.50) and previous falls (OR = 2.01, 95% CI 1.16–3.49).</p> <p>Conclusion</p> <p>Wrist fracture patients perceive themselves to be as healthy as the controls before fracture. Our data indicate that patients with favourable and unfavourable HRQOL measures may be at increased risk of wrist fracture.</p