Damage tolerance of fully orthotropic laminates in compression

The compression after impact (CAI) strength of fully orthotropic composite laminates with up to 21 plies is presented, as analysed by an existing strip model. Candidate layups, which can be symmetric, anti-symmetric or non-symmetric, are preselected to exhibit no elastic coupling response, with manufacturing rules applied. These criteria, along with the use of a simple surrogate sublaminate buckling model, were chosen to allow analysis of all feasible laminates in the design space without excessive computation time. Results indicate that although the inclusion of non-symmetric layups in the design space does not give benefits with respect to maximum achievable damage tolerance, these laminates can exhibit damage tolerance close to that of an anti-symmetric design for some ply counts, and better than symmetric solutions in most cases. It is also noted that in some instances increasing the number of plies in a laminate can actually reduce the highest achievable threshold load for damage tolerance, as a result of the large influence Poisson’s ratio has on sublaminate buckling. Average errors in the surrogate model were low in all cases, with maximum non-conservative errors less than 1%. The surrogate buckling model reduced computational time by over 99% when compared to the fully exhaustive search

Nasal Congestion on the International Space Station

No abstract availabl

Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against Mycobacterium tuberculosis

Effective tuberculosis treatment requires at least 6 months of combination therapy. Alterations in the physiological state of the bacterium during infection are thought to reduce drug efficacy and prolong the necessary treatment period, but the nature of these adaptations remain incompletely defined. To identify specific bacterial functions that limit drug effects during infection, we employed a comprehensive genetic screening approach to identify mutants with altered susceptibility to the first-line antibiotics in the mouse model. We identified many mutations that increase the rate of bacterial clearance, suggesting new strategies for accelerating therapy. In addition, the drug-specific effects of these mutations suggested that different antibiotics are limited by distinct factors. Rifampin efficacy is inferred to be limited by cellular permeability, whereas isoniazid is preferentially affected by replication rate. Many mutations that altered bacterial clearance in the mouse model did not have an obvious effect on drug susceptibility using in vitro assays, indicating that these chemical-genetic interactions tend to be specific to the in vivo environment. This observation suggested that a wide variety of natural genetic variants could influence drug efficacy in vivo without altering behavior in standard drug-susceptibility tests. Indeed, mutations in a number of the genes identified in our study are enriched in drug-resistant clinical isolates, identifying genetic variants that may influence treatment outcome. Together, these observations suggest new avenues for improving therapy, as well as the mechanisms of genetic adaptations that limit it. IMPORTANCE Understanding how Mycobacterium tuberculosis survives during antibiotic treatment is necessary to rationally devise more effective tuberculosis (TB) chemotherapy regimens. Using genome-wide mutant fitness profiling and the mouse model of TB, we identified genes that alter antibiotic efficacy specifically in the infection environment and associated several of these genes with natural genetic variants found in drug-resistant clinical isolates. These data suggest strategies for synergistic therapies that accelerate bacterial clearance, and they identify mechanisms of adaptation to drug exposure that could influence treatment outcome

Comprehensive identification of host modulators of HIV-1 replication using multiple orthologous RNAi reagents

RNAi screens have implicated hundreds of host proteins as HIV-1 dependency factors (HDFs). While informative, these early studies overlap poorly due to false positives and false negatives. To ameliorate these issues, we combined information from the existing HDF screens together with new screens performed with multiple orthologous RNAi reagents (MORR). In addition to being traditionally validated, the MORR screens and the historical HDF screens were quantitatively integrated by the adaptation of an established analysis program, RIGER, for the collective interpretation of each gene\u27s phenotypic significance. False positives were addressed by the removal of poorly expressed candidates through gene expression filtering, as well as with GESS, which identifies off-target effects. This workflow produced a quantitatively integrated network of genes that modulate HIV-1 replication. We further investigated the roles of GOLGI49, SEC13, and COG in HIV-1 replication. Collectively, the MORR-RIGER method minimized the caveats of RNAi screening and improved our understanding of HIV-1-host cell interactions

The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male Mice

Female mice lacking ATRX in the pancreas have increased sensitivity to pancreatic cancer, whereas male mice without ATRX are protected. This study identifies such susceptibility in pancreatic cancer and highlights the need for sex-specific approaches in cancer treatment. BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in North America, accounting for \u3e30,000 deaths annually. Although somatic activating mutations in KRAS appear in 97% of PDAC patients, additional factors are required to initiate PDAC. Because mutations in genes encoding chromatin remodelling proteins have been implicated in KRAS-mediated PDAC, we investigated whether loss of chromatin remodeler.-thalassemia, mental-retardation, X-linked (ATRX) affects oncogenic KRAS\u27s ability to promote PDAC. ATRX affects DNA replication, repair, and gene expression and is implicated in other cancers including glioblastomas and pancreatic neuroendocrine tumors. The hypothesis was that deletion of Atrx in pancreatic acinar cells will increase susceptibility to injury and oncogenic METHODS: Mice allowing conditional loss of Atrx within pancreatic acinar cells were examined after induction of recurrent cerulein-induced pancreatitis or oncogenic KRAS (KRASG12D). Histologic, biochemical, and molecular analysis examined pancreatic pathologies up to 2 months after induction of Atrx deletion. RESULTS: Mice lacking Atrx showed more progressive damage, inflammation, and acinar-to-duct cell metaplasia in response to injury relative to wild-type mice. In combination with KRASG12D, Atrx-deficient acinar cells showed increased fibrosis, inflammation, progression to acinar-to-duct cell metaplasia, and pre-cancerous lesions relative to mice expressing only KRASG12D. This sensitivity appears only in female mice, mimicking a significant prevalence of ATRX mutations in human female PDAC patients. CONCLUSIONS: Our results indicate the absence of ATRX increases sensitivity to injury and oncogenic KRAS only in female mice. This is an instance of a sex-specific mutation that enhances oncogenic KRAS\u27s ability to promote pancreatic intraepithelial lesion formation

Wild to domestic and back again: the dynamics of fallow deer management in medieval England (c.11th-16th century AD)

This paper presents the results of the first comprehensive scientific study of the fallow deer, a non-native species whose medieval-period introduction to Britain transformed the cultural landscape. It brings together data from traditional zooarchaeological analyses with those derived from new ageing techniques as well as the results of a programme of radiocarbon dating, multi-element isotope studies and genetic analyses. These new data are here integrated with historical and landscape evidence to examine changing patterns of fallow deer translocation and management in medieval England between the 11th and 16th century AD

Statistical analysis of variability in TnSeq data across conditions using zero-inflated negative binomial regression

BACKGROUND: Deep sequencing of transposon mutant libraries (or TnSeq) is a powerful method for probing essentiality of genomic loci under different environmental conditions. Various analytical methods have been described for identifying conditionally essential genes whose tolerance for insertions varies between two conditions. However, for large-scale experiments involving many conditions, a method is needed for identifying genes that exhibit significant variability in insertions across multiple conditions. RESULTS: In this paper, we introduce a novel statistical method for identifying genes with significant variability of insertion counts across multiple conditions based on Zero-Inflated Negative Binomial (ZINB) regression. Using likelihood ratio tests, we show that the ZINB distribution fits TnSeq data better than either ANOVA or a Negative Binomial (in a generalized linear model). We use ZINB regression to identify genes required for infection of M. tuberculosis H37Rv in C57BL/6 mice. We also use ZINB to perform a analysis of genes conditionally essential in H37Rv cultures exposed to multiple antibiotics. CONCLUSIONS: Our results show that, not only does ZINB generally identify most of the genes found by pairwise resampling (and vastly out-performs ANOVA), but it also identifies additional genes where variability is detectable only when the magnitudes of insertion counts are treated separately from local differences in saturation, as in the ZINB model

London and beyond: essays in honour of Derek Keene

This volume contains selected papers from a major conference held in October 2008 to celebrate the 20th anniversary of the setting up of the Centre for Metropolitan History at the IHR, and the contribution of Professor Derek Keene to the Centre, the IHR and the wider world of scholarship. 'One of the pioneer volumes in the handsomely produced new Institute of Historical Research Conference series, this book serves as a fitting tribute to one of the most influential urban historians of our time.' - Ian Archer, Urban History, May 2013