Jumble Java Byte Code to Measure the Effectiveness of Unit Tests

Jumble is a byte code level mutation testing tool for Java which inter-operates with JUnit. It has been designed to operate in an industrial setting with large projects. Heuristics have been included to speed the checking of mutations, for example, noting which test fails for each mutation and running this first in subsequent mutation checks. Significant effort has been put into ensuring that it can test code which uses custom class loading and reflection. This requires careful attention to class path handling and coexistence with foreign class-loaders. Jumble is currently used on a continuous basis within an agile programming environment with approximately 370,000 lines of Java code under source control. This checks out project code every fifteen minutes and runs an incremental set of unit tests and mutation tests for modified classes. Jumble is being made available as open source

Defective Synaptic Plasticity in a Model of Coffin-Lowry Syndrome Is Rescued by Simultaneously Targeting PKA and MAPK Pathways

Empirical and computational methods were combined to examine whether individual or dual-drug treatments can restore the deficit in long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse observed in a cellular model of Coffin–Lowry syndrome (CLS). The model was produced by pharmacological inhibition of p90 ribosomal S6 kinase (RSK) activity. In this model, coapplication of an activator of the mitogen-activated protein kinase (MAPK) isoform ERK and an activator of protein kinase A (PKA) resulted in enhanced phosphorylation of RSK and enhanced LTF to a greater extent than either drug alone and also greater than their additive effects, which is termed synergism. The extent of synergism appeared to depend on another MAPK isoform, p38 MAPK. Inhibition of p38 MAPK facilitated serotonin (5-HT)-induced RSK phosphorylation, indicating that p38 MAPK inhibits activation of RSK. Inhibition of p38 MAPK combined with activation of PKA synergistically activated both ERK and RSK. Our results suggest that cellular models of disorders that affect synaptic plasticity and learning, such as CLS, may constitute a useful strategy to identify candidate drug combinations, and that combining computational models with empirical tests of model predictions can help explain synergism of drug combinations

Dynamics and Mechanisms of ERK Activation after Different Protocols that Induce Long-Term Synaptic Facilitation in Aplysia

Phosphorylation of the MAPK family member extracellular signal–regulated kinase (ERK) is required to induce long-term synaptic plasticity, but little is known about its persistence. We examined ERK activation by three protocols that induce long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse – the standard protocol (five 5-min pulses of 5-HT with interstimulus intervals (ISIs) of 20 min), the enhanced protocol (five pulses with irregular ISIs, which induces greater and longer-lasting LTF) and the two-pulse protocol (two pulses with ISI 45 min). Immunofluorescence revealed complex ERK activation. The standard and two-pulse protocols immediately increased active, phosphorylated ERK (pERK), which decayed within 5 h. A second wave of increased pERK was detected 18 h post-treatment for all protocols. This late phase was blocked by inhibitors of protein kinase A, TrkB and TGF-β. These results suggest that complex interactions among kinase pathways and growth factors contribute to the late increase of pERK. ERK activity returned to basal 24 h after the standard or two-pulse protocols, but remained elevated 24 h for the enhanced protocol. This 24-h elevation was also dependent on PKA and TGF-β, and partly on TrkB. These results begin to characterize long-lasting ERK activation, plausibly maintained by positive feedback involving growth factors and PKA, that appears essential to maintain LTF and LTM. Because many processes involved in LTF and late LTP are conserved among Aplysia and mammals, these findings highlight the importance of examining the dynamics of kinase cascades involved in vertebrate long-term memory

Sentence Repetition in Deaf Children with Specific Language Impairment in British Sign Language

Children with specific language impairment (SLI) perform poorly on sentence repetition tasks across different spoken languages, but until now, this methodology has not been investigated in children who have SLI in a signed language. Users of a natural sign language encode different sentence meanings through their choice of signs and by altering the sequence and inflections of these signs. Grammatical information is expressed through movement and configurational changes of the hands and face. The visual modality thus influences how grammatical morphology and syntax are instantiated. How would language impairment impact on the acquisition of these types of linguistic devices in child signers? We investigated sentence repetition skills in a group of 11 deaf children who display SLI in British Sign Language (BSL) and 11 deaf controls with no language impairment who were matched for age and years of BSL exposure. The SLI group was significantly less accurate on an overall accuracy score, and they repeated lexical items, overall sentence meaning, sign order, facial expressions, and verb morphological structures significantly less accurately than controls. This pattern of language deficits is consistent with the characterization of SLI in spoken languages even though expression is in a different modality. We conclude that explanations of SLI, and of poor sentence repetition by children with this disorder, must be able to account for both the spoken and signed modalities

Stellar Collisions During Binary-Binary and Binary-Single Star Interactions

Physical collisions between stars occur frequently in dense star clusters, either via close encounters between two single stars, or during strong dynamical interactions involving binary stars. Here we study stellar collisions that occur during binary-single and binary-binary interactions, by performing numerical scattering experiments. Our results include cross sections, branching ratios, and sample distributions of parameters for various outcomes. For interactions of hard binaries containing main-sequence stars, we find that the normalized cross section for at least one collision to occur (between any two of the four stars involved) is essentially unity, and that the probability of collisions involving more than two stars is significant. Hydrodynamic calculations have shown that the effective radius of a collision product can be 2-30 times larger than the normal main-sequence radius for a star of the same total mass. We study the effect of this expansion, and find that it increases the probability of further collisions considerably. We discuss these results in the context of recent observations of blue stragglers in globular clusters with masses exceeding twice the main-sequence turnoff mass. We also present Fewbody, a new, freely available numerical toolkit for simulating small-N gravitational dynamics that is particularly suited to performing scattering experiments.Comment: Accepted for publication in MNRAS; 29 pages, 22 figures, 7 table

Metastatic colorectal cancer outcomes by age among ARCAD first- and second-line Clinical trials

Background We evaluated the time to progression (TTP) and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared with younger adults following progression on first-line clinical trials. Methods Associations between clinical and disease characteristics, time to initial progression, and rate of receipt of second-line therapy were evaluated. TTP and overall survival (OS) were compared between older and younger adults in first- and second-line trials by Cox regression, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, number of metastatic sites and presence of metastasis in the lung, liver, or peritoneum. All statistical tests were 2-sided. Results Older adults comprised 16.4% of patients on first-line trials (870 total older adults aged >70 years; 4419 total younger adults aged ≤70 years, on first-line trials). Older adults and those with Eastern Cooperative Oncology Group Performance Status >0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariable analysis (odds ratio = 1.11, 95% confidence interval = 1.02 to 1.21, P = .01). Older and younger adults enrolled in second-line trials experienced similar median TTP and median OS (median TTP = 5.1 vs 5.2 months, respectively; median OS = 11.6 vs 12.4 months, respectively). Conclusions Older adults were less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes vs younger adults following second-line therapy. Further study should examine factors affecting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide better criteria regarding the risks and benefits of second-line therapy

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Alzheimer's Therapeutics Targeting Amyloid Beta 1-42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

Amyloid beta (Abeta) 1–42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics