Default Mode Dynamics for Global Functional Integration.

UNLABELLED: The default mode network (DMN) has been traditionally assumed to hinder behavioral performance in externally focused, goal-directed paradigms and to provide no active contribution to human cognition. However, recent evidence suggests greater DMN activity in an array of tasks, especially those that involve self-referential and memory-based processing. Although data that robustly demonstrate a comprehensive functional role for DMN remains relatively scarce, the global workspace framework, which implicates the DMN in global information integration for conscious processing, can potentially provide an explanation for the broad range of higher-order paradigms that report DMN involvement. We used graph theoretical measures to assess the contribution of the DMN to global functional connectivity dynamics in 22 healthy volunteers during an fMRI-based n-back working-memory paradigm with parametric increases in difficulty. Our predominant finding is that brain modularity decreases with greater task demands, thus adapting a more global workspace configuration, in direct relation to increases in reaction times to correct responses. Flexible default mode regions dynamically switch community memberships and display significant changes in their nodal participation coefficient and strength, which may reflect the observed whole-brain changes in functional connectivity architecture. These findings have important implications for our understanding of healthy brain function, as they suggest a central role for the DMN in higher cognitive processing. SIGNIFICANCE STATEMENT: The default mode network (DMN) has been shown to increase its activity during the absence of external stimulation, and hence was historically assumed to disengage during goal-directed tasks. Recent evidence, however, implicates the DMN in self-referential and memory-based processing. We provide robust evidence for this network's active contribution to working memory by revealing dynamic reconfiguration in its interactions with other networks and offer an explanation within the global workspace theoretical framework. These promising findings may help redefine our understanding of the exact DMN role in human cognition.This research was supported by the Evelyn Trust (RUAG/018). In addition, DV received funding from the Yousef Jameel Academic Program; DKM is supported by the NIHR Cambridge Biomedical Centre (RCZB/004), and an NIHR Senior Investigator Award (RCZB/014), and EAS is funded by the Stephen Erskine Fellowship Queens’ College Cambridge.This is the author accepted manuscript. The final version is available from Society for Neuroscience via http://dx.doi.org/10.1523/JNEUROSCI.2135-15.201

Spectral Diversity in Default Mode Network Connectivity Reflects Behavioral State.

Default mode network (DMN) functional connectivity is thought to occur primarily in low frequencies (<0.1 Hz), resulting in most studies removing high frequencies during data preprocessing. In contrast, subtractive task analyses include high frequencies, as these are thought to be task relevant. An emerging line of research explores resting fMRI data at higher-frequency bands, examining the possibility that functional connectivity is a multiband phenomenon. Furthermore, recent studies suggest DMN involvement in cognitive processing; however, without a systematic investigation of DMN connectivity during tasks, its functional contribution to cognition cannot be fully understood. We bridged these concurrent lines of research by examining the contribution of high frequencies in the relationship between DMN and dorsal attention network at rest and during task execution. Our findings revealed that the inclusion of high frequencies alters between network connectivity, resulting in reduced anticorrelation and increased positive connectivity between DMN and dorsal attention network. Critically, increased positive connectivity was observed only during tasks, suggesting an important role for high-frequency fluctuations in functional integration. Moreover, within-DMN connectivity during task execution correlated with RT only when high frequencies were included. These results show that DMN does not simply deactivate during task execution and suggest active recruitment while performing cognitively demanding paradigms

Pragmatic factors of deontic reasoning

This thesis is concerned with pragmatic factors of deontic reasoning, namely scale of violation, aggravating and mitigating circumstances and power of source. Nine experiments are reported investigating deontic reasoning and judgement revision. Experiment 1 established scale of violation as a modifying factor of a working rule with an inferential reasoning task, however, the effects were not transferred to a deductive reasoning task in Experiment 2. Scale of violation and circumstances were found to influence the reasoning of motoring violations with a major offence and aggravating circumstances being rated as more serious and receiving greater fines than a minor offence or mitigating circumstances (Experiments 3 &amp; 4). These effects were also observed with a judgement revision task (Experiment 5). Power of source was included as an additional pragmatic factor and was found to influence the reasoning of conditional statements (Experiment 6), inducements (Experiment 7) and ratings of credibility and probability of outcomes (Experiment 8). The final study (Experiment 9) found significant effects for scale of violation / compliance and power of source within a judgement revision task. However, no difference was observed in the reasoning of superordinate and non-superordinate statements. The findings are explained in terms of the conditional probability hypothesis.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Strong environment X genotype interactions determine the fitness costs of antibiotic resistance in vitro and in an insect model of infection (article)

This is the author accepted manuscript. The final version is available from the American Society for Microbiology via the DOI in this record.The dataset associated with this article is located in ORE at: https://doi.org/10.24378/exe.2503The acquisition of antibiotic resistance commonly imposes fitness costs, a reduction in the fitness of bacteria in the absence of drugs. These costs have been primarily quantified using in vitro experiments and a small number of in vivo studies in mice, and it is commonly assumed that these diverse methods are consistent. Here, we used an insect model of infection to compare the fitness costs of antibiotic resistance in vivo relative to in vitro conditions. Experiments explored diverse mechanisms of resistance in a Gram-positive pathogen, Bacillus thuringiensis, and a Gram-negative intestinal symbiont, Enterobacter cloacae. Rifampicin resistance in B. thuringiensis showed fitness costs that were typically elevated in vivo, although these were modulated by genotype-environment interactions. In contrast, resistance to cefotaxime via de-repression of AmpC β-lactamase in E. cloacae resulted in undetectable costs in vivo or in vitro, while spontaneous resistance to nalidixic acid, and carriage of the IncP plasmid RP4, imposed costs that increased in vivo. Overall, fitness costs in vitro were a poor predictor of fitness costs in vivo because of strong genotype environment interactions throughout this study. Insect infections provide a cheap and accessible means of assessing fitness consequences of resistance mutations, data that is important to understand the evolution and spread of resistance. This study emphasizes that the fitness costs imposed by particular mutations or different modes of resistance are extremely variable, and that only a subset of these mutations are likely to be prevalent outside of the laboratory.Medical Research Council (MRC

Description and evaluation of GLOMAP-mode: a modal global aerosol microphysics model for the UKCA composition-climate model

A new version of the Global Model of Aerosol Processes (GLOMAP) is described, which uses a two-moment pseudo-modal aerosol dynamics approach rather than the original two-moment bin scheme. GLOMAP-mode simulates the multi-component global aerosol, resolving sulfate, sea-salt, dust, black carbon (BC) and particulate organic matter (POM), the latter including primary and biogenic secondary POM. Aerosol processes are simulated in a size-resolved manner including primary emissions, secondary particle formation by binary homogeneous nucleation of sulfuric acid and water, particle growth by coagulation, condensation and cloud-processing and removal by dry deposition, in-cloud and below-cloud scavenging. A series of benchmark observational datasets are assembled against which the skill of the model is assessed in terms of normalised mean bias (&lt;i&gt;b&lt;/i&gt;) and correlation coefficient (&lt;i&gt;R&lt;/i&gt;). Overall, the model performs well against the datasets in simulating concentrations of aerosol precursor gases, chemically speciated particle mass, condensation nuclei (CN) and cloud condensation nuclei (CCN). Surface sulfate, sea-salt and dust mass concentrations are all captured well, while BC and POM are biased low (but correlate well). Surface CN concentrations compare reasonably well in free troposphere and marine sites, but are underestimated at continental and coastal sites related to underestimation of either primary particle emissions or new particle formation. The model compares well against a compilation of CCN observations covering a range of environments and against vertical profiles of size-resolved particle concentrations over Europe. The simulated global burden, lifetime and wet removal of each of the simulated aerosol components is also examined and each lies close to multi-model medians from the AEROCOM model intercomparison exercise

Physicochemical analysis of rotavirus segment 11 supports a 'modified panhandle' structure and not the predicted alternative tRNA-like structure (TRLS)

.Rotaviruses are a major cause of acute gastroenteritis, which is often fatal in infants. The viral genome consists of 11 double-stranded RNA segments, but little is known about their cis-acting sequences and structural elements. Covariation studies and phylogenetic analysis exploring the potential structure of RNA11 of rotaviruses suggested that, besides the previously predicted "modified panhandle" structure, the 5' and 3' termini of one of the isoforms of the bovine rotavirus UKtc strain may interact to form a tRNA-like structure (TRLS). Such TRLSs have been identified in RNAs of plant viruses, where they are important for enhancing replication and packaging. However, using tRNA mimicry assays (in vitro aminoacylation and 3'- adenylation), we found no biochemical evidence for tRNA-like functions of RNA11. Capping, synthetic 3' adenylation and manipulation of divalent cation concentrations did not change this finding. NMR studies on a 5'- and 3'-deletion construct of RNA11 containing the putative intra-strand complementary sequences supported a predominant panhandle structure and did not conform to a cloverleaf fold despite the strong evidence for a predicted structure in this conserved region of the viral RNA. Additional viral or cellular factors may be needed to stabilise it into a form with tRNA-like properties