Alteration-weakening leading to localized deformation in a damage aureole adjacent to a dormant shear zone

Deformation adjacent to faults and shear zones is traditionally thought to correlate with slip. Inherited structures may control damage geometry, localizing fluid flow and deformation in a damage aureole around structures, even after displacement has ceased. In this paper we document a post-shearing anastomosing foliation and fracture network that developed to one side of the Mesoarchean Marmion Shear Zone. This fracture network hosts the low-grade, disseminated Hammond Reef gold deposit. The shear zone juxtaposed a greenstone belt against tonalite gneiss and was locked by an intrusion that was emplaced during the final stages of suturing. After cessation of activity, fluids channeled along fault- and intrusion-related fractures led to the pervasive sericitization of feldspars. Foliated zones resulted from flattening in the weaker sericite-rich tonalite during progressive alteration without any change in the regional NW-SE shortening direction. The anastomosing pattern may have been inherited from an earlier ductile fabric, but sericite alteration and flattening fabrics all formed post-shearing. Thus, the apparent foliated fracture network adjacent to the Marmion Shear Zone is a second-order effect of shear-related damage, distinct in time from shear activity, adjacent to an effectively dormant shear zone. This phenomenon has implications for understanding the relative timing of fault zone activity, alteration and (in this case) gold mineralization related to long-term fault zone permeability

<i>Salmonella</i>succinate utilisation is inhibited by multiple regulatory systems

AbstractSuccinate is a potent immune signalling molecule that is present in the mammalian gut and within macrophages. Both of these niches are colonised by the pathogenic bacteriumSalmonella entericaserovar Typhimurium during infection. Succinate is a C4-dicarboyxlate that can serve as a source of carbon for bacteria. When succinate is provided as the sole carbon source forin vitrocultivation,Salmonellaand other enteric bacteria exhibit a slow growth rate and a long lag phase. This growth inhibition phenomenon was known to involve the sigma factor RpoS, but the genetic basis of the repression of bacterial succinate utilisation was poorly understood. Here, we used an experimental evolution approach to isolate fast-growing mutants during growth ofS. Typhimurium on succinate containing minimal medium.Our approach reveals novel RpoS-independent systems that inhibit succinate utilisation. The CspC RNA binding protein restricts succinate utilisation, an inhibition that is antagonised by high levels of the small regulatory RNA (sRNA) OxyS. We discovered that the Fe-S cluster regulatory protein IscR inhibits succinate utilisation by repressing the C4-dicarboyxlate transporter DctA.The RNA chaperone Hfq, the exoribonuclease PNPase and their cognate sRNAs function together to repress succinate utilisationviaRpoS induction. Furthermore, the ribose operon repressor RbsR is required for the complete RpoS-driven repression of succinate utilisation, suggesting a novel mechanism of RpoS regulation.Our discoveries shed light on redundant regulatory systems that tightly regulate the utilisation of succinate. We propose that the control of central carbon metabolism by multiple regulatory systems inSalmonellagoverns the infection niche-specific utilisation of succinate.</jats:p

MultiSig: a new high-precision approach to the analysis of complex biomolecular systems

MultiSig is a newly developed mode of analysis of sedimentation equilibrium (SE) experiments in the analytical ultracentrifuge, having the capability of taking advantage of the remarkable precision (~0.1 % of signal) of the principal optical (fringe) system employed, thus supplanting existing methods of analysis through reducing the ‘noise’ level of certain important parameter estimates by up to orders of magnitude. Long-known limitations of the SE method, arising from lack of knowledge of the true fringe number in fringe optics and from the use of unstable numerical algorithms such as numerical differentiation, have been transcended. An approach to data analysis, akin to ‘spatial filtering’, has been developed, and shown by both simulation and practical application to be a powerful aid to the precision with which near-monodisperse systems can be analysed, potentially yielding information on protein-solvent interaction. For oligo- and poly-disperse systems the information returned includes precise average mass distributions over both cell radial and concentration ranges and mass-frequency histograms at fixed radial positions. The application of MultiSig analysis to various complex heterogenous systems and potentially multiply-interacting carbohydrate oligomers is described

Public health surveillance in the UK revolutionises our understanding of the invasive Salmonella Typhimurium epidemic in Africa

Background:The ST313 sequence type ofSalmonellaTyphimurium causes invasive non-typhoidal salmonellosis and wasthought to be confined to sub-Saharan Africa. Two distinct phylogenetic lineages of African ST313 have been identified.Methods:We analysed the whole genome sequences ofS. Typhimurium isolates from UK patients that weregenerated following the introduction of routine whole-genome sequencing (WGS) ofSalmonella entericabyPublic Health England in 2014.Results:We found that 2.7% (84/3147) ofS. Typhimurium from patients in England and Wales were ST313 and wereassociated with gastrointestinal infection. Phylogenetic analysis revealed novel diversity of ST313 that distinguishedUK-linked gastrointestinal isolates from African-associated extra-intestinal isolates. The majority of genome degradationof African ST313 lineage 2 was conserved in the UK-ST313, but the African lineages carried a characteristic prophageand antibiotic resistance gene repertoire. These findings suggest that a strong selection pressure exists for certainhorizontally acquired genetic elements in the African setting. One UK-isolated lineage 2 strain that probably originatedin Kenya carried a chromosomally locatedblaCTX-M-15, demonstrating the continual evolution of this sequence type inAfrica in response to widespread antibiotic usage.Conclusions:The discovery of ST313 isolates responsible for gastroenteritis in the UK reveals new diversity in thisimportant sequence type. This study highlights thepower of routine WGS by public health agencies to makeepidemiologically significant deductions that would be missed by conventional microbiological methods. Wespeculate that the niche specialisation of sub-Saharan African ST313 lineages is driven in part by the acquisitionof accessory genome elements

Predictability of evolutionary trajectories in fitness landscapes

Experimental studies on enzyme evolution show that only a small fraction of all possible mutation trajectories are accessible to evolution. However, these experiments deal with individual enzymes and explore a tiny part of the fitness landscape. We report an exhaustive analysis of fitness landscapes constructed with an off-lattice model of protein folding where fitness is equated with robustness to misfolding. This model mimics the essential features of the interactions between amino acids, is consistent with the key paradigms of protein folding and reproduces the universal distribution of evolutionary rates among orthologous proteins. We introduce mean path divergence as a quantitative measure of the degree to which the starting and ending points determine the path of evolution in fitness landscapes. Global measures of landscape roughness are good predictors of path divergence in all studied landscapes: the mean path divergence is greater in smooth landscapes than in rough ones. The model-derived and experimental landscapes are significantly smoother than random landscapes and resemble additive landscapes perturbed with moderate amounts of noise; thus, these landscapes are substantially robust to mutation. The model landscapes show a deficit of suboptimal peaks even compared with noisy additive landscapes with similar overall roughness. We suggest that smoothness and the substantial deficit of peaks in the fitness landscapes of protein evolution are fundamental consequences of the physics of protein folding.Comment: 14 pages, 7 figure

Earthquake lubrication and healing explained by amorphous nanosilica

During earthquake propagation, geologic faults lose their strength, then strengthen as slip slows and stops. Many slip-weakening mechanisms are active in the upper-mid crust, but healing is not always well-explained. Here we show that the distinct structure and rate-dependent properties of amorphous nanopowder (not silica gel) formed by grinding of quartz can cause extreme strength loss at high slip rates. We propose a weakening and related strengthening mechanism that may act throughout the quartz-bearing continental crust. The action of two slip rate-dependent mechanisms offers a plausible explanation for the observed weakening: thermally-enhanced plasticity, and particulate flow aided by hydrodynamic lubrication. Rapid cooling of the particles causes rapid strengthening, and inter-particle bonds form at longer timescales. The timescales of these two processes correspond to the timescales of post-seismic healing observed in earthquakes. In natural faults, this nanopowder crystallizes to quartz over 10s–100s years, leaving veins which may be indistinguishable from common quartz veins

The Epstein-Barr Virus G-Protein-Coupled Receptor Contributes to Immune Evasion by Targeting MHC Class I Molecules for Degradation

Epstein-Barr virus (EBV) is a human herpesvirus that persists as a largely subclinical infection in the vast majority of adults worldwide. Recent evidence indicates that an important component of the persistence strategy involves active interference with the MHC class I antigen processing pathway during the lytic replication cycle. We have now identified a novel role for the lytic cycle gene, BILF1, which encodes a glycoprotein with the properties of a constitutive signaling G-protein-coupled receptor (GPCR). BILF1 reduced the levels of MHC class I at the cell surface and inhibited CD8+ T cell recognition of endogenous target antigens. The underlying mechanism involves physical association of BILF1 with MHC class I molecules, an increased turnover from the cell surface, and enhanced degradation via lysosomal proteases. The BILF1 protein of the closely related CeHV15 c1-herpesvirus of the Rhesus Old World primate (80% amino acid sequence identity) downregulated surface MHC class I similarly to EBV BILF1. Amongst the human herpesviruses, the GPCR encoded by the ORF74 of the KSHV c2-herpesvirus is most closely related to EBV BILF1 (15% amino acid sequence identity) but did not affect levels of surface MHC class I. An engineered mutant of BILF1 that was unable to activate G protein signaling pathways retained the ability to downregulate MHC class I, indicating that the immune-modulating and GPCR-signaling properties are two distinct functions of BILF1. These findings extend our understanding of the normal biology of an important human pathogen. The discovery of a third EBV lytic cycle gene that cooperates to interfere with MHC class I antigen processing underscores the importance of the need for EBV to be able to evade CD8+ T cell responses during the lytic replication cycle, at a time when such a large number of potential viral targets are expressed

Building capacity for HIV/AIDS program leadership and management in Uganda through mentored Fellowships

Background: Around the world, health professionals and program managers are leading and managing public and private health organizations with little or no formal management and leadership training and experience. Objective: To describe an innovative 2-year, long-term apprenticeship Fellowship training program implemented by Makerere University School of Public Health (MakSPH) to strengthen capacity for leadership and management of HIV/AIDS programs in Uganda. Implementation process: The program, which began in 2002, is a 2-year, full-time, non-degree Fellowship. It is open to Ugandan nationals with postgraduate training in health-related disciplines. Enrolled Fellows are attached to host institutions implementing HIV/AIDS programs and placed under the supervision of host institution and academic mentors. Fellows spend 75% of their apprenticeship at the host institutions while the remaining 25% is dedicated to didactic short courses conducted at MakSPH to enhance their knowledge base. Achievements: Overall, 77 Fellows have been enrolled since 2002. Of the 57 Fellows who were admitted between 2002 and 2008, 94.7% (54) completed the Fellowship successfully and 50 (92.3%) are employed in senior leadership and management positions in Uganda and internationally. Eighty-eight percent of those employed (44/54) work in institutions registered in Uganda, indicating a high level of in-country retention. Nineteen of the 20 Fellows who were admitted between 2009 and 2010 are still undergoing training. A total of 67 institutions have hosted Fellows since 2002. The host institutions have benefited through staff training and technical expertise from the Fellows as well as through grant support to Fellows to develop and implement innovative pilot projects. The success of the program hinges on support from mentors, stakeholder involvement, and the hands-on approach employed in training. Conclusion: The Fellowship Program offers a unique opportunity for hands-on training in HIV/AIDS program leadership and management for both Fellows and host institutions

Atomoxetine Enhances Connectivity of Prefrontal Networks in Parkinson's Disease.

Cognitive impairment is common in Parkinson's disease (PD), but often not improved by dopaminergic treatment. New treatment strategies targeting other neurotransmitter deficits are therefore of growing interest. Imaging the brain at rest ('task-free') provides the opportunity to examine the impact of a candidate drug on many of the brain networks that underpin cognition, while minimizing task-related performance confounds. We test this approach using atomoxetine, a selective noradrenaline reuptake inhibitor that modulates the prefrontal cortical activity and can facilitate some executive functions and response inhibition. Thirty-three patients with idiopathic PD underwent task-free fMRI. Patients were scanned twice in a double-blind, placebo-controlled crossover design, following either placebo or 40-mg oral atomoxetine. Seventy-six controls were scanned once without medication to provide normative data. Seed-based correlation analyses were used to measure changes in functional connectivity, with the right inferior frontal gyrus (IFG) a critical region for executive function. Patients on placebo had reduced connectivity relative to controls from right IFG to dorsal anterior cingulate cortex and to left IFG and dorsolateral prefrontal cortex. Atomoxetine increased connectivity from the right IFG to the dorsal anterior cingulate. In addition, the atomoxetine-induced change in connectivity from right IFG to dorsolateral prefrontal cortex was proportional to the change in verbal fluency, a simple index of executive function. The results support the hypothesis that atomoxetine may restore prefrontal networks related to executive functions. We suggest that task-free imaging can support translational pharmacological studies of new drug therapies and provide evidence for engagement of the relevant neurocognitive systems.This work was funded by the Wellcome trust (103838), Parkinson’s UK, National Institute for Health Research’s Cambridge Biomedical Research Centre and the Medical Research Council (MC_US_A060_0016 and RG62761) and the James F McDonnell Foundation (21st century science initiative on Understanding Human Cognition). The BCNI is supported by a joint award from the Wellcome Trust and Medical Research Council.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/npp.2016.1