Subversion of actin dynamics by EspM effectors of attaching and effacing bacterial pathogens

Rho GTPases are common targets of bacterial toxins and type III secretion system effectors. IpgB1 and IpgB2 of Shigella and Map of enteropathogenic (EPEC) and enterohemorrhagic (EHEC) Escherichia coli were recently grouped together on the basis that they share a conserved WxxxE motif. In this study, we characterized six WxxxE effectors from attaching and effacing pathogens: TrcA and EspM1 of EPEC strain B171, EspM1 and EspM2 of EHEC strain Sakai and EspM2 and EspM3 of Citrobacter rodentium. We show that EspM2 triggers formation of global parallel stress fibres, TrcA and EspM1 induce formation of localized parallel stress fibres and EspM3 triggers formation of localized radial stress fibres. Using EspM2 and EspM3 as model effectors, we report that while substituting the conserved Trp with Ala abolished activity, conservative Trp to Tyr or Glu to Asp substitutions did not affect stress-fibre formation. We show, using dominant negative constructs and chemical inhibitors, that the activity of EspM2 and EspM3 is RhoA and ROCK-dependent. Using Rhotekin pull-downs, we have shown that EspM2 and EspM3 activate RhoA; translocation of EspM2 and EspM3 triggered phosphorylation of cofilin. These results suggest that the EspM effectors modulate actin dynamics by activating the RhoA signalling pathway

Progressive transformation of a flux rope to an ICME

The solar wind conditions at one astronomical unit (AU) can be strongly disturbed by the interplanetary coronal mass ejections (ICMEs). A subset, called magnetic clouds (MCs), is formed by twisted flux ropes that transport an important amount of magnetic flux and helicity which is released in CMEs. At 1 AU from the Sun, the magnetic structure of MCs is generally modeled neglecting their expansion during the spacecraft crossing. However, in some cases, MCs present a significant expansion. We present here an analysis of the huge and significantly expanding MC observed by the Wind spacecraft during 9 and 10 November, 2004. After determining an approximated orientation for the flux rope using the minimum variance method, we precise the orientation of the cloud axis relating its front and rear magnetic discontinuities using a direct method. This method takes into account the conservation of the azimuthal magnetic flux between the in- and out-bound branches, and is valid for a finite impact parameter (i.e., not necessarily a small distance between the spacecraft trajectory and the cloud axis). Moreover, using the direct method, we find that the ICME is formed by a flux rope (MC) followed by an extended coherent magnetic region. These observations are interpreted considering the existence of a previous larger flux rope, which partially reconnected with its environment in the front. These findings imply that the ejected flux rope is progressively peeled by reconnection and transformed to the observed ICME (with a remnant flux rope in the front part).Comment: Solar Physics (in press

International Consortium for Health Outcomes Measurement (ICHOM): Standardized Patient-Centered Outcomes Measurement Set for Heart Failure Patients

Whereas multiple national, international, and trial registries for heart failure have been created, international standards for clinical assessment and outcome measurement do not currently exist. The working group's objective was to facilitate international comparison in heart failure care, using standardized parameters and meaningful patient-centered outcomes for research and quality of care assessments. The International Consortium for Health Outcomes Measurement recruited an international working group of clinical heart failure experts, researchers, and patient representatives to define a standard set of outcomes and risk-adjustment variables. This was designed to document, compare, and ultimately improve patient care outcomes in the heart failure population, with a focus on global feasibility and relevance. The working group employed a Delphi process, patient focus groups, online patient surveys, and multiple systematic publications searches. The process occurred over 10 months, employing 7 international teleconferences. A 17-item set has been established, addressing selected functional, psychosocial, burden of care, and survival outcome domains. These measures were designed to include all patients with heart failure, whether entered at first presentation or subsequent decompensation, excluding cardiogenic shock. Sources include clinician report, administrative data, and validated patient-reported outcome measurement tools: the Kansas City Cardiomyopathy Questionnaire; the Patient Health Questionnaire-2; and the Patient-Reported Outcomes Measurement Information System. Recommended data included those to support risk adjustment and benchmarking across providers and regions. The International Consortium for Health Outcomes Measurement developed a dataset designed to capture, compare, and improve care for heart failure, with feasibility and relevance for patients and clinicians worldwide

Main Cause of the Poloidal Plasma Motion Inside a Magnetic Cloud Inferred from Multiple-Spacecraft Observations

Although the dynamical evolution of magnetic clouds (MCs) has been one of the foci of interplanetary physics for decades, only few studies focus on the internal properties of large-scale MCs. Recent work by Wang et al. (J. Geophys. Res.120, 1543, 2015) suggested the existence of the poloidal plasma motion in MCs. However, the main cause of this motion is not clear. In order to find it, we identify and reconstruct the MC observed by the Solar Terrestrial Relations Observatory (STEREO)-A, Wind, and STEREO-B spacecraft during 19 – 20 November 2007 with the aid of the velocity-modified cylindrical force-free flux-rope model. We analyze the plasma velocity in the plane perpendicular to the MC axis. It is found that there was evident poloidal motion at Wind and STEREO-B, but this was not clear at STEREO-A, which suggests a local cause rather than a global cause for the poloidal plasma motion inside the MC. The rotational directions of the solar wind and MC plasma at the two sides of the MC boundary are found to be consistent, and the values of the rotational speeds of the solar wind and MC plasma at the three spacecraft show a rough correlation. All of these results illustrate that the interaction with ambient solar wind through viscosity might be one of the local causes of the poloidal motion. Additionally, we propose another possible local cause: the existence of a pressure gradient in the MC. The significant difference in the total pressure at the three spacecraft suggests that this speculation is perhaps correct

Vibrio parahaemolyticus, enterotoxigenic Escherichia coli, enterohemorrhagic Escherichia coli and Vibrio cholerae

This review highlighted the following: (i) pathogenic mechanism of the thermostable direct hemolysin produced by Vibrio parahaemolyticus, especially on its cardiotoxicity, (ii) heat-labile and heat-stable enterotoxins produced by enterotoxigenic Escherichia coli, especially structure–activity relationship of heat-stable enterotoxin, (iii) RNA N-glycosidase activity of Vero toxins (VT1 and VT2) produced by enterohemorrhagic Escherichia coli O157:H7, (iv) discovery of Vibrio cholerae O139, (v) isolation of new variant of Vibrio cholerae O1 El Tor that carries classical ctxB, and production of high concentration of cholera toxin by these strains, and (vi) conversion of viable but nonculturable (VBNC) Vibrio cholerae to culturable state by co-culture with eukaryotic cells

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele