A Yersinia Effector with Enhanced Inhibitory Activity on the NF-κB Pathway Activates the NLRP3/ASC/Caspase-1 Inflammasome in Macrophages

A type III secretion system (T3SS) in pathogenic Yersinia species functions to translocate Yop effectors, which modulate cytokine production and regulate cell death in macrophages. Distinct pathways of T3SS-dependent cell death and caspase-1 activation occur in Yersinia-infected macrophages. One pathway of cell death and caspase-1 activation in macrophages requires the effector YopJ. YopJ is an acetyltransferase that inactivates MAPK kinases and IKKβ to cause TLR4-dependent apoptosis in naïve macrophages. A YopJ isoform in Y. pestis KIM (YopJKIM) has two amino acid substitutions, F177L and K206E, not present in YopJ proteins of Y. pseudotuberculosis and Y. pestis CO92. As compared to other YopJ isoforms, YopJKIM causes increased apoptosis, caspase-1 activation, and secretion of IL-1β in Yersinia-infected macrophages. The molecular basis for increased apoptosis and activation of caspase-1 by YopJKIM in Yersinia-infected macrophages was studied. Site directed mutagenesis showed that the F177L and K206E substitutions in YopJKIM were important for enhanced apoptosis, caspase-1 activation, and IL-1β secretion. As compared to YopJCO92, YopJKIM displayed an enhanced capacity to inhibit phosphorylation of IκB-α in macrophages and to bind IKKβ in vitro. YopJKIM also showed a moderately increased ability to inhibit phosphorylation of MAPKs. Increased caspase-1 cleavage and IL-1β secretion occurred in IKKβ-deficient macrophages infected with Y. pestis expressing YopJCO92, confirming that the NF-κB pathway can negatively regulate inflammasome activation. K+ efflux, NLRP3 and ASC were important for secretion of IL-1β in response to Y. pestis KIM infection as shown using macrophages lacking inflammasome components or by the addition of exogenous KCl. These data show that caspase-1 is activated in naïve macrophages in response to infection with a pathogen that inhibits IKKβ and MAPK kinases and induces TLR4-dependent apoptosis. This pro-inflammatory form of apoptosis may represent an early innate immune response to highly virulent pathogens such as Y. pestis KIM that have evolved an enhanced ability to inhibit host signaling pathways

YopJ-Induced Caspase-1 Activation in Yersinia-Infected Macrophages: Independent of Apoptosis, Linked to Necrosis, Dispensable for Innate Host Defense

Yersinia outer protein J (YopJ) is a type III secretion system (T3SS) effector of pathogenic Yersinia (Yersinia pestis, Yersinia enterocolitica and Yersinia pseudotuberculosis) that is secreted into host cells. YopJ inhibits survival response pathways in macrophages, causing cell death. Allelic variation of YopJ is responsible for differential cytotoxicity in Yersinia strains. YopJ isoforms in Y. enterocolitica O:8 (YopP) and Y. pestis KIM (YopJKIM) strains have high cytotoxic activity. In addition, YopJKIM-induced macrophage death is associated with caspase-1 activation and interleukin-1β (IL-1β secretion. Here, the mechanism of YopJKIM-induced cell death, caspase-1 activation, and IL-1β secretion in primary murine macrophages was examined. Caspase-3/7 activity was low and the caspase-3 substrate poly (ADP-ribose) polymerase (PARP) was not cleaved in Y. pestis KIM5-infected macrophages. In addition, cytotoxicity and IL-1β secretion were not reduced in the presence of a caspase-8 inhibitor, or in B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 homologous antagonist/killer (Bak) knockout macrophages, showing that YopJKIM-mediated cell death and caspase-1 activation occur independent of mitochondrial-directed apoptosis. KIM5-infected macrophages released high mobility group protein B1 (HMGB1), a marker of necrosis, and microscopic analysis revealed that necrotic cells contained active caspase-1, indicating that caspase-1 activation is associated with necrosis. Inhibitor studies showed that receptor interacting protein 1 (RIP1) kinase and reactive oxygen species (ROS) were not required for cytotoxicity or IL-β release in KIM5-infected macrophages. IL-1β secretion was reduced in the presence of cathepsin B inhibitors, suggesting that activation of caspase-1 requires cathepsin B activity. Ectopically-expressed YopP caused higher cytotoxicity and secretion of IL-1β in Y. pseudotuberculosis-infected macrophages than YopJKIM. Wild-type and congenic caspase 1 knockout C57BL/6 mice were equally susceptible to lethal infection with Y. pseudotuberculosis ectopically expressing YopP. These data suggest that YopJ-induced caspase-1 activation in Yersinia-infected macrophages is a downstream consequence of necrotic cell death and is dispensable for innate host resistance to a strain with enhanced cytotoxicity

'Biomedical nemesis? Critical deliberations with regard health and social care integration for social work with older people’

This document is the Accepted Manuscript version of a published work that appeared in final form in International Social Work. To access the final edited and published work see http://dx.doi.org/10.1177/0020872816651698.This paper questions ongoing moves towards integration into health care for social work with older people in the UK. Whilst potentially constructing clearer pathways to support integration risks reducing welfare provisions for a traditional low priority user group, while further extending privatisation. Integration models also understate the ideological impact of biomedical perspectives within health and social care domains, conflate roles and undermine the potential positive role of ‘holistic’ multi-agency care. Constructive social work for older people is likely to further dilute within aggressive integrated models of welfare: which will be detrimental for meeting many of the complex needs of ageing populations

Sensorless control of matrix converter-fed synchronous reluctance motor drives

This paper presents a sensorless control technique based on direct flux vector control (DFVC) method for synchronous reluctance (SyR) motor drives fed by a three-phase to three-phase matrix converter (MC). Rotor position is estimated based on active flux (AF) concept down to 50 [rpm]. Furthermore, the effect of nonlinear voltage errors of the MC is compensated, and a self-commissioning method capable of identifying the voltage error before compensation is presented and tested. The proposed drive combines the advantages of matrix converters and SyR motors in sensorless fashion, for application into a number of fields, spanning from compact drives for aviation to line-supplied drives for industry applications. Experimental results are provided to prove the feasibility of the proposed technique. ©2017 IEEE

Sensorless control of matrix converter-fed synchronous reluctance motor drives

This paper presents a sensorless control technique based on direct flux vector control (DFVC) method for synchronous reluctance (SyR) motor drives fed by a three-phase to three-phase matrix converter (MC). Rotor position is estimated based on active flux (AF) concept down to 50 [rpm]. Furthermore, the effect of nonlinear voltage errors of the MC is compensated, and a self-commissioning method capable of identifying the voltage error before compensation is presented and tested. The proposed drive combines the advantages of matrix converters and SyR motors in sensorless fashion, for application into a number of fields, spanning from compact drives for aviation to line-supplied drives for industry applications. Experimental results are provided to prove the feasibility of the proposed technique. ©2017 IEEE

The WHO START study: suicidal behaviors across different areas of the world

Background: The World Health Organization (WHO) study entitled Suicide Trends in At-Risk Territories (START) is an international multisite initiative that aims to stimulate suicide research and prevention across different areas of the globe. A central component of the study is the development of registration systems for fatal and nonfatal suicidal behaviors. Aims: This paper provides an overview of the data collected on suicidal behaviors from the participating locations in the START study. Method: Descriptive statistics on the data are presented in terms of age, sex, and method. Results: Agreater proportion of suicide deaths occurred among males. In all areas except the Philippines more females than males engaged in nonfatal suicidal behaviors. Compared to Australia, Italy, New Zealand, the Philippines, and Hong Kong SAR, in the Pacific Islands suicide most often occurs in younger age groups. Results indicate notable variations between countries in choice of method. A greater proportion of suicides occurred by hanging in Pacific Islands, while inhalation of carbon monoxide, use of firearms, ingestion of chemicals and poisons, and drug overdose were the most frequent methods of choice in other areas. Conclusion: The information drawn from this study demonstrates the enormous variation in suicidal behavior across the areas involved in the START Study. Further research is needed to assess the reliability of the established data-recording systems for suicidal behaviors. The baseline data established in START may allow the development of suicide prevention initiatives sensitive to variation in the profile of suicide across different locations. © 2013 Hogrefe Publishing

The who start study suicidal behaviors across different areas of the world

Background: The World Health Organization (WHO) study entitled Suicide Trends in At-Risk Territories (START) is an international multisite initiative that aims to stimulate suicide research and prevention across different areas of the globe. A central component of the study is the development of registration systems for fatal and nonfatal suicidal behaviors. Aims: This paper provides an overview of the data collected on suicidal behaviors from the participating locations in the START study. Method: Descriptive statistics on the data are presented in terms of age, sex, and method. Results: Agreater proportion of suicide deaths occurred among males. In all areas except the Philippines more females than males engaged in nonfatal suicidal behaviors. Compared to Australia, Italy, New Zealand, the Philippines, and Hong Kong SAR, in the Pacific Islands suicide most often occurs in younger age groups. Results indicate notable variations between countries in choice of method. A greater proportion of suicides occurred by hanging in Pacific Islands, while inhalation of carbon monoxide, use of firearms, ingestion of chemicals and poisons, and drug overdose were the most frequent methods of choice in other areas. Conclusion: The information drawn from this study demonstrates the enormous variation in suicidal behavior across the areas involved in the START Study. Further research is needed to assess the reliability of the established data-recording systems for suicidal behaviors. The baseline data established in START may allow the development of suicide prevention initiatives sensitive to variation in the profile of suicide across different locations. © 2013 Hogrefe Publishing