The Leishmania major BBSome subunit BBS1 is essential for parasite virulence in the mammalian host

Bardet–Biedl syndrome (BBS) is a human genetic disorder with a spectrum of symptoms caused by primary cilium dysfunction. The disease is caused by mutations in one of at least 17 identified genes, of which seven encode subunits of the BBSome, a protein complex required for specific trafficking events to and from the primary cilium. The molecular mechanisms associated with BBSome function remain to be fully elucidated. Here, we generated null and complemented mutants of the BBSome subunit BBS1 in the protozoan parasite, Leishmania. In the absence of BBS1, extracellular parasites have no apparent defects in growth, flagellum assembly, motility or differentiation in vitro but there is accumulation of vacuole-like structures close to the flagellar pocket. Infectivity of these parasites for macrophages in vitro is reduced compared with wild-type controls but the null parasites retain the ability to differentiate to the intracellular amastigote stage. However, infectivity of BBS1 null parasites is severely compromised in a BALB/c mouse footpad model. We hypothesize that the absence of BBS1 in Leishmania leads to defects in specific trafficking events that affect parasite persistence in the host. This is the first report of an association between the BBSome complex and pathogen infectivity

Recall of a live and personally experienced eyewitness event by adults with autism spectrum disorder

The aim of the present study was to (a) extend previous eyewitness research in autism spectrum disorder (ASD) using a live and personally experienced event; (b) examine whether witnesses with ASD demonstrate a facilitative effect in memory for self- over other-performed actions; (c) explore source monitoring abilities by witnesses with ASD in discriminating who performed which actions within the event. Eighteen high-functioning adults with ASD and 18 age- and IQ-matched typical counterparts participated in a live first aid scenario in which they and the experimenter each performed a number of actions. Participants were subsequently interviewed for their memory of the event using a standard interview procedure with free recall followed by questioning. The ASD group recalled just as many correct details as the comparison group from the event overall, however they made more errors. This was the case across both free recall and questioning phases. Both groups showed a self-enactment effect across both interview phases, recalling more actions that they had performed themselves than actions that the experimenter had performed. However, the ASD group were more likely than their typical comparisons to confuse the source of self-performed actions in free recall, but not in questioning, which may indicate executive functioning difficulties with unsupported test procedures. Findings are discussed in terms of their theoretical and practical implications

Eyewitness Testimony in Autism Spectrum Disorder: A Review

Autism spectrum disorder (ASD) is estimated to affect around 1% of the population, and is characterised by impairments in social interaction, communication, and behavioural flexibility. A number of risk factors indicate that individuals with ASD may become victims or witnesses of crimes. In addition to their social and communication deficits, people with ASD also have very specific memory problems, which impacts on their abilities to recall eyewitnessed events. We begin this review with an overview of the memory difficulties that are experienced by individuals with ASD, before discussing the studies that have specifically examined eyewitness testimony in this group and the implications for investigative practice. Finally, we outline related areas that would be particularly fruitful for future research to explore

Response of Pseudomonas aeruginosa to the innate immune system-derived oxidants hypochlorous acid and hypothiocyanous acid

P. aeruginosa is an opportunistic pathogen that causes infections in immunocompromised hosts including chronic infections in the lungs of Cystic Fibrosis (CF) patients, which are ineffectively cleared by the host immune response and associated with a poor prognosis. The host’s innate immune cells produce reactive species to target the bacteria, including the neutrophil-derived oxidant hypochlorous acid (HOCl) and the epithelial cell-derived oxidant hypothiocyanous acid (HOSCN). Both systems are implicated in CF due to the proposed ion transport roles of the CF transmembrane conductance regulator (CFTR) channel, which is mutated in CF. CFTR is proposed to transport chloride ions into the phagosome, where they are required for HOCl production and to transport thiocyanate ions into the airway surface liquid where they form HOSCN. Little is known about how P. aeruginosa responds to and avoids being killed by these oxidants, therefore my thesis aimed to address this. A screening approach to determine PA14 transposon mutants with altered HOCl susceptibility was performed to reveal regulators involved in bacterial protection from HOCl. This identified regulators involved in methionine biosynthesis, catabolite repression, and antibiotic resistance, and demonstrated a role for the novel regulator HcsR, a homolog of the E. coli HOCl-sensor RclR, in HOCl protection. Characterisation of this regulator found that it binds to the promoter region of hcsA and responds specifically to HOCl and HOSCN stress, perhaps via oxidation of its redox-active residues; this results in its activation and expression of hcsA encoding a putative peroxiredoxin required for HOCl protection. Investigation of the HcsR regulon revealed that HcsR predominately regulates hcsA expression in response to HOCl. However it positively regulates 132 genes and negatively regulates 213 genes in response to HOSCN, including activation of pyocyanin and denitrification genes and repression of heat shock and Type III secretion system (T3SS) genes. Transcriptome profiling of P. aeruginosa following HOCl or HOSCN exposure revealed significant overlap in the bacterial response to these oxidants, including expression of T3SS, taurine transport systems, the MexEF-OprN multidrug efflux pump, and non-coding RNAs. These data indicate that the bacterial response to HOCl and HOSCN is multifaceted, with HcsR playing an essential role, and additionally involves various mechanisms involved in virulence factor production, metabolism, antibiotic resistance and repairing oxidised macromolecules. This work forms the foundation from which the importance of these mechanisms in protecting P. aeruginosa against these oxidants in the context of CF infection can be further explored.Open Acces

Is the Exchange Rate a Shock Absorber or a Source of Shocks? New Empirical Evidence

This paper analyses the role of the real exchange rate in a structural vector autoregression framework for the United Kingdom, Euro area, Japan, and Canada vis-a-vis the United States. A new identification strategy is proposed building on sign restrictions. The results are compared to the benchmark conventional approach of Clarida and Gali (1994) based on long-run zero restrictions. Although the restrictions are derived from the same theoretical model, the results are strikingly different. In contrast to the benchmark model, an important role for nominal shocks in explaining real exchange rate fluctuations is found. Hence, the exchange rate can rather be considered as a source of shocks instead of a shock absorber.

Accounting for the source of exchange rate movements: new evidence

This paper analyses the role of the real exchange rate in a structural vector autoregression framework for the United Kingdom, euro area, Japan and Canada versus the United States. A new identification strategy is proposed building on sign restrictions. The results are compared to the benchmark conventional approach of Clarida and Gali based on long-run zero restrictions. Although the restrictions are derived from the same theoretical model, the results are strikingly different. In contrast to the benchmark model, an important role for nominal shocks in explaining real exchange rate fluctuations is found.

Mindfulness based stress reduction for medical students: optimising student satisfaction and engagement

Background: Medical practitioners and students are at increased risk of a number of personal and psychological problems. Stress and anxiety due to work-load and study requirements are common and self-care methods are important in maintaining well-being. The current study examines perceptions of and satisfaction ratings with a mindfulness based stress reduction (MBSR) programme for 1st year (compulsory) and 2nd year (optional) Graduate Entry Medical School students. Methods: A mixed method pre and post study of Year 1 (n = 140) and Year 2 (n = 88) medical students completing a 7 week MBSR course compared student satisfaction ratings. Thematic analysis of feedback from the students on their perception of the course was also carried out. Results: Year 1 students (compulsory course) were less satisfied with content and learning outcomes than Year 2 students (optional course) (p < .0005). Thematic analysis of year 1 student feedback identified themes including great concept, poorly executed; and less discussion, more practice. Year 2 themes included session environment and satisfaction with tutors. Conclusions: The MBSR course was associated with high levels of satisfaction and positive feedback when delivered on an optional basis. Catering for the individual needs of the participant and promoting a safe environment are core elements of a successful self-care programme

Stimulation of a protease targeting the LRIM1/APL1C complex reveals specificity in complement-like pathway activation in Anopheles gambiae.

The complement-like pathway of the African malaria mosquito Anopheles gambiae provides protection against infection by diverse pathogens. A functional requirement for a core set of proteins during infections by rodent and human malaria parasites, bacteria, and fungi suggests a similar mechanism operates against different pathogens. However, the extent to which the molecular mechanisms are conserved is unknown. In this study we probed the biochemical responses of complement-like pathway to challenge by the Gram-positive bacterium Staphyloccocus aureus. Western blot analysis of the hemolymph revealed that S. aureus challenge activates a TEP1 convertase-like activity and promotes the depletion of the protein SPCLIP1. S. aureus challenge did not lead to an apparent change in the abundance of the LRIM1/APL1C complex compared to challenge by the Gram-negative bacterium, Escherichia coli. Following up on this observation using a panel of LRIM1 and APL1C antibodies, we found that E. coli challenge, but not S. aureus, specifically activates a protease that cleaves the C-terminus of APL1C. Inhibitor studies in vivo and in vitro protease assays suggest that a serine protease is responsible for APL1C cleavage. This study reveals that despite different challenges converging on activation of a TEP1 convertase-like activity, the mosquito complement-like pathway also includes pathogen-specific reactions

Additional file 2: Practice Points. of Mindfulness based stress reduction for medical students: optimising student satisfaction and engagement

List of practice points relevant to the study. (DOCX 51 kb