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This collection of short essays utilizes a narrative approach to present the RISE framework, with four pillars centered on promoting student Resilience, Identity, Strength in Scholarship and Empowerment. Each short essay aims to draw attention to the spectrum of challenges that students currently face during their higher education journeys in Canada and what innovative solutions have been or could be implemented to address these adversities in accordance with RISE. The application of the framework to evaluate and reorient learning environments in Canadian higher education holds immense potential to help all students grow as collaborative thinkers, partners, and leaders that will leave academic settings well prepared for their life as leaders in their community. Dans cet article qui rassemble de courts essais, nous utilisons une approche narrative pour présenter le cadre RISE en l’appuyant sur quatre piliers permettant de promouvoir la Résilience, l’Identité, la Solidité universitaire et l’Émancipation. Chacun des courts essais vise à mettre en relief, d’une part, l’éventail des défis auxquels les étudiants font face actuellement dans l’enseignement supérieur au Canada et, d’autre part, les solutions novatrices qui ont été mises en œuvre – ou qui pourraient l’être – pour s’attaquer à ces difficultés dans le contexte de RISE. L’application de ce cadre dans l’examen et la reconfiguration des environnements d’apprentissage de l’enseignement supérieur au Canada est pleine de promesses. Voilà qui pourrait aider tous les étudiants à devenir des penseurs collaboratifs, des partenaires et des leaders qui, lorsqu’ils quitteront l’université, seront prêts à agir comme des chefs de file de leur communauté.

Pseudomonas aeruginosa is a human pathogen that relies on quorum sensing to establish infections. The PqsE quorum-sensing protein is required for P. aeruginosa virulence factor production and infection. PqsE has a reported enzymatic function in the biosynthesis of the quorum-sensing autoinducer called PQS. However, this activity is redundant because, in the absence of PqsE, this role is fulfilled by alternative thioesterases. Rather, PqsE drives P. aeruginosa pathogenic traits via a protein-protein interaction with the quorum-sensing receptor/transcription factor RhlR, an interaction that enhances the affinity of RhlR for target DNA sequences. PqsE catalytic activity is dispensable for interaction with RhlR. Thus, the virulence function of PqsE can be decoupled from its catalytic function. Here, we present an immunoprecipitation-mass spectrometry method employing enhanced green fluorescent protein-PqsE fusions to define the protein interactomes of wild-type PqsE and the catalytically inactive PqsE(D73A) variant in P. aeruginosa and their dependence on RhlR. Several proteins were identified to have specific interactions with wild-type PqsE while not forming associations with PqsE(D73A). In the Δ rhlR strain, an increased number of specific PqsE interactors were identified, including the partner autoinducer synthase for RhlR, called RhlI. Collectively, these results suggest that specific protein-protein interactions depend on PqsE catalytic activity and that RhlR may prevent proteins from interacting with PqsE, possibly due to competition between RhlR and other proteins for PqsE binding. Our results provide a foundation for the identification of the in vivo PqsE catalytic function and, potentially, new proteins involved in P. aeruginosa quorum sensing. IMPORTANCE Pseudomonas aeruginosa causes hospital-borne infections in vulnerable patients, including immunocompromised individuals, burn victims, and cancer patients undergoing chemotherapy. There are no effective treatments for P. aeruginosa infections, which are usually broadly resistant to antibiotics. Animal models show that, to establish infection and to cause illness, P. aeruginosa relies on an interaction between two proteins, namely, PqsE and RhlR. There could be additional protein-protein interactions involving PqsE, which, if defined, could be exploited for the design of new therapeutic strategies to combat P. aeruginosa. Here, we reveal previously unknown protein interactions in which PqsE participates, which will be investigated for potential roles in pathogenesis.

The opportunistic pathogen Pseudomonas aeruginosa causes antibiotic-resistant, nosocomial infections in immuno-compromised individuals and is a high priority for antimicrobial development. Key to pathogenicity in P. aeruginosa are biofilm formation and virulence factor production. Both traits are controlled by the cell-to-cell communication process called quorum sensing (QS). QS involves the synthesis, release, and population-wide detection of signal molecules called autoinducers. We previously reported that the activity of the RhlR QS transcription factor depends on a protein-protein interaction with the hydrolase, PqsE, and PqsE catalytic activity is dispensable for this interaction. Nonetheless, the PqsE-RhlR interaction could be disrupted by the substitution of an active site glutamate residue with tryptophan [PqsE(E182W)]. Here, we show that disruption of the PqsE-RhlR interaction via either the E182W change or alteration of PqsE surface residues that are essential for the interaction with RhlR attenuates P. aeruginosa infection in a murine host. We use crystallography to characterize the conformational changes induced by the PqsE(E182W) substitution to define the mechanism underlying disruption of the PqsE-RhlR interaction. A loop rearrangement that repositions the E280 residue in PqsE(E182W) is responsible for the loss of interaction. We verify the implications garnered from the PqsE(E182W) structure using mutagenic, biochemical, and additional structural analyses. We present the next generation of molecules targeting the PqsE active site, including a structure of the tightest binding of these compounds, BB584, in complex with PqsE. The findings presented here provide insights into drug discovery against P. aeruginosa with PqsE as the target.

Castration-resistant prostate cancer (CRPC) is associated with an increased reliance on heat shock protein 70 (HSP70), but it is not clear what other protein homeostasis (proteostasis) factors might be involved. To address this question, we performed functional and synthetic lethal screens in four prostate cancer cell lines. These screens confirmed key roles for HSP70, HSP90, and their co-chaperones, but also suggested that the mitochondrial chaperone, HSP60/HSPD1, is selectively required in CRPC cell lines. Knockdown of HSP60 does not impact the stability of androgen receptor (AR) or its variants; rather, it is associated with loss of mitochondrial spare respiratory capacity, partly owing to increased proton leakage. Finally, transcriptional data revealed a correlation between HSP60 levels and poor survival of prostate cancer patients. These findings suggest that re-wiring of the proteostasis network is associated with CRPC, creating selective vulnerabilities that might be targeted to treat the disease., Competing Interests: Declaration of interests J.E.G. holds patents to the use of HSP70 inhibitors and is a member of the Cell Chemical Biology Scientific Advisory Board. The authors declare no other competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Pseudomonas aeruginosa is an opportunistic pathogen that causes disease in immunocompromised individuals and individuals with underlying pulmonary disorders. P. aeruginosa virulence is controlled by quorum sensing (QS), a bacterial cell-cell communication mechanism that underpins transitions between individual and group behaviors. In P. aeruginosa, the PqsE enzyme and the QS receptor RhlR directly interact to control the expression of genes involved in virulence. Here, we show that three surface-exposed arginine residues on PqsE comprise the site required for interaction with RhlR. We show that a noninteracting PqsE variant [PqsE(NI)] possesses catalytic activity, but is incapable of promoting virulence phenotypes, indicating that interaction with RhlR, and not catalysis, drives these PqsE-dependent behaviors. Biochemical characterization of the PqsE-RhlR interaction coupled with RNA-seq analyses demonstrates that the PqsE-RhlR complex increases the affinity of RhlR for DNA, enabling enhanced expression of genes encoding key virulence factors. These findings provide the mechanism for PqsE-dependent regulation of RhlR and identify a unique regulatory feature of P. aeruginosa QS and its connection to virulence. IMPORTANCE Bacteria use a cell-cell communication process called quorum sensing (QS) to orchestrate collective behaviors. QS relies on the group-wide detection of molecules called autoinducers (AI). QS is required for virulence in the human pathogen Pseudomonas aeruginosa, which can cause fatal infections in patients with underlying pulmonary disorders. In this study, we determine the molecular basis for the physical interaction between two virulence-driving QS components, PqsE and RhlR. We find that the ability of PqsE to bind RhlR correlates with virulence factor production. Since current antimicrobial therapies exacerbate the growing antibiotic resistance problem because they target bacterial growth, we suggest that the PqsE-RhlR interface discovered here represents a new candidate for targeting with small molecule inhibition. Therapeutics that disrupt the PqsE-RhlR interaction should suppress virulence. Targeting bacterial behaviors such as QS, rather than bacterial growth, represents an attractive alternative for exploration because such therapies could potentially minimize the development of resistance.

Pseudomonas aeruginosa is an opportunistic human pathogen that causes fatal infections. There exists an urgent need for new antimicrobial agents to combat P. aeruginosa . We conducted a screen for molecules that bind the virulence-controlling protein PqsE and characterized hit compounds for inhibition of PqsE enzymatic activity. The binding conformations of two inhibitory molecules, BB391 and BB393, were identified by crystallography, and inhibitor binding was mimicked by the substitution of PqsE residues E182 and S285 with tryptophan. Comparison of the inhibitor-mimetic mutations to the catalytically inactive PqsE D73A protein demonstrated that catalysis is not responsible for the role PqsE plays in driving virulence factor production. Rather, the PqsE E182W protein fails to interact with the quorum-sensing receptor, RhlR, and our results suggest that it is this interaction that is responsible for promoting virulence factor production in P. aeruginosa . These findings provide a new route for drug discovery efforts targeting PqsE.

Prion protein (PrP) adopts either a helical conformation (PrP C ) or an alternative, beta sheet-rich, misfolded conformation (PrP Sc ). The PrP Sc form has the ability to "infect" PrP C and force it into the misfolded state. Accumulation of PrP Sc is associated with a number of lethal neurodegenerative disorders, including Creutzfeldt-Jacob disease (CJD). Knockout of PrP C protects cells and animals from PrP Sc infection; thus, there is interest in identifying factors that regulate PrP C stability, with the therapeutic goal of reducing PrP C levels and limiting infection by PrP Sc . Here, we assembled a short-hairpin RNA (shRNA) library composed of 25+ shRNA sequences for each of 133 protein homeostasis (aka proteostasis) factors, such as molecular chaperones and co-chaperones. This Proteostasis shRNA Library was used to identify regulators of PrP C stability in HEK293 Hu129M cells. Strikingly, the screen identified a number of Hsp70 family members and their co-chaperones as putative targets. Indeed, a chemical pan-inhibitor of Hsp70s reduced PrP C levels and limited conversion to PrP Sc in N2a cells. These results implicate specific proteostasis sub-networks, especially the Hsp70 system, as potential new targets for the treatment of CJD. More broadly, the Proteostasis shRNA Library might be a useful tool for asking which proteostasis factors are important for a given protein.

Background: This case discusses the importance of echocardiography, or transthoracic echocardiography (TTE), in detecting and diagnosing pulmonary embolisms (PE). The patient described in this case study, who underwent an echocardiography examination a few years before, had little reason to suspect the result of his PE would be a metastatic tumor showering masses of cancerous material and blood clots to his lungs., Discussion: Although computed tomography angiography is the gold standard for diagnosing PE, echocardiography is the preferred modality for identifying heart masses or tumors and provides vital PE information. Four testing components provide essential information for PE detection (ie, right ventricle dysfunction, McConnell sign, elevated pulmonary artery pressures, and visualization of the mass or thrombus). Through these components, TTE has a vital role in patient care, which other imaging modalities lack. The patient in this case study is an example of why protocols should be standardized for preventive hepatocellular carcinoma screenings and sonography implemented as a routine PE detection tool., Conclusion: Echocardiography is noninvasive, causes no known adverse effects to the patient, presents instantaneous results, and is cost effective and time efficient. Although PE is treatable, it is a common cause of death; the use of echocardiography to diagnose PE might change that outcome., (© 2021 American Society of Radiologic Technologists.)

Pseudomonas aeruginosa is a leading cause of hospital-acquired infections in the United States. PqsE, a thioesterase enzyme, is vital for virulence of P. aeruginosa , making PqsE an attractive target for inhibition. Neither the substrate nor the product of PqsE catalysis has been identified. A library of 550 million DNA-encoded drug-like small molecules was screened for those that bind to the purified PqsE protein. The structures of the bound molecules were identified by high throughput sequencing of the attached DNA barcodes. Putative PqsE binders with the strongest affinity features were examined for inhibition of PqsE thioesterase activity in vitro . The most potent inhibitors were resynthesized off DNA and examined for the ability to alter PqsE thermal melting and for PqsE thioesterase inhibition. Here, we report the synthesis, biological activity, mechanism of action, and early structure-activity relationships of a series of 2-(phenylcarbamoyl)benzoic acids that noncompetitively inhibit PqsE. A small set of analogs designed to probe initial structure-activity relationships showed increases in potency relative to the original hits, the best of which has an IC 50 = 5 μM. Compound refinement is required to assess their in vivo activities as the current compounds do not accumulate in the P. aeruginosa cytosol. Our strategy validates DNA-encoded compound library screening as a rapid and effective method to identify catalytic inhibitors of the PqsE protein, and more generally, for discovering binders to bacterial proteins revealed by genetic screening to have crucial in vivo activities but whose biological functions have not been well-defined.

Understanding the selectivity of a small molecule for its target(s) in cells is an important goal in chemical biology and drug discovery. One powerful way to address this question is with dominant negative (DN) mutants, in which an active site residue in the putative target is mutated. While powerful, this approach is less straightforward for allosteric sites. Here, we introduce tryptophan scanning mutagenesis as an expansion of this idea. As a test case, we focused on the challenging drug target, heat shock cognate protein 70 (Hsc70), and its allosteric inhibitor JG-98. Structure-based modelling predicted that mutating Y149W in human Hsc70 or Y145W in the bacterial ortholog DnaK would place an indole side chain into the allosteric pocket normally occupied by the compound. Indeed, we found that the tryptophan mutants acted as if they were engaged with JG-98. We then used DnaK Y145W to suggest that this protein may be an anti-bacterial target. Indeed, we found that DnaK inhibitors have minimum inhibitory concentration (MIC) values <0.125 μg mL -1 against several pathogens, including multidrug-resistant Staphylococcus aureus (MRSA) strains. We propose that tryptophan scanning mutagenesis may provide a distinct way to address the important problem of target engagement., Competing Interests: The authors claim no competing financial interests., (This journal is © The Royal Society of Chemistry.)

Legionella pneumophila (L.p.), the microbe responsible for Legionnaires' disease, secretes ∼300 bacterial proteins into the host cell cytosol. A subset of these proteins affects a wide range of post-translational modifications (PTMs) to disrupt host cellular pathways. L.p. has 5 conserved eukaryotic-like Ser/Thr effector kinases, LegK1-4 and LegK7, which are translocated during infection. Using a chemical genetic screen, we identified the Hsp70 chaperone family as a direct host target of LegK4. Phosphorylation of Hsp70s at T495 in the substrate-binding domain disrupted Hsp70's ATPase activity and greatly inhibited its protein folding capacity. Phosphorylation of cytosolic Hsp70 by LegK4 resulted in global translation inhibition and an increase in the amount of Hsp70 on highly translating polysomes. LegK4's ability to inhibit host translation via a single PTM uncovers a role for Hsp70 in protein synthesis and directly links it to the cellular translational machinery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Allosteric inhibitors can be more difficult to optimize without an understanding of how their binding influences the conformational motions of the target. Here, we used an integrated computational and experimental approach to probe the molecular mechanism of an allosteric inhibitor of heat shock protein 70 (Hsp70). The anticancer compound, MKT-077, is known to bind a conserved site in members of the Hsp70 family, which favors the ADP-bound state and interferes with a protein-protein interaction (PPI) at long range. However, the binding site does not overlap with either the nucleotide-binding cleft or the PPI contact surface, so its mechanism is unclear. To this end, we modeled Hsp70's internal dynamics and studied how MKT-077 alters local sampling of its allosteric states. The results pointed to a set of concerted motions between five loops in Hsp70's nucleotide-binding domain (NBD), surrounding the MKT-077 binding site. To test this prediction, we mutated key residues and monitored chaperone activities in vitro. Together, the results indicate that MKT-077 interacts with loop222 to favor a pseudo-ADP bound conformer of Hsp70's NBD, even when ATP is present. We used this knowledge to synthesize an analog of MKT-077 that would better prevent motions of loop222 and confirmed that it had improved antiproliferative activity in breast cancer cells. These results provide an example of how to unlock and leverage the complex mechanisms of allosteric inhibitors.

Hsp70 chaperones bind to various protein substrates for folding, trafficking, and degradation. Considerable structural information is available about how prokaryotic Hsp70 (DnaK) binds substrates, but less is known about mammalian Hsp70s, of which there are 13 isoforms encoded in the human genome. Here, we report the interaction between the human Hsp70 isoform heat shock cognate 71-kDa protein (Hsc70 or HSPA8) and peptides derived from the microtubule-associated protein Tau, which is linked to Alzheimer's disease. For structural studies, we used an Hsc70 construct (called BETA) comprising the substrate-binding domain but lacking the lid. Importantly, we found that truncating the lid does not significantly impair Hsc70's chaperone activity or allostery in vitro Using NMR, we show that BETA is partially dynamically disordered in the absence of substrate and that binding of the Tau sequence GKVQIINKKG (with a K D = 500 nm) causes dramatic rigidification of BETA. NOE distance measurements revealed that Tau binds to the canonical substrate-binding cleft, similar to the binding observed with DnaK. To further develop BETA as a tool for studying Hsc70 interactions, we also measured BETA binding in NMR and fluorescent competition assays to peptides derived from huntingtin, insulin, a second Tau-recognition sequence, and a KFERQ-like sequence linked to chaperone-mediated autophagy. We found that the insulin C-peptide binds BETA with high affinity ( K D < 100 nm), whereas the others do not ( K D > 100 μm). Together, our findings reveal several similarities and differences in how prokaryotic and mammalian Hsp70 isoforms interact with different substrate peptides., (© 2018 Taylor et al.)

Protein-protein interactions (PPIs) are an important category of putative drug targets. Improvements in high-throughput screening (HTS) have significantly accelerated the discovery of inhibitors for some categories of PPIs. However, methods suitable for screening multiprotein complexes ( e.g. those composed of three or more different components) have been slower to emerge. Here, we explored an approach that uses reconstituted multiprotein complexes (RMPCs). As a model system, we chose heat shock protein 70 (Hsp70), which is an ATP-dependent molecular chaperone that interacts with co-chaperones, including DnaJA2 and BAG2. The PPIs between Hsp70 and its co-chaperones stimulate nucleotide cycling. Thus, to re-create this ternary protein system, we combined purified human Hsp70 with DnaJA2 and BAG2 and then screened 100,000 diverse compounds for those that inhibited co-chaperone-stimulated ATPase activity. This HTS campaign yielded two compounds with promising inhibitory activity. Interestingly, one inhibited the PPI between Hsp70 and DnaJA2, whereas the other seemed to inhibit the Hsp70-BAG2 complex. Using secondary assays, we found that both compounds inhibited the PPIs through binding to allosteric sites on Hsp70, but neither affected Hsp70's intrinsic ATPase activity. Our RMPC approach expands the toolbox of biochemical HTS methods available for studying difficult-to-target PPIs in multiprotein complexes. The results may also provide a starting point for new chemical probes of the Hsp70 system., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Heat shock protein 70 (Hsp70) is a molecular chaperone that plays critical roles in protein homeostasis. Hsp70's chaperone activity is coordinated by intra-molecular interactions between its two domains, as well as inter-molecular interactions between Hsp70 and its co-chaperones. Each of these contacts represents a potential opportunity for the development of chemical inhibitors. To illustrate this concept, we review three classes of recently identified molecules that bind distinct pockets on Hsp70. Although all three compounds share the ability to interrupt core biochemical functions of Hsp70, they stabilize different conformers. Accordingly, each compound appears to interrupt a specific subset of inter- and intra-molecular interactions. Thus, an accurate definition of an Hsp70 inhibitor may require a particularly detailed understanding of the molecule's binding site and its effects on protein-protein interactions.

AH197, a trinuclear Ru(III)/Pt(II) metal complex, is strikingly more effective than the hallmark anticancer drug cisplatin and the Ru(III) clinical candidate NAMI-A in its binding to RNA and inhibition of primer DNA synthesis. Heteromultinuclear complexes could potentially serve as far better chemotherapeutics than mononuclear complexes.

Hetero-multinuclear, platinum/ruthenium species were synthesized and tested for their effect on the motility of A549 (nonsmall cell lung) and MDA-MB-231 (breast) cancer cells and for their ability to inhibit DNA mobility using gel electrophoresis. It was found that the Ru(2)Pt trinuclear species [Na(2)]{[Ru(III)Cl(4)(DMSO-S)(-μ-pyz)](2)Pt(II)Cl(2)}, AH197, was much more efficient at inhibiting cell motility than [C(3)N(2)H(5)][Ru(III)Cl(4)(DMSO-S)(C(3)N(2)H(4))], NAMI-A, while the dinuclear RuPt species [K][Ru(III)Cl(4)(DMSO-S)(-μ-pyz)Pt(II)(DMSO-S)Cl(2)], IT127, was slightly better than NAMI-A. However, the dinuclear species retarded the electrophoretic mobility of DNA greater than both the trinuclear complex and cisplatin. The metal complexes and their respective BSA protein/metal adducts were studied by X-ray absorption spectroscopy. The spectra led to the conclusion that BSA donor atoms have substituted for the chloride ligands and perhaps the DMSO ligands.

A course in communication skills has been developed specifically for veterinary students, based on those delivered at many medical schools, and making extensive use of professional actors as simulated clients. Its aim is to raise awareness of the importance of communication among veterinary undergraduates at all stages of the curriculum, and it allows them to role-play in acted-out scenarios. Facilitated small groups provide an environment in which students can receive feedback on their own performance and also give feedback to their colleagues. An independent evaluation suggests that the opportunity to role-play increased the students' confidence in communicating with others. They were able to identify their personal strengths as communicators and gain insights into the aspects of communication they could improve. Feedback and subsequent discussions were highly valued, with the actors playing a crucial role in providing feedback from the client's perspective. Students were able to use the knowledge they acquired when consulting with real clients. Most of the students suggested that the course should continue in its current format, but with more time provided for it in the curriculum.

This study was designed to measure anxiety levels in 91 partners of women undergoing elective Caesarean section under regional anaesthesia and to outline potential relieving factors. Twenty-eight percent of partners were pathologically anxious. There was a positive association between anxiety and prior attendance at the anaesthetic assessment clinic (p=0.008). There was no statistically significant association between anxiety and education, occupation, gender, relationship to the patient or previous attendance at Caesarean section. Concern about a safe outcome for the mother and child caused most anxiety, less being expressed regarding presence in the operating theatre or anaesthesia per se. Over 70% of partners expressed the view that attendance at the anaesthetic assessment clinic or provision of written information would reduce their anxiety.

Postal surveys or personal interviews of 76 recent veterinary graduates and their 49 employers were undertaken to establish their perceptions of good practice when integrating a new graduate into a business and their preferred methods of assessment and development. Practice type and location were the main influences on graduates looking for their first job. Interviews were mostly informal. Employers expected basic veterinary competence and candidates expected good quality support. Most graduates (93 per cent) had their own consultations on the first day. During early consultations 2 per cent of senior vets accompanied the new graduate, 95 per cent of practices provided senior back-up either in person or by telephone but in 3 per cent no back-up was available. Most new graduates (90 per cent) were satisfied with their workload. Three-fifths were on-call within the first week, and 95 per cent within a month. Graduates received calls directly in 45 per cent of practices, in 9 per cent seniors screened the calls, and the remainder used a third party. Assistance from experienced lay staff varied greatly. Discussion of problems was mainly informal. There was little spontaneous feedback and problems resulted from inadequate communication. One in three new graduates left their first job within two years, and one in six identified lack of support, heavy workload, stress or clashes with staff as a primary reason. This high turnover was a problem for employers. From the new graduates' perspectives, initial problems included: being on call (59 per cent), financial aspects (47 per cent) and surgery (43 per cent). Communicating with clients and learning to prioritise jobs were also difficult. New graduates took longer over procedures (79 per cent of employers commented) and required extra back-up (91 per cent) both of which reduced income (59 per cent). Nearly all the seniors felt that their current new graduates had coped 'quite well', although it was claimed that new graduates lacked the ability to talk to clients at the appropriate level, wanted to bring all their scientific knowledge to bear on every case, and often failed to consider the obvious or to appreciate clients' needs. Only 18 per cent of practices had formal and regular review procedures but all monitored the response of clients and watched the new graduate perform. Feedback to their new colleague was considered 'adequate' by 85 per cent of seniors, although 45 per cent of graduates felt they had not received enough. Eighty-three per cent of new graduates felt 'moderately prepared' by their undergraduate course, and 76 per cent of senior vets were 'generally satisfied' Both wanted improvements in extramural studies and increased exposure to routine cases. Senior partners sought greater commitment in the undergraduate curriculum to financial/legal issues and communication skills. Over a third of employers (38 per cent) had a 'great influence' on the choice of continuing professional development courses for their recent graduates. New graduates chose courses to deal with a perceived weakness, or to specialise, and welcomed opportunities to meet other new graduates and share early experiences. It was concluded that turnover and staff problems would be reduced if practices became more effective in coping with new arrivals, especially by supporting their development.

(1) The energy savings associated with the roosting behaviour of barn owls (Tyto alba) were determined with a biophysical model using measurements of microclimate from a roost and nest site in SW Scotland (55 degrees 10' N 3 degrees 12' W) from April 1991-March 1992. (2) The roost building provided complete shelter from wind and precipitation. Air temperature inside the roost building was 1.4 degrees C greater than ambient and matched the seasonal change in temperature. Air temperature inside the nest box was on average only 0.8 degrees C greater than ambient but was 2-3 degrees C warmer when adults and chicks were in the nest during the breeding season. (3) Estimated metabolic heat production was significantly different between locations and averaged 67.9, 68.1, 75.5 and 84.2Wm(-2) for a barn owl roosting in the building, nest box, spruce tree and in the open, respectively. At night metabolic heat production was greater by 4-12% compared with daytime, depending on location. (4) Heat loss was 30% greater in winter months than in the summer in all locations. By roosting in the building an owl would make savings of 21.6Wm(-2) in March but only 12.9Wm(-2) in August. In a tree roost a barn owl would save 11.8Wm(-2) in March and 5.8Wm(-2) in August. (5) Barn owls were estimated to reduce metabolic heat production by 19% by roosting in the building and by 10% by roosting in a tree. In the building and tree savings of 21 and 9% occurred during the day compared with 17 and 12% at night. (6) Metabolic savings were strongly dependent on weather conditions with average metabolic savings of 26% occurring in wet and windy conditions compared with only 12% on dry-calm days. Maximum savings of 29-36% occurred on wet days. (7) Barn owls appear to compensate for high metabolic demands for heat production by taking advantage of better thermal conditions within buildings, especially during the day when metabolic savings are greatest.

We report the case of a 47-year-old woman with Guillain-Barré syndrome who developed autonomic instability and hypertension and subsequently developed a subarachnoid haemorrhage. This was manifested clinically by a seizure which began focally and became generalised. Computer tomography demonstrated a localised haemorrhage in the left central sulcus. Control of the hypertension was achieved with intravenous labetolol. Autonomic instability and hypertension are frequently reported in Guillain-Barré syndrome. Subarachnoid haemorrhage is an uncommon but serious complication.

This paper presents the results of a questionnaire completed by 331 UK veterinary practitioners which focused on the quality assurance of extramural studies. The questionnaire considered the attributes of practitioners as extramural teachers and the suitability of host practices for extramural studies, the students' evaluation of their quality, and the role of the veterinary schools. The questionnaire identified two broad roles for the practitioner, first, as teacher and, secondly, as professional role model, and there was strong support for students being allowed to evaluate their role as teacher. The findings are discussed in relation to aspects of good practice associated with quality assurance, and in relation to the need to develop stronger links between the schools and the veterinary profession.

This paper presents the responses of veterinary surgeons to a pilot scheme initiated by the SILVER project. The scheme was designed to increase communication between a veterinary school, host practices and students undertaking extramural study ("seeing practice') and to provide a more structured use of the students' time. The work is set in the context of recent interest in work-based learning as part of undergraduate education, the approach being based on experience gained from a number of professions, including veterinary science. Students were required to identify and communicate their personal learning objectives to host practices in advance of their arrival, and practices were asked to collaborate in a new system for recording students' progress. The paper presents an analysis of the evidence obtained from questionnaires sent to pilot practices. It shows that all the elements of the scheme had been received favourably and had had a positive impact on student learning. The findings are discussed in relation to the development and implications of an educational strategy for extramural study.

In 1988, the Faculty of Veterinary Science, University of Liverpool, introduced a system of teacher appraisal, following the report of a faculty working party. The system is designed to provide information which will help the personal development of teaching skills, and also to provide the information required by the university for promoting a lecturer to senior lecturer. It incorporates opinions from students, collected formally by means of questionnaires, and from personal peers chosen by the lecturer, and a self-appraisal record which forms the basis of an annual review from the head of department. Official peers, drawn from both the veterinary faculty and the department of education and extension studies, are trained and used in pairs, to assess and report on staff eligible for promotion. The system has been evaluated by a research assistant funded by the University Funding Council.