Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site.

Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquid malignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/ß-tubulin either promoting microtubule stabilization or depolymerization. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/ß-tubulin-GB1 complex.

Comparative Effectiveness of Training with Simulators Versus Traditional Instruction in Veterinary Education: Meta-Analysis and Systematic Review.

One of the greatest challenges in veterinary education is adequately preparing students with the clinical skills they need to be successful health care providers. Integration of simulators, devices used to represent real world phenomena under test conditions, into the veterinary curriculum can help address challenges to clinical instruction. The use of simulators in veterinary education is increasing; however, their effectiveness remains unclear. This meta-analysis seeks to synthesize the evidence for simulator training in veterinary education to provide a consensus of effect, guide the integration of simulators into the curriculum, and direct the development of future simulation-based research in veterinary medicine. A systematic search identified 416 potential manuscripts from which 60 articles were included after application of inclusion criteria. Information was extracted from 71 independent experiments. The overall weighted mean effect size for simulator training was g = 0.49 for the random-effects model. The outcome measures of knowledge, time, process, and product all produced statistically significant mean effect sizes favoring simulation (d = 0.41, 0.35, 0.70, 0.53, respectively). A moderator analysis revealed that study characteristics and instructional design features moderated the effectiveness of simulator training. Overall, the results indicate that simulator training in veterinary education can be effective for knowledge and clinical skill outcomes.

Bifunctional Doscadenamides Activate Quorum Sensing in Gram-Negative Bacteria and Synergize with TRAIL to Induce Apoptosis in Cancer Cells.

New cyanobacteria-derived bifunctional analogues of doscadenamide A, a LasR-dependent quorum sensing (QS) activator in Pseudomonas aeruginosa, characterized by dual acylation of the pyrrolinone core structure and the pendant side chain primary amine to form an imide/amide hybrid are reported. The identities of doscadenamides B-J were confirmed through total synthesis and a strategic focused library with different acylation and unsaturation patterns was created. Key molecular interactions for binding with LasR and a functional response through mutation studies coupled with molecular docking were identified. The structure-activity relationships (SARs) were probed in various Gram-negative bacteria, including P. aeruginosa and Vibrio harveyi, indicating that the pyrrolinone-N acyl chain is critical for full agonist activity, while the other acyl chain is dispensable or can result in antagonist activity, depending on the bacterial system. Since homoserine lactone (HSL) quorum sensing activators have been shown to act in synergy with TRAIL to induce apoptosis in cancer cells, selected doscadenamides were tested in orthogonal eukaryotic screening systems. The most potent QS agonists, doscadenamides S10-S12, along with doscadenamides F and S4 with partial or complete saturation of the acyl side chains, exhibited the most pronounced synergistic effects with TRAIL in triple negative MDA-MB-231 breast cancer cells. The overall correlation of the SAR with respect to prokaryotic and eukaryotic targets may hint at coevolutionary processes and intriguing host-bacteria relationships. The doscadenamide scaffold represents a non-HSL template for combination therapy with TRAIL pathway stimulators.

Qualitative Research in Veterinary Medical Education: Part 1-Principles of Qualitative Design.

Qualitative methodologies are relative newcomers to health sciences education research. While they may look very different to their quantitative counterparts in terms of size and scope, when well-applied they offer a fresh perspective and generate valuable research findings. Although qualitative research is being increasingly conducted in veterinary medical education, there are few contextualized resources to assist those who would like to develop their expertise in this area. In this article, we address this by introducing the principles of qualitative research design in a veterinary medical education context. Drawing from a range of contemporary resources, we explore the types of research goals and questions that are amenable to qualitative inquiry and discuss the process of formulating a worthwhile research question. We explain what research paradigms are and introduce readers to some of the methodological options available to them in qualitative research. Examples from veterinary medical education are used to illustrate key points. In a second companion article, we will focus on the decisions that need to be made regarding data sampling, collection, and analysis. We will also consider how qualitative research is evaluated, and discuss how qualitative findings are applied. Taken together, the two articles build an understanding of qualitative research, illuminate its potential to contribute to the scholarship of teaching and learning in veterinary medical education, and equip readers with an improved capacity to appraise its value.

Qualitative Research in Veterinary Medical Education: Part 2-Carrying Out Research Projects.

This is the second of two articles that together comprise an orientation and introduction to qualitative research for veterinary medical educators who may be new to research, or for those whose research experience is based on the quantitative traditions of biomedicine. In the first article (Part 1-Principles of Qualitative Design), we explored the types of research interests and goals suited to qualitative inquiry and introduced the concepts of research paradigms and methodologies. In this second article, we move to the strategies and actions involved in conducting a qualitative study, including selection and sampling of research sites and participants, data collection and analysis. We introduce some guidelines for reporting qualitative research and explore the ways in which qualitative research is evaluated and the findings applied. Throughout, we provide illustrative examples from veterinary and human medical education and suggest useful resources for further reading. Taken together, the two articles build an understanding of qualitative research, outline how it may be conducted, and equip readers with an improved capacity to appraise its value.

Is a Picture Worth a Thousand Words? Evaluating the Design of Instructional Animations in Veterinary Education.

Empirical evidence demonstrates that student learning outcomes improve when animations are developed in alignment with the design principles of the cognitive theory of multimedia learning (CTML). The extent to which these principles are used in the design of veterinary instructional animations is unknown. In this study, we reviewed the veterinary education literature for articles that discussed specific veterinary medical animations as learning resources. The 30 referenced animations accessed through this search were analyzed to determine whether they used the CTML's 11 major design principles. Analysis revealed that the animations most commonly adhered to only 4 principles: coherence, redundancy, modality, and spatial contiguity. The majority of the 11 CTML principles were used in fewer than 40% of the animations. We also examined the alignment between raters' perceptions of the effectiveness and enjoyment of the animations and adherence to the design principles. Analyses revealed that the animations deemed by raters as most enjoyable and effective did not utilize more design principles than animations they viewed as least enjoyable and effective. The results of this study indicate many missed opportunities to increase learning by developing animated learning resources according to empirically based design principles. Decisions to include specific animations in instruction should be based on whether the resources include elements that have been shown to increase learning rather than subjective perceptions of effectiveness and enjoyment.

Qualitative Research in Veterinary Medical Education: Part 1-Principles of Qualitative Design.

Qualitative methodologies are relative newcomers to health sciences education research. While they may look very different to their quantitative counterparts in terms of size and scope, when well-applied they offer a fresh perspective and generate valuable research findings. Although qualitative research is being increasingly conducted in veterinary medical education, there are few contextualized resources to assist those who would like to develop their expertise in this area. In this article, we address this by introducing the principles of qualitative research design in a veterinary medical education context. Drawing from a range of contemporary resources, we explore the types of research goals and questions that are amenable to qualitative inquiry and discuss the process of formulating a worthwhile research question. We explain what research paradigms are and introduce readers to some of the methodological options available to them in qualitative research. Examples from veterinary medical education are used to illustrate key points. In a second companion article, we will focus on the decisions that need to be made regarding data sampling, collection, and analysis. We will also consider how qualitative research is evaluated, and discuss how qualitative findings are applied. Taken together, the two articles build an understanding of qualitative research, illuminate its potential to contribute to the scholarship of teaching and learning in veterinary medical education, and equip readers with an improved capacity to appraise its value.

Collaborative Development of Core Entrustable Professional Activities for Veterinary Education.

Entrustable professional activities (EPAs) have been proposed as a practical framework for the implementation of competency-based education. As veterinary education moves toward a competency-based approach, core EPAs provide a context for assessment of workplace activities. This article reports on the development of eight core clinical EPAs for veterinary education created through multi-institutional collaboration, with international input from veterinary educators and veterinary educational leaders. These core EPAs are intended as minimal expectations for clinical activities that should be assessed for every graduate of Association of American Veterinary Medical Colleges member institutions. Adoption of the core EPAs and the associated Competency-Based Veterinary Education (CBVE) framework by veterinary schools is intended to promote Day One graduate competence and thereby enhance patient care and client service.

Collaborative Development of a Shared Framework for Competency-Based Veterinary Education.

Competency-based medical education is an educational innovation implemented in health professions worldwide as a means to ensure graduates meet patient and societal needs. The focus on student-centered education and programmatic outcomes offers a series of benefits to learners, institutions and society. However, efforts to establish a shared, comprehensive competency-based framework in veterinary education have lagged. This article reports on the development and outcome of a competency-based veterinary education (CBVE) framework created through multi-institutional collaboration with international input from veterinary educators and veterinary educational leaders. The CBVE Framework is designed to reflect the competencies expected of new graduates from member institutions of the Association of American Veterinary Medical Colleges (AAVMC). The CBVE Framework consists of nine domains of competence and 32 competencies, each supplemented with illustrative sub-competencies to guide veterinary schools in implementing competency-based education in their local context. The nine domains of competence are: clinical reasoning and decision-making; individual animal care and management; animal population care and management; public health; communication; collaboration; professionalism and professional identity; financial and practice management; and scholarship. Developed through diverse input to facilitate broad adoption, the CBVE Framework provides the foundation for competency-based curricula and outcomes assessment in veterinary education internationally. We believe that other groups seeking to design a collective product for broad adoption might find useful the methods used to develop the CBVE Framework, including establishing expertise diversity within a small-to-medium size working group, soliciting progressive input and feedback from stakeholders, and engaging in consensus building and critical reflection throughout the development process.

Development of core entrustable professional activities linked to a competency-based veterinary education framework.

Purpose: Despite the adoption of competency-based education in some veterinary schools over the past 15 years, only recently has a concerted effort been directed toward this in veterinary education internationally.Methods: In 2015, educational leaders from the Association of American Veterinary Medical Colleges (AAVMC) member schools came together with a strong call to action to create shared tools for clinical competency assessment.Results: This resulted in the formation of the AAVMC Competency-Based Veterinary Education (CBVE) Working Group, which then embarked on the creation of a shared competency framework and the development of eight core entrustable professional activities (EPAs) linked to this framework.Conclusions: This paper will report on the development of these EPAs and their integration with the concurrently-developed CBVE Framework.

An Exploration of the Career Motivations Stated by Early-Career Veterinarians in Australia.

Despite the critical influence of motivation on education and work outcomes, little is known about the motivations driving people to become and remain veterinarians. This qualitative study explored the career motivations stated by Australian veterinary graduates (n = 43) using a free-response Ten Statements Test (TST) at graduation, with follow-up interviews 6-8 months later (n = 10). TST responses were coded using an alternate inductive-deductive approach that tested their fit against existing theories of motivation. Results showed that the stated motivations were predominantly oriented to perceived value, rather than self-beliefs such as expectancy of success. About a quarter of the statements were animal-related, principally themed around intrinsic animal orientation (e.g., I like animals) or extrinsic animal-related purpose (e.g., I want to help animals). However, many non-animal themes also emerged, including both intrinsic (e.g., love of learning, challenge/problem solving, variety, social relatedness) and extrinsic (e.g., helping people, social contribution, career opportunity) motivations. Interview data revealed a motivational narrative of early formative influences, with some interviewees describing a later transition toward more people- or goal-oriented motivations. This exploratory study, outlining a broad taxonomy of veterinary career motivations and their alignment to self-determination theory in particular, may provide a useful framework for exploring career motivations in veterinary education.

Flipped Classroom Use in Veterinary Education: A Multinational Survey of Faculty Experiences.

Active teaching approaches such as the flipped classroom are linked to better quality student learning outcomes across health care disciplines, with the potential to support students' preparedness for practice. In the flipped classroom instructional approach, students engage in significant pre-class preparation to learn foundational knowledge and skills, then undertake instructional activities in the classroom that require them to integrate, apply and extend their learning to new contexts. This study reports the results of a multinational survey of flipped classroom use in veterinary education. Participants' ( n = 165) familiarity with and extent of use of the flipped classroom technique were investigated, together with the teaching strategies used and the perceived benefits and barriers to implementation. Relationships between respondent characteristics and flipped classroom use were also explored. The results indicated that 95% of participants were familiar with the flipped classroom technique, although fewer (64%) used it in their teaching. Pre-class activities included reviewing online and printed material, and engaging in preparatory learning activities such as quizzes, case analyses, reflective assignments and group activities. A variety of active learning strategies were used in class, including discussions, presentations, quizzes, group activities, problem solving and laboratory/practical exercises. Most participants perceived that the flipped classroom technique benefited student learning, with some also identifying benefits for the faculty involved. A range of student-, faculty- and institution-related barriers to implementing the flipped classroom technique were identified. These barriers need to be considered and addressed by teachers and administrators seeking to improve students' preparedness for practice by implementing flipped classrooms in veterinary education.

Discovery of new A- and B-type laxaphycins with synergistic anticancer activity.

Two new cyclic lipopeptides termed laxaphycins B4 (1) and A2 (2) were discovered from a collection of the marine cyanobacterium Hormothamnion enteromorphoides, along with the known compound laxaphycin A. The planar structures were solved based on a combined interpretation of 1D and 2D NMR data and mass spectral data. The absolute configurations of the subunits were determined by chiral LC-MS analysis of the hydrolysates, advanced Marfey's analysis and 1D and 2D ROESY experiments. Consistent with similar findings on other laxaphycin A- and B-type peptides, laxaphycin B4 (1) showed antiproliferative effects against human colon cancer HCT116 cells with IC50 of 1.7 µM, while laxaphycins A and A2 (2) exhibited weak activities. The two major compounds isolated from the sample, laxaphycins A and B4, were shown to act synergistically to inhibit the growth of HCT116 colorectal cancer cells.

Magnetic resonance imaging versus computed tomography to plan hemilaminectomies in chondrodystrophic dogs with intervertebral disc extrusion.

OBJECTIVE: To determine the influence of preoperative computed tomography (CT) versus magnetic resonance (MR) on hemilaminectomies planned to treat thoracolumbar (TL) intervertebral disc (IVD) extrusions in chondrodystrophic dogs. STUDY DESIGN: Prospective clinical study. SAMPLE POPULATION: Forty chondrodystrophic dogs with TL IVD extrusion and preoperative CT and MR studies. METHODS: MR and CT images were randomized and reviewed by 4 observers masked to the dog's identity and corresponding imaging studies. Observers planned the location along the spine, side, and extent (number of articular facets to be removed) based on individual reviews of CT and MR studies. Intra-observer agreement was determined between overall surgical plan, location, side, and size of the hemilaminectomy planned on CT versus MR of the same dog. RESULTS: Similar surgical plans were developed based on MR versus CT in 43.5%-66.6% of dogs, depending on the observer. Intra-observer agreement in location, side, and size of the planned hemilaminectomy based on CT versus MR ranged between 48.7%-66.6%, 87%-92%, and 51.2%-71.7% of dogs, respectively. Observers tended to plan larger laminectomy defects based on MR versus CT of the same dog. CONCLUSION: Findings from this study indicated considerable differences in hemilaminectomies planned on preoperative MR versus CT imaging. Surgical location and size varied the most; the side of planned hemilaminectomies was most consistent between imaging modalities.

Evaluating the Quality of Veterinary Students' Experiences of Learning in Clinics.

Educators seeking to evaluate the quality of students' experiences of clinic-based learning (CBL) face a challenging task. CBL programs provide multiple opportunities for learning and aim to develop a wide range of skills, knowledge, and capacities. While direct observation of learners provides important information about students' proficiency in performing various clinical tasks, more comprehensive measures are required to unpack and identify factors relating to practice readiness as a whole. This study identified variables that have a logical and statistically significant association with learning outcomes across the broad range of attributes expected of new graduate veterinarians. The research revealed that the extent of final-year veterinary students' practice readiness, as assessed by placement supervisors against criteria relevant to new graduate practice, is related to the quality of their conceptions of and approaches to CBL. Students' conceptions of and approaches to CBL were evaluated using quantitative survey instruments, with a 93% response rate (N=100) obtained for the two questionnaires. Descriptive and exploratory statistics were used to link qualitative differences in students' conceptions of and approaches to CBL with performance against criteria relevant to new graduate practice. Students who reported poorer-quality conceptions of and approaches to CBL (n=38) attained lower levels of achievement than students who reported better-quality conceptions of and approaches to CBL (n=55). Evaluation of students' conceptions of and approaches to CBL can be used by educators seeking to evaluate and improve the extent to which CBL programs are achieving their desired goals.

Resilience in Veterinary Students and the Predictive Role of Mindfulness and Self-Compassion.

Resilience is a dynamic and multifaceted process in which individuals draw on personal and contextual resources. In difficult situations, resilient people use specific strategies to learn from the situation without being overcome by it. As stressors are inherent to veterinary work, including long work hours, ethical dilemmas, and challenging interactions with clients, resilience is an important component of professional quality of life. However, while resilience in other health professionals has received attention, it has received little in the veterinary field. In this cross-sectional study, veterinary students from six veterinary schools in Australia completed an online survey, with 193 responses (23%). Very few veterinary students (6%) reached the threshold to be considered highly resilient using the Brief Resilience Scale, and approximately one third classified as having low levels of resilience. In the final linear multiple regression model, predictors of resilience included nonjudgmental and nonreactive mindfulness (Five Facet Mindfulness Questionnaire) and self-compassion (Neff Self-Compassion Scale). Students with higher nonjudgmental and nonreactive mindfulness and self-compassion had higher resilience scores. These findings indicate that fostering these qualities of mindfulness and self-compassion may be aligned with strengthening veterinary student resilience. Importantly, if the factors that help veterinary students develop a capacity for resilience can be identified, intervention programs can be targeted to educate future veterinary professionals with a high quality of life, both professional and personal.

Finding the Balance: Uncovering Resilience in the Veterinary Literature.

Resilience is an issue of emerging importance in veterinary education and research, as in other professional contexts. The aim of this study was to perform an appraisal of how resilience is portrayed in the contemporary (1995-present) research and education literature around veterinary mental health, and to attempt a provisional synthesis informing a conception of resilience in the veterinary context. Qualitative analysis of the literature (59 sources included) revealed a dominant emphasis on mental health problems, particularly stress, which outweighs and potentially obscures complementary approaches to well-being and resilience. We found the construct of resilience underdeveloped in the veterinary literature and in need of further research, but provide a preliminary synthesis of key themes emerging from the current literature (emotional competence, motivation, personal resources, social support, organizational culture, life balance, and well-being strategies). We advocate for greater balance between complementary perspectives in veterinary mental health education and research, and propose that an increasing focus on resilience (here endorsed as a dynamic and multi-dimensional process involving personal and contextual resources, strategies, and outcomes) will help to address this balance.

Apoptosis induction by 13-acetoxyrolandrolide through the mitochondrial intrinsic pathway.

The aim of this study was to evaluate the mechanisms of cytotoxicity of the sesquiterpene lactone 13-acetoxyrolandrolide, a nuclear factor kappa B (NF-κB) inhibitor that was previously isolated from Rolandra fruticosa. The effects associated with the inhibition of the NF-κB pathway included dose-dependent inhibition of the NF-κB subunit p65 (RelA) and inhibition of upstream mediators IKKß and oncogenic Kirsten rat sarcoma (K-Ras). The inhibitory concentration of 13-acetoxyrolandrolide on K-Ras was 7.7 µM. The downstream effects of the inhibition of NF-κB activation were also investigated in vitro. After 24 h of treatment with 13-acetoxyrolandrolide, the mitochondrial transmembrane potential was depolarized in human colon cancer (HT-29) cells. The mitochondrial oxidative phosphorylation was also negatively affected, and reduced levels of nicotinamine adenine dinucleotide phosphate (NAD(P)H) were detected after 2 h of 13-acetoxyrolandrolide exposure. Furthermore, the expression of the pro-apoptotic protein caspase-3 increased in a concentration-dependent manner. Cell flow cytometry showed that 13-acetoxyrolandrolide induced cell cycle arrest at G1 , indicating that the treated cells had undergone caspase-3-mediated apoptosis, indicating negative effects on cancer cell proliferation. These results suggest that 13-acetoxyrolandrolide inhibits NF-κB and K-Ras and promotes cell death mediated through the mitochondrial apoptotic pathway.

The moral deliberation pathway in veterinary practice: a qualitative study.

BACKGROUND: Veterinarians may face various ethical decisions and potential moral conflicts in clinical practice. The ethical decision-making process often leads to a satisfying resolution. However, when such a process is accompanied by a perceived inability to act according to a person's values, it can lead to psychological distress that characterises moral distress. Theoretical models in professions such as nursing attempt to explain the evolution of moral conflict into moral distress. In veterinary professionals, a model has been proposed to explain this pathway (the moral deliberation pathway). However, empirical data are still lacking on whether veterinary clinicians experience a moral deliberation pathway as hypothesised. METHODS: Using thematic analysis, this qualitative study investigates veterinary clinicians' experiences with moral distress and aims to explain the moral deliberation pathway in these veterinarians. RESULTS: The results suggest that veterinarians' experiences with moral distress follow a deliberation process that can be explained by the proposed moral deliberation pathway. Experiencing a moral conflict leads to moral stress, then either to moral distress or resolution into moral comfort. LIMITATIONS: Self-selection of participants and possible recollection bias may have biased the findings. CONCLUSIONS: The empirical data provided by this study can inform future research and intervention strategies to identify, measure and manage moral distress in the veterinary context.