The genetics, structure and function of the M1 aminopeptidase oxytocinase subfamily and their therapeutic potential in immune-mediated disease

The oxytocinase subfamily of M1 aminopeptidases plays an important role in processing and trimming of peptides for presentation on major histocompatibility (MHC) Class I molecules. Several large-scale genomic studies have identified association of members of this family of enzymes, most notably ERAP1 and ERAP2, with immune-mediated diseases including ankylosing spondylitis, psoriasis and birdshot chorioretinopathy. Much is now known about the genetics of these enzymes and how genetic variants alter their function, but how these variants contribute to disease remains largely unresolved. Here we discuss what is known about their structure and function and highlight some of the knowledge gaps that affect development of drugs targeting these enzymes

Solution Structure of the Link Module: A Hyaluronan-Binding Domain Involved in Extracellular Matrix Stability and Cell Migration

AbstractLink modules are hyaluronan-binding domains found in proteins involved in the assembly of extracellular matrix, cell adhesion, and migration. The solution structure of the Link module from human TSG-6 was determined and found to consist of two α helices and two antiparallel β sheets arranged around a large hydrophobic core. This defines the consensus fold for the Link module superfamily, which includes CD44, cartilage link protein, and aggrecan. The TSG-6 Link module was shown to interact with hyaluronan, and a putative binding surface was identified on the structure. A structural database search revealed close similarity between the Link module and the C-type lectin domain, with the predicted hyaluronan-binding site at an analogous position to the carbohydrate-binding pocket in E-selectin

Personalizing neoadjuvant chemotherapy for locally advanced colon cancer:protocols for the international phase III FOxTROT2 and FOxTROT3 randomized controlled trials

AIM: FOxTROT1 established a new standard of care for managing locally advanced colon cancer (CC) with neoadjuvant chemotherapy (NAC). Six weeks of neoadjuvant oxaliplatin and fluoropyrimidine (OxFp) chemotherapy was associated with greater 2-year disease-free survival (DFS) when compared with proceeding straight to surgery (STS). There is now a need to refine the use of NAC and identify those most likely to benefit. FOxTROT2 will aim to investigate NAC in older adults and those with frailty. FOxTROT3 will aim to assess whether intensified triplet NAC provides additional benefits over OxFp.METHOD: FOxTROT2 and FOxTROT3 are international, open-label, phase III randomized controlled trials. Eligible patients will be identified by the multidisciplinary team. Patient age, frailty and comorbidities will be considered to guide trial entry. Participants will be randomized 2:1 to the intervention or control arm: 6 weeks of dose-adapted neoadjuvant OxFp versus STS in FOxTROT2 and 6 weeks of neoadjuvant modified oxaliplatin, 5-fluorouracil and irinotecan versus OxFp in FOxTROT3. The primary endpoint in FOxTROT2 is 3-year DFS. In FOxTROT3, tumour regression grade and 3-year DFS are co-primary endpoints.DISCUSSION: FOxTROT2 and FOxTROT3 will establish the FOxTROT platform, a key part of our long-term strategy to develop neoadjuvant treatments for CC. FOxTROT2 will investigate NAC in a population under-represented in FOxTROT1 and wider research. FOxTROT3 will assess whether it is possible to induce greater early tumour responses and whether this translates to superior long-term outcomes. Looking ahead, the FOxTROT platform will facilitate further trial comparisons and extensive translational research to optimize the use of NAC in CC.</p

Does moderate intensity exercise attenuate the postprandial lipemic and airway inflammatory response to a high-fat meal?

Citation: Stephanie P. Kurti, Sara K. Rosenkranz, Morton Levitt, et al., “Does Moderate Intensity Exercise Attenuate the Postprandial Lipemic and Airway Inflammatory Response to a High-Fat Meal?,” BioMed Research International, vol. 2015, Article ID 647952, 10 pages, 2015. doi:10.1155/2015/647952We investigated whether an acute bout of moderate intensity exercise in the postprandial period attenuates the triglyceride and airway inflammatory response to a high-fat meal (HFM) compared to remaining inactive in the postprandial period. Seventeen (11 M/6 F) physically active (≥150 min/week of moderate-vigorous physical activity (MVPA)) subjects were randomly assigned to an exercise (EX; 60% VO[subscript 2peak]) or sedentary (CON) condition after a HFM (10 kcal/kg, 63% fat). Blood analytes and airway inflammation via exhaled nitric oxide (eNO) were measured at baseline, and 2 and 4 hours after HFM. Airway inflammation was assessed with induced sputum and cell differentials at baseline and 4 hours after HFM. Triglycerides doubled in the postprandial period (~113 ± 18%, P < 0.05 ), but the increase did not differ between EX and CON. Percentage of neutrophils was increased 4 hours after HFM (~17%), but the increase did not differ between EX and CON. Exhaled nitric oxide changed nonlinearly from baseline to 2 and 4 hours after HFM (P < 0.05, ƞ² = 0.36) . Our findings suggest that, in active individuals, an acute bout of moderate intensity exercise does not attenuate the triglyceride or airway inflammatory response to a high-fat meal

Structured near-infrared Magnetic Circular Dichroism spectra of the Mn₄CaO₅ cluster of PSII in T. vulcanus are dominated by Mn(IV) d-d 'spin-flip' transitions

Photosystem II passes through four metastable S-states in catalysing light-driven water oxidation. Variable temperature variable field (VTVH) Magnetic Circular Dichroism (MCD) spectra in PSII of Thermosynochococcus (T.) vulcanus for each S-state are reported. These spectra, along with assignments, provide a new window into the electronic and magnetic structure of Mn₄CaO₅. VTVH MCD spectra taken in the S₂state provide a clear g=2, S=1/2 paramagnetic characteristic, which is entirely consistent with that known by EPR. The three features, seen as positive (+) at 749nm, negative (-) at 773nm and (+) at 808nm are assigned as ⁴A→²E spin-flips within the d³ configuration of the Mn(IV) centres present. This assignment is supported by comparison(s) to spin-flips seen in a range of Mn(IV) materials. S₃ exhibits a more intense (-) MCD peak at 764nm and has a stronger MCD saturation characteristic. This S₃ MCD saturation behaviour can be accurately modelled using parameters taken directly from analyses of EPR spectra. We see no evidence for Mn(III) d-d absorption in the near-IR of any S-state. We suggest that Mn(IV)-based absorption may be responsible for the well-known near-IR induced changes induced in S₂ EPR spectra of T. vulcanus and not Mn(III)-based, as has been commonly assumed. Through an analysis of the nephelauxetic effect, the excitation energy of S-state dependent spin-flips seen may help identify coordination characteristics and changes at each Mn(IV). A prospectus as to what more detailed S-state dependent MCD studies promise to achieve is outlined.We recognise the support of the Australian Research Council through grants DP110104565 and DP150103137 (E.K.), FT140100834 (N.C) and MEXT/JSPS of Japan through a Grant-in-Aid for Specially Promoted Research No. 24000018 (J.R.S.)

Work in Progress: Rigorously Assessing the Anecdotal Evidence of Increased Student Persistence in an Active, Blended, and Collaborative Mechanical Engineering Environment

This work in progress describes an ongoing study of an active, blended, and collaborative (ABC) course environment used in a core mechanical engineering course. This course has built on the growing body of literature citing active learning (Freeman et al., 2014), blended structures (Bowen & Ithaka, 2012), and collaborative engagement (Jeong & Chi, 2007) as positive influences on college and university science, technology, engineering, and math (STEM) outcomes. For the last six years, “Dynamics”, a core mechanical engineering course at a large public university, has utilized in-class activities, frequently-watched problem-solving videos, and a collaborative blog space to realize an ABC environment. On one key metric of course success, the rate of students who drop, fail, or withdraw from (DFW), the course has experienced near-constant improvements since the ABC structures were introduced. In this study, the authors utilize rigorous longitudinal methods to determine whether this drop in DFW rates can be directly attributed to increased implementation of ABC features. The authors hypothesize that as instructors become accustomed to the ABC environment and increase the level of in-class activity, use of blended resources, and collaboration, the likelihood of DFW in each subsequent year would drop. However, in the same time period, each subsequent class entered with higher levels of performance on proxy measures for prior knowledge. We therefore build a logistic regression model to predict individual-level DFW and determine whether the anecdotal drops in DFW that we observe can be attributed to the expansion of the ABC environment. More specifically, we predict likelihood of DFW based on students’ prior knowledge (grade in the preceding course, SAT math score), key demographics (gender, race/ethnicity), the semester and year they took Dynamics, their instructor, their year in school, and their major. We test for year fixed effects {year_t, t = 1, 2, ..., 7} to determine whether odds ratios for DFW consistently and significantly decrease over time. We also test for instructor effects, in particular for differences between the instructors who were involved in the design and development of the ABC environment and more independent instructors who only partially implemented the ABC course components. We anticipate results that will provide more rigorous, less biased, and efficient estimates for the individual- and class-level components that explain variance in DFW rates. These results would provide immediate implications for the next phase of our work, as we assess the next on-term implementation of the course in 2016. Our findings would also have long-term significance for other classes in mechanical engineering and related disciplines and for classes at other institutions that are considering implementing a comprehensive ABC learning environment

Transforming a Dynamics Course to an Active, Blended, and Collaborative Format: Focus on the Faculty

Mechanical engineering programs are increasingly applying educational research by transforming courses to be more interactive and to use a blend of online and face-to-face materials. However, the process of an existing course adopting these new practices is not well studied, and even less is understood about the faculty experience from on-boarding to delivery of a new curriculum or pedagogy. In this study, we follow the translation of an active, blended, and collaborative (ABC) curriculum for a core dynamics course from a large public university (where the ABC curriculum was developed) to a small private university. We use interpretive phenomenology to focus on the lived experience of the instructor newly implementing these course materials, format, and pedagogical approach. Specifically, we address the following research questions: (1) What is the lived experience of a mechanical engineering instructor at a different institution as she adopts and adapts the provided materials and format? (2) How does the experience of this instructor evolve throughout the semester? We use rich qualitative data to understand the experience of the instructor, who taught this course in its prior format and, in Fall 2015, taught the “off-term” core dynamics course via the new ABC structure. Through weekly reflection prompts, pre- and post-semester interviews, and supplementary process data (e.g., notes of weekly meetings between the new implementer and ABC team at the large public university), we describe and characterize the multi-faceted instructor experience. This includes her experience learning about the curriculum and online tools, implementing the class and adjusting her teaching practices, and assessing her students’ engagement with the course and understanding of dynamics concepts. Our findings suggest further areas of inquiry for studies of faculty practices around curriculum adoption, including probing opportunities for cross-institutional collaborations to share materials and transform courses, interrogating variation in mechanical engineering department and student cultures, and studying sources of faculty development and support throughout the course transformation process

Analyzing an Abbreviated Dynamics Concept Inventory and Its Role as an Instrument for Assessing Emergent Learning Pedagogies

The Dynamics Concept Inventory (DCI) is a validated assessment tool commonly used to evaluate student growth within core, gateway-level mechanics courses. This research explored the evaluative use of this tool within the context of Freeform – an emergent course system that buttresses active class meetings with blended and collaborative virtual learning environments, themselves founded upon extensive multimedia content and interactive forums – at Purdue University. The paper specifically considers a number of related issues including: (i) the thoughtful development (via expert content validation) and statistical reliability of an abbreviated DCI instrument, which is more amenable to in-class implementation than the much longer full DCI; (ii) the correlation of abbreviated-DCI performance with exam scores and final course grades for a dynamics course using the Freeform framework with an emphasis on both conceptual understanding and traditional problem-solving skills; and (iii) various inter-section performance metrics in a preliminary study on how an implementation of the abbreviated-DCI may help elucidate the impact of the instructor within the Freeform framework. The results of these analyses supported the validity and reliability of the abbreviated DCI tool, and demonstrated its usefulness in a formal research setting. The preliminary study suggested that the Freeform framework might normalize differences in instructor pedagogical choices and student performance across class sections. These findings indicate that the abbreviated DCI holds promise as a research instrument and lay the groundwork for future inquiry into the impact of the Freeform instructional framework on students and instructors alike

Personalising Neoadjuvant Chemotherapy for Locally Advanced Colon Cancer: Protocols for the International Phase III FOxTROT2 and FOxTROT3 Randomised-Controlled Trials

Aim FOxTROT1 established a new standard of care for managing locally advanced colon cancer (CC) with neoadjuvant chemotherapy (NAC). Six weeks of neoadjuvant oxaliplatin and fluoropyrimidine (OxFp) chemotherapy was associated with greater 2-year disease-free survival (DFS) when compared to proceeding straight to surgery (STS). There is now a need to refine the use of NAC and identify those most likely to benefit. FOxTROT2 will investigate NAC in older adults and those with frailty. FOxTROT3 will assess whether intensified triplet NAC provides additional benefits over OxFp. Methods FOxTROT2 and FOxTROT3 are international, open-label, phase III randomised-controlled trials. Eligible patients will be identified by the multidisciplinary team. Patient age, frailty and comorbidities will be considered to guide trial entry. Participants will be randomised 2:1 to the intervention or control arm: six weeks of dose-adapted neoadjuvant OxFp vs. STS in FOxTROT2 and six weeks of neoadjuvant modified oxaliplatin, 5FU and irinotecan (mFOLFOXIRI) vs. OxFp in FOxTROT3. The primary endpoint in FOxTROT2 is 3-year DFS. In FOxTROT3, tumour regression grade and 3-year DFS are co-primary endpoints. Discussion FOxTROT2 and FOxTROT3 will establish the FOxTROT platform, a key part of our long-term strategy to develop neoadjuvant treatments for CC. FOxTROT2 will investigate NAC in a population under-represented in FOxTROT1 and wider research. FOxTROT3 will assess whether it is possible to induce greater early tumour responses and whether this translates to superior long-term outcomes. Looking ahead, the FOxTROT platform will facilitate further trial comparisons and extensive translational research to optimise the use of NAC in CC