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CONTRIBUTION: This paper highlights one approach to fostering the entrepreneurial mindset in the engineering classroom. BACKGROUND: Entrepreneurship and innovation are currently trending topics in engineering education and will continue developing for the foreseeable future. INTENDED OUTCOMES: The guiding research question is: How can an entrepreneurial mindset focused learning experience improve student self-regulation, seeing value, and lifelong learning through metacognitive reflections? APPLICATION DESIGN: The study is implemented within a five-week module focused on developing the entrepreneurial mindset as part of a required course on supply chain management technology. The supporting pedagogical interventions include authentic learning, information literacy, a mix of low stakes and high stakes assessment, and parallel scaffold and collaborative learning. The module is assessed through a metacognitive reflection centered around self-regulated learning, seeing value, and lifelong learning. FINDINGS: First, the metacognitive reflections showed ~50% of participants would approach their work differently (e.g., make changes to management and scheduling, using credible sources, obtaining writing assistance through the university writing lab). Second, participants were able to articulate soft skill development and/or subject matter expertise as benefits as it relates to entering the workforce. Third, participants were able to express opportunities for extending their knowledge in the future.

The ATPase family, AAA domain containing 2B (ATAD2B) protein has a C-terminal bromodomain that functions as a ‘reader’ of acetylated lysine residues on histone proteins. However, the molecular mechanisms by which it recognizes chromatin with multiple post-translational modifications remain poorly understood. To gain insights into the recognition of acetylated lysines by the ATAD2B bromodomain, we investigated the recognition of combinatorial histone H4 post-translational modifications using structural and functional approaches. Using isothermal titration calorimetry, we assessed the binding affinities of the ATAD2B bromodomain with distinct histone H4 peptides harboring multiple modifications. Our results show that the ATAD2B bromodomain selectively recognizes acetyllysine residues amongst multiple histone H4 modifications. Most of these adjacent modifications are permissive and exhibit distinctive binding affinities, however, some combinations weaken the acetyllysine interaction. Three novel protein-ligand structures reveal a unique binding mode for the ATAD2B bromodomain compared to the ATAD2 bromodomain, and highlight distinctive residues involved in the coordination of acetylated lysines in the context of adjacent post-translational modifications. To investigate the association of ATAD2B with chromatin, we performed CUT&RUN experiments in human breast cancer cells and compared the genome-wide chromatin binding sites to different regulatory histone modifications. Our results support an association of ATAD2B with endogenous acetylated histone H4. Overall, our study highlights how the interplay between various histone modifications, and combinations thereof, impact the ‘reader’ activity of the ATAD2B bromodomain.

Bromodomains are chromatin reader modules that recognize acetylated lysine. Different bromodomains exhibit a preference for specific patterns of lysine acetylation marks on core and variant histone proteins, however, the functional relationships that exist between histone acetyllysine ligands and bromodomain recognition remain poorly understood. In this study, we examined the ligand specificity of the ATAD2B bromodomain and compared it to its closely related paralog in ATAD2. We show that the ATAD2B bromodomain selects for mono- and di-acetylated histones, and structural analysis identified key residues in the acetyllysine binding pocket that dictate ligand binding specificity. The X-ray crystal structure of the ATAD2B bromodomain in complex with an ATAD2 bromodomain inhibitor was solved at 2.4 Å resolution. This structure demonstrated that critical contacts required for bromodomain inhibitor coordination are conserved between the ATAD2/B bromodomains, and many of these residues play a dual role in acetyllysine recognition. We further characterized a variant of the ATAD2B bromodomain that through alternative splicing loses critical amino acids required for histone ligand and inhibitor coordination. Altogether our results outline the structural and functional features of the ATAD2B bromodomain and identify a novel mechanism important for regulating the interaction of the ATAD2B protein with chromatin.HIGHLIGHTSThe ATAD2B bromodomain recognizes mono- and di-acetylated histone ligands.Chemical shift perturbations outline the ATAD2B bromodomain acetyllysine binding pocket.An ATAD2B bromodomain-inhibitor complex reveals important binding contacts.An alternate splice variant in the ATAD2B bromodomain abolishes histone and inhibitor binding.

The extracellular transporter, lipocalin-type prostaglandin D synthase (L-PGDS) binds to heme and heme metabolites with high affinity. It has been reported that L-PGDS protects neuronal cells against apoptosis induced by exposure to hydrogen peroxide. Our study demonstrates that when human WT L-PGDS is in complex with heme, it exhibits a strong peroxidase activity thus behaving as a pseudo-peroxidase. Electron paramagnetic resonance studies confirm that heme in the L-PGDS-heme complex is hexacoordinated with high-spin Fe(III). NMR titration of heme in L-PGDS points to hydrophobic interaction between heme and several residues within the β-barrel cavity of L-PGDS. In addition to the transporter function, L-PGDS is a key amyloid β chaperone in human cerebrospinal fluid. The presence of high levels of bilirubin and its derivatives, implicated in Alzheimer's disease, by binding to L-PGDS may reduce its chaperone activity. Nevertheless, our ThT binding assay establishes that heme and heme metabolites do not significantly alter the neuroprotective chaperone function of L-PGDS. Guided by NMR data we reconstructed the heme L-PGDS complex using extensive molecular dynamics simulations providing a platform for mechanistic interpretation of the catalytic and transporting functions and their modulation by secondary ligands like Aβ peptides and heme metabolites. Ministry of Education (MOE) Published version The research for this paper was supported by the MOE-Tier 2 grant M4020231. J.R.H. acknowledges support from the ARC (FT120100421).

Technical standards are important documents that academic libraries collect to support education and research, particularly for engineering and technology programs. However, standards documents present many unique discovery and access challenges that are confusing and cumbersome for users. To help alleviate these issues, Elsevier started indexing technical standards in their Abstracting & Indexing (A&I) database Compendex in 2018. This column provides a brief overview of Compendex, a summary of the standards collections currently indexed in the database, and a discussion about using Compendex as a tool for standards discovery and access.

The ATPase family, AAA domain-containing protein 2 (ATAD2/ANCCA), is an AAA nuclear co-regulator protein containing two ATPase domains and a bromodomain. Its closely related paralog, ATAD2B (KIAA1240), also contains two ATPase domains and a bromodomain. The AAA ATPase domains are broadly associated with ATP-driven molecular remodeling reactions while the bromodomains are evolutionarily conserved, chromatin ‘reader’ domains known to regulate gene expression by binding to acetyllysine on histones. Extensive studies on ATAD2 discuss its upregulation and correlation with poor prognosis in various cancers. Despite sharing high structural and sequence similarity with ATAD2, ATAD2B remains a poorly understood paralog. While previous immunostaining studies detected high expression levels of ATAD2B in breast carcinoma, there is minimal information on its role in oncogenesis. Previously, we have shown that the ATAD2B BRD can recognize mono- and di-acetyllysine modifications on N-terminal tails of histones H4 and H2A. However, since initiation and progression of cancer are characterized by multivalent histone marks, our goal is to understand how crosstalk between combinatorial histone modifications affects the acetyllysine recognition activity of the ATAD2B BRD. We hypothesize that the bromodomain recognizes the acetyllysine mark on multivalent histones and interacts with the chromatin and the ATPase domain. We expect that our results will explain the function of the ATAD2B bromodomain in the context of the overall role of ATAD2B in normal biological and cellular processes. Since bromodomains are excellent drug targets, blocking their activity will also suggest how to disrupt their possible role in oncogenesis. In this study, we have combined various innovative and interdisciplinary approaches ranging from biochemistry and structural biology to functional genomics and cellular biology to gain insights into how crosstalk between different histone H4 PTMs can modulate the chromatin ‘reader’ activity of the ATAD2B BRD. Binding affinities obtained from ITC indicate that the ATAD2B BRD can recognize the acetyllysine mark amongst multiple histone H4 PTMs. Most of these adjacent PTMs are permissible and show high affinities, while some combinations weaken the acetyllysine interaction. Our novel X-ray structures demonstrate a unique binding mode of ATAD2B BRD compared to ATAD2. While the difference in ligand selectivity could suggest that ATAD2B may regulate different biological functions, our cellular assays, including western blot and functional genomic studies, indicate that ATAD2B is conserved in its ability to bind the chromatin. Finally, we discuss how known ‘onco’ mutations within the histone H4 tail region, occurring at or around sites of PTMs, can affect the ATAD2B BRD - acetyllysine coordination. Overall, our study highlights how crosstalk between various histone PTMs regulates the ‘reader’ domain of ATAD2B and affects its recruitment to the chromatin, thus providing new insights for developing therapeutic interventions for treating various diseases. Citation Format: Margaret Phillips, Kathleen Quinn, Cameron Montgomery, Samuel P. Boyson, Sunsik Chang, Jay C. Nix, Seth E. Frietze, Karen C. Glass. Insights into the histone code recognition by the ATAD2B bromodomain. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr PR002.

With a significant proportion of the global population growing older (>60 years), the low success rates of current diagnoses for early neurodegeneration signs are disappointing. Early detection of Alzheimer's disease (AD) can improve acclimatization and quality of life for patients in their later years. Endogenous proteins, such as the most abundant secreted protein in cerebrospinal fluid, lipocalin‐type prostaglandin d synthase (L‐PGDS), can bind the early toxic oligomers of amyloid β (Aβ) peptides implicated in AD and prevent their aggregation. Herein, the utility of L‐PGDS for detection of amyloids is demonstrated. L‐PGDS is conjugated with different iron‐oxide magnetic nanoparticles for contrast‐enhanced visualization using magnetic resonance imaging (MRI). These conjugates inhibit amyloid aggregation in vitro and improve viability in neuronal cells incubated with amyloid fibrils, showing a potential neuroprotective function. L‐PGDS‐ferritin conjugates, when administered intraventricularly, localize to AD‐associated amyloid‐rich regions in mice brain imaged using MRI and histological stains. As a proof‐of‐concept, it is demonstrated that L‐PGDS conjugates could reach the brain regions through non‐invasive intranasal administration. These conjugates are developed as the first entirely protein‐based nanoprobes for early detection of brain amyloids. The results of this study open a wider avenue for study of endogenous proteins as potential theranostics for AD.

The ATPase Family, AAA domain-containing protein 2 (ATAD2) bromodomain (BRD) has a canonical bromodomain structure consisting of four α-helices. ATAD2 functions as a co-activator of the androgen and estrogen receptors as well as the MYC and E2F transcription factors. ATAD2 also functions during DNA replication, recognizing newly synthesized histones. In addition, ATAD2 is shown to be up regulated in multiple forms of cancer including breast, lung, gastric, endometrial, renal, and prostate. Furthermore, up-regulation of ATAD2 is strongly correlated with poor prognosis in many types of cancer, making the ATAD2 bromodomain an innovative target for cancer therapeutics. In this study, we describe the recognition of histone acetyllysine modifications by the ATAD2 bromodomain. Residue-specific information on the complex formed between the histone tail and the ATAD2 bromodomain, obtained through nuclear magnetic resonance spectroscopy (NMR) and X-ray crystallography, illustrates key residues lining the binding pocket, which are involved in coordination of di-acetylated histone tails. Analytical ultracentrifugation, NMR relaxation data, and isothermal titration calorimetry further confirm the monomeric state of the functionally active ATAD2 bromodomain in complex with di-acetylated histone ligands. Overall, we describe histone tail recognition by ATAD2 BRD and illustrate that one acetyllysine group is primarily engaged by the conserved asparagine (N1064), the “RVF” shelf residues, and the flexible ZA loop. Coordination of a second acetyllysine group also occurs within the same binding pocket, but is essentially governed by unique hydrophobic and electrostatic interactions making the di-acetyllysine histone coordination more specific than previously presumed.

Misfolding of Amyloid β (Aβ) peptides leads to the formation of extracellular amyloid plaques. Molecular chaperones can facilitate the refolding or degradation of such misfolded proteins. Here, for the first time, we report the unique ability of Lipocalin-type Prostaglandin D synthase (L-PGDS) protein to act as a disaggregase on the pre-formed fibrils of Aβ(1–40), abbreviated as Aβ40, and Aβ(25–35) peptides, in addition to inhibiting the aggregation of Aβ monomers. Furthermore, our proteomics results indicate that L-PGDS can facilitate extraction of several other proteins from the insoluble aggregates extracted from the brain of an Alzheimer’s disease patient. In this study, we have established the mode of binding of L-PGDS with monomeric and fibrillar Aβ using Nuclear Magnetic Resonance (NMR) Spectroscopy, Small Angle X-ray Scattering (SAXS), and Transmission Electron Microscopy (TEM). Our results confirm a direct interaction between L-PGDS and monomeric Aβ40 and Aβ(25–35), thereby inhibiting their spontaneous aggregation. The monomeric unstructured Aβ40 binds to L-PGDS via its C-terminus, while the N-terminus remains free which is observed as a new domain in the L-PGDS-Aβ40 complex model.

Technical standards are a form of gray literature that describe consensus for a wide variety of applications. They promote safety, quality, and interchangeability of parts. In academic libraries, standards have largely been associated with engineering collections, despite having connections to many disciplines. Engineering and technology accreditation bodies and employers continue to expect graduates to have knowledge and experience with standards upon graduation. This article provides a brief history of standards collection development in academic libraries, discusses the challenges of standards collections, shares a case study of standards information literacy curricula integration, and offers considerations for the future of standards collections.

Practicing engineers and undergraduate engineering and technology students seek and use information differently within the research and design process. This paper presents the results of a survey conducted by librarians at Purdue University and information specialists at Caterpillar Inc. to analyze self-reported information habits and challenges of both user populations. The authors created surveys containing similar questions for each user group, using a framework that asked participants to think about their information needs and use during a recent engineering project. The survey questions discerned users' confidence in their information abilities, and their preferences and barriers for finding and using information. The results of this study reveal differences between students and engineers and are informative for both academic and corporate librarians. Key findings affirm previous research that novices are more confident in their abilities than experts. Additionally, the findings suggest undergraduates prefer quick, easy to digest content like online videos and news, while engineers are more likely to learn by consulting a colleague or other subject expert, and through reading journals and trade literature. While students rated themselves as more confident information users, engineers reported working in a more complex information landscape, which includes internal document management systems and numerous places to look for technical information. Findings within this paper can inform the development of information literacy curricula that better parallels the corporate environment, and can give corporate librarians insight into how recent graduates may expect to interact with information in a new work environment.

The spiroindimicins are a unique class of chlorinated indole alkaloids characterized by three heteroaromatic rings structured around a congested spirocyclic stereocenter. Here, we report the first total synthesis of (+)-spiroindimicin A, which bears a challenging C-3’/C-5’’-linked spiroindolenine. We detail our initial efforts to effect a biomimetic oxidative spirocyclization from its proposed natural precursor, lynamicin D, and describe how these studies shaped our final abiotic 9-step solution to this complex alkaloid built around a key asymmetric Pd-catalyzed spirocyclization. Scalable access to spiroindimicins A, H, and their congeners has enabled discovery of their activity against several parasites relevant to human health, providing potential starting points for new therapeutics for the neglected tropical diseases leishmaniasis and African sleeping sickness.

Contributions: The main contribution is to share a series of practical methods that improve the writing quality of capstone reports. Background: The ability to write well is critical to the success of an engineering technology graduate. However, the evidence points to the fact that industries are disappointed with the quality of writing skills graduates demonstrate. Intended Outcomes: A faculty review of capstone reports showed little improvement in writing quality from the first course to the second in a two-semester capstone sequence. Therefore, the instructors explored what actions were needed to improve the writing quality of the capstone reports. Application Design: Several changes in the capstone courses were developed and implemented. The changes included: 1) using instructional technology as a scaffolding to help frame the writing required for the course and 2) engaging students in iterative writing with feedback. Findings: The assessment data showed a significant improvement, at the 5% level. The iterative process of writing and rewriting the report, coupled with frequent meetings with faculty mentors, proved to be a powerful combination for improving the writing process of the students.

A population of more than six million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aβ-preventing (Aβ1–19) and Aβ-degradation products (Aβ1–20 and Aβ1–34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.

This research work-in-progress paper is a scoping review of published systematic literature reviews (SLRs) in engineering. SLRs are considered one of the highest levels of proof for evidence based decision making, but they are only as good as the methods used, starting with the search strategy. With studies described as "systematic literature reviews" proliferating through engineering disciplines, including engineering education, it is necessary to examine how well these studies reflect a methodologically sound understanding of established SLR processes. The initial search returned 4,992 results, after removing duplicates. After completing the abstract review, we included 2,674 results for full text review. A preliminary analysis of the citations included for full text shows that SLRs have increased dramatically over the past decade in engineering education and approximately 14.1% of included results for full text analysis contain an education related term in the title, abstract, or publication title. This trend implies that more education on the SLR research method may be needed in engineering education graduate programs and through professional development opportunities.

The goal of this research category work-in-progress study is to investigate the information literacy needs and expectations of employers who hire new engineering and technology graduates, through content analysis of job postings. It seeks to answer two questions: (1) Which information sources do employers expect engineering and technology graduates to know and to use on the job and (2) in what ways are new engineering and technology hires expected to interact with information? A collection of 1502 entry-level job postings aimed at undergraduate engineering and engineering technology students was gathered from a university career center database for the time period May 2017 to May 2018. Three researchers coded a sample of the job postings to calibrate and to develop a code book consisting of the types of information mentioned (journal articles, laws and regulations, technical requirements and specifications, product literature, technical reports, patents, and technical standards and codes) and specific ways of interacting with information (gathering, learning, evaluating, using, managing, creating, and communicating). Next, each researcher utilized NVivo to analyze a subset of the postings using the code book. The researchers will conduct additional analysis in order to make sure the data is reliably coded, but some trends are already obvious. Preliminary results suggest that employers often place their emphasis on different sources of information than those traditionally emphasized in academic settings. Job postings that deal with information sources list experience with standards and codes, both in general and citing specific organizations or documents, as the most common information source requirement. In contrast, journal articles and conference proceedings, often the focus of IL instruction, are barely mentioned in this data set. These findings indicate the need for a new approach to information literacy by engineering educators and librarians to better align with workplace information use.

Background – There is a body of information literacy (IL) literature applied to undergraduate engineering students, much of which discusses different methods for teaching, such as classes/one-shots, online tutorials, gaming, and other interventions. It is important for librarians to know which methods of teaching engineering information literacy (EIL) are most effective for student learning, in order to make efficient and effective use of student and librarian time. Purpose/Hypothesis – The authors reviewed the existing literature to find indications of the most effective methods for teaching and/or integrating EIL, both in face-to-face and online instruction. Design/Method – The authors have completed the first stages of a systematic literature review (SLR), through the creation of the final dataset. The initial searches generated a set of 1224 papers prior to duplicate removal. Duplicate removal and multiple rounds of review, using authors-created inclusion and exclusion criteria, narrowed the final dataset to 13 papers. Scope/Method – The lessons learned in the process around searching, tools for data evaluation, and articulation of criteria are presented. As a result of this portion of the SLR process, the authors identified characteristics of the undergraduate-focused EIL literature that are shared. Results/Discussion – A brief summary of the process to arrive at a final dataset of 13 papers, the challenges in the process, and the refinements made at each step are outlined. Conclusion – There are several preliminary conclusions to be drawn, many of which will not be surprising to the engineering librarian community. The dataset came down to just 13 items because much of the EIL literature is based on student self-report data on how the class went, or was it enjoyable, rather than on actual student learning gains. As such, these papers did not meet the criteria for demonstrated learning gains as a measure of effectiveness. In addition, some papers were excluded for lack of clarity about methods. In these studies it is not evident how either the intervention and/or the assessment was conducted, with regard to timing, instrument used, etc. Some additional papers were excluded because a control or comparison group was not included to establish “effectiveness” of the intervention. Overall, the authors note the EIL literature frequently reports descriptive statistics, showing that data has been gathered, but sometimes falls short of a full analysis that allows the researchers to draw meaningful/well- grounded conclusions from the data.

Anticholinergic drugs can be used as a treatment for many diseases. However, anticholinergic drugs are also known for their cognition-related side effects. Recently, there has been an increasing number of reports indicating a positive association between exposure to anticholinergic drugs and Alzheimer's disease (AD). Our novel study provides evidence of interactions between two representative anticholinergic drugs [Chlorpheniramine (CPM), a common antihistamine, and Trazodone (TRD), an antidepressant] with neuroprotective amyloid-beta (Aβ) chaperone, lipocalin-type prostaglandin D synthase (L-PGDS) and the amyloid beta-peptide (1–40). Here, we demonstrate that CPM and TRD bind to L-PGDS with high affinity where chlorpheniramine exhibited higher inhibitory effects on L-PGDS as compared to Trazodone. We also show that the interactions between the drug molecules and Aβ(1–40) peptides result in a higher fibrillar content of Aβ(1–40) fibrils with altered fibril morphology. These altered fibrils possess higher cytotoxicity compared to Aβ(1–40) fibrils formed in the absence of the drugs. Overall, our data suggest a mechanistic link between exposure to anticholinergic drugs and increased risk of Alzheimer's disease via inhibition of the neuroprotective chaperone L-PGDS and direct modification of Aβ amyloid morphology and cytotoxicity. Ministry of Education (MOE) Nanyang Technological University Published version The research reported in this publication was supported by the Ministry of Education, AcRF Tier 2, Singapore under grant number M4020231 and funding is provided by Singapore Ministry of Education, AcRF Tier 1, ‘Structural basis of amyloid seeds disaggregation’ to K. P. under grant number of M4012175. Electron microscopy work was undertaken at the NTU Institute of Structural Biology Cryo-EM lab at Nanyang Technological University, Singapore. We thank P. Padmanabhan and Y. Xia for their assistance in MTT cell assays.

Endogenous brain proteins can recognize the toxic oligomers of amyloid-β (Aβ) peptides implicated in Alzheimer’s disease (AD) and interact with them to prevent their aggregation. Lipocalin-type Prostaglandin D Synthase (L-PGDS) is a major Aβ-chaperone protein in the human cerebrospinal fluid. Here we demonstrate that L-PGDS detects amyloids in diseased mouse brain. Conjugation of L-PGDS with magnetic nanoparticles enhanced the contrast for magnetic resonance imaging. We conjugated the L-PGDS protein with ferritin nanocages to detect amyloids in the AD mouse model brain. We show here that the conjugates administered through intraventricular injections co-localize with amyloids in the mouse brain. These conjugates can target the brain regions through non-invasive intranasal administration, as shown in healthy mice. These conjugates can inhibit the aggregation of amyloids in vitro and show potential neuroprotective function by breaking down the mature amyloid fibrils.

A population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grownin vitrofrom non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss.Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-geneBACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21-organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1-inhibitors. Combined, our data prove the physiological role ofBACE2as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ∼30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.

The objective of this study was to investigate effective methods of teaching information literacy to engineering undergraduate students. The authors searched several databases (e.g., Compendex, Scopus, ERIC) for English language studies published between January 2000 and January 2016 that contained both an information literacy intervention for engineering undergraduate students and an assessment method for evaluating the intervention's effectiveness. Thirteen studies were included in the final data set, of which eleven studies reported effective results based largely upon descriptive statistical analysis. The strongest indicator of effectiveness that emerged in the data was collaboration with disciplinary faculty. With few articles in the final results set containing inferential statistics, the authors were only able to draw limited conclusions regarding effectiveness. The low use of such statistical methods highlights a need for librarian researchers to develop skills with research design and statistical analysis. This study is one of few systematic reviews on the topic of information literacy and the first systematic review on engineering information literacy effectiveness. It intends to serve as a baseline for future work.

Introduction Little is known about long-term work sustainability of stroke survivors. A feasibility trial of early stroke specialist vocational rehabilitation had 32/46 (69.5%) participants available for follow-up at 12 months post stroke. Of these, 19/32 (59.4%) were in work. This study aims to determine the feasibility of longer-term follow-up and explore work status 6 years post stroke. Method Forty-eight participants fitting criteria for the feasibility trial were sent postal questionnaires measuring employment, income, mood, functional ability and quality of life, and were invited for interview to explore working 6 years after stroke. Ethical approval was obtained. Results Of the 48 participants, five (10.4%) had died; 19/43 (44.2%) responded. Fourteen were men; mean age 62 (24–78) years. Fourteen (74%) reported working (paid work n = 10, voluntary work n = 3, full-time education n = 1). Five had retired. Most (11/13) remained with preinjury employers. Half (8/15, 53%) reported decreased income since stroke. Compared to one year, median functional ability was marginally higher (extended activities of daily living 63 (IQR 8, range 32–66) to 60 (IQR 9, range 17–66)), but health-related quality of life was lower (EuroQuol Visual Analogue Scale mean 77.4 [SD 11] to 70.7 [SD14]). Six interviewees felt returning to work was the correct decision but struggled with invisible impairments. Conclusion This study suggests that long-term follow-up is feasible and that those who made a good recovery were more likely to respond. Work remains important to stroke survivors 6 years post stroke.

Cytochromes P450 (CYP) are one of the major xenobiotic metabolizing enzymes with increasing importance in pharmacogenetics. The CYP2C9 enzyme is responsible for the metabolism of a wide range of clinical drugs. More than sixty genetic variations have been identified in CYP2C9 with many demonstrating reduced activity compared to the wild-type (WT) enzyme. The CYP2C9*8 allele is predominantly found in persons of African ancestry and results in altered clearance of several drug substrates of CYP2C9. The X-ray crystal structure of CYP2C9*8, which represents an amino acid variation from arginine to histidine at position 150 (R150H), was solved in complex with losartan. The overall conformation of the CYP2C9*8-losartan complex was similar to the previously solved complex with wild type (WT) protein, but it differs in the occupancy of losartan. One molecule of losartan was bound in the active site and another on the surface in an identical orientation to that observed in the WT complex. However, unlike the WT structure, the losartan in the access channel was not observed in the *8 complex. Furthermore, isothermal titration calorimetry studies illustrated weaker binding of losartan to *8 compared to WT. Interestingly, the CYP2C9*8 interaction with losartan was not as weak as the CYP2C9*3 variant, which showed up to three-fold weaker average dissociation constant compared to the WT. Taken together, the structural and solution characterization yields insights into the similarities and differences of losartan binding to CYP2C9 variants and provides a useful framework for probing the role of amino acid substitution and substrate dependent activity.

NVivo (QSR International, n.d.a) is software developed by QSR International for qualitative data analysis, such as content analysis and narrative analysis. The software provides a workspace for researchers to store, manage, query, and analyze unstructureddata, including text, images, audio, video, and other data types. NVivo has been used inmany library and information science studies, including to analyze interview data (Wiley& Mischo, 2016), student assignments (Insua, Lantz, & Armstrong, 2018; Phillips & Zwicky, 2017), and survey data (Gibbs, Boettcher, Hollingsworth & Slania, 2012). NVivo allows users to complete multiple qualitative analysis functions on the platform, including sorting and filtering raw data, discovering and building relationships amongdata, assigning and defining themes and categories for data, visualizing data analysis results, and creating reports. This article reviews NVivo on the following five criteria: functionality, learnability, collaboration, support, and cost.

ObjectivesAdults with knee instability related to neuromuscular disorders or central nervous conditions often experience mobility problems and rely on orthoses to improve function and mobility. Patient views of device effectiveness and acceptability are underexplored. Our study aimed to elicit device users’ perspectives regarding fitting, acceptability, effectiveness and use of orthoses, and identify important treatment outcomes.DesignQualitative descriptive study using in-depth semistructured interviews. Interview transcriptions were coded and thematically analysed, using ‘Framework’.Setting and participantsA purposive sample of 24 adult users of orthotic devices. Nineteen patients were recruited across three National Health Service sites, and five people through charities/patient support groups in England. Half of the participants had been diagnosed with poliomyelitis, and the remainder with multiple sclerosis, Charcot-Marie-Tooth disease, spinal injury or spina bifida, and stroke. The median age of participants was 64.5 years (range 36–80 years).ResultsPatients’ medical condition impacted significantly on daily life. Participants relied on orthotic devices to enable engagement in daily activities. Patient goals for mobility were linked to individual circumstances. Desired treatment outcomes included reduction in pain, trips and falls, with improved balance and stability. Effectiveness, reliability, comfort and durability were the most valued features of orthoses and associated with reported use. Obtaining suitable footwear alongside orthotic devices was a significant concern. Time pressures during device fitting were viewed negatively.ConclusionsOrthotic devices for knee instability play a crucial role in promoting, maintaining and enhancing physical and psychological health and well-being, enabling patients to work, engage in family life and enjoy social activities. Future research should consider how best to measure the impact of orthotic devices on patient quality of life and daily functioning outside the clinic setting, as well as device use and any adverse effects.Trial registration numberThis qualitative study was retrospectively registered as Current Controlled TrialsISRCTN65240228.

Epidemiology is the study of the frequency and distribution of disease, and of the causes, associations, and effects of those diseases. It allows us to think of how these aspects of a condition apply to whole populations. In rehabilitation, this can help with planning of rehabilitation services at international, national, regional, and local levels; identifying deficits in service provision to assist in advocacy and to highlight where change may be needed; comparing services in different areas in order to explore different models of practice; and identifying future trends. This chapter contains useful definitions and describes methods for collecting epidemiological data and factors that are affected for people with disabilities (participation, activities, cost of living, rehabilitation needs, etc.), covering the basics of epidemiology in rehabilitation medicine.

This chapter first describes common musculoskeletal disorders of the upper limb, including adhesive capsulitis of the shoulder, glenohumeral joint arthritis, acromioclavicular joint arthritis, rotator cuff disease, tennis elbow/lateral epicondylalgia and golfer’s elbow/medial epicondylalgia, De Quervain’s tenosynovitis/intersection syndrome, Dupuytren’s contracture, carpal tunnel syndrome, and work-related upper limb disorders. It then goes on to describe common musculoskeletal disorders of the lower limb including osteoarthritis, greater trochanter pain syndrome, tendinopathy: patellar tendon/Achilles tendon/tibialis posterior tendon, plantar fasciopathy, and Morton’s neuroma. Management of symptoms and assessment of cases are all described and suggestions for further reading and useful websites are given.

Freedom of movement is an essential component of independence and mobility is closely associated with quality of life. People who have difficulty with independent walking often require a wheelchair to assist with mobility. The International Classification of Functioning, Disability and Health model can be used to guide the provision of wheelchairs and seating through consideration of the individual personal factors and preferences, environmental limitations, the person’s desired activities and participation in life roles, as well as the person’s health condition or impairments of body structure and function. This chapter describes the steps in prescribing a wheelchair, types of manual and powered wheelchairs, and specialized seating and positioning components.

This chapter focuses on those situations where the effects of a critical illness can produce additional morbidity with the potential to affect later rehabilitation. In the context of critical illness, much of this additional morbidity takes the form of readily predictable complications resulting from the disease process or the consequences of its early management. In this sense, rehabilitation principles should be an essential and integrated part of management in the intensive care unit (ICU) setting. Even though it is occurring in ICU, the goals of rehabilitation are unchanged—to maximize the potential for the person to maximize their short- and long-term functional capacity and quality of life. This chapter also describes rehabilitation in specific critical illnesses.

The neurodegenerative conditions (NDGCs) encompass a wide variety of neurological conditions, with varying signs, symptoms, age of onset, prognoses, and underlying pathologies. However, they share a number of features. The aims of this chapter are to describe the essentials of some of the more frequent NDGCs that are not covered elsewhere in this handbook, to indicate symptoms that are common features, and to provide an overview of some of the strategies that may be useful. The individual conditions are not described in depth; a textbook of neurology is recommended for this.

Amputee rehabilitation involves the multidisciplinary assessment of all amputees and the resultant advice and therapy delivered. It is essential that treatment is delivered in a patient-centred manner and timely fashion. Amputee rehabilitation includes patients over a wide spectrum of ages—from a baby born with an upper or lower limb deformity or deficiency to an elderly patient with vascular disease and multiple medical comorbidities. Amputee rehabilitation is no longer concerned with only patients who are suitable for limb fitting. It is inclusive of all amputees and the specialist amputee multidisciplinary team should be able to provide valuable advice and therapy to all amputees

This chapter discusses spasticity, a positive feature of disruption of the upper motor neuron pathways following acquired brain injury. After defining spasticity, it covers the prevalence and impact on limb function, methods of measurement (to monitor the outcomes of rehabilitation), goal setting, and management. Physical interventions by the physiotherapist and occupational therapist are described (as well as interventions to manage paresis and develop motor control), and pharmacological interventions (such as oral and intrathecal medications, and injectables) and their use in both treatment and management are discussed. The case for surgical intervention is also made for certain cases.

Injection-based interventions are a useful addition to the rehabilitation physician’s practice. These can occur in either inpatient or outpatient settings and be for musculoskeletal (e.g. joint/soft tissue injections) or neurological conditions (such as antispasticity injections and nerve blocks). Local steroid injection is a well-proven and effective treatment for focal pain and inflammation, and this chapter covers commonly used steroid injections, as well as different agents and procedures with their indications (including botulinum toxin injection). It provides a guide to the use of appropriate general injection techniques and includes tables showing the dose and duration of action of commonly used steroids and local anaesthetics for injections.

Mobility is a function of everyday life that allows us the freedom to move between places for work, social events, and activities of daily living. Reduction in mobility leads to activity limitations and participation restrictions, may increase dependence on others, and adversely affects the quality of life of the person, carers, and family. This chapter covers the anatomy and physiology of mobility and the gait cycle, then the effect of pathology on the gait. Assessing and examining mobility is covered in the context of planning rehabilitation programmes. Gait analysis, including three-dimensional computerized biomechanical assessment, is explained. Interventions and goals in gait rehabilitation are outlined, and avoidance and reduction of falls is also explained.