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Contains fulltext : 250880.pdf (Publisher’s version ) (Open Access) In recent years, unobtrusive measures of self-regulated learning (SRL) processes based on log data recorded by digital learning environments have attracted increasing attention. However, researchers have also recognised that simple navigational log data or time spent on pages are often not fine-grained enough to study complex SRL processes. Recent advances in data-capturing technologies enabled researchers to go beyond simple navigational logs to measure SRL processes with multi-channel data. What multi-channel data can reveal about SRL processes, and to what extent can the addition of peripheral and eye-tracking data with navigational log data change and improve the measurement of SRL are key questions that require further investigation. Hence, we conducted a study and collected learning trace data generated by 25 university students in a laboratory setting, that aimed to address this problem by enhancing navigational log data with peripheral and eye-tracking data. We developed a trace-based measurement protocol of SRL, which interpreted raw trace data from multi-channel data into SRL processes. Specifically, the study compared the frequency and duration of SRL processes detected, how much duration and times of occurrences of the detected SRL processes were affected or refined. We also used a process mining technique to analyses how temporal sequencing of the detected SRL processes changed by enriching navigational log data with peripheral and eye-tracking data. The results revealed that by adding new data channels, we improved the capture of learning actions and detected SRL processes while enhancing the granularity of the measurement. In comparison to the use of navigational logs only, the completeness of temporal sequencing relationships between SRL processes with multi-channel data improved. In addition, we concluded that eye-tracking data is valuable for measuring and extracting SRL processes, and it should receive more attention in the future. 31 p.

Contains fulltext : 250033.pdf (Publisher’s version ) (Open Access) Contemporary research that looks at self-regulated learning (SRL) as processes of learning events derived from trace data has attracted increasing interest over the past decade. However, limited research has been conducted that looks into the validity of trace-based measurement protocols. In order to fill this gap in the literature, we propose a novel validation approach that combines theory-driven and data-driven perspectives to increase the validity of interpretations of SRL processes extracted from trace-data. The main contribution of this approach consists of three alignments between trace data and think aloud data to improve measurement validity. In addition, we define the match rate between SRL processes extracted from trace data and think aloud as a quantitative indicator together with other three indicators (sensitivity, specificity and trace coverage), to evaluate the "degree" of validity. We tested this validation approach in a laboratory study that involved 44 learners who learned individually about the topic of artificial intelligence in education with the use of a technology-enhanced learning environment for 45 minutes. Following this new validation approach, we achieved an improved match rate between SRL processes extracted from trace-data and think aloud data (training set: 54.24%; testing set: 55.09%) compared to the match rate before applying the validation approach (training set: 38.97%; test set: 34.54%). By considering think aloud data as "reference point", this improvement of the match rate quantified the extent to which validity can be improved by using our validation approach. In conclusion, the novel validation approach presented in this study used both empirical evidence from think aloud data and rationale from our theoretical framework of SRL, which now, allows testing and improvement of the validity of trace-based SRL measurements. 39 p.

This work aims at the elucidation of the interfacial interactions established between an epoxy-amine coating and hot-dip galvanized (HDG) steel. The influence of the Zr-based conversion treatment of the substrate and the use of the Cu(II) additive on interfacial bonding is studied. To this purpose, an amine-functionalized molecule – diethylenetriamine (DETA) – is adsorbed. The complex multi-metal oxide surface of the Cu-modified Zr-based converted substrate is decomposed in derivative (simpler) systems. The resulting DETA-adsorbed model and multi-metal surfaces are investigated by X-ray photo-electron spectroscopy (XPS), and by examination of the N 1s peak, the interfacial bond density is determined. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is performed to discriminate between the different metal oxide contributions present on the substrate surface. Preferential adsorption of the DETA molecule on the zinc atoms is found on converted substrates. The interfacial bonding with the Cu cationic sites introduced by the copper additive is proven.

Aim Discharge summaries (DS) form the mainstay of communication between primary and secondary care following inpatient episodes. Poor quality DS often leads to poor continuity of care. We aim to audit the quality of DS following admission under general surgery and improve DS by implementing a DS checklist. Methodology A prospective audit was conducted for 100 DS across 4 surgical wards (emergency and elective) between 1/1/2021 to 1/3/2021. Data collection included the clinical summary, operation details, significant investigation results and follow up plans. A DS checklist was created and introduced at junior doctor induction. A re-audit was conducted prospectively on 100 DS produced from 1/8/2021 to 1/10/2021. Results A general improvement in quality of DS is seen across different domains. In particular, operation date (76.1% vs 90.1%, p=0.019), abnormal blood test results (89% vs 97%, p=0.323), outpatient investigations (72% vs 85%, p=0.025) and their urgency (39.6% vs 43.3%, p=0.741), GP plans and actions (73% vs 81%, p=0.178) and outpatient appointments (85% vs 93%, p=0.037). Interestingly, details of clinical summary (98% vs 94%, p=0.149) and duration of venous thromboembolism (VTE) prophylaxis (99% vs 90%, p=0.005) were worse on reauditing. Conclusion The introduction of DS checklist has significantly improved the quality of documentation and instructions for primary care for most domains. This was not seen for the domain of duration of VTE prophylaxis.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the loss of tolerance to nuclear antigens. Activation of type I interferon (IFN) induced by immune recognition of self-nucleic acids by endosomal Toll-like receptors (TLR) is central to SLE pathogenesis. In two siblings with early-onset SLE, we identified a homozygous mutation in UNC93B1, encoding a multi-transmembrane protein required for trafficking and maturation of endosomal nucleic acid-sensing TLRs. The mutation alters the interaction of UNC93B1 with TLR7 leading to TLR7 hyperactivation with constitutive type I IFN signaling. Moreover, we demonstrate that treatment with the Janus kinase inhibitor ruxolitinib is of therapeutic value.

Regulatory T cells (Tregs) expressing the transcription factor Foxp3 play a critical role in the control of immune homeostasis including the regulation of humoral immunity. Recently, it has become clear that a specialized subset of Tregs, T-follicular regulatory cells (Tfr), have a particular role in the control of T-follicular helper (Tfh) cell-driven germinal center (GC) responses. Following similar differentiation signals as received by Tfh, Tfr gain expression of characteristic chemokine receptors and transcription factors such as CXCR5 and BCL6 allowing them to travel to the B-cell follicle and deliver in situ suppression. It seems clear that Tfr are critical for the prevention of autoimmune antibody induction. However, their role in the control of foreign antigen-specific antibody responses appears more complex with various reports demonstrating either increased or decreased antigen-specific antibody responses following inhibition of Tfr function. Due to their recent discovery, our understanding of Tfr formation and function still has many gaps. In this review, we discuss our current knowledge of both Tregs and Tfr in the context of humoral immunity and how these cells might be manipulated in order to better control vaccine responses.

Contains fulltext : 251952.pdf (Publisher’s version ) (Open Access) Self-regulated learning (SRL) has been linked to improved learning and corresponding learning outcomes. However, there is a need for more precise insights into how SRL during learning contributes to specific learning outcomes. We operationalised four learning outcomes that varied on two dimensions: structure/connectedness and level/deepness of knowledge. Specifically, we assessed how surface knowledge measured with a domain knowledge test (independent concepts) and a concept map (connected concepts), and deep knowledge measured with a transfer test (independent concepts) and an essay (connected concepts) were associated with frequencies of SRL activities during learning, assessed by concurrent think aloud, while taking into account students’ metacognitive and prior knowledge. Forty-four university students performed a 45-minute problem-solving task integrating information about three topics to write a vision essay on the future of education. Results of the pre-/post-test analysis revealed a learning gain in domain knowledge and concept maps. Low cognitive activities were associated with all knowledge measures, except the concept maps and transfer. Furthermore, specific low cognitive activities showed either a positive or negative association; for example, processing showed a positive association with essay, but a negative association with domain knowledge. High cognitive activities were associated with the essay (connected concepts), but not with the concept map. Both metacognitive activities and knowledge were related to transfer. To conclude, taking the level and structure of knowledge into account helps specify the association between SRL activities during learning and the related learning outcomes. 27 p.

Aims To assess the use of polymeric clips (PC) as an alternative to Endoloops (EL) to secure appendicular stump in adult emergency laparoscopic appendicectomy. Method A retrospective analysis of all patients who underwent emergency laparoscopic appendicectomy from 1/11/19 to 31/10/20, following introduction of polymeric clips in our institute as a safe alternative to endoloops to secure appendicular stump in October 2019. Patient demographics, operative duration, intraoperative findings, methods to control the appendicular mesentery and stump, post-operative length of stay, complications and grade of operating surgeon were compared in both groups (PCvsEL) and data analysed using SPSS. Results A total of 333 patients were included, who underwent laparoscopic appendicectomy and satisfied the inclusion criteria. PC were used in 160 (48%) patients and EL in 173 (52%). Patient demographics, surgeon grade and intra-operative severity of disease were statistically similar between both groups. Mean operative time was 10 minutes shorter in PC group (71 vs 81minutes, p = 0.001). Mesoappendix was ligated by applying laparoscopic titanium clips in EL group 25%, vs 6% PC group (p Conclusion The use of PC in emergency laparoscopic appendicectomy is a safe and effective way to secure the appendicular stump, which results in, not only reduced operating time, but also a significant cost saving (£49/3x Endoloops vs £21/pack of 6x Polymeric clips) to NHS.

Tumour infiltration by regulatory T (Treg) cells contributes to suppression of the anti‐tumour immune response, which limits the efficacy of immune‐mediated cancer therapies. The phosphoinositide 3‐kinase (PI3K) pathway has key roles in mediating the function of many immune cell subsets, including Treg cells. Treg function is context‐dependent and depends on input from different cell surface receptors, many of which can activate the PI3K pathway. In this review, we explore how PI3Kδ contributes to signalling through several major immune cell receptors, including the T‐cell receptor and co‐stimulatory receptors such as CD28 and ICOS, but is antagonized by the immune checkpoint receptors CTLA‐4 and PD‐1. Understanding how PI3Kδ inhibition affects Treg signalling events will help to inform how best to use PI3Kδ inhibitors in clinical cancer treatment.

Item does not contain fulltext Researchers have been struggling with the measurement of Self-Regulated Learning (SRL) for decades. Instrumentation tools have been proposed to help capture SRL processes that are difficult to capture. The aim of the present study was to improve measurement of SRL by embedding instrumentation tools in a learning environment and validating the measurement of SRL with these instrumentation tools using think aloud. Synchronizing log data and concurrent think aloud data helped identify which SRL processes were captured by particular instrumentation tools. One tool was associated with a single SRL process: the timer co-occurred with monitoring. Other tools co-occurred with a number of SRL processes, i.e., the highlighter and note taker captured superficial writing down, organizing, and monitoring, whereas the search and planner tools revealed planning and monitoring. When specific learner actions with the tool were analyzed, a clearer picture emerged of the relation between the highlighter and note taker and SRL processes. By aligning log data with think aloud data, we showed that instrumentation tool use indeed reflects SRL processes. The main contribution is that this paper is the first to show that SRL processes that are difficult to measure by trace data can indeed be captured by instrumentation tools such as high cognition and metacognition. Future challenges are to collect and process log data real time with learning analytic techniques to measure ongoing SRL processes and support learners during learning with personalized SRL scaffolds. LAK21: 11th International Learning Analytics and Knowledge Conference (Irvine, CA, USA, 12-16 April, 2021)

Anti–CTLA-4 mAb is efficacious in enhancing tumor immunity in humans. CTLA-4 is expressed by conventional T cells upon activation and by naturally occurring FOXP3(+)CD4(+) Treg cells constitutively, raising a question of how anti–CTLA-4 mAb can differentially control these functionally opposing T cell populations in tumor immunity. Here we show that FOXP3(high) potently suppressive effector Treg cells were abundant in melanoma tissues, expressing CTLA-4 at higher levels than tumor-infiltrating CD8(+) T cells. Upon in vitro tumor-antigen stimulation of peripheral blood mononuclear cells from healthy individuals or melanoma patients, Fc-region–modified anti–CTLA-4 mAb with high antibody-dependent cell-mediated cytotoxicity (ADCC) and cellular phagocytosis (ADCP) activity selectively depleted CTLA-4(+)FOXP3(+) Treg cells and consequently expanded tumor-antigen–specific CD8(+)T cells. Importantly, the expansion occurred only when antigen stimulation was delayed several days from the antibody treatment to spare CTLA-4(+) activated effector CD8(+)T cells from mAb-mediated killing. Similarly, in tumor-bearing mice, high-ADCC/ADCP anti–CTLA-4 mAb treatment with delayed tumor-antigen vaccination significantly prolonged their survival and markedly elevated cytokine production by tumor-infiltrating CD8(+) T cells, whereas antibody treatment concurrent with vaccination did not. Anti–CTLA-4 mAb modified to exhibit a lesser or no Fc-binding activity failed to show such timing-dependent in vitro and in vivo immune enhancement. Thus, high ADCC anti–CTLA-4 mAb is able to selectively deplete effector Treg cells and evoke tumor immunity depending on the CTLA-4–expressing status of effector CD8(+) T cells. These findings are instrumental in designing cancer immunotherapy with mAbs targeting the molecules commonly expressed by FOXP3(+) Treg cells and tumor-reactive effector T cells.

Redundancy and compensation provide robustness to biological systems but may contribute to therapy resistance. Both tumor-associated macrophages (TAMs) and Foxp3+ regulatory T (Treg) cells promote tumor progression by limiting antitumor immunity. Here we show that genetic ablation of CSF1 in colorectal cancer cells reduces the influx of immunosuppressive CSF1R+ TAMs within tumors. This reduction in CSF1-dependent TAMs resulted in increased CD8+ T cell attack on tumors, but its effect on tumor growth was limited by a compensatory increase in Foxp3+ Treg cells. Similarly, disruption of Treg cell activity through their experimental ablation produced moderate effects on tumor growth and was associated with elevated numbers of CSF1R+ TAMs. Importantly, codepletion of CSF1R+ TAMs and Foxp3+ Treg cells resulted in an increased influx of CD8+ T cells, augmentation of their function, and a synergistic reduction in tumor growth. Further, inhibition of Treg cell activity either through systemic pharmacological blockade of PI3Kδ, or its genetic inactivation within Foxp3+ Treg cells, sensitized previously unresponsive solid tumors to CSF1R+ TAM depletion and enhanced the effect of CSF1R blockade. These findings identify CSF1R+ TAMs and PI3Kδ-driven Foxp3+ Treg cells as the dominant compensatory cellular components of the immunosuppressive tumor microenvironment, with implications for the design of combinatorial immunotherapies.

Multiple modes of immunosuppression restrain immune function within tumors. We previously reported that phosphoinositide 3-kinase δ (PI3Kδ) inactivation in mice confers resistance to a range of tumor models by disrupting immunosuppression mediated by regulatory T cells (Tregs). The PI3Kδ inhibitor idelalisib has proven highly effective in the clinical treatment of chronic lymphocytic leukemia and the potential to extend the use of PI3Kδ inhibitors to nonhematological cancers is being evaluated. In this work, we demonstrate that the antitumor effect of PI3Kδ inactivation is primarily mediated through the disruption of Treg function, and correlates with tumor dependence on Treg immunosuppression. Compared with Treg-specific PI3Kδ deletion, systemic PI3Kδ inactivation is less effective at conferring resistance to tumors. We show that PI3Kδ deficiency impairs the maturation and reduces the capacity of CD8+ cytotoxic T lymphocytes (CTLs) to kill tumor cells in vitro, and to respond to tumor antigen–specific immunization in vivo. PI3Kδ inactivation antagonized the antitumor effects of tumor vaccines and checkpoint blockade therapies intended to boost the CD8+ T cell response. These findings provide insights into mechanisms by which PI3Kδ inhibition promotes antitumor immunity and demonstrate that the mechanism is distinct from that mediated by immune checkpoint blockade.

Dissimilar metal joining is of increasing interest in many structural applications due to its potential to enable light weighting. Light-weight substrates such as aluminum alloys, magnesium alloys and carbon-fiber reinforced polymer (CFRP) are increasingly used in place of conventional steels due to their high strength-to-weight ratios. Two of the main challenges associated with the increased usage of mixed metal systems are galvanic corrosion and challenges with classical joining methods. 1,2. Most joining methods such as riveting, mechanical fasteners, and welding, results in electrical connection between the joined metals, which poses galvanic corrosion issues. Even galvanic isolation approaches such as the use of adhesives can cause galvanic corrosion problems due to the complexity of mixed metal assemblies. In galvanic coupling scenarios, the less noble material experiences severe corrosion and more noble material is protected. It is important to build a fundamental understanding of this phenomenon relative to the metallurgy and electrochemistry of the substrates, as well as the coupling method, to provide effective corrosion mitigation solutions. Electrochemical test techniques such as zero resistance ammeter measurements, open circuit potential measurements, and potentiodynamic polarization were utilized to understand effect of substrate type and solution pH on galvanic corrosion. In addition to the substrate effect, the effect of fastener type on galvanic corrosion between substrate and fasteners was also investigated for selected systems. The influence of joining methods such as self-piercing rivets, adhesives, and mechanical fasteners on galvanic corrosion was also studied. Galvanic and self-coupled coupons were exposed to standard laboratory accelerated life cycle test methods. Wedging by corrosion products, scribe creep, and corrosion volume loss were each characterized to quantify the extent of galvanic corrosion after environmental testing. Preliminary results indicated that galvanic coupling enhanced the wedging of substrate by corrosion products when aluminum alloy 6111-T4 (AA 6111-T4) is coupled with cold rolled steel (CRS). In addition, the pitting corrosion of AA 6111-T4 increased when it is coupled with CRS (Figure 1). Although hot dip galvanized (HDG) based galvanic coupons showed no significant wedging by corrosion products, galvanic coupling of CRS with HDG aggravate the scribe creep of HDG. Galvanic isolation methods such as coating before joining or utilizing adhesives significantly reduced galvanic corrosion in the model mixed-material systems. Figure 1. Average pit depth of AA 6111-T4 substrate coupled with different mixed-metal substrates after various exposure times in neutral and acidic cyclic corrosion tests (CCT). Acknowledgements: Research was sponsored by the Army Research Laboratory, the Tank Automotive Research Design Engineering Center, and Drexel University under Cooperative Agreement W911NF-13-2-0046 and related sub awards. References: LeBozec, N., LeGac, A., Thierry, D., Materials and Corrosion, 2012, 63 (5), pp 408 - 415. Calabrese, L., Proverbio, E., Pollicino, E., Galtieri, G., Borsellino, C., Corrosion Engineering, Science and Technology, 2015, 50 (1), pp 10-17 Figure 1

Wang Xiaotong’s 王孝通 Jigu suanjing 緝古算經 is primarily concerned with problems in solid and plane geometry leading to polynomial equa­tions which are to be solved numerically using a procedure similar to Horner’s Method. We translate and analyze here six problems in plane geometry. In each case the solution is derived using a dissection of a 3-dimensional object. We suggest an interpretation of one fragmentary comment which at first sight appears to refer to a dissection of a 4-dimensional object.

The oncomir microRNA-125b (miR-125b) is upregulated in a variety of human neoplastic blood disorders and constitutive upregulation of miR-125b in mice can promote myeloid and B-cell leukemia. We found that miR-125b promotes myeloid and B-cell neoplasm by inducing tumorigenesis in hematopoietic progenitor cells. Our study demonstrates that miR-125b induces myeloid leukemia by enhancing myeloid progenitor output from stem cells as well as inducing immortality, self-renewal, and tumorigenesis in myeloid progenitors. Through functional and genetic analyses, we demonstrated that miR-125b induces myeloid and B-cell leukemia by inhibiting interferon regulatory factor 4 (IRF4) but through distinct mechanisms; it induces myeloid leukemia through repressing IRF4 at the messenger RNA (mRNA) level without altering the genomic DNA and induces B-cell leukemia via genetic deletion of the gene encoding IRF4.

Inhibitors against the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias. As p110δ is primarily expressed in leukocytes, drugs against p110δ have not been considered for the treatment of solid tumours. Here we report that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110δ inactivation in regulatory T cells unleashes CD8(+) cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.

Nature 510, 407–411 (2014); doi:10.1038/nature13444 Queen Mary University London notified Nature and University College London that there is reason to question the provenance of the data for Fig. 5b, d, e of this Letter (Fig. 5a, c data are unaffected). Ongoing studies are investigating the reportedeffect of p110δ inhibition in the pancreatic cancer mouse model.

Recent advances in genome-wide association studies (GWAS) have enabled us to identify thousands of genetic variants (GVs) that are associated with human diseases. As next-generation sequencing technologies become less expensive, more GVs will be discovered in the near future. Existing databases, such as NHGRI GWAS Catalog, collect GVs with only genome-wide level significance. However, many true disease susceptibility loci have relatively moderate P values and are not included in these databases. We have developed GWASdb that contains 20 times more data than the GWAS Catalog and includes less significant GVs (P < 1.0 × 10 -3) manually curated from the literature. In addition, GWASdb provides comprehensive functional annotations for each GV, including genomic mapping information, regulatory effects (transcription factor binding sites, microRNA target sites and splicing sites), amino acid substitutions, evolution, gene expression and disease associations. Furthermore, GWASdb classifies these GVs according to diseases using Disease-Ontology Lite and Human Phenotype Ontology. It can conduct pathway enrichment and PPI network association analysis for these diseases. GWASdb provides an intuitive, multifunctional database for biologists and clinicians to explore GVs and their functional inferences. It is freely available at http://jjwanglab.org/gwasdb and will be updated frequently. © The Author(s) 2011., published_or_final_version

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Crystal modifications and dissolution rate of piroxicam Piroxicam is a nonsteroidal anti-inflammatory drug with low aqueous solubility which exhibits polymorphism. The present study was carried out to develop polymorphs of piroxicam with enhanced solubility and dissolution rate by the crystal modification technique using different solvent mixtures prepared with PEG 4000 and PVP K30. Physicochemical characteristics of the modified crystal forms of piroxicam were investigated by X-ray powder diffractometry, FT-IR spectrophotometry and differential scanning calorimetry. Dissolution and solubility profiles of each modified crystal form were studied and compared with pure piroxicam. Solvent evaporation method (method I) produced both needle and cubic shaped crystals. Slow crystallization from ethanol with addition of PEG 4000 or PVP K30 at room temperature (method II) produced cubic crystal forms. Needle forms produced by method I improved dissolution but not solubility. Cubic crystals produced by method I had a dissolution profile similar to that of untreated piroxicam but showed better solubility than untreated piroxicam. Cubic shaped crystals produced by method II showed improved dissolution, without a significant change in solubility. Based on the XRPD results, modified piroxicam crystals obtained by method I from acetone/benzene were cube shaped, which correlates well with the FTIR spectrum; modified needle forms obtained from ethanol/methanol and ethanol/acetone showed a slight shift of FTIR peak that may be attributed to differences in the internal structure or conformation.