Introduction Distributed simulations of complex systems to date have focused on scalability and correctness rather than interactive visualization. Interactive visual simulations have particular advantages for exploring emergent behaviors of complex systems. Interpretation of simulations of complex systems such as cancer cell tumors is a challenge and can be greatly assisted by using "built-in" real-time user interaction and subsequent visualization. Methods We explore this approach using a multi-scale model which couples a cell physics model with a cell signaling model. This paper presents a novel communication protocol for real-time user interaction and visualization with a large-scale distributed simulation with minimal impact on performance. Specifically, we explore how optimistic synchronization can be used to enable real-time user interaction and visualization in a densely packed parallel agent-based simulation, whilst maintaining scalability and determinism. We also describe the software framework created and the distribution strategy for the models utilized. The key features of the High-Performance Computing (HPC) simulation that were evaluated are scalability, deterministic verification, speed of real-time user interactions, and deadlock avoidance. Results We use two commodity HPC systems, ARCHER (118,080 CPU cores) and ARCHER2 (750,080 CPU cores), where we simulate up to 256 million agents (one million cells) using up to 21,953 computational cores and record a response time overhead of ≃350 ms from the issued user events. Discussion The approach is viable and can be used to underpin transformative technologies offering immersive simulations such as Digital Twins. The framework explained in this paper is not limited to the models used and can be adapted to systems biology models that use similar standards (physics models using agent-based interactions, and signaling pathways using SBML) and other interactive distributed simulations.


Objective The aim of this study was to evaluate the subclinical influence of uncomplicated cataract surgery on foveal thickness and volume in the early postoperative period in diabetic and nondiabetic patients. Background Diabetic patients pose a particular challenge because of the tendency for early formation of cataract in them and propensity to develop macular edema after cataract surgery. Patients and methods A prospective nonrandomized study was carried out on 50 eyes of 43 patients, which were divided into two groups. Group 1 included 25 eyes of diabetic patients and group 2 included 25 eyes of nondiabetic patients. Optical coherence tomography was performed to measure initial and 1-month postoperative mean foveal thickness (MFT). Exclusion criteria were as follows: dense cataract that did not permit the measurement of the central macular thickness, proliferative diabetic retinopathy (DR), chronic uveitis, and any posterior segment pathologies other than nonproliferative DR. Results MFT increased significantly in both groups. In group 1 it increased initially from 254.88 ± 32.53 to 310.52 ± 64.74 at 1 month postoperatively (P = 0.001). In group 2 it increased initially from 228.28 ± 18.65 to 269.16 ± 23.59 at 1 month postoperatively (P = 0.001). There was no difference in initial logarithm of minimal angle of resolution visual acuity between the two groups: in group 1 it was 0.80 ± 0.05 and in group 2 it was 0.80 ± 0.06 (P = 0.801). Postoperative logarithm of minimal angle of resolution visual acuity was significantly different: in group 1 it was 0.43 ± 0.23 and in group 2 it was 0.25 ± 0.11 (P = 0.001). Conclusion Increase in MFT occurred after uncomplicated phacoemulsification in diabetic and nondiabetic eyes; the range of increased MFT was more in diabetic patients with higher initial MFT or higher grade of DR preoperatively.


In the present study, the AZ 31B Mg alloy was isothermally upsetted by multi axial forging. Two increasing temperatures (350°C and 400°C) and working ratios (0.3 and 0.4 per direction) were selected as variables in the multi axial forging. The forging operation was performed in a 10000 kN industrial hydraulic press at a forging speed of 33.3 mm/s. The grain structure and microstructure of the forged alloy were investigated using an optical microscope. The hardness measurements were taken and correlated with the grain size of the alloy. The key findings from the present investigation are: (1) the grain refinement can be retained by decreasing the forging temperature (350°C) and the reduction ratio (0.3 per direction), (2) increasing working ratio favours the preferential grain growth resulting in bimodal size distribution of grains in the microstructure and that results in significant variation in the hardness, (3) the grain growth is severe for the case of higher temperature (400°C) and working ratio (0.4 per direction) forging condition, and (4) the forging temperature affects the grain growth larger extent than the working ratio. The mechanisms responsible for the grain refinement and abnormal grain growth are discussed in detail.


In Turkey, the profession orientation programs for elementary education students have a critical importance. In the aspect of profession orientation application, the least dealt population is unfortunately the elementary school students. In this study, the problems caused by insufficient orientation and guidance of profession for those students are investigated and a web based software is developed to reduce these problems as much as possible. Mentality fields are determined in accordance with Multi-Intelligence theory and recommendations are presented to students in order to get more achievement for profession selection using a software developed for this purpose.


Biologics are being used increasingly in the treatment of Inflammatory Bowel Disease. However, up to 40% of patients do not respond to biologics. Therefore, methods to predict response are imperative. We aimed to identify novel genes and pathways predictive of anti-TNF response in patients with Ulcerative Colitis (UC) undergoing electronic chromoendoscopy and probe confocal laser endomicroscopy (pCLE). We further evaluated the ex-vivo binding of fluorescent labelled biologics as markers of response

 26 UC patients starting anti-TNF therapy as standard of care were recruited. Pre-treatment colonoscopy, with electronic chromoendoscopy and pCLE (Cellvizio, Mauna Kea) by injecting intravenous fluorescein (2.5-5mls), was performed to assess disease activity. Targeted biopsies were taken for fluorescein isothiocyanate (FITC)-labelled infliximab staining and RNA extraction and gene expression analysis. Ex vivo labelling was evaluated by an automated analysis: after a first pre-processing step to remove biases, the labelled regions were identified using statistical multi-level thresholding, and evaluated as area and intensity. To assess response, the same endoscopic procedure was repeated at week 12–14 after anti-TNF. cDNA libraries were prepared using QIAseq UPX 3'Transcriptome reagents and sequenced. Normalised gene expressions were obtained through the CLC Genomics Workbench. Differentially expressed genes (DEGs) (FDR-corrected P-value<0.05) were determined using the Limma package and PLS-DA modelling performed to calculate their importance (VIP score). Functionally related genes were identified and classified using DAVID tools. Strongest indicators of response were predicted by Random Forest area under the curve (AUC) analysis in this cohort and a similar validation cohort

 At baseline increased binding of the labelled biologic was associated with a higher likelihood of response to treatment (AUROC81%, accuracy77%, PPV100%, NPV63%). 342 DEGs (75 up-regulated, 267 down-regulated) distinguished responders from non-responders, 76 fell within enriched pathways. Pathways related to inflammation, chemotaxis, TGF-beta signalling, extracellular matrix and carbohydrate metabolism were reduced and cell-cell adhesion increased in responders pre-treatment. Among the 37 genes with VIP>1, CRIP2, CXCL6,EMILIN1,GADD45B, LAMA4 and MAPKAPK2 were upregulated in non-responders pre-treatment and were good predictors of response (AUROC>0.7) in this cohort and validation cohort

 A higher mucosal binding of the biologics before treatment was observed in anti-TNF responders. Responsive UC patients have a less inflamed and fibrotic state pre-treatment. Chemotactic pathways, involving CXCL6 may be novel targets to treat non-responders


The publication of pattern-books for embroidery and lace work, which began in the 1520s, went on to enjoy extraordinary commercial success. Traditionally regarded chiefly as a virtuous domestic pastime for women, these activities have been considered devoid of any productive or economic significance. This essay, by contrast, connects their fortunes with the evolution of urban manufacture, specifically to transformations in the production of clothing and domestic furnishings for both men and women, particularly in Venice. It explores the reasons for the transition from embroidery on cloth, until the fifteenth century a monopoly of men, to precise needlework and the refinement of laceworking technique, now associated with female practitioners. This evolution thus encourages reflection on the fluidity of the sexual division of labor. In addition, however, embroidery pattern-books were not destined for workers, whether male or female, solely in the field of textile decoration. Rather, they also served as a repertoire of figuration adopted by a wide range of artists and artisans, such as metalworkers, goldsmiths, leatherworkers, and ceramists and potters.


Androgenic hormones regulate many aspects of animal social behavior, including the elaborate display routines on which many species rely for advertisement and competition. One way that this might occur is through peripheral effects of androgens, particularly on skeletal muscles that control complex movements and postures of the body and its limbs. However, the specific contribution of peripheral androgen-muscle interactions to the performance of elaborate behavioral displays in the natural world has never been examined. We study this issue in one of the only natural physiological models of animal acrobatics: the golden-collared manakin (Manacus vitellinus). In this tropical bird, males compete with each other and court females by producing firecracker-like wing- snaps and by rapidly dancing among saplings over the forest floor. To test how activation of peripheral androgen receptors (AR) influences this display, we treat reproductively active adult male birds with the peripherally selective antiandrogen bicalutamide (BICAL) and observe the effects of this manipulation on male display performance. We not only validate the peripheral specificity of BICAL in this species, but we also show that BICAL treatment reduces the frequency with which adult male birds perform their acrobatic display maneuvers and disrupts the overall structure and fine-scale patterning of these birds' main complex wing-snap sonation. In addition, this manipulation has no effect on the behavioral metrics associated with male motivation to display. Together, our findings help differentiate the various effects of peripheral and central AR on the performance of a complex sociosexual behavioral phenotype by indicating that peripheral AR can optimize the motor skills necessary for the production of an elaborate animal display.


ABSTRACT Argumentation is widely recognised as a core practice of science, but the relation between argumentation in the teaching of science in contrast to the teaching of other school subjects has not been sufficiently addressed. In this study, we investigate science and religious education (RE) teachers' instructional practices related to argumentation in lower secondary lessons in England. Through qualitative analysis of a pair of science and RE teachers' instructional practices, we characterise how the teachers participating in a professional development project understand and teach argumentation. Data sources included questionnaires, lesson materials, classroom video recordings, and written teacher reflections. Findings suggest that both teachers recognised the value of argumentation in their subject, but some variations existed in the nuances of their views and particularly how different instructional strategies were utilised to achieve the lesson goals related to argumentation. The study highlights the teachers' different understandings and enactments of argumentation as a disciplinary practice and an instructional objective in science and RE lessons. We call for further consideration of argumentation in different school subjects and how argumentation can enrich science teaching in interdisciplinary contexts.


During aging the electrical and mechanical phenomena of the heart are impaired. We studied the effect of aging using standard microelectrode technique on action potentials obtained in papillary muscle from 1, 3, 6 and 18 month old rats. The action potential of myocardial cells is significantly prolonged and changes resemble those observed during cardiac overload. The possible cause of the slower action potentials is the alteration of Ca2+ transients due to a reduced rate of Ca2+ sequestration by the sarcoplasmic reticulum associated with a possible alteration of K+ currents. These developmental changes are considered as an expression of adaptation of the heart with aging.


Techniques for predicting the availability of CPU resources associated with the execution of multiple concurrent Java threads on a multi-core architecture are introduced. Prediction of CPU availability is important in the context of making thread assignment and scheduling decisions. Theoretically derived upper and lower bound formulas for estimating CPU availability are introduced. Input parameters to the formulas include: number of cores; number of threads; and the unloaded CPU usage factor for each thread. Extensive experimental studies and statistical analysis are performed to validate the theoretical bounds and provide a basis for an empirical model for predicting CPU availability. To facilitate scientific and controlled empirical evaluation, synthetically generated threads are employed that are parameterized by their unloaded CPU usage factor, defined as the fraction of time a thread spends utilizing CPU resources on an unloaded system.


Introduction: Breakfast is considered the most important meal of the day, providing the essential nutrient for the day's activities for children and adolescents ( kleinman et al 2002;kawafha et al 2013). Breakfast skipping among adolescents and children which lead to lifestyle disorders (Keski-rahkonen et al 2003; Rampersaud et al 2005) Aims and Objectives: To analyse and promote health awareness in the society about the danger of skipping breakfast among children and adolescents. Materials and Methodology: From this systematic review analytical study from more than 30 journals we have studied that how skipping breakfast is harmful to health and it creates dangerous consequences to both children and adolescents in their physical and psychological aspects. Conclusion: Thus, highlighting the impact of health education on diet and its influence on health of human health and how life gets more pronounced were major outcome of this study findings.


This paper examines the changed situation in the field of Christian Old Testament theology in the aftermath of the Shoah or Holocaust. It begins by pointing to the paradigm shift now taking place in the field as it moves from Enlightenment epistemological paradigms of historical objectivity and universality to postmodern paradigms that emphasize the subjectivity of the interpreter and the validity of particularistic truth claims in a pluralistic world. It points to the dominance of Protestant theology and theologians in the field during the Enlightenment and the impact that Protestant Christianity had in presenting its own subjective theological views of the Old Testament as objective and universal, often with anti-Jewish overtones. With the emergence of Jews and other previously marginalized groups in the field of biblical studies since the end of World War II, the time has come to recognize that Jews are legitimate theological interpreters of the Bible and that the specific concerns of Judaism and the Jewish people are valid topics for theological reflection in the field of Christian Old Testament theology. This new situation has tremendous implications for the theological interpretation of biblical writings in that issues and writings that were previously overlooked, ignored, or rejected must come to the forefront. Two examples, the book of Amos and the book of Esther, demonstrate the potential for such change. Recognition of Amos' particular national identity as a Judean points to his partisan nature as an advocate of a vassal state of Judah that is subject to the control of the northern kingdom of Israel. The absence of G-d in the book of Esther points to the human responsibility to take action when confronted with evil. Altogether, this points to the possibility of more comprehensive theological reading of the Hebrew Bible.


The proteasomal system is a promising target for cancer treatment. Quercetin (Que), a flavonoid compound with antitumor ability, displays the inhibitory effect on proteasome activity. However, the underlying molecular mechanisms are ill defined. The present study found that Que treatment significantly reduced the chymotrypsin-like protease activity of proteasome whereas the trypsin- and caspase-like protease activities remained unchanged in HepG2 cancer cells, along with activation of p38 MAPK and JNK and reduction of ERK1/2 phosphorylation. Que-reduced proteasome activity could not be reverted by inhibition of p38 MAPK and JNK signaling pathway. In addition, MEK1 overexpression or knockdown upregulated or downregulated the chymotrypsin-like protease activity of proteasome, respectively. Both Que and MEK1/ERK1/2 inhibitor attenuated the expression levels of proteasome β subunits. These results indicate that Que-induced suppression of MEK1/ERK1/2 signaling and subsequent reduction of proteasome β subunits is responsible for its inhibitory impacts on proteasome activity.


Economic data gathering via Internet and other sources, data entry into spreadsheets and graphic techniques, statistics using spreadsheets, and introduction to basic regression.


Two types of representations for relation between queue-size and waiting-time distributions are studied. By using these, an incomplete but conceptually nice generalization of Pollaczek–Khinchine formula for mean waiting time for M/G/c is obtained.


Under s 23 of the Crimes Act 1961, defendants in New Zealand that are deemed insane at the time of committing the actus reus of an offence are able to be found not guilty by reason of insanity. As the defendant cannot be found criminally responsible for their actions, they are not punished with a criminal record or prison sentence. However, due to public safety concerns, those acquitted under the insanity defence are usually required to undertake compulsory mental health treatment and are therefore dealt with under the health system, in lieu of the criminal justice system. Due to this, victims of those found not guilty by reason of insanity are not afforded the same rights as victims that fall under the ambit of the criminal justice system. With the current focus on victims' rights following the Te Tangi o te Manawanui Recommendations for Reform as part of the H paitia te Oranga Tangata Safe and Effective Justice initiative, attention is also being focused on improving the experience for victims of those found not guilty by reason of insanity. The recent drawing from the ballot of the Rights for Victims of Insane Offenders Private Member's Bill and the publicity surrounding Wendy Hamer's victims' rights petition has highlighted the need to discuss this issue. Using cases from New Zealand, Canada and Australia, this paper considers why reform is needed and considers how the rights and interests of victims of defendants found not guilty by reason of insanity can be strengthened, whilst still ensuring the overarching rationale of the insanity defence is protected. A number of suggested reforms intended to improve victims' rights are found to be inappropriate due to the fact they undermine the key rationales of the defence: treatment, not punishment; community safety; and the medical nature of decision making. The paper recommends and concludes that strengthening service rights and providing specialised assistance will provide a better system for victims of those found not guilty by reason of insanity without undermining the working of the defence itself.


This letter reports the impact of metal work function (/spl Phi//sub M/) on memory properties of charge-trap-Flash memory devices using Fowler-Nordheim program/erase mode. For eliminating electron back tunneling and hole back tunneling through the blocking oxide during an program/erase operation, a gate with /spl Phi//sub M/ of 5.1-5.7 eV on an Al/sub 2/O/sub 3/-SiN-SiO/sub 2/ (ANO) stack is necessary. Compared to a thickness optimized n/sup +/ poly-Si/ONO stack, a high-work-function gate on an ANO stack shows dramatic improvements in retention versus minimum erase state.


Stress shielding and subsequent implant loosening is a very common challenge in a total hip arthroplasty (THA) and hip resurfacing surgeries. Load path in the bone altered by implant need to be studied carefully to develop implants having long term success. Stress distribution in the proximal femur is found to produce mechanical stimuli which activate the mechanotransduction pathways to induce bone remodeling in surrounding region. In current study, Computer aided (CAD) model of intact femur, implanted femur and femur bone with resurfacing cup were modeled to represent pre and post operating geometry. Finite element analysis was performed by imposing 3D muscle forces and hip contact force during normal activity. The von mises stress distribution in the geometries was calculated. Study reveals that the stress distribution in the proximal femur is strongly affected by the patient activity and surgical procedure. Predominant stress shielding was observed in implanted femur, especially in lateral region of trochanters. Resurfaced cup model found to retain the physiological load transfer across the femur.


In this study, security and safety in rural parts of Sweden is investigated. New ways of organizing for efficient response can be found in the extended collaboration between societal sectors and in utilizing the local social capital. New categories of first responders and their requirements are identified and we propose non-technical and technical solutions as support. The results' application to large-scale crises is discussed.


OBJECTIVES
Cutaneous dermatomyositis (DM) is often refractory to multiple medications. Repository corticotropin injection (RCI) is FDA-approved for DM, but little is known about its efficacy and safety for treating cutaneous DM. We conducted a prospective, open-label trial assessing efficacy and safety of RCI for treating refractory cutaneous DM.

METHODS
DM patients with moderate-to-severe cutaneous activity [Cutaneous Dermatomyositis Disease Area and Severity Index activity (CDASI-A)] >14 despite prior treatment with ≥2 systemic agents were enrolled. Patients were initiated on 80 u RCI twice weekly for 6 months. Primary outcomes included significant decreases in CDASI-A and Physician's Global Assessment (PGA) scores at 6 months.

RESULTS
Of nineteen patients enrolled, fifteen patients (11 females, 4 males) with DM (7 classic, 8 amyopathic) completed 6 months of RCI treatment. Patients were treated with a median 3.0 systemic medications prior to enrolment and were taking a median of 2.0 systemic medications at enrolment. Median baseline CDASI-A score was 19.0 and median PGA activity score was 2.5/10. For patient-reported outcomes, baseline median patient global skin score (PtGSS) was 3.0/10 and median dermatology life quality index (DLQI) score was 7.0/10. At 6 months, there were statistically significant improvements in CDASI-A scores (median= 10.0), PGA scores (median= 0.8/10), PtGSS scores (median= 7.0) and DLQI scores (median= 2.0), among others. Adverse effects were mild.

CONCLUSIONS
RCI treatment resulted in statistically significant and clinically meaningful improvement in cutaneous DM activity and quality of life. Our results suggest RCI is an effective, safe, and well-tolerated treatment for patients with refractory cutaneous dermatomyositis.

CLINICAL TRIAL REGISTRATION
This clinical trial was registered with ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT01906372).