118 research outputs found
A design tool for novice programmers: Working paper series--00-01
Most program design methods are intended for experienced programmers. Beginner friendly program design methods date back to procedural languages, such as Pascal and Basic. These methods lack connections to objects and events since the languages contained neither objects nor events. This paper presents a summary table and a sketch to get novice programmers started in the process of designing a program. The table organizes information about the program requirements and aides in creating a design for a program that may contain events and objects. The sketch represents the calling relationships among the modules in the program. The table and the sketch can be use with an existing method, such as pseudocode. The tools enhance existing methods of design. A new method is not proposed. The most important philosophies in developing the tools were simplicity and guidance. The table guides the student's design efforts and is simple. The columns collect data about what the program does, when it does its tasks, and what data it uses. The rows relate tasks, events, and objects. The table prompts identification of objects and events and makes high-level functionality stand out. The high-level functional design captured by the table is made explicit in the relations sketch
Cognitive, affective and social mechanisms in depression risk: cognition, hostility, and coping style
Although some research has assessed cognitive variables in individuals at risk for depression, few studies have specifically assessed the role of automatic thinking, and virtually no studies have assessed anger and coping in this group. The current study compared measures of these variables in a high-risk group that was defined on the basis of a previous episode of depression, and a control group comprised of low-risk/never depressed individuals. Even though neither group evidenced depressive symptoms at the time of assessment, group comparisons and regression analyses indicated that high-risk individuals reported more negative automatic thoughts than did low-risk participants and that social support seeking, self-blame, and avoidance emerged as coping predictors of risk as did higher levels of anger and hostility. These data thus suggest patterns of interpersonal, behavioural, and cognitive variables that may characterise depression risk. A number of factors make depression a significant public-health concern. Depression is not only associated with substantial emotional distress and psychological impairment, but also with impaired interpersonal, marital, and occupational functionin
A central role for hepatic conventional dendritic cells in supporting Th2 responses during helminth infection
Dendritic cells (DCs) are the key initiators of T-helper (Th) 2 immune responses against the parasitic helminth Schistosoma mansoni. Although the liver is one of the main sites of antigen deposition during infection with this parasite, it is not yet clear how distinct DC subtypes in this tissue respond to S. mansoni antigens in vivo, or how the liver microenvironment might influence DC function during establishment of the Th2 response. In this study, we show that hepatic DC subsets undergo distinct activation processes in vivo following murine infection with S. mansoni. Conventional DCs (cDCs) from schistosome-infected mice upregulated expression of the costimulatory molecule CD40 and were capable of priming naive CD4+ T cells, whereas plasmacytoid DCs (pDCs) upregulated expression of MHC class II, CD86 and CD40 but were unable to support the expansion of either naive or effector/memory CD4+ T cells. Importantly, in vivo depletion of pDCs revealed that this subset was dispensable for either maintenance or regulation of the hepatic Th2 effector response during acute S. mansoni infection. Our data provides strong evidence that S. mansoni infection favors the establishment of an immunogenic, rather than tolerogenic, liver microenvironment that conditions cDCs to initiate and maintain Th2 immunity in the context of ongoing antigen exposure
Coherent Detector Arrays for Millimeter and Submillimeter Astronomy
Progress in many areas of astronomy requires large-area surveys and observations of
extended objects. This includes the cosmic microwave background, nearby galaxies, the
Milky Way, and regions of star-forming regions within our galaxy. The ability to carry
out such studies is critically dependent on the development of affordable high-sensitivity
focal plane arrays, for both spectral line and continuum observations. We discuss a
program for the next decade to develop such technology for ground-based and spacebased
millimeter and submillimeter astronomy. Appropriate technologies exist, but
significant effort is required to make the transition from simply replicating individual
pixels to approaching focal plane array design in an integrated fashion from feeds to
spectrometers for spectral analysis. This advance is essential to realize the full potential
of major new ground-based, suborbital, and future space facilities, and is relevant to the
RMS and EOS panels. The recommended budget for this activity is $65M
Rating the intelligibility of dysarthic speech amongst people with Parkinsonâs Disease: a comparison of trained and untrained listeners
Intelligibility of speech is a key outcome in speech and language therapy (SLT) and research. SLT students frequently participate as raters of intelligibility but we lack information about whether they rate intelligibility in the same way as the general public. This paper aims to determine if there is a difference in the intelligibility ratings made by SLT students (trained in speech related topics) compared to individuals from the general public (untrained). The SLT students were in year 2 of a BSc programme or the first 6 months of a MSc programme. We recorded 10 speakers with Parkinsonâs disease (PD) related speech reading aloud the words and sentences from the Assessment of Intelligibility of Dysarthric Speech. These speech recordings were rated for intelligibility by âtrainedâ raters and âuntrainedâ raters. The effort required to understand the speech was also reported. There were no significant differences in the measures of intelligibility from the trained and untrained raters for words or sentences after adjusting for speaker by including them as a covariate in the model. There was a slight increase in effort reported by the untrained raters for the sentences. This difference in reported effort was not evident with the words. SLT students can be recruited alongside individuals from the general public as naĂŻve raters for evaluating intelligibility in people with speech disorders
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Downwind Coning Concept Rotor for a 25 MW Offshore Wind Turbine
The size of offshore wind turbines over the next decade is expected to continually increase due to reduced balance of station costs per MW and also the higher wind energy at increased altitudes that can lead to higher capacity factors. However, there are challenges that may limit the degree of upscaling which is possible. In this paper, a two-bladed downwind turbine system is upscaled from 13.2 MW to 25 MW, by redesigning aerodynamics, structures, and controls. In particular, three 25 MW rotors have been developed: V1 is the upscaled model, V2 is a partial redesigned model, and V3 is a fully redesigned model. Despite their radically large sizes, it is found that these 25 MW turbine rotors satisfy this limited set of design drivers at the rated condition and that larger blade lengths are possible with cone-wise load-alignment. In addition, flapwise morphing (varying the cone angle with a wind-speed schedule) is investigated in terms of minimizing mean and fluctuating root bending loads using steady inflow proxies for the maximum and damage equivalent load moments. The resulting series of 25 MW rotors, which are the largest ever designed, can be a useful baseline for further development and assessment.
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Adipose tissue macrophage heterogeneity and the role of Tim4âș macrophages in lipid homeostasis
Resident macrophages are essential for the maintenance of tissue homeostasis as they
participate in clearance of apoptotic cells and tissue remodelling and repair. In recent
years, there has been an increased interest in the study of adipose tissue macrophages
(ATMs). In lean individuals, ATMs are important for the control of insulin sensitivity,
thermogenesis, angiogenesis and adipose tissue development. In obesity, the number
and phenotype of ATMs is altered, and is associated with chronic low grade systemic
and local inflammation. These âpro-inflammatoryâ changes are postulated to
contribute to the manifestation of metabolic syndrome. These findings have suggested
that the pool of ATMs is heterogeneous and may change, especially during obesity.
To date, the characterisation of ATMs has been limited largely to the F4/80/CD11b
markers, however the hypothesis of this thesis is that ATMs have distinct phenotype
and function that could influence, in different ways, tissue homeostasis. This thesis
aims to characterise and phenotype ATM subsets in order to better understand their
potential specific role in the tissue. During the course of this research, a novel
population of Tim4+ resident ATMs were identified. An additional aim of this thesis
was to elucidate their role in adipose tissue homeostasis.
Partial bone marrow chimeras were used to identify macrophage origin. The main AT
depots were shielded from irradiation and a donor BM was injected intravenously.
After 8 weeks, the origin of macrophages was analysed using flow cytometry. Tim4,
a phosphatidylserine receptor mediating phagocytosis of apoptotic cells and a marker
found on resident macrophages in other tissues, was used for the first time in adipose
tissue. Four subsets of ATMs were identified: F4/80highCD11c-Tim4+, F4/80highCD11c-
Tim4-; F4/80lowCD11c+Tim4-; F4/80lowCD11c-Tim4-. Interestingly, this newly
described F4/80highTim4+ ATM subset showed the lowest non-host chimerism
compared to the other ATMs, suggesting this is a main self-replenishing resident ATM
population.
To study the impact of obesity on ATM turnover, partial chimeric mice were fed HFD
for 8 weeks. This increased the number of macrophages in AT. However, the different
subsets of ATMs were differentially affected by the diet. Indeed, only a small
proportion of Tim4+ ATMs derived from the bone marrow. In contrast, replenishment
of the 3 other subsets was almost fully dependent on the arrival of monocyte-derived
cells from the bone marrow.
TIMD4, the gene encoding for Tim4, has been highlighted in genetic studies as being
linked with dyslipidaemia. This suggests that Tim4+ ATMs might play a role in lipid
homeostasis. Further characterisation of Tim4 ATMs demonstrated that these Tim4+
ATMs are highly charged in neutral lipid, and also have an increased lysosomal
activity (shown by lysotracker staining) compared to the other ATM subsets. Using
blocking anti-Tim4 antibodies in vivo, I found that Tim4 contributed markedly to free
fatty acid (FFA) release into the plasma after short-term and long term HFD feeding.
In addition, in vitro and in vivo experiments demonstrated that Tim4 could be required
for the uptake of neutral lipids and their integration into lysosomes for degradation,
though this seems to be dependent on the nature of the lipid.
Collectively, these results indicate that Tim4 plays a crucial role in the control of lipid
trafficking under conditions when dietary lipid is in excess. Tim4 allows uptake of
lipids by Tim4+ ATMs and subsequent release of FFA into the circulation. Finally, the
presence of Tim4+ lipid laden ATMs was demonstrated in the human omentum. This
finding may lead to the discovery of new targets to improve metabolic health in obese
patients.
This work stresses the importance of resident ATM population in body lipid
homeostasis as they could be involved in coping with lipid availability in the body and
influence the amount of FFA in the plasma
Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma
© 2014 American Cancer Society. BACKGROUND A current recommendation for locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy with concurrent cisplatin plus adjuvant cisplatin and fluorouracil (PF). In this randomized trial, the authors evaluated the potential therapeutic benefit from changing to an induction-concurrent chemotherapy sequence, replacing fluorouracil with oral capecitabine, and/or using accelerated rather than conventional radiotherapy fractionation. METHODS Patients with stage III through IVB, nonkeratinizing NPC were randomly allocated to 1 of 6 treatment arms. The protocol was amended in 2009 to permit confining randomization to the conventional fractionation arms. The primary endpoint was progression-free survival. Secondary endpoints included overall survival and safety. RESULTS In total, 803 patients were accrued, and 706 patients were randomly allocated to all 6 treatment arms. Comparisons of induction PF versus adjuvant PF did not indicate a significant improvement. Unadjusted comparisons of induction cisplatin and capecitabine (PX) versus adjuvant PF indicated a favorable trend in progression-free survival for the conventional fractionation arm (P = .045); analyses that were adjusted for other significant factors and fractionation reflected a significant reduction in the hazards of disease progression (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.36-0.80) and death (HR, 0.42; 95% CI, 0.25-0.70). Unadjusted comparisons of induction sequences versus adjuvant sequences did not reach statistical significance, but adjusted comparisons indicated favorable improvements by induction sequence. Comparisons of induction PX versus induction PF revealed fewer toxicities (neutropenia and electrolyte disturbance), unadjusted comparisons of efficacy were statistically insignificant, but adjusted analyses indicated that induction PX had a lower hazard of death (HR, 0.57; 95% CI, 0.34-0.97). Changing the fractionation from conventional to accelerated did not achieve any benefit but incurred higher toxicities (acute mucositis and dehydration). CONCLUSIONS Preliminary results indicate that the benefit of changing to an induction-concurrent sequence remains uncertain; replacing fluorouracil with oral capecitabine warrants further validation in view of its convenience, favorable toxicity profile, and favorable trends in efficacy; and accelerated fractionation is not recommended for patients with locoregionally advanced NPC who receive chemoradiotherapy.postprin
CD11c depletion severely disrupts Th2 induction and development in vivo
Although dendritic cells (DCs) are adept initiators of CD4+ T cell responses, their fundamental importance in this regard in Th2 settings remains to be demonstrated. We have used CD11câdiphtheria toxin (DTx) receptor mice to deplete CD11c+ cells during the priming stage of the CD4+ Th2 response against the parasitic helminth Schistosoma mansoni. DTx treatment significantly depleted CD11c+ DCs from all tissues tested, with 70â80% efficacy. Even this incomplete depletion resulted in dramatically impaired CD4+ T cell production of Th2 cytokines, altering the balance of the immune response and causing a shift toward IFN-Îł production. In contrast, basophil depletion using Mar-1 antibody had no measurable effect on Th2 induction in this system. These data underline the vital role that CD11c+ antigen-presenting cells can play in orchestrating Th2 development against helminth infection in vivo, a response that is ordinarily balanced so as to prevent the potentially damaging production of inflammatory cytokines
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