Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation.

BACKGROUND: Mutations in podocin (NPHS2) are the most common cause of childhood onset autosomal recessive steroid-resistant nephrotic syndrome (SRNS). The disease is characterized by early-onset proteinuria, resistance to immunosuppressive therapy and rapid progression to end-stage renal disease. Compound heterozygous changes involving the podocin variant R229Q combined with another pathogenic mutation have been associated with a mild phenotype with disease onset often in adulthood. METHODS: We screened 19 families with early-onset SRNS for mutations in NPHS2 and WT1 and identified four disease-causing mutations (three in NPHS2 and one in WT1) prior to planned whole-exome sequencing. RESULTS: We describe two families with three individuals presenting in childhood who are compound heterozygous for R229Q and one other pathogenic NPHS2 mutation, either L327F or A297V. One child presented at age 4 years (A297V plus R229Q) and the other two at age 13 (L327F plus R229Q), one with steadily deteriorating renal function. CONCLUSIONS: These cases highlight the phenotypic variability associated with the NPHS2 R229Q variant plus pathogenic mutation. Individuals may present with early aggressive disease.

Dolutegravir plus Abacavir-Lamivudine for the treatment of HIV-1 infection

BACKGROUND: Dolutegravir (S/GSK1349572), a once-daily, unboosted integrase inhibitor, was recently approved in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. Dolutegravir, in combination with abacavir-lamivudine, may provide a simplified regimen. METHODS: We conducted a randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1000 copies per milliliter or more. Participants were randomly assigned to dolutegravir at a dose of 50 mg plus abacavir-lamivudine once daily (DTG-ABC-3TC group) or combination therapy with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine once daily (EFV-TDF-FTC group). The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. Secondary end points included the time to viral suppression, the change from baseline in CD4+ T-cell count, safety, and viral resistance. RESULTS: A total of 833 participants received at least one dose of study drug. At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (88% vs. 81%, P = 0.003), thus meeting the criterion for superiority. The DTG-ABC-3TC group had a shorter median time to viral suppression than did the EFV-TDF-FTC group (28 vs. 84 days, P<0.001), as well as greater increases in CD4+ T-cell count (267 vs. 208 per cubic millimeter, P<0.001). The proportion of participants who discontinued therapy owing to adverse events was lower in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (2% vs. 10%); rash and neuropsychiatric events (including abnormal dreams, anxiety, dizziness, and somnolence) were significantly more common in the EFV-TDF-FTC group, whereas insomnia was reported more frequently in the DTG-ABC-3TC group. No participants in the DTG-ABC-3TC group had detectable antiviral resistance; one tenofovir DF-associated mutation and four efavirenz-associated mutations were detected in participants with virologic failure in the EFV-TDF-FTC group. CONCLUSIONS: Dolutegravir plus abacavir-lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz-tenofovir DF-emtricitabine. Copyright © 2013 Massachusetts Medical Society.

Reactions of One-Electron-Oxidized Methionine with Oxygen: An ab initio study

A one-electron oxidation of a methionine residue is thought to be a key step in the neurotoxicity of the beta amyloid peptide of Alzheimer's disease. The chemistry of the radical cation of N-formylmethioninamide (11+) and two model systems, dimethyl sulfide (1+) and ethyl methyl sulfide (6+), in the presence of oxygen have been studied by B3LYP/6-31G(d) and CBS-RAD calculations. The stable form of 11+ has a three-electron bond between the sulfur radical cation and the carbonyl oxygen atom of the i - 1 residue. The radical cation may lose a proton from the methyl or methylene groups flanking the oxidized sulfur. Both 11+ and the resultant C-centered radicals may add oxygen to form peroxy radicals. The calculations indicate that unlike C-centered radicals the sulfur radical cation does not form a covalent bond to oxygen but rather forms a loose ion-induced dipole complex with an S-O separation of about 2.7 Å, and is bound by about 13 kJ mol-1 (on the basis of 1+ + O2). Direct intramolecular abstraction of an H atom from the C site is unlikely. It is endothermic by more than 20 kJ mol-1 and involves a high barrier (G = 79 kJ mol-1). The -to-S C-centered radicals will add oxygen to form peroxy radicals. The OH BDEs of the parent hydroperoxides are in the range of 352-355 kJ mol-1, similar to SH BDEs (360 kJ mol-1) and C-H BDEs (345-350 kJ mol-1). Thus, the peroxy radicals are oxidizing species comparable in strength to thiyl radicals and peptide backbone C-centered radicals. Each peroxy radical can abstract a hydrogen atom from the backbone C site of the Met residue to yield the corresponding C-centered radical/hydroperoxide in a weakly exothermic process with modest barriers in the range of 64-92 kJ mol-1.

The back 2 activity trial: education and advice versus education and advice plus a structured walking programme for chronic low back pain.:education and advice versus education and advice plus a structured walking programme for chronic low back pain

BACKGROUND: Current evidence supports the use of exercise-based treatment for chronic low back pain that encourages the patient to assume an active role in their recovery. Walking has been shown it to be an acceptable type of exercise with a low risk of injury. However, it is not known whether structured physical activity programmes are any more effective than giving advice to remain active.

METHODS/DESIGN: The proposed study will test the feasibility of using a pedometer-driven walking programme, as an adjunct to a standard education and advice session in participants with chronic low back pain. Fifty adult participants will be recruited via a number of different sources. Baseline outcome measures including self reported function; objective physical activity levels; fear-avoidance beliefs and health-related quality of life will be recorded. Eligible participants will be randomly allocated under strict, double blind conditions to one of two treatments groups. Participants in group A will receive a single education and advice session with a physiotherapist based on the content of the 'Back Book'. Participants in group B will receive the same education and advice session. In addition, they will also receive a graded pedometer-driven walking programme prescribed by the physiotherapist. Follow up outcomes will be recorded by the same researcher, who will remain blinded to group allocation, at eight weeks and six months post randomisation. A qualitative exploration of participants' perception of walking will also be examined by use of focus groups at the end of the intervention. As a feasibility study, treatment effects will be represented by point estimates and confidence intervals. The assessment of participant satisfaction will be tabulated, as will adherence levels and any recorded difficulties or adverse events experienced by the participants or therapists. This information will be used to modify the planned interventions to be used in a larger randomised controlled trial.

DISCUSSION: This paper describes the rationale and design of a study which will test the feasibility of using a structured, pedometer-driven walking programme in participants with chronic low back pain.

TRIAL REGISTRATION: [ISRCTN67030896].

Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial

BACKGROUND:
Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE--an international, open-label, randomised controlled trial--uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A).
METHODS:
Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544.
FINDINGS:
2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·94 (95% CI 0·74-1·20). [corrected]. 2-year FFS was 51% (95% CI 46-56) in arm A and 51% (95% CI 43-58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20-27] patients in arm A and 64 [25%, 19-30] in arm D). The most common grade 3-5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee.
INTERPRETATION:
Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival.

Detecting Deception in Movement: The Case of the Side-Step in Rugby

Although coordinated patterns of body movement can be used to communicate action intention, they can also be used to deceive. Often known as deceptive movements, these unpredictable patterns of body movement can give a competitive advantage to an attacker when trying to outwit a defender. In this particular study, we immersed novice and expert rugby players in an interactive virtual rugby environment to understand how the dynamics of deceptive body movement influence a defending player’s decisions about how and when to act. When asked to judge final running direction, expert players who were found to tune into prospective tau-based information specified in the dynamics of ‘honest’ movement signals (Centre of Mass), performed significantly better than novices who tuned into the dynamics of ‘deceptive’ movement signals (upper trunk yaw and out-foot placement) (p<.001). These findings were further corroborated in a second experiment where players were able to move as if to intercept or ‘tackle’ the virtual attacker. An analysis of action responses showed that experts waited significantly longer before initiating movement (p<.001). By waiting longer and picking up more information that would inform about future running direction these experts made significantly fewer errors (p<.05). In this paper we not only present a mathematical model that describes how deception in body-based movement is detected, but we also show how perceptual expertise is manifested in action expertise. We conclude that being able to tune into the ‘honest’ information specifying true running action intention gives a strong competitive advantage.

Using Pedometer Step-Count Goals to Promote Physical Activity in Cardiac Rehabilitation: A Feasibility Study of a Controlled Trial

Background: There is a need to improve the effectiveness of strategies to help cardiac rehabilitation patients achieve recommended levels of physical activity; the use of pedometers requires further research. We aimed to examine the feasibility of a randomised controlled trial, of an intervention using pedometer step-count goals, to promote physical activity for cardiac rehabilitation patients. Methods: We invited patients who completed a supervised cardiac rehabilitation programme to participate in this community-based study. Consenting participants wore a Yamax CW-701 pedometer for one week, blinded to stepcount readings, before being randomly allocated to groups. Intervention groups were told their step-counts; working with a clinical facilitator (nurse or physiotherapist) individually, they set daily step-count goals and reviewed these weekly. Baseline step-counts were hidden from controls, who were not given pedometers but received ongoing weekly facilitator support. After six weeks both groups wore ‘blinded’ pedometers for outcome assessment and participated in semi-structured interviews which explored their experiences of the study. Outcomes included rates of uptake, adherence and completion of measures, including step-counts, quality of life (EQ-5D) and stage of behaviour change. Results: Four programme groups were recruited; two received the intervention. Of 68 invitees, 45 participated (66%) (19 intervention; 26 control). Forty-two (93%) completed the outcomes. Baseline characteristics were comparable between groups. Mean steps/day increased more for intervention participants (2,742; 95%CI 1,169 to 4,315) than controls (-42; 95%CI -1,102 to 1,017) (p=0.004). The intervention and on-going clinical contact were welcomed; participants considered that step-counts, compared to time-related targets, encouraged them to become more active. Conclusion: These findings suggest that an intervention using individually tailored step-count goals may help increase and sustain physical activity following a cardiac rehabilitation programme. A definitive randomised controlled trial using blinded outcome measurements is feasible and of potential value in determining how best to translate physical activity advice into practice.

Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial

Background: Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.

Methods: COIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681.

Findings: We registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]).

Interpretation: Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.

Leniency (Amnesty) Plus: A Building Block or a Trojan Horse?

Leniency (amnesty) plus is one of the tools used in the fight against anticompetitive agreements. It allows a cartelist who did not manage to secure complete immunity under general leniency, to secure an additional reduction of sanctions in exchange for cooperation with the authorities with respect to operation of another prohibited agreement on an unrelated market. The instrument was developed in the United States and, in recent years, it was introduced in a number of jurisdictions. This article contextualises the operation of and rationale behind leniency plus, forewarning about its potential procollusive effects and the possibility of its strategic (mis)use by cartelists. It discusses theoretical, moral, and systemic (deterrence-related) problems surrounding this tool. It also provides a comparison of leniency plus in eleven jurisdictions, identifying common design flaws. This piece argues that leniency plus tends to be a problematic and poorly transplanted US legal innovation. Policy-makers considering its introduction should analyse it in light of institutional limits and local realities. Some of the regimes which already introduced it would be better off abandoning it.

One-Electron Reduction of 2-Nitrotoluene, Nitrocyclopentane, and 1-Nitrobutane in Room Temperature Ionic Liquids: A Comparative Study of Butler–Volmer and Symmetric Marcus–Hush Theories Using Microdisk Electrodes

The voltammetry for the reduction of 2-nitrotoluene at a gold microdisk electrode is reported in two ionic liquids: trihexyltetradecylphosphonium tris(pentafluoroethyl)trifluorophosphate ([P-14,P-6,P-6,P-6][FAP]) and 1-ethyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([Emim][NTf2]). The reduction of nitrocyclopentane (NCP) and 1-nitrobutane (BuN) was investigated using voltammetry at a gold microdisk electrode in the ionic liquid [P-14,P-6,P-6,P-6][FAP]. Simulated voltammograms, generated through the use of ButlerVolmer theory and symmetric MarcusHush theory, were compared to experimental data, with both theories parametrizing the data similarly well. An experimental value for the Marcusian parameter, 1 was also determined in all cases. For the reduction of 2-nitrotoluene, this was 0.5 +/- 0.1 eV in both solvents, while for NCP and BuN in [P-14,P-6,P-6,P-6][FAP], it was 2 +/- 0.1 and 5 +/- 0.1 eV, respectively. This is attributed to the localization of charge on the nitro group and the primary nitro alkyls increased interaction with the environment, resulting in a larger reorganization energy.

Plus Ça Change: The 2014 Local Elections in Northern Ireland

The local government elections of 22 May 2014 in Northern Ireland were the first to be held under revised district boundaries, with 11 'super councils' replacing the 26-council model used since 1973. Despite the structural reform, little changed in terms of political party support. Although they suffered some losses, the Democratic Unionist Party and Sinn Féin remained firmly entrenched as the two dominant players at local government level in Northern Ireland. The Ulster Unionist Party enjoyed only a marginal increase in its vote share, while the Social Democratic and Labour Party recorded one of the worst electoral performances in its history. Elsewhere, the Traditional Unionist Voice enjoyed a 'breakthrough' election and the Alliance Party defied widely held predictions that it would suffer at the polls as a result of its role in the Union flag crisis. The campaign was overshadowed by both the concurrent European Parliament contest and several crises of power-sharing at Stormont. As a result, distinctly local government issues received scant and fleeting attention. The contest saw the lowest local election turnout in Northern Ireland's history, continuing a general trend of increasing voter apathy in the province.

Regularity of Wiener-Hopf plus Hankel operators

In this thesis we consider Wiener-Hopf-Hankel operators with Fourier symbols in the class of almost periodic, semi-almost periodic and piecewise almost periodic functions. In the first place, we consider Wiener-Hopf-Hankel operators acting between L2 Lebesgue spaces with possibly different Fourier matrix symbols in the Wiener-Hopf and in the Hankel operators. In the second place, we consider these operators with equal Fourier symbols and acting between weighted Lebesgue spaces Lp(R;w), where 1 < p < 1 and w belongs to a subclass of Muckenhoupt weights. In addition, singular integral operators with Carleman shift and almost periodic coefficients are also object of study. The main purpose of this thesis is to obtain regularity properties characterizations of those classes of operators. By regularity properties we mean those that depend on the kernel and cokernel of the operator. The main techniques used are the equivalence relations between operators and the factorization theory. An invertibility characterization for the Wiener-Hopf-Hankel operators with symbols belonging to the Wiener subclass of almost periodic functions APW is obtained, assuming that a particular matrix function admits a numerical range bounded away from zero and based on the values of a certain mean motion. For Wiener-Hopf-Hankel operators acting between L2-spaces and with possibly different AP symbols, criteria for the semi-Fredholm property and for one-sided and both-sided invertibility are obtained and the inverses for all possible cases are exhibited. For such results, a new type of AP factorization is introduced. Singular integral operators with Carleman shift and scalar almost periodic coefficients are also studied. Considering an auxiliar and simpler operator, and using appropriate factorizations, the dimensions of the kernels and cokernels of those operators are obtained. For Wiener-Hopf-Hankel operators with (possibly different) SAP and PAP matrix symbols and acting between L2-spaces, criteria for the Fredholm property are presented as well as the sum of the Fredholm indices of the Wiener-Hopf plus Hankel and Wiener-Hopf minus Hankel operators. By studying dependencies between different matrix Fourier symbols of Wiener-Hopf plus Hankel operators acting between L2-spaces, results about the kernel and cokernel of those operators are derived. For Wiener-Hopf-Hankel operators acting between weighted Lebesgue spaces, Lp(R;w), a study is made considering equal scalar Fourier symbols in the Wiener-Hopf and in the Hankel operators and belonging to the classes of APp;w, SAPp;w and PAPp;w. It is obtained an invertibility characterization for Wiener-Hopf plus Hankel operators with APp;w symbols. In the cases for which the Fourier symbols of the operators belong to SAPp;w and PAPp;w, it is obtained semi-Fredholm criteria for Wiener-Hopf-Hankel operators as well as formulas for the Fredholm indices of those operators.

Colaboração em didática: utopia, desencanto e possibilidade

O presente estudo ocupa-se de uma problemática em Didática – as relações entre a investigação científica e o desenvolvimento do campo – e assenta no pressuposto de que essas relações se constroem conjugando o pensamento e a atuação de investigadores, académicos, professores, e formadores de professores, numa ação conjunta conduzida com a participação comprometida das suas instituições profissionais e orientada para o desenvolvimento de todos os intervenientes, da sua área de atividade e, assim, do ensino/aprendizagem e dos alunos. Nesse sentido, o estudo foi concebido no intuito de criar condições propícias ao estreitamento das relações em foco, tendo em vista, simultaneamente, o aprofundamento do conhecimento sobre a problemática. Assumiu, pois, uma finalidade de intervenção no terreno e uma finalidade científica de avaliação da experiência proporcionada por essa intervenção, na expectativa do alargamento da compreensão do objeto de estudo. Na confluência dessas finalidades, a investigação desenvolveu-se como um estudo de caso norteado por duas proposições teóricas: - A colaboração entre académicos e professores, no âmbito de projetos de investigação em Didática, e o comprometimento das instituições profissionais de ambos com essas iniciativas colaborativas poderão favorecer o desenvolvimento do campo, dos atores que nele intervêm e das instituições implicadas. - A formação contínua de professores centrada na investigação em Didática poderá constituir espaço privilegiado para o desenvolvimento dessas dinâmicas de colaboração. No alinhamento destas proposições com a finalidade interventiva do estudo, diferentes atores em Didática foram desafiados a envolver-se numa iniciativa de investigação/formação colaborativa e daí resultou o caso analisado nesta investigação, o projeto ICA/DL (Investiga, Colabora e Atua em Didática de Línguas). Tal projeto, realizado no âmbito de uma parceria formalizada num Protocolo de Colaboração, envolveu uma equipa composta por cinco docentes do Departamento de Didática e Tecnologia Educativa (atual Departamento de Educação) da Universidade de Aveiro e por 4 professores da Escola Secundária Dr. João Carlos Celestino Gomes – Ílhavo e implicou ainda, institucionalmente, a universidade, a escola e o Centro de Formação das Escolas do Concelho de Ílhavo (atualmente, Centro de Formação de Associação de Escolas dos Concelhos de Ílhavo, Vagos e Oliveira do Bairro). As atividades do projeto iniciaram-se no final de 2003, com os primeiros encontros de negociação da parceria, e prolongaram-se até meados de 2007, altura em que a equipa reuniu pela última vez. O programa operacional central desenvolveu-se entre janeiro de 2004 e novembro de 2005 e concretizou-se num percurso de investigação e de formação em colaboração entre académicos e professores, concebido e implementado pela equipa e acreditado pelo Conselho Científico-Pedagógico da Formação Contínua. Tal programa centrou-se no estudo de um tópico em Didática de Línguas (a competência de aprendizagem plurilingue), na realização de intervenções de ensino/aprendizagem, no âmbito do mesmo tópico, junto dos alunos na escola e na avaliação da experiência com base em dados empíricos. A investigação que sobre o caso se conduziu, ao orientar-se, na prossecução da segunda finalidade estabelecida, para a compreensão da influência das dinâmicas colaborativas de investigação/formação sobre o desenvolvimento dos intervenientes (equipa, parceiros institucionais e alunos na escola), é também um estudo de impacte. A condução do processo empírico deu prioridade à produção de uma leitura integrada e complexa, capaz de evidenciar os impactes do projeto, interpretando-os com base na análise dos processos que terão condicionado a sua ocorrência. Nessa medida, a metodologia revestiu-se, intencionalmente, de uma natureza eminentemente interpretativa e qualitativa, socorrendo-se da triangulação de fontes, dados e procedimentos de análise. Contudo, o método integrou também procedimentos quantitativos, em particular, um exercício estatístico que, correlacionando totais de evidências verificadas e totais de evidências possíveis, procurou tornar mais precisa a avaliação da dimensão do impacte alcançado pelo projeto. Ensaiou-se, assim, uma abordagem metodológica em estudos de impacte em Educação, que propõe potenciar a compreensão de casos complexos, conjugando interpretação e objetivação/quantificação. A análise desvendou constrangimentos e obstáculos na vivência dos princípios conceptuais fundadores da noção de investigação/formação colaborativa que sustentou as proposições de partida e que fez emergir o ICA/DL. Tais dificuldades limitaram a assunção de responsabilidades partilhadas na condução processual da experiência, condicionaram dinâmicas supervisivas nem sempre colaborativas e facilitadoras e manifestaram-se em atitudes de compromisso por vezes frágil com o projeto. E terão afetado a concretização das expectativas iniciais de desenvolvimento de todos os participantes, determinando impactes de dimensão globalmente algo dececionante, assimetrias substantivas de influência da experiência levada a cabo no desenvolvimento profissional dos elementos da equipa e no desenvolvimento institucional e repercutindo-se em efeitos pouco expressivos no desenvolvimento dos alunos, no que toca a capacidades ativas de comunicação e de aprendizagem, enquadradas pelo tópico didático trabalhado no âmbito do projeto. Mas revelaram-se também sinais claros de que se avançou no sentido da concretização dos pressupostos colaborativos que sustentaram a iniciativa. Foi possível reunir académicos, professores e instituições educativas em torno da ideia de investigação/formação em colaboração e mobilizá-los como parceiros que se comprometeram na construção de um projeto assente nessa ideia. E percebeu-se que, apesar de pouco expressivo, houve impacte, pois há indicadores de que o projeto contribuiu positivamente para o desenvolvimento dos intervenientes. Na equipa, sinalizaram-se efeitos sobretudo nas práticas de ensino/aprendizagem das professoras e, no caso particular de uma delas, que teve uma participação mais envolvida em atividades de investigação, manifestaram-se impactes substancialmente mais notórios do que nos restantes elementos do grupo e que abrangeram diferentes dimensões da profissionalidade. As académicas, embora menos do que as professoras, também evidenciaram desenvolvimento, dominantemente, nos planos da investigação em Didática de Línguas e da formação de professores. E o ICA/DL parece ter proporcionado também impactes positivos junto das instituições implicadas, especialmente junto da universidade, designadamente, no que toca ao aprofundamento do pensamento sobre a problemática que sustentou a experiência e ao desenvolvimento de projetos de investigação. Por seu turno, os alunos, tendo revelado sinais modestos de reforço das suas capacidades de ação como interlocutores em situações de comunicação plurilingue e como aprendentes de línguas, deram mostras claras de terem tomado consciência de atitudes e de recursos que favorecem o desenvolvimento desses dois papéis. Para além disso, os responsáveis pela parceria, apesar dos obstáculos que limitaram o alcance dos seus propósitos, reafirmaram, na conclusão do projeto, a sua confiança nos princípios colaborativos que os uniram, antecipando a continuidade de uma experiência que entenderam como primeiro passo na concretização desses princípios. No balanço das fragilidades vividas e dos ganhos conquistados pelo ICA/DL, o estudo permite renovar a convicção inicial no poder transformador das práticas de investigação/formação colaborativa em Didática, e assim, na emergência de uma comunidade una de professores e de académicos, movida por um projeto comum de desenvolvimento da Educação. Nessa perspetiva, avançam-se sugestões que abrangem a investigação, o processo de ensino/aprendizagem nas escolas, a formação de professores, as políticas em Didática e a Supervisão.

Development of new approaches for the synthesis and decoding of one-bead one-compound cyclic peptide libraries

La plupart des processus cellulaires et biologiques reposent, à un certain niveau, sur des interactions protéine-protéine (IPP). Leur manipulation avec des composés chimiques démontre un grand potentiel pour la découverte de nouveaux médicaments. Malgré la demande toujours croissante en molécules capables d’interrompre sélectivement des IPP, le développement d’inhibiteurs d’IPP est fortement limité par la grande taille de la surface d’interaction. En considérant la nature de cette surface, la capacité à mimer des structures secondaires de protéines est très importante pour lier une protéine et inhiber une IPP. Avec leurs grandes capacités peptidomimétiques et leurs propriétés pharmacologiques intéressan-tes, les peptides cycliques sont des prototypes moléculaires de choix pour découvrir des ligands de protéines et développer de nouveaux inhibiteurs d’IPP. Afin d’exploiter pleinement la grande diversité accessible avec les peptides cycliques, l’approche combinatoire «one-bead-one-compound» (OBOC) est l’approche la plus accessible et puissante. Cependant, l’utilisation des peptides cycliques dans les chimiothèques OBOC est limitée par les difficultés à séquencer les composés actifs après le criblage. Sans amine libre en N-terminal, la dégradation d’Edman et la spectrométrie de masse en tandem (MS/MS) ne peuvent pas être utilisées. À cet égard, nous avons développé de nouvelles approches par ouverture de cycle pour préparer et décoder des chimiothèques OBOC de peptides cycliques. Notre stratégie était d’introduire un résidu sensible dans le macrocycle et comme ancrage pour permettre la linéarisation des peptides et leur largage des billes pour le séquençage par MS/MS. Tout d’abord, des résidus sensibles aux nucléophiles, aux ultraviolets ou au bromure de cyanogène ont été introduits dans un peptide cyclique et leurs rendements de clivage évalués. Ensuite, les résidus les plus prometteurs ont été utilisés dans la conception et le développement d’approches en tandem ouverture de cycle / clivage pour le décodage de chimiothèques OBOC de peptides cycliques. Dans la première approche, une méthionine a été introduite dans le macrocycle comme ancrage pour simultanément permettre l’ouverture du cycle et le clivage des billes par traitement au bromure de cyanogène. Dans la seconde approche, un résidu photosensible a été utilisé dans le macrocycle comme ancrage pour permettre l’ouverture du cycle et le clivage suite à une irradiation aux ultraviolets. Le peptide linéaire généré par ces approches peut alors être efficacement séquencé par MS/MS. Enfin, une chimiothèque OBOC a été préparée et criblée la protéine HIV-1 Nef pour identifier des ligands sélectifs. Le développement de ces méthodologies permttra l’utilisation de composés macrocycliques dans les chimiothèques OBOC et constitue une contribution importante en chimie médicinale pour la découverte de ligands de protéines et le développement d’inhibiteurs d’IPP.

The Professional Legitimacy of the Taiwan-educated versus US-educated Taiwanese English Teachers

Thesis (Ph.D.)--University of Washington, 2015