Preparation of Composite Electrospun Membranes Containing Strontium-Substituted Bioactive Glasses for Bone Tissue Regeneration

Barrier membranes used for the treatment of bone tissue defects caused by periodontitis lack the ability to promote new bone tissue regeneration. However, the addition of an osteogenic component to membranes may enhance their regenerative potential. Here the manufacturing of composite membranes made of poly(caprolactone) and strontium-substituted bioactive glass is described using the solution-electrospinning technique, with particles located both inside and on the surface of the fibers. All membranes are characterized using scanning electron microscopy and energy dispersive X-ray spectroscopy, and glass dissolution from within the fibers is investigated in water. In vitro material cytotoxicity is determined using a rat osteosarcoma cell line. Electrospun fibers exhibit porous surfaces and regions of increased diameter where the particles are accumulated. The glass dissolves after immersion in water, releasing dissolution products that are associated with increased pH. Further evidence suggests accelerated polymer degradation due to interactions between both components, which may provide the additional benefit of reducing the pH changes associated with glass dissolution. All compositions are biocompatible in vitro, with the exception of membranes with >50 μg of glass on their surface. In conclusion, these membranes show great potential for bone healing applications, including guided bone regeneration and scaffolds for musculoskeletal tissue engineering

X-ray micro-tomography and pore network modeling of single-phase fixed-bed reactors.

A three-dimensional (3D) irregular and unstructured pore network was built using local topological and geometrical properties of an isometric bead pack imaged by means of a high-resolution X-ray computed micro-tomography technique. A pore network model was developed to analyze the 3D laminar/inertial(non-Darcy) flows at the mesoscopic (pore level) and macroscopic (after ensemble-averaging) levels. The non-linear laminar flow signatures were captured at the mesoscale on the basis of analogies with contraction and expansion friction losses. The model provided remarkably good predictions of macroscopic frictional loss gradient in Darcy and non-Darcy regimes with clear-cut demarcation using channel-based Reynolds number statistics. It was also able to differentiate contributions due to pore and channel linear losses, and contraction/expansion quadratic losses. Macroscopic mechanical dispersion was analyzed in terms of retroflow channels, and transverse and longitudinal Péclet numbers. The model qualitatively retrieved the Péclet-Reynolds scaling law expected for heterogeneous networks with predominance of mechanical dispersion. Advocated in watermark is the potential of pore network modeling to build a posteriori constitutive relations for the closures of the more conventional macroscopic Euler approaches to capture more realistically single-phase flow phenomena in fixed-bed reactor applications in chemical engineering

IL-21 and IL-6 Are Critical for Different Aspects of B Cell Immunity and Redundantly Induce Optimal Follicular Helper CD4 T Cell (Tfh) Differentiation

Cytokines are important modulators of lymphocytes, and both interleukin-21 (IL-21) and IL-6 have proposed roles in T follicular helper (Tfh) differentiation, and directly act on B cells. Here we investigated the absence of IL-6 alone, IL-21 alone, or the combined lack of IL-6 and IL-21 on Tfh differentiation and the development of B cell immunity in vivo. C57BL/6 or IL-21−/− mice were treated with a neutralizing monoclonal antibody against IL-6 throughout the course of an acute viral infection (lymphocytic choriomeningitis virus, LCMV). The combined absence of IL-6 and IL-21 resulted in reduced Tfh differentiation and reduced Bcl6 protein expression. In addition, we observed that these cytokines had a large impact on antigen-specific B cell responses. IL-6 and IL-21 collaborate in the acute T-dependent antiviral antibody response (90% loss of circulating antiviral IgG in the absence of both cytokines). In contrast, we observed reduced germinal center formation only in the absence of IL-21. Absence of IL-6 had no impact on germinal centers, and combined absence of both IL-21 and IL-6 revealed no synergistic effect on germinal center B cell development. Studying CD4 T cells in vitro, we found that high IL-21 production was not associated with high Bcl6 or CXCR5 expression. TCR stimulation of purified naïve CD4 T cells in the presence of IL-6 also did not result in Tfh differentiation, as determined by Bcl6 or CXCR5 protein expression. Cumulatively, our data indicates that optimal Tfh formation requires IL-21 and IL-6, and that cytokines alone are insufficient to drive Tfh differentiation

Generative Embedding for Model-Based Classification of fMRI Data

Decoding models, such as those underlying multivariate classification algorithms, have been increasingly used to infer cognitive or clinical brain states from measures of brain activity obtained by functional magnetic resonance imaging (fMRI). The practicality of current classifiers, however, is restricted by two major challenges. First, due to the high data dimensionality and low sample size, algorithms struggle to separate informative from uninformative features, resulting in poor generalization performance. Second, popular discriminative methods such as support vector machines (SVMs) rarely afford mechanistic interpretability. In this paper, we address these issues by proposing a novel generative-embedding approach that incorporates neurobiologically interpretable generative models into discriminative classifiers. Our approach extends previous work on trial-by-trial classification for electrophysiological recordings to subject-by-subject classification for fMRI and offers two key advantages over conventional methods: it may provide more accurate predictions by exploiting discriminative information encoded in ‘hidden’ physiological quantities such as synaptic connection strengths; and it affords mechanistic interpretability of clinical classifications. Here, we introduce generative embedding for fMRI using a combination of dynamic causal models (DCMs) and SVMs. We propose a general procedure of DCM-based generative embedding for subject-wise classification, provide a concrete implementation, and suggest good-practice guidelines for unbiased application of generative embedding in the context of fMRI. We illustrate the utility of our approach by a clinical example in which we classify moderately aphasic patients and healthy controls using a DCM of thalamo-temporal regions during speech processing. Generative embedding achieves a near-perfect balanced classification accuracy of 98% and significantly outperforms conventional activation-based and correlation-based methods. This example demonstrates how disease states can be detected with very high accuracy and, at the same time, be interpreted mechanistically in terms of abnormalities in connectivity. We envisage that future applications of generative embedding may provide crucial advances in dissecting spectrum disorders into physiologically more well-defined subgroups

The structure and function of Alzheimer's gamma secretase enzyme complex

The production and accumulation of the beta amyloid protein (Aβ) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer’s disease (AD). A multi-subunit enzyme complex, referred to as gamma (γ) secretase, plays a pivotal role in the generation of Aβ from its parent molecule, the amyloid precursor protein (APP). Four core components (presenilin, nicastrin, aph-1, and pen-2) interact in a high-molecular-weight complex to perform intramembrane proteolysis on a number of membrane-bound proteins, including APP and Notch. Inhibitors and modulators of this enzyme have been assessed for their therapeutic benefit in AD. However, although these agents reduce Aβ levels, the majority have been shown to have severe side effects in pre-clinical animal studies, most likely due to the enzymes role in processing other proteins involved in normal cellular function. Current research is directed at understanding this enzyme and, in particular, at elucidating the roles that each of the core proteins plays in its function. In addition, a number of interacting proteins that are not components of γ-secretase also appear to play important roles in modulating enzyme activity. This review will discuss the structural and functional complexity of the γ-secretase enzyme and the effects of inhibiting its activity

Bridging the gap in precision medicine: TranSYS training programme for next-generation scientists

IntroductionIn the evolving healthcare landscape, precision medicine's rise necessitates adaptable doctoral training. The European Union has recognized this and promotes the development of international, training-focused programmes called Innovative Training Networks (ITNs). In this article, we introduce TranSYS, an ITN focused on educating the next generation of precision medicine researchers. In an ambition to go beyond describing the consortium goals, our article explores two key aspects of ITNs: the training and collaboration.MethodsUsing self-report questionnaires, we evaluate the scientific, professional, and personal growth of ESRs over the duration of the ITN and investigate whether this can be linked to network activities.ResultsOur quantitative analysis approach reveals substantial improvements in scientific, professional, and social skills among young researchers facilitated by the engagement in this interdisciplinary network. We provide case studies underlining the advantages of collaborative environments, featuring innovative scientific exchange within TranSYS.DiscussionWhile challenging, ITNs foster positive growth in young researchers, yet exhibit weaknesses such as balancing stakeholder interests and partner commitment. We believe this study may benefit a variety of stakeholders, from prospective ITN creators to industry partners, to design better sustainable training networks going forward

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Contraste de condutividade hidráulica em solos de texturas arenosa e argilosa encontrados nos tributários da margem esquerda do rio tijuco, município de Ituiutaba (MG) / DISTINCTION OF THE HYDRAULIC CONDUCTIVITY BETWEEN SAND AND CLAYEY TEXTURE SOILS FROM TRIBUTARY OF THE TIJUCO LEFT BORDER RIVER, ITUIUTABA, MINAS GERAIS STATE, BRAZIL

O objetivo principal deste trabalho é determinar as diferenças de condutividade hidráulica entre solos de textura arenosa e argilosa nos tributários da margem esquerda do Rio Tijuco, município de Ituiutaba/MG. Utilizou-se as técnicas de anéis concêntricos e open end hole para a determinação das condutividades hidráulicas na superfície do terreno e nas profundidades de 0,5, 1,0 e 1,5 m. Análise granulométrica indicou texturas franco-argilo-arenosa para os latossolos vermelhos, e argilosa para os nitossolos vermelhos férricos. Os valores de condutividade hidráulica de superfície nos pontos P1, P2, P3, P4, P5 e P6 variaram entre 1x10-4 a 9x10-5. A 0,5 m de profundidade os valores variaram entre 9x10-7 a 9x10-6; para a profundidade de 1,0 m, os valores estiveram entre 5x10-6 e 1x10-6, finalmente, os resultados para a profundidade de 1,5 m, os valores variaram entre 5x10-6 a 1x10-6. Análise dos resultados demonstra que a estrutura do solo exerce maior controle na condutividade hidráulica (respectiva eficiência de infiltração) de que a granulometria. Nesse caso, os nitossolos, mesmo sendo solos mais argilosos que os latossolos, de modo geral, apresentaram resultados maiores de condutividade hidráulica em função da alta densidade de fendas, típicas de expansão e contração de argilas de alta atividade