Ordovician volcanic and hypabyssal rocks in the central and southern Miramichi Highlands: their tectonic setting and relationship to contemporary volcanic rocks in northern New Brunswick

New analyses of mafic igneous rocks from the central Miramichi Highlands have led us to modify the interpretation of its tectonic setting. New samples have been obtained from the Bam ford Brook and Trousers Lake areas of New Brunswick, and the Danforth area in Maine. All subalkalic mafic rocks, including the Trousers Lake striped amphibolites, are associated with a thick sequence of metasedimentary rocks and all are continental tholeiites, analogous to tholeiitic suites in the Tetagouche Group of the northern Miramichi Highlands. The presence of alkalic basalt and comendite in this area supports this correlation. In the southern Miramichi Highlands of Maine, silicic and intermediate volcanic rocks form part of the Woodstock-Meductic arc-related volcanic suite. RÉSUMÉ De nouvelles analyses de roches ignées mafiques provenant du centre des hautes-terres de la Miramichi nous ont conduit à modifier l’interprétation de leur environnement tectonique. De nouveaux échantillons ont été recueillis dans les régions du ruisseau Bamford et du lac Trousers au Nouveau-Brunswick, et dans la région de Danforth au Maine. Toutes les roches mafiques subalcalines, incluant les amphibolites rubannées du lac Trousers, sont associées avec une séquence épaisse de roches métasédimentaires et sont toutes des tholéiites continentales, similaires aux suites tholéiitiques appartenant au Groupe de Tétagouche du nord des hautes-terres de la Miramichi. La présence de basaltes alcalins et de comendites dans cette région appuie cette corrélation. Dans le sud des hautes-terres de la Miramichi au Maine, les volcanites siliceuses et inlermddiaires constituent une partie de la suite volcanique d'arc de Woodstock-Meductic. [Traduit par le journal

Different carbon isotope fractionation patterns during the development of phototrophic freshwater and marine biofilms

Natural phototrophic biofilms are influenced by a broad array of abiotic and biotic factors and vary over temporal and spatial scales. Different developmental stages can be distinguished and growth rates will vary due to the thickening of the biofilm, which is expected to lead to a limitation of light or mass transport. This study shows that variation in CO<sub>2(aq)</sub> availability leads to a fractionation shift and thereby affects δ<sup>13</sup>C signatures during biofilm development. For phototrophic freshwater biofilms it was found that the δ<sup>13</sup>C value became less negative with the thickening of the biofilm, while the opposite trend was found in marine biofilms. Modeling and pH profiling indicated that the trend in the freshwater system was caused by an increase in CO<sub>2(aq)</sub> limitation resulting in an increase of HCO<sub>3</sub><sup>−</sup> as C-source. The opposite trend in the marine system could be explained by a higher heterotrophic biomass and activity causing a higher carbon recycling and thereby lower δ<sup>13</sup>C values. We conclude that δ<sup>13</sup>C was more related to the net areal photosynthesis rate and carbon recycling, rather than to the growth rate of the biofilms

Feedback between deformation and magmatism in the Lloyds River Fault Zone : an example of episodic fault reactivation in an accretionary setting, Newfoundland Appalachians

Author Posting. © American Geophysical Union, 2006. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Tectonics 25 (2006): TC4004, doi:10.1029/2005TC001789.The Lloyds River Fault Zone is a 10–15 km wide amphibolite-grade shear zone that formed during the Ordovician Taconic Orogeny. It separates ophiolites and arc–back-arc complexes formed in Iapetus from a peri-Laurentian microcontinent (Dashwoods microcontinent). The Lloyds River Fault Zone comprises three high-strain zones, dominantly composed of mylonitic amphibolites, separated by less deformed plutonic rocks. Structural, age and metamorphic data suggest the Lloyds River Fault Zone accommodated sinistral-oblique underthrusting of ophiolites underneath the Dashwoods microcontinent prior to 471 ± 5 Ma at 800°C and 6 kbar. Plutonic rocks within the Lloyds River Fault Zone comprise two suites dated at 464 ± 2 plus 462 ± 2 and 459 ± 3 Ma, respectively. The younger age of the plutons with respect to some of the amphibolites, evidence for magmatic deformation, and the elongate nature of the plutons parallel to the Lloyds River Fault Zone suggest they were emplaced within the fault zone during deformation. Both intrusive episodes triggered renewed deformation at high temperatures (770–750°C), illustrating the positive feedback between deformation and magmatism. Offshoots of the plutons intruded undeformed ophiolitic gabbros outside the Lloyds River Fault Zone. Deformation localized within the intrusive sheets, coeval with static contact metamorphism of the host gabbros, leading to the development of new, small-scale shear zones. This illustrates that channeling of plutons into shear zones and nucleation of shear zones in melt-rich zones may occur simultaneously within the same fault system.This research is funded by a scholarship from the Faculty of Graduate and Postdoctoral Studies, University of Ottawa, to C.J.L. and a NSERC grant to C.v.S in his position as Adjunct Professor at the University of Ottawa

Wnt3a deficiency irreversibly impairs hematopoietic stem cell self-renewal and leads to defects in progenitor cell differentiation

Canonical Wnt signaling has been implicated in various aspects of hematopoiesis. Its role is controversial due to different outcomes between various inducible Wnt-signaling loss-of-function models and also compared with gain-of-function systems. We therefore studied a mouse deficient for a Wnt gene that seemed to play a nonredundant role in hematopoiesis. Mice lacking Wnt3a die prenatally around embryonic day (E) 12.5, allowing fetal hematopoiesis to be studied using in vitro assays and transplantation into irradiated recipient mice. Here we show that Wnt3a deficiency leads to a reduction in the numbers of hematopoietic stem cells (HSCs) and progenitor cells in the fetal liver (FL) and to severely reduced reconstitution capacity as measured in secondary transplantation assays. This deficiency is irreversible and cannot be restored by transplantation into Wnt3a competent mice. The impaired long-term repopulation capacity of Wnt3a-/- HSCs could not be explained by altered cell cycle or survival of primitive progenitors. Moreover, Wnt3a deficiency affected myeloid but not B-lymphoid development at the progenitor level, and affected immature thymocyte differentiation. Our results show that Wnt3a signaling not only provides proliferative stimuli, such as for immature thymocytes, but also regulates cell fate decisions of HSC during hematopoiesis

Development and internal validation of a machine learning prediction model for low back pain non-recovery in patients with an acute episode consulting a physiotherapist in primary care

BACKGROUND: While low back pain occurs in nearly everybody and is the leading cause of disability worldwide, we lack instruments to accurately predict persistence of acute low back pain. We aimed to develop and internally validate a machine learning model predicting non-recovery in acute low back pain and to compare this with current practice and 'traditional' prediction modeling. METHODS: Prognostic cohort-study in primary care physiotherapy. Patients (n = 247) with acute low back pain (≤ one month) consulting physiotherapists were included. Candidate predictors were assessed by questionnaire at baseline and (to capture early recovery) after one and two weeks. Primary outcome was non-recovery after three months, defined as at least mild pain (Numeric Rating Scale > 2/10). Machine learning models to predict non-recovery were developed and internally validated, and compared with two current practices in physiotherapy (STarT Back tool and physiotherapists' expectation) and 'traditional' logistic regression analysis. RESULTS: Forty-seven percent of the participants did not recover at three months. The best performing machine learning model showed acceptable predictive performance (area under the curve: 0.66). Although this was no better than a'traditional' logistic regression model, it outperformed current practice. CONCLUSIONS: We developed two prognostic models containing partially different predictors, with acceptable performance for predicting (non-)recovery in patients with acute LBP, which was better than current practice. Our prognostic models have the potential of integration in a clinical decision support system to facilitate data-driven, personalized treatment of acute low back pain, but needs external validation first

Androgen Deprivation therapy for Oligo-recurrent Prostate cancer in addition to radioTherapy (ADOPT):study protocol for a randomised phase III trial

BACKGROUND: More than 60% of oligo-recurrent prostate cancer (PCa) patients treated with metastasis-directed radiotherapy (MDRT) develop biochemical recurrence within 2 years. This recurrence rate emphasises the need for improved treatment and patient selection. In line with the treatment of primary PCa, the efficacy of MDRT may be enhanced when combined with androgen-deprivation therapy (ADT). Furthermore, the availability of PSMA PET/CT offers an excellent tool for optimal patient selection for MDRT. This phase III randomised controlled trial will investigate the role of the addition of ADT to MDRT in oligo-recurrent PCa patients selected with PSMA PET/CT to enhance oncological outcome. METHODS: Two hundred and eighty patients will be randomised in a 1:1 ratio to the standard treatment arm (MDRT alone) or the experimental arm (MDRT + 6 months ADT). Patients with biochemical recurrence after primary treatment of PCa presenting with ≤ 4 metastases will be included. The primary endpoint is the 2.5-year metastases progression-free survival (MPFS). Secondary endpoints are acute and late toxicity, quality of life, biochemical progression-free survival, overall survival, and the sensitivity of the PSMA PET/CT for detecting oligometastases at low PSA-levels. So far, between March 2020 and December 2021, one hundred patients have been included. DISCUSSION: This phase III randomised controlled trial will assess the possible benefit of the addition of 6 months ADT to MDRT on metastases progression-free survival, toxicity, QoL and survival in PCa patients with 1-4 recurrent oligometastatic lesions. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04302454 . Registered 10 March 2020

Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.

Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants

A novel germline mutation of PTEN associated with brain tumours of multiple lineages

We have identified a novel germline mutation in the PTEN tumour suppressor gene. The mutation was identified in a patient with a glioma, and turned out to be a heterozygous germline mutation of PTEN (Arg234Gln), without loss of heterozygosity in tumour DNA. The biological consequences of this germline mutation were investigated by means of transfection studies of the mutant PTEN molecule compared to wild-type PTEN. In contrast to the wild-type molecule, the mutant PTEN protein is not capable of inducing apoptosis, induces increased cell proliferation and leads to high constitutive PKB/Akt activation, which cannot be increased anymore by stimulation with insulin. The reported patient, in addition to glioma, had suffered from benign meningioma in the past but did not show any clinical signs of Cowden disease or other hereditary diseases typically associated with PTEN germline mutations. The functional consequences of the mutation in transfection studies are consistent with high proliferative activity. Together, these findings suggest that the Arg234Gln missense mutation in PTEN has oncogenic properties and predisposes to brain tumours of multiple lineages

An integrated care program to prevent work disability due to chronic low back pain: a process evaluation within a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>In the past decade, a considerable amount of research has been carried out to evaluate the effectiveness of innovative low back pain (LBP) interventions. Although some interventions proved to be effective, they are not always applied in daily practice. To successfully implement an innovative program it is important to identify barriers and facilitators in order to change practice routine. Because usual care is not directly aimed at return to work (RTW), we evaluated an integrated care program, combining a patient-directed and a workplace-directed intervention provided by a multidisciplinary team, including a clinical occupational physician to reduce occupational disability in chronic LBP patients. The aims of this study were to describe the feasibility of the implementation of the integrated care program, to assess the satisfaction and expectations of the involved stakeholders and to describe the needs for improvement of the program.</p> <p>Methods</p> <p>Eligible for this study were patients who had been on sick leave due to chronic LBP. Data were collected from the patients, their supervisors and the involved health care professionals, by means of questionnaires and structured charts, during 3-month follow-up. Implementation, satisfaction and expectations were investigated.</p> <p>Results</p> <p>Of the 40 patients who were eligible to participate in the integrated care program, 37 patients, their supervisors and the health care professionals actually participated in the intervention. Adherence to the integrated care program was in accordance with the protocol, and the patients, their supervisors and the health care professionals were (very) satisfied with the program. The role of the clinical occupational physician was of additional value in the RTW process. Time-investment was the only barrier for implementation reported by the multidisciplinary team.</p> <p>Conclusion</p> <p>The implementation of this program will not be influenced by any flaws in its application that are related to the program itself, or to the adherence of patients with chronic LBP and their health care professionals.</p> <p>This program is promising in terms of feasibility, satisfaction and compliance of the patients, their supervisors and the health care professionals. Before implementation on a wider scale, the communication and the information technology of the program should be improved.</p> <p>Trials Registration</p> <p>[ISRCTN28478651]</p

Global Regulator SATB1 Recruits β-Catenin and Regulates TH2 Differentiation in Wnt-Dependent Manner

Chromatin organizer SATB1 and Wnt transducer β-catenin form a complex and regulate expression of GATA3 and TH2 cytokines in Wnt-dependent manner and orchestrate TH2 lineage commitment