A new diethylenetriamine-derived macrocycle known as L, bearing 2-methylquinoline arms and containing m-xylyl spacers, was prepared in good yield by a one-pot 2 + 2 Schiff base condensation ...procedure, followed by reduction with sodium borohydride. Up to now this is the first hexaazamacrocycle with appended fluorophore units. Single-crystal X-ray diffraction determination of the dinuclear zinc(II) complex of L showed that metal centers are located at about 7.20(2) Å from one another. This complex exhibits only weak fluorescence in aqueous solution, but the addition of 1 equiv of pyrophosphate (PPi) caused a 21-fold enhancement of the fluorescence intensity. The sensor response is linear up to a value of 10 μM HPPi3– and has a detection limit of 300 nM. The receptor behaves as a highly selective sensor for pyrophosphate as other anions, including phosphate, phenylphosphate (PhP), adenosine monophosphate (AMP), adenosine diphosphate (ADP), and adenosine triphosphate (ATP), failed to induce any fluorescence change and practically do not affect the fluorescence intensity of the sensor in the presence of HPPi3–. Competition titrations carried out in aqueous solution at pH 7.4 in 20 mM 3-(N-morpholino)propanesulfonic acid (MOPS) buffer by spectrofluorometry revealed a high association constant value of 6.22 log units for binding of PPi by the dinuclear zinc(II) receptor, one of the highest reported values for colorimetric/fluorometric sensors able to work under real aqueous physiological conditions, while association constant values for binding of the other phosphorylated substrates are in the 5.51–4.03 log unit range.
Autisme : une rencontre avec un « visage brisé Mesquita, M.; Bidaud, E.
Neuropsychiatrie de l'enfance et de l'adolescence,
October-November 2013, Volume:
61, Issue:
7-8
Journal Article
Peer reviewed
Beaucoup a déjà été dit en ce qui concerne l’étude de la fonction du visage dans la constitution de la subjectivité, faisant référence à la phase spéculaire. Cependant, lorsqu’on parle d’autisme, on ...est amené systématiquement à la phase pré-spéculaire, moment où l’accès à l’imaginaire et au symbolique apparaît de façon très esquissée. La présente étude repose sur une analyse du rapport du sujet au visage, encore dans une phase pré-spéculaire afin d’asseoir une métapsychologie des premières mises en place de l’appareil psychique apte à rendre compte des failles autistiques de la fonction/visage. Cette analyse nous permet de soutenir que le rapport du sujet au visage s’initie encore dans une phase pré-spéculaire, comme un moment d’ancrage instinctuel et primordial du sujet chez un précurseur de l’Autre symbolique, caractérisé par une forme première. L’autisme serait le résultat de l’échec de cette première rencontre avec le proto-Autre, caractérisant le phénomène du « visage brisé ». Nous prétendons contribuer ainsi aux études sur l’intervention précoce chez des bébés à risque d’autisme.
Much has already been said regarding the study of the function of the face in the constitution of subjectivity, referring to the mirror's phase. However, when it comes to autism, it is necessary to consider the pre-mirror's phase, when the access to the imaginary and the symbolic appears very sketched. This study is based on an analysis of the relation of the subject to the face, in a pre-mirror phase. It claims to establish a metapsychology of the draft of the psychic system capable of signaling failures of the autistic function/face. This analysis allows us to argue that the relation of the subject to the face still initiates a pre-mirror phase. It represents a moment of instinctual and primordial settlement for the subject in a precursory of the other symbolic, characterized by a first shape. Autism is characterized by the failure of this first meeting with the proto-Other, characterizing the phenomenon of “broken face”. This paper intends to contribute to studies about early intervention in infants at risk of autism.
The 70‐gene signature (MammaPrint™) has been developed on retrospective series of breast cancer patients to predict the risk of breast cancer distant metastases. The ...microarRAy‐prognoSTics‐in‐breast‐cancER (RASTER) study was the first study designed to prospectively evaluate the performance of the 70‐gene signature, which result was available for 427 patients (cT1–3N0M0). Adjuvant systemic treatment decisions were based on the Dutch CBO 2004 guidelines, the 70‐gene signature and doctors' and patients' preferences. Five‐year distant‐recurrence‐free‐interval (DRFI) probabilities were compared between subgroups based on the 70‐gene signature and Adjuvant! Online (AOL) (10‐year survival probability <90% was defined as high‐risk). Median follow‐up was 61.6 months. Fifteen percent (33/219) of the 70‐gene signature low‐risk patients received adjuvant chemotherapy (ACT) versus 81% (169/208) of the 70‐gene signature high‐risk patients. The 5‐year DRFI probabilities for 70‐gene signature low‐risk (n = 219) and high‐risk (n = 208) patients were 97.0% and 91.7%. The 5‐year DRFI probabilities for AOL low‐risk (n = 132) and high‐risk (n = 295) patients were 96.7% and 93.4%. For 70‐gene signature low‐risk–AOL high‐risk patients (n = 124), of whom 76% (n = 94) had not received ACT, 5‐year DRFI was 98.4%. In the AOL high‐risk group, 32% (94/295) less patients would be eligible to receive ACT if the 70‐gene signature was used. In this prospective community‐based observational study, the 5‐year DRFI probabilities confirmed the additional prognostic value of the 70‐gene signature to clinicopathological risk estimations such as AOL. Omission of adjuvant chemotherapy as judged appropriate by doctors and patients and instigated by a low‐risk 70‐gene signature result, appeared not to compromise outcome.
What's new?
The “MammaPrint” is a 70‐gene signature developed to predict the risk of breast cancer metastases. This study, the RASTER study, provides the first prospective data looking at this 70‐gene signature to evaluate it's performance. For 427 patients, treatment decisions were based on standard guidelines, the 70‐gene signature, and doctors' and patients' preferences. Here, 124 patients were categorized as “low‐risk” by the 70‐gene signature, but high‐risk by other measures, such as age, tumor size, nodal status, and other clinicopathological factors. Of these, 76% did not receive adjuvant chemotherapy, and 98% survived 5 years with no recurrence of disease. Thus, withholding chemotherapy based on the low‐risk gene signature result, and in accordance with doctors' and patients' preferences, did not negatively impact recurrence rate, confirming the prognostic value of this new tool.
This review will discuss, under the Circular Economy and Biorefinery concepts, the performance of the alternative solvents in the downstream process to recover natural pigments in a more sustainable ...way. Conventionally, pigments marketed on an industrial scale are produced through chemical synthesis by using petroleum derivatives as the main raw material. Also, the current production chain of the synthetic dyes is linear, with no solvent recycling and waste generation. Thus, the most promising processes of extraction and purification of natural pigments and strategies on the polishing of the solvents are here reviewed. In this review, the use of alternative solvents, namely, ionic liquids, eutectic solvents, aqueous solutions of surfactants, and edible oils, for recovering natural pigments was reviewed. Works discussing higher extraction yields and selectivity, while maintaining the stability of the target pigments, were reported. Also, a panorama between Sustainability and Circular Economy prospection was discussed for better comprehension of the main advances in the field. Behind the analysis of the works published so far on the theme, the most important lacunas to overcome in the next years on the field were pointed out and discussed. Also, the future trends and new perspectives to achieve the economic viability and sustainability of the processes using alternative solvents will be scrutinized.
A cyclic tetrapeptide L comprising two l-proline and two 3-amino-5-(pyridin-4-yl)benzoic acid subunits assembles into a dimetallic metallamacrocycle Pd 2 L 2 and a trimetallic coordination cage Pd 3 ...L 6 in the presence of suitable palladium(II) precursors. Pd 2 L 2 recognizes organic anions in aqueous media, forming a particularly stable complex with sodium 2,6-naphthalenedisulfonate, in which two dianionic guest molecules reside in the cavity surrounded by the cyclopeptide ligands.
Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and ...safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition.
30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood.
A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001) and fit a sigmoid E(max) pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators.
Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development of models more predictive of microbicide efficacy.
ClinicalTrials.gov NCT00594373.
A safe and effective topical prevention strategy will likely require sustained delivery of potent antiviral drugs and a delivery system that simultaneously maximizes drug distribution and overcomes ...the behavioural challenges related to adherence. Activity against HIV and herpes simplex virus (HSV) would be advantageous, given the epidemiological link between the two pathogens. We hypothesize that tenofovir disoproxil fumarate (tenofovir DF), a prodrug of tenofovir, may be more potent than tenofovir and ideal for sustained intravaginal ring (IVR) delivery.
The anti-HIV and anti-HSV activity of tenofovir and tenofovir DF were assessed in cell and explant models. Cumulative tenofovir DF release and stability from polyether urethane (PEU), ethylene-co-vinyl acetate (EVA) and silicone IVRs were compared, and the activity and safety of drug released were evaluated in cervical explants and in a polarized dual-chamber model.
Tenofovir DF inhibited HIV and HSV at ≈ 100-fold lower concentrations than tenofovir and retained activity in the presence of semen. PEU rings delivered >1 mg/day of tenofovir DF for 30 days. Pre-treatment of cervical explants with 10 μg/mL tenofovir DF or eluants from PEU minirings resulted in >90% inhibition of HIV and reduced HSV-2 yields by 2.5 log. Tenofovir DF and eluants did not prevent cell growth or polarization, or have any deleterious effects on an epithelial barrier.
The findings support the development of a PEU tenofovir DF ring, which may provide potent and sustained protection against HIV and HSV.
BackgroundThe lack of biomarkers that are predictive of safety is a critical gap in the development of microbicides. The present experiments were designed to evaluate the predictive value of in vitro ...models of microbicide safety MethodsChanges in the epithelial barrier were evaluated by measuring transepithelial electrical resistance (TER) after exposure of human epithelial cells to candidate microbicides in a dual-chamber system. The significance of observed changes was addressed by challenging cultures with human immuodeficiency virus (HIV) and measuring the ability of virus to cross the epithelium and infect target T cells cultured in the lower chamber ResultsExposure to nonoxynol-9 (N-9) or cellulose sulfate (CS), but not 9-2-(phosphonomethoxy)propyladenine (also referred to as tenofovir) or PRO2000, resulted in a rapid and sustained reduction in TER and a marked increase in HIV infection of T cells cultured in the lower chamber. Moreover, CS triggered nuclear factor κB activation in peripheral blood mononuclear cells and increased HIV replication in chronically infected U1 cells ConclusionsEpithelial barrier disruption and enhanced viral replication may have contributed to the increased risk of HIV acquisition observed in phase 3 trials of N-9 and CS. Expansion of in vitro safety testing to include these models would provide a more stringent preclinical assessment of microbicide safety and may prove to be more predictive of clinical outcomes
When running on a curve, the lower limbs interact with the ground to redirect the trajectory of the centre of mass of the body (CoM). The goal of this paper is to understand how the trajectory of the ...CoM and the work done to maintain its movements relative to the surroundings (Wcom) are modified as a function of running speed and radius of curvature. Eleven participants ran at different speeds on a straight line and on circular curves with a 6 m and 18 m curvature. The trajectory of the CoM and Wcom were calculated using force-platforms measuring the ground reaction forces and infrared cameras recording the movements of the pelvis. To follow a circular path, runners overcompensate the rotation of their trajectory during contact phases. The deviation from the circular path increases when the radius of curvature decreases and speed increases. Interestingly, an asymmetry between the inner and outer lower limbs emerges as speed increases. The method to evaluate Wcom on a straight-line was adapted using a referential that rotates at heel strike and remains fixed during the whole step cycle. In an 18 m radius curve and at low speeds on a 6 m radius, Wcom changes little compared to a straight-line run. Whereas at 6 m s-1 on a 6 m radius, Wcom increases by ~25%, due to an augmentation in the work to move the CoM laterally. Understanding these adaptations provides valuable insight for sports sciences, aiding in optimizing training and performance in sports with multidirectional movements.
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