Safety and preliminary efficacy on cognitive performance and adaptive functionality of epigallocatechin gallate (EGCG) in children with Down syndrome. A randomized phase Ib clinical trial (PERSEUS study)

Purpose: Although some caregivers are using epigallocatechin gallate (EGCG) off label in hopes of improving cognition in young adults with Down syndrome (DS), nothing is known about its safety, tolerability, and efficacy in the DS pediatric population. We aimed to evaluate safety and tolerability of a dietary supplement containing EGCG and if EGCG improves cognitive and functional performance. Methods: A total of 73 children with DS (aged 6-12 years) were randomized. Participants received 0.5% EGCG (10 mg/kg daily dose) or placebo for 6 months with 3 months follow up after treatment discontinuation. Results: In total, 72 children were treated and 66 completed the study. A total of 38 participants were included in the EGCG group and 35 in the placebo group. Of 72 treated participants, 62 (86%) had 229 treatment-emergent adverse events (AEs). Of 37 participants in the EGCG group, 13 (35%) had 18 drug-related treatment-emergent AEs and 12 of 35 (34%) from the placebo group had 22 events. In the EGCG group, neither severe AEs nor increase in the incidence of AEs related to safety biomarkers were observed. Cognition and functionality were not improved compared with placebo. Secondary efficacy outcomes in girls point to a need for future work. Conclusion: The use of EGCG is safe and well-tolerated in children with DS, but efficacy results do not support its use in this population. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics

The TOP-SCOPE Survey of Planck Galactic Cold Clumps : Survey Overview and Results of an Exemplar Source, PGCC G26.53+0.17

The low dust temperatures (<14 K) of Planck Galactic cold clumps (PGCCs) make them ideal targets to probe the initial conditions and very early phase of star formation. "TOP-SCOPE" is a joint survey program targeting similar to 2000 PGCCs in J = 1-0 transitions of CO isotopologues and similar to 1000 PGCCs in 850 mu m continuum emission. The objective of the "TOP-SCOPE" survey and the joint surveys (SMT 10 m, KVN 21 m, and NRO 45 m) is to statistically study the initial conditions occurring during star formation and the evolution of molecular clouds, across a wide range of environments. The observations, data analysis, and example science cases for these surveys are introduced with an exemplar source, PGCC G26.53+0.17 (G26), which is a filamentary infrared dark cloud (IRDC). The total mass, length, and mean line mass (M/L) of the G26 filament are similar to 6200 M-circle dot, similar to 12 pc, and similar to 500 M-circle dot pc(-1), respectively. Ten massive clumps, including eight starless ones, are found along the filament. The most massive clump as a whole may still be in global collapse, while its denser part seems to be undergoing expansion owing to outflow feedback. The fragmentation in the G26 filament from cloud scale to clump scale is in agreement with gravitational fragmentation of an isothermal, nonmagnetized, and turbulent supported cylinder. A bimodal behavior in dust emissivity spectral index (beta) distribution is found in G26, suggesting grain growth along the filament. The G26 filament may be formed owing to large-scale compression flows evidenced by the temperature and velocity gradients across its natal cloud.Peer reviewe

Magnetic Fields in the Infrared Dark Cloud G34.43+0.24

We present the B-fields mapped in IRDC G34.43+0.24 using 850 mu m polarized dust emission observed with the POL-2 instrument at the James Clerk Maxwell telescope. We examine the magnetic field geometries and strengths in the northern, central, and southern regions of the filament. The overall field geometry is ordered and aligned closely perpendicular to the filament's main axis, particularly in regions containing the central clumps MM1 and MM2, whereas MM3 in the north has field orientations aligned with its major axis. The overall field orientations are uniform at large (POL-2 at 14 '' and SHARP at 10 '') to small scales (TADPOL at 2 ''.5 and SMA at 1 ''.5) in the MM1 and MM2 regions. SHARP/CSO observations in MM3 at 350 mu m from Tang et al. show a similar trend as seen in our POL-2 observations. TADPOL observations demonstrate a well-defined field geometry in MM1/MM2 consistent with MHD simulations of accreting filaments. We obtained a plane-of-sky magnetic field strength of 470 +/- 190 mu G, 100 +/- 40 mu G, and 60 +/- 34 mu G in the central, northern, and southern regions of G34, respectively, using the updated Davis-Chandrasekhar-Fermi relation. The estimated value of field strength, combined with column density and velocity dispersion values available in the literature, suggests G34 to be marginally critical with criticality parameter lambda values 0.8 +/- 0.4, 1.1 +/- 0.8, and 0.9 +/- 0.5 in the central, northern, and southern regions, respectively. The turbulent motions in G34 are sub-AlfvEnic with Alfvenic Mach numbers of 0.34 +/- 0.13, 0.53 +/- 0.30, and 0.49 +/- 0.26 in the three regions. The observed aligned B-fields in G34.43+0.24 are consistent with theoretical models suggesting that B-fields play an important role in guiding the contraction of the cloud driven by gravity.Peer reviewe

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Nature et fonctions du pouvoir de représenter chez Johann Nikolaus Tetens

In his Philosophical Essays, Johann Nikolaus Tetens (1736-1807) distinguishes three main functions of the power of representing (perceiving, reproducing, inventing) to which relate, respectively, the faculty of apprehension, imagination (or, reproducing fantasy) and the power of invention. For each of these faculties it appears that the power of representing is essentially synthetic: perception makes the synthesis of the continuum, unifying the diversity of impressions, imagination creates new links between pre-existing representations and the power of invention shapes new images, transforming the representations kept in memory and uniting them in one simple representation. Thus, we can argue that a triple synthesis of the power of representing does exist thanks to which all our representations are made. Tetens raises the question of whether these three faculties could be brought down to one fundamental force. We will wonder to what extend Tetens’ triple synthesis could be related to Kant’s as it is presented in his transcendental deduction of 1781. Moreover, we will point out similarities between the concept of general image (or sensible abstraction) in Tetens’ work and the concept of (empirical) scheme by Kant

Der spekulative Empirismus von Johann Nikolaus Tetens

Notre étude porte sur l’émergence du problème de l’objectivité dans la philosophie de Johannes Nicolaus Tetens (1736-1807). Prenant acte de l’échec du système wolffien, Tetens s’interroge dès le début des années 1760 sur les obstacles au progrès de la métaphysique. Pour lui la difficulté est principalement d’ordre méthodologique. Une réforme de l’ontologie lui parait nécessaire. Mais la lecture de l’"Anlage zur Architectonic" de Lambert le convainc que la difficulté centrale ne tient pas tant au manque d’intelligibilité des concepts fondamentaux ou au manque de rigueur dans l’application de la méthode euclidienne mais à l’incertitude dans laquelle se trouve l’entendement concernant la « réalité » de ses propres concepts. L’enquête sur les fondements de la métaphysique conduit ainsi Tetens en 1775 à formuler le projet d’une philosophie transcendante. La métaphysique doit partir de l’expérience et la raison être guidée dans ses spéculations par des principes transcendants. Ces principes ontologiques issus de la « théorie de la raison » doivent cependant être objectivés. La « physique de l’entendement humain », propédeutique à l’ontologie, a alors pour tâche d’examiner les modes d’action et les lois par lesquels le pouvoir de penser élabore ses propres connaissances à partir des sensations. Le problème est le suivant : comment une vérité peut-elle être objective si toutes nos représentations sont subjectives ? La solution est apportée dans les "Essais philosophiques sur la nature humaine et son développement" (1777) : Tetens propose une théorie de l’objectivité fondée sur les principes a priori de la raison. Certes nous ne connaissons que l’apparence des choses mais les rapports invariants entre les phénomènes sont des rapports objectifs. En suivant la voie de l’analogie, la raison spéculative est ainsi en mesure de s’élever aux vérités métaphysiques les plus éloignées de l’expérience humaine.Our study shall focus on the emergence of Objectivity as a philosophical concern for Johannes Nicolaus Tetens (1736-1807). By the early 1760’s, aware of the failures of the Wolffian system, Tetens began reflecting on the obstacles to the progress of metaphysics, concluding that the core difficulties stem from the lack of an appropriate methodology. A reform of ontology seemed necessary; however, upon reading Lambert’s Anslage zur Architectonic, Tetens became convinced that the main difficulty resulted from the intellect’s uncertainty concerning the reality of its fundamental metaphysical concepts, and not from the lack of intelligibility of fundamental concepts, or to the lack of rigor when applying the Euclidian method. The enquiry into the foundations of metaphysics lead Tetens, in 1775, to undertake the project of a transcendent philosophy; one based on the insights that metaphysics must be grounded in experience, and reason must be guided, when speculating about transcendent principles. These ontological principles which come from the “theory of reason” must, however, be objectified. Reforming ontology seemed to him necessary. The task of the « physics of human understanding », propaedeutic to ontology, is to examine the modes of action and the laws through which knowledge is derived from sensations. The crux of the issue is: how can a truth be objective if all our representations are subjective? The solution is given by Tetens in “Philosophical Essays on Human Nature and its Development” (1777). There he suggests a theory of objectivity based on a priori principles of reason. Indeed, although we only know the appearance of things, the unchanging relations between phenomena are objective; consequently, by following the path of analogy, speculative reason is able to establish metaphysical truths beyond the bounds of human experience.Die Dissertation behandelt das Aufkommen des Problems der Objektivität in der Philosophie von Johann Nikolaus Tetens (1736–1807). In Kenntnis des Scheiterns des Wolff‘schen Systems, arbeitet Tetens seit Beginn der 1760er-Jahre daran, die Hindernisse beim Fortschritt der Metaphysik zu überwinden. Für ihn sind die Schwierigkeiten in erster Linie methodologischer Natur. Eine Reform der Ontologie scheint ihm daher zunächst unumgänglich. Die Lektüre von Lamberts Anlage zur Architectonic überzeugt ihn jedoch davon, dass die zentrale Schwierigkeit weniger in der Deutlichkeit der Grundbegriffe oder in einer mangelnden Anwendung der Methode Euklids liegt, als vielmehr in der Unsicherheit, in der sich der Verstand gegenüber der Realität seiner eigenen Begriffe sieht. Die Suche nach den Grundlagen der Metaphysik bringt Tetens 1775 dazu, das Vorhaben einer „transzendenten Philosophie“ zu formulieren. Ihr zufolge soll die Metaphysik von der Erfahrung ausgehen und die Vernunft in ihren Spekulationen von transzendenten Grundsätzen geleitet werden. Diese ontologischen Prinzipien, die aus der „Vernunfttheorie“ abgeleitet sind, müssen für Tetens allerdings objektiviert werden. Die „Physik des Verstandes“, eine Propädeutik der Ontologie, hat daher die Aufgabe, die Wirkungsarten und Gesätze zu untersuchen, denen sich die Denkkraft bedient, um aus Empfindungen ihr eigene Erkenntnisse zu gewinnen. Das Problem lautet dabei wie folgt: Wie kann eine Wahrheit objektiv sein, wenn all unsere Vorstellungen subjektiv sind? Die Lösung präsentiert Tetens in den „Philosophischen Versuchen über die menschliche Natur und ihre Entwicklung“ (1777). In ihr schlägt er eine Theorie der Objektivität vor, die auf apriorischen Prinzipien der Vernunft basiert: Zwar kennen wir die Dinge nur dem Anschein nach, die unveränderlichen Verhältnisse zwischen den Phänomenen sind allerdings objektiv. Durch Analogiebildungen ist die spekulative Vernunft so in der Lage, auch die von der menschlichen Erfahrung an den weitesten entfernten metaphysischen Wahrheiten zu ergründen

Traduction des textes n°62 et 63: Johann Nikolaus Tetens, "Essais philosophiques sur la nature humaine et son développement", extraits de l'Essai 14

International audienc

Mol Brain

Hippocampal CA1 parvalbumin-expressing interneurons (PV INs) play a central role in controlling principal cell activity and orchestrating network oscillations. PV INs receive excitatory inputs from CA3 Schaffer collaterals and local CA1 pyramidal cells, and they provide perisomatic inhibition. Schaffer collateral excitatory synapses onto PV INs express Hebbian and anti-Hebbian types of long-term potentiation (LTP), as well as elicit LTP of intrinsic excitability (LTPIE). LTPIE requires the activation of type 5 metabotropic glutamate receptors (mGluR5) and is mediated by downregulation of potassium channels Kv1.1. It is sensitive to rapamycin and thus may involve activation of the mammalian target of rapamycin complex 1 (mTORC1). LTPIE facilitates PV INs recruitment in CA1 and maintains an excitatory-inhibitory balance. Impaired CA1 PV INs activity or LTP affects network oscillations and memory. However, whether LTPIE in PV INs plays a role in hippocampus-dependent memory remains unknown. Here, we used conditional deletion of the obligatory component of mTORC1, the Regulatory-Associated Protein of mTOR (Raptor), to directly manipulate mTORC1 in PV INs. We found that homozygous, but not heterozygous, conditional knock-out of Rptor resulted in a decrease in CA1 PV INs of mTORC1 signaling via its downstream effector S6 phosphorylation assessed by immunofluorescence. In whole-cell recordings from hippocampal slices, repetitive firing of CA1 PV INs was impaired in mice with either homozygous or heterozygous conditional knock-out of Rptor. High frequency stimulation of Schaffer collateral inputs that induce LTPIE in PV INs of control mice failed to do so in mice with either heterozygous or homozygous conditional knock-out of Rptor in PV INs. At the behavioral level, mice with homozygous or heterozygous conditional knock-out of Rptor showed similar long-term contextual fear memory or contextual fear memory discrimination relative to control mice. Thus, mTORC1 activity in CA1 PV INs regulates repetitive firing and LTPIE but not consolidation of long-term contextual fear memory and context discrimination. Our results indicate that mTORC1 plays cell-specific roles in synaptic plasticity of hippocampal inhibitory interneurons that are differentially involved in hippocampus-dependent learning and memory. © 2022, The Author(s)

Tetens et la philosophie transcendantale. Psychologie, philosophie transcendante et perfectibilité

L’histoire des idées est structurée par des choix téléologiques aveugles qu’il faut mettre en cause, en redonnant de la liberté à la pensée. Ainsi Johann Nikolaus Tetens (1736-1807) est totalement ignoré. Il joue pourtant un rôle central dans les débats philosophiques du XVIIIe siècle en Allemagne. Les textes présentés ici tentent de rendre visibles ses apports originaux, en nous libérant de nos fausses évidences. Tetens a discuté les premiers écrits de Kant et a influencé la Critique de la raison pure. En prenant position dans le débat concernant les forces de l’âme, il a tenté de montrer que l’âme a une parfaite spontanéité propre. Dans ce but, il s’écarte aussi bien du dogmatisme spéculatif que de la psychologie empirique. Il n’est donc pas seulement le « Locke allemand ». De plus, sa démonstration engage une réélaboration de la notion rousseauiste de perfectibilité. On peut alors considérer que Tetens a développé avant Kant le problème kantien de l’objectivité de la connaissance. La question est de déterminer comment il l’a posé et ce que cela nous apprend. The history of ideas is structured by blind teleological choices that must be questioned, restoring freedom to thought. Johann Nikolaus Tetens (1736-1807) is completely ignored, yet he played a central role in the philosophical debates of eighteenth-century Germany. The texts presented here have been selected to bring his original contributions to light and put an end to preconceived notions.Tetens discussed the early writings of Kant and influenced the Critique of Pure Reason. As a participant in the debate on the powers of the soul, he tried to show that the soul has its own perfect spontaneity. To do so, he distanced himself from both speculative dogmatism and empirical psychology. He therefore is not merely the “German Locke”. Furthermore, his demonstration implies a reformulation of the Rousseauist idea of perfectibility.It can then be considered that Tetens developed the Kantian problem of the objectivity of knowledge before Kant himself. The question is how he set out the problem, and what that teaches us