Differentiation of Human Adipose-Derived Stem Cells into “Brite” (Brown-in-White) Adipocytes

It is well established now that adult humans possess active brown adipose tissue (BAT) which represents a potential pharmacological target to combat obesity and associated diseases. Moreover thermogenic brown-like adipocytes (“brite adipocytes”) appear also in mouse white adipose tissue (WAT) upon β3-adrenergic stimulation. We had previously shown that human multipotent adipose-derived stem cells (hMADS) are able to differentiate into cells which exhibit the key properties of human white adipocytes, and then to convert into functional brown adipocytes upon PPARγ activation. In light of a wealth of data indicating that thermogenic adipocytes from BAT and WAT have a distinct cellular origin, we have characterized at the molecular level UCP1 positive hMADS adipocytes from both sexes as brite adipocytes. Conversion of white to brown hMADS adipocytes is dependent on PPARγ activation with rosiglitazone as the most potent agonist and is inhibited by a PPARγ antagonist. In contrast to mouse cellular models, hMADS cells conversion into brown adipocytes is weakly induced by BMP7 treatment and not modulated by activation of the Hedgehog pathway. So far no primary or clonal precursor cells of human brown adipocytes have been obtained that can be used as a tool to develop therapeutic drugs and to gain further insights into the molecular mechanisms of brown adipogenesis in humans. Thus hMADS cells represent a suitable human cell model to delineate the formation and/or the uncoupling capacity of brown/brite adipocytes that could help to dissipate caloric excess intake among individuals

The failed liberalisation of Algeria and the international context: a legacy of stable authoritarianism

The paper attempts to challenge the somewhat marginal role of international factors in the study of transitions to democracy. Theoretical and practical difficulties in proving causal mechanisms between international variables and domestic outcomes can be overcome by defining the international dimension in terms of Western dominance of world politics and by identifying Western actions towards democratising countries. The paper focuses on the case of Algeria, where international factors are key in explaining the initial process of democratisation and its following demise. In particular, the paper argues that direct Western policies, the pressures of the international system and external shocks influence the internal distribution of power and resources, which underpins the different strategies of all domestic actors. The paper concludes that analysis based purely on domestic factors cannot explain the process of democratisation and that international variables must be taken into more serious account and much more detailed

Surface solitons at interfaces of arrays with spatially-modulated nonlinearity

We address the properties of two-dimensional surface solitons supported by the interface of a waveguide array whose nonlinearity is periodically modulated. When the nonlinearity strength reaches its minima at the points where the linear refractive index attains its maxima, we found that nonlinear surface waves exist and can be made stable only within a limited band of input energy flows, and for lattice depths exceeding a lower threshold.Comment: 13 pages, 3 figures, to appear in Optics Letter

Development of novel low-mass module concepts based on MALTA monolithic pixel sensors

The MALTA CMOS monolithic silicon pixel sensors has been developed in the Tower 180 nm CMOS imaging process. It includes an asynchronous readout scheme and complies with the ATLAS inner tracker requirements for the HL-LHC. Several 4-chip MALTA modules have been built using Al wedge wire bonding to demonstrate the direct transfer of data from chip-to-chip and to read out the data of the entire module via one chip only. Novel technologies such as Anisotropic Conductive Films (ACF) and nanowires have been investigated to build a compact module. A lightweight flex with 17 {\mu}m trace spacing has been designed, allowing compact packaging with a direct attachment of the chip connection pads to the flex using these interconnection technologies. This contribution shows the current state of our work towards a flexible, low material, dense and reliable packaging and modularization of pixel detectors.Comment: 5 pages + 1 page references,8 figure

Timing performance of radiation hard MALTA monolithic Pixel sensors

The MALTA family of Depleted Monolithic Active Pixel Sensor (DMAPS) produced in Tower 180 nm CMOS technology targets radiation hard applications for the HL-LHC and beyond. Several process modifications and front-end improvements have resulted in radiation hardness up to $2 \times 10^{15}~1~\text{MeV}~\text{n}_{eq}/\text{cm}^2$ and time resolution below 2 ns, with uniform charge collection efficiency across the Pixel of size $36.4 \times 36.4~\mu\text{m}^2$ with a $3~\mu\text{m}^2$ electrode size. The MALTA2 demonstrator produced in 2021 on high-resistivity epitaxial silicon and on Czochralski substrates implements a new cascoded front-end that reduces the RTS noise and has a higher gain. This contribution shows results from MALTA2 on timing resolution at the nanosecond level from the CERN SPS test-beam campaign of 2021.Comment: 8 pages, 8 figures. Submitted to Journal of Instrumentation (JINST). Proceedings of the 23rd International Workshop on Radiation Imaging Detectors IWORID 202

Depletion depth studies with the MALTA2 sensor, a depleted monolithic active pixel sensor

MALTA2 is a depleted monolithic active pixel sensor (DMAPS) developed in the Tower 180 nm CMOS imaging process. Monolithic CMOS sensors offer advantages over current hybrid imaging sensors both in terms of increased tracking performance due to lower material budget but also in terms of ease of integration and construction costs due to the monolithic design. Current research and development efforts are aimed towards radiation-hard designs up to 100 Mrad in Total Ionizing Dose and 3 × 1015 1 MeV neq / cm2 in Non-Ionizing Energy Loss. One important property of a sensor’s radiation hardness is the depletion depth at which efficient charge collection is achieved via drift movement. Grazing angle test-beam data was taken during the 2023 SPS CERN test beam with the MALTA telescope and Edge Transient Current Technique studies were performed at DESY in order to develop a quantitative study of the depletion depth for un-irradiated, epitaxial MALTA2 samples. The study is planned to be extended for irradiated and Czochralski MALTA2 samples

Dynamics of Action Potential Initiation in the GABAergic Thalamic Reticular Nucleus In Vivo

Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold

Activation of Protein Kinase A and Exchange Protein Directly Activated by cAMP Promotes Adipocyte Differentiation of Human Mesenchymal Stem Cells

Human mesenchymal stem cells are primary multipotent cells capable of differentiating into several cell types including adipocytes when cultured under defined in vitro conditions. In the present study we investigated the role of cAMP signaling and its downstream effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) in adipocyte conversion of human mesenchymal stem cells derived from adipose tissue (hMADS). We show that cAMP signaling involving the simultaneous activation of both PKA- and Epac-dependent signaling is critical for this process even in the presence of the strong adipogenic inducers insulin, dexamethasone, and rosiglitazone, thereby clearly distinguishing the hMADS cells from murine preadipocytes cell lines, where rosiglitazone together with dexamethasone and insulin strongly promotes adipocyte differentiation. We further show that prostaglandin I2 (PGI2) may fully substitute for the cAMP-elevating agent isobutylmethylxanthine (IBMX). Moreover, selective activation of Epac-dependent signaling promoted adipocyte differentiation when the Rho-associated kinase (ROCK) was inhibited. Unlike the case for murine preadipocytes cell lines, long-chain fatty acids, like arachidonic acid, did not promote adipocyte differentiation of hMADS cells in the absence of a PPARγ agonist. However, prolonged treatment with the synthetic PPARδ agonist L165041 promoted adipocyte differentiation of hMADS cells in the presence of IBMX. Taken together our results emphasize the need for cAMP signaling in concert with treatment with a PPARγ or PPARδ agonist to secure efficient adipocyte differentiation of human hMADS mesenchymal stem cells

Constraints on the interpretation of S-to-P receiver functions

We present results from forward modelling to study the feasibility of using S-to-P converted phases to image the seismic discontinuity structure of the crust and upper mantle. We show that a significant level of P-wave energy arriving before the direct S-wave arrival can interfere with the S-to-P converted phases of interest and may result in Sp receiver function phases that do not represent true earth structure. The source of this P-wave energy is attributable to a number of phases, including those that have undergone multiple reflections off the Earth's surface. For deep focus earthquakes (300–600 km deep), a significant amount of P-wave energy is observed from pPPP, pPPPP and sPPPP phases, and arrives within the same time window as predicted for S-to-P converted phases from the direct S phase arrival. Furthermore, for earthquakes at all depths, interfering P-wave energy arrives within the same time window as predicted for S-to-P converted phases from the SKS phase arrival, limiting the usefulness of SKSp receiver functions for upper mantle imaging. To isolate true Sp receiver function phases from contamination due to other P-wave phases, we find it necessary to stack receiver functions from a range of epicentral distances and depths in order to aid the suppression of noise and other unwanted phases. We provide constraints on the noise levels to be expected as a function of epicentral distance and earthquake depth. We find that the lowest noise levels are achievable by restricting epicentral distance to less than 75 degrees and the depth of earthquakes used to less than 300 km