REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion

The repressor-element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) controls hundreds of neuron-specific genes. We showed that REST/NRSF downregulates glutamatergic transmission in response to hyperactivity, thus contributing to neuronal homeostasis. However, whether GABAergic transmission is also implicated in the homeostatic action of REST/NRSF is unknown. Here, we show that hyperactivity-induced REST/NRSF activation, triggers a homeostatic rearrangement of GABAergic inhibition, with increased frequency of miniature inhibitory postsynaptic currents (IPSCs) and amplitude of evoked IPSCs in mouse cultured hippocampal neurons. Notably, this effect is limited to inhibitory-onto-excitatory neuron synapses, whose density increases at somatic level and decreases in dendritic regions, demonstrating a complex target- and area-selectivity. The upscaling of perisomatic inhibition was occluded by TrkB receptor inhibition and resulted from a coordinated and sequential activation of the Npas4 and Bdnf gene programs. On the opposite, the downscaling of dendritic inhibition was REST-dependent, but BDNF-independent. The findings highlight the central role of REST/NRSF in the complex transcriptional responses aimed at rescuing physiological levels of network activity in front of the ever-changing environment.

SAR Image Simulation of Complex Target Including Multiple Scattering

We present a GPU-based computation for simulating the synthetic aperture radar (SAR) image of the complex target. To be more realistic, we included the multiple scattering field and antenna pattern tracking in producing the SAR echo signal for both Stripmap and Spotlight modes. Of the signal chains, the computation of the backscattering field is the most computationally intensive. To resolve the issue, we implement a computation parallelization for SAR echo signal generation. By profiling, the overall processing was identified to find which is the heavy loading stage. To further accommodate the hardware structure, we made extensive modifications in the CUDA kernel function. As a result, the computation efficiency is much improved, with over 224 times the speed up. The computation complexity by comparing the CPU and GPU computations was provided. We validated the proposed simulation algorithm using canonical targets, including a perfectly electric conductor (PEC), dielectric spheres, and rotated/unrotated dihedral corner reflectors. Additionally, the targets can be a multi-layered dielectric coating or a layered medium. The latter case aimed to evaluate the polarimetric response quantitively. Then, we simulated a complex target with various poses relative to the SAR imaging geometry. We show that the simulated images have high fidelity in geometric and radiometric specifications. The decomposition of images from individual scattering bounce offers valuable exploitation of the scattering mechanisms responsible for imaging certain target features.

Azulene-based Protecting Groups

<p>Protecting groups form an indispensable part of modern organic synthetic chemistry. Besides the benefits of selectively passivating certain reactive functionalities, they often provide handling benefits – such as a decrease in the polarity of the compound that facilitates purification, an increase in the structural order of a compound that allows for easier crystallisation, and chromophores that enable easy visualisation on fluorescent TLC plates under UV light. Coloured protecting groups offer additional advantages in synthetic chemistry. They expedite purification by allowing the material to be tracked visually. Phase separation and column chromatography are easier to perform, and reduce the need for the collection of large numbers of fractions, while small-scale loss of material (left behind on taps or in flasks during routine handling) and spillages are much more readily apparent. Despite these advantages, only a few coloured protecting groups have been reported in the literature. The azulenes are a class of compounds with several attractive qualities that can be exploited for use as protecting groups. They are coloured, but not overwhelmingly so. The colour is tunable through placement of electron-donating or electron-withdrawing groups at positions on the ring system, which further allows for protection/deprotection reactions to be designed that incorporate a colour change. Azulene itself is both non-polar and structurally compact, unlike many other organic chromophores such as triarylmethane dyes and carotenoids. Furthermore, azulene’s ability to stabilise both positive and negative charges through resonance with tropylium and cyclopentadienide motifs allows for unusual chemistry, and therefore potentially orthogonal modes of deprotection. Four protecting group candidates incorporating azulene were devised. The 1-azulenylmethylene amine 79 and the 1-azulenesulfonamide 82 protecting group candidates for amines had fatal flaws that were discovered early, such as a tendency to rapidly degrade in open air. The 1-azulenecarboxylate protecting group candidate 74 for alcohols showed some promise, with a high-yielding protection reaction, but none of the deprotection conditions that were developed were sufficiently mild to be usable in a late-stage deprotection strategy on a complex target molecule. The final protecting group candidate, 6-(2-[oxycarbonyl]ethyl)azulene 89, can be used for the protection of carboxylic acids, amines and alcohols as esters, carbamates and carbonates, respectively. The substitution at the 6-position of azulene allows for deprotection through an E1cB mechanism with mild base, involving a cyclopentadienide-stabilised carbanion intermediate, in a similar fashion to the FMOC protecting group. Mild conditions for the protection of all three were found: for carboxylic acids Steglich esterification is employed, and for alcohols and amines coupling with CDI is used. A selection of mild protocols for deprotection were developed, using bases such as DBU or TBAF, or involving two-step activation-deprotection procedures. Finally, the compatibility of the protecting group 89 (dubbed Azul) with common and representative procedures in synthetic chemistry was investigated, such as with bases and with reaction conditions such as oxidations, reductions, cross-couplings, etc. Orthogonality with other common protecting groups (such as TBS, MOM, FMOC) was also explored. Some incompatibilities were found with strongly acidic conditions, high-temperature Suzuki cross-coupling reactions and Swern oxidations, but otherwise the Azul protecting group shows promise as a protecting group that expedites total synthesis through its colourful properties.</p>

Azulene-based Protecting Groups

<p>Protecting groups form an indispensable part of modern organic synthetic chemistry. Besides the benefits of selectively passivating certain reactive functionalities, they often provide handling benefits – such as a decrease in the polarity of the compound that facilitates purification, an increase in the structural order of a compound that allows for easier crystallisation, and chromophores that enable easy visualisation on fluorescent TLC plates under UV light. Coloured protecting groups offer additional advantages in synthetic chemistry. They expedite purification by allowing the material to be tracked visually. Phase separation and column chromatography are easier to perform, and reduce the need for the collection of large numbers of fractions, while small-scale loss of material (left behind on taps or in flasks during routine handling) and spillages are much more readily apparent. Despite these advantages, only a few coloured protecting groups have been reported in the literature. The azulenes are a class of compounds with several attractive qualities that can be exploited for use as protecting groups. They are coloured, but not overwhelmingly so. The colour is tunable through placement of electron-donating or electron-withdrawing groups at positions on the ring system, which further allows for protection/deprotection reactions to be designed that incorporate a colour change. Azulene itself is both non-polar and structurally compact, unlike many other organic chromophores such as triarylmethane dyes and carotenoids. Furthermore, azulene’s ability to stabilise both positive and negative charges through resonance with tropylium and cyclopentadienide motifs allows for unusual chemistry, and therefore potentially orthogonal modes of deprotection. Four protecting group candidates incorporating azulene were devised. The 1-azulenylmethylene amine 79 and the 1-azulenesulfonamide 82 protecting group candidates for amines had fatal flaws that were discovered early, such as a tendency to rapidly degrade in open air. The 1-azulenecarboxylate protecting group candidate 74 for alcohols showed some promise, with a high-yielding protection reaction, but none of the deprotection conditions that were developed were sufficiently mild to be usable in a late-stage deprotection strategy on a complex target molecule. The final protecting group candidate, 6-(2-[oxycarbonyl]ethyl)azulene 89, can be used for the protection of carboxylic acids, amines and alcohols as esters, carbamates and carbonates, respectively. The substitution at the 6-position of azulene allows for deprotection through an E1cB mechanism with mild base, involving a cyclopentadienide-stabilised carbanion intermediate, in a similar fashion to the FMOC protecting group. Mild conditions for the protection of all three were found: for carboxylic acids Steglich esterification is employed, and for alcohols and amines coupling with CDI is used. A selection of mild protocols for deprotection were developed, using bases such as DBU or TBAF, or involving two-step activation-deprotection procedures. Finally, the compatibility of the protecting group 89 (dubbed Azul) with common and representative procedures in synthetic chemistry was investigated, such as with bases and with reaction conditions such as oxidations, reductions, cross-couplings, etc. Orthogonality with other common protecting groups (such as TBS, MOM, FMOC) was also explored. Some incompatibilities were found with strongly acidic conditions, high-temperature Suzuki cross-coupling reactions and Swern oxidations, but otherwise the Azul protecting group shows promise as a protecting group that expedites total synthesis through its colourful properties.</p>

Autophagy in Cancer Therapy—Molecular Mechanisms and Current Clinical Advances

Autophagy is a crucial general survival tactic of mammalian cells. It describes the capability of cells to disassemble and partially recycle cellular components (e.g., mitochondria) in case they are damaged and pose a risk to cell survival or simply if their resources are urgently needed elsewhere at the time. Autophagy-associated pathomechanisms have been increasingly recognized as important disease mechanisms in non-malignant (neurodegeneration, diffuse parenchymal lung disease) and malignant conditions alike. However, the overall consequences of autophagy for the organism depend particularly on the greater context in which autophagy occurs, such as the cell type or whether the cell is proliferating. In cancer, autophagy sustains cancer cell survival under challenging, i.e., resource-depleted, conditions. However, this leads to situations in which cancer cells are completely dependent on autophagy. Accordingly, autophagy represents a promising yet complex target in cancer treatment with therapeutically induced increase and decrease of autophagic flux as important therapeutic principles.

Chaos Based Frequency Modulation for Joint Monostatic and Bistatic Radar-Communication Systems

In this article, we propose the utilization of chaos-based frequency modulated (CBFM) waveforms for joint monostatic and bistatic radar-communication systems. Short-duration pulses generated via chaotic oscillators are used for wideband radar imaging, while information is embedded in the pulses using chaos shift keying (CSK). A self-synchronization technique for chaotic systems decodes the information at the communication receiver and reconstructs the transmitted waveform at the bistatic radar receiver. Using a nonlinear detection scheme, we show that the CBFM waveforms closely follow the theoretical bit-error rate (BER) associated with bipolar phase-shift keying (BPSK). We utilize the same nonlinear detection scheme to optimize the target detection at the bistatic radar receiver. The ambiguity function for both the monostatic and bistatic cases resembles a thumbtack ambiguity function with a pseudo-random sidelobe distribution. Furthermore, we characterize the high-resolution imaging capability of the CBFM waveforms in the presence of noise and considering a complex target.

Set-to-Sequence Methods in Machine Learning: A Review

Machine learning on sets towards sequential output is an important and ubiquitous task, with applications ranging from language modelling and meta-learning to multi-agent strategy games and power grid optimization. Combining elements of representation learning and structured prediction, its two primary challenges include obtaining a meaningful, permutation invariant set representation and subsequently utilizing this representation to output a complex target permutation. This paper provides a comprehensive introduction to the _eld as well as an overview of important machine learning methods tackling both of these key challenges, with a detailed qualitative comparison of selected model architectures.

Computational design of 3D-printed active lattice structures for reversible shape morphing

Active structures can adapt to varying environmental conditions and functional requirements by changing their shapes and properties, which makes them suitable for applications in changing environments as found in aerospace and automotive. Of special interest are light and stiff structures with shape morphing capabilities, which is naturally contradictory. Existing concepts in literature can be limited to a single, non-reversible actuation and are difficult to design due to the inherent complexity of large-scale lattices with many elements and complex target deformations. Here, we show how 3D-printed active materials can be combined with an efficient computational framework to design large-scale lattice structures that can change their shape between an initial state and a target state. The reversible deformation is controlled by a single actuation input and heating of the structure. Numerical and experimental results show the generality of the proposed method and the applicability to different problems such as morphing airfoils. Graphic Abstract

Optimization of shot peen forming patterns to achieve complex target shapes the inverse problem

The inverse problem of determining how to shot peen a plate such that it deforms into a desired target shape is a challenge in the peen forming industry. While peening thick plates uniformly on one side results in a spherical shape, with the same curvature in all directions, complex peening patterns are required to form other shapes, such as cylinders and saddles found on fuselages and wing skin panels. In this study, we present an optimization procedure to automatically compute shot peening patterns. This procedure relies on an idealized model of the peen forming process, where the effect of the treatment is modeled by in-plane expansion of the peened areas, and on an off-the-shelf optimization algorithm. For validation purposes, we peen formed three 305 X 305 X 4.9 mm and two 762 X 762 X 4.9mm 2024--T3 aluminium alloy plates into cylindrical and saddle shapes using the same peening treatment. The obtained shapes qualitatively match simulations. For 305 X 305 X 4.9mm plates, the relative differences had the same distribution and were of the same order of magnitude as initial out-of-plane deviations measured on the as-received plates.