Notes

Closing with the femoral medullary tunel right after retrograde securing utilizing an in-situ osteochondral autograft-Technical trick and a scenario sequence.
Recent advances in the structural biology of disease-relevant α-synuclein fibrils have revealed a variety of structures, yet little is known about the process of fibril aggregate formation. Characterization of intermediate species that form during aggregation is crucial; however, this has proven very challenging because of their transient nature, heterogeneity, and low population. Here, we investigate the aggregation of α-synuclein bound to negatively charged phospholipid small unilamellar vesicles. Through a combination of kinetic and structural studies, we identify key time points in the aggregation process that enable targeted isolation of prefibrillar and early fibrillar intermediates. By using solid-state nuclear magnetic resonance, we show the gradual buildup of structural features in an α-synuclein fibril filament, revealing a segmental folding process. We identify distinct membrane-binding domains in α-synuclein aggregates, and the combined data are used to present a comprehensive mechanism of the folding of α-synuclein on lipid membranes.The four-pass transmembrane proteins Vangl1 and Vangl2 are dedicated core components of Wnt/planar cell polarity (Wnt/PCP) signaling that critically regulate polarized cell behaviors in many morphological and physiological processes. Here, we found that the abundance of Vangl proteins is tightly controlled by the ubiquitin-proteasome system through endoplasmic reticulum-associated degradation (ERAD). The key ERAD component p97/VCP directly binds to Vangl at a highly conserved VCP-interacting motif and recruits the E3 ligase KBTBD7 via its UBA-UBX adaptors to promote Vangl ubiquitination and ERAD. We found that Wnt5a/CK1 prevents Vangl ubiquitination and ERAD by inducing Vangl phosphorylation, which facilitates Vangl export from the ER to the plasma membrane. We also provide in vivo evidence that KBTBD7 regulates convergent extension during zebrafish gastrulation and functions as a tumor suppressor in breast cancer by promoting Vangl degradation. Our findings reveal a previously unknown regulatory mechanism of Wnt/PCP signaling through the p97/VCP-KBTBD7-mediated ERAD pathway.Mid-infrared (IR) spectroscopic imaging using inherent vibrational contrast has been broadly used as a powerful analytical tool for sample identification and characterization. However, the low spatial resolution and large water absorption associated with the long IR wavelengths hinder its applications to study subcellular features in living systems. Recently developed mid-infrared photothermal (MIP) microscopy overcomes these limitations by probing the IR absorption-induced photothermal effect using a visible light. MIP microscopy yields submicrometer spatial resolution with high spectral fidelity and reduced water background. In this review, we categorize different photothermal contrast mechanisms and discuss instrumentations for scanning and widefield MIP microscope configurations. We highlight a broad range of applications from life science to materials. We further provide future perspective and potential venues in MIP microscopy field.The dynamic processing of optoelectronic signals carrying temporal and sequential information is critical to various machine learning applications including language processing and computer vision. Despite extensive efforts to emulate the visual cortex of human brain, large energy/time overhead and extra hardware costs are incurred by the physically separated sensing, memory, and processing units. JQ1 mouse The challenge is further intensified by the tedious training of conventional recurrent neural networks for edge deployment. Here, we report in-sensor reservoir computing for language learning. High dimensionality, nonlinearity, and fading memory for the in-sensor reservoir were achieved via two-dimensional memristors based on tin sulfide (SnS), uniquely having dual-type defect states associated with Sn and S vacancies. Our in-sensor reservoir computing demonstrates an accuracy of 91% to classify short sentences of language, thus shedding light on a low training cost and the real-time solution for processing temporal and sequential signals for machine learning applications at the edge.Inspired by the formation of hierarchically structured natural biominerals (e.g., bone and tooth), various sequence-defined polymers have been synthesized and exploited for design and synthesis of functional hybrid materials. Here, we synthesized a series of organic-inorganic hybrid peptoids by using polyhedral oligomeric silsesquioxane (POSS) nanoclusters as side chains at a variety of backbone locations. We further demonstrated the use of these hybrid peptoids as sequence-defined building blocks to assemble a new class of programmable two-dimensional (2D) nanocrystals. They are highly stable and exhibit an enhanced mechanical property and electron scattering due to the incorporated POSS nanoclusters. link2 By varying peptoid side-chain chemistry, we further demonstrated the precise displacement of a large variety of function groups within these 2D nanocrystals and developed a highly efficient aqueous light-harvesting system for live cell imaging. Because these 2D nanocrystals are biocompatible and highly programmable, we expect that they offer unique opportunities for applications.The assignment of enantiomorphs by diffraction methods shows fundamental differences for x-rays and electrons. This is particularly evident for the chiral allotrope of β-Mn. While it is not possible to determine the sense of chirality of β-Mn with established x-ray diffraction methods, Kikuchi pattern simulation of the enantiomorphs reveals differences, if dynamical electron diffraction is considered. Quantitative comparison between experimental and simulated Kikuchi patterns allows the spatially resolved assignment of the enantiomorph in polycrystalline materials of β-Mn, as well as the structurally strongly related phase Pt2Cu3B. On the basis of enantiomorph distribution maps, crystals were extracted from enantiopure domains by micropreparation techniques. The x-ray diffraction analyses confirm the assignment of the Kikuchi pattern evaluations for Pt2Cu3B and do not allow to distinguish between the enantiomorphs of β-Mn.T cell receptor (TCR) antigen-specific recognition is essential for the adaptive immune system. However, building a TCR-antigen interaction map has been challenging due to the staggering diversity of TCRs and antigens. Accordingly, highly multiplexed dextramer-TCR binding assays have been recently developed, but the utility of the ensuing large datasets is limited by the lack of robust computational methods for normalization and interpretation. Here, we present a computational framework comprising a novel method, ICON (Integrative COntext-specific Normalization), for identifying reliable TCR-pMHC (peptide-major histocompatibility complex) interactions and a neural network-based classifier TCRAI that outperforms other state-of-the-art methods for TCR-antigen specificity prediction. We further demonstrated that by combining ICON and TCRAI, we are able to discover novel subgroups of TCRs that bind to a given pMHC via different mechanisms. Our framework facilitates the identification and understanding of TCR-antigen-specific interactions for basic immunological research and clinical immune monitoring.Sensory processing is subjected to modulation by behavioral contexts that are often mediated by long-range inputs to cortical interneurons, but their selectivity to different types of interneurons remains largely unknown. Using rabies-virus tracing and optogenetics-assisted recording, we analyzed the long-range connections to various brain regions along the hierarchy of visual processing, including primary visual cortex, medial association cortices, and frontal cortices. We found that hierarchical corticocortical and thalamocortical connectivity is reflected by the relative weights of inputs to parvalbumin-positive (PV+) and vasoactive intestinal peptide-positive (VIP+) neurons within the conserved local circuit motif, with bottom-up and top-down inputs preferring PV+ and VIP+ neurons, respectively. Our algorithms based on innervation weights for these two types of local interneurons generated testable predictions of the hierarchical position of many brain areas. These results support the notion that preferential long-range inputs to specific local interneurons are essential for the hierarchical information flow in the brain.Land-use intensification poses major threats to biodiversity, such as to insect herbivore communities. The stability of these communities depends on interactions linking herbivores and host plants. How interaction network structure begets robustness, and thus stability, in different ecosystems and how network structure and robustness are altered along land-use intensity gradients are unclear. We analyzed plant-herbivore networks based on literature-derived interactions and long-term sampling from 289 grasslands and forests in three regions of Germany. Network size and nestedness were the most important determinants of network robustness in both ecosystems. Along land-use intensity gradients, networks in moderately grazed grasslands were more robust than in those managed by frequent mowing or fertilization. In forests, changes of network robustness along land-use intensity gradients relied on changes in plant species richness. Our results expand our knowledge of the stability of plant-herbivore networks and indicate options for management aimed at stabilizing herbivore communities.The technique of neutron tomography has, after 350 years, enabled a first look inside the iconic single-lens microscopes of Antoni van Leeuwenhoek. Van Leeuwenhoek's 17th-century discovery of "animalcules" marks the birth of microbiology. His skillfully self-produced microscope lenses remained unsurpassed for over 150 years. Neutron tomography now enabled us to reveal the lens types Van Leeuwenhoek used. We argue that Van Leeuwenhoek's instruments incorporate some innovations that testify to an awareness of concurrent developments. link3 In particular, our analysis shows that for making his best-performing microscopes, Van Leeuwenhoek deployed a lens-making procedure popularized in 1678 by Robert Hooke. This is notable, as Hooke always wanted to find the secret of Van Leeuwenhoek's lenses, but never managed to do so. Therefore, Van Leeuwenhoek was far from the isolated scholar he is often claimed to be; rather, his secrecy about his lenses was motivated by an attempt to conceal his indebtedness to Hooke.Misregulated gene expression in human hearts can result in cardiovascular diseases that are leading causes of mortality worldwide. However, the limited information on the genomic location of candidate cis-regulatory elements (cCREs) such as enhancers and promoters in distinct cardiac cell types has restricted the understanding of these diseases. Here, we defined >287,000 cCREs in the four chambers of the human heart at single-cell resolution, which revealed cCREs and candidate transcription factors associated with cardiac cell types in a region-dependent manner and during heart failure. We further found cardiovascular disease-associated genetic variants enriched within these cCREs including 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Additional functional studies revealed that two of these variants affect a cCRE controlling KCNH2/HERG expression and action potential repolarization. Overall, this atlas of human cardiac cCREs provides the foundation for illuminating cell type-specific gene regulation in human hearts during health and disease.
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