Glial cell line-derived neurotrophic factor (GDNF) and its canonical receptor Ret can signal together or independently to fulfill many important functions in the midbrain dopaminergic (DA) system. ...While Ret signaling clearly impacts on the development, maintenance and regeneration of the mesostriatal DA system, the physiological functions of GDNF for the DA system are still unclear. Nevertheless, GDNF is still considered to be an excellent candidate to protect and/or regenerate the mesostriatal DA system in Parkinson disease (PD). Clinical trials with GDNF on PD patients are, however, so far inconclusive. Here, we review the current knowledge of GDNF and Ret signaling and function in the midbrain DA system, and their crosstalk with proteins and signaling pathways associated with PD.
With the assistance of sophisticated training methods applied to single labeled datasets, the performance of fully-supervised person re-identification (Person Re-ID) has been improved significantly ...in recent years. However, these models trained on a single dataset usually suffer from considerable performance degradation when applied to videos of a different camera network. To make Person Re-ID systems more practical and scalable, several cross-dataset domain adaptation methods have been proposed, which achieve high performance without the labeled data from the target domain. However, these approaches still require the unlabeled data of the target domain during the training process, making them impractical. A practical Person Re-ID system pre-trained on other datasets should start running immediately after deployment on a new site without having to wait until sufficient images or videos are collected and the pre-trained model is tuned. To serve this purpose, in this paper, we reformulate person re-identification as a multi-dataset domain generalization problem. We propose a multi-dataset feature generalization network (MMFA-AAE), which is capable of learning a universal domain-invariant feature representation from multiple labeled datasets and generalizing it to `unseen' camera systems. The network is based on an adversarial auto-encoder to learn a generalized domain-invariant latent feature representation with the Maximum Mean Discrepancy (MMD) measure to align the distributions across multiple domains. Extensive experiments demonstrate the effectiveness of the proposed method. Our MMFA-AAE approach not only outperforms most of the domain generalization Person Re-ID methods, but also surpasses many state-of-the-art supervised methods and unsupervised domain adaptation methods by a large margin.
Caspase-8 activation can be triggered by death receptor-mediated formation of the death-inducing signaling complex (DISC) and by the inflammasome adaptor ASC. Caspase-8 assembles with FADD at the ...DISC and with ASC at the inflammasome through its tandem death effector domain (tDED), which is regulated by the tDED-containing cellular inhibitor cFLIP and the viral inhibitor MC159. Here we present the caspase-8 tDED filament structure determined by cryoelectron microscopy. Extensive assembly interfaces not predicted by the previously proposed linear DED chain model were uncovered, and were further confirmed by structure-based mutagenesis in filament formation in vitro and Fas-induced apoptosis and ASC-mediated caspase-8 recruitment in cells. Structurally, the two DEDs in caspase-8 use quasi-equivalent contacts to enable assembly. Using the tDED filament structure as a template, structural analyses reveal the interaction surfaces between FADD and caspase-8 and the distinct mechanisms of regulation by cFLIP and MC159 through comingling and capping, respectively.
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•Caspase-8 tDED assembles into filaments through quasi-equivalent contacts•The assembly of caspase-8 filaments is nucleated by the upstream Fas/FADD complex•cFLIP tDED also forms filaments, which interact with caspase-8 by comingling•MC159 inhibits caspase-8 filament assembly by a unique capping mechanism
How caspase-8 is activated has been a long-standing question. Fu et al. show that its tDED forms filaments using quasi-equivalent interactions. Cryo-EM structure of the filament reveals mechanisms of caspase-8 activation and its regulation by cFLIP and MC159.
The NLRP3 inflammasome can be activated by stimuli that include nigericin, uric acid crystals, amyloid-β fibrils and extracellular ATP. The mitotic kinase NEK7 licenses the assembly and activation of ...the NLRP3 inflammasome in interphase. Here we report a cryo-electron microscopy structure of inactive human NLRP3 in complex with NEK7, at a resolution of 3.8 Å. The earring-shaped NLRP3 consists of curved leucine-rich-repeat and globular NACHT domains, and the C-terminal lobe of NEK7 nestles against both NLRP3 domains. Structural recognition between NLRP3 and NEK7 is confirmed by mutagenesis both in vitro and in cells. Modelling of an active NLRP3-NEK7 conformation based on the NLRC4 inflammasome predicts an additional contact between an NLRP3-bound NEK7 and a neighbouring NLRP3. Mutations to this interface abolish the ability of NEK7 or NLRP3 to rescue NLRP3 activation in NEK7-knockout or NLRP3-knockout cells. These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome.
Protein interactions are the foundation of cell biology. For robust signal transduction to occur, proteins interact selectively and modulate their behavior to direct specific biological outcomes. ...Frequently, modular protein interaction domains are central to these processes. Some of these domains bind proteins bearing post‐translational modifications, such as phosphorylation, whereas other domains recognize and bind to specific amino acid motifs. Other modules act as diverse protein interaction scaffolds or can be multifunctional, forming head‐to‐head homodimers and binding specific peptide sequences or membrane phospholipids. Additionally, the so‐called head‐to‐tail oligomerization domains (SAM, DIX, and PB1) can form extended polymers to regulate diverse aspects of biology. Although the mechanism and structures of these domains are diverse, they are united by their modularity. Together, these domains are versatile and facilitate the evolution of complex protein interaction networks. In this review, we will highlight the role of select modular protein interaction domains in various aspects of plant biology.
The ability for proteins to interact is central to their biological functions. Modular protein domains act as a biological toolkit that allow evolution of protein interactions. In this review, we provide a snapshot of how individual domains drive protein versatility and lay the groundwork for complex protein interactions in plants.
Pathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration
. Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) ...is a central regulator of this neurodegenerative process
, and its Toll/interleukin-1 receptor (TIR) domain exerts its pro-neurodegenerative action through NADase activity
. However, the mechanisms by which the activation of SARM1 is stringently controlled are unclear. Here we report the cryo-electron microscopy structures of full-length SARM1 proteins. We show that NAD
is an unexpected ligand of the armadillo/heat repeat motifs (ARM) domain of SARM1. This binding of NAD
to the ARM domain facilitated the inhibition of the TIR-domain NADase through the domain interface. Disruption of the NAD
-binding site or the ARM-TIR interaction caused constitutive activation of SARM1 and thereby led to axonal degeneration. These findings suggest that NAD
mediates self-inhibition of this central pro-neurodegenerative protein.
With the widespread use of automatic speaker recognition in realistic world, it suffers a lot when there is a domain mismatch, including channel, language, distance etc. Recent research studies have ...introduced the adversarial-learning mechanism into deep neural networks to reduce the distribution mismatch between different domains. However, they only aligned the domain distributions between the background training and evaluation data. Few focused on the diverse distribution underlying the enrol and test data. In this Letter, the authors propose a domain adversarial siamese (DAS) network trying to eliminate the domain influence on speech representation. Specifically, they feed a network with speech pairs from the same speaker. Then a domain discriminator is introduced to capture the domain consistence or difference between pairs. Final embeddings become domain-invariant and more speaker-discriminative. A cross-channel data set is sort out from NIST speaker recognition evaluation and more experiments are conducted on AISHELL-Wake-Up-1 data set. Results show that DAS performs equally effective with typical domain adversarial methods, improving results at least $10\%$10% on energy efficiency rating. Furthermore, it is proved to be more valid for scenarios such as unbalanced data amount and unknown domain, achieving relatively $11\%$11% improvements.
Efficient multiscale electromagnetic simulations require several major challenges that need to be addressed, such as flexible and robust geometric modeling schemes, efficient and stable time-stepping ...methods, etc. Due to the versatile choices of spatial discretization and temporal integration, discontinuous Galerkin time-domain (DGTD) methods can be very promising in simulating transient multiscale problems. This paper provides a comprehensive review of different DGTD schemes, highlighting the fundamental issues arising in each step of constructing a DGTD system. The issues discussed include the selection of governing equations for transient electromagnetic analysis, different basis functions for spatial discretization, as well as the implementation of different time-stepping schemes. Numerical examples demonstrate the advantages of DGTD for multiscale electromagnetic simulations.
The worldwide spread of COVID-19 highlights the need for an efficient approach to rapidly develop therapeutics and prophylactics against SARS-CoV-2. The SARS-CoV-2 spike protein, containing the ...receptor-binding domain (RBD) and S1 subunit involved in receptor engagement, is a potential therapeutic target. We describe the development of a phage-displayed single-domain antibody library by grafting naive complementarity-determining regions (CDRs) into framework regions of a human germline immunoglobulin heavy chain variable region (IGHV) allele. Panning this library against SARS-CoV-2 RBD and S1 subunit identified fully human single-domain antibodies targeting five distinct epitopes on SARS-CoV-2 RBD with subnanomolar to low nanomolar affinities. Some of these antibodies neutralize SARS-CoV-2 by targeting a cryptic epitope located in the spike trimeric interface. Collectively, this work presents a versatile platform for rapid antibody isolation and identifies promising therapeutic anti-SARS-CoV-2 antibodies as well as the diverse immogneic profile of the spike protein.
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•A phage-displayed human single-domain antibody library is developed•Single-domain antibodies targeting five types of SARS-CoV-2 epitopes are identified•Some neutralizing antibodies target cryptic SARS-CoV-2 spike trimeric interface•Unique immunogenic profile of SARS-CoV-2 RBD is revealed
Wu et al. describe the development of a versatile platform for rapid isolation of fully human single-domain antibodies and apply this methodology to identify SARS-CoV-2-specific antibodies. These human single-domain antibodies target diverse epitopes within the SARS-CoV-2 spike protein receptor binding domain (RBD) and may yield potential therapeutic candidates for COVID-19.
Regulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core ...FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIP
into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome.
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