Potassium (K+) efflux across the plasma membrane is thought to be an essential mechanism for ATP-induced NLRP3 inflammasome activation, yet the identity of the efflux channel has remained elusive. ...Here we identified the two-pore domain K+ channel (K2P) TWIK2 as the K+ efflux channel triggering NLRP3 inflammasome activation. Deletion of Kcnk6 (encoding TWIK2) prevented NLRP3 activation in macrophages and suppressed sepsis-induced lung inflammation. Adoptive transfer of Kcnk6−/− macrophages into mouse airways after macrophage depletion also prevented inflammatory lung injury. The K+ efflux channel TWIK2 in macrophages has a fundamental role in activating the NLRP3 inflammasome and consequently mediates inflammation, pointing to TWIK2 as a potential target for anti-inflammatory therapies.
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•Macrophage NLRP3 inflammasome activation is inhibited by potassium channel inhibition•TWIK2 is a potassium efflux channel required for NLRP3 inflammasome activation•Genetic deletion of TWIK2 prevents endotoxemia-induced inflammatory lung injury•P2X7 receptor and TWIK2 act in cooperation to regulate NLRP3 inflammasome activation
Potassium efflux is required for NLRP3 inflammasome activation, but the channel mediating the efflux has remained elusive. Di et al. identify the potassium channel TWIK2 as a mediator of potassium efflux and NLRP3 activation in macrophages. Targeting TWIK2 could form the basis for therapeutic approaches in inflammatory injury.
Faster-than-Nyquist (FTN) signaling has been recognized as a promising technique for next-generation high data rate communications. By intentionally reducing the symbol interval, FTN signaling is ...capable of transmitting more symbols than classic Nyquist signaling within the same time period and bandwidth. However, the intentional non-orthogonality of the bandlimited signaling pulses imposes severe inter-symbol interference (ISI), which requires powerful equalization at the receiver. Hence, we embark on the comparison of time- and frequency-domain equalization for FTN signaling both by theoretical analysis and numerical simulations. It is shown that frequency-domain equalization fails to reliably detect the FTN signal with a low FTN packing factor, while the time-domain equalization still performs well.
Coronaviruses make use of a large envelope protein called spike (S) to engage host cell receptors and catalyze membrane fusion. Because of the vital role that these S proteins play, they represent a ...vulnerable target for the development of therapeutics. Here, we describe the isolation of single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs neutralize MERS-CoV or SARS-CoV-1 S pseudotyped viruses, respectively. Crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs interfere with receptor binding. We also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S and demonstrate that this cross-reactive VHH neutralizes SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fc-fusion. These data provide a molecular basis for the neutralization of pathogenic betacoronaviruses by VHHs and suggest that these molecules may serve as useful therapeutics during coronavirus outbreaks.
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•VHHs isolated from a llama immunized with prefusion-stabilized coronavirus spikes•Structural characterization of VHHs reveals conserved mechanism of neutralization•SARS-CoV-1 S-directed VHH cross-reacts with SARS-CoV-2 S•Bivalent VHH neutralizes SARS-CoV-2 pseudoviruses
Using llamas immunized with prefusion-stabilized betacoronavirus spike proteins, Wrapp et al. identify neutralizing cross-reactive single-domain camelid antibodies, which may serve not only as useful reagents for researchers studying the viruses causing MERS, SARS, and COVID-19, but also potential therapeutic candidates. Crystal structures further reveal how these antibodies bind spike proteins to prevent virus entry into cells.
Domain adaptation is an important emerging topic in computer vision. In this paper, we present one of the first studies of domain shift in the context of object recognition. We introduce a method ...that adapts object models acquired in a particular visual domain to new imaging conditions by learning a transformation that minimizes the effect of domain-induced changes in the feature distribution. The transformation is learned in a supervised manner and can be applied to categories for which there are no labeled examples in the new domain. While we focus our evaluation on object recognition tasks, the transform-based adaptation technique we develop is general and could be applied to non-image data. Another contribution is a new multi-domain object database, freely available for download. We experimentally demonstrate the ability of our method to improve recognition on categories with few or no target domain labels and moderate to large changes in the imaging conditions.
Shuttle protein UBQLN2 functions in protein quality control (PQC) by binding to proteasomal receptors and ubiquitinated substrates via its N‐terminal ubiquitin‐like (UBL) and C‐terminal ...ubiquitin‐associated (UBA) domains, respectively. Between these two folded domains are low‐complexity STI1‐I and STI1‐II regions, connected by disordered linkers. The STI1 regions bind other components, such as HSP70, that are important to the PQC functions of UBQLN2. We recently determined that the STI1‐II region enables UBQLN2 to undergo liquid–liquid phase separation (LLPS) to form liquid droplets in vitro and biomolecular condensates in cells. However, how the interplay between the folded (UBL/UBA) domains and the intrinsically disordered regions mediates phase separation is largely unknown. Using engineered domain deletion constructs, we found that removing the UBA domain inhibits UBQLN2 LLPS while removing the UBL domain enhances LLPS, suggesting that UBA and UBL domains contribute asymmetrically in modulating UBQLN2 LLPS. To explain these differential effects, we interrogated the interactions that involve the UBA and UBL domains across the entire UBQLN2 molecule using nuclear magnetic resonance spectroscopy. To our surprise, aside from well‐studied canonical UBL:UBA interactions, there also exist moderate interactions between the UBL and several disordered regions, including STI1‐I and residues 555–570, the latter of which is a known contributor to UBQLN2 LLPS. Our findings are essential for the understanding of both the molecular driving forces of UBQLN2 LLPS and the effects of ligand binding to UBL, UBA, or disordered regions on the phase behavior and physiological functions of UBQLN2.
SAMHD1 regulates cellular nucleotide homeostasis, controlling dNTP levels by catalysing their hydrolysis into 2'-deoxynucleosides and triphosphate. In differentiated CD4+ macrophage and resting ...T-cells SAMHD1 activity results in the inhibition of HIV-1 infection through a dNTP blockade. In cancer, SAMHD1 desensitizes cells to nucleoside-analogue chemotherapies. Here we employ time-resolved cryogenic-EM imaging and single-particle analysis to visualise assembly, allostery and catalysis by this multi-subunit enzyme. Our observations reveal how dynamic conformational changes in the SAMHD1 quaternary structure drive the catalytic cycle. We capture five states at high-resolution in a live catalytic reaction, revealing how allosteric activators support assembly of a stable SAMHD1 tetrameric core and how catalysis is driven by the opening and closing of active sites through pairwise coupling of active sites and order-disorder transitions in regulatory domains. This direct visualisation of enzyme catalysis dynamics within an allostery-stabilised platform sets a precedent for mechanistic studies into the regulation of multi-subunit enzymes.
Since the start of the COVID-19 pandemic, SARS-CoV-2 has caused millions of deaths worldwide. Although a number of vaccines have been deployed, the continual evolution of the receptor-binding domain ...(RBD) of the virus has challenged their efficacy. In particular, the emerging variants B.1.1.7, B.1.351 and P.1 (first detected in the UK, South Africa and Brazil, respectively) have compromised the efficacy of sera from patients who have recovered from COVID-19 and immunotherapies that have received emergency use authorization
. One potential alternative to avert viral escape is the use of camelid VHHs (variable heavy chain domains of heavy chain antibody (also known as nanobodies)), which can recognize epitopes that are often inaccessible to conventional antibodies
. Here, we isolate anti-RBD nanobodies from llamas and from mice that we engineered to produce VHHs cloned from alpacas, dromedaries and Bactrian camels. We identified two groups of highly neutralizing nanobodies. Group 1 circumvents antigenic drift by recognizing an RBD region that is highly conserved in coronaviruses but rarely targeted by human antibodies. Group 2 is almost exclusively focused to the RBD-ACE2 interface and does not neutralize SARS-CoV-2 variants that carry E484K or N501Y substitutions. However, nanobodies in group 2 retain full neutralization activity against these variants when expressed as homotrimers, and-to our knowledge-rival the most potent antibodies against SARS-CoV-2 that have been produced to date. These findings suggest that multivalent nanobodies overcome SARS-CoV-2 mutations through two separate mechanisms: enhanced avidity for the ACE2-binding domain and recognition of conserved epitopes that are largely inaccessible to human antibodies. Therefore, although new SARS-CoV-2 mutants will continue to emerge, nanobodies represent promising tools to prevent COVID-19 mortality when vaccines are compromised.
This paper proposes a new learning mechanism for a fully convolutional neural network (CNN) to address speech enhancement in the time domain. The CNN takes as input the time frames of noisy utterance ...and outputs the time frames of the enhanced utterance. At the training time, we add an extra operation that converts the time domain to the frequency domain. This conversion corresponds to simple matrix multiplication, and is hence differentiable implying that a frequency domain loss can be used for training in the time domain. We use mean absolute error loss between the enhanced short-time Fourier transform (STFT) magnitude and the clean STFT magnitude to train the CNN. This way, the model can exploit the domain knowledge of converting a signal to the frequency domain for analysis. Moreover, this approach avoids the well-known invalid STFT problem since the proposed CNN operates in the time domain. Experimental results demonstrate that the proposed method substantially outperforms the other methods of speech enhancement. The proposed method is easy to implement and applicable to related speech processing tasks that require time-frequency masking or spectral mapping.
Micromagnetics has been the method of choice to interpret experimental data in the area of microscopic magnetism for several decades. In this article, we show how progress has been made to extend ...this formalism to include thermal and quantum fluctuations in order to describe recent experimental developments in nanoscale magnetism. For experimental systems with constrained dimensions such as nanodots, atomic chains, nanowires, and thin films, topological defects such as solitons, vortices, skyrmions, and monopoles start to play an increasingly important role, all forming novel types of quasiparticles in patterned low-dimensional magnetic systems. We discuss in detail how soliton-antisoliton pairs of opposite chirality form non-uniform energy barriers against thermal fluctuations in nanowires or pillars. As a consequence of their low barrier energy compared to uniform reversal, they limit the thermal stability of perpendicular recording media. For sufficiently short samples, the non-uniform energy barrier continuously merges into the conventional uniform Néel-Brown barrier. Partial formation of chiral domain walls also determines the magnetic properties of granular nanostructured magnets and exchange spring systems. For a long time, the reconciliation between micromagnetics and quantum mechanics has remained an unresolved challenge. Here it is demonstrated how inclusion of Berry's phase in a micromagnetic action allows for a semiclassical quantization of spin systems, a method that is demonstrated by the simple example of an easy-plane spin. This powerful method allows for a description of quantum dynamics of solitons and breathers which in the latter case agrees with the anisotropic spin-½ XYZ-model. The domain wall or soliton chirality plays an important role as it is coupled to the wavevector of the quasiparticle dispersion. We show how this quantum soliton chirality is detected by polarized neutron scattering in one-dimensional quantum antiferromagnets.
Death receptors (DRs) are members of the tumor necrosis factor receptor superfamily that possess a cytoplasmic death domain (DD). DRs regulate important operational and homeostatic aspects of the ...immune system. They transmit signals through apical protein complexes, which are nucleated by the DD adaptors FADD and TRADD, to control cellular outcomes that range from apoptosis to gene activation. FADD and TRADD also nucleate several distal signaling complexes, which mediate cross-talk between distinct DR signaling pathways. Moreover, together with other DR signal transducers, FADD and TRADD participate in functional complexes assembled by certain non-DR immune cell receptors, such as pattern-recognition receptors. Thus, DR signal transducers may provide important nodes of coordination in immune signaling networks.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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