Abstract
In a retrospective study of 39 COVID-19 patients and 32 control participants in China, we collected clinical data and examined the expression of endothelial cell adhesion molecules by ...enzyme-linked immunosorbent assays. Serum levels of fractalkine, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular adhesion protein-1 (VAP-1) were elevated in patients with mild disease, dramatically elevated in severe cases, and decreased in the convalescence phase. We conclude the increased expression of endothelial cell adhesion molecules is related to COVID-19 disease severity and may contribute to coagulation dysfunction.
Synapses are fundamental units of communication in the brain. The prototypical synapse-organizing complex neurexin-neuroligin mediates synapse development and function and is central to a shared ...genetic risk pathway in autism and schizophrenia. Neurexin’s role in synapse development is thought to be mediated purely by its protein domains, but we reveal a requirement for a rare glycan modification. Mice lacking heparan sulfate (HS) on neurexin-1 show reduced survival, as well as structural and functional deficits at central synapses. HS directly binds postsynaptic partners neuroligins and LRRTMs, revealing a dual binding mode involving intrinsic glycan and protein domains for canonical synapse-organizing complexes. Neurexin HS chains also bind novel ligands, potentially expanding the neurexin interactome to hundreds of HS-binding proteins. Because HS structure is heterogeneous, our findings indicate an additional dimension to neurexin diversity, provide a molecular basis for fine-tuning synaptic function, and open therapeutic directions targeting glycan-binding motifs critical for brain development.
Display omitted
•Brain central synaptic organizers neurexins are heparan sulfate (HS) proteoglycans•A dual HS and protein domain mode mediates neurexin binding to neuroligin and LRRTM•HS increases neurexin heterogeneity and expands its interactome to HS binding factors•HS glycan on neurexin is required for normal synaptic development and mouse survival
Neurexins, major synaptic-organizing proteins, are heparan sulfate (HS) proteoglycans, and HS modification is required for neurexin functions in synaptic transmission, development, and behavior.
Axonal initial segments (IS) and nodes of Ranvier are functionally important membrane subdomains in which the clustering of electrogenic channels enables action potential initiation and propagation. ...In addition, the initial segment contributes to neuronal polarity by serving as a diffusion barrier. To study the mechanisms of axonal compartmentalization, we focused on two L1 family of cell adhesion molecules (L1-CAMs) L1/neuron-glia cell adhesion molecule (L1/NgCAM) and neurofascin (NF) and two neuronal ankyrins (ankB and ankG). NF and ankG accumulate specifically at the initial segment, whereas L1/NgCAM and ankB are expressed along the entire lengths of axons. We find that L1/NgCAM and NF show distinct modes of steady-state accumulation during axon outgrowth in cultured hippocampal neurons. Despite their different steady-state localizations, both L1/NgCAM and NF show slow diffusion and low detergent extractability specifically in the initial segment but fast diffusion and high detergent extractability in the distal axon. We propose that L1-CAMs do not strongly bind ankB in the distal axon because of spatial regulation of ankyrin affinity by phosphorylation. NF, conversely, is initially enriched in an ankyrin-independent manner in the axon generally and accumulates progressively in the initial segment attributable to preferential binding to ankG. Our results suggest that NF and L1/NgCAM accumulate in the axon by an ankyrin-independent pathway, but retention at the IS requires ankyrin binding.
Despite their apparent lack of catalytic activity, pseudokinases are essential signaling molecules. Here, we describe the structural and dynamic properties of pseudokinase domains from the ...Wnt-binding receptor tyrosine kinases (PTK7, ROR1, ROR2, and RYK), which play important roles in development. We determined structures of all pseudokinase domains in this family and found that they share a conserved inactive conformation in their activation loop that resembles the autoinhibited insulin receptor kinase (IRK). They also have inaccessible ATP-binding pockets, occluded by aromatic residues that mimic a cofactor-bound state. Structural comparisons revealed significant domain plasticity and alternative interactions that substitute for absent conserved motifs. The pseudokinases also showed dynamic properties that were strikingly similar to those of IRK. Despite the inaccessible ATP site, screening identified ATP-competitive type-II inhibitors for ROR1. Our results set the stage for an emerging therapeutic modality of “conformational disruptors” to inhibit or modulate non-catalytic functions of pseudokinases deregulated in disease.
Display omitted
•Pseudokinases share autoinhibitory interactions of their closest kinase relatives•Structural dynamics of pseudokinases closely resemble those of canonical kinases•ROR1 ATP-binding site can be targeted with small molecules despite being occluded•Inhibitor binding disrupts pseudokinase conformation and may inhibit signaling
Sheetz et al. ask how Wnt-binding receptor tyrosine kinases can signal through intracellular “pseudokinase” domains. They find that these domains resemble autoinhibited kinases but are dynamic enough to regulate signaling through conformational switching. They find small molecules that can alter pseudokinase conformation, suggesting routes for modulating this receptor class therapeutically.
Super-resolution optical imaging based on the switching and localization of individual fluorescent molecules photoactivated localization microscopy (PALM), stochastic optical reconstruction ...microscopy (STORM), etc. has evolved remarkably over the last decade. Originally driven by pushing technological limits, it has become a tool of biological discovery. The initial demand for impressive pictures showing well-studied biological structures has been replaced by a need for quantitative, reliable data providing dependable evidence for specific unresolved biological hypotheses. In this review, we highlight applications that showcase this development, identify the features that led to their success, and discuss remaining challenges and difficulties. In this context, we consider the complex topic of defining resolution for this imaging modality and address some of the more common analytical methods used with this data.
In the developing brain, cell-surface proteins play crucial roles, but their protein-protein interaction network remains largely unknown. A proteomic screen identified 200 interactions, 89 of which ...were not previously published. Among these interactions, we find that the IgLONs, a family of five cell-surface neuronal proteins implicated in various human disorders, interact as homo- and heterodimers. We reveal their interaction patterns and report the dimeric crystal structures of Neurotrimin (NTRI), IgLON5, and the neuronal growth regulator 1 (NEGR1)/IgLON5 complex. We show that IgLONs maintain an extended conformation and that their dimerization occurs through the first Ig domain of each monomer and is Ca2+ independent. Cell aggregation shows that NTRI and NEGR1 homo- and heterodimerize in trans. Taken together, we report 89 unpublished cell-surface ligand-receptor pairs and describe structural models of trans interactions of IgLONs, showing that their structures are compatible with a model of interaction across the synaptic cleft.
Display omitted
•A proteomic screen found 200 neuronal cell-surface protein-protein interactions•89 of these interactions appeared to be previously unpublished•The five interacting IgLON proteins were identified and further characterized•The structures of NTRI, IgLON5, and the NEGR1/IgLON5 complex are presented
Many aspects of synapse formation, specification, and maturation rely on interactions among a rich repertoire of cell-surface glycoproteins with adhesive and repulsive properties. Although the identity of these proteins is known, their network of interactions remains largely untapped. Ranaivoson et al. have identified a number of protein-protein interactions and have determined the structures of three members of the IgLONs, a family of five proteins of the immunoglobulin superfamily that has recently been implicated in a wide range of human disease.
Volatile solids with symmetric π‐backbone are intensively implemented on manipulating the nanomorphology for improving the operability and stability of organic solar cells. However, due to the ...isotropic stacking, the announced solids with symmetric geometry cannot modify the microscopic phase separation and component distribution collaboratively, which will constrain the promotion of exciton splitting and charge collection efficiency. Inspired by the superiorities of asymmetric configuration, a novel process‐aid solid (PAS) engineering is proposed. By coupling with BTP core unit in Y‐series molecule, an asymmetric, volatile 1,3‐dibromo‐5‐chlorobenzene solid can induce the anisotropic dipole direction, elevated dipole moment, and interlaminar interaction spontaneously. Due to the synergetic effects on the favorable phase separation and desired component distribution, the PAS‐treated devices feature the evident improvement of exciton splitting, charge transport, and collection, accompanied by the suppressed trap‐assisted recombination. Consequently, an impressive fill factor of 80.2% with maximum power conversion efficiency (PCE) of 18.5% in the PAS‐treated device is achieved. More strikingly, the PAS‐treated devices demonstrate a promising thickness‐tolerance character, where a record PCE of 17.0% is yielded in PAS devices with a 300 nm thickness photoactive layer, which represents the highest PCE for thick‐film organic solar cells.
A low‐cost, high volatile, and asymmetric halogen benzene derivate, 1,3‐dibromo‐5‐chlorobenzene, is applied as process‐aid solid to manipulate the blend nanomorphology and enhance the crystallinity in Y‐series small molecule‐based photoactive layer system. A champion power conversion efficiency of 17.0% is yielded, which is one of the highest performances for thick‐film organic solar cells.
Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, ...and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.
The goal of the present article is to review the major developments that have led to the current understanding of molecule-field interactions and experimental methods for manipulating molecules with ...electromagnetic fields. Molecule-field interactions are at the core of several, seemingly distinct areas of molecular physics. This is reflected in the organisation of this article, which includes sections on field control of molecular beams, external field traps for cold molecules, control of molecular orientation and molecular alignment, manipulation of molecules by non-conservative forces, ultracold molecules and ultracold chemistry, controlled many-body phenomena, entanglement of molecules and dipole arrays, and stability of molecular systems in high-frequency super-intense laser fields. The article contains 852 references.
PDF
