Inpainting Saturation Artifact in Anterior Segment Optical Coherence Tomography.

The cornea is an important refractive structure in the human eye. The corneal segmentation technique provides valuable information for clinical diagnoses, such as corneal thickness. Non-contact anterior segment optical coherence tomography (AS-OCT) is a prevalent ophthalmic imaging technique that can visualize the anterior and posterior surfaces of the cornea. Nonetheless, during the imaging process, saturation artifacts are commonly generated due to the tangent of the corneal surface at that point, which is normal to the incident light source. This stripe-shaped saturation artifact covers the corneal surface, causing blurring of the corneal edge, reducing the accuracy of corneal segmentation. To settle this matter, an inpainting method that introduces structural similarity and frequency loss is proposed to remove the saturation artifact in AS-OCT images. Specifically, the structural similarity loss reconstructs the corneal structure and restores corneal textural details. The frequency loss combines the spatial domain with the frequency domain to ensure the overall consistency of the image in both domains. Furthermore, the performance of the proposed method in corneal segmentation tasks is evaluated, and the results indicate a significant benefit for subsequent clinical analysis.

Ca2+-induced release of IQSEC2/BRAG1 autoinhibition under physiological and pathological conditions.

IQSEC2 (aka BRAG1) is a guanine nucleotide exchange factor (GEF) highly enriched in synapses. As a top neurodevelopmental disorder risk gene, numerous mutations are identified in Iqsec2 in patients with intellectual disabilities accompanied by other developmental, neurological, and psychiatric symptoms, though with poorly understood underlying molecular mechanisms. The atomic structures of IQSECs, together with biochemical analysis, presented in this study reveal an autoinhibition and Ca2+-dependent allosteric activation mechanism for all IQSECs and rationalize how each identified Iqsec2 mutation can alter the structure and function of the enzyme. Transgenic mice modeling two pathogenic variants of Iqsec2 (R359C and Q801P), with one activating and the other inhibiting the GEF activity of the enzyme, recapitulate distinct clinical phenotypes in patients. Our study demonstrates that different mutations on one gene such as Iqsec2 can have distinct neurological phenotypes and accordingly will require different therapeutic strategies.

Inhibitory postsynaptic density from the lens of phase separation.

To faithfully transmit and decode signals released from presynaptic termini, postsynaptic compartments of neuronal synapses deploy hundreds of various proteins. In addition to distinct sets of proteins, excitatory and inhibitory postsynaptic apparatuses display very different organization features and regulatory properties. Decades of extensive studies have generated a wealth of knowledge on the molecular composition, assembly architecture and activity-dependent regulatory mechanisms of excitatory postsynaptic compartments. In comparison, our understanding of the inhibitory postsynaptic apparatus trails behind. Recent studies have demonstrated that phase separation is a new paradigm underlying the formation and plasticity of both excitatory and inhibitory postsynaptic molecular assemblies. In this review, we discuss molecular composition, organizational and regulatory features of inhibitory postsynaptic densities through the lens of the phase separation concept and in comparison with the excitatory postsynaptic densities.

Clustering acetylcholine receptors in neuromuscular junction by phase-separated Rapsn condensates.

In this issue of Neuron, Xing et al. (2021) demonstrate that the multidomain scaffold protein Rapsn can form dense molecular condensates in vitro and in vivo via phase separation. The formation of Rapsn condensates is essential for clustering acetylcholine receptors on muscle membranes and for forming neuromuscular junctions.

Gephyrin-mediated formation of inhibitory postsynaptic density sheet via phase separation.

Inhibitory synapses are also known as symmetric synapses due to their lack of prominent postsynaptic densities (PSDs) under a conventional electron microscope (EM). Recent cryo-EM tomography studies indicated that inhibitory synapses also contain PSDs, albeit with a rather thin sheet-like structure. It is not known how such inhibitory PSD (iPSD) sheet might form. Here, we demonstrate that the key inhibitory synapse scaffold protein gephyrin, when in complex with either glycine or GABAA receptors, spontaneously forms highly condensed molecular assemblies via phase separation both in solution and on supported membrane bilayers. Multivalent and specific interactions between the dimeric E-domain of gephyrin and the glycine/GABAA receptor multimer are essential for the iPSD condensate formation. Gephyrin alone does not form condensates. The linker between the G- and E-domains of gephyrin inhibits the iPSD condensate formation via autoinhibition. Phosphorylation of specific residues in the linker or binding of target proteins such as dynein light chain to the linker domain regulates gephyrin-mediated glycine/GABAA receptor clustering. Thus, analogous to excitatory PSDs, iPSDs are also formed by phase separation-mediated condensation of scaffold protein/neurotransmitter receptor complexes.

Anchoring high concentrations of SynGAP at postsynaptic densities via liquid-liquid phase separation.

SynGAP, encoded by SYNGAP1, is a Ras/Rap GTPase activator specifically expressed in the nervous systems. SynGAP is one of the most abundant proteins in the postsynaptic densities (PSDs) of excitatory synapses and acts as a critical synaptic activity brake by tuning down synaptic GTPase activities. Mutations of SYNGAP1 have been frequently linked to brain disorders including intellectual disability, autisms, and seizure. SynGAP has been shown to undergo fast dispersions from synapses in response to stimulations, a strategy that neurons use to control the specific activities of the enzyme within the tiny, semi-open compartments in dendritic spines. However, the mechanism governing the activity-dependent synaptic localization modulations of SynGAP is poorly understood. It has been shown recently that SynGAP α1, via specifically binding to PSD-95, can undergo liquid-liquid phase separation forming membraneless, condensed protein-rich sub-compartments. This phase transition-mediated, PSD-95-dependent synaptic enrichment of SynGAP α1 not only suggests a dynamic anchoring mechanism of the protein within the PSD, but also implies a new model for the PSD formation in living neurons.