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Objective The aim of this study was to assess COVID‐19‐related gray matter (GM) structural alterations in two distinct groups of patients presenting with the prevailing and distinctive COVID‐19‐related neurological symptoms – isolated olfactory disorders as sole neurological manifestation (COVID‐OD) and cognitive disorders (COVID‐CD) – as compared to a control group of unaffected individuals. Methods The study included 61 COVID‐CD patients (57 [60–63] years, 62% females), 84 COVID‐OD patients (49 [35–57] years, 60% females), and 17 controls (51 [41–52] years, 41% females). Region‐based morphometry (RBM) and voxel‐based morphometry (VBM) were performed on T1‐weighted MRI scans to assess GM regional volume and voxel‐wise density differences between COVID‐19 patients and controls. Surface‐based morphometry (SBM) was applied to investigate cortical thickness alterations. The statistical models built to assess GM structural differences among groups included total intracranial volume and age as nuisance variables. Results The multi‐morphometric analysis revealed statistically significant (p < 0.05 corrected for multiple comparisons) reduction in GM regional volumes, in voxel‐wise GM density and in cortical thickness in both COVID‐CD and COVID‐OD patient groups as compared to controls. Across all three analyses, COVID‐CD patients showed more distributed and severe GM loss than COVID‐OD patients. The most prominently affected GM regions in the COVID‐CD group included the hippocampus, putamen, cingulate gyrus, precuneus, precentral and postcentral gyri, amygdala, lingual gyrus, and caudate nucleus. Interpretation Our MRI findings show that COVID‐19‐related olfactory and cognitive disorders both induce GM atrophy, although at different degrees of severity, likely indicative of neurodegeneration and neuroinflammation.

The ubiquitin (Ub) system controls almost every aspect of eukaryotic cell biology. Protein ubiquitination depends on the sequential action of three classes of enzymes (E1, E2 and E3). E2 Ub-conjugating enzymes have a central role in the ubiquitination pathway, interacting with both E1 and E3, and influencing the ultimate fate of the substrates. Several E2s are characterized by an extended acidic insertion in loop 7 (L7), which if mutated is known to impair the proper E2-related functions. In the present contribution, we show that acidic loop is a conserved ancestral motif in E2s, relying on the presence of alternate hydrophobic and acidic residues. Moreover, the dynamic properties of a subset of family 3 E2s, as well as their binary and ternary complexes with Ub and the cognate E3, have been investigated. Here we provide a model of L7 role in the different steps of the ubiquitination cascade of family 3 E2s. The L7 hydrophobic residues turned out to be the main determinant for the stabilization of the E2 inactive conformations by a tight network of interactions in the catalytic cleft. Moreover, phosphorylation is known from previous studies to promote E2 competent conformations for Ub charging, inducing electrostatic repulsion and acting on the L7 acidic residues. Here we show that these active conformations are stabilized by a network of hydrophobic interactions between L7 and L4, the latter being a conserved interface for E3-recruitment in several E2s. In the successive steps, L7 conserved acidic residues also provide an interaction interface for both Ub and the Rbx1 RING subdomain of the cognate E3. Our data therefore suggest a crucial role for L7 of family 3 E2s in all the E2-mediated steps of the ubiquitination cascade. Its different functions are exploited thank to its conserved hydrophobic and acidic residues in a finely orchestrate mechanism.

•Cdc34 is an E2 enzyme involved in protein ubiquitination and associated with some cancers.•Cdc34 activity is modulated by phosphorylation-induced conformational changes of the acidic loop.•We used computational approaches to identify potential inhibitory compounds for Cdc34.•These inhibitors as molecular hinges stabilizing the acid loop in its inactive, closed conformation. Among the different classes of enzymes involved in the ubiquitin pathway, E2 ubiquitin-conjugating enzymes occupy a central role in the ubiquitination cascade. Cdc34-like E2 enzymes are characterized by a 12–14 residue insertion in the proximity of the catalytic site, known as the acidic loop. Cdc34 ubiquitin-charging activity is regulated by CK2-dependent phosphorylation and the regulatory mechanism involves the acidic loop. Indeed, the phosphorylation stabilizes the loop in an open conformation that is competent for ubiquitin charging. Cdc34 is associated with a variety of diseases, such as hepatocellular carcinomas and prostatic adenocarcinomas. In light of its role, the discovery of potential inhibitory compounds would provide the mean to effectively modulate its activity. Here, we carried out a computational study based on molecular dynamics, virtual screening and docking to identify potential inhibitory compounds of Cdc34, modulating the acidic loop conformation. The molecules identified in this study have been designed to act as molecular hinges that can bind the acidic loop in its closed conformation, thus inhibiting the Cdc34-mediated ubiquitination cascade at the ubiquitin-charging step. In particular, we proposed a pharmacophore model featuring two amino groups in the central part of the model and two lateral aromatic chains, which respectively establish electrostatic interactions with the acidic loop (Asp 108 and Glu 109) and a hydrogen bond with Ser 139, which is one of the key residues for Cdc34 activity.

Long intergenic noncoding RNAs (lincRNAs) contribute to the regulation of gene expression. Pagani and colleagues identify hundreds of unique lincRNAs expressed in human lymphocytes and demonstrate a role for the lincRNA linc-MAF-4 in the differentiation of CD4 + T cells. Long noncoding RNAs are emerging as important regulators of cellular functions, but little is known of their role in the human immune system. Here we investigated long intergenic noncoding RNAs (lincRNAs) in 13 subsets of T lymphocytes and B lymphocytes by next-generation sequencing–based RNA sequencing (RNA-seq analysis) and de novo transcriptome reconstruction. We identified over 500 previously unknown lincRNAs and described lincRNA signatures. Expression of linc-MAF-4, a chromatin-associated lincRNA specific to the T H 1 subset of helper T cells, was inversely correlated with expression of MAF, a T H 2-associated transcription factor. Downregulation of linc-MAF-4 skewed T cell differentiation toward the T H 2 phenotype. We identified a long-distance interaction between the genomic regions of the gene encoding linc-MAF-4 and MAF , where linc-MAF-4 associated with the chromatin modifiers LSD1 and EZH2; this suggested that linc-MAF-4 regulated MAF transcription through the recruitment of chromatin modifiers. Our results demonstrate a key role for lincRNA in T lymphocyte differentiation.

Background and objective Despite olfactory disorders being among the most common neurological complications of coronavirus disease 2019 (COVID-19), their pathogenesis has not been fully elucidated yet. Brain MR imaging is a consolidated method for evaluating olfactory system’s morphological modification, but a few quantitative studies have been published so far. The aim of the study was to provide MRI evidence of olfactory system alterations in patients with COVID-19 and neurological symptoms, including olfactory dysfunction. Methods 196 COVID-19 patients (median age: 53 years, 56% females) and 39 controls (median age 55 years, 49% females) were included in this cross-sectional observational study; 78 of the patients reported olfactory loss as the only neurological symptom. MRI processing was performed by ad-hoc semi-automatic processing procedures. Olfactory bulb (OB) volume was measured on T2-weighted MRI based on manual tracing and normalized to the brain volume. Olfactory tract (OT) median signal intensity was quantified on fluid attenuated inversion recovery (FLAIR) sequences, after preliminary intensity normalization. Results COVID-19 patients showed significantly lower left, right and total OB volumes than controls ( p  < 0.05). Age-related OB atrophy was found in the control but not in the patient population. No significant difference was found between patients with olfactory disorders and other neurological symptoms. Several outliers with abnormally high OT FLAIR signal intensity were found in the patient group. Conclusions Brain MRI findings demonstrated OB damage in COVID-19 patients with neurological complications. Future longitudinal studies are needed to clarify the transient or permanent nature of OB atrophy in COVID-19 pathology. Graphical abstract

To help better understand the role of long noncoding RNAs in the human immune system, we recently generated a comprehensive RNA-seq data set using 63 RNA samples from 13 subsets of T (CD4 +  naive, CD4 +  T H 1, CD4 +  T H 2, CD4 +  T H 17, CD4 +  T reg , CD4 +  T CM , CD4 +  T EM , CD8 +  T CM , CD8 +  T EM, CD8 +  naive) and B (B naive, B memory, B CD5 + ) lymphocytes. There were five biological replicates for each subset except for CD8 +  T CM and B CD5 +  populations that included 4 replicates. RNA-Seq data were generated by an Illumina HiScanSQ sequencer using the TruSeq v3 Cluster kit. 2.192 billion of paired-ends reads, 2×100 bp, were sequenced and after filtering a total of about 1.7 billion reads were mapped. Using different de novo transcriptome reconstruction techniques over 500 previously unknown lincRNAs were identified. The current data set could be exploited to drive the functional characterization of lincRNAs, identify novel genes and regulatory networks associated with specific cells subsets of the human immune system. Design Type(s) cell type comparison design • in vitro design • replicate design Measurement Type(s) long non-coding RNA microarray profiling Technology Type(s) RNA sequencing Factor Type(s) cell type • replicate type Sample Characteristic(s) Homo sapiens • blood • Th1 cell • Th17 cell • Th2 cell • regulatory T-lymphocyte • thymocyte • B-lymphocyte • memory T-lymphocyte • cytotoxic T-lymphocyte Machine-accessible metadata file describing the reported data (ISA-Tab format)

Long non-coding-RNAs are emerging as important regulators of cellular functions but little is known on their role in human immune system. Here we investigated long intergenic non-coding-RNAs (lincRNAs) in thirteen T and B lymphocyte subsets by RNA-seq analysis and de novo transcriptome reconstruction. Over five hundred new lincRNAs were identified and lincRNAs signatures were described. Expression of linc-MAF-4, a chromatin-associated TH1-specific lincRNA, was inversely correlated with MAF, a TH2-associated transcription factor. Linc-MAF-4 down-regulation skewed T cell differentiation toward TH2. We identified a long-distance interaction between linc-MAF-4 and MAF genomic regions, where linc-MAF-4 associates with LSD1 and EZH2, suggesting linc-MAF-4 regulated MAF transcription by recruitment of chromatin modifiers. Our results demonstrate a key role of lincRNAs in T lymphocyte differentiation.

Protein-molecule interactions are promoted by the physicochemical characteristics of the actors involved, but structural information alone does not capture expression patterns, localization and pharmacokinetics. In this work we propose an integrative strategy for protein-molecule interaction discovery that combines different layers of information through the use of convolutional operators on graph, and frame the problem as missing link prediction task on an heterogeneous graph constituted by three node types: 1) molecules 2) proteins 3) diseases. Physicochemical information of the actors are encoded using shallow embedding techniques (SeqVec, Mol2Vec, Doc2Vec respectively) and are supplied as feature vectors to a Graph AutoEncoer (GAE) that uses a Heterogeneous Graph Transformer (HGT) in the encoder module. We show in this work that HGT Autoencoder can be used to accurately recapitulate the proteinmolecule interactions set and propose novel relationships in inductive settings that are grounded in biological and functional information extracted from the graph.

•Visuomotor PAS drives the emergence of atypical corticospinal motor resonance at the cost of the typical response.•Typical motor resonance is characterized by prominent alpha-band and reduced beta-band M1-connectivity.•PAS-induced motor resonance is specifically supported by beta-band M1 cortical networks.•Sensorimotor learning within the action observation network exploits connectivity mechanisms distinct from those established throughout lifetime experience. Motor resonance – the facilitation of corticospinal excitability during action observation – is considered a proxy of Action Observation Network (AON) recruitment in humans, with profound implications for social cognition and action understanding. Despite extensive research, the neural underpinnings supporting motor resonance emergence and rewriting remain unexplored. In this study, we investigated the role of sensorimotor associative learning in neural mechanisms underlying the motor resonance phenomenon. To this aim, we applied cross-systems paired associative stimulation (PAS) to induce novel visuomotor associations in the human brain. This protocol, which repeatedly pairs transcranial magnetic stimulation (TMS) pulses over the primary motor cortex (M1) with visual stimuli of actions, drives the emergence of an atypical, PAS-conditioned motor resonance response. Using TMS and electroencephalography (EEG) co-registration during action observation, we tracked the M1 functional connectivity profile during this process to map the inter-areal connectivity profiles associated with typical and PAS-induced motor resonance phenomena. Besides confirming, at the corticospinal level, the emergence of newly acquired motor resonance responses at the cost of typical ones after PAS administration, our results reveal dissociable aspects of motor resonance in M1 interregional communication. On the one side, typical motor resonance effects acquired through the lifespan are associated with prominent M1 alpha-band and reduced beta-band connectivity, which might facilitate the corticospinal output while integrating visuomotor information. Conversely, the atypical PAS-induced motor resonance is linked to M1 beta-band cortical connectivity modulations, only partially overlapping with interregional communication patterns related to the typical mirroring responses. This evidence suggests that beta-phase synchronization may be the critical mechanism supporting the formation of motor resonance by coordinating the activity of motor regions during action observation, which also involves alpha-band top-down control of frontal areas. These findings provide new insights into the neural dynamics underlying (typical and newly acquired) motor resonance, highlighting the role of large-scale interregional communication in sensorimotor associative learning within the AON.

This paper presents Multiple Traffic Light Advisor (MTLA), a novel Green Light Optimal Speed Advisory (GLOSA) system that leverages 5G communication technology. GLOSA systems are emerging as a key component in intelligent transportation systems, thanks to the development of effective communication technologies. At its core, MTLA serves as a guidance system for drivers, providing real-time instructions to adjust vehicle speed to optimize the utilization of current and future states of traffic lights along their route.The work addresses several limitations in the current state-of-the-art approaches, including the use of an overly simplified velocity profile, the omission of potential grip and jerk in problem formulation, and the absence of a detailed description of the algorithm’s implementation aspects. Initially, we comprehensively present an optimization-free implementation of the overall control architecture based on an unconventional speed profile. Subsequently, MTLA is improved within a non-linear Model Predictive Control (MPC) framework which uses the latter nonoptimal solution as an initial guess and considers potential grip and jerk in the problem formulation. The developed systems are numerically tested and compared within a high-fidelity simulation environment using the IPG CarMaker simulator. The results demonstrate promising performance in terms of energy savings, with a significant reduction of 37% in energy usage, as well as improved overall comfort with respect to the case where no guidance is given to the driver. These findings suggest a high potential for future developments in this domain.