Confronting Focus Strategies in Finnish and in Italian: An Experimental Study on Object Focusing

Focus is cross-linguistically associated with a number of different strategies, such as fronting, clefting, markers, and prosody. In some cases, the choice between one strategy or another is determined by language-specific rules, while in others, two or more strategies seem to be optional, and thus, somehow “unpredictable”. In this experimental study, we investigate the syntactic strategies employed in object focusing in Finnish and in Italian by examining the syntactic, semantic, and pragmatic features underlying the choice of a specific Focus strategy. In particular, the present experiment is aimed to investigate two strategies employed in both languages for object Focus realization, namely, Focus in situ and fronting, in order to verify whether the choice between them is influenced by a specific type of feature, a combination of Focus-related features, the verb category involved, or the interplay between these three factors. The incidence of alternative constructions, in particular clefting in Italian and the -hAn discourse marker in Finnish, is also taken into consideration, and relevant asymmetries are analyzed in a comprehensive, comparative account

Italian Factive islands are not ‘that weak’: new evidence from the factive/bridge distinction.

Long-distance dependencies are a major property of human language, deriving from the successive application of movement operations across sentences. Nevertheless, this possibility seems to be restricted by the presence of barriers, which ‘trap’ constituents in more or less 'resistant' syntactic islands. Given this scenario, this paper paper investigates a specific type of island, namely factive complements, which are traditionally considered ‘weak’ islands. The main goal is thus to verify the status of factive islands in Italian, based on original experimental data. Moreover, since island effects have been generally tested against wh-extractions, a secondary goal of the present study is to verify whether other types of A’-movement, such as Focus fronting, can be restricted by island effects as well. The results obtained from two experimental tests, carried out with the collaboration of a total of 310 informants, provide evidence that Italian factive islands seem to lie somewhere between strong and weak islands, qualifying as a sort of ‘intermediate’ island. Indeed, direct objects appear to be less constrained than subjects, indirect objects and adjuncts. Furthermore, the extraction of a Focus constituent from a factive complement lowers the acceptability of the sentence, thus indicating that (factive) islands are indeed sensible to Focus fronting

BEAT: Bioinformatics Exon Array Tool to store, analyze and visualize Affymetrix GeneChip Human Exon Array data from disease experiments

<p>Abstract</p> <p>Background</p> <p>It is known from recent studies that more than 90% of human multi-exon genes are subject to Alternative Splicing (AS), a key molecular mechanism in which multiple transcripts may be generated from a single gene. It is widely recognized that a breakdown in AS mechanisms plays an important role in cellular differentiation and pathologies. Polymerase Chain Reactions, microarrays and sequencing technologies have been applied to the study of transcript diversity arising from alternative expression. Last generation Affymetrix GeneChip Human Exon 1.0 ST Arrays offer a more detailed view of the gene expression profile providing information on the AS patterns. The exon array technology, with more than five million data points, can detect approximately one million exons, and it allows performing analyses at both gene and exon level. In this paper we describe BEAT, an integrated user-friendly bioinformatics framework to store, analyze and visualize exon arrays datasets. It combines a data warehouse approach with some rigorous statistical methods for assessing the AS of genes involved in diseases. Meta statistics are proposed as a novel approach to explore the analysis results. BEAT is available at <url>http://beat.ba.itb.cnr.it</url>.</p> <p>Results</p> <p>BEAT is a web tool which allows uploading and analyzing exon array datasets using standard statistical methods and an easy-to-use graphical web front-end. BEAT has been tested on a dataset with 173 samples and tuned using new datasets of exon array experiments from 28 colorectal cancer and 26 renal cell cancer samples produced at the Medical Genetics Unit of IRCCS Casa Sollievo della Sofferenza.</p> <p>To highlight all possible AS events, alternative names, accession Ids, Gene Ontology terms and biochemical pathways annotations are integrated with exon and gene level expression plots. The user can customize the results choosing custom thresholds for the statistical parameters and exploiting the available clinical data of the samples for a multivariate AS analysis.</p> <p>Conclusions</p> <p>Despite exon array chips being widely used for transcriptomics studies, there is a lack of analysis tools offering advanced statistical features and requiring no programming knowledge. BEAT provides a user-friendly platform for a comprehensive study of AS events in human diseases, displaying the analysis results with easily interpretable and interactive tables and graphics.</p

A STUDY ON CORRELATION BETWEEN ELECTROMYOGRAPHICAL AND MORPHOLOGICAL FINDINGS OF BACK MUSCLES IN SCOLIOSIS, ESPECIALLY CHANGES IN THE INTRAMUSCULAR NERVE ENDINGS.

3. In the cases of neurofibromatosis with scoliosis, intramuscular nerve endings showed almost normal morphological appearances but, comparative histograms of the diameters of the end-plates in each 5μ. group showed 2 peak formations.. One of these cases recorded fibrillation voltage at the concave side showed abnormal staining of terminal filamints of the end-plates in deep back muscles at the same side. The sensory nerve endings showed perfectly preserved histological appearances. 4. In cases of rachitogenic scoliosis, motor end-plates of the back muscles were observed using the histochemical method of cholinesterase staining and vital staining with methylene blue. Histograms of the diameters of the end-plates showed a noted reduction in size and in number of units, but no apparent degenerative changes in sensory and motor endings or in terminal axons were seen. 5. In a case of discogenic scoliosis, silver impregnation was applied on the back muscles at both sides of the curvature. In the convex side, collateral branching and swelling of the nerve fibers was observed and also the motor end-plates showed an abnormality of staining in terminal arborization, but, fibrillation voltage was not recorded. 6. In congenital scoliosis, electromyographic findings failed to trace fibrillation voltage, but, terminal axons in deep muscles, showed collateral branchig and an increased terminal innervation ratio in a highly affected case. In slightly curved cases, atrophic changes, and intramuscular fibers and endings appeared almost normal. 7. In the so-called idiopathic scoliosis , about 50% had not traced fibrillation voltage in the paravertebral back muscles. Degenerative findings.of the intramuscular nerve fibers and endings were not observed, but comparative histograms of the diameters of the end -plates showed 2 peak formations in the convex side of the back muscles. Innervation ratio was not changed and sensory nerve endings showed normal appearances.8. In idiopathic scoliosis, characterised by fibrillation voltage which was traced in the paravertebral back muscles, intramuscular motor nerve endings were degenerated in deep muscles of the convex side, and disseminated muscle atrophy in the concave side. In deep muscles of the convex side, terminal axons showed collateral branching and motor endplates, club-like swelling, and 2 peak formations of the histograms of the diameters. However, sensory nerve endings were normal in appearance. These findings lead to a conclusion that changes in the motor endings observed in paralytic scoliosis differed from histological changes in the cases of idiopathic scoliosis, in which fibrillation voltage had been traced. In paralytic scoliosis, histological changes of the back muscles showed various kinds of degenerative findings, but, in cases of idiopathic scoliosis with fibrillation voltage they showed collateral branching and degenerative changes of the end-plates, respectively, in deep back muscles especially in the convex side. In other kinds of scoliosis, neuromuscular changes were largely influenced by their own basic disorders such as, degeneration of discs, abnormality of vertebral bodies, nutritional deficiencies and metablic disorders. In the cases of idiopathic scoliosis without fibrillation voltage intramuscular nerve endings were preserved in good condition, but almost all of the cases of non-paralytic scoliosis showed an abnormality of the histograms of the endplates, or atrophic changes in deep muscles. Prophylactic treatment must be employed on the back muscles for the prevention of further deformity and progression of scoliosis.An electromyographical and histological study on 20 cases of various kinds of scoliosis was carried out. In particular, a biopsy of the back muscles at the apex of the primary curve was performed using the methods of gold chloride staining, silver impregnation modified by Seto, vital staining with methylene blue, and the histochemical demonstration of cholinesterase on the subneural apparatuses of the endplates. Specimens were taken from superficial (M. longissimus dorsi) and deep (M. multifidus) back muscles of scoliosis patients and in all cases, an electromyographic fibrillation voltage was picked up under deep general anesthesia with ether. This was done from the paravertebral back muscles and a comparison of histologic and electromyographic findings was performed. The results obtained are summarized as follows : 1. Motor end-plates of normal back muscles, dissected at autopsy from adults were found to be concentrated in band-like narrow zones and situated at the mid-point of the muscle fibers. Through comparative histograms of the diameters of subneural apparatuses and those of the end-plates of gold chloride staining showed a close correlation. 2. Intramuscular endings in the cases of paralytic scoliosis showed remarkable collateral axonic sprouting and various kinds of pathological changes of the end-plates, multiple innervation, large and and small end-plates, thickened terminal filaments, failure to stain, irregular swelling, and abnormal terminal expansion. The motor endings of the musclespindle were also remarkably degenerated but sensory nerve fibers and endings remained undisturbed. In neuromuscular endings, pathological changes of the back muscles at the apex of the primary curve, displayed a distinguishing feature in a lack of uniformity in the degree of alignment and curvature, but, compared with superficial muscles, the deep muscles were significantly involved. In all cases a giant spike and fibrillation voltage was recorded from wide-spread various parts of the back muscles

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

: The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways

Pathogen-sugar interactions revealed by universal saturation transfer analysis

Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an “end-on” manner. uSTA-guided modeling and a high-resolution cryo–electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis