Biology subjects

Rigoni, M.

Publications and source records attributed to Rigoni, M..

7 recordsLinked to original sources

bioRxiv2026

Challenging the right-hemisphere assumption in post-stroke pragmatics: largely comparable impairment profiles across lesion sides

Traditional views assume that pragmatic deficits after stroke, which compromise the interpretation of communicative intentions and non-literal meanings, follow damage to the right hemisphere (RHD), with left-hemisphere damage (LHD) primarily linked to aphasia and structural language impairment. To examine hemispheric contributions to post-stroke pragmatic profiles, we assessed 99 stroke patients (40 LHD, including 14 with aphasia of minimal-to-moderate severity; 59 RHD) and 60 healthy controls with the Assessment of Pragmatic Abilities and Cognitive Substrates (APACS). While stroke patients overall performed worse than controls, LHD and RHD profiles were largely comparable across three converging analyses: (1) permutation tests revealed no hemispheric differences except on the two tasks requiring expressive components (Interview and Figurative Language 2), which in turn lowered the composites (APACS Production and Total); (2) equivalence testing established equivalence for most measures, with only these same tasks and composites remaining inconclusive; and (3) unsupervised clustering did not group patients by lesion side. Theory of Mind was robustly associated with pragmatic performance in both groups, whereas structural language abilities related specifically to LHD performance and general cognition only to RHD. Excluding aphasic LHD patients strengthened the evidence for comparable profiles, indicating that aphasic LHD patients largely drove the residual differences. In conclusion, primary pragmatic impairment, especially in the receptive domain, emerged comparably after LHD and RHD, with the only residual LHD disadvantage limited to tasks demanding open verbal output. These findings challenge the assumption of right-hemispheric specialization for pragmatics, stressing the need for pragmatic assessment in all post-stroke patients.

neuroscience↗

bioRxiv2026

Perinatal ischemic stroke impairs motor and cognitive development, muscle structure, and gut microbiota composition, with functional improvement following fecal microbiota transplantation in a mouse model

Perinatal ischemic stroke is an early developmental brain injury caused by obstruction of cerebral blood vessels and is a leading cause of cerebral palsy and cognitive disability in survivors. However, progress in understanding its impact on the brain and other organ systems, as well as in developing effective therapies, remains limited, in part due to the scarcity of relevant preclinical models. Here, we induced ischemic stroke via middle cerebral artery occlusion in perinatal mice and investigated its effects within and beyond the brain across development into adulthood. We found that perinatal stroke disrupted fine motor development and impaired memory. In addition, it induced structural alterations in skeletal muscle and significant changes in gut microbiota composition. Notably, gut-targeted intervention using fecal microbiota transplantation improved fine motor function. Our findings demonstrate, for the first time, the multisystem developmental impact of perinatal stroke, extending beyond the brain, and identify gut microbiota modulation as a promising and potentially safe therapeutic strategy to improve motor outcomes after stroke.

neuroscience↗

bioRxiv2025

Spatiotemporal multi-omics atlas of the aging neuromuscular junction

The demographic shift toward a global aging population, coupled with rising prevalence of neurodegenerative diseases, poses major public health challenges. Aging is the primary risk factor for most neurodegenerative conditions, making the elucidation of its molecular mechanisms critical for developing effective interventions. Dysfunction of the neuromuscular junction (NMJ), the specialized synapse essential for motor function, is an early hallmark of aging and several neurodegenerative disorders, yet its molecular determinants remain incompletely understood. To shed light on potential common underlying mechanisms, we performed a spatiotemporal multi-omics analysis of the murine NMJ during aging, uncovering several genes showing decoupling between transcript and protein trajectories that may drive the related progressive motor decline. NMJs of soleus (SOL) and extensor digitorum longus (EDL) muscles, differing in fiber composition and vulnerability to aging and disease, displayed distinct spatiotemporal dynamics: fast-twitch EDL, more susceptible to degeneration, exhibited stronger mRNA-protein decoupling than aged slow-twitch SOL or younger SOL and EDL muscles. Elevated expression of miRNAs and RNA-binding proteins in aged EDL highlights the key role of post-transcriptional regulation in NMJ aging. This study provides new insights into the physiopathology of neuromuscular aging and offers a resource for investigating mechanisms shared between aging and neurodegenerative diseases. Additionally, it opens avenues for AI-driven discovery of drug targets and early biomarkers, potentially accelerating the development of therapeutic strategies.

neuroscience↗

bioRxiv2025

Targeting Neuromuscular Junction Regeneration is a Therapeutic Strategy in ALS

Instability and denervation of the neuromuscular junction (NMJ) are early events in Amyotrophic Lateral Sclerosis (ALS), likely reflecting a progressive decline in the regenerative capacity of motor neurons (MNs) and their environment. To investigate this, we evaluated NMJ regeneration throughout disease progression in SOD1G93A mice following reversible axon terminal degeneration induced by -Latrotoxin. In parallel, we monitored the expression of CXCR4, a GPCR upregulated during axonal regeneration, and tested whether its pharmacological activation could mitigate ALS- related functional decline. We found that NMJ regenerative capacity is largely preserved during pre- and early symptomatic stages, and remains active in subsets of NMJs even at later stages. CXCR4 is expressed at axon terminals from early disease stages, declining only at end stage. Its expression is conserved across ALS models, including SOD1G93A pigs, hiPSC-derived MN with ALS mutations, and biopsies from sporadic ALS patients. CXCR4 stimulation improved motor function, NMJ innervation, MN survival, and respiratory performance in ALS mice, and axon outgrowth in iPSC-derived MN. These findings identify the NMJ and CXCR4 as viable therapeutic targets in ALS.

neuroscience↗

bioRxiv2024

ALTERATIONS IN PEROXISOMAL-MITOCHONDRIAL INTERPLAY IN SKELETAL MUSCLE ACCELERATES MUSCLE DYSFUNCTION

Whole-body energy expenditure, as well as glucose and lipid metabolism, are regulated by skeletal muscles, which account for 40-50% of human body mass. Peroxisomes are dynamic organelles that play a crucial role in lipid metabolism and clearance of reactive oxygen species, however their role in muscles remains poorly understood. To clarify this issue, we generated a muscle-specific transgenic mouse line with peroxisome import deficiency resulting from deletion of peroxisomal biogenesis factor 5 (Pex5). Pex5 inhibition disrupted the tethering between peroxisomes and mitochondria, impaired lipid metabolism and reduced muscle force and exercise performance. Moreover, mitochondrial content and function were also altered, accelerating age-related structural defects, neuromuscular junction degeneration, and muscle atrophy. Altogether, our findings show the importance of preserving peroxisomal function and their contact sites with mitochondria to maintain muscle health during aging.

cell biology↗

bioRxiv2023

Agonists of melatonin receptors strongly promote the functional recovery from the neuroparalysis induced by neurotoxic snakes

Snake envenoming is a major, but neglected, tropical disease. Among venomous snakes, those inducing neurotoxicity such as kraits (Bungarus genus) cause a potentially lethal peripheral neuroparalysis with respiratory deficit in a large number of people each year. In order to prevent the development of a deadly respiratory paralysis, hospitalization with pulmonary ventilation and use of antivenoms are the primary therapies currently employed. However, hospitals are frequently out of reach for envenomated patients and there is a general consensus that additional, non-expensive treatments, deliverable even long after the snake bite, are needed. Traumatic or toxic degenerations of peripheral motor neurons cause a neuroparalysis that activates a pro-regenerative intercellular signaling program taking place at the neuromuscular junction (NMJ). We recently reported that the intercellular signaling axis melatonin-melatonin receptor 1 (MT1) plays a major role in the recovery of function of the NMJs after degeneration of motor axon terminals caused by massive Ca2+ influx. Here we show that the small chemical MT1 agonists: Ramelteon and Agomelatine, already licensed for the treatment of insomnia and depression, respectively, are strong promoters of the neuroregeneration after paralysis induced by krait venoms in mice, which is also Ca2+ mediated. The venom from a Bungarus species representative of the large class of neurotoxic snakes (including taipans, coral snakes, some Alpine vipers in addition to other kraits) was chosen. The functional recovery of the NMJ was demonstrated using electrophysiological, imaging and lung ventilation detection methods. According to the present results, we propose that Ramelteon and Agomelatine should be tested in human patients bitten by neurotoxic snakes acting presynaptically to promote their recovery of health. Noticeably, these drugs are commercially available, safe, non-expensive, have a long bench life and can be administered long after a snakebite even in places far away from health facilities. SynopsisSnakebite envenomings cause important tropical human diseases that often include a lethal muscle paralysis. Current treatments consist in hospitalization and antivenoms, which are not always quickly accessible to victims. In fact, these snakebites take place mainly in rural and low income countries. In this work, researchers discovered, in mice, a novel function of melatonin and of its type 1 receptor in promoting functional recovery after snake-induced peripheral neuroparalysis with nerve terminal degeneration. In particular, researchers found that drugs approved for the treatment of insomnia (Ramelteon) and depression (Agomelatine), activate melatonin receptor and promote the functional recovery after a krait venom induced paralysis. These drugs are on sell in pharmacies, are safe and stable, and are ready to be tried for promoting the recovery from peripheral neuroparalysis in human victims bitten by neurotoxic snakes, even without hospitalization.

pharmacology and toxicology↗

bioRxiv2020

TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients.

ObjectivesTwo of the main target tissues of SARS-coronavirus 2 are the oral cavity pharynx-larynx epithelium, the main virus entry site, and the lung epithelium. The virus enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. Herein we aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity-pharynx-larynx and lung tissues as well as neoplastic tissues from the same histological areas. The information provided in this study may contribute to better understanding of SARS-coronavirus 2 ability to interact with different biological systems and contributes to cumulative knowledge on potential mechanisms to inhibit its diffusion. Materials and MethodsThe study has been conducted using The Cancer Genome Atlas (TCGA) and the Regina Elena Institute (IRE) databases and validated by experimental model in HNSCC and Lung cancer cells. Data from one COVID19 positive patient who was operated on for HNSCC was also included. We have analyzed 478 tumor samples and 44 normal samples from TCGA HNSCC cohort for whom both miRNA and mRNA sequencing was available. The dataset included 391 HPV- and 85 HPV+ cases, with 331 P53 mutated and 147 P53 wild type cases respectively. 352 out of 478 samples were male and 126 female. In IRE cohort we analyzed 66 tumor samples with matched normal sample for miRNA profiling and 23 tumor\normal matched samples for mRNA profiling. 45 out of 66 tumors from IRE cohort were male and 21 female, 38 were P53 mutated and 27 wild type. Most patients (63 of 66) in IRE cohort were HPV negative. Normalized TCGA HNSCC gene expression and miRNA expression data were obtained from Broad Institute TCGA Genome Data Analysis Center (http://gdac.broadinstitute.org/). mRNA expression data from IRE cohort used in this study has been deposited to NCBIs Gene Expression Omnibus and is accessible through GEO series accession number GSE107591. In order to inference about potential molecular modulation of TMPRSS2, we also included miRNAs expression for the 66 IRE cohort matched tumor and normal samples from Agilent platform. DNA methylation data for TCGA tumors were obtained from Wanderer (http://maplab.imppc.org/wanderer/). We used miRWalk and miRNet web tools for miRNA-target interaction prediction and pathway enrichment analysis. The correlation and regression analyses as well as the miRNA and gene modulation and the survival analysis were conducted using Matlab R2019. ResultsTMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues and had a prognostic value in HNSCC patients. Reduction of TMPRSS2 expression was more evident in women than in men, in TP53 mutated versus wild TP53 tumors as well as in HPV negative patients compared to HPV positive counterparts. Functionally, we assessed the multivariate effect on TMPRSS2 in a single regression model. We observed that all variables had an independent effect on TMPRSS2 in HNSCC patients with HPV negative, TP53 mutated status and with elevated TP53-dependent Myc-target genes associated with low TMPRSS2 expression. Investigation of the molecular modulation of TMPRSS2 in both HNSCC and lung cancers revealed that expression of microRNAs targeting TMPRSS2 anti-correlated in both TCGA and IRE HNSCC datasets, while there was not evidence of TMPRSS2 promoter methylation in both tumor cohorts. Interestingly, the anti-correlation between microRNAs and TMPRSS2 expression was corroborated by testing this association in a SARS-CoV-2 positive HNSCC patient. ConclusionsCollectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. The protective mechanism might occur, at least partially, through the aberrant activation of TMPRSS2 targeting microRNAs; thereby providing strong evidence on the role of non-coding RNA molecule in host viral infection. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.

cancer biology↗