Virtual reality (VR) is a technology that allows users to experience multisensory and interactive environments that simulate real or imaginary scenarios. The effect of different VR immersive technology on mental workload (MWL), i.e., the amount of resources required to perform a task, is still debated; however the potential role of EEG in this context was never exploited. This paper aims to investigate the effects on MWL of performing a cognitive task in a VR environment in two conditions characterized by different degrees of immersion using a multimodal approach which combines well-assessed subjective evaluations of MWL with physiological EEG measures. A cognitive task based on the n-back test was proposed to compare the performance and MWL of participants who used either a head-mounted display (HMD) or a desktop computer to present the stimuli. The task had four different complexity levels (n = 1 or 2 with either visual or visual and audio stimuli). Twenty-seven healthy participants were enrolled in this study and performed the tasks in both conditions. EEG data and NASA Task Load indeX (NASA-TLX) were used to assess changes in objective and subjective MWL, respectively. Error rates (ERs) and reaction times (RTs) were also collected for each condition and task level. Task levels had significant effects on MWL, increasing subjective measures and decreasing performance, in both conditions. EEG MWL index have shown a significant increase especially if compared to rest. Different degrees of immersion did not show significant differences neither in individual's performance nor in MWL as estimated by subjective ratings. However, HMD reduced the EEG-derived MWL in most conditions indicating a lower cognitive load. In conclusion, HMD may reduce the cognitive load of some tasks. The reduced level of MWL, as depicted by the EEG MWL index, may have implications for the design and future evaluation of VR-based applications.

Self-assembled multivalent DNA nanocages are an emerging class of molecules useful for biomedicine applications. Here, we investigated the molecular mechanisms of cytotoxicity induced by AS1411 free aptamer, AS1411-linked nanocages (Apt-NCs) and nanocages harboring both folate and AS1411 functionalization (Fol-Apt-NCs) in HeLa and MDA-MB-231 cancer cell lines. The three treatments showed different cytotoxic efficacy and Fol-Apt-NCs resulted the most effective in inhibiting cell proliferation and inducing apoptotic pathways and ROS activation in both HeLa and MDA-MB-231 cells. RNA-seq analysis allowed to identify biological functions and genes altered by the various treatments, depending on the AS1411 route of intracellular entry, highlighting the different behavior of the two cancer cell lines. Notably, Fol-Apt-NCs altered the expression of a subset of genes associated to cancer chemoresistance in MDA-MB-231, but not in HeLa cells, and this may explain the increased chemosensitivity to drugs delivered through DNA nanocages of the triple-negative breast cancer cells.

Background: In plants, RNase III Dicer-like proteins (DCLs) act as sensors of dsRNAs and process them into short 21- to 24-nucleotide (nt) (s)RNAs. Plant DCL4 is involved in the biogenesis of either functional endogenous or exogenous (i.e. viral) short interfering (si)RNAs, thus playing crucial antiviral roles. Methods: In this study we expressed plant DCL4 in Saccharomyces cerevisiae, an RNAi-depleted organism, in which we could highlight the role of dicing as neither Argonautes nor RNA-dependent RNA polymerase is present. We have therefore tested the DCL4 functionality in processing exogenous dsRNA-like substrates, such as a replicase-assisted viral replicon defective-interfering RNA and RNA hairpin substrates, or endogenous antisense transcripts. Results: DCL4 was shown to be functional in processing dsRNA-like molecules in vitro and in vivo into 21- and 22-nt sRNAs. Conversely, DCL4 did not efficiently process a replicase-assisted viral replicon in vivo, providing evidence that viral RNAs are not accessible to DCL4 in membranes associated in active replication. Worthy of note, in yeast cells expressing DCL4, 21- and 22-nt sRNAs are associated with endogenous loci. Conclusions: We provide new keys to interpret what was studied so far on antiviral DCL4 in the host system. The results all together confirm the role of sense/antisense RNA-based regulation of gene expression, expanding the sense/antisense atlas of S. cerevisiae. The results described herein show that S. cerevisiae can provide insights into the functionality of plant dicers and extend the S. cerevisiae tool to new biotechnological applications.

Microcephalic Osteodysplastic Primordial Dwarfism type II (MOPDII) represents the most common form of primordial dwarfism. MOPD clinical features include severe prenatal and postnatal growth retardation, postnatal severe microcephaly, hypotonia, and an increased risk for cerebrovascular disease and insulin resistance. Autosomal recessive biallelic loss-of-function genomic variants in the centrosomal pericentrin (PCNT) gene on chromosome 21q22 cause MOPDII. Over the past decade, exome sequencing (ES) and massive RNA sequencing have been effectively employed for both the discovery of novel disease genes and to expand the genotypes of well-known diseases. In this paper we report the results both the RNA sequencing and ES of three patients affected by MOPDII with the aim of exploring whether differentially expressed genes and previously uncharacterized gene variants, in addition to PCNT pathogenic variants, could be associated with the complex phenotype of this disease. We discovered a downregulation of key factors involved in growth, such as IGF1R, IGF2R, and RAF1, in all three investigated patients. Moreover, ES identified a shortlist of genes associated with deleterious, rare variants in MOPDII patients. Our results suggest that Next Generation Sequencing (NGS) technologies can be successfully applied for the molecular characterization of the complex genotypic background of MOPDII.

Simple Summary A large population of bacteria, protozoa, fungi, and algae colonizes an animal's body surface. The complex community of microbes that occupies a specific area of the organism and develops symbiotic relationships with the host is referred to as the microbiota. In this context, the gut microbiota plays an important physiological role as it influences the digestion and absorption of nutrients, the development and maturation of the immune system, and thus the growth, resistance to disease, and welfare of the animal. For these reasons, it is important to know the role of the microbiota in these specific functions, as well as which factors can impact the composition of bacterial populations, because changes in the microbiota can result in both beneficial and detrimental effects (dysbiosis) on the host. This study, in addition to providing information on the composition of the microbiota in the jejunum and cecum of rabbits, also evaluates the effect of breed and different growth rates using a modern methodological approach. Since the effect of these factors on the modulation of the gut microbiota has been little studied, this research could be the starting point for new experimental investigations aimed at enhancing rabbit productivity and welfare. This study aimed to evaluate the productive performance and microbiota variation in the jejunum and cecum of two rabbit breeds with different growth rates. This study was carried out on Native Middle-Egypt Breed (NMER) and Giant Flanders (GF) rabbits from 5 weeks to 12 weeks of age. Twenty NMER (NM) and GF male rabbits were slaughtered, and the jejunum and cecum tracts were collected to assay gut microbiota composition via 16S ribosomal RNA (rRNA) gene sequencing and histology examination. At 12 weeks of age, daily weight gain, villus height in the jejunum, total protein, and albumin were higher in GF rabbits than in NMER rabbits. Also, the jejunal villi of GF were well arranged in their dense borders. The microbiota between the jejunum and cecum was significantly different in terms of Beta-diversity. A significant correlation between Enterococcus (jejunum NM samples) and Lactobacillus (cecum GF samples) with body weight and weight gain was found (p < 0.05). Moreover, Escherichia-Shigella in the cecum of NM was significantly correlated with weight gain (p < 0.05). The most abundant genera identified in the jejunal and cecal contents of GF were generally beneficial microbiota. They may also play a role in reducing the pathogenic effects of Escherichia coli in these rabbits.

IntroductionOsteosarcoma (OS) is a rare pediatric cancer for which therapeutic approaches, including chemotherapy and surgery, show a wide interindividual variability in patient response, both in terms of adverse events and therapy efficacy. There is growing evidence that this individual variable response to therapies is also influenced by inherited genetic variations. However, the results obtained to date in these pediatric cancers have been contradictory and often lack validation in independent series. Additionally, these studies frequently focused only on a limited number of polymorphisms in candidate genes. MethodsIn order to identify germline coding variations associated with individual differences in adverse events occurrence in pediatric patients affected by localized OS, we carried out an exome-wide association study in 24 OS patients treated with methotrexate, cisplatin, and doxorubicin, using the SNP-Set (Sequence) Kernel Association Test (SKAT), optimized for small sample size. ResultsGene sets significantly associated (FDR < .05) with neutropenia and hepatotoxicity induced by methotrexate were identified. Some of the identified genes map in loci previously associated with similar phenotypes (e.g., leukocyte count, alkaline phosphatase levels). ConclusionFurther studies in larger series and with functional characterization of the identified associations are needed; nonetheless, this pilot study prompts the relevance of broadly investigating variants along the whole genome, to identify new potential pharmacogenes, beyond drug metabolism, transport, and receptor candidate genes.

Background/Objectives: It has been demonstrated the inter-individual susceptibility to SARS-CoV-2 infection and variability in COVID-19 severity are in part due to host genetics. Among the GWASs so far performed, none looked for variants associated with mortality by analyzing the association between genotypes and time-to-event data. Methods: We performed a case-only genome-wide survival analysis, 60 days after infection/hospitalization, of 3,904 COVID-19 patients from the GEN-COVID cohort and other European cohorts included in the EGAS00001005304 study. Patients were genotyped using Illumina Infinium Global Screening Arrays. PLINK software was used for data quality check and principal component analysis. Imputation was carried out using the TopMed server. GeneAbel R package was used for survival analysis and age, sex, cohort, time of infection, and the first ten principal components were used as covariates in the Cox model. Results: Four variants associated with survival at P-value<5.0x10-8 and 13 at false discovery rate (FDR) < 0.10. Their minor alleles were associated with a higher mortality risk. Five variants are intergenic, the top one is upstream FGF19 gene, one is intronic of GPRC5C gene, and six are intronic of PSD3 gene. Looking at the 281 variants with a P-value<1.0x10-5, we found that 19 variants mapped in this latter locus, another 20 mapped in a locus on chromosome 6, and 77 polymorphisms map on chromosome 9, in WDR5 locus. Conclusion: These results suggest that COVID-19 mortality risk variants differed from those associated with susceptibility and severity. Grant References: "PATCOVID" - 2020-2016_Ric_3 - Istituto Buddista Italiano Soka Gakkai

Peripheral neuropathies are common conditions whose treatment, in most cases, is still lacking. Preclinical animal models are crucial to solve this unmet need, but highly translational outcome measures are needed to promptly translate data from bench to bedside. High resolution diffusion MRI could be a surrogate, translational, biomarker to characterise early morphological changes as neuropathy ensues, creating a virtuous link between bench and bedside. We tested this approach in a well-characterised animal model of axonopathy. We aimed at characterising MRI changes in a consistent model of axonopathy. We relied on paclitaxel (PTX) as a neurotoxic agent, given the expected relevant axonal damage (Pozzi et al., IJMS 2023). We compared 2 groups (n=12 each) of female Wistar rats: control (CTRL, vehicle treated, iv) and PTX (10mg/kg, 1qwx4, iv). At the end of treatment, neuropathy development was verified via Dynamic test, nerve conduction studies (NCS) and light microscopy of the caudal nerve. In a proof-of-concept and a feasibility setting, 7T MRI was performed on rat tails (collected after sacrifice and formalin-fixed, n=3/group) to study caudal nerves and the anatomical relationship with surrounding structures. High resolution anatomical images were acquired by means of a T1w sequence with a voxel size of 50x50x50 ?m3. Diffusion weighted images were acquired in five b-shells: b of 500, 2000, 4500, 6000, 8000 sec*mm-2 with 15, 24, 33, 42, 51 isotropically distributed gradient directions and a voxel size of 125x125x125 ?m3. Diffusion data were fitted with the Diffusion Tensor Imaging (DTI) classical model and Fractional Anisotropy (FA), Axial, Radial and Mean Diffusitìvity (AD, RD and MD) were computed. Dynamic test confirmed allodynia development in PTX group, and NCS showed a moderate-severe axonal polyneuropathy, confirmed by histopathological observations. Therefore, we confirmed PTX group had a relevant neuropathy to be used as a test bench for 7T MRI acquisitions. DTI showed a decrease of FA (by 5%) and an increase of diffusivity, being the more relevant variation in RD (by 15%), in the PTX group if compared to control. These preliminary results may sustain the hypothesis of axonal damage in the murine model leading to an increased water diffusivity in the PTX tissue microstructure. We provided preliminary promising evidence of the 7T MRI exploitation in the preclinical setting. This technique has a high translational potential and, if confirmed as valuable, may have clinical relevance.

Missing aspects of the heritability of chronic neuropathic pain, as a complex adult-onset trait, may be hidden within rare variants with low effect on disease risk, unlikely to be resolved by a single-variant approach. To identify new risk genes, we performed a next-generation sequencing of 107 pain genes and collapsed the rare variants through gene-wise aggregation analysis. The optimal unified sequence kernel association test was applied to 169 patients with painful neuropathy, 223 patients with nociplastic pain (82 diagnosed with chronic widespread pain and 141 with fibromyalgia), and 216 healthy controls. Frequency and features of variants in TRPA1, which was the most significant gene, were further validated in 2 independent cohorts of 140 patients with chronic pain (90 with painful neuropathy and 50 with chronic widespread pain) and 34 with painless neuropathy. The effect of aminoacidic changes were modeled in silico according to physicochemical characteristics. TRPA1 was significantly enriched of rare variants which significantly discriminated chronic pain patients from healthy controls after Bonferroni correction (P = 6.7 × 10-4, ? = 1), giving a risk of 4.8-fold higher based on the simple burden test (P = 0.0015, OR = 4.8). Among the 32 patients harboring TRPA1 variants, 24 (75%) were diagnosed with nociplastic pain, either fibromyalgia (12; 37.5%) or chronic widespread pain (12; 37.5%), whereas 8 (25%) with painful neuropathy. Irrespective of the clinical diagnosis, 12 patients (38%) complained of itch and 10 (31.3%) of cold-induced or cold-accentuated pain, mostly episodic. Our study widens the spectrum of channelopathy-related chronic pain disorders and contributes to bridging the gap between phenotype and targeted therapies based on patients' molecular profile.

Developmental and Epileptic Encephalopathy (DEE) is a pediatric epilepsy characterized by abundant epileptiform activity resistant to traditional anti-epileptic therapies. A severe form of DEE, affecting only male children, is caused by expanded runs of consecutive GCN repeats in Aristaless-related homeobox (ARX) gene. This is an X-chromosome gene encoding a bifunctional transcription factor with a key role in mammalian corticogenesis. This Arx knockin mutant develops severe tonic-clonic seizures in a phenotype that recapitulates the chronic epilepsy associated to the c.304ins (GCG)7 mutation detected in DEE male patients. We examined the cellular diversity and the transcriptome landscapes of the epileptogenic neocortex in the Arx polyalanine mouse Arx(GCG)7/Y at the embryonic day 15.5 compared to the male control one by a single-cell RNASeq approach (scRNASeq). scRNASeq data revealed an altered cell composition in the diseased neocortex with lower proportion of radial glia cells (RGCs) and higher proportion of immature neurons (INs). Analysis of differentially expressed genes (DEGs) involved in cell cycle and immunofluorescence studies upon in vivo BrdU pulse-chase assay confirmed that neurogenesis and corticogenesis are both damaged in Arx(GCG)7/Y developing cortex. Enrichment analysis showed altered pathways in RGC and IN populations implicating in chromatin remodelling and RNA metabolism, neuronal motility and structure, and synapse organization. Concerning the alterations in morphology-related genes, immunocytochemistry followed by morphometric analysis revealed a defective neurite arborization with hypoconnectivity in Arx(GCG)7/Y primary cortical neurons. Taken together, our scRNAseq and functional studies disclose a complex cell-type-specific dysregulation of cortical projections and neuronal morphology that potentially underlies DEE pathogenesis.

Obiettivo dello studio è di indagare l'associazione tra caratteristiche demografiche, sociali e attitudinali di segmenti di popolazione con differenti livelli di esitanza nei confronti della vaccinazione per SARS-CoV-2, tra le persone che hanno partecipato alla fase II dell'indagine EPICOVID19 via web, tra gennaio e febbraio 2021, volontari adulti residenti in Italia.

Simple Summary Recently, research has focused on the modulation of the gut microbiota because of its central role in several digestive physiological functions and its involvement in the onset of not only gastrointestinal but also systemic diseases. Supplementing rabbit diets with nutraceutical substances could be a strategy to prevent dysbiosis, strengthen the immune system, and reduce mortality during the critical weaning period. Bovine colostrum (BC) is a by-product of the dairy industry and is very rich in compounds with several biological activities. Its use as an intestinal microbiota modulator in rabbits has never been investigated. This study evaluates the effects of diet supplementation with two different percentages of BC (2.5 and 5%) on luminal and mucosa-associated microbiota and its metabolism-associated pathways in the jejunum, caecum, and colon of rabbits. Although our results showed no effect of BC on microbiota biodiversity, there were significant differences between experimental groups in the microbial composition, mainly at the level of sub-dominant components depending on the dose of supplementation. The metabolism-associated pathways have also been affected, and particularly interesting are the results on the amino acids and lactose metabolism. Overall, findings suggest that BC could be used as a supplement in rabbit feed, although its effects on productive and reproductive performances, intestinal disease resistance, and economic aspects need to be further evaluated. BC is a nutraceutical that can modulate intestinal microbiota. This study investigates the effects of BC diet supplementation on luminal and mucosa-associated microbiota in the jejunum, caecum, and colon of rabbits. Twenty-one New Zealand White female rabbits were divided into three experimental groups (n = 7) receiving a commercial feed (CTRL group) and the same diet supplemented with 2.5% and 5% BC (2.5% BC and 5% BC groups, respectively), from 35 (weaning) to 90 days of age (slaughtering). At slaughter, the digestive tract was removed from each animal, then both content and mucosa-associated microbiota of jejunum, caecum, and colon were collected and analysed by Next Generation 16SrRNA Gene Sequencing. Significant differences were found in the microbial composition of the three groups (i.e., beta-diversity: p < 0.01), especially in the caecum and colon of the 2.5% BC group. The relative abundance analysis showed that the families most affected by the BC administration were Clostridia UCG-014, Barnesiellaceae, and Eggerthellaceae. A trend was also found for Lachnospiraceae, Akkermansiaceae, and Bacteroidaceae. A functional prediction has revealed several altered pathways in BC groups, with particular reference to amino acids and lactose metabolism. Firmicutes:Bacteroidetes ratio decreased in caecum luminal samples of the 2.5% BC group. These findings suggest that BC supplementation could positively affect the intestinal microbiota. However, further research is needed to establish the optimal administration dose.

ObjectivesThis study aimed (i) to compare the vaginal microbiome profiles of women suffering from vulvovaginal atrophy with that of healthy postmenopausal women and to (ii) assess the effect of ospemifene and systemic hormone treatment on the composition of the vaginal microbiome.MethodsSixty-seven postmenopausal women attending the Gynecology Clinic of Azienda Ospedaliero-Universitaria of Bologna (Italy) were enrolled. Of them, 39 received a diagnosis of atrophy and 28 were considered healthy controls. In the group of atrophic women, 20 were prescribed ospemifene and 19 received hormone treatment. The vaginal health index was calculated, and a vaginal swab was collected for the assessment of vaginal maturation index and the analysis of vaginal microbiome through 16S rRNA gene sequencing. Clinical/microbiological analyses were repeated after 3 months of treatment.ResultsThe vaginal microbiome of atrophic women was characterized by a significant reduction of Lactobacillus (P = 0.002) and an increase of Streptococcus (P = 0.008) and Sneathia (P = 0.02). A positive correlation between vaginal health index/vaginal maturation index and Lactobacillus abundance was found (P = 0.002 and P = 0.035, respectively). Both therapeutic approaches effectively improved vaginal indices. Systemic hormone treatment induced changes in minority bacterial groups of the vaginal microbiome, whereas ospemifene was able to eliminate specific bacterial taxa, such as Staphylococcus (P = 0.04) and Clostridium (P = 0.01). Both treatments induced a trend in the increase of bifidobacteria.ConclusionsThe vaginal microbiome of atrophic women differs significantly from that of healthy postmenopausal women. Ospemifene may lead to a condition of vaginal health, likely characterized by the reduction of "potentially harmful" bacteria.

The dark pigment neuromelanin (NM) is abundant in cell bodies of dopamine (DA) neurons in the substantia nigra (SN) and norepinephrine (NE) neurons in the locus coeruleus (LC) in the human brain. During the progression of Parkinson's disease (PD), together with the degeneration of the respective catecholamine (CA) neurons, the NM levels in the SN and LC markedly decrease. However, questions remain among others on how NM is associated with PD and how it is synthesized. The biosynthesis pathway of NM in the human brain has been controversial because the presence of tyrosinase in CA neurons in the SN and LC has been elusive. We propose the following NM synthesis pathway in these CA neurons: (1) Tyrosine is converted by tyrosine hydroxylase (TH) to L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted by aromatic L-amino acid decarboxylase to DA, which in LC neurons is converted by dopamine beta-hydroxylase to NE; (2) DA or NE is autoxidized to dopamine quinone (DAQ) or norepinephrine quinone (NEQ); and (3) DAQ or NEQ is converted to eumelanic NM (euNM) and pheomelanic NM (pheoNM) in the absence and presence of cysteine, respectively. This process involves proteins as cysteine source and iron. We also discuss whether the NM amounts per neuromelanin-positive (NM+) CA neuron are higher in PD brain, whether NM quantitatively correlates with neurodegeneration, and whether an active lifestyle may reduce NM formation.

Neuromelanin (NM) in dopaminergic neurons of human substantia nigra (SN) has a melanic component that consists of pheomelanin and eumelanin moieties and has been proposed as a key factor contributing to dopa-minergic neuron vulnerability in Parkinson's disease (PD). While eumelanin is considered as an antioxidant, pheomelanin and related oxidative stress are associated with compromised drug and metal ion binding and melanoma risk. Using postmortem SN from patients with PD or Alzheimer's disease (AD) and unaffected controls, we identified increased L-3,4-dihydroxyphenylalanine (DOPA) pheomelanin and increased ratios of dopamine (DA) pheomelanin markers to DA in PD SN compared to controls. Eumelanins derived from both DOPA and DA were reduced in PD group. In addition, we report an increase in DOPA pheomelanin relative to DA pheomelanin in PD SN. In AD SN, we observed unaltered melanin markers despite reduced DOPA compared to controls. Furthermore, synthetic DOPA pheomelanin induced neuronal cell death in vitro while synthetic DOPA eumelanin showed no significant effect on cell viability. Our findings provide insights into the different roles of pheome-lanin and eumelanin in PD pathophysiology. We anticipate our study will lead to further investigations on pheomelanin and eumelanin individually as biomarkers and possibly therapeutic targets for PD.

To date, the factors which affect the age at diagnosis of lung adenocarcinoma are not fully understood. In our study, we examined the relationships of age at diagnosis with smoking, pathological stage, sex, and year of diagnosis in a discovery (n = 1694) and validation (n = 1384) series of lung adenocarcinoma patients who had undergone pulmonary resection at hospitals in the Milan area and at Thoraxklinik (Heidelberg), respectively. In the discovery series, younger age at diagnosis was associated with ever-smoker status (OR = 1.5, p = 0.0035) and advanced stage (taking stage I as reference: stage III OR = 1.4, p = 0.0067; stage IV OR = 1.7, p = 0.0080), whereas older age at diagnosis was associated with male sex (OR = 0.57, p < 0.001). Analysis in the validation series confirmed the ever versus never smokers' association (OR = 2.9, p < 0.001), the association with highest stages (stage III versus stage I OR = 1.4, p = 0.0066; stage IV versus stage I OR = 2.0, p = 0.0022), and the male versus female sex association (OR = 0.78, p = 0.032). These data suggest the role of smoking in affecting the natural history of the disease. Moreover, aggressive tumours seem to have shorter latency from initiation to clinical detection. Finally, younger age at diagnosis is associated with the female sex, suggesting that hormonal status of young women confers risk to develop lung adenocarcinoma. Overall, this study provided novel findings on the mechanisms underlying age at diagnosis of lung adenocarcinoma.

Tubulointerstitial fibrosis is observed in diabetic nephropathy. It is still debated whether tubular cells, undergoing epithelial-mesenchymal transition (EMT) in high glucose (HG) conditions, may contribute to interstitial fibrosis development. In this study, we investigated the phenotypic and molecular EMT-like changes and the alteration of inflammatory and fibrogenic secretome induced by HG in human primary tubular cell cultures. Taking advantage of this in vitro cell model composed of proximal and distal tubular cells, we showed that HG-treated tubular cells acquired a fibroblast-like morphology with increased cytoplasmic stress fibers, maintaining the expression of the epithelial markers specific of proximal and distal tubular cells. HG increased Snail1, miRNA210 and Vimentin mesenchymal markers, decreased N-cadherin expression and migration ability of primary tubular cells, while E-cadherin expression and focal adhesion distribution were not affected. Furthermore, HG treatment of tubular cells altered the inflammatory cytokine secretion creating a secretome able to enhance the proliferation and migration of fibroblasts. Our findings show that HG promotes an activated state of partial EMT in human tubular primary cells and induces a pro-inflammatory and pro-fibrogenic microenvironment, supporting the active role of tubular cells in diabetic nephropathy onset.

The term "neurodegenerative diseases" (ND s) identifies a group of heterogeneous diseases characterized by progressive loss of selectively vulnerable populations of neurons, which progressively deteriorates over time, leading to neuronal dysfunction. Protein aggregation and neuronal loss have been considered the most characteristic hallmarks of NDs, but growing evi-dence confirms that significant dysregulation of innate immune pathways plays a crucial role as well. NDs vary from multiple sclerosis, in which the autoimmune inflammatory component is predominant, to more "classical" NDs, such as Parkinson's disease, Alzheimer's disease, amyo-trophic lateral sclerosis, and spinal muscular atrophy. Of interest, many of the clinical differences reported in NDs seem to be closely linked to sex, which may be justified by the significant changes in immune mechanisms between affected females and males. In this review, we examined some of the most studied NDs by looking at their pathogenic and phenotypical features to highlight sex-related discrepancies, if any, with particular interest in the individuals' responses to treatment. We believe that pointing out these differences in clinical practice may help achieve more successful precision and personalized care.