Biology subjects

Seminara, S.

Publications and source records attributed to Seminara, S..

7 recordsLinked to original sources

bioRxiv2026

Glycan-coated nanoparticles mimicking the ischemic glycocalyx scavenge the complement system conferring protection after experimental ischemic stroke

Glycoproteins lining the luminal endothelial surface form the glycocalyx, composing the tripartite blood brain barrier. We explored the glycocalyx as a source of danger signals for complement lectin pathway after ischemic stroke. Our data indicate that hypoxic microvascular cells increased -D-mannosyl and N-acetylglucosaminyl exposure after re-oxygenation, favoring mannose binding lectin (MBL) pathogenic deposition, and overexpression of inflammatory genes (ICAM-1 and MMP-2). The hypoxia-conditioned medium induced neuronal damage (reduced MAP-2), microglia and astrocytic reactivity (increased/thickened ramifications) when applied to induced pluripotent stem cell-derived neurons, astrocytes and microglia co-cultures. All these effects were counteracted by mannose-capped gold nanoparticles (Man-GNPs), shown to bind and sequester MBL from the medium. We then tested the Man-GNPs in vivo, in an ischemic stroke model using humanized mice, knocked-in for human MBL. The ischemic mice (males:females 1:1) treated with Man-GNPs (3h after the ischemic onset) exhibited less anxiety at the elevated plus maze and reduced neuronal loss at 8d after ischemia compared to vehicle-treated. Thus, multivalent Man-GNPs represent a promising approach to take MBL away from its glycoproteic targets on the ischemic endothelium, hence preventing downstream pathogenesis. Moreover, these data support circulating MBL as a druggable pharmacological target to prevent the thrombo-inflammatory events following acute brain injury.

neuroscience↗

bioRxiv2025

Multi-center Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke (TRICS BASIC)

BackgroundBasic science studies have reported remote ischemic conditioning (RIC) as neuroprotective in acute ischemic stroke, while clinical evidence remains conflicting. The TRICS BASIC study investigated the efficacy and safety of RIC in experimental ischemic stroke using a rigorous clinical trial methodology. MethodsMulti-center, multi-species, parallel group, randomized, controlled, preclinical trial of transient femoral artery clipping to induce RIC in female and male rats and mice subjected to transient endovascular occlusion of the middle cerebral artery. Animals were randomized to receive RIC, or sham surgery, after reperfusion. The primary endpoint was good functional outcome at 48 hours, assessed using a composite functional neuroscore. Secondary endpoints was infarct volume at 48 hours and safety, assessed using a standardized health report at 24 and 48 hours. Pre-enrollment harmonization, centralized monitoring, allocation concealment, blinded outcome assessment and intention-to-treat analysis were applied. ResultsThe trial enrolled 164 rodents (82 mice and 82 rats) of both sexes (53% females), across seven laboratories. A greater proportion of RIC-treated rodents achieved a favorable functional outcome compared to controls, at 48 hours post-ischemia (55% versus 36%; OR 2.2, 95% CI [1.23-4.4], p=0.009). RIC was associated with a small reduction in infarct volume (standardized mean difference -0.38, 95% CI [-0.70, -0.05], p=0.024). Health monitoring indicated no major safety concerns, and post-operative analgesia requirements were lower in RIC-treated mice. ConclusionsSurgically-induced RIC provided a modest but evident neuroprotective effect in experimental ischemic stroke, underscoring the potential of this strategy as an adjunctive treatment in stroke care. The findings of the TRICS BASIC study highlighted the importance of multicenter preclinical trials in addressing variability and enhancing translational validity. Registrationregistered at preclinicaltrials.eu, identifier PCTE0000177.

neuroscience↗

bioRxiv2022

POU6F2 mutation identified in humans with pubertal failure shifts isoform formation and alters GnRH transcript expression

Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent pubertal development and infertility, often due to gonadotropin-releasing hormone (GnRH) deficits. Exome sequencing of two independent cohorts of IHH patients identified 12 rare missense variants in POU6F2. POU6F2 encodes two distinct isoforms. In mouse, pituitary and gonads expressed both isoforms, but only isoform1 was detected in GnRH cells. Although the function of isoform2 is well known, using bioinformatics and cells assays on a human-derived GnRH cell line, we demonstrate isoform1 can also act as a transcriptional regulator, decreasing GNRH1 expression. The impact of two POU6F2 variants (MT1 and MT2) was then examined. MT1, but not MT2, reduced transcriptional activity of either isoform, preventing Hes5 promoter activation by isoform2 and repression of GnRH transcripts by isoform1. GnRH transcription increases as the cells migrate into the brain. Augmentation earlier can disrupt normal GnRH cell migration, consistent with POU6F2 variants contributing to IHH pathogenesis.

genetics↗

bioRxiv2019

The genetic architecture of sporadic and recurrent miscarriage

Miscarriage is a common complex trait that affects 10-25% of clinically confirmed pregnancies1,2. Here we present the first large-scale genetic association analyses with 69,118 cases from five different ancestries for sporadic miscarriage and 750 cases of European ancestry for recurrent miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association on chromosome 13 (rs146350366, minor allele frequency (MAF) 1.2%, Pmeta=3.2x -8 (CI) 1.2-1.6) for sporadic miscarriage in our European ancestry meta-analysis (50,060 cases and 174,109 controls), located near FGF9 involved in pregnancy maintenance3 and progesterone production4. Additionally, we identified three genome-wide significant associations for recurrent miscarriage, including a signal on chromosome 9 (rs7859844, MAF=6.4%, Pmeta=1.3x -8 in controlling extravillous trophoblast motility5. We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability and, genetic correlation analyses. Our results implicate that miscarriage etiopathogenesis is partly driven by genetic variation related to gonadotropin regulation, placental biology and progesterone production.

genetics↗

bioRxiv2019

Biodiversity lost: The phylogenetic relationships of a complete mitochondrial DNA genome sequenced from the extinct wolf population of Sicily

Using next-generation sequencing, we obtained for the first time a complete mitochondrial DNA genome from a museum specimen of the extinct wolf (Canis lupus) population of the island of Sicily (Italy). Phylogenetic analyses showed that this genome, which was aligned with a number of historical and extant complete wolf and dog mtDNAs sampled worldwide, was closely related to an Italian wolf mtDNA genome (TN93 and p-distances = 0.0012), five to seven times shorter than divergence among Sicilian and any other known wolf mtDNA genomes (distance range = 0.0050 - 0.0070). Sicilian and Italian haplotypes joined a basal clade belonging to the mtDNA haplogroup-2 of ancient western European wolf populations (Pilot et al. 2010). Bayesian calibration of divergence times indicated that this clade coalesced at MRCA = 13.400 years (with 95% HPD = 4000 - 21.230 years). These mtDNA findings suggest that wolves probably colonized Sicily from southern Italy towards the end of the last Pleistocene glacial maximum, when the Strait of Messina was almost totally dry. Additional mtDNA and genomic data will further clarify the origin and population dynamics before the extinction of wolves in Sicily.

zoology↗

bioRxiv2018

Redundancy in the central tachykinin systems safeguards puberty onset and fertility

The tachykinin neurokinin B (NKB, Tac2) is critical for GnRH release. NKB signaling deficiency leads to infertility in humans. However, some patients reverse this hypogonadism resembling the fertile phenotype of Tac2KO and Tacr3KO (encoding NKB receptor, NK3R) mice despite the absence of NKB signaling. Here, we demonstrate that in the absence of NKB signaling, other tachykinins (substance P and neurokinin A [NKA], encoded by Tac1) may take over to preserve fertility. The complete absence of tachykinins in Tac1/Tac2KO mice leads to delayed puberty onset in both sexes and infertility in 80% of females (but not males), in contrast to the 100% fertile phenotype of Tac1KO and Tac2KO mice separately. Furthermore, we demonstrate that NKA controls puberty onset and LH release through NKB-independent mechanisms in the presence of sex steroids and NKB-dependent mechanisms in their absence. In summary, tachykinins interact in a coordinated manner to ensure reproductive success in female mice.

physiology↗

bioRxiv2018

GWAS meta-analysis highlights the hypothalamic-pituitary-gonadal axis (HPG axis) in the genetic regulation of menstrual cycle length

The normal menstrual cycle requires a delicate interplay between the hypothalamus, pituitary, and ovary. Therefore, its length is an important indicator of female reproductive health. Menstrual cycle length has been shown to be partially controlled by genetic factors, especially in the follicle stimulating hormone beta-subunit (FSHB) locus. GWAS meta-analysis of menstrual cycle length in 44,871 women of European ancestry confirmed the previously observed association with the FSHB locus and identified four additional novel signals in, or near, the GNRH1, PGR, NR5A2 and INS-IGF2 genes. These findings confirm the role of the hypothalamic-pituitary-gonadal axis in the genetic regulation of menstrual cycle length, but also highlight potential novel local regulatory mechanisms, such as those mediated by IGF2.

genetics↗