Role of Neurotrophins in Orofacial Pain Modulation: A Review of the Latest Discoveries

Orofacial pain represents a multidisciplinary biomedical challenge involving basic and clinical research for which no satisfactory solution has been found. In this regard, trigeminal pain is described as one of the worst pains perceived, leaving the patient with no hope for the future. The aim of this review is to evaluate the latest discoveries on the involvement of neurotrophins in orofacial nociception, describing their role and expression in peripheral tissues, trigeminal ganglion, and trigeminal nucleus considering their double nature as “supporters” of the nervous system and as “promoters” of nociceptive transmission. In order to scan recent literature (last ten years), three independent researchers referred to databases PubMed, Embase, Google Scholar, Scopus, and Web of Science to find original research articles and clinical trials. The researchers selected 33 papers: 29 original research articles and 4 clinical trials. The results obtained by the screening of the selected articles show an interesting trend, in which the precise modulation of neurotrophin signaling could switch neurotrophins from being a “promoter” of pain to their beneficial neurotrophic role of supporting the nerves in their recovery, especially when a structural alteration is present, as in neuropathic pain. In conclusion, neurotrophins could be interesting targets for orofacial pain modulation but more studies are necessary to clarify their role for future application in clinical practice

Dust in the reionization era: ALMA observations of a zz=8.38 Galaxy

We report on the detailed analysis of a gravitationally-lensed Y-band dropout, A2744_YD4, selected from deep Hubble Space Telescope imaging in the Frontier Field cluster Abell 2744. Band 7 observations with the Atacama Large Millimeter Array (ALMA) indicate the proximate detection of a significant 1mm continuum flux suggesting the presence of dust for a star-forming galaxy with a photometric redshift of $z\simeq8$. Deep X-SHOOTER spectra confirms the high redshift identity of A2744_YD4 via the detection of Lyman $\alpha$ emission at a redshift $z$=8.38. The association with the ALMA detection is confirmed by the presence of [OIII] 88$\mu$m emission at the same redshift. Although both emission features are only significant at the 4 $\sigma$ level, we argue their joint detection and the positional coincidence with a high redshift dropout in the HST images confirms the physical association. Analysis of the available photometric data and the modest gravitational magnification ($\mu\simeq2$) indicates A2744_YD4 has a stellar mass of $\sim$ 2$\times$10$^9$ M$_{\odot}$, a star formation rate of $\sim20$ M$_{\odot}$/yr and a dust mass of $\sim$6$\times$10$^{6}$ M$_{\odot}$. We discuss the implications of the formation of such a dust mass only $\simeq$200 Myr after the onset of cosmic reionisation.Comment: Accepted for publication in ApJ

In silico identification of new putative pathogenic variants in the NEU1 sialidase gene affecting enzyme function and subcellular localization

The NEU1 gene is the first identified member of the human sialidases, glycohydrolitic enzymes that remove the terminal sialic acid from oligosaccharide chains. Mutations in NEU1 gene are causative of sialidosis (MIM 256550), a severe lysosomal storage disorder showing autosomal recessive mode of inheritance. Sialidosis has been classified into two subtypes: sialidosis type I, a normomorphic, late-onset form, and sialidosis type II, a more severe neonatal or early-onset form. A total of 50 causative mutations are reported in HGMD database, most of which are missense variants. To further characterize the NEU1 gene and identify new functionally relevant protein isoforms, we decided to study its genetic variability in the human population using the data generated by two large sequencing projects: the 1000 Genomes Project (1000G) and the NHLBI GO Exome Sequencing Project (ESP). Together these two datasets comprise a cohort of 7595 sequenced individuals, making it possible to identify rare variants and dissect population specific ones. By integrating this approach with biochemical and cellular studies, we were able to identify new rare missense and frameshift alleles in NEU1 gene. Among the 9 candidate variants tested, only two resulted in significantly lower levels of sialidase activity (pC and c.700G>A. These two mutations give rise to the amino acid substitutions p.V217A and p.D234N, respectively. NEU1 variants including either of these two amino acid changes have 44% and 25% residual sialidase activity when compared to the wild-type enzyme, reduced protein levels and altered subcellular localization. Thus they may represent new, putative pathological mutations resulting in sialidosis type I. The in silico approach used in this study has enabled the identification of previously unknown NEU1 functional alleles that are widespread in the population and could be tested in future functional studies

Resolving Ambiguities in the Inferred Star Formation Histories of Intense [O III] Emitters in the Reionisation Era

Early JWST spectroscopic campaigns have confirmed the presence of strong [O III] line-emitting galaxies in the redshift interval $7<z<9$. Although deduced earlier from Spitzer photometry as indicative of young stellar populations, some studies suggested the relevant photometric excesses attributed to [O III] emission could, in part, be due to Balmer breaks arising from older stars. We demonstrate that this is likely the case by exploiting medium-band near-infrared JWST photometry in the Hubble Ultra Deep Field. We locate a sample of 6 galaxies with redshifts 8.2$<z<$8.6 for which the relevant medium-band filters enables us to separate the contributions of [O III] emission and a Balmer break, thereby breaking earlier degeneracies of interpretation. The technique is particularly valuable since it provides photometric redshifts whose precision, $\Delta\,z\simeq\,\pm0.08$, approaches that of spectroscopic campaigns now underway with JWST. Although some sources are young, a third of our sample have prominent Balmer breaks consistent with stellar ages of $\geq$150 Myr. Our results indicate that even intense [O III] emitters experienced episodes of earlier star formation to $z\sim$10 and beyond, as is now being independently deduced from direct detection of the progenitors of similar systems.Comment: 8 pages, submitted to MNRA

Properties of recombinant human cytosolic sialidase HsNEU2. The enzyme hydrolyzes monomerically dispersed GM1 ganglioside molecules

Recombinant human cytosolic sialidase (HsNEU2), expressed in Escherichia coli, was purified to homogeneity, and its substrate specificity was studied. HsNEU2 hydrolyzed 4-methylumbelliferyl alpha-NeuAc, alpha 2-->3 sialyllactose, glycoproteins (fetuin, alpha-acid glycoprotein, transferrin, and bovine submaxillary gland mucin), micellar gangliosides GD1a, GD1b, GT1b, and alpha 2-->3 paragloboside, and vesicular GM3. alpha 2-->6 sialyllactose, colominic acid, GM1 oligosaccharide, whereas micellar GM2 and GM1 were resistant. The optimal pH was 5.6, kinetics Michaelis-Menten type, V(max) varying from 250 IU/mg protein (GD1a) to 0.7 IU/mg protein (alpha(1)-acid glycoprotein), and K(m) in the millimolar range. HsNEU2 was activated by detergents (Triton X-100) only with gangliosidic substrates; the change of GM3 from vesicular to mixed micellar aggregation led to a 8.5-fold V(max) increase. HsNEU2 acted on gangliosides (GD1a, GM1, and GM2) at nanomolar concentrations. With these dispersions (studied in detailed on GM1), where monomers are bound to the tube wall or dilutedly associated (1:2000, mol/mol) to Triton X-100 micelles, the V(max) values were 25 and 72 microIU/mg protein, and K(m) was 10 and 15 x 10(-9) m, respectively. Remarkably, GM1 and GM2 were recognized only as monomers. HsNEU2 worked at pH 7.0 with an efficiency (compared with that at pH 5.6) ranging from 4% (on GD1a) to 64% (on alpha(1)-acid glycoprotein), from 7% (on GD1a) to 45% (on GM3) in the presence of Triton X-100, and from 30 to 40% on GM1 monomeric dispersion. These results show that HsNEU2 differentially recognizes the type of sialosyl linkage, the aglycone part of the substrate, and the supramolecular organization (monomer/micelle/vesicle) of gangliosides. The last ability might be relevant in sialidase interactions with gangliosides under physiological conditions

Characterization of the AP-1 μ1A and μ1B adaptins in zebrafish (Danio rerio)

Protein transport between the trans-Golgi network and endosomes is mediated by transport vesicles formed by the adaptor-protein complex AP-1, consisting of the adaptins γ1, β1, μ1, σ1. Mammalia express μ1A ubiquitously and isoform μ1B in polarized epithelia. Mouse γ1 or μ1A 'knock out's revealed that AP-1 is indispensable for embryonic development. We isolated μ1A and μ1B from Danio rerio. Analysis of μ1A and μ1B expression revealed tissue-specific expression for either one during embryogenesis and in adult tissues in contrast to their expression in mammalia. μ1B transcript was detected in organs of endodermal derivation and "knock-down" experiments gave rise to embryos defective in formation of intestine, liver, and pronephric ducts. Development ceased at 7-8 dpf. μ1B is not expressed in murine liver, indicating loss of μ1B expression and establishment of alternative sorting mechanisms during mammalian development

Prokineticin 2 upregulation in the peripheral nervous system has a major role in triggering and maintaining neuropathic pain in the chronic constriction injury model

The new chemokine Prokineticin 2 (PROK2) and its receptors (PKR1 and PKR2) have a role in inflammatory pain and immunomodulation. Here we identified PROK2 as a critical mediator of neuropathic pain in the chronic constriction injury (CCI) of the sciatic nerve in mice and demonstrated that blocking the prokineticin receptors with two PKR1-preferring antagonists (PC1 and PC7) reduces pain and nerve damage. PROK2 mRNA expression was upregulated in the injured nerve since day 3 post injury (dpi) and in the ipsilateral DRG since 6 dpi. PROK2 protein overexpression was evident in Schwann Cells, infiltrating macrophages and axons in the peripheral nerve and in the neuronal bodies and some satellite cells in the DRG. Therapeutic treatment of neuropathic mice with the PKR-antagonist, PC1, impaired the PROK2 upregulation and signalling. This fact, besides alleviating pain, brought down the burden of proinflammatory cytokines in the damaged nerve and prompted an anti-inflammatory repair program. Such a treatment also reduced intraneural oedema and axon degeneration as demonstrated by the physiological skin innervation and thickness conserved in CCI-PC1 mice. These findings suggest that PROK2 plays a crucial role in neuropathic pain and might represent a novel target of treatment for this disease

Multiwavelength characterisation of an ACT-selected, lensed dusty star-forming galaxy at z=2.64

We present \ci\,(2--1) and multi-transition $^{12}$CO observations of a dusty star-forming galaxy, ACT\,J2029+0120, which we spectroscopically confirm to lie at $z$\,=\,2.64. We detect CO(3--2), CO(5--4), CO(7--6), CO(8--7), and \ci\,(2--1) at high significance, tentatively detect HCO$^{+}$(4--3), and place strong upper limits on the integrated strength of dense gas tracers (HCN(4--3) and CS(7--6)). Multi-transition CO observations and dense gas tracers can provide valuable constraints on the molecular gas content and excitation conditions in high-redshift galaxies. We therefore use this unique data set to construct a CO spectral line energy distribution (SLED) of the source, which is most consistent with that of a ULIRG/Seyfert or QSO host object in the taxonomy of the \textit{Herschel} Comprehensive ULIRG Emission Survey. We employ RADEX models to fit the peak of the CO SLED, inferring a temperature of T$\sim$117 K and $n_{\text{H}_2}\sim10^5$ cm$^{-3}$, most consistent with a ULIRG/QSO object and the presence of high density tracers. We also find that the velocity width of the \ci\ line is potentially larger than seen in all CO transitions for this object, and that the $L'_{\rm C\,I(2-1)}/L'_{\rm CO(3-2)}$ ratio is also larger than seen in other lensed and unlensed submillimeter galaxies and QSO hosts; if confirmed, this anomaly could be an effect of differential lensing of a shocked molecular outflow.Comment: Accepted for publication in Ap