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G protein-coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR with largely unknown functions. Here, we report that Gpr37l1/GRP37L1 ranks among the most highly expressed GPCR transcripts in mouse and human dorsal root ganglia (DRGs) and is selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy induced by streptozotoxin (STZ) and paclitaxel (PTX) led to reduced GPR37L1 expression on the plasma membrane in mouse and human DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptoms following PTX- and STZ-induced pain, whereas overexpression of Gpr37l1 in mouse DRGs reversed pain. GPR37L1 is coexpressed with potassium channels, including KCNJ10 (Kir4.1) in mouse SGCs and both KCNJ3 (Kir3.1) and KCNJ10 in human SGCs. GPR37L1 regulates the surface expression and function of the potassium channels. Notably, the proresolving lipid mediator maresin 1 (MaR1) serves as a ligand of GPR37L1 and enhances KCNJ10- or KCNJ3-mediated potassium influx in SGCs through GPR37L1. Chemotherapy suppressed KCNJ10 expression and function in SGCs, which MaR1 rescued through GPR37L1. Finally, genetic analysis revealed that the GPR37L1-E296K variant increased chronic pain risk by destabilizing the protein and impairing the protein's function. Thus, GPR37L1 in SGCs offers a therapeutic target for the protection of neuropathy and chronic pain.

The space industry has made significant strides, leading to an era of commercial spaceflight. Meanwhile, understanding molecular responses to spaceflight is crucial for astronauts’ safety. To this end, we examined transcriptomic and epigenetic changes in two astronauts’ blood samples at three timepoints: two weeks before spaceflight (T0), 24 hours after spaceflight (T2), and three months after spaceflight (T3). Transcriptomic analysis identified two gene clusters with opposing transient expression trends post-flight (T2), normalized at T3: one upregulated and the other downregulated. Mapped immune cell types through the CIBERSORT coupled with the pathway analysis suggested monocytes’ role in coordinated cellular response. Epigenetic analysis identified four methylation patterns with transient and persistent changes post-flight, enriched in nervous system development and cell apoptosis pathways. Methylation changes implicated genes associated with bone disorders, including FBLIM1, IHH, and SCAMP2. eQTM analysis suggested a link between RNA transcriptional level and DNA methylation through transcriptional regulator ZNF684. In conclusion, our study revealed significant short-term transcriptional and methylation changes as well as long-term methylation changes.

Galectins are moving closer to center stage in detecting glycosylation aberration in cancer cells. Here, we have investigated the expression of galectins in ovarian cancer (OC) and examined their potential as biomarkers in tissues and blood plasma samples of high grade serous ovarian carcinoma (HGSC) patients. In tissues, we found that increased protein expression of stromal gal-1 and epithelial gal-8/9 was associated with a poor response to treatment of HGSC patients. Gal-8/9 were both independent predictors of chemoresistance and overall survival (OS), respectively. This galectin signature increased the predictive value of the cancer antigen 125 (CA125) on 5-year disease-free survival (DFS), post-chemotherapy treatment and 5-year OS. In CA125 LOW patients, epithelial gal-9 was associated with a lower 5-year OS while stromal gal-1 and epithelial gal-8 were both associated with a lower 5-year DFS. Such negative predictive value of gal-8 and gal-9 was also found using plasma samples. In both cases, high plasma levels of gal-8 and gal-9 was associated with a lower OS and DFS. Overall, these data suggest that galectins may be promising biomarkers to identify subgroups of HGSC patients with poorer prognosis. Our study also contributes to better define the heterogeneity of the disease.

Les galectines sont des protéines multifonctionnelles dont l'expression change dans différentes conditions physiologiques ou pathologiques, y compris le cancer. En fait, il a été démontré que ces protéines induisent une immunosuppression locale et systémique en tuant les cellules immunitaires. Cependant, jusqu'à présent, la plupart des études se sont concentrées sur la galectine-1 et la galectine-3, et nous en savons très peu sur les autres galectines, en particulier celles récemment découvertes, comme la galectine-14. La galectine-14 est une galectine du type prototype hautement exprimée à l'interface mère-foetus et dont l'expression et les fonctions dans les cellules cancéreuses sont encore inconnues.L'objectif global de ce projet était de caractériser l'expression de cette galectine méconnue et d'explorer son rôle dans le cancer. Plus précisément, nos objectifs comprenaient: 1) l'analyse in silico de l'expression du gène de la galectine-14; 2) des expériences in vitro pour l'analyse de l'expression de la galectine-14 dans les lignées cellulaires cancéreuses, et enfin, 3) la création d'un modèle cellulaire in vitro afin d'explorer les fonctions de cette galectine dans le cancer. Nos résultats montrent qu'il existe une corrélation entre l’ARNm de la galectin-14 et le cancer de l'ovaire, et qu'une expression élevée de cette galectine dans les cellules cancéreuses ovariennes est associée à une survie plus courte. De plus, l'expression de la galectine-14 est détectable dans certaines lignées de cellules cancéreuses ovariennes au niveau de l'ARNm, en particulier dans les lignées d'adénocarcinomes séreux de haut grade (HGSA). Enfin, notre modèle in vitro nous a permis d'observer une augmentation de l'activité apoptotique des cellules HEK-293 exprimant des taux élevés de galectine-14.Ainsi, bien que l'étude de cette galectine n'en soit qu'à ses débuts, nous avons été en mesure de fournir de nouvelles connaissances sur les modes d'expression de cette protéine et son implication dans le cancer. À long terme, nos résultats contribueront à l'élaboration de nouvelles stratégies visant à cibler ces molécules afin de surmonter l'immunosuppression associée au cancer, de freiner la croissance tumorale et de prévenir les métastases dans le carcinome ovarien et d'autres types de cancer.

Objective The aim of this study was to determine the degree of conversion (DC) for five orthodontic resins with different viscosities, to examine a probable relationship between the viscosity factor and the degree of conversion of the materials. Methods Five commercially-available light-cured orthodontic bonding resins were used in this study: two medium viscosity resins [transbond XT (TR); opal bond MV (OB)]; two low viscosity resins [vertise flow (VF); opal bond flow (OF)]; and a fluoride-releasing sealant [opal seal (OS)]. The specimens were made and polymerized for 20 s. Fourier Transformed Infrared spectroscopy (FTIR) was used to assess the DC of carbon-carbondouble bonds from all samples. Results The DC was significantly different among the materials: (TR, 24.6 ± 0.04 %; OB, 39 ± 0.02 %; VF, 44.3 ± 0.01 %; OS, 52.5 ± 0.01 %; OF, 53 ± 0.04 %; p < 0.05) and the lowest viscosity materials had the highest DC values. Conclusion The resins studied have different DC values, which can be explained by the unique composition of each brand of resin. There is a relationship between the viscosity of a material and its degree of conversion, which is shown in this study by the two low-viscosity orthodontic resins that had a higher DC.

Galectins (gal) are multifunctional proteins whose expression changes under different physiological or pathological conditions, including cancer. However, so far, most studies have focused on gal-1 and gal-3, and to a lesser extent to gal-7 and gal-9. We still know very little about other galectins, especially the recently discovered ones, such as gal-14, a prototype galectin highly expressed at the maternal-fetal interface. Here, using in silico and in vitro approaches, we report a correlation between lgals14 expression and ovarian cancer. We found that high expression of gal-14 mRNA in ovarian cancer cells is associated with a shorter survival. Consistent with this observation, we also found that lgals14 is preferentially expressed in high grade serous adenocarcinoma (HGSA) ovarian cancer. Our in vitro data with ovarian cancer cell lines confirmed that lgals14 is readily expressed in HGSA. Interestingly, de novo expression of gal-14 in HEK-293 cells increased apoptosis, both at the basal level and following exposure to low doses of etoposide. Thus, although the study of this galectin is still in its infancy, we were able to provide novel insights into the expression patterns of this galectin and its involvement in cancer.

G protein coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR and its function remains largely unknown. Here we report that GPR37L1 transcript is highly expressed compared to all known GPCRs in mouse and human dorsal root ganglia (DRGs) and selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy following diabetes and chemotherapy by streptozotocin and paclitaxel resulted in downregulations of surface GPR37L1 in mouse and human DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptom (mechanical allodynia), whereas overexpression of Gpr37l1 in mouse DRGs can reverse neuropathic pain. Notably, GPR37L1 is co-expressed and coupled with potassium channels in SGCs. We found striking species differences in potassium channel expression in SGCs, with predominant expression of KCNJ10 and KCNJ3 in mouse and human SGCs, respectively. GPR37L1 regulates the surface expression and function of KCNJ10 and KCNJ3. We identified the pro-resolving lipid mediator maresin 1 (MaR1) as a GPR37L1 ligand. MaR1 increases KCNJ10/KCNJ3-mediated potassium influx in SGCs via GPR37L1. MaR1 protected chemotherapy-induced suppression of KCNJ13/KCNJ10 expression and function in SGCs. Finally, genetic analysis revealed that the GPR37L1-E296K variant is associated with increased chronic pain risk by destabilizing the protein. Thus, GPR37L1 in SGCs offers a new target for neuropathy protection and pain control.Competing Interest StatementThe authors have declared no competing interest.

This study aimed to assess the impact of yeast beta-1,3/1,6-glucans (BG) on apparent digestibility coefficients (ADC) of nutrients, intestinal fermentative metabolites, fecal microbiota profile, and immune and antioxidant variables in puppies before and after surgical challenge. Two treatments were evaluated: control, without, and test, with oral supplementation of 65 mg/kg body weight/day of purified BG from Saccharomyces cerevisiae for 120 days. For this, 16 growing Beagle dogs were distributed in a completely randomized design (n = 8/treatment). On day 31, dogs were submitted to spay or neutering surgery. Diet ADC and fecal characteristics analyses were performed on days 55–60. Fecal (days 0, 15, 30, 34, and 60) and blood (days 0, 30, 34, and 60) samples were collected to evaluate intestinal fermentative metabolites, fecal IgA and microbiota, intestinal permeability, and immune and antioxidant variables. On day 80, all dogs were vaccinated for rabies and blood samples were collected on day 120 to determine antibody titers. The supplementation of BG promoted an increase in fecal IgA concentrations on day 15 (P < 0.05) and an increase in fecal concentrations of butyrate (P < 0.05) when day 30 minus day 0 were compared. Dogs of the BG group presented higher fecal concentrations of serotonin (day 15), spermidine (days 15, 30, and 34), and a reduction in tyramine, histamine, and cadaverine on day 60 (P < 0.001). BG consumption promoted an increase in richness and a clear differentiation in the fecal microbiota profile on days 34 and 60 (P < 0.05). BG group also presented an increase in fecal Faecalibacterium , Blautia , and Turicibacter on day 34 (P < 0.05). Reduced glutathione and catalase activities were higher in the BG group (P < 0.05), regardless of the day. In conclusion, the supplementation of BG does not alter the ADC of nutrients, beneficially modulates the intestinal functionality, and stimulates the activity of antioxidant enzymes in growing dogs submitted to a surgical challenge.

Proteins are found both outside and inside of extracellular vesicles (EVs) and govern the properties and functions of EVs, while also constituting a signature of the cell of origin and of biological function and disease. Outer proteins on EVs can be directly bound by antibodies to either enrich EVs, or probe the expression of a protein on EVs, including in a combinatorial manner. However, co-profiling of inner proteins remains challenging. Here, we present the high-throughput, multiplexed analysis of extracellular vesicle inner and outer proteins (EVPio). We describe the optimization of fixation and heat-induced protein epitope retrieval for EVs, along with oligo-barcoded antibodies and branched DNA signal amplification for sensitive, multiplexed and high-throughput assays. We captured 4 subpopulations of EVs from colorectal cancer cell lines HT29 and SW403 based on EpCAM, CD9, CD63 and CD81 expression, and quantified the co-expression of 8 outer (integrins and tetraspanins) and 4 inner (heat shock, endosomal and inner leaflet) proteins. The differences in co-expression patterns were consistent with the literature and known biological function. In conclusion, EVPio analysis can simultaneously detect multiple inner and outer proteins in EVs immobilized on a surface, opening the way to extensive combinatorial protein profiles for both discovery and clinical translation.

Extracellular vesicles (EVs) are nanometric lipid vesicles that shuttle cargo between cells. Their analysis could shed light on health and disease conditions, but EVs must first be preserved, extracted and often pre-concentrated. Here we firstly compare plasma preservation agents, and secondly, using both plasma and cell supernatant, four EV-extraction methods including (i) ultracen-trifugation (UC), (ii) size exclusion chromatography (SEC), (iii) centrifugal filtration (LoDF), and (iv) accousto-sorting (AcS). We benchmarked them by characterizing integrity, size-distribution, concentration, purity and the expression profiles for nine proteins of EVs, as well as overall throughput, time-to-result and cost. We found that the difference between EDTA and citrate anticoagulants vary with the extraction method. In our hands, ultracentrifugation produced a high yield of EVs with low contamination; SEC is low-cost, fast, and easy to implement, but the purity of EVs is lower; LoDF and AcS are both compatible with process automation, small volume requirement, and rapid processing times. When using plasma, the LoDF was susceptible to clogging and sample contamination, while the AcS featured high purity but a lower yield of extraction. Analysis of protein profiles suggest that extraction methods extract different sub-population of EVs. Our study highlights the strength and weakness of sample preprocessing methods, and the variability in concentration, purity, and EV expression profiles of the extracted EVs. Pre-analytical parameters such as collection or pre-processing protocols must be considered as part of the entire process in order to address EV diversity and their use as clinically actionable indicators.