Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder

Several studies have demonstrated that allelic variants related to inflammation and the immune system may increase the risk for major depressive disorder (MDD) and reduce patient responsiveness to antidepressant treatment. Proteasomes are fundamental complexes that contribute to the regulation of T-cell function. Only one study has shown a putative role of proteasomal PSMA7, PSMD9 and PSMD13 genes in the susceptibility to an antidepressant response, and sparse data are available regarding the potential alterations in proteasome expression in psychiatric disorders such as MDD. The aim of this study was to clarify the role of these genes in the mechanisms underlying the response/resistance to MDD treatment. We performed a case-control association study on 621 MDD patients, of whom 390 were classified as treatment-resistant depression (TRD), and we collected peripheral blood cells and fibroblasts for mRNA expression analyses. The analyses showed that subjects carrying the homozygous GG genotype of PSMD13 rs3817629 had a twofold greater risk of developing TRD and exhibited a lower PSMD13 mRNA level in fibroblasts than subjects carrying the A allele. In addition, we found a positive association between PSMD9 rs1043307 and the presence of anxiety disorders in comorbidity with MDD, although this result was not significant following correction for multiple comparisons. In conclusion, by confirming the involvement of PSMD13 in the MDD treatment response, our data corroborate the hypothesis that the dysregulation of the complex responsible for the degradation of intracellular proteins and potentially controlling autoimmunity- and immune tolerance–related processes may be involved in several phenotypes, including the TRD

Efficacy of High-Ozonide Oil in Prevention of Cancer Relapses Mechanisms and Clinical Evidence

Background: Cancer tissue is characterized by low oxygen availability triggering neo angiogenesis and metastatisation. Accordingly, oxidation is a possible strategy for counteracting cancer progression and relapses. Previous studies used ozone gas, administered by invasive methods, both in experimental animals and clinical studies, transiently decreasing cancer growth. This study evaluated the effect of ozonized oils (administered either topically or orally) on cancer, exploring triggered molecular mechanisms. Methods: In vitro, in lung and glioblastoma cancer cells, ozonized oils having a high ozonide content suppressed cancer cell viability by triggering mitochondrial damage, intracellular calcium release, and apoptosis. In vivo, a total of 115 cancer patients (age 58 \ub1 14 years; 44 males, 71 females) were treated with ozonized oil as complementary therapy in addition to standard chemo/radio therapeutic regimens for up to 4 years. Results: Cancer diagnoses were brain glioblastoma, pancreas adenocarcinoma, skin epithelioma, lung cancer (small and non-small cell lung cancer), colon adenocarcinoma, breast cancer, prostate adenocarcinoma. Survival rate was significantly improved in cancer patients receiving HOO as integrative therapy as compared with those receiving standard treatment only. Conclusions: These results indicate that ozonized oils at high ozonide may represent an innovation in complementary cancer therapy worthy of further clinical studies

A population genomics insight by 2b‐RAD reveals populations' uniqueness along the Italian coastline in Leptopsammia pruvoti (Scleractinia, Dendrophylliidae)

Aim Marine bioconstructions such as coralligenous formations are hotspot of biodiversity and play a relevant ecological role in the preservation of biodiversity by providing carbon regulation, protection and nursery areas for several marine species. For this reason, the European Union Habitat Directive included them among priority habitats to be preserved. Although their ecological role is well established, connectivity patterns are still poorly investigated, representing a limit in conservation planning. The present study pioneers a novel approach for the analysis of connectivity in marine bioconstructor species, which often lack suitable genetic markers, by taking advantage of next‐generation sequencing techniques. We assess the geographical patterns of genomic variation of the sunset cup coral Leptopsammia pruvoti Lacaze‐Duthiers, 1897, an ahermatypic, non‐zooxanthellate and solitary scleractinian coral species common in coralligenous habitats and distributed across the Mediterranean Sea. Location The Italian coastline (Western and Central Mediterranean). Methods We applied the restriction site‐associated 2b‐RAD approach to genotype over 1,000 high‐quality and filtered single nucleotide polymorphisms in 10 population samples. Results The results revealed the existence of a strongly supported genetic structure, with highly significant pairwise FST values between all the population samples, including those collected about 5 km apart from each other. Moreover, genomic data indicate that the strongest barriers to gene flow are between the western (Ligurian–Tyrrhenian Sea) and the eastern side (Adriatic Sea) of the Italian peninsula. Main conclusions The strong differentiation found in L. pruvoti is similar to that found in other species of marine bioconstructors investigated in this area, but it strongly contrasts with the small differences found in many fish and invertebrates at the same geographical scale. All in one, our results highlight the importance of assessing connectivity in species belonging to coralligenous habitats as, due to their limited dispersal ability, they might require specific spatial conservation measures

Chandra and Magellan/FIRE follow-up observations of PSO167-13: an X-ray weak QSO at z=6.515z=6.515

The discovery of hundreds of QSOs in the first Gyr of the Universe powered by already grown SMBHs challenges our knowledge of SMBH formation. In particular, investigations of $z>6$ QSOs presenting notable properties can provide unique information on the physics of fast SMBH growth in the early universe. We present the results of follow-up observations of the $z=6.515$ radio-quiet QSO PSO167-13, which is interacting with a close companion galaxy. The PSO167-13 system has been recently proposed to host the first heavily obscured X-ray source at high redshift. We observed PSO167-13 with Chandra/ACIS-S (177 ks), and obtained new spectroscopic observations (7.2 h) with Magellan/FIRE. No significant X-ray emission is detected from the PSO167-13 system, suggesting that the obscured X-ray source previously tentatively detected was either due to a strong background fluctuation or is highly variable. The upper limit (90% confidence level) on the X-ray emission of PSO167-13 ($L_{2-10\,\mathrm{keV}}<8.3\times10^{43}\,\mathrm{erg s^{-1}}$) is the lowest available for a $z>6$ QSO. The ratio between the X-ray and UV luminosity of $\alpha_{ox}<-1.95$ makes PSO167-13 a strong outlier from the $\alpha_{ox}-L_{UV}$ and $L_X-L_{\mathrm{bol}}$ relations. In particular, its X-ray emission is $>6$ times weaker than the expectation based on its UV luminosity. The new Magellan/FIRE spectrum of PSO167-13 is strongly affected by the unfavorable sky conditions, but the tentatively detected C IV and Mg II emission lines appear strongly blueshifted. The most plausible explanations for the X-ray weakness of PSO167-13 are intrinsic weakness or small-scale absorption by Compton-thick material. The possible strong blueshift of its emission lines hints at the presence of nuclear winds, which could be related to its X-ray weakness.Comment: Accepted for publication on A&

Microsatellites from the genome and the transcriptome of the tetraploid Adriatic sturgeon, Acipenser naccarii (Bonaparte, 1836) and cross-species applicability to the diploid beluga sturgeon, Huso huso (Linnaeus, 1758)

Ninety-five microsatellite loci were isolated from the output of two Next Generation Sequencing projects: a genomic Illumina RADSeq and a transcriptomic Roche 454 cDNA sequencing of the Adriatic sturgeon (Acipenser naccarii). From a total of 7697 loci identified, 72 were characterized and 57 were polymorphic in the tetraploid A. naccarii, providing new markers suitable for parental allocations to be performed for future conservation actions. Loci isolated from the transcriptome showed a higher level of polymorphism, which could be related to the different sequencing approaches used. Notably, a higher rate of duplication was observed in the transcribed loci, pointing to a preferential retention of sequences with a functional role after whole genome duplications occurred in sturgeons. Cross-species amplification of these markers was also assessed in the diploid beluga sturgeon (Huso huso), with the aim of setting up a panel of markers to be applied in future conservation programmes regarding this species

The role of GRIK4 gene in treatment-resistant depression

SummarySeveral lines of evidence implicate abnormalities in glutamatergic neural transmission in major depressive disorder (MDD) and treatment response. A high percentage of MDD patients do not respond adequately to antidepressants and are classified as having treatment-resistant depression (TRD). In this study we investigated five GRIK4 variants, previously associated with antidepressants response, in an Italian cohort of 247 MDD no-TRD and 380 TRD patients. We found an association between rs11218030 G allele and TRD. Moreover, significant associations between rs11218030 and rs1954787 and the presence of psychotic symptoms were observed. In conclusion, our data support the involvement of GRIK4 in TRD and in the risk of developing psychotic symptoms during depressive episodes.</jats:p

Characterization of Captive Breeders to Preserve the Residual Genetic Diversity of Adriatic Sturgeon (Acipenser naccarii)

Since 1996, the Adriatic sturgeon (Acipenser naccarii) has been inscribed on the IUCN Red List as "Critically Endangered and possibly extinct in the wild". Nowadays, its survival totally depends on restocking programs conducted by releasing juveniles generated from adult breeders reared in aquaculture. Conducting accurate genetic characterizations of all individuals potentially involved in reproduction activities is therefore of primary importance to avoid inbreeding and to maximize the genetic diversity transmitted to following generations. Since all animals reared in captivity descend from a single stock of wild origin, this offers the ideal condition for carrying out relatedness analysis based on parentage allocations. In this study, we provided the most complete characterization of about 500 individuals representing the most diverse extant stock of Adriatic sturgeon. Through the analyses of mitochondrial d-loop and 15 microsatellite loci selected from 24 genotyped loci, we identified about 30 different familiar groups, updating data on breeding stocks, increasing the genetic information already available, and extending the analyses to animals never genotyped before. Given its completeness, it will represent a reference database for any future parental allocation of recaptured animals for the inclusion of all other stocks present, as well as for the development of a long-term breeding plan. The approach used has also been proven useful on individuals of unknown genealogy, allowing for the identification of family groups and thus being proven to be promising for the analysis of stocks of other tetraploid sturgeon species

Role of allelic variants of FK506-binding protein 51 (FKBP5) gene in the development of anxiety disorders

Background: Anxiety disorders exhibit remarkably high rates of comorbidity with major depressive disorder (MDD). Mood and anxiety disorders are considered stress-related diseases. Genetic variations in the co-chaperone FK506-binding protein 51, FKBP5, which modulates the function of glucocorticoid receptors, have been associated with an increased risk for the development of posttraumatic stress disorder, but data regarding its role in MDD are controversial. The aims of this study were to clarify the role of the FKBP5 gene in depression and anxiety disorders through a case–control study and an associationstudy with personality traits using the Temperament and Character Inventory (TCI) in healthy subjects. Methods: Six hundred fifty-sevenMDDpatients, with or without an anxiety disorder in comorbidity, and 462 healthy volunteers were enrolled in the study. Two hundred fifty-six controls agreed to fill out the TCI. Results: The results showed that the T allele of rs1360780 was more frequent among the patients affected by MDD with a comorbidity of anxiety disorders, compared to those without (P < .001). Among the controls, we found that the T allele more often exhibited personality traits associated with an increased vulnerability to anxiety. Conclusions: These results support the hypothesis that allelic variants of FKBP5 are a risk factor for anxiety disorders. The identification ofgenetic variants involved in anxiety may have implications for the optimization of therapeutic interventions

Influence of GRIK4 genetic variants on the electroconvulsive therapy response

Several lines of evidence have shown the involvement of the glutamatergic system in the function of electroconvulsive therapy (ECT). In particular, patients with treatment resistant depression (TRD) and chronic depression have lower levels of glutamate/glutamine than controls, and ECT can reverse this deficit. Genetic factors might contribute to modulating the mechanisms underlying ECT. This study aimed to evaluate the relationship between three polymorphisms (rs1954787, rs4936554 and rs11218030) of the glutamate receptor ionotropic kainate 4 (GRIK4) gene and responsiveness to ECT treatment in a sample of one hundred individuals, TRD or depressive Bipolar Disorder patients resistant to pharmacological treatments. The results revealed that GRIK4 variants were significantly associated with the response to ECT. In particular, we found that patients carrying the G allele of the GRIK4 rs11218030 had a significantly poorer response to ECT (p = 2.71 × 10-4), showing five times the risk of relapse after ECT compared to the AA homozygotes. Analogously, patients carrying the GG rs1954787 genotype and rs4936554 A allele carriers presented a double risk of lack of response after ECT (p = 0.013 and p = 0.040, respectively). In conclusion, the current study provides new evidence, indicating that some GRIK4 variants modulate the response to ECT in patients with depression resistant to treatment, suggesting a role for kainate receptor modulation. © 2016 Elsevier Ireland Ltd