Effectiveness of a pharmacogenetic tool at Improving treatment efficacy in major depressive disorder: A meta-analysis of three clinical studies

Several pharmacogenetic tests to support drug selection in psychiatric patients have recently become available. The current meta-analysis aimed to assess the clinical utility of a commercial pharmacogenetic-based tool for psychiatry (Neuropharmagen®) in the treatment management of depressive patients. Random-effects meta-analysis of clinical studies that had examined the effect of this tool on the improvement of depressive patients was performed. Effects were summarized as standardized differences between treatment groups. A total of 450 eligible subjects from three clinical studies were examined. The random effects model estimated a statistically significant effect size for the pharmacogenetic-guided prescription (d = 0.34, 95% CI = 0.11-0.56, p-value = 0.004), which corresponded to approximately a 1.8-fold increase in the odds of clinical response for pharmacogenetic-guided vs. unguided drug selection. After exclusion of patients with mild depression, the pooled estimated effect size increased to 0.42 (95% CI = 0.19-0.65, p-value = 0.004, n = 287), corresponding to an OR = 2.14 (95% CI = 1.40-3.27). These results support the clinical utility of this pharmacogenetic-based tool in the improvement of health outcomes in patients with depression, especially those with moderate-severe depression. Additional pragmatic RCTs are warranted to consolidate these findings in other patient populations

ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins

BACKGROUND: Annotations of completely sequenced genomes reveal that nearly half of the genes identified are of unknown function, and that some belong to uncharacterized gene families. To help resolve such issues, information can be obtained from the comparative analysis of homologous genes in model organisms. RESULTS: While characterizing genes from the retinitis pigmentosa locus RP26 at 2q31-q33, we have identified a new gene, ORMDL1, that belongs to a novel gene family comprising three genes in humans (ORMDL1, ORMDL2 and ORMDL3), and homologs in yeast, microsporidia, plants, Drosophila, urochordates and vertebrates. The human genes are expressed ubiquitously in adult and fetal tissues. The Drosophila ORMDL homolog is also expressed throughout embryonic and larval stages, particularly in ectodermally derived tissues. The ORMDL genes encode transmembrane proteins anchored in the endoplasmic reticulum (ER). Double knockout of the two Saccharomyces cerevisiae homologs leads to decreased growth rate and greater sensitivity to tunicamycin and dithiothreitol. Yeast mutants can be rescued by human ORMDL homologs. CONCLUSIONS: From protein sequence comparisons we have defined a novel gene family, not previously recognized because of the absence of a characterized functional signature. The sequence conservation of this family from yeast to vertebrates, the maintenance of duplicate copies in different lineages, the ubiquitous pattern of expression in human and Drosophila, the partial functional redundancy of the yeast homologs and phenotypic rescue by the human homologs, strongly support functional conservation. Subcellular localization and the response of yeast mutants to specific agents point to the involvement of ORMDL in protein folding in the ER

Scaling new heights in the genetic diagnosis of inherited retinal dystrophies

During the last 20 years, our group has focused on identifying the genes and mutations causative of inherited retinal dystrophies (IRDs). By applying massive sequencing approaches (NGS) in more than 500 familial and sporadic cases, we attained high diagnostic efficiency (85%) with a custom target gene panel and over 75% using whole exome sequencing (WES). Close to 40% of pathogenic alleles are novel mutations, which demand specific in silico tests and in vitro assays. Notably, missense variants are by far the most common type of mutation identified (around 40%), with small in-frame indels being less frequent (2%). To fill the gap of unsolved cases, when no candidate gene or only a single pathogenic allele has been identified, additional scientific and technical issues remain to be addressed. Reliable detection of genomic rearrangements and copy number variants (partial or complete), deep intronic mutations, variants that cause aberrant splicing events in retina-specific transcripts, functional assessment of hypomorphic missense alleles, mutations in regulatory sequences, the contribution of modifier genes to the IRD phenotype, and detection of low heteroplasmy mtDNA mutations are among the new challenges to be met

Primary Cilia Are Not Required for Normal Canonical Wnt Signaling in the Mouse Embryo

Sonic hedgehog (Shh) signaling in the mouse requires the microtubule-based organelle, the primary cilium. The primary cilium is assembled and maintained through the process of intraflagellar transport (IFT) and the response to Shh is blocked in mouse mutants that lack proteins required for IFT. Although the phenotypes of mouse IFT mutants do not overlap with phenotypes of known Wnt pathway mutants, recent studies report data suggesting that the primary cilium modulates responses to Wnt signals.We therefore carried out a systematic analysis of canonical Wnt signaling in mutant embryos and cells that lack primary cilia because of loss of the anterograde IFT kinesin-II motor (Kif3a) or IFT complex B proteins (Ift172 or Ift88). We also analyzed mutant embryos with abnormal primary cilia due to defects in retrograde IFT (Dync2h1). The mouse IFT mutants express the canonical Wnt target Axin2 and activate a transgenic canonical Wnt reporter, BAT-gal, in the normal spatial pattern and to the same quantitative level as wild type littermates. Similarly, mouse embryonic fibroblasts (MEFs) derived from IFT mutants respond normally to added Wnt3a. The switch from canonical to non-canonical Wnt also appears normal in IFT mutant MEFs, as both wild-type and mutant cells do not activate the canonical Wnt reporter in the presence of both Wnt3a and Wnt5a.We conclude that loss of primary cilia or defects in retrograde IFT do not affect the response of the midgestation embryo or embryo-derived fibroblasts to Wnt ligands

A resonant sextuplet of sub-Neptunes transiting the bright star HD 110067

Planets with radii between that of the Earth and Neptune (hereafter referred to as sub-Neptunes) are found in close-in orbits around more than half of all Sun-like stars. Yet, their composition, formation, and evolution remain poorly understood. The study of multi-planetary systems offers an opportunity to investigate the outcomes of planet formation and evolution while controlling for initial conditions and environment. Those in resonance (with their orbital periods related by a ratio of small integers) are particularly valuable because they imply a system architecture practically unchanged since its birth. Here, we present the observations of six transiting planets around the bright nearby star HD 110067. We find that the planets follow a chain of resonant orbits. A dynamical study of the innermost planet triplet allowed the prediction and later confirmation of the orbits of the rest of the planets in the system. The six planets are found to be sub-Neptunes with radii ranging from 1.94 to 2.85 Re. Three of the planets have measured masses, yielding low bulk densities that suggest the presence of large hydrogen-dominated atmospheres.Comment: Published in Nature on November 30, 2023. Supplementary Information can be found in the online version of the paper in the journa

A resonant sextuplet of sub-Neptunes transiting the bright star HD 110067

Funding: A.C.Ca. and T.G.Wi. acknowledge support from STFC consolidated grant numbers ST/R000824/1 and ST/V000861/1, and UKSA grant number ST/R003203/1. O.Ba. acknowledges that has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 865624). M.La. acknowledges funding from a UKRI Future Leader Fellowship, grant number MR/S035214/1. A.Br. was supported by the SNSA. Contributions at the Mullard Space Science Laboratory by E.M.Br. were supported by STFC through the consolidated grant ST/W001136/1. A.Br. was supported by the SNSA. Contributions at the Mullard Space Science Laboratory by E.M.Br. were supported by STFC through the consolidated grant ST/W001136/1. Ch.He. acknowledges support from the European Union H2020-MSCA-ITN-2019 under Grant Agreement no. 860470 (CHAMELEON).Planets with radii between that of the Earth and Neptune (hereafter referred to as 'sub-Neptunes') are found in close-in orbits around more than half of all Sun-like stars . However, their composition, formation and evolution remain poorly understood . The study of multiplanetary systems offers an opportunity to investigate the outcomes of planet formation and evolution while controlling for initial conditions and environment. Those in resonance (with their orbital periods related by a ratio of small integers) are particularly valuable because they imply a system architecture practically unchanged since its birth. Here we present the observations of six transiting planets around the bright nearby star HD 110067. We find that the planets follow a chain of resonant orbits. A dynamical study of the innermost planet triplet allowed the prediction and later confirmation of the orbits of the rest of the planets in the system. The six planets are found to be sub-Neptunes with radii ranging from 1.94R to 2.85R . Three of the planets have measured masses, yielding low bulk densities that suggest the presence of large hydrogen-dominated atmospheres.PostprintPeer reviewe

A resonant sextuplet of sub-Neptunes transiting the bright star HD 110067.

Planets with radii between that of the Earth and Neptune (hereafter referred to as 'sub-Neptunes') are found in close-in orbits around more than half of all Sun-like stars . However, their composition, formation and evolution remain poorly understood . The study of multiplanetary systems offers an opportunity to investigate the outcomes of planet formation and evolution while controlling for initial conditions and environment. Those in resonance (with their orbital periods related by a ratio of small integers) are particularly valuable because they imply a system architecture practically unchanged since its birth. Here we present the observations of six transiting planets around the bright nearby star HD 110067. We find that the planets follow a chain of resonant orbits. A dynamical study of the innermost planet triplet allowed the prediction and later confirmation of the orbits of the rest of the planets in the system. The six planets are found to be sub-Neptunes with radii ranging from 1.94R to 2.85R . Three of the planets have measured masses, yielding low bulk densities that suggest the presence of large hydrogen-dominated atmospheres. [Abstract copyright: © 2023. The Author(s), under exclusive licence to Springer Nature Limited.

Pigments, granotes i optogrames. Una història sobre les bases moleculars de la visió

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Overexpression of CERKL, a gene responsible for retinitis pigmentosa in humans, protects cells from apoptosis induced by oxidative stress

Purpose: Retinitis pigmentosa (RP), a retinal neurodegenerative disorder characterized by apoptosis of photoreceptorcells, is caused by mutations in many different genes. We analyzed the RP gene ceramide kinase-like (CERKL) to determineCERKL function and contribution to pathogenesis.Methods: RT-PCR was performed to characterize CERKLexpression in many human adult and fetal tissues, includingretina. We analyzed the protein subcellular localization by confocal microscopy and further verified it by sucrose gradients.We performed lipid kinase activity assays. And finally, we studied the effects on cell apoptosis after CERKLoverexpression in transiently transfected cultured cells by propidium iodide staining and poly-(ADP-ribose)-polymerase(PARP) caspase-dependent cleavage.Results: CERKLtranscripts underwent alternative splicing. In the human retina, four different CERKL isoforms of 532,558, 419, and 463 amino acids were expressed. CERKL proteins were mainly localized in the endoplasmic reticulum andGolgi compartments, but they also shifted localization to nuclei and nucleoli. We also found that CERKL prevented cellsfrom entering apoptosis induced by oxidative-stress conditions.Conclusions: CERKL remains a unique orphan lipid kinase in that no candidate substrate has been identified after intenseresearch. The dynamic localization of CERKL suggests multiple sites of action. Remarkably, CERKL (but not the RPR257X mutant) exerts a protective role in cells against oxidative stress, consistent with RP mutations impairing the normalprotein function in photoreceptors and thus tilting the balance toward apoptosis. These results provide valuable insightsinto the molecular mechanisms causing retinal degeneration