The transient receptor potential melastatin 4 (TRPM4) channel contributes to disease severity in the murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and to neuronal ...cell death in models of excitotoxicity and traumatic brain injury. As TRPM4 is activated by intracellular calcium and conducts monovalent cations, we hypothesized that TRPM4 may contribute to and boost excitatory synaptic transmission in CA1 pyramidal neurons of the hippocampus. Using single-spine calcium imaging and electrophysiology, we found no effect of the TRPM4 antagonists 9-phenanthrol and glibenclamide on synaptic transmission in hippocampal slices from healthy mice. In contrast, glibenclamide but not 9-phenanthrol reduced excitatory synaptic potentials in slices from EAE mice, an effect that was absent in slices from EAE mice lacking TRPM4. We conclude that TRPM4 plays little role in basal hippocampal synaptic transmission, but a glibenclamide-sensitive TRPM4-mediated contribution to excitatory postsynaptic responses is upregulated at the acute phase of EAE.
Weight gain is a common adverse effect of lithium augmentation. Previous studies indicate an impact of genetic variants at the leptin gene on weight gain as a consequence of psychopharmacological ...treatment. The primary aim of our study was to identify variants at the leptin locus that might predict lithium-induced weight gain. The secondary aim was to investigate if these variants modulate leptin levels. In 180 patients with acute major depressive disorder, body mass index was measured before and after 4 weeks of lithium augmentation, in a subsample also after 4 and/or 7 months. In a subsample of 89 patients, leptin serum concentrations were measured before and during lithium augmentation. We used linear mixed model analyzes to investigate the effects of 2 polymorphisms at the leptin locus (rs4731426 and rs7799039, employing the respective proxy SNPs rs2278815 and rs10487506) on changes in body mass index and leptin levels. For both polymorphisms, which are in high linkage disequilibrium, body mass index was significantly lower in homozygous A-allele carriers than in carriers of other genotypes at baseline. Over the follow-up period, body mass index increased less in homozygous A-allele carriers of rs4731426 than in carriers of other genotypes. This was not the case for rs7799039. Neither polymorphism modulated leptin protein expression. Our study strongly supports the hypothesis that genetic variability at the leptin locus is involved in lithium augmentation-associated weight gain in major depressive disorder. Furthermore, Genotype-Tissue Expression data provide strong evidence that rs4731426 influences the expression of leptin messenger ribonucleic acid in fibroblasts.
Objectives
Health disparities between individuals of African and European ancestry are well documented. The disparities in bipolar disorder may be driven by racial bias superimposed on established ...factors contributing to misdiagnosis, including: evolving empirically based diagnostic criteria (International Classification of Diseases ICD, Research Diagnostic Criteria RDC and Diagnostic and Statistical Manual DSM), multiple symptom domains (i.e. mania, depression and psychosis), and multimodal medical and additional psychiatric comorbidity.
Methods
For this paper, we reviewed the phenomenological differences between bipolar individuals of African and European ancestry in the context of diagnostic criteria and clinical factors that may contribute to a potential racial bias.
Results
Published data show that bipolar persons of African ancestry, compared with bipolar persons of non‐African ancestry, are more often misdiagnosed with a disease other than bipolar disorder (i.e. schizophrenia). Additionally, studies show that there are disparities in recruiting patients of African ancestry to participate in important genomic studies. This gap in biological research in this underrepresented minority may represent a missed opportunity to address potential racial differences in the risk and course of bipolar illness.
Conclusion
A concerted effort by the research community to increase inclusion of diverse persons in studies of bipolar disorder through community engagement may facilitate fully addressing these diagnostic and treatment disparities in bipolar individuals of African ancestry.
Antipsychotic-induced weight gain (AIWG) is a common adverse event in schizophrenia. Genome-wide association studies (GWAS) and polygenic risk scores (PRS) for other diseases or traits are recent ...approaches to disentangling the genetic architecture of AIWG. 200 patients with schizophrenia treated monotherapeutically with antipsychotics were included in this study. A multiple linear regression analysis with ten-fold crossvalidation was performed to predict the percentage weight change after five weeks of treatment. Independent variables were sex, age, body mass index (BMI) at baseline, medication-associated risk, and PRSs (BMI, schizophrenia, diabetes, and metabolic syndrome). An explorative GWAS analysis was performed on the same subjects and traits. PRSs for BMI (β = 3.78; p = 0.0041), schizophrenia (β = 5.38; p = 0.021) and diabetes type 2 (β = 13.4; p = 0.046) were significantly associated with AIWG. Other significant factors were sex, baseline BMI and medication. Compared to the model without genetic factors, the addition of PRSs for BMI, schizophrenia, and diabetes type 2 increased the goodness of fit by 6.5 %. The GWAS identified the association of three variants (rs10668573, rs10249381 and rs1988834) with AIWG at a genome-wide level of p < 1 · 10
. Using PRS for schizophrenia, BMI, and diabetes type 2 increased the explained variation of predicted weight gain, compared to a model without PRSs. For more precise results, PRSs derived from other traits (ideally AIWG) should be investigated. Potential risk variants identified in our GWAS need to be further investigated and replicated in independent samples.
Research into the genetic basis of bipolar disorder (BD) has reached a turning point. Genome-wide association studies (GWAS), encompassing several thousand samples, have produced replicated evidence ...for some novel susceptibility genes; however, the genetic variants implicated so far account for only a fraction of disease liability, a phenomenon not limited to psychiatric phenotypes but characteristic of all complex genetic traits studied to date. It appears that pure genomic approaches, such as GWAS alone, will not suffice to unravel the genetic basis of a complex illness like BD. Genomic approaches will need to be complemented by a variety of strategies, including phenomics, epigenomics, pharmacogenomics, and neurobiology, as well as the study of environmental factors. This review highlights the most promising findings from recent GWAS and candidate gene studies in BD. It furthermore sketches out a potential research framework integrating various lines of research into the molecular biological basis of BD.
Abstract We present the discovery and analysis of SN 2022oqm, a Type Ic supernova (SN) detected <1 day after the explosion. The SN rises to a blue and short-lived (2 days) initial peak. Early-time ...spectral observations of SN 2022oqm show a hot (40,000 K) continuum with high ionization C and O absorption features at velocities of 4000 km s −1 , while its photospheric radius expands at 20,000 km s −1 , indicating a pre-existing distribution of expanding C/O material. After ∼2.5 days, both the spectrum and light curves evolve into those of a typical SN Ic, with line velocities of ∼10,000 km s −1 , in agreement with the evolution of the photospheric radius. The optical light curves reach a second peak at t ≈ 15 days. By t = 60 days, the spectrum of SN 2022oqm becomes nearly nebular, displaying strong Ca ii and Ca ii emission with no detectable O i , marking this event as Ca-rich. The early behavior can be explained by 10 −3 M ⊙ of optically thin circumstellar material (CSM) surrounding either (1) a massive compact progenitor such as a Wolf–Rayet star, (2) a massive stripped progenitor with an extended envelope, or (3) a binary system with a white dwarf. We propose that the early-time light curve is powered by both the interaction of the ejecta with the optically thin CSM and shock cooling (in the massive star scenario). The observations can be explained by CSM that is optically thick to X-ray photons, is optically thick in the lines as seen in the spectra, and is optically thin to visible-light continuum photons that come either from downscattered X-rays or from the shock-heated ejecta. Calculations show that this scenario is self-consistent.
Lithium-treated patients often suffer from weight gain as a common adverse event. In an earlier investigation, we found an impact of two single-nucleotide polymorphisms (rs10487506 and rs2278815) at ...the leptin gene on weight gain but not on leptin protein levels in serum under lithium augmentation. A recent genome-wide association study identified a polymorphism at the leptin gene locus (rs10487505) associated with circulating leptin protein levels. To characterize potential effects of this variant in acute major depressive disorder, we investigated body mass indices from 180 lithium-augmented patients and serum concentrations of leptin protein from 89 patients using linear mixed model analyses and rs6979832, a proxy SNP of rs10487505. Body mass index was measured before and after 4 weeks of lithium augmentation, in a subsample also after 4 and 7 months. Leptin serum levels were measured before and during lithium augmentation. G-allele homozygotes of rs6979832 had a significantly lower body mass index increase during observation compared to A-allele hetero- and homozygotes. However, we found no influence on leptin serum levels. Joint analyses of rs6979832 with the previously investigated polymorphisms rs10487506 and rs2278815, and expressed quantitative trait data, suggest a complex interplay between SNP alleles at the leptin locus. These results strongly support our earlier findings that common genetic variation at the leptin gene locus may be involved in lithium augmentation-associated weight gain in major depressive disorder.
Abstract
Summary
Accurate clustering of mixed data, encompassing binary, categorical, and continuous variables, is vital for effective patient stratification in clinical questionnaire analysis. To ...address this need, we present longmixr, a comprehensive R package providing a robust framework for clustering mixed longitudinal data using finite mixture modeling techniques. By incorporating consensus clustering, longmixr ensures reliable and stable clustering results. Moreover, the package includes a detailed vignette that facilitates cluster exploration and visualization.
Availability and implementation
The R package is freely available at https://cran.r-project.org/package=longmixr with detailed documentation, including a case vignette, at https://cellmapslab.github.io/longmixr/.
Cancer cells display an increased plasticity in their lipid metabolism, which includes the conversion of palmitate to sapienate via the enzyme fatty acid desaturase 2 (FADS2). We find that FADS2 ...expression correlates with mammalian target of rapamycin (mTOR) signaling and sterol regulatory element-binding protein 1 (SREBP-1) activity across multiple cancer types and is prognostic in some cancer types. Accordingly, activating mTOR signaling by deleting tuberous sclerosis complex 2 (Tsc2) or overexpression of SREBP-1/2 is sufficient to increase FADS2 mRNA expression and sapienate metabolism in mouse embryonic fibroblasts (MEFs) and U87 glioblastoma cells, respectively. Conversely, inhibiting mTOR signaling decreases FADS2 expression and sapienate biosynthesis in MEFs with Tsc2 deletion, HUH7 hepatocellular carcinoma cells, and orthotopic HUH7 liver xenografts. In conclusion, we show that mTOR signaling and SREBP activity are sufficient to activate sapienate metabolism by increasing FADS2 expression. Consequently, targeting mTOR signaling can reduce sapienate metabolism in vivo.
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•FADS2 expression is prognostic in some cancers•FADS2 is a target of SREBP-1 and SREBP-2•SREBP activity and mTOR signaling regulate FADS2-mediated sapienate metabolism•Torin1 treatment reduces FADS2 expression and sapienate metabolism in xenografts
Triki et al. report that FADS2 expression is prognostic in some cancers and that FADS2-mediated sapienate metabolism is regulated by mTOR signaling. Mechanistically, FADS2 is a target of SREBP-1/2. Inhibition of mTOR or SREBP reduces FADS2 expression and sapienate metabolism in cancer cells and liver xenografts.
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