Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression

Alterations in the folate pathway have been related to both major depression and cognitive inflexibility; however, they have not been investigated in the genetic background of ruminative response style, which is a form of perseverative cognition and a risk factor for depression. In the present study, we explored the association of rumination (measured by the Ruminative Responses Scale) with polymorphisms of two distinct folate pathway genes, MTHFR rs1801133 (C677T) and MTHFD1L rs11754661, in a combined European white sample from Budapest, Hungary (n=895) and Manchester, United Kingdom (n=1309). Post hoc analysis investigated whether the association could be replicated in each of the two samples, and the relationship between folate pathway genes, rumination, lifetime depression and Brief Symptom Inventory depression score. Despite its functional effect on folate metabolism, the MTHFR rs1801133 showed no effect on rumination. However, the A allele of MTHFD1L rs11754661 was significantly associated with greater rumination, and this effect was replicated in both the Budapest and Manchester samples. In addition, rumination completely mediated the effects of MTHFD1L rs11754661 on depression phenotypes. These findings suggest that the MTHFD1L gene, and thus the C1-THF synthase enzyme of the folate pathway localized in mitochondria, has an important effect on the pathophysiology of depression through rumination, and maybe via this cognitive intermediate phenotype on other mental and physical disorders. Further research should unravel whether the reversible metabolic effect of MTHFD1L is responsible for increased rumination or other long-term effects on brain development

Therapeutic target-site variability in α1-antitrypsin characterized at high resolution

The intrinsic propensity of [alpha]1-antitrypsin to undergo conformational transitions from its metastable native state to hyperstable forms provides a motive force for its antiprotease function. However, aberrant conformational change can also occur via an intermolecular linkage that results in polymerization. This has both loss-of-function and gain-of-function effects that lead to deficiency of the protein in human circulation, emphysema and hepatic cirrhosis. One of the most promising therapeutic strategies being developed to treat this disease targets small molecules to an allosteric site in the [alpha]1-antitrypsin molecule. Partial filling of this site impedes polymerization without abolishing function. Drug development can be improved by optimizing data on the structure and dynamics of this site. A new 1.8 Å resolution structure of [alpha]1-antitrypsin demonstrates structural variability within this site, with associated fluctuations in its upper and lower entrance grooves and ligand-binding characteristics around the innermost stable enclosed hydrophobic recess. These data will allow a broader selection of chemotypes and derivatives to be tested in silico and in vitro when screening and developing compounds to modulate conformational change to block the pathological mechanism while preserving function

Computer simulation of syringomyelia in dogs

Syringomyelia is a pathological condition in which fluid-filled cavities (syringes) form and expand in the spinal cord. Syringomyelia is often linked with obstruction of the craniocervical junction and a Chiari malformation, which is similar in both humans and animals. Some brachycephalic toy breed dogs such as Cavalier King Charles Spaniels (CKCS) are particularly predisposed. The exact mechanism of the formation of syringomyelia is undetermined and consequently with the lack of clinical explanation, engineers and mathematicians have resorted to computer models to identify possible physical mechanisms that can lead to syringes. We developed a computer model of the spinal cavity of a CKCS suffering from a large syrinx. The model was excited at the cranial end to simulate the movement of the cerebrospinal fluid (CSF) and the spinal cord due to the shift of blood volume in the cranium related to the cardiac cycle. To simulate the normal condition, the movement was prescribed to the CSF. To simulate the pathological condition, the movement of CSF was blocked

Changes in the neural correlates of self-blame following mindfulness-based cognitive therapy in remitted depressed participants

Mindfulness-Based-Cognitive-Therapy (MBCT) reduces vulnerability for relapse into depression by helping individuals to counter tendencies to engage in maladaptive repetitive patterns of thinking and respond more compassionately to negative self-judgment. However, little is known about the neural correlates underlying these effects. To elucidate these correlates, we investigated fMRI brain activation during a task eliciting feelings of blaming oneself or others. Sixteen participants in remission from major depressive disorder (MDD) completed fMRI assessments before and after MBCT, alongside self-reported levels of self-compassion, mindfulness, and depression symptoms. Analyses of self-blame versus other-blame contrasts showed a reduction in activation in the bilateral dorsal anterior cingulate/medial superior frontal gyrus after MBCT compared to baseline. Further, exploratory analyses showed that increases in self-kindness after MBCT correlated with reduced activation in the posterior cingulate cortex (PCC)/precuneus in self-blame versus rest contrasts. These findings suggest that MBCT is associated with a reduction in activations in cortical midline regions to self-blame which may be mediated by increasing self-kindness. However, this is a small, uncontrolled study with 16 participants and therefore our results will need confirmation in a controlled study

Unemployment in Greece: Evidence from Greek regions using panel unit root tests

The purpose of the paper is to examine the nature of Greek regional unemployment. The paper contributes to the literature assessing the stochastic properties of Greek unemployment rate in the context of the Greek regions by relying on various univariate and panel unit root tests. In particular, recently developed and more powerful panel unit-root tests that control for structural breaks, heterogeneity and cross-sectional dependence in the panel are employed. The results show that in all cases, after taking into account the fact that regional unemployment rates in Greece are subject to a structural break, the null hypothesis of a unit root is not rejected, indicating that the Greek regional unemployment series are non-stationary with the presence of a structural break