Med5(Nut1) and Med17(Srb4) Are Direct Targets of Mediator Histone H4 Tail Interactions

The Mediator complex transmits activation signals from DNA bound transcription factors to the core transcription machinery. In addition to its canonical role in transcriptional activation, recent studies have demonstrated that S. cerevisiae Mediator can interact directly with nucleosomes, and their histone tails. Mutations in Mediator subunits have shown that Mediator and certain chromatin structures mutually impact each other structurally and functionally in vivo. We have taken a UV photo cross-linking approach to further delineate the molecular basis of Mediator chromatin interactions and help determine whether the impact of certain Mediator mutants on chromatin is direct. Specifically, by using histone tail peptides substituted with an amino acid analog that is a UV activatible crosslinker, we have identified specific subunits within Mediator that participate in histone tail interactions. Using Mediator purified from mutant yeast strains we have evaluated the impact of these subunits on histone tail binding. This analysis has identified the Med5 subunit of Mediator as a target for histone tail interactions and suggests that the previously observed effect of med5 mutations on telomeric heterochromatin and silencing is direct

Sp6 and Sp8 transcription factors control AER formation and dorsal-ventral patterning in limb development

The formation and maintenance of the apical ectodermal ridge (AER) is critical for the outgrowth and patterning of the vertebrate limb. The induction of the AER is a complex process that relies on integrated interactions among the Fgf, Wnt, and Bmp signaling pathways that operate within the ectoderm and between the ectoderm and the mesoderm of the early limb bud. The transcription factors Sp6 and Sp8 are expressed in the limb ectoderm and AER during limb development. Sp6 mutant mice display a mild syndactyly phenotype while Sp8 mutants exhibit severe limb truncations. Both mutants show defects in AER maturation and in dorsal-ventral patterning. To gain further insights into the role Sp6 and Sp8 play in limb development, we have produced mice lacking both Sp6 and Sp8 activity in the limb ectoderm. Remarkably, the elimination or significant reduction in Sp6;Sp8 gene dosage leads to tetra-amelia; initial budding occurs, but neither Fgf8 nor En1 are activated. Mutants bearing a single functional allele of Sp8 (Sp6-/-;Sp8+/-) exhibit a split-hand/foot malformation phenotype with double dorsal digit tips probably due to an irregular and immature AER that is not maintained in the center of the bud and on the abnormal expansion of Wnt7a expression to the ventral ectoderm. Our data are compatible with Sp6 and Sp8 working together and in a dose-dependent manner as indispensable mediators of Wnt/βcatenin and Bmp signaling in the limb ectoderm. We suggest that the function of these factors links proximal-distal and dorsal-ventral patterning

As cold as a fish? Relationships between the Dark Triad personality traits and affective experience during the day: A day reconstruction study

The Dark Triad of personality is a cluster of three socially aversive personality traits: Machiavellianism, narcissism and psychopathy. These traits are associated with a selfish, aggressive and exploitative interpersonal strategy. The objective of the current study was to establish relationships between the Dark Triad traits (and their dimensions) and momentary affect. Machiavellianism, grandiose narcissism, vulnerable narcissism and the dimensions of the Triarchic model of psychopathy (namely, boldness, meanness and disinhibition) were examined. We used the Day Reconstruction Method, which is based on reconstructing affective states experienced during the previous day. The final sample consisted of 270 university students providing affective ratings of 3047 diary episodes. Analyses using multilevel modelling showed that only boldness had a positive association with positive affective states and affect balance, and a negative association with negative affective states. Grandiose narcissism and its sub-dimensions had no relationship with momentary affect. The other dark traits were related to negative momentary affect and/or inversely related to positive momentary affect and affect balance. As a whole, our results empirically demonstrated distinctiveness of the Dark Triad traits in their relationship to everyday affective states. These findings are not congruent with the notion that people with the Dark Triad traits, who have a dispositional tendency to manipulate and exploit others, are generally cold and invulnerable to negative feelings. The associations between the Dark Triad and momentary affect were discussed in the contexts of evolutionary and positive psychology, in relation to the role and adaptive value of positive and negative emotions experienced by individuals higher in Machiavellianism, narcissism and psychopathy

Normal and abnormal development of the aortic wall and valve: correlation with clinical entities

Dilation of the wall of the thoracic aorta can be found in patients with a tricuspid (TAV) as well as a bicuspid aortic valve (BAV) with and without a syndromic component. BAV is the most common congenital cardiovascular malformation, with a population prevalence of 0.5–2 %. The clinical course is often characterised by aneurysm formation and in some cases dissection. The non-dilated aortic wall is less well differentiated in all BAV as compared with TAV, thereby conferring inherent developmental susceptibility. Furthermore, a turbulent flow, caused by the inappropriate opening of the bicuspid valve, could accelerate the degenerative process in the aortic wall. However, not all patients with bicuspidy develop clinical complications during their life. We postulate that the increased vulnerability for aortic complications in a subset of patients with BAV is caused by a defect in the early development of the aorta and aortic valve. This review discusses histological and molecular genetic aspects of the normal and abnormal development of the aortic wall and semilunar valves. Aortopathy associated with BAV could be the result of a shared developmental defect during embryogenesis

Crim1 Haploinsufficiency Causes Defects In Eye Development In Human And Mouse

Colobomatous macrophthalmia with microcornea syndrome (MACOM, Online Mendelian Inheritance in Man (OMIM) 602499) is an autosomal dominantly inherited malformation of the eye, which is characterized by microcornea with increased axial length, coloboma of the iris and of the optic disc, and severe myopia. We performed whole-exome sequencing (WES) in two affected individuals from the 2p23-p16-linked MACOM family, which includes 13 affected individuals in 3 generations. As no shared novel variation was found on the linked haplotype, we performed copy number variation (CNV) analysis by comparing the coverage of all exons in the WES data sets of the 2 patients with the coverage of 26 control exomes. We identified a heterozygous deletion predicted to span 22 kb including exons 14-17 of CRIM1 (cysteine-rich transmembrane bone morphogenetic protein (BMP) regulator 1). Quantitative PCR (qPCR) analysis confirmed the deletion, which was present in 11 affected individuals. Split-read analysis of WES data followed by breakpoint PCR and Sanger sequencing determined both breakpoints flanked by a 4-bp microhomology (CTTG). In the mouse, Crim1 is a growth-factor-binding protein with pleiotropic roles in the development of multiple organs, including the eye. To investigate the role of Crim1 during eye development in mice, we crossed a Crim1(flox) mouse line with the Ap2 alpha-cre mouse line, which expresses Cre in the head surface ectoderm. Strikingly, we observed alterations of eye development in homozygous mice leading to severe anatomical and morphological changes overlapping with the anomalies observed in MACOM patients. Taken together, these findings identify CRIM1 as the causative gene for MACOM syndrome and emphasize the importance of CRIM1 in eye development.Wo

IL-6, but not TNF-α, response to alcohol cues and acute consumption associated with neural cue reactivity, craving, and future drinking in binge drinkers

Objective and design: Preclinical studies suggest learned immune system responses to alcohol cues and consumption may contribute to alcohol's pharmacodynamic properties and/or Alcohol Use Disorder (AUD) pathogenesis. Mechanistically, these immune alterations may be associated with increased craving and alcohol consumption, both acutely and over time. We sought to characterize this relationship in a randomized, counter-balanced, crossover neuroimaging experiment which took place between June 2020–November 2021. Methods: Thirty-three binge drinkers (BD) and 31 non-binge, social drinkers (SD), matched for demographic and psychological variables, were exposed to alcohol cues and water cues in two separate 7 T functional magnetic resonance imaging (fMRI) scans. Each scan was followed by the Alcohol Taste Test (ATT) of implicit motivation for acute alcohol. Craving measures and blood cytokine levels were collected repeatedly during and after scanning to examine the effects of alcohol cues and alcohol consumption on craving levels, Tumor necrosis factor alpha (TNF-α), and Interleukin 6 (IL-6) levels. A post-experiment one-month prospective measurement of participants’ “real world” drinking behavior was performed to approximate chronic effects. Results: BD demonstrated significantly higher peak craving and IL-6 levels than SD in response to alcohol cues and relative to water cues. Ventromedial Prefrontal Cortex (VmPFC) signal change in the alcohol-water contrast positively related to alcohol cue condition craving and IL-6 levels, relative to water cue condition craving and IL-6 levels, in BD only. Additionally, peak craving and IL-6 levels were each independently related to ATT alcohol consumption and the number of drinks consumed in the next month for BD, again after controlling for craving and IL-6 repones to water cues. However, TNF-α release in the alcohol cue condition was not related to craving, neural activation, IL-6 levels, immediate and future alcohol consumption in either group after controlling for water cue condition responses. Conclusions: In sum, BD show greater craving and IL-6 release in the alcohol cue condition than SD, both of which were associated with prefrontal cue reactivity, immediate alcohol consumption, and future alcohol consumption over the subsequent 30 days. Alcohol associated immune changes and craving effects on drinking behavior may be independent of one another or may be indicative of a common pathway by which immune changes in BD could influence motivation to consume alcohol. Trial registration: Clinical Trials NCT04412824