Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation

Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood. The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is a broad transcription regulator. It is essential in Drosophila, and haploinsufficiency of the human KANSL1 subunit results in the Koolen-de Vries syndrome. Here, we perform a genome-wide RNAi screen and identify the BET protein BRD4 as an evolutionary conserved co-factor of the NSL complex. Using Drosophila and mouse embryonic stem cells, we characterise a recruitment hierarchy, where NSL-deposited histone acetylation enables BRD4 recruitment for transcription of constitutively active genes. Transcriptome analyses in Koolen-de Vries patient-derived fibroblasts reveals perturbations with a cellular homeostasis signature that are evoked by the NSL complex/BRD4 axis. We propose that BRD4 represents a conserved bridge between the NSL complex and transcription activation, and provide a new perspective in the understanding of their functions in healthy and diseased states

Recognition of "mirror-image" DNA by small molecules

May the force be with you: “Mirror-image” hairpin polyamides distinguish the L enantiomer of DNA (L-DNA) in the presence of natural DNA (D-DNA). This specificity is investigated by a molecular force balance at a single-molecule level. The “DNA balance” allows the measurement of rupture forces of match/mismatch diastereomeric complexes in a single experiment

Recognition of "mirror-image" DNA by small molecules

May the force be with you: “Mirror-image” hairpin polyamides distinguish the L enantiomer of DNA (L-DNA) in the presence of natural DNA (D-DNA). This specificity is investigated by a molecular force balance at a single-molecule level. The “DNA balance” allows the measurement of rupture forces of match/mismatch diastereomeric complexes in a single experiment

Ultrastable cellulosome-adhesion complex tightens under load

Challenging environments have guided nature in the development of ultrastable protein complexes. Specialized bacteria produce discrete multi-component protein networks called cellulosomes to effectively digest lignocellulosic biomass. While network assembly is enabled by protein interactions with commonplace affinities, we show that certain cellulosomal ligand-receptor interactions exhibit extreme resistance to applied force. Here, we characterize the ligand-receptor complex responsible for substrate anchoring in the Ruminococcus flavefaciens cellulosome using single-molecule force spectroscopy and steered molecular dynamics simulations. The complex withstands forces of 600-750 pN, making it one of the strongest bimolecular interactions reported, equivalent to half the mechanical strength of a covalent bond. Our findings demonstrate force activation and inter-domain stabilization of the complex, and suggest that certain network components serve as mechanical effectors for maintaining network integrity. This detailed understanding of cellulosomal network components may help in the development of biocatalysts for production of fuels and chemicals from renewable plant-derived biomass

Inertial picobalance reveals fast mass fluctuations in mammalian cells

The regulation of size, volume and mass in living cells is physiologically important, and dysregulation of these parameters gives rise to many diseases. Cell mass is largely determined by the amount of water, proteins, lipids, carbohydrates and nucleic acids present in a cell, and is tightly linked to metabolism, proliferation and gene expression. Technologies have emerged in recent years that make it possible to track the masses of single suspended cells and adherent cells. However, it has not been possible to track individual adherent cells in physiological conditions at the mass and time resolutions required to observe fast cellular dynamics. Here we introduce a cell balance (a 'picobalance'), based on an optically excited microresonator, that measures the total mass of single or multiple adherent cells in culture conditions over days with millisecond time resolution and picogram mass sensitivity. Using our technique, we observe that the mass of living mammalian cells fluctuates intrinsically by around one to four per cent over timescales of seconds throughout the cell cycle. Perturbation experiments link these mass fluctuations to the basic cellular processes of ATP synthesis and water transport. Furthermore, we show that growth and cell cycle progression are arrested in cells infected with vaccinia virus, but mass fluctuations continue until cell death. Our measurements suggest that all living cells show fast and subtle mass fluctuations throughout the cell cycle. As our cell balance is easy to handle and compatible with fluorescence microscopy, we anticipate that our approach will contribute to the understanding of cell mass regulation in various cell states and across timescales, which is important in areas including physiology, cancer research, stem-cell differentiation and drug discovery

Assessment and Etiology of Attention Deficit Hyperactivity Disorder and Oppositional Defiant Disorder in Boys and Girls

Attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) are more common in boys than girls. In this paper, we investigated whether the prevalence differences are attributable to measurement bias. In addition, we examined sex differences in the genetic and environmental influences on variation in these behaviors. Teachers completed the Conners Teacher Rating Scale-Revised:Short version (CTRS-R:S) in a sample of 800 male and 851 female 7-year-old Dutch twins. No sex differences in the factor structure of the CTRS-R:S were found, implying the absence of measurement bias. The heritabilities for both ADHD and ODD were high and were the same in boys and girls. However, partly different genes are expressed in boys and girls

Sex differences in the Simon task help to interpret sex differences in selective attention.

In the last decade, a number of studies have reported sex differences in selective attention, but a unified explanation for these effects is still missing. This study aims to better understand these differences and put them in an evolutionary psychological context. 418 adult participants performed a computer-based Simon task, in which they responded to the direction of a left or right pointing arrow appearing left or right from a fixation point. Women were more strongly influenced by task-irrelevant spatial information than men (i.e., the Simon effect was larger in women, Cohen's d = 0.39). Further, the analysis of sex differences in behavioral adjustment to errors revealed that women slow down more than men following mistakes (d = 0.53). Based on the combined results of previous studies and the current data, it is proposed that sex differences in selective attention are caused by underlying sex differences in core abilities, such as spatial or verbal cognition

Sex matters during adolescence: Testosterone-related cortical thickness maturation differs between boys and girls

Age-related changes in cortical thickness have been observed during adolescence, including thinning in frontal and parietal cortices, and thickening in the lateral temporal lobes. Studies have shown sex differences in hormone-related brain maturation when boys and girls are age-matched, however, because girls mature 1-2 years earlier than boys, these sex differences could be confounded by pubertal maturation. To address puberty effects directly, this study assessed sex differences in testosterone-related cortical maturation by studying 85 boys and girls in a narrow age range and matched on sexual maturity. We expected that testosterone-by-sex interactions on cortical thickness would be observed in brain regions known from the animal literature to be high in androgen receptors. We found sex differences in associations between circulating testosterone and thickness in left inferior parietal lobule, middle temporal gyrus, calcarine sulcus, and right lingual gyrus, all regions known to be high in androgen receptors. Visual areas increased with testosterone in boys, but decreased in girls. All other regions were more impacted by testosterone levels in girls than boys. The regional pattern of sex-by-testosterone interactions may have implications for understanding sex differences in behavior and adolescent-onset neuropsychiatric disorders. © 2012 Bramen et al