Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci

We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; P(NSCLP) = 6.51 × 10(-11); homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84-3.16).     

Loss of Trim24 (Tif1alpha) gene function confers oncogenic activity to retinoic acid receptor alpha

Hepatocellular carcinoma (HCC) is a major cause of death worldwide. Here, we provide evidence that the ligand-dependent nuclear receptor co-regulator Trim24 (also known as Tif1alpha) functions in mice as a liver-specific tumor suppressor. In Trim24-null mice, hepatocytes fail to execute proper cell cycle withdrawal during the neonatal-to-adult transition and continue to cycle in adult livers, becoming prone to a continuum of cellular alterations that progress toward metastatic HCC. Using pharmacological approaches, we show that inhibition of retinoic acid signaling markedly reduces hepatocyte proliferation in Trim24-/- mice. We further show that deletion of a single retinoic acid receptor alpha (Rara) allele in a Trim24-null background suppresses HCC development and restores wild-type expression of retinoic acid-responsive genes in the liver, thus demonstrating that in this genetic background Rara expresses an oncogenic activity correlating with a dysregulation of the retinoic acid signaling pathway. Our results not only provide genetic evidence that Trim24 and Rara co-regulate hepatocarcinogenesis in an antagonistic manner but also suggest that aberrant activation of Rara is deleterious to liver homeostasis.     

The 'Higgs' amplitude mode at the two-dimensional superfluid/Mott insulator transition

Spontaneous symmetry breaking plays a key role in our understanding of nature. In relativistic quantum field theory, a broken continuous symmetry leads to the emergence of two types of fundamental excitation: massless Nambu-Goldstone modes and a massive 'Higgs' amplitude mode. An excitation of Higgs type is of crucial importance in the standard model of elementary particle physics, and also appears as a fundamental collective mode in quantum many-body systems. Whether such a mode exists in low-dimensional systems as a resonance-like feature, or whether it becomes overdamped through coupling to Nambu-Goldstone modes, has been a subject of debate. Here we experimentally find and study a Higgs mode in a two-dimensional neutral superfluid close to a quantum phase transition to a Mott insulating phase. We unambiguously identify the mode by observing the expected reduction in frequency of the onset of spectral response when approaching the transition point. In this regime, our system is described by an effective relativistic field theory with a two-component quantum field, which constitutes a minimal model for spontaneous breaking of a continuous symmetry. Additionally, all microscopic parameters of our system are known from first principles and the resolution of our measurement allows us to detect excited states of the many-body system at the level of individual quasiparticles. This allows for an in-depth study of Higgs excitations that also addresses the consequences of the reduced dimensionality and confinement of the system. Our work constitutes a step towards exploring emergent relativistic models with ultracold atomic gases.     

Open structure of the Ca2+ gating ring in the high-conductance Ca2+-activated K+ channel

High-conductance voltage- and Ca(2+)-activated K(+) channels function in many physiological processes that link cell membrane voltage and intracellular Ca(2+) concentration, including neuronal electrical activity, skeletal and smooth muscle contraction, and hair cell tuning. Like other voltage-dependent K(+) channels, Ca(2+)-activated K(+) channels open when the cell membrane depolarizes, but in contrast to other voltage-dependent K(+) channels, they also open when intracellular Ca(2+) concentrations rise. Channel opening by Ca(2+) is made possible by a structure called the gating ring, which is located in the cytoplasm. Recent structural studies have defined the Ca(2+)-free, closed, conformation of the gating ring, but the Ca(2+)-bound, open, conformation is not yet known. Here we present the Ca(2+)-bound conformation of the gating ring. This structure shows how one layer of the gating ring, in response to the binding of Ca(2+), opens like the petals of a flower. The degree to which it opens explains how Ca(2+) binding can open the transmembrane pore. These findings present a molecular basis for Ca(2+) activation of K(+) channels and suggest new possibilities for targeting the gating ring to treat conditions such as asthma and hypertension.     

Double deficiency of cathepsins B and L results in massive secretome alterations and suggests a degradative cathepsin-MMP axis

Endolysosomal cysteine cathepsins functionally cooperate. Cathepsin B (Ctsb) and L (Ctsl) double-knockout mice die 4 weeks after birth accompanied by (autophago-) lysosomal accumulations within neurons. Such accumulations are also observed in mouse embryonic fibroblasts (MEFs) deficient for Ctsb and Ctsl. Previous studies showed a strong impact of Ctsl on the MEF secretome. Here we show that Ctsb alone has only a mild influence on extracellular proteome composition. Protease cleavage sites dependent on Ctsb were identified by terminal amine isotopic labeling of substrates (TAILS), revealing a prominent yet mostly indirect impact on the extracellular proteolytic cleavages. To investigate the cooperation of Ctsb and Ctsl, we performed a quantitative secretome comparison of wild-type MEFs and Ctsb ^?/? Ctsl ^?/? MEFs. Deletion of both cathepsins led to drastic alterations in secretome composition, highlighting cooperative functionality. While many protein levels were decreased, immunodetection corroborated increased levels of matrix metalloproteinase (MMP)-2. Re-expression of Ctsl rescues MMP-2 abundance. Ctsl and to a much lesser extent Ctsb are able to degrade MMP-2 at acidic and neutral pH. Addition of active MMP-2 to the MEF secretome degrades proteins whose levels were also decreased by Ctsb and Ctsl double deficiency. These results suggest a degradative Ctsl—MMP-2 axis, resulting in increased MMP-2 levels upon cathepsin deficiency with subsequent degradation of secreted proteins such as collagen α-1 (I).     

Cognitive? Science?

Cognitive Science is a promising field of research that deals with one of the most fundamental questions ever: how do beings know? However, despite the long and extensive tradition of the field it has not yet become an area of knowledge with scientific identity. This is primarily due to three reasons: the lack of boundaries in defining the object of study, i.e. cognition, the lack of a precise, robust and consistent scientific methodology and results, and the inner problems derived from its interdisciplinary nature. This paper presents a background review, a theoretical frame and a humble reflection on these topics in order to arouse the internal debate among readers once more.     

A high-resolution map of human evolutionary constraint using 29 mammals

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ～4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ～60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.