561975 research outputs found
Sort by
Brain age in conduct disorder: A mega-analysis of the ENIGMA antisocial behavior working group
No full textConduct disorder (CD) is the leading global cause of mental health burden in children and adolescents and has recently been hypothesized to be a neurodevelopmental disorder. Although prior research has identified neuroanatomical differences associated with CD, it remains unclear whether these differences reflect atypical brain development. Here, we investigated the difference between an individual’s brain age and chronological age as a proxy for variations in brain maturation. Using a pretrained model, we estimated brain age from structural neuroimaging data obtained from 1,119 youth with CD and 1,183 typically developing controls across 14 international cohorts participating in the ENIGMA-Antisocial Behavior Working Group. Youth with CD exhibited a statistically robust but small acceleration in brain age compared to typically developing youth (around 0.50 years), which was restricted to the adolescence-onset subtype of the disorder. Our large-scale, coordinated analysis provides the first evidence of accelerated neurodevelopment as a potential mechanism underlying CD.Competing Interest StatementAAM is the cofounder of the 501(c)(3) non-profit organization Psychopathy Is. ALWB received honorarium from Elsevier Inc for work as Associate Editor in Neuroimage. BF received educational speaking fees and travel support from Medice. CA has been a consultant to or has received honoraria or grants from Abbot, Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion, Takeda, and Teva. CMF receives royalties for books on ADHD, autism spectrum disorder, and depression. She received speakers fees for talks on mental disorders by clinical, public and teaching organisations in 2023 and 2024. She worked as consultant for the German Institute for Quality and Efficiency in Health Care (Institut fur Qualitat und Wirtschaftlichkeit im Gesundheitswesen, IQWiG) in 2023. CS receives royalties for a book on aggression. DGS receives royalties from Guilford Press for a treatment manual on cognitive behavioral therapy for anger and aggression in children; the present work is unrelated to this relationship. EJSS-B has received speaker fees from Medice and Takeda and research support from QBTech. LP is currently an employee of Biogen (Cambridge, MA, USA) but the work and the data presented in this manuscript are not related to his current functions at Biogen. All other authors declare no competing interests. NMR received honoraria and speaker fees for public talks on brain development, learning, and wellbeing and serves on the board of the Citizen Science Center Zurich and the FENS Kavli Network of Excellence. SADB has received speaker fees from the Child Mental Health Centre and the Centre for Integrated Molecular Brain Imaging. TB served in an advisory or consultancy role for eye level, Infectopharm, Medice, Neurim Pharmaceuticals, Oberberg GmbH and Takeda; received conference support or speakers fees from Janssen-Cilag, Medice, and Takeda; and received royalties from Hogrefe, Kohlhammer, CIP Medien, and Oxford University Press; the present work is unrelated to these relationships. The other authors report no potential conflicts of interest
Investigation of the Na-Ga Phase Diagram
No full textThe Na-Ga phase diagram was reinvestigated by heat-flux differential scanning calorimetry (HF-DSC) and powder X-ray diffraction (PXRD). The most sodium-rich phase, Na22Ga39, melts congruently (549(2) degrees C), while Na7Ga13 (545(2) degrees C), Na2Ga7 (501(2) degrees C), and NaGa4 (495(2) degrees C) decompose peritectically. In the sodium-rich region, a monotectic reaction between Na22Ga39 and melt occurs at 495(2) degrees C. The critical temperature of the liquid two-phase region was estimated to 523(2) degrees C. The subtle differences in the decomposition temperatures of neighboring phases were resolved by differential thermal analysis using a mutual sample reference method
Real-time imaging of rotation during synthesis by the replisome
No full textDuring chromosome replication, unwinding by the helicase and synthesis by the polymerases can lead to overwinding and supercoiling of DNA. The mechanical consequences of these events and resulting local dynamics at the replication fork are not well understood. To address these issues, we developed a transverse DNA flow-stretching approach to spatially resolve the parental, leading, and lagging strands in real time. Using bacteriophage T7 as a model system, this approach revealed bursts of high-speed replisome rotation that support continuous DNA synthesis. Unexpectedly, excessive rotation does not reduce replisome speed, but increases pausing, reduces processivity, and increases the number of polymerases. Together, our observations reveal intrinsic pathways to overcome challenges posed by unfavorable DNA topologies during DNA replication
Decolonising expert evidence in international law? Cultural and environmental rights’ litigation before the Inter-American Court of Human Rights
No full textPiercing the veil of the panel: The power of the justice referee in the German Constitutional Court
No full textMonovalent pseudo-natural products supercharge degradation of IDO1 by its native E3 KLHDC3
No full textTargeted protein degradation modulates protein function beyond the inhibition of enzyme activity or protein-protein interactions. Most degrader drugs function by directly mediating the proximity between a neosubstrate and a hijacked E3 ligase. Here we identify pseudo-natural products derived from (-)-myrtanol, termed iDegs, that inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs boost IDO1 ubiquitination and degradation by the cullin-RING E3 ligase CRL2KLHDC3, which we identified to natively mediate ubiquitin-mediated degradation of IDO1. Therefore, iDegs increase IDO1 turnover using the native proteolytic pathway. In contrast to clinically explored IDO1 inhibitors, iDegs reduce the formation of kynurenine by both inhibition and induced degradation of the enzyme and thus also modulate the non-enzymatic functions of IDO1. This unique mechanism of action may open up alternative therapeutic opportunities for the treatment of cancer beyond classical inhibition of IDO1
Fused 3D boron heterocycles via EnT catalysis : synthesis, modification and validation as beta-lactamase inhibitors
No full textThe installation of a boron unit into bioactive scaffolds continues to unlock novel modes of molecular recognition in drug discovery. As such, de novo strategies to access 3D boron-containing frameworks, that modulate the intrinsic reactivity at boron, are being intensively pursued. Herein, we report a visible light-mediated energy transfer (EnT) catalysis strategy that enables the [2 + 2] cycloaddition of boron-containing heterocycles to construct 3D frameworks with high structural complexity. Leveraging both inter- and intramolecular cycloadditions, a suite of angularly fused boron heterocycles was accessed, offering enhanced steric shielding and modular handles for additional interactions. A boron deletion strategy permits the synthesis of benzofuran scaffolds, otherwise inaccessible via direct EnT. Crucially, the resulting 3D architectures mimic structural motifs found in the potent β-lactamase inhibitor Xeruborbactam. The biological relevance of these frameworks was validated by NMR titration, pKa analysis, and co-crystallisation with serine β-lactamase CTX-M-14, revealing enantiospecific binding and a well-defined hydrogen bonding network. These results establish a versatile platform for the synthesis of functionalised boron heterocycles with direct translational potential in medicinal chemistry
Deep evolutionary conservation of a sex-determining locus without sequence homology
No full textSex determination is fundamental to eukaryotic life, yet its molecular basis varies widely across the tree of life. In most animal clades, sex-determining mechanisms are highly diverse and evolve rapidly. Here, we identify an exception in aculeate Hymenoptera, an ancient and diverse clade of haplodiploid insects that includes ants, bees, and stinging wasps. By integrating comparative genomics across Hymenoptera with genetic mapping in bumblebees and hornets, we reveal that the ANTSR locus, a multiallelic noncoding locus, has been maintained for over 150 My as the primary instructive signal for female development. This locus is located in a conserved synteny block that originated at the base of Aculeata and functions as a highly polymorphic, zygosity-based sex determiner, with only heterozygous individuals developing as females across lineages. Despite its deep evolutionary conservation, this sex locus shows no detectable sequence homology among lineages. These findings demonstrate that an essential noncoding locus can retain its function over deep evolutionary time without sequence conservation. More broadly, our results highlight haplodiploid insects as a powerful model for studying the evolution of sex determination mechanisms beyond those linked to sex chromosomes
Coupled climate-ice sheet simulations reveal novel teleconnection between Northern Hemisphere ice sheets and the Antarctic ice sheet
No full textFirst Observation of CP Violation and Measurement of Polarization in B<sup>+</sup> →p(770)<sup>0</sup>K*(892)<sup>+</sup> Decays
No full textAn amplitude analysis of the B⁺ → (π⁺π⁻)(KS⁰ π⁺) decay is performed in the mass regions 0.30 π⁺π⁻ KS⁰ π⁺ CP = 0.507 ± 0.062 (stat) ± 0.017 (syst) and the CP-averaged longitudinal polarization fraction of fL = 0.720 ± 0.028 (stat) ± 0.009 (syst). The measurements help to shed light on the polarization puzzle of B mesons decaying to two vector mesons