Donated chemical probes for open science

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (https://openscienceprobes.sgc-frankfurt.de/). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project

Does adult ADHD interact with COMT val 158 met genotype to influence working memory performance?

Peer reviewedPostprin

Graduate students lend their voices : reflections on the 10th seminar in health and environmental education research

Graduate students were invited by their faculty advisors to attend the 10th Seminar in Health and Environmental Education Research. Afterward, they were encouraged to comment on their experiences, involvement, and positioning. Two main authors developed survey questions and retrieved, analyzed, and synthesized the responses of four other graduate students. The overall experience of attending an invitational research seminar evoked various ideas about graduate students’ present and future roles in research communities

ALMA Observations of the Physical and Chemical Conditions in Centaurus A

Centaurus A, with its gas-rich elliptical host galaxy, NGC 5128, is the nearest radio galaxy at a distance of 3.8 Mpc. Its proximity allows us to study the interaction between an active galactic nucleus, radio jets, and molecular gas in great detail. We present ALMA observations of low J transitions of three CO isotopologues, HCN, HCO$^{+}$, HNC, CN, and CCH toward the inner projected 500 pc of NGC 5128. Our observations resolve physical sizes down to 40 pc. By observing multiple chemical probes, we determine the physical and chemical conditions of the nuclear interstellar medium of NGC 5128. This region contains molecular arms associated with the dust lanes and a circumnuclear disk (CND) interior to the molecular arms. The CND is approximately 400 pc by 200 pc and appears to be chemically distinct from the molecular arms. It is dominated by dense gas tracers while the molecular arms are dominated by $^{12}$CO and its rare isotopologues. The CND has a higher temperature, elevated CN/HCN and HCN/HNC intensity ratios, and much weaker $^{13}$CO and C$^{18}$O emission than the molecular arms. This suggests an influence from the AGN on the CND molecular gas. There is also absorption against the AGN with a low velocity complex near the systemic velocity and a high velocity complex shifted by about 60 km s$^{-1}$. We find similar chemical properties between the CND in emission and both the low and high velocity absorption complexes implying that both likely originate from the CND. If the HV complex does originate in the CND, then that gas would correspond to gas falling toward the supermassive black hole

Radio continuum and X-ray emission from the most extreme far-IR-excess galaxy NGC 1377: An extremely obscured AGN revealed

Context. Galaxies which strongly deviate from the radio-far infrared (FIR) correlation are of great importance for studies of galaxy evolution as they may be tracing early, short-lived stages of starbursts and active galactic nuclei (AGNs). The most extreme FIR-excess galaxy NGC 1377 has long been interpreted as a young dusty starburst, but millimeter observations of CO lines revealed a powerful collimated molecular outflow which cannot be explained by star formation alone. Aims. This paper aims to determine the nature of the energy source in the nucleus of NGC 1377 and to study the driving mechanism of the collimated CO outflow. Methods. We present new radio observations of NGC 1377 at 1.5 and 10 GHz obtained with the Jansky Very Large Array (JVLA) and Chandra X-ray observations. The observations are compared to synthetic starburst models to constrain the properties of the central energy source. Results. We obtained the first detection of the cm radio continuum and X-ray emission in NGC 1377. We found that the radio emission is distributed in two components, one on the nucleus and another offset by 4?5 to the south-west. We confirm the extreme FIR-excess of the galaxy, with a qFIR ? 4.2, which deviates by more than 7? from the radio-FIR correlation. Soft X-ray emission is detected on the off-nucleus component. From the radio emission we estimated for a young (<10 Myr) starburst a star formation rate (SFR) of <0.1 M? yr-1. Such a SFR is not sufficient to power the observed IR luminosity and to drive the CO outflow. Conclusions. We found that a young starburst cannot reproduce all the observed properties of the nucleus of NGC 1377. We suggest that the galaxy may be harboring a radio-quiet, obscured AGN of 106M?, accreting at near-Eddington rates. We speculate that the off-nucleus component may be tracing an hot-spot in the AGN jet

Bromodomains as therapeutic targets

Acetylation of lysine residues is a post-translational modification with broad relevance to cellular signalling and disease biology. Enzymes that ‘write’ (histone acetyltransferases, HATs) and ‘erase’ (histone deacetylases, HDACs) acetylation sites are an area of extensive research in current drug development, but very few potent inhibitors that modulate the ‘reading process’ mediated by acetyl lysines have been described. The principal readers of ɛ-N-acetyl lysine (Kac) marks are bromodomains (BRDs), which are a diverse family of evolutionary conserved protein-interaction modules. The conserved BRD fold contains a deep, largely hydrophobic acetyl lysine binding site, which represents an attractive pocket for the development of small, pharmaceutically active molecules. Proteins that contain BRDs have been implicated in the development of a large variety of diseases. Recently, two highly potent and selective inhibitors that target BRDs of the BET (bromodomains and extra-terminal) family provided compelling data supporting targeting of these BRDs in inflammation and in an aggressive type of squamous cell carcinoma. It is likely that BRDs will emerge alongside HATs and HDACs as interesting targets for drug development for the large number of diseases that are caused by aberrant acetylation of lysine residues

Structural basis of fumarate hydratase deficiency

Fumarate hydratase catalyzes the stereospecific hydration across the olefinic double bond in fumarate leading to L-malate. The enzyme is expressed in mitochondrial and cytosolic compartments, and participates in the Krebs cycle in mitochondria, as well as in regulation of cytosolic fumarate levels. Fumarate hydratase deficiency is an autosomal recessive trait presenting as metabolic disorder with severe encephalopathy, seizures and poor neurological outcome. Heterozygous mutations are associated with a predisposition to cutaneous and uterine leiomyomas and to renal cancer. The crystal structure of human fumarate hydratase shows that mutations can be grouped into two distinct classes either affecting structural integrity of the core enzyme architecture, or are localized around the enzyme active site

The opaque heart of the galaxy IC 860: Analogous protostellar, kinematics, morphology, and chemistry

Compact Obscured Nuclei (CONs) account for a significant fraction of the population of luminous and ultraluminous infrared galaxies (LIRGs and ULIRGs). These galaxy nuclei are compact, with radii of 10-100 pc, with large optical depths at submm and far-infrared wavelengths, and characterized by vibrationally excited HCN emission. It is not known what powers the large luminosities of the CON host galaxies because of the extreme optical depths towards their nuclei. CONs represent an extreme phase of nuclear growth, hiding either a rapidly accreting supermassive black hole or an abnormal mode of star formation. Regardless of their power source, the CONs allow us to investigate the processes of nuclear growth in galaxies. Here we apply principal component analysis (PCA) tomography to high-resolution (000:06) ALMA observations at frequencies 245 to 265 GHz of the nearby CON (59 Mpc) IC 860. PCA is a technique to unveil correlation in the data parameter space, and we apply it to explore the morphological and chemical properties of species in our dataset. The leading principal components reveal morphological features in molecular emission that suggest a rotating, infalling disk or envelope, and an outflow analogous to those seen in Galactic protostars. One particular molecule of astrochemical interest is methanimine (CH2NH), a precursor to glycine, three transitions of which have been detected towards IC 860.We estimate the average CH2NH column density towards the nucleus of IC 860 to be _1017cm2, with an abundance exceeding 108 relative to molecular hydrogen, using the rotation diagram method and non-LTE radiative transfer models. This CH2NH abundance is consistent with those found in hot cores of molecular clouds in the Milky Way. Our analysis suggests that CONs are an important stage of chemical evolution in galaxies, that are chemically and morphologically similar to Milky Way hot cores

Retinol and Retinol Binding Protein 4 Levels and Cardiometabolic Disease Risk

Background: Despite mechanistic studies linking retinol and RBP4 (retinol binding protein 4) to the pathogenesis of cardiovascular diseases (CVD) and type 2 diabetes (T2D), epidemiological evidence is still conflicting. We investigated whether conflicting results of previous studies may be explained by differences in the association of retinol and RBP4 with cardiometabolic risk across subgroups with distinct sex, hypertension state, liver, or kidney function. Methods: We used case-cohorts nested in the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Potsdam cohort (N=27 548) comprising a random sample of participants (n=2500) and all physician-verified cases of incident CVD (n=508, median follow-up time 8.2 years) and T2D (n=820, median follow-up time 6.3 years). We estimated nonlinear and linear multivariable-adjusted associations between the biomarkers and cardiometabolic diseases by restricted cubic splines and Cox regression, respectively, testing potential interactions with hypertension, liver, and kidney function. Additionally, we performed 2-sample Mendelian Randomization analyses in publicly available data. Results: The association of retinol with cardiometabolic risk was modified by hypertension state (P interaction CVDP interaction T2D<0.001). Retinol was associated with lower cardiometabolic risk in participants with treated hypertension (hazard ratio(per SD) [95% CI]: CVD, 0.71 [0.56-0.90]; T2D, 0.81 [0.70-0.94]) but with higher cardiometabolic risk in normotensive participants (CVD, 1.32 [1.06-1.64]; T2D, 1.15 [0.98-1.36]). Our analyses also indicated a significant interaction between RBP4 and hypertension on CVD risk (P interaction=0.04). Regarding T2D risk, we observed a u-shaped association with RBP4 in women (P nonlinearity=0.01, P effect=0.02) and no statistically significant association in men. The biomarkers\u27 interactions with liver or kidney function were not statistically significant. Hypertension state-specific associations for retinol concentrations with cardiovascular mortality risk were replicated in National Health and Nutrition Examination Survey III. Conclusions: Our findings suggest a hypertension-dependent relationship between plasma retinol and cardiometabolic risk and complex interactions of RBP4 with sex and hypertension on cardiometabolic risk