Rotational spectrum of cis–cis HOONO

The pure rotational spectrum of cis-cis peroxynitrous acid, HOONO, has been observed. Over 220 transitions, sampling states up to J(')=67 and K-a(')=31, have been fitted with an rms uncertainty of 48.4 kHz. The experimentally determined rotational constants agree well with ab initio values for the cis-cis conformer, a five-membered ring formed by intramolecular hydrogen bonding. The small, positive inertial defect Delta=0.075667(60) amu A(2) and lack of any observable torsional splittings in the spectrum indicate that cis-cis HOONO exists in a well-defined planar structure at room temperature

Rotational spectroscopy and dipole moment of cis-cis HOONO and DOONO

The rotational spectrum of cis-cis HOONO has been studied over a broad range of frequencies, 13–840 GHz, using pulsed beam Fourier-transform microwave spectroscopy and room-temperature flow cell submillimeter spectroscopy. The rotational spectrum of the deuterated isotopomer, cis-cis DOONO, has been studied over a subset of this range, 84–640 GHz. Improved spectroscopic constants have been determined for HOONO, and the DOONO spectrum is analyzed for the first time. Weak-field Stark effect measurements in the region of 84–110 GHz have been employed to determine the molecular dipole moments of cis-cis HOONO [µa=0.542(8) D,µb=0.918(15) D,µ=1.07(2) D] and DOONO [µa=0.517(9) D,µb=0.930(15) D,µ=1.06(2) D]. The quadrupole coupling tensor in the principal inertial axis system for the 14N nucleus has been determined to be chiaa=1.4907(25) MHz,chibb=–4.5990(59) MHz,chiab=3.17(147) MHz, and chicc=3.1082(59) MHz. Coordinates of the H atom in the center-of-mass frame have been determined with use of the Kraitchman equations, |aH|=0.516 Å and |bH|=1.171 Å. The inertial defects of HOONO and DOONO are consistent with a planar equilibrium structure with significant out-of-plane H atom torsional motion. Comparisons of the present results are made to ab initio calculations

HI studies of the Sculptor group galaxies. VIII. The background galaxies: NGC 24 and NGC 45

In order to complete our HI survey of galaxies in the Sculptor group area, VLA observations of NGC 24 and NGC 45 are presented. These two galaxies of similar magnitude M_B ~ -17.4 lie in the background of the Sculptor group and are low surface brightness galaxies, especially NGC 45. The HI distribution and kinematics are regular for NGC 24 while NGC 45 exhibits a kinematical twist of its major axis. A tilted-ring model shows that the position angle of the major axis changes by ~25 degrees. A best-fit model of their mass distribution gives mass-to-light ratios for the stellar disk of 2.5 and 5.2 for NGC 24 and NGC 45 respectively. These values are higher than the ones expected from stellar population synthesis models. Despite the large dark matter contribution, the galaxy mass is still dominated by the stellar component in their very inner regions. These high mass-to-light ratios are typical of what is seen in low surface brightness galaxies and may indicate that, in those galaxies, disks are far from the maximum disk case. The halo parameters derived from the best-fit models are thus lower limits.Comment: 23 pages, 10 figures, accepted for publication in The Astronomical Journa

Dermal fibroblasts from patients with Parkinson’s disease have normal GCase activity and autophagy compared to patients with PD and GBA mutations

Background: Recently, the development of Parkinson’s disease (PD) has been linked to a number of genetic risk factors, of which the most common is glucocerebrosidase (GBA) mutations. Methods: We investigated PD and Gaucher Disease (GD) patient derived skin fibroblasts using biochemistry assays. Results: PD patient derived skin fibroblasts have normal glucocerebrosidase (GCase) activity, whilst patients with PD and GBA mutations have a selective deficit in GCase enzyme activity and impaired autophagic flux. Conclusions: This data suggests that only PD patients with a GBA mutation have altered GCase activity and autophagy, which may explain their more rapid clinical progression.We are grateful to an NIHR award of a Biomedical Research Centre to Addenbrookes Hospital and the University of Cambridge. We are also grateful to the Rosetrees Trust, the WT-MRC Stem Cell Institute and the Canadian Institutes of Health Research (CIHR) fellowship (358492) for the funding for this work

Gender specific factors contributing to cognitive resilience in APOE ɛ4 positive older adults in a population-based sample

Although APOE ɛ4 has been identified as the strongest genetic risk factor for Alzheimer’s Disease, there are some APOE ɛ4 carriers who do not go on to develop Alzheimer’s disease or cognitive impairment. This study aims to investigate factors contributing to this “resilience” separately by gender. Data were drawn from APOE ɛ4 positive participants who were aged 60 + at baseline in the Personality and Total Health Through Life (PATH) Study (N = 341, Women = 46.3%). Participants were categorised into “resilient” and “non-resilient” groups using Latent Class Analysis based on their cognitive impairment status and cognitive trajectory across 12 years. Logistic regression was used to identify the risk and protective factors that contributed to resilience stratified by gender. For APOE ɛ4 carriers who have not had a stroke, predictors of resilience were increased frequency of mild physical activity and being employed at baseline for men, and increased number of mental activities engaged in at baseline for women. The results provide insights into a novel way of classifying resilience among APOE ɛ4 carriers and risk and protective factors contributing to resilience separately for men and women

Laboratory Characterization and Astrophysical Detection of Vibrationally Excited States of Vinyl Cyanide in Orion-KL

New laboratory data of CH$_2$CHCN (vinyl cyanide) in its ground and vibrationally excited states at the microwave to THz domain allow searching for these excited state transitions in the Orion-KL line survey. Frequency-modulated spectrometers combined into a single broadband 50-1900 GHz spectrum provided measurements of CH$_2$CHCN covering a spectral range of 18-1893 GHz, whose assignments was confirmed by Stark modulation spectra in the 18-40 GHz region and by ab-initio anharmonic force field calculations. For analyzing the emission lines of CH$_2$CHCN species detected in Orion-KL we used the excitation and radiative transfer code (MADEX) at LTE conditions. The rotational transitions of the ground state of this molecule emerge from four cloud components of hot core nature which trace the physical and chemical conditions of high mass star forming regions in the Orion-KL Nebula. The total column density of CH$_2$CHCN in the ground state is (3.0$\pm$0.9)x10$^{15}$ cm$^{-2}$. We report on the first interstellar detection of transitions in the v10=1/(v11=1,v15=1) dyad in space, and in the v11=2 and v11=3 states in Orion-KL. The lowest energy vibrationally excited states of vinyl cyanide such as v11=1 (at 328.5 K), v15=1 (at 478.6 K), v11=2 (at 657.8 K), the v10=1/(v11=1,v15=1) dyad (at 806.4/809.9 K), and v11=3 (at 987.9 K) are populated under warm and dense conditions, so they probe the hottest parts of the Orion-KL source. Column density and rotational and vibrational temperatures for CH$_2$CHCN in their ground and excited states, as well as for the isotopologues, have been constrained by means of a sample of more than 1000 lines in this survey. Moreover, we present the detection of methyl isocyanide (CH$_3$NC) for the first time in Orion-KL and a tentative detection of vinyl isocyanide (CH$_2$CHNC) and give column density ratios between the cyanide and isocyanide isomers.Comment: 46 pages, 22 figures, 14 tables, 9 online table

Structure-Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1.

TLE1 is an oncogenic transcriptional co-repressor that exerts its repressive effects through binding of transcription factors. Inhibition of this protein-protein interaction represents a putative cancer target, but no small-molecule inhibitors have been published for this challenging interface. Herein, the structure-enabled design and synthesis of a constrained peptide inhibitor of TLE1 is reported. The design features the introduction of a four-carbon-atom linker into the peptide epitope found in many TLE1 binding partners. A concise synthetic route to a proof-of-concept peptide, cycFWRPW, has been developed. Biophysical testing by isothermal titration calorimetry and thermal shift assays showed that, although the constrained peptide bound potently, it had an approximately five-fold higher Kd than that of the unconstrained peptide. The co-crystal structure suggested that the reduced affinity was likely to be due to a small shift of one side chain, relative to the otherwise well-conserved conformation of the acyclic peptide. This work describes a constrained peptide inhibitor that may serve as the basis for improved inhibitors

A Manifesto for project management research

Project management research has evolved over the past five decades and is now a mature disciplinary field investigating phenomena of interest to academics, practitioners and policymakers. Studies of projects and project management practices are theoretically rich and scientifically rigorous. They are practically relevant and impactful when addressing the pursuit of operational, tactical and strategic advancements in the world of organisations. We want to broaden the conversation between project management scholars and other scholars from cognate disciplines, particularly business and management, in a true scholarship of integration and cross-fertilisation. This Manifesto invites the latter scholars to join efforts providing a foundation for further creative, theoretical and empirical contributions, including but not limited to tackling grand challenges such as climate change, pandemics, and global poverty. To this end, we identify five theses: Projects are often ‘agents of change’ and hence fundamental to driving the innovation and change required to tackle grand challenges. Much project management research leverages and challenges theories across disciplines, including business, organisation and management studies, contributing to developing new theories, including those specific to projects and temporary organisations. ‘Projects’ are useful units of analysis, project management research is ideal for scientific cross-fertilisation and project management scholars welcome academics from other communities to engage in fruitful conversations. As in many other fields of knowledge, the project management research community embraces diversity, welcoming researchers of different genders and various scientific and social backgrounds. Historically rooted in ‘problem-solving’ and normative studies, project management research has become open to interpretative and emancipatory research, providing opportunities for other business, management and organisational scholars to advance their knowledge communities

Approximate probabilistic verification of hybrid systems

Hybrid systems whose mode dynamics are governed by non-linear ordinary differential equations (ODEs) are often a natural model for biological processes. However such models are difficult to analyze. To address this, we develop a probabilistic analysis method by approximating the mode transitions as stochastic events. We assume that the probability of making a mode transition is proportional to the measure of the set of pairs of time points and value states at which the mode transition is enabled. To ensure a sound mathematical basis, we impose a natural continuity property on the non-linear ODEs. We also assume that the states of the system are observed at discrete time points but that the mode transitions may take place at any time between two successive discrete time points. This leads to a discrete time Markov chain as a probabilistic approximation of the hybrid system. We then show that for BLTL (bounded linear time temporal logic) specifications the hybrid system meets a specification iff its Markov chain approximation meets the same specification with probability $1$. Based on this, we formulate a sequential hypothesis testing procedure for verifying -approximately- that the Markov chain meets a BLTL specification with high probability. Our case studies on cardiac cell dynamics and the circadian rhythm indicate that our scheme can be applied in a number of realistic settings