Fluorescence lifetime imaging microscopy: in vivo application to diagnosis of oral carcinoma

A compact clinically compatible fluorescence lifetime imaging microscopy (FLIM) system was designed and built for intraoperative disease diagnosis and validated in vivo in a hamster oral carcinogenesis model. This apparatus allows for the remote image collection via a flexible imaging probe consisting of a gradient index objective lens and a fiber bundle. Tissue autofluorescence (337 nm excitation) was imaged using an intensified CCD with a gate width down to 0.2 ns. We demonstrate a significant contrast in fluorescence lifetime between tumor (1.77±0.26 ns) and normal (2.50±0.36 ns) tissues at 450 nm and an over 80% intensity decrease at 390 nm emission in tumor versus normal areas. The time-resolved images were minimally affected by tissue morphology, endogenous absorbers, and illumination. These results demonstrate the potential of FLIM as an intraoperative diagnostic technique

Novel 1-hydroxypyridin-2-one metal chelators prevent and res-cue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson’s disease

Ubiquitin proteasome system (UPS) impairment, excessive cellular oxidative stress and iron dyshomeostasis are key to substantia nigra dopaminergic neuronal de-generation in Parkinson's disease (PD); however, a link between these features remains unconfirmed. By using the proteasome inhibitor lactacystin we confirm that nigral injury via UPS impairment disrupts iron homeostasis, in turn increasing oxi-dative stress and promoting protein aggregation. We demonstrate the neuroprotec-tive potential of two novel 1-hydroxy-2(1H)-pyridinone (1,2-HOPO) iron chelators, compounds C6 and C9, against lactacystin-induced cell death. We demonstrate that this cellular preservation relates to the compounds’ iron chelating capabilities and subsequent reduced capacity of iron to form reactive oxygen species (ROS), where we also show that the ligands act as antioxidant agents. Our results also de-monstrate the ability of C6 and C9 to reduce intracellular lactacystin-induced α-synuclein burden. Stability constant measurements confirmed a high affinity of C6 and C9 for Fe3+ and display a 3:1 HOPO:Fe3+ complex formation at physiological pH. Reducing iron reactivity could prevent the demise of nigral dopaminergic neurons. We provide evidence that the lactacystin model presents with several neuropatho-logical hallmarks of PD related to iron dyshomeostasis and that the novel chelating compounds C6 and C9 can protect against lactacystin-related neurotoxicity

Discovery of a Gas-Rich Companion to the Extremely Metal-Poor Galaxy DDO 68

We present HI spectral-line imaging of the extremely metal-poor galaxy DDO 68. This system has a nebular oxygen abundance of only 3% Z$_{\odot}$, making it one of the most metal-deficient galaxies known in the local volume. Surprisingly, DDO 68 is a relatively massive and luminous galaxy for its metal content, making it a significant outlier in the mass-metallicity and luminosity-metallicity relationships. The origin of such a low oxygen abundance in DDO 68 presents a challenge for models of the chemical evolution of galaxies. One possible solution to this problem is the infall of pristine neutral gas, potentially initiated during a gravitational interaction. Using archival HI spectral-line imaging obtained with the Karl G. Jansky Very Large Array, we have discovered a previously unknown companion of DDO 68. This low-mass (M$_{\rm HI}$ $=$ 2.8$\times$10$^{7}$ M$_{\odot}$), recently star-forming (SFR$_{\rm FUV}$ $=$ 1.4$\times$10$^{-3}$ M$_{\odot}$ yr$^{-1}$, SFR$_{\rm H\alpha}$ $<$ 7$\times$10$^{-5}$ M$_{\odot}$ yr$^{-1}$) companion has the same systemic velocity as DDO 68 (V$_{\rm sys}$ $=$ 506 km s$^{-1}$; D $=$ 12.74$\pm$0.27 Mpc) and is located at a projected distance of 42 kpc. New HI maps obtained with the 100m Robert C. Byrd Green Bank Telescope provide evidence that DDO 68 and this companion are gravitationally interacting at the present time. Low surface brightness HI gas forms a bridge between these objects.Comment: Accepted for publication in the Astrophysical Journal Letter

Observations and Implications of the Star Formation History of the LMC

We present derivations of star formation histories based on color-magnitude diagrams of three fields in the LMC from HST/WFPC2 observations. A significant component of stars older than 4 Gyr is required to match the observed color-magnitude diagrams. Models with a dispersion-free age-metallicity relation are unable to reproduce the width of the observed main sequence; models with a range of metallicity at a given age provide a much better fit. Such models allow us to construct complete ``population boxes'' for the LMC based entirely on color-magnitude diagrams; remarkably, these qualitatively reproduce the age-metallicity relation observed in LMC clusters. We discuss some of the uncertainties in deriving star formation histories. We find, independently of the models, that the LMC bar field has a larger relative component of older stars than the outer fields. The main implications suggested by this study are: 1) the star formation history of field stars appears to differ from the age distribution of clusters, 2) there is no obvious evidence for bursty star formation, but our ability to measure bursts shorter in duration than $\sim$ 25% of any given age is limited by the statistics of the observed number of stars, 3) there may be some correlation of the star formation rate with the last close passage of the LMC/SMC/Milky Way, but there is no dramatic effect, and 4) the derived star formation history is probably consistent with observed abundances, based on recent chemical evolution models.Comment: Accepted by AJ, 36 pages including 12 figure

Stellar Populations in Three Outer Fields of the LMC

We present HST photometry for three fields in the outer disk of the LMC extending approximately four magnitudes below the faintest main sequence turnoff. We cannot detect any strongly significant differences in the stellar populations of the three fields based on the morphologies of the color-magnitude diagrams, the luminosity functions, and the relative numbers of stars in different evolutionary stages. Our observations therefore suggest similar star formation histories in these regions, although some variations are certainly allowed. The fields are located in two regions of the LMC: one is in the north-east field and two are located in the north-west. Under the assumption of a common star formation history, we combine the three fields with ground-based data at the same location as one of the fields to improve statistics for the brightest stars. We compare this stellar population with those predicted from several simple star formation histories suggested in the literature, using a combination of the R-method of Bertelli et al (1992) and comparisons with the observed luminosity function. The only model which we consider that is not rejected by the observations is one in which the star formation rate is roughly constant for most of the LMC's history and then increases by a factor of three about 2 Gyr ago. Such a model has roughly equal numbers of stars older and younger than 4 Gyr, and thus is not dominated by young stars. This star formation history, combined with a closed box chemical evolution model, is consistent with observations that the metallicity of the LMC has doubled in the past 2 Gyr.Comment: 30 pages, includes 10 postscript figures. Figure 1 avaiable at ftp://charon.nmsu.edu/pub/mgeha/LMC. Accepted for publication in Astronomical Journa

Utility of whole-genome sequencing during an investigation of multiple foodborne outbreaks of Shigella sonnei

In April 2018, Public Health England was notified of cases of Shigella sonnei who had eaten food from three different catering outlets in England. The outbreaks were initially investigated as separate events, but whole-genome sequencing (WGS) showed they were caused by the same strain. The investigation included analyses of epidemiological data, the food chain and microbiological examination of food samples. WGS was used to determine the phylogenetic relatedness and antimicrobial resistance profile of the outbreak strain. Ultimately, 33 cases were linked to this outbreak; the majority had eaten food from seven outlets specialising in Indian or Middle Eastern cuisine. Five outlets were linked to two or more cases, all of which used fresh coriander although a shared supplier was not identified. An investigation at one of the venues recorded that 86% of cases reported eating dishes with coriander as an ingredient or garnish. Four cases were admitted to hospital and one had evidence of treatment failure with ciprofloxacin. Phylogenetic analysis showed that the outbreak strain was part of a wider multidrug-resistant clade associated with travel to Pakistan. Poor hygiene practices during cultivation, distribution or preparation of fresh produce are likely contributing factors

Loss of ATM kinase activity leads to embryonic lethality in mice

Ataxia telangiectasia (A-T) mutated (ATM) is a key deoxyribonucleic acid (DNA) damage signaling kinase that regulates DNA repair, cell cycle checkpoints, and apoptosis. The majority of patients with A-T, a cancer-prone neurodegenerative disease, present with null mutations in Atm. To determine whether the functions of ATM are mediated solely by its kinase activity, we generated two mouse models containing single, catalytically inactivating point mutations in Atm. In this paper, we show that, in contrast to Atm-null mice, both D2899A and Q2740P mutations cause early embryonic lethality in mice, without displaying dominant-negative interfering activity. Using conditional deletion, we find that the D2899A mutation in adult mice behaves largely similar to Atm-null cells but shows greater deficiency in homologous recombination (HR) as measured by hypersensitivity to poly (adenosine diphosphate-ribose) polymerase inhibition and increased genomic instability. These results may explain why missense mutations with no detectable kinase activity are rarely found in patients with classical A-T. We propose that ATM kinase-inactive missense mutations, unless otherwise compensated for, interfere with HR during embryogenesis

Which factors explain variation in intention to disclose a diagnosis of dementia? A theory-based survey of mental health professionals

Background: For people with dementia, patient-centred care should involve timely explanation of the diagnosis and its implications. However, this is not routine. Theoretical models of behaviour change offer a generalisable framework for understanding professional practice and identifying modifiable factors to target with an intervention. Theoretical models and empirical work indicate that behavioural intention represents a modifiable predictor of actual professional behaviour. We identified factors that predict the intentions of members of older people's mental health teams (MHTs) to perform key behaviours involved in the disclosure of dementia. Design: Postal questionnaire survey. Participants: Professionals from MHTs in the English National Health Service. Methods: We selected three behaviours: Determining what patients already know or suspect about their diagnosis; using explicit terminology when talking to patients; and exploring what the diagnosis means to patients. The questionnaire was based upon the Theory of Planned Behaviour (TPB), Social Cognitive Theory (SCT), and exploratory team variables. Main outcomes: Behavioural intentions. Results: Out of 1,269 professionals working in 85 MHTs, 399 (31.4%) returned completed questionnaires. Overall, the TPB best explained behavioural intention. For determining what patients already know, the TPB variables of subjective norm, perceived behavioural control and attitude explained 29.4% of the variance in intention. For the use of explicit terminology, the same variables explained 53.7% of intention. For exploring what the diagnosis means to patients, subjective norm and perceived behavioural control explained 48.6% of intention. Conclusion: These psychological models can explain up to half of the variation in intention to perform key disclosure behaviours. This provides an empirically- supported, theoretical basis for the design of interventions to improve disclosure practice by targeting relevant predictive factors. Trial Registration: ISRCTN15871014

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals

Publisher Copyright: © 2022, The Author(s).We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12–16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI’s magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.Peer reviewe