FXN promoter silencing in the humanized mouse model of Friedreich Ataxia

Background - Friedreich ataxia is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene that results in epigenetic silencing of the FXN promoter. This silencing mechanism is seen in patient-derived lymphoblastoid cells but it remains unknown if it is a widespread phenomenon affecting multiple cell types and tissues. Methodology / Principal Findings - The humanized mouse model of Friedreich ataxia (YG8sR), which carries a single transgenic insert of the human FXN gene with an expanded GAA triplet-repeat in intron 1, is deficient for FXN transcript when compared to an isogenic transgenic mouse lacking the expanded repeat (Y47R). We found that in YG8sR the deficiency of FXN transcript extended both upstream and downstream of the expanded GAA triplet-repeat, suggestive of deficient transcriptional initiation. This pattern of deficiency was seen in all tissues tested, irrespective of whether they are known to be affected or spared in disease pathogenesis, in both neuronal and non-neuronal tissues, and in cultured primary fibroblasts. FXN promoter function was directly measured via metabolic labeling of newly synthesized transcripts in fibroblasts, which revealed that the YG8sR mouse was significantly deficient in transcriptional initiation compared to the Y47R mouse. Conclusions / Significance- Deficient transcriptional initiation accounts for FXN transcriptional deficiency in the humanized mouse model of Friedreich ataxia, similar to patient-derived cells, and the mechanism underlying promoter silencing in Friedreich ataxia is widespread across multiple cell types and tissues.This research was supported by grants from the National Institutes of Health (R01 NS072418), and the Muscular Dystrophy Association to S.I.B. Y.K.C. is supported by a postdoctoral research fellowship from the Million Dollar Bike Ride Grant Program of the Orphan Disease Center at University of Pennsylvania. T.T.H. was supported by the American College of Medical Genetics Foundation. A.C.P. and M.G.M. were supported by the SURE and OSCTR programs at OUHSC, respectively

Learning Optimal Deep Projection of 18^{18}F-FDG PET Imaging for Early Differential Diagnosis of Parkinsonian Syndromes

Several diseases of parkinsonian syndromes present similar symptoms at early stage and no objective widely used diagnostic methods have been approved until now. Positron emission tomography (PET) with $^{18}$F-FDG was shown to be able to assess early neuronal dysfunction of synucleinopathies and tauopathies. Tensor factorization (TF) based approaches have been applied to identify characteristic metabolic patterns for differential diagnosis. However, these conventional dimension-reduction strategies assume linear or multi-linear relationships inside data, and are therefore insufficient to distinguish nonlinear metabolic differences between various parkinsonian syndromes. In this paper, we propose a Deep Projection Neural Network (DPNN) to identify characteristic metabolic pattern for early differential diagnosis of parkinsonian syndromes. We draw our inspiration from the existing TF methods. The network consists of a (i) compression part: which uses a deep network to learn optimal 2D projections of 3D scans, and a (ii) classification part: which maps the 2D projections to labels. The compression part can be pre-trained using surplus unlabelled datasets. Also, as the classification part operates on these 2D projections, it can be trained end-to-end effectively with limited labelled data, in contrast to 3D approaches. We show that DPNN is more effective in comparison to existing state-of-the-art and plausible baselines.Comment: 8 pages, 3 figures, conference, MICCAI DLMIA, 201

Manganese and Parkinson’s Disease: A Critical Review and New Findings

The goal of this review was to examine whether chronic Mn exposure produces dopamine neuron degeneration and PD or whether it has a distinct neuropathology and clinical presentation. I reviewed available clinical, neuroimaging, and neuropathological studies in humans and nonhuman primates exposed to Mn or other human conditions that result in elevated brain Mn concentrations. Human and nonhuman primate literature was examined to compare clinical, neuroimaging, and neuropathological changes associated with Mn-induced parkinsonism. Clinical, neuroimaging, and neuropathological evidence was used to examine whether Mn-induced parkinsonism involves degeneration of the nigrostriatal dopaminergic system as is the case in PD. The overwhelming evidence shows that Mn-induced parkinsonism does not involve degeneration of midbrain dopamine neurons and that l-dopa is not an effective therapy. New evidence is presented on a putative mechanism by which Mn may produce movement abnormalities. Confirmation of this hypothesis in humans is essential to make rational decisions about treatment, devise effective therapeutic strategies, and set regulatory guidelines

Maximizing the impact of malaria funding through allocative efficiency: using the right interventions in the right locations.

BACKGROUND: The high burden of malaria and limited funding means there is a necessity to maximize the allocative efficiency of malaria control programmes. Quantitative tools are urgently needed to guide budget allocation decisions. METHODS: A geospatial epidemic model was coupled with costing data and an optimization algorithm to estimate the optimal allocation of budgeted and projected funds across all malaria intervention approaches. Interventions included long-lasting insecticide-treated nets (LLINs), indoor residual spraying (IRS), intermittent presumptive treatment during pregnancy (IPTp), seasonal mass chemoprevention in children (SMC), larval source management (LSM), mass drug administration (MDA), and behavioural change communication (BCC). The model was applied to six geopolitical regions of Nigeria in isolation and also the nation as a whole to minimize incidence and malaria-attributable mortality. RESULTS: Allocative efficiency gains could avert approximately 84,000 deaths or 15.7 million cases of malaria in Nigeria over 5 years. With an additional US$300 million available, approximately 134,000 deaths or 37.3 million cases of malaria could be prevented over 5 years. Priority funding should go to LLINs, IPTp and BCC programmes, and SMC should be expanded in seasonal areas. To minimize mortality, treatment expansion is critical and prioritized over some LLIN funding, while to minimize incidence, LLIN funding remained a priority. For areas with lower rainfall, LSM is prioritized over IRS but MDA is not recommended unless all other programmes are established. CONCLUSIONS: Substantial reductions in malaria morbidity and mortality can be made by optimal targeting of investments to the right malaria interventions in the right areas

Vigorous star formation hidden by dust in a galaxy at z=1.4z=1.4

Near-infrared surveys have revealed a substantial population of enigmatic faint galaxies with extremely red optical-to-near-infrared colours and with a sky surface density comparable to that of faint quasars. There are two scenarios for these extreme colours: (i) these distant galaxies have formed virtually all their stars at very high redshifts and, due to the absence of recently formed stars, the colours are extremely red and (ii) these distant galaxies contain large amounts of dust, severely reddening the rest-frame UV--optical spectrum. HR10 ($z = 1.44$) is considered the archetype of the extremely red galaxies. Here we report the detection of the continuum emission from HR10 at 850$\mu$m and at 1250$\mu$m, demonstrating that HR10 is a very dusty galaxy undergoing a major episode of star formation. Our result provides a clear example of a high-redshift galaxy where the star formation rate inferred from the ultraviolet luminosity would be underestimated by a factor up to 1000, and shows that great caution should be used to infer the global star formation history of the Universe from optical observations only.Comment: 12 pages, 1 figure, Nature, in press (30 April 1998

Association between amebic liver abscess and Human Immunodeficiency Virus infection in Taiwanese subjects

<p>Abstract</p> <p>Purpose</p> <p>Invasive amebiasis is an emerging parasitic disorder in Taiwan, especially in patients diagnosed with human immunodeficiency virus (HIV) infection. Thirty-three Taiwanese subjects with amebic liver abscess (ALA) were examined and a possible correlation between ALA and HIV infection was investigated.</p> <p>Results</p> <p>Among ALA patients, the proportion of HIV-positive individuals increased during the study period. ALA was the first major clinical presentation in 54% of HIV patients with ALA. Overall, 58% (14/24) of HIV-infected patients had a CD4+ count > 200 cells/μL and 82.1% (23/28) had no concurrent opportunistic infection or other evidence of HIV infection. There was no marked difference in clinical characteristics between HIV-positive and HIV-negative ALA patients except the level of leukocytosis.</p> <p>Conclusion</p> <p>While the clinical characteristics described herein cannot be used to determine whether ALA patients have HIV infection, routine HIV testing is recommended in patients with ALA, even in the absence of HIV symptoms.</p

Building resilience in practice to support coral communities in the Western Indian Ocean

Global environmental change and other site specific pressures (e.g. over fishing and pollution) are threating coral reefs and the livelihoods of dependent coastal communities. Multiple strategies are used to build the resilience of both coral reefs and reef dependent communities but the effectiveness of these strategies is largely unknown. Using the Western Indian Ocean (WIO) as a case study, this paper combines published literature and expert opinion elicited through a multi-stakeholder workshop to assess the intended and realised social and ecological implications of strategies commonly applied in the region. Findings suggest that all strategies can contribute to building social and ecological resilience, but this varies with context and the overall strategy objectives. The ability of strategies to be successful in the future is questioned. To support effective resilience policy development more nuanced lesson learning requires effective monitoring and evaluation as well as a disaggregated understanding of resilience in terms of gender, agency and the interaction between ecological and social resilience. Opportunities for further lesson sharing between experts in the region are needed

Early-life course factors and oral health among young Norwegian adults

Objective Using a national sample of young Norwegian adults, we examined whether unpleasant experience with dental care during childhood is associated with tooth loss and oral health–related quality of life in adulthood after accounting for early- and later-life socio-behavioural circumstances and dental avoidance behaviour. Methods 2433 individuals aged 25-35 years participated in an electronic survey. Oral quality of life was measured using the oral impact of daily performance (OIDP) inventory. Generalized linear models and negative binomial regression models were used to estimate the association of early unpleasant experiences with dental care and tooth loss and OIDP scores. Incidence rate ratio (IRR) and 95% confidence intervals (CI) were used to estimate the relative differences in prevalence of tooth loss and OIDP scores. Results Adjusting for early-life characteristics only, the prevalence of tooth loss was 1.42 (IRR = 1.42, 95% CI: 1.24-1.64) and 1.96 (IRR = 1.96, 95% CI: 1.70-2.26) times higher among individuals who reported unpleasant experiences a few times or several times, than in individuals who did not report unpleasant experiences with dental care in childhood. Adjusting further for educational level, smoking and tooth brushing attenuated the relative differences (IRR = 1.40, 95% CI: 1.22-1.62 and IRR = 1.88, 95% CI: 1.62-2.17, respectively). Lastly, when adjusting for dental avoidance behaviour, the prevalence of tooth loss was 1.29 (IRR = 1.29, 95% CI: 1.11-1.50) and 1.58 (IRR = 1.58, 95% CI: 1.32-1.88) times higher among individuals who reported unpleasant experiences a few times or several times than in those who did not. Corresponding associations of early unpleasant experience with OIDP were (IRR = 1.41 95% CI: 1.22-1.63) and (IRR = 1.69, 95% CI: 1.42-2.01) when adjusting for early-life characteristics, and (IRR = 1.39, 95% CI: 1.20-1.60) and (IRR = 1.51, 95% CI: 1.27-1.80) when adjusting for education, smoking and tooth brushing. When adjusting for dental avoidance behaviour, the association of early unpleasant experience with OIDP became nonsignificant. Conclusion Unpleasant dental care experiences during childhood are associated with poor oral health in adulthood, independent of later-life socio-behavioural characteristics including negative dental care seeking. This highlights the importance of tailoring regular contacts with dental healthcare services in childhood to build confidence in children and thus has implications for healthcare policy.publishedVersio

ACCORD (ACcurate COnsensus Reporting Document): A reporting guideline for consensus methods in biomedicine developed via a modified Delphi

\ua9 2024 Gattrell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background In biomedical research, it is often desirable to seek consensus among individuals who have differing perspectives and experience. This is important when evidence is emerging, inconsistent, limited, or absent. Even when research evidence is abundant, clinical recommendations, policy decisions, and priority-setting may still require agreement from multiple, sometimes ideologically opposed parties. Despite their prominence and influence on key decisions, consensus methods are often poorly reported. Our aim was to develop the first reporting guideline dedicated to and applicable to all consensus methods used in biomedical research regardless of the objective of the consensus process, called ACCORD (ACcurate COnsensus Reporting Document). Methods and findings We followed methodology recommended by the EQUATOR Network for the development of reporting guidelines: a systematic review was followed by a Delphi process and meetings to finalize the ACCORD checklist. The preliminary checklist was drawn from the systematic review of existing literature on the quality of reporting of consensus methods and suggestions from the Steering Committee. A Delphi panel (n = 72) was recruited with representation from 6 continents and a broad range of experience, including clinical, research, policy, and patient perspectives. The 3 rounds of the Delphi process were completed by 58, 54, and 51 panelists. The preliminary checklist of 56 items was refined to a final checklist of 35 items relating to the article title (n = 1), introduction (n = 3), methods (n = 21), results (n = 5), discussion (n = 2), and other information (n = 3). Conclusions The ACCORD checklist is the first reporting guideline applicable to all consensus-based studies. It will support authors in writing accurate, detailed manuscripts, thereby improving the completeness and transparency of reporting and providing readers with clarity regarding the methods used to reach agreement. Furthermore, the checklist will make the rigor of the consensus methods used to guide the recommendations clear for readers. Reporting consensus studies with greater clarity and transparency may enhance trust in the recommendations made by consensus panels

Some Rare Indo-Pacific Coral Species Are Probable Hybrids

Background: coral reefs worldwide face a variety of threats and many coral species are increasingly endangered. It is often assumed that rare coral species face higher risks of extinction because they have very small effective population sizes, a predicted consequence of which is decreased genetic diversity and adaptive potential.\ud \ud Methodology/Principal Findings: here we show that some Indo-Pacific members of the coral genus Acropora have very small global population sizes and are likely to be unidirectional hybrids. Whether this reflects hybrid origins or secondary hybridization following speciation is unclear.\ud \ud Conclusions/Significance: the interspecific gene flow demonstrated here implies increased genetic diversity and adaptive potential in these coral species. Rare Acropora species may therefore be less vulnerable to extinction than has often been assumed because of their propensity for hybridization and introgression, which may increase their adaptive potential