2,107 research outputs found
Quantitative oculomotor assessment in hereditary ataxia: systematic review and consensus by the ataxia global initiative working group on digital-motor biomarkers
Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia. MEDLINE was searched for articles reporting on oculomotor/vestibular properties in ataxia patients and a study-tailored quality-assessment was performed. One-hundred-and-seventeen articles reporting on subjects with genetically confirmed (n=1134) or suspected hereditary ataxia (n=198), and degenerative ataxias with sporadic presentation (n=480) were included and subject to data extraction. Based on robust discrimination from controls, correlation with disease-severity, sensitivity to change, and feasibility in international multicenter settings as prerequisite for clinical trials, we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex. We provide detailed guidelines for their acquisition, and recommendations on the quantitative parameters to extract. Limitations include low study quality, heterogeneity in patient populations, and lack of longitudinal studies. Standardization of quantitative oculomotor assessments will facilitate their implementation, interpretation, and validation in clinical trials, and ultimately advance our understanding of the evolution of oculomotor network dysfunction in hereditary ataxias
Towards inclusive funding practices for early career researchers
Securing research funding is a challenge faced by most scientists in academic institutions worldwide. Funding success rates for all career stages are low, but the burden falls most heavily on early career researchers (ECRs). These are young investigators in training and new principal investigators who have a shorter track record. ECRs are dependent on funding to establish their academic careers. The low number of career development awards and the lack of sustained research funding result in the loss of ECR talent in academia. Several steps in the current funding process, from grant conditions to review, play significant roles in the distribution of funds. Furthermore, there is an imbalance where certain research disciplines and labs of influential researchers receive more funding. As a group of ECRs with global representation, we examined funding practices, barriers, and facilitators to the current funding systems. We also identified alternatives to the most common funding distribution practices, such as diversifying risk or awarding grants on a partly random basis. Here, we detail recommendations for funding agencies and grant reviewers to improve ECR funding prospects worldwide and promote a fairer and more inclusive funding landscape for ECRs.Instituto de VirologíaFil: de Winde, Charlotte M. University College London. MRC Laboratory for Molecular Cell Biology; Reino UnidoFil: de Winde, Charlotte M. Amsterdam University Medical Center. Department of Molecular Cell Biology & Immunology; Países BajosFil: Sarabipour, Sarvenaz. Johns Hopkins University. Department of Biomedical Engineering. Institute for Computational Medicine; Estados UnidosFil: Carignano, Hugo Adrian. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología e Innovaciones Tecnológicas; ArgentinaFil: Davla, Sejal. City University of New York. Advanced Science Research Center; Estados UnidosFil: Eccles, David. Malaghan Institute of Medical Research; Nueva ZelandaFil: Hainer, Sarah J. University of Pittsburgh. Department of Biological Sciences; Estados UnidosFil: Haidar, Mansour. Hasselt University; BélgicaFil: Ilangovan, Vinodh. Aarhus University; DinamarcaFil: Jadavji, Nafisa M. Midwestern University. Department of Biomedical Sciences; Estados UnidosFil: Jadavji, Nafisa M. Carleton University. Department of Neuroscience; CanadáFil: Kritsiligkou, Paraskevi. German Cancer Research Center; AlemaniaFil: Lee, Tai-Ying. University of Oxford; Reino UnidoFil: Ólafsdóttir, H. Freyja. Radboud University. Donders Institute for Brain, Cognition and Behaviour; Países Bajo
Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma.
Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B
C9orf72 repeat expansions as genetic modifiers for depression in spinocerebellar ataxias
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142479/1/mds27258.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142479/2/mds27258_am.pd
Label-free detection of DNA hybridization based on hydration-induced tension in nucleic acid films
The properties of water at the nanoscale are crucial in many areas of biology, but the confinement of water molecules in sub-nanometre channels in biological systems has received relatively little attention. Advances in nanotechnology make it possible to explore the role played by water molecules in living systems, potentially leading to the development of ultrasensitive biosensors. Here we show that the adsorption of water by a self-assembled monolayer of single-stranded DNA on a silicon microcantilever can be detected by measuring how the tension in the monolayer changes as a result of hydration. Our approach relies on the microcantilever bending by an amount that depends on the tension in the monolayer. In particular, we find that the tension changes dramatically when the monolayer interacts with either complementary or single mismatched single-stranded DNA targets. Our results suggest that the tension is mainly governed by hydration forces in the channels between the DNA molecules and could lead to the development of a label-free DNA biosensor that can detect single mutations. The technique provides sensitivity in the femtomolar range that is at least two orders of magnitude better than that obtained previously with label-free nanomechanical biosensors and with label-dependent microarrays.D.R. acknowledges the fellowship funded by the Autonomic Community of Madrid (CAM). J.T, M.C, J.M and D.R acknowledge financial support by Spanish Ministry of Science (MEC) under grant No. TEC2006-10316 and CAM under grant No. 200550M056. C.B. acknowledges funding provided by MEC under grant No. BIO2007-67523. Work at Centro de Astrobiología was supported by European Union (EU), Instituto Nacional de Técnica Aeroespacial (INTA), MEC and CAM. All the authors acknowledge A. Cebollada, J.M. García-Martín, J. García, J.L. Costa-Kramer, M. Arroyo-Hernández and J.V. Anguita for their assistance in the gold deposition on the cantilevers.Peer reviewe
Debiased ambient vibrations optical coherence elastography to profile cell, organoid and tissue mechanical properties
The role of the mechanical environment in defining tissue function, development and growth has been shown to be fundamental. Assessment of the changes in stiffness of tissue matrices at multiple scales has relied mostly on invasive and often specialist equipment such as AFM or mechanical testing devices poorly suited to the cell culture workflow.In this paper, we have developed a unbiased passive optical coherence elastography method, exploiting ambient vibrations in the sample that enables real-time noninvasive quantitative profiling of cells and tissues. We demonstrate a robust method that decouples optical scattering and mechanical properties by actively compensating for scattering associated noise bias and reducing variance. The efficiency for the method to retrieve ground truth is validated in silico and in vitro, and exemplified for key applications such as time course mechanical profiling of bone and cartilage spheroids, tissue engineering cancer models, tissue repair models and single cell. Our method is readily implementable with any commercial optical coherence tomography system without any hardware modifications, and thus offers a breakthrough in on-line tissue mechanical assessment of spatial mechanical properties for organoids, soft tissues and tissue engineering
Design of Personal Health Libraries for People Returning from Incarceration in the United States
Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective observational study
Background: All spinocerebellar ataxias (SCAs) are rare diseases. SCA1, 2, 3 and 6 are the four most common SCAs, all caused by expanded polyglutamine-coding CAG repeats. Their pathomechanisms are becoming increasingly clear and well-designed clinical trials will be needed. Methods: To characterize the clinical manifestations of spinocerebellar ataxia (SCA) 1, 2, 3 and 6 and their natural histories in the United States (US), we conducted a prospective multicenter study utilized a protocol identical to the European consortium study, using the Scale for the Assessment and Rating of Ataxia (SARA) score as the primary outcome, with follow-ups every 6 months up to 2 years. Results: We enrolled 345 patients (60 SCA1, 75 SCA2, 138 SCA3 and 72 SCA6) at 12 US centers. SCA6 patients had a significantly later onset, and SCA2 patients showed greater upper-body ataxia than patients with the remaining SCAs. The annual increase of SARA score was greater in SCA1 patients (mean ± SE: 1.61 ± 0.41) than in SCA2 (0.71 ± 0.31), SCA3 (0.65 ± 0.24) and SCA6 (0.87 ± 0.28) patients (p = 0.049). The functional stage also worsened faster in SCA1 than in SCA2, 3 and 6 (p = 0.002). Conclusions: The proportions of different SCA patients in US differ from those in the European consortium study, but as in the European patients, SCA1 progress faster than those with SCA2, 3 and 6. Later onset in SCA6 and greater upper body ataxia in SCA2 were noted. We conclude that progression rates of these SCAs were comparable between US and Europe cohorts, suggesting the feasibility of international collaborative clinical studies
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