Project description:An ambitious plan to collect, curate, and make accessible information on genetic variations affecting human health is beginning to be realized.
Project description:In the past decades, actigraphy has emerged as a promising, cost-effective, and easy-to-use tool for ambulatory sleep recording. Polysomnography (PSG) validation studies showed that actigraphic sleep estimates fare relatively well in healthy sleepers. Additionally, round-the-clock actigraphy recording has been used to study circadian rhythms in various populations. To this date, however, there is little evidence that the diagnosis, monitoring, or treatment of insomnia can significantly benefit from actigraphy recordings. Using a case-control design, we therefore critically examined whether mean or within-subject variability of actigraphy sleep estimates or circadian patterns add to the understanding of sleep complaints in insomnia. We acquired actigraphy recordings and sleep diaries of 37 controls and 167 patients with varying degrees of insomnia severity for up to 9 consecutive days in their home environment. Additionally, the participants spent one night in the laboratory, where actigraphy was recorded alongside PSG to check whether sleep, in principle, is well estimated. Despite moderate to strong agreement between actigraphy and PSG sleep scoring in the laboratory, ambulatory actigraphic estimates of average sleep and circadian rhythm variables failed to successfully differentiate patients with insomnia from controls in the home environment. Only total sleep time differed between the groups. Additionally, within-subject variability of sleep efficiency and wake after sleep onset was higher in patients. Insomnia research may therefore benefit from shifting attention from average sleep variables to day-to-day variability or from the development of non-motor home-assessed indicators of sleep quality.
Project description:The majority of musculoskeletal modelling studies investigating healthy populations use generic models linearly scaled to roughly match an individual's anthropometry. Generic models disregard the considerable variation in musculoskeletal geometry and tissue properties between individuals. This study investigated the physiological implications of personalizing musculoskeletal model geometry (body segment mass, inertia, joint center, and maximum isometric muscle force). Nine healthy athletes performed ten repetitions of 15 meter sprints at 75-95% of their maximum sprinting speed and ten repetitions of unanticipated sidestep cut trials with a 4.5-5.5 m/s approach running speed. Structural magnetic resonance imaging was collected on the lower extremities, from which subject-specific musculoskeletal models were developed. A one-dimensional statistical parametric mapping paired t-test was used to compare generic and subject-specific musculoskeletal models for: lower-limb kinematics, kinetics, torque matching, as well as hamstrings, adductors, and quadriceps muscle activations and fiber dynamics. Percentage change of geometric parameters between generic and subject-specific models were determined. Compared to generic models, subject-specific models showed significantly lower ankle dorsi/plantar flexion angle during sprinting and several significantly different net joint moments during sprint and cut tasks. Additionally, subject-specific models demonstrated better torque matching, more physiologically plausible fiber lengths, higher fiber velocities, lower muscle forces, and lower simulated activations in a subset of investigated muscles and motor tasks. Furthermore, subject-specific models identified between-limb differences that were not identified with generic models. Use of subject-specific modeling, even in healthy populations, may result in more physiologically plausible muscle fiber mechanics. Implementing subject-specific models may be especially beneficial when investigating populations with substantial geometric between-limb differences, or unilateral musculoskeletal pathologies, as these are not captured by a generic model.
Project description:When identifying conservation priorities, the accuracy of conservation assessments is constrained by the quality of data available. Despite previous efforts exploring how to deal with imperfect datasets, little is known about how data uncertainty translates into errors in conservation planning outcomes. Here, we evaluate the magnitude of commission and omission error, effectiveness and efficiency of conservation planning outcomes derived from three datasets with increasing data quality. We demonstrate that investing in data acquisition might not always be the best strategy as the magnitude of errors introduced by new sites/species can exceed the benefits gained. There was a trade-off between effectiveness and efficiency due to poorly sampled rare species. Given that data acquisition is limited by the high cost and time required, we recommend focusing on improving the quality of data for those species with the highest level of uncertainty (rare species) when acquiring new data.
Project description:Charcot-Marie-Tooth (CMT) neuropathies comprise a group of monogenic disorders affecting the peripheral nervous system. CMT is characterized by a clinically and genetically heterogeneous group of neuropathies, involving all types of Mendelian inheritance patterns. Over 1,000 different mutations have been discovered in 80 disease-associated genes. Genetic research of CMT has pioneered the discovery of genomic disorders and aided in understanding the effects of copy number variation and the mechanisms of genomic rearrangements. CMT genetic study also unraveled common pathomechanisms for peripheral nerve degeneration, elucidated gene networks, and initiated the development of therapeutic approaches. The reference genome, which became available thanks to the Human Genome Project, and the development of next generation sequencing tools, considerably accelerated gene and mutation discoveries. In fact, the first clinical whole genome sequence was reported in a patient with CMT. Here we review the history of CMT gene discoveries, starting with technologies from the early days in human genetics through the high-throughput application of modern DNA analyses. We highlight the most relevant examples of CMT genes and mutation mechanisms, some of which provide promising treatment strategies. Finally, we propose future initiatives to accelerate diagnosis of CMT patients through new ways of sharing large datasets and genetic variants, and at ever diminishing costs.
Project description:BackgroundThe sandwich principle is an educational concept that regularly alternates between collective and individual learning phases within one learning unit. Applying sandwich principle to lectures has proven to be more effective for learning outcomes than classical lectures. Supposedly, this teaching format also leads to a beneficial knowledge transfer when applied to other teaching formats. Therefore, the aim of this study was to investigate the effect of the sandwich principle on instructional videos and how its use was evaluated by students.MethodsParticipants (n = 51) were randomly allocated into two groups. Both groups were given a test to assess the baseline level of knowledge. Afterwards, the control group watched the normal instructional video on cleft lips and palates, while the sandwich group watched the same video modified according to the sandwich principle. The participants then had to answer 30 single-choice questions to assess their knowledge gain and evaluate the instructional video. Long-term retention of the knowledge was tested again 6 months later using the same test questions. The unpaired t-test and ANOVA were used to compare the results.ResultsComparison of the pre-test and post-test results of both groups showed significantly increased test scores (p < 0.0001). Regarding long-term retention, the mean test scores were still significantly higher in both groups than before watching the video (p < 0.0001). For all test results, there was no significant difference between the groups (p > 0.05). The evaluation showed that the students highly appreciated the modified video and found the interruptions for repetition of previously learned knowledge useful.ConclusionThe hypothesis that the modification of instructional videos according to the sandwich principle would lead to an improved learning outcome could not be proved subjectively or objectively. Nevertheless, the teaching format was highly appreciated by the students and may have increased their motivation to learn with instructional videos.
Project description:Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa.
Project description:Drug delivery schedules are key factors in the efficacy of cancer therapies, and mathematical modeling of population dynamics and treatment responses can be applied to identify better drug administration regimes as well as provide mechanistic insights. To capitalize on the promise of this approach, the cancer field must meet the challenges of moving this type of work into clinics.
Project description:PremiseHerbaria harbor a tremendous number of plant specimens that are rarely used for molecular systematic studies, largely due to the difficulty in extracting sufficient amounts of high-quality DNA from the preserved plant material.MethodsWe compared the standard Qiagen DNeasy Plant Mini Kit and a specific protocol for extracting ancient DNA (aDNA) (the N-phenacylthiazolium bromide and dithiothreitol [PTB-DTT] extraction method) from two different plant genera (Xanthium and Salix). The included herbarium materials covered about two centuries of plant collections. To analyze the success of DNA extraction using each method, a subset of samples was subjected to a standard library preparation as well as target-enrichment approaches.ResultsThe PTB-DTT method produced a higher DNA yield of better quality than the Qiagen kit; however, extracts from the Qiagen kit over a certain DNA yield and quality threshold produced comparable sequencing results. The sequencing resulted in high proportions of endogenous reads. We were able to successfully sequence 200-year-old samples.DiscussionThis method comparison revealed that, for younger specimens, DNA extraction using a standard kit might be sufficient. For old and precious herbarium specimens, aDNA extraction methods are better suited to meet the requirements for next-generation sequencing.
Project description:Chronic myeloid leukemia (CML) is a classical example of stem cell cancer since it arises in a multipotent hematopoietic stem cell upon the acquisition of the t(9;22) chromosomal translocation, that converts it into a leukemic stem cell (LSC). The resulting BCR-ABL1 fusion gene encodes a deregulated tyrosine kinase that is recognized as the disease driver. Therapy with tyrosine kinase inhibitors (TKIs) eliminates progenitor and more differentiated cells but fails to eradicate quiescent LSCs. Thus, although many patients obtain excellent responses and a proportion of them can even attempt treatment discontinuation (treatment free remission [TFR]) after some years of therapy, LSCs persist, and represent a potentially dangerous reservoir feeding relapse and hampering TFR. Over the past two decades, intensive efforts have been devoted to the characterization of CML LSCs and to the dissection of the cell-intrinsic and -extrinsic mechanisms sustaining their persistence, in an attempt to find druggable targets enabling LSC eradication. Here we provide an overview and an update on these mechanisms, focusing in particular on the most recent acquisitions. Moreover, we provide a critical appraisal of the clinical relevance and feasibility of LSC targeting in CML.