Singlet fission is the spin-allowed conversion of a spin-singlet exciton into a pair of spin-triplet excitons residing on neighbouring molecules. To rationalize this phenomenon, a multiexcitonic ...spin-zero triplet-pair state has been hypothesized as an intermediate in singlet fission. However, the nature of the intermediate states and the underlying mechanism of ultrafast fission have not been elucidated experimentally. Here, we study a series of pentacene derivatives using ultrafast two-dimensional electronic spectroscopy and unravel the origin of the states involved in fission. Our data reveal the crucial role of vibrational degrees of freedom coupled to electronic excitations that facilitate the mixing of multiexcitonic states with singlet excitons. The resulting manifold of vibronic states drives sub-100 fs fission with unity efficiency. Our results provide a framework for understanding singlet fission and show how the formation of vibronic manifolds with a high density of states facilitates fast and efficient electronic processes in molecular systems.
Amyotrophic lateral sclerosis (ALS) or motor neuron disease is a rapidly progressive neurodegenerative disorder. The primary involvement is of motor neurons in the brain, spinal cord and ...peripherally. There is secondary weakness of muscles and primary involvement of other brain regions, especially involving cognition.
Peer-reviewed journal articles and reviews. PubMed.gov
The pathogenesis of ALS remains largely unknown. There are a wide range of potential mechanisms related to neurodegeneration. An increasing number of genetic factors are recognized.
There remains controversy, or lack of knowledge, in explaining how cellular events manifest as the complex human disease. There is controversy as to how well cellular and animal models of disease relate to the human disease.
Large-scale international collaborative genetic epidemiological studies are replacing local studies. Therapies related to pathogenesis remain elusive, with the greatest advances to date relating to provision of care (including multidisciplinary management) and supportive care (nutrition and respiratory support).
The identification of C9orf72 hexanucleotide repeats as the most frequent genetic background to ALS, and the association with frontotemporal dementia, gives the potential of a genetic background against which to study other risk factors, triggers and pathogenic mechanisms, and to develop potential therapies.
Bioinformatics is recognized as part of the essential knowledge base of numerous career paths in biomedical research and healthcare. However, there is little agreement in the field over what that ...knowledge entails or how best to provide it. These disagreements are compounded by the wide range of populations in need of bioinformatics training, with divergent prior backgrounds and intended application areas. The Curriculum Task Force of the International Society of Computational Biology (ISCB) Education Committee has sought to provide a framework for training needs and curricula in terms of a set of bioinformatics core competencies that cut across many user personas and training programs. The initial competencies developed based on surveys of employers and training programs have since been refined through a multiyear process of community engagement. This report describes the current status of the competencies and presents a series of use cases illustrating how they are being applied in diverse training contexts. These use cases are intended to demonstrate how others can make use of the competencies and engage in the process of their continuing refinement and application. The report concludes with a consideration of remaining challenges and future plans.
ToxR and TcpP, two winged helix-turn-helix (w-HTH) family transcription factors, co-activate expression of the toxT promoter in Vibrio cholerae. ToxT then directly regulates a number of genes ...required for virulence. In addition to co-activation of toxT, ToxR can directly activate the ompU promoter and repress the ompT promoter. Based on a previous study suggesting that certain wing residues of ToxR are preferentially involved in toxT co-activation compared to direct ompU activation, we employed alanine-scanning mutagenesis to determine which residues in the wing of ToxR are required for activation of each promoter. All of the ToxR wing residues tested that were critical for transcriptional activation of toxT and/or ompU were also critical for DNA binding. While some ToxR wing mutants had reduced interaction with TcpP, that reduced interaction did not correlate with a specific defect in toxT activation. Rather, such mutants also affected ompU activation and DNA binding. Based on these findings we conclude that the primary role of the wing of ToxR is to bind DNA, along with the DNA recognition helix of ToxR, and this function is required both for direct activation of ompU and co-activation of toxT.
Epstein-Barr virus (EBV) persists in human B-cells by maintaining its chromatinized episomes within the nucleus. We have previously shown that cellular factor Poly ADP-ribose polymerase 1 (PARP1) ...binds the EBV genome, stabilizes CTCF binding at specific loci, and that PARP1 enzymatic activity correlates with maintaining a transcriptionally active latency program. To better understand PARP1's role in regulating EBV latency, here we functionally characterize the effect of PARP enzymatic inhibition on episomal structure through in situ HiC mapping, generating a complete 3D structure of the EBV genome. We also map intragenomic contact changes after PARP inhibition to global binding of chromatin looping factors CTCF and cohesin across the EBV genome. We find that PARP inhibition leads to fewer total unique intragenomic interactions within the EBV episome, yet new chromatin loops distinct from the untreated episome are also formed. This study also illustrates that PARP inhibition alters gene expression at the regions where chromatin looping is most effected. We observe that PARP1 inhibition does not alter cohesin binding sites but does increase its frequency of binding at those sites. Taken together, these findings demonstrate that PARP has an essential role in regulating global EBV chromatin structure and latent gene expression.
Neurodevelopmental disorders have a heritable component and are associated with region specific alterations in brain anatomy. However, it is unclear how genetic risks for neurodevelopmental disorders ...are translated into spatially patterned brain vulnerabilities. Here, we integrated cortical neuroimaging data from patients with neurodevelopmental disorders caused by genomic copy number variations (CNVs) and gene expression data from healthy subjects. For each of the six investigated disorders, we show that spatial patterns of cortical anatomy changes in youth are correlated with cortical spatial expression of CNV genes in neurotypical adults. By transforming normative bulk-tissue cortical expression data into cell-type expression maps, we link anatomical change maps in each analysed disorder to specific cell classes as well as the CNV-region genes they express. Our findings reveal organizing principles that regulate the mapping of genetic risks onto regional brain changes in neurogenetic disorders. Our findings will enable screening for candidate molecular mechanisms from readily available neuroimaging data.
While there are reports of group-based projects being used in university-level bioinformatics education 10-12 and there are a small number of training courses worldwide that take such an approach ...(e.g., Cold Spring Harbor’s “Programming for Biology” 13, SFU’s “Problem-based learning in bioinformatics” course for PhD & MSc students 9), project-based learning is not yet embedded in mainstream bioinformatics training practice. Key tips for mentors * The project should ask interesting research questions and have a realistic biological context relevant for the whole group of participants, based on their research interests and prior experience in computational biology. * You should provide participants with a starting dataset (or links to appropriate data resources so that they can obtain the dataset), background information about the data and biology, and 2-3 open-ended research objectives. * Selecting this dataset can be the hardest part of designing a project; it is important to check that it is suitable for meaningful analysis. Complete list of participant comments from the long-term feedback survey, “Please comment on the best aspect of working on the group project this year” * The best aspect was to figure out the gene of origin with different tools and discovering and sharing new methodologies to search the genome. * Very practical: with problem solving, you are forced to critically apply what you learn and therefore test your comprehension. * It is always good to work as a group because we can unite our skills and knowledge. ...we would like to offer tips to others who might be thinking about doing the same, based on our experience: * Projects do not need a defined end point, but initial scope is key to their success; it needs to be wide enough to allow groups to use their own initiative but without the potential for groups to go completely off topic. * Initial project development is fairly time-consuming but, once defined, a project does have the potential to be reused, with minor revisions as appropriate. * Providing shared lab notebooks to record details of the project is important for reproducibility and as post-course reference material. * Mentors should be researchers with broad and current knowledge of theoretical and practical aspects of bioinformatics approaches in their discipline. * Mentors need to be present in enough numbers (2-3 per group of 3-5 students) and be flexible in their approach to the trainees and the support they provide. * Providing the opportunity for participants to demonstrate what they have achieved during the project to others external to their group is an important element in their learning path.
Despite the shrinking of the gender wage gap, women with children continue to experience earnings and career disadvantages that women without children do not experience. This review first summarizes ...how the severity of the “motherhood penalty” is influenced by a woman's marital status and class in ways that perpetuate existing inequalities. Next, it outlines how the same factors also play salient roles in determining women's workforce behaviors upon transitioning to motherhood, largely dictating the extent to which women's earnings and careers are negatively impacted by the arrival of children. After establishing the stratified lines upon which mothers' decisions are made, and the disparate financial ramifications of their decisions, the paper concludes with a call for future research into the mechanisms that propel mothers' labor market decisions.
Schizophrenia has been conceived as a disorder of brain connectivity, but it is unclear how this network phenotype is related to the underlying genetics. We used morphometric similarity analysis of ...MRI data as a marker of interareal cortical connectivity in three prior case–control studies of psychosis: in total, n = 185 cases and n = 227 controls. Psychosis was associated with globally reduced morphometric similarity in all three studies. There was also a replicable pattern of case–control differences in regional morphometric similarity, which was significantly reduced in patients in frontal and temporal cortical areas but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case–control differences in morphometric similarity was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally overexpressed in cortical areas with reduced morphometric similarity were significantly up-regulated in three prior post mortem studies of schizophrenia. We propose that this combined analysis of neuroimaging and transcriptional data provides insight into how previously implicated genes and proteins as well as a number of unreported genes in their topological vicinity on the protein interaction network may drive structural brain network changes mediating the genetic risk of schizophrenia.
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