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"Clark, Alexander (Alexander Simon)"
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The handbook of computational linguistics and natural language processing
This comprehensive reference work provides an overview of the concepts, methodologies, and applications in computational linguistics and natural language processing (NLP). Features contributions by the top researchers in the field, reflecting the work that is driving the discipline forward Includes an introduction to the major theoretical issues in these fields, as well as the central engineering applications that the work has produced Presents the major developments in an accessible way, explaining the close connection between scientific understanding of the computational properties of natural language and the creation of effective language technologies Serves as an invaluable state-of-the-art reference source for computational linguists and software engineers developing NLP applications in industrial research and development labs of software companies
eBook
Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation
New therapies to treat pancreatic cancer are direly needed. However, efficacious interventions lack a strong preclinical model that can recapitulate patients’ anatomy and physiology. Likewise, the availability of human primary malignant tissue for ex vivo studies is limited. These are significant limitations in the biomedical device field. We have developed
RAG2/IL2RG
deficient pigs using CRISPR/Cas9 as a large animal model with the novel application of cancer xenograft studies of human pancreatic adenocarcinoma. In this proof-of-concept study, these pigs were successfully generated using on-demand genetic modifications in embryos, circumventing the need for breeding and husbandry. Human Panc01 cells injected subcutaneously into the ears of
RAG2/IL2RG
deficient pigs demonstrated 100% engraftment with growth rates similar to those typically observed in mouse models. Histopathology revealed no immune cell infiltration and tumor morphology was highly consistent with the mouse models. The electrical properties and response to irreversible electroporation of the tumor tissue were found to be similar to excised human pancreatic cancer tumors. The ample tumor tissue produced enabled improved accuracy and modeling of the electrical properties of tumor tissue. Together, this suggests that this model will be useful and capable of bridging the gap of translating therapies from the bench to clinical application.
Journal Article
Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues
Molecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of cell renewal in adult tissues. Here, we show that fluctuating DNA methylation marks can be used as clocks in cells where ongoing methylation and demethylation cause repeated ‘flip–flops’ between methylated and unmethylated states. We identify endogenous fluctuating CpG (fCpG) sites using standard methylation arrays and develop a mathematical model to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than the colon, with slower stem cell replacement in the small intestine. Germline
APC
mutation increased the number of replacements per crypt. In blood, we measured rapid expansion of acute leukemia and slower growth of chronic disease. Thus, the patterns of human somatic cell birth and death are measurable with fluctuating methylation clocks (FMCs).
Lineage tracing of human stem cells is achieved by measuring fluctuating DNA methylation.
Journal Article
Integrated genomic analyses of de novo pathways underlying atypical meningiomas
Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (
de novo
) atypical meningiomas display loss of
NF2
, which co-occurs either with genomic instability or recurrent
SMARCB1
mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets.
Meningiomas are mostly benign brain tumours with the potential for becoming atypical or malignant. Here, the authors show that primary atypical meningiomas are epigenetically and genetically distinct from benign and progressed tumours, highlighting possible therapeutic targets such as PRC2.
Journal Article
Small-scale societies exhibit fundamental variation in the role of intentions in moral judgment
Intent and mitigating circumstances play a central role in moral and legal assessments in large-scale industrialized societies. Although these features of moral assessment are widely assumed to be universal, to date, they have only been studied in a narrow range of societies. We show that there is substantial cross-cultural variation among eight traditional small-scale societies (ranging from hunter-gatherer to pastoralist to horticulturalist) and two Western societies (one urban, one rural) in the extent to which intent and mitigating circumstances influence moral judgments. Although participants in all societies took such factors into account to some degree, they did so to very different extents, varying in both the types of considerations taken into account and the types of violations to which such considerations were applied. The particular patterns of assessment characteristic of large-scale industrialized societies may thus reflect relatively recently culturally evolved norms rather than inherent features of human moral judgment.
Journal Article
Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas
Murat Günel and colleagues identify recurrent mutations in
POLR2A
, which encodes the catalytic subunit of RNA polymerase II, in a subset of meningiomas. They find that
POLR2A
-mutant tumors can be distinguished on the basis of their super-enhancer and gene expression profiles, which show dysregulation of key meningeal identity genes.
RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in
POLR2A
, which encodes the catalytic subunit of RNA polymerase II (ref.
1
), hijack this essential enzyme and drive neoplasia.
POLR2A
mutant tumors show dysregulation of key meningeal identity genes
2
,
3
, including
WNT6
and
ZIC1
/
ZIC4
. In addition to mutations in
POLR2A
,
NF2
,
SMARCB1, TRAF7
,
KLF4
,
AKT1
,
PIK3CA
, and
SMO
4
,
5
,
6
,
7
,
8
, we also report somatic mutations in
AKT3
,
PIK3R1
,
PRKAR1A
, and
SUFU
in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.
Journal Article
A multi-omic atlas of human embryonic skeletal development
Human embryonic bone and joint formation is determined by coordinated differentiation of progenitors in the nascent skeleton. The cell states, epigenetic processes and key regulatory factors that underlie lineage commitment of these cells remain elusive. Here we applied paired transcriptional and epigenetic profiling of approximately 336,000 nucleus droplets and spatial transcriptomics to establish a multi-omic atlas of human embryonic joint and cranium development between 5 and 11 weeks after conception. Using combined modelling of transcriptional and epigenetic data, we characterized regionally distinct limb and cranial osteoprogenitor trajectories across the embryonic skeleton and further described regulatory networks that govern intramembranous and endochondral ossification. Spatial localization of cell clusters in our in situ sequencing data using a new tool, ISS-Patcher, revealed mechanisms of progenitor zonation during bone and joint formation. Through trajectory analysis, we predicted potential non-canonical cellular origins for human chondrocytes from Schwann cells. We also introduce SNP2Cell, a tool to link cell-type-specific regulatory networks to polygenic traits such as osteoarthritis. Using osteolineage trajectories characterized here, we simulated in silico perturbations of genes that cause monogenic craniosynostosis and implicate potential cell states and disease mechanisms. This work forms a detailed and dynamic regulatory atlas of bone and cartilage maturation and advances our fundamental understanding of cell-fate determination in human skeletal development.
A multiomic atlas of human embryonic joint and cranium development enables detailed analysis of bone and cartilage maturation.
Journal Article