Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy ...Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.
The greatest difference between species is size; however, the developmental mechanisms determining organism growth remain poorly understood. Primordial dwarfism is a group of human single-gene ...disorders with extreme global growth failure (which includes Seckel syndrome, microcephalic osteodysplastic primordial dwarfism I MOPD types I and II, and Meier-Gorlin syndrome). Ten genes have now been identified for microcephalic primordial dwarfism, encoding proteins involved in fundamental cellular processes including genome replication (ORC1 origin recognition complex 1, ORC4, ORC6, CDT1, and CDC6), DNA damage response (ATR ataxia-telangiectasia and Rad3-related), mRNA splicing (U4atac), and centrosome function (CEP152, PCNT, and CPAP). Here, we review the cellular and developmental mechanisms underlying the pathogenesis of these conditions and address whether further study of these genes could provide novel insight into the physiological regulation of organism growth.
Benralizumab is an IL5-receptor monoclonal antibody licensed for the treatment of severe eosinophilic asthma (SEA). It has demonstrated efficacy in clinical trials in reducing asthma exacerbation ...rates and maintenance oral corticosteroids (mOCSs).
What is the real-world effectiveness of benralizumab and what baseline characteristics are associated with response to therapy?
We assessed outcomes in all SEA patients who began benralizumab treatment at our specialist center. At each dosing visit, exacerbation history, mOCS dose, spirometry, and Asthma Control Questionnaire (ACQ6) and Mini-Asthma Quality of Life Questionnaire (mAQLQ) scores were recorded. Response to treatment was defined as a reduction of ≥ 50% in annualized exacerbation rate (AER) or in mOCS dose after 48 weeks of treatment. Super response was defined as zero exacerbations and no mOCSs for asthma.
One hundred thirty patients were included in the analysis. At 48 weeks, a 72.8% reduction in AER was noted, from 4.92 ± 3.35 per year in the year preceding biologic treatment to 1.34 ± 1.71 per year (P < .001), including 57 patients (43.8%) who were exacerbation-free with benralizumab. In those receiving mOCSs (n = 74 56.9%), the median daily prednisolone dose fell from 10 mg (interquartile range, 5-20 mg) to 0 mg (interquartile range, 0-5 mg; P < .001), and 38 of 74 patients (51.4%) were able to discontinue mOCS therapy. Clinically and statistically significant improvements were found in ACQ6 scores, mAQLQ scores, and FEV1. Overall, 51 patients (39%) met the super responder definition and 112 patients (86%) met the responder definition. The optimal regression model of super responders vs other responders included baseline characteristics associated with a strongly eosinophilic phenotype and less severe disease. Eighteen patients (13.8%) were nonresponders to benralizumab. Evidence of chronic airway infection was observed in 6 of 18 patients, and an increase in the blood eosinophil count consistent with the development of anti-drug antibodies was observed in 5 of 18 patients.
In a large real-world SEA cohort, benralizumab led to significant improvements in all clinical outcome measures. A lack of response was seen in a minority of patients and should be a focus for future investigation.
A decade of genome sequencing has transformed our understanding of how
trypanosomatid parasites have evolved and provided fresh impetus to explaining
the origins of parasitism in the Kinetoplastida. ...In this review, I will consider
the many ways in which genome sequences have influenced our view of genomic
reduction in trypanosomatids; how species-specific genes, and the genomic
domains they occupy, have illuminated the innovations in trypanosomatid genomes;
and how comparative genomics has exposed the molecular mechanisms responsible
for innovation and adaptation to a parasitic lifestyle.
Geophysical inversion and optimal transport Sambridge, Malcolm; Jackson, Andrew; Valentine, Andrew P
Geophysical journal international,
06/2022, Volume:
231, Issue:
1
Journal Article
Peer reviewed
Open access
SUMMARY
We propose a new approach to measuring the agreement between two oscillatory time-series, such as seismic waveforms, and demonstrate that it can be used effectively in inverse problems. Our ...approach is based on Optimal Transport theory and the Wasserstein distance, with a novel transformation of the time-series to ensure that necessary normalization and positivity conditions are met. Our measure is differentiable, and can readily be used within an optimization framework. We demonstrate performance with a variety of synthetic examples, including seismic source inversion, and observe substantially better convergence properties than achieved with conventional L2 misfits. We also briefly discuss the relationship between Optimal Transport and Bayesian inference.
To improve replication fidelity, mismatch repair (MMR) must detect non-Watson-Crick base pairs and direct their repair to the nascent DNA strand. Eukaryotic MMR in vitro requires pre-existing strand ...discontinuities for initiation; consequently, it has been postulated that MMR in vivo initiates at Okazaki fragment termini in the lagging strand and at nicks generated in the leading strand by the mismatch-activated MLH1/PMS2 endonuclease. We now show that a single ribonucleotide in the vicinity of a mismatch can act as an initiation site for MMR in human cell extracts and that MMR activation in this system is dependent on RNase H2. As loss of RNase H2 in S.cerevisiae results in a mild MMR defect that is reflected in increased mutagenesis, MMR in vivo might also initiate at RNase H2-generated nicks. We therefore propose that ribonucleotides misincoporated during DNA replication serve as physiological markers of the nascent DNA strand.
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► Ribonucleotides incorporated into eukaryotic DNA are not mismatch repair substrates ► Intermediates of rNMP processing can act as initiation sites for mismatch repair ► RNase H2 deficiency in S. cerevisiae decreases MMR efficiency ► rNMPs can act as markers of nascent DNA strands
DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, which encodes the DNA ...methyltransferase DNMT3A. These mutations cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2 and H3K36me3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3a
pluripotent cells in vitro, and is also evident in Dnmt3a
dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2 and H3K36me3 normally limits DNA methylation of Polycomb-marked regions. Our findings implicate the interplay between DNA methylation and Polycomb at key developmental regulators as a determinant of organism size in mammals.
The presence of ribonucleotides in genomic DNA is undesirable given their increased susceptibility to hydrolysis. Ribonuclease (RNase) H enzymes that recognize and process such embedded ...ribonucleotides are present in all domains of life. However, in unicellular organisms such as budding yeast, they are not required for viability or even efficient cellular proliferation, while in humans, RNase H2 hypomorphic mutations cause the neuroinflammatory disorder Aicardi-Goutières syndrome. Here, we report that RNase H2 is an essential enzyme in mice, required for embryonic growth from gastrulation onward. RNase H2 null embryos accumulate large numbers of single (or di-) ribonucleotides embedded in their genomic DNA (>1,000,000 per cell), resulting in genome instability and a p53-dependent DNA-damage response. Our findings establish RNase H2 as a key mammalian genome surveillance enzyme required for ribonucleotide removal and demonstrate that ribonucleotides are the most commonly occurring endogenous nucleotide base lesion in replicating cells.
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► Ribonucleotides are the most common nucleotide base lesion in the mouse genome ► RNase H2 is a key genome surveillance enzyme required for removal of nucleotides ► RNase H2 is essential for mammalian development ► Without RNase H2, cells exhibit genome instability and p53 pathway activation
DNA polymerases can incorporate more than a million ribonucleotides into replicating mouse DNA in each cell, making ribonucleotides the most abundant kind of DNA lesion. RNase H2, which removes this “damage,” has an essential role in genome surveillance and is required for embryonic development.
The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human ...phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.
SUMMARY
Concerns raised by Okazaki & Ueda (2022) on the paper by Sambridge et al. (2022) are addressed. Two issues are discussed and some new numerical results presented. The first concerns whether ...the properties of the Wasserstein time-series misfit introduced in our earlier paper will translate to model space non-uniqueness in a seismic waveform inversion setting. It is argued that this is unlikely, given the special conditions, which must exist between all observed/predicted seismic waveform pairs for non-uniqueness to result. The second issue discussed is the efficacy of using the Sliced Wasserstein algorithm of Bonneel et al. (2015) as an alternate to the marginal Wasserstein algorithm, as proposed by Okazaki & Ueda (2022). It is argued that for optimization-based waveform fitting, the Sliced Wasserstein algorithm is a viable alternate provided care is taken to ensure that conditions arise which do invalidate analytical derivative expressions of the resulting Wasserstein misfit. In practice, this would likely mean recasting the 2D Optimal Transport problem posed in our earlier paper onto unstructured grids.
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