Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence‐associated secretory phenotype (SASP). Many types of stress induce senescence, including ...genotoxic stress. ERCC1‐XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome. Humans or mice with reduced expression of this enzyme age rapidly due to increased levels of spontaneous, genotoxic stress. Here, we asked whether this corresponds to an increased level of senescent cells. p16Ink4a and p21Cip1 mRNA were increased ~15‐fold in peripheral lymphocytes from 4‐ to 5‐month‐old Ercc1−/∆ and 2.5‐year‐old wild‐type (WT) mice, suggesting that these animals exhibit a similar biological age. p16Ink4a and p21Cip1 mRNA were elevated in 10 of 13 tissues analyzed from 4‐ to 5‐month‐old Ercc1−/∆ mice, indicating where endogenous DNA damage drives senescence in vivo. Aged WT mice had similar increases of p16Ink4a and p21Cip1 mRNA in the same 10 tissues as the mutant mice. Senescence‐associated β–galactosidase activity and p21Cip1 protein also were increased in tissues of the progeroid and aged mice, while Lamin B1 mRNA and protein levels were diminished. In Ercc1−/Δ mice with a p16Ink4a luciferase reporter, bioluminescence rose steadily with age, particularly in lung, thymus, and pancreas. These data illustrate where senescence occurs with natural and accelerated aging in mice and the relative extent of senescence among tissues. Interestingly, senescence was greater in male mice until the end of life. The similarities between Ercc1−/∆ and aged WT mice support the conclusion that the DNA repair‐deficient mice accurately model the age‐related accumulation of senescent cells, albeit six‐times faster.
Senescent cells contribute to aging and its associated morbidities. Senescent cells accumulate in vertebrates with aging. Here, we survey where (in what tissues) senescence occurs with aging in mice, by measuring p16Ink4a and p21Cip1 mRNA. A similar survey in Ercc1−/Δ mice illustrates where (in what tissues) senescence occurs in vivo as a consequence of endogenous DNA damage.
Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and ...diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.
Angiosperms are by far the most species-rich clade of land plants, but their origin and early evolutionary history remain poorly understood. We reconstructed angiosperm phylogeny based on 80 genes ...from 2,881 plastid genomes representing 85% of extant families and all orders. With a well-resolved plastid tree and 62 fossil calibrations, we dated the origin of the crown angiosperms to the Upper Triassic, with major angiosperm radiations occurring in the Jurassic and Lower Cretaceous. This estimated crown age is substantially earlier than that of unequivocal angiosperm fossils, and the difference is here termed the 'Jurassic angiosperm gap'. Our time-calibrated plastid phylogenomic tree provides a highly relevant framework for future comparative studies of flowering plant evolution.
Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly
. To define the contribution of immune system ageing to organism ageing, here we ...selectively deleted Ercc1, which encodes a crucial DNA repair protein
, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence
in the immune system only. We show that Vav-iCre
;Ercc1
mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice
. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre
;Ercc1
or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre
;Ercc1
mice with rapamycin reduced markers of senescence in immune cells and improved immune function
. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal muscle disease caused by mutations in the desmin (DES) gene. Mutations in the central 2B domain of DES cause skeletal muscle ...disease that typically precedes cardiac involvement. However, the prevalence of DES mutations in dilated cardiomyopathy (DCM) without skeletal muscle disease is not known.
Denaturing high-performance liquid chromatography was used to screen DES for mutations in 116 DCM families from the Familial Dilated Cardiomyopathy Registry and in 309 subjects with DCM from the Beta-Blocker Evaluation of Survival Trial (BEST). DES mutations were transfected into SW13 and human smooth muscle cells and neonatal rat cardiac myocytes, and the effects on cytoskeletal desmin network architecture were analyzed with confocal microscopy. Five novel missense DES mutations, including the first localized to the highly conserved 1A domain, were detected in 6 subjects (1.4%). Transfection of DES mutations in the 2B domain severely disrupted the fine intracytoplasmic staining of desmin, causing clumping of the desmin protein. A tail domain mutation (Val459Ile) showed milder effects on desmin cytoplasmic network formation and appears to be a low-penetrant mutation restricted to black subjects.
The prevalence of DES mutations in DCM is between 1% and 2%, and mutations in the 1A helical domain, as well as the 2B rod domain, are capable of causing a DCM phenotype. The lack of severe disruption of cytoskeletal desmin network formation seen with mutations in the 1A and tail domains suggests that dysfunction of seemingly intact desmin networks is sufficient to cause DCM.
Flowering plants (angiosperms) are dominant components of global terrestrial ecosystems, but phylogenetic relationships at the familial level and above remain only partially resolved, greatly ...impeding our full understanding of their evolution and early diversification. The plastome, typically mapped as a circular genome, has been the most important molecular data source for plant phylogeny reconstruction for decades.
Here, we assembled by far the largest plastid dataset of angiosperms, composed of 80 genes from 4792 plastomes of 4660 species in 2024 genera representing all currently recognized families. Our phylogenetic tree (PPA II) is essentially congruent with those of previous plastid phylogenomic analyses but generally provides greater clade support. In the PPA II tree, 75% of nodes at or above the ordinal level and 78% at or above the familial level were resolved with high bootstrap support (BP ≥ 90). We obtained strong support for many interordinal and interfamilial relationships that were poorly resolved previously within the core eudicots, such as Dilleniales, Saxifragales, and Vitales being resolved as successive sisters to the remaining rosids, and Santalales, Berberidopsidales, and Caryophyllales as successive sisters to the asterids. However, the placement of magnoliids, although resolved as sister to all other Mesangiospermae, is not well supported and disagrees with topologies inferred from nuclear data. Relationships among the five major clades of Mesangiospermae remain intractable despite increased sampling, probably due to an ancient rapid radiation.
We provide the most comprehensive dataset of plastomes to date and a well-resolved phylogenetic tree, which together provide a strong foundation for future evolutionary studies of flowering plants.
Abstract
The Protein Data Bank (PDB) is the single global archive of experimentally determined three-dimensional (3D) structure data of biological macromolecules. Since 2003, the PDB has been managed ...by the Worldwide Protein Data Bank (wwPDB; wwpdb.org), an international consortium that collaboratively oversees deposition, validation, biocuration, and open access dissemination of 3D macromolecular structure data. The PDB Core Archive houses 3D atomic coordinates of more than 144 000 structural models of proteins, DNA/RNA, and their complexes with metals and small molecules and related experimental data and metadata. Structure and experimental data/metadata are also stored in the PDB Core Archive using the readily extensible wwPDB PDBx/mmCIF master data format, which will continue to evolve as data/metadata from new experimental techniques and structure determination methods are incorporated by the wwPDB. Impacts of the recently developed universal wwPDB OneDep deposition/validation/biocuration system and various methods-specific wwPDB Validation Task Forces on improving the quality of structures and data housed in the PDB Core Archive are described together with current challenges and future plans.
Abstract
Path analysis was used to assess direct and mediating relationships of an a priori mediation model. Data were collected from 210 black, Hispanic/Latino, and Asian undergraduate college ...students. Authors found that microaggression was positively associated with ethnic identity. Microaggression had a significant positive association with psychological distress but no other direct relationships with the outcome variables. Ethnic identity was negatively associated with psychological distress but positively associated with self-esteem and academic self-efficacy. A positive effect was found between ethnic identity and substance abuse. Ethnic identity mediated the effect of microaggression on psychological distress. Moreover, including ethnic identity in the equation revealed that microaggression has a positive effect on self-esteem and academic self-efficacy through participants’ reported degree of ethnic identity. The results suggest that racial microaggressions have damaging impacts on the emotional health of racial and ethnic minority young adults. However, microaggressive experiences may also elicit stronger ethnic identity, which appears to serve as a protective factor to the negative influence of microaggression on psychological well-being. Post hoc exploratory multigroup analysis revealed some differential findings for each group. The article concludes with a discussion of the implications for social work practice, education, and research.
Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk. While genetic association studies have successfully identified common genetic variants ...associated with susceptibility, these studies are not practical for identifying rare variants. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.
The American College of Obstetricians and Gynecologists currently recommends that antibiotic treatment should be considered for women with isolated maternal fevers during labor. However, there is ...little known about the maternal and neonatal impact of antibiotic treatment in this scenario.
We sought to assess the outcomes in women with a nonsustained, isolated maternal fever treated with antibiotics and compare it with expectant management.
This was a retrospective cohort study of laboring women with a singleton gestation at term and a single temperature of between 38.0°C and 38.9°C without other evidence of infection (leukocytosis >15,000/mm3, fetal tachycardia, malodorous amniotic fluid, suspected alternate source of infection) at a tertiary teaching hospital. A contemporaneously maintained, validated obstetrical database was used to identify women for our cohort. Women with rheumatologic or renal disease, nongestational diabetes, preterm labor, placental abruption, vaginal bleeding, HIV, malpresentation, and fetal anomalies were excluded. The primary outcome was a postpartum fever above 38.0°C. Secondary maternal outcomes were treatment for postpartum endometritis, uterine atony, postpartum hemorrhage, admission to the intensive care unit, and postpartum length of stay. Secondary neonatal outcomes were neonatal intensive care unit admission, 5-minute Apgar score of <7, 5-minute Apgar score of <4, neonatal intensive care unit length of stay, and neonatal antibiotic administration. The results were compared using univariable and multivariable analyses.
From January 1, 2015, to December 31, 2018, 359 women were identified; 85 received antibiotics and 274 did not. The baseline characteristics were similar between the groups, except for gestational age at the time of delivery (39.2 weeks vs 39.5 weeks for the antibiotic and no antibiotic groups, respectively; P=.02). The incidence in postpartum fever showed a downward trend in the antibiotic group (10.59% for the antibiotic group vs 18.98% for the no antibiotic group; P=.07). Significantly fewer women in the antibiotic group were treated for postpartum endometritis (3.53% vs 11.31%; P=.03). Neonatal intensive care unit admission and neonatal antibiotic administration rates were higher in the antibiotic group (41.18% vs 17.88%; P<.001 and 36.47% vs 12.41%; P<.001, respectively). The incidence of 5-minute Apgar score of <7 was higher in the antibiotic group (8.25% vs 2.19%; P=.016). After controlling for age, gestational age, body mass index, group B streptococci status, delivery method, parity, administration of epidural, and receipt of acetaminophen, the odds for postpartum fever were reduced by a factor of 0.42 (95% confidence interval, 0.18–0.99) among women who received antibiotics when compared with those who did not receive antibiotics. Outcome results are presented in Table 2.
Although there was a lower rate of treatment for endometritis among women who received antibiotics for a single isolated maternal fever, there was a higher rate of neonatal intensive care unit admissions and 5-minute Apgar score of <7. This indicates that there likely is maternal benefit associated with antibiotic use, however, there are concerns about the neonatal risk.
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