The repair of DNA by homologous recombination is an essential, efficient, and high-fidelity process that mends DNA lesions formed during cellular metabolism; these lesions include double-stranded DNA ...breaks, daughter-strand gaps, and DNA cross-links. Genetic defects in the homologous recombination pathway undermine genomic integrity and cause the accumulation of gross chromosomal abnormalities-including rearrangements, deletions, and aneuploidy-that contribute to cancer formation. Recombination proceeds through the formation of joint DNA molecules-homologously paired but metastable DNA intermediates that are processed by several alternative subpathways-making recombination a versatile and robust mechanism to repair damaged chromosomes. Modern biophysical methods make it possible to visualize, probe, and manipulate the individual molecules participating in the intermediate steps of recombination, revealing new details about the mechanics of genetic recombination. We review and discuss the individual stages of homologous recombination, focusing on common pathways in bacteria, yeast, and humans, and place particular emphasis on the molecular mechanisms illuminated by single-molecule methods.
Iron doping of nickel oxide films results in enhanced activity for promoting the oxygen evolution reaction (OER). Whereas this enhanced activity has been ascribed to a unique iron site within the ...nickel oxide matrix, we show here that Fe doping influences the Ni valency. The percent of Fe3+ doping promotes the formation of formal Ni4+, which in turn directly correlates with an enhanced activity of the catalyst in promoting OER. The role of Fe3+ is consistent with its behavior as a superior Lewis acid.
The expression of the insulin-like growth factor 2 (Igf2) and
H19 genes is imprinted. Although these neighbouring genes share an enhancer, H19 is expressed only from the maternal allele, and
Igf2 ...only from the paternally inherited allele. A region
of paternal-specific methylation upstream of H19 appears to be the
site of an epigenetic mark that is required for the imprinting of these genes. A deletion within this region results in loss of imprinting
of both H19 and Igf2 (ref. 5). Here
we show that this methylated region contains an element that blocks enhancer
activity. The activity of this element is dependent upon the vertebrate enhancer-blocking
protein CTCF. Methylation of CpGs within the CTCF-binding sites eliminates
binding of CTCF in vitro, and deletion of these sites results in loss
of enhancer-blocking activity in vivo, thereby allowing gene expression.
This CTCF-dependent enhancer-blocking element acts as an insulator. We suggest
that it controls imprinting of Igf2. The activity of this insulator
is restricted to the maternal allele by specific DNA methylation of the paternal
allele. Our results reveal that DNA methylation can control gene expression
by modulating enhancer access to the gene promoter through regulation of an
enhancer boundary.
A kagome lattice of 3d transition metal ions is a versatile platform for correlated topological phases hosting symmetry-protected electronic excitations and magnetic ground states. However, the ...paradigmatic states of the idealized two-dimensional kagome lattice-Dirac fermions and flat bands-have not been simultaneously observed. Here, we use angle-resolved photoemission spectroscopy and de Haas-van Alphen quantum oscillations to reveal coexisting surface and bulk Dirac fermions as well as flat bands in the antiferromagnetic kagome metal FeSn, which has spatially decoupled kagome planes. Our band structure calculations and matrix element simulations demonstrate that the bulk Dirac bands arise from in-plane localized Fe-3d orbitals, and evidence that the coexisting Dirac surface state realizes a rare example of fully spin-polarized two-dimensional Dirac fermions due to spin-layer locking in FeSn. The prospect to harness these prototypical excitations in a kagome lattice is a frontier of great promise at the confluence of topology, magnetism and strongly correlated physics.
Abstract
The ocean is experiencing unprecedented rapid change, and visually monitoring marine biota at the spatiotemporal scales needed for responsible stewardship is a formidable task. As baselines ...are sought by the research community, the volume and rate of this required data collection rapidly outpaces our abilities to process and analyze them. Recent advances in machine learning enables fast, sophisticated analysis of visual data, but have had limited success in the ocean due to lack of data standardization, insufficient formatting, and demand for large, labeled datasets. To address this need, we built FathomNet, an open-source image database that standardizes and aggregates expertly curated labeled data. FathomNet has been seeded with existing iconic and non-iconic imagery of marine animals, underwater equipment, debris, and other concepts, and allows for future contributions from distributed data sources. We demonstrate how FathomNet data can be used to train and deploy models on other institutional video to reduce annotation effort, and enable automated tracking of underwater concepts when integrated with robotic vehicles. As FathomNet continues to grow and incorporate more labeled data from the community, we can accelerate the processing of visual data to achieve a healthy and sustainable global ocean.
Two major mechanisms are involved in the formation of blood vasculature: vasculogenesis and angiogenesis. The former term describes the formation of a capillary-like network from either a dispersed ...or a monolayered population of endothelial cells, reproducible also in vitro by specific experimental assays. The latter term describes the sprouting of new vessels from an existing capillary or post-capillary venule. Similar mechanisms are also involved in the formation of the lymphatic system through a process generally called lymphangiogenesis. A number of mathematical approaches have been used to analyze these phenomena. In this paper, we review the different types of models, with special emphasis on their ability to reproduce different biological systems and to predict measurable quantities which describe the overall processes. Finally, we highlight the advantages specific to each of the different modelling approaches.
•Review on mathematical modelling of angiogenesis, vacsulogenesis and lympangiogenesis.•Explanation of the main features of discrete, continuum, mechanics-based, individual-based models.•Explanation of the multiscale aspects related to the phenomena.•Description of hybrid and nested approaches.
Alternative route to a 2D superconductor
Single layers of transition metal dichalcogenides exhibit exotic properties, including superconductivity. The usual route to obtaining such samples is to ...exfoliate a three-dimensional (3D) crystal. Devarakonda
et al.
instead grew a superlattice comprising alternating layers of the transition metal dichalcogenide hexagonal NbS
2
and the material Ba
3
NbS
5
(see the Perspective by Schoop). The inert Ba
3
NbS
5
layers serve to dissociate the superconducting NbS
2
layers from one another, resulting in 2D superconductivity with high carrier mobility. The combination of high mobility and reduced dimensionality may give rise to exotic quantum phases.
Science
, this issue p.
231
see also p.
170
A superlattice of alternating layers of
H
-NbS
2
and Ba
3
NbS
5
exhibits 2D superconductivity and high carrier mobility.
Advances in low-dimensional superconductivity are often realized through improvements in material quality. Apart from a small group of organic materials, there is a near absence of clean-limit two-dimensional (2D) superconductors, which presents an impediment to the pursuit of numerous long-standing predictions for exotic superconductivity with fragile pairing symmetries. We developed a bulk superlattice consisting of the transition metal dichalcogenide (TMD) superconductor 2
H
-niobium disulfide (2
H
-NbS
2
) and a commensurate block layer that yields enhanced two-dimensionality, high electronic quality, and clean-limit inorganic 2D superconductivity. The structure of this material may naturally be extended to generate a distinct family of 2D superconductors, topological insulators, and excitonic systems based on TMDs with improved material properties.
Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide ...important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.
The past six decades have seen remarkable improvements in health outcomes for people with cystic fibrosis, which was once a fatal disease of infants and young children. However, although life ...expectancy for people with cystic fibrosis has increased substantially, the disease continues to limit survival and quality of life, and results in a large burden of care for people with cystic fibrosis and their families. Furthermore, epidemiological studies in the past two decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognised in many regions of the world. The Lancet Respiratory Medicine Commission on the future of cystic fibrosis care was established at a time of great change in the clinical care of people with the disease, with a growing population of adult patients, widespread genetic testing supporting the diagnosis of cystic fibrosis, and the development of therapies targeting defects in the cystic fibrosis transmembrane conductance regulator (CFTR), which are likely to affect the natural trajectory of the disease. The aim of the Commission was to bring to the attention of patients, health-care professionals, researchers, funders, service providers, and policy makers the various challenges associated with the changing landscape of cystic fibrosis care and the opportunities available for progress, providing a blueprint for the future of cystic fibrosis care. The discovery of the CFTR gene in the late 1980s triggered a surge of basic research that enhanced understanding of the pathophysiology and the genotype-phenotype relationships of this clinically variable disease. Until recently, available treatments could only control symptoms and restrict the complications of cystic fibrosis, but advances in CFTR modulator therapies to address the basic defect of cystic fibrosis have been remarkable and the field is evolving rapidly. However, CFTR modulators approved for use to date are highly expensive, which has prompted questions about the affordability of new treatments and served to emphasise the considerable gap in health outcomes for patients with cystic fibrosis between high-income countries, and low-income and middle-income countries (LMICs). Advances in clinical care have been multifaceted and include earlier diagnosis through the implementation of newborn screening programmes, formalised airway clearance therapy, and reduced malnutrition through the use of effective pancreatic enzyme replacement and a high-energy, high-protein diet. Centre-based care has become the norm in high-income countries, allowing patients to benefit from the skills of expert members of multidisciplinary teams. Pharmacological interventions to address respiratory manifestations now include drugs that target airway mucus and airway surface liquid hydration, and antimicrobial therapies such as antibiotic eradication treatment in early-stage infections and protocols for maintenance therapy of chronic infections. Despite the recent breakthrough with CFTR modulators for cystic fibrosis, the development of novel mucolytic, anti-inflammatory, and anti-infective therapies is likely to remain important, especially for patients with more advanced stages of lung disease. As the median age of patients with cystic fibrosis increases, with a rapid increase in the population of adults living with the disease, complications of cystic fibrosis are becoming increasingly common. Steps need to be taken to ensure that enough highly qualified professionals are present in cystic fibrosis centres to meet the needs of ageing patients, and new technologies need to be adopted to support communication between patients and health-care providers. In considering the future of cystic fibrosis care, the Commission focused on five key areas, which are discussed in this report: the changing epidemiology of cystic fibrosis (section 1); future challenges of clinical care and its delivery (section 2); the building of cystic fibrosis care globally (section 3); novel therapeutics (section 4); and patient engagement (section 5). In panel 1, we summarise key messages of the Commission. The challenges faced by all stakeholders in building and developing cystic fibrosis care globally are substantial, but many opportunities exist for improved care and health outcomes for patients in countries with established cystic fibrosis care programmes, and in LMICs where integrated multidisciplinary care is not available and resources are lacking at present. A concerted effort is needed to ensure that all patients with cystic fibrosis have access to high-quality health care in the future.
The incidence and number of deaths from non-tuberculous mycobacterial (NTM) disease have been steadily increasing globally. These lesser known "cousins" of
(TB) were once thought to be harmless ...environmental saprophytics and only dangerous to individuals with defective lung structure or the immunosuppressed. However, NTM are now commonly infecting seemingly immune competent children and adults at increasing rates through pulmonary infection. This is of concern as the pathology of NTM is difficult to treat. Indeed, NTM have become extremely antibiotic resistant, and now have been found to be internationally dispersed through person-to-person contact. The reasons behind this NTM increase are only beginning to be elucidated. Solutions to the problem are needed given NTM disease is more common in the tropics. Importantly, 40% of the world's population live in the tropics and due to climate change, the Tropics are expanding which will increase NTM infection regions. This review catalogs the global and economic disease burden, at risk populations, treatment options, host-bacterial interaction, immune dynamics, recent developments and research priorities for NTM disease.
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