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The DNA damage response is essential to safeguard genome integrity. Although the contribution of chromatin in DNA repair has been investigated1,2, the contribution of chromosome folding to these processes remains unclear3. Here we report that, after the production of double-stranded breaks (DSBs) in mammalian cells, ATM drives the formation of a new chromatin compartment (D compartment) through the clustering of damaged topologically associating domains, decorated with γH2AX and 53BP1. This compartment forms by a mechanism that is consistent with polymer-polymer phase separation rather than liquid-liquid phase separation. The D compartment arises mostly in G1 phase, is independent of cohesin and is enhanced after pharmacological inhibition of DNA-dependent protein kinase (DNA-PK) or R-loop accumulation. Importantly, R-loop-enriched DNA-damage-responsive genes physically localize to the D compartment, and this contributes to their optimal activation, providing a function for DSB clustering in the DNA damage response. However, DSB-induced chromosome reorganization comes at the expense of an increased rate of translocations, also observed in cancer genomes. Overall, we characterize how DSB-induced compartmentalization orchestrates the DNA damage response and highlight the critical impact of chromosome architecture in genomic instability.

Plastic pollution is distributed patchily around the worlds oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and non-breeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species.

Our understanding of Earth's paleogeography relies heavily on paleomagnetic apparent polar wander paths (APWPs), which represent the time-dependent position of Earth's spin axis relative to a given block of lithosphere. However, conventional approaches to APWP construction have significant limitations. First, the paleomagnetic record contains substantial noise that is not integrated into APWPs. Second, parametric assumptions are adopted to represent spatial and temporal uncertainties even where the underlying data do not conform to the assumed distributions. The consequences of these limitations remain largely unknown. Here, we address these challenges with a bottom-up Monte Carlo uncertainty propagation scheme that operates on site-level paleomagnetic data. To demonstrate our methodology, we present an extensive compilation of site-level Cenozoic paleomagnetic data from North America, which we use to generate a high-resolution APWP. Our results demonstrate that even in the presence of substantial noise, polar wandering can be assessed with unprecedented temporal and spatial resolution.

In the published version of this paper, the list of members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium and their affiliations contained minor errors in the affiliations. The original Article has been corrected to include the corrected list.

BackgroundMagnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS).ObjectiveTo examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM).MethodsPatients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo (n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions.ResultsCompared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity.ConclusionSiponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.

La végétalisation des pistes de ski est l'opération qui vise à introduire une strate herbacée et/ou arborée dans un site, afin de l'insérer dans le paysage, de limiter l'érosion et les impacts négatifs sur l'environnement (pollution de l'air, de l'eau ). Classiquement, il s'agit de projeter dans un flux hydraulique un mélange de semences et de fertilisants, à l'aide d'un appareil appelé hydroseeder. Depuis quelques années, la reconstitution de sol, qui précède la projection hydraulique, se développe dans les stations d'altitude. Il s'agit d'apporter des produits organiques (composts, fumiers) en forte dose. Dans un contexte d'incertitude réglementaire, nous avons mis en place des dispositifs de suivi de la qualité de l'eau dans plusieurs stations alpines. Les résultats montrent que les travaux de terrassement, ainsi que certaines pratiques de végétalisation (épandage de compost en automne) peuvent entraîner des transferts importants d'éléments traces métalliques (ETM) dans les eaux superficielles, notamment à la période critique de la fonte des neiges. Ce travail met en évidence la nécessité de conduire des recherches complémentaires.

Transcriptionally active loci are particularly prone to breakage and mounting evidence suggests that DNA Double-Strand Breaks arising in active genes are handled by a dedicated repair pathway, Transcription-Coupled DSB Repair (TC-DSBR), that entails R-loop accumulation and dissolution. Here, we uncover a function for the Bloom RecQ DNA helicase (BLM) in TC-DSBR in human cells. BLM is recruited in a transcription dependent-manner at DSBs where it fosters resection, RAD51 binding and accurate Homologous Recombination repair. However, in an R-loop dissolution-deficient background, we find that BLM promotes cell death. We report that upon excessive RNA:DNA hybrid accumulation, DNA synthesis is enhanced at DSBs, in a manner that depends on BLM and POLD3. Altogether our work unveils a role for BLM at DSBs in active chromatin, and highlights the toxic potential of RNA:DNA hybrids that accumulate at transcription-associated DSBs.

L'histoire des aménagements forestiers est interrogée d'un triple point de vue. 1) Si les forestiers ont une incontestable légitimité en matière d'aménagement, ils n'ont pas toujours été et ils ne sont plus les seuls à traiter de ces questions qui concernent de plus en plus d'acteurs. 2) Quand se font les révisions des conceptions aménagistes ? En période de crise ou en temps de calme ? Quel système joue un rôle moteur dans les logiques historiques des aménagements ? 3) Comment comprendre la réalisation d'aménagements forestiers hors du cadre classique des théories et des documents d'aménagement ?

Substantial variation in foraging strategies can exist within populations, even those typically regarded as generalists. Specializations arise from the consistent exploitation of a narrow behavioral, spatial or dietary niche over time, which may reduce intraspecific competition and influence adaptability to environmental change. However, few studies have investigated whether behavioral consistency confers benefits at the individual and/or population level. While still recovering from commercial sealing overexploitation, Australian fur seals (AUFS; Arctocephalus pusillus doriferus) represent the largest marine predator biomass in south-eastern Australia. During lactation, female AUFS adopt a central-place foraging strategy and are, thus, vulnerable to changes in prey availability. The present study investigated the population-level repeatability and individual consistency in foraging behavior of 34 lactating female AUFS at a south-east Australian breeding colony between 2006 and 2019. Additionally, the influence of individual-level behavioral consistency on indices of foraging success and efficiency during benthic diving was determined. Low to moderate population-level repeatability was observed across foraging behaviors, with the greatest repeatability in the mean bearing and modal dive depth. Individual-level consistency was greatest for the proportion of benthic diving, total distance travelled, and trip duration. Indices of benthic foraging success and efficiency were positively influenced by consistency in the proportion of benthic diving, trip duration and dive rate but not influenced by consistency in bearing to most distal point, dive depth or foraging site fidelity. The results of the present study provide evidence of the benefits of consistency for individuals, which may have flow-on effects at the population level.

The endangered Galapagos sea lion (GSL, Zalophus wollebaeki) exhibits a range of foraging strategies utilising various dive types including benthic, epipelagic and mesopelagic dives. In the present study, potential prey captures (PPC), prey energy consumption and energy expenditure in lactating adult female GSLs (n = 9) were examined to determine their foraging efficiency relative to the foraging strategy used. Individuals displayed four dive types: (a) epipelagic (100 m; MP) with a characteristic V-shape or U-shape diving profile; and (c) shallow benthic (100 m; DB) with square or flat-bottom dive profiles. These dive types varied in the number of PPC, assumed prey types, and the energy expended. Prey items and their energetic value were assumed from previous GSL diet studies in combination with common habitat and depth ranges of the prey. In comparison to pelagic dives occurring at similar depths, when diving benthically, GSLs had both higher prey energy consumption and foraging energy expenditure whereas PPC rate was lower. Foraging efficiency varied across dive types, with benthic dives being more profitable than pelagic dives. Three foraging trip strategies were identified and varied relative to prey energy consumed, energy expended, and dive behaviour. Foraging efficiency did not significantly vary among the foraging trip strategies suggesting that, while individuals may diverge into different foraging habitats, they are optimal within them. These findings indicate that these three strategies will have different sensitivities to habitat-specific fluctuations due to environmental change.

Understanding the factors which influence foraging behaviour and success in marine mammals is crucial to predicting how their populations may respond to environmental change. The Australian fur seal (Arctocephalus pusillus doriferus, AUFS) is a predominantly benthic forager on the shallow continental shelf of Bass Strait, and represents the greatest biomass of marine predators in south-eastern Australia. The south-east Australian region is experiencing rapid oceanic warming, predicted to lead to substantial alterations in prey diversity, distribution and abundance. In the present study, foraging effort and indices of foraging success and efficiency were investigated in 138 adult female AUFS (970 foraging trips) during the winters of 1998-2019. Large scale climate conditions had a strong influence on foraging effort, foraging success and efficiency. Foraging effort and foraging success were also strongly influenced by winter chlorophyll-a concentrations and sea-surface height anomalies in Bass Strait. The results suggest increasing foraging effort and decreasing foraging success and efficiency under anticipated environmental conditions, which may have population-level impacts.

Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD)-the major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology. Our objective was to test whether telomere dysfunction contributes to the pathologic changes observed in CLAD. Histopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells, and increased expression of senescence markers (β-galactosidase, p16, p53, and p21) in lung epithelial cells. TRF1F/F (telomere repeat binding factor 1 flox/flox) mice were crossed with tamoxifen-inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1F/F mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on microcomputed tomography, a fourfold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II aveolar epithelial cell numbers, expression of senescence-associated β-galactosidase in epithelial cells, and decreased SCGB1a1 expression in airway epithelial cells. These findings demonstrate that telomere dysfunction isolated to airway epithelial cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.