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The Mre11-Rad50-Nbs1 (MRN) complex recognizes and processes DNA double-strand breaks for homologous recombination by performing short-range removal of 5ʹ strands. Endonucleolytic processing by MRN requires a stably bound protein at the break site—a role we postulate is played by DNA-dependent protein kinase (DNA-PK) in mammals. Here we interrogate sites of MRN-dependent processing by identifying sites of CtIP association and by sequencing DNA-PK-bound DNA fragments that are products of MRN cleavage. These intermediates are generated most efficiently when DNA-PK is catalytically blocked, yielding products within 200 bp of the break site, whereas DNA-PK products in the absence of kinase inhibition show greater dispersal. Use of light-activated Cas9 to induce breaks facilitates temporal resolution of DNA-PK and Mre11 binding, showing that both complexes bind to DNA ends before release of DNA-PK-bound products. These results support a sequential model of double-strand break repair involving collaborative interactions between homologous and non-homologous repair complexes. Deshpande et al show that MRN nuclease-dependent processing of DNA ends in human cells occurs at sites bound by DNA-PK. Chromatin immunoprecipitation analysis of DNA-PK, MRN, and CtIP supports a sequential model of pathway choice.

Areas covered: This paper offers a practical framework for addressing infidelity by integrating Woolley's (2011) motivation-based typology of affairs into the practice of Emotionally Focused Therapy (EFT) and the Attachment Injury Repair Model (AIRM). The typology categorizes infidelity into three broad categories, and seven specific types based on motivations, offering a lens through which couple therapists can focus their approach.

Background Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) and cardiomegaly have not been described. Objectives To investigate the effect of pimobendan on clinical variables and the relationship between a change in heart size and the time to congestive heart failure (CHF) or cardiac‐related death (CRD) in dogs with MMVD and cardiomegaly. To determine whether pimobendan‐treated dogs differ from dogs receiving placebo at onset of CHF. Animals Three hundred and fifty‐four dogs with MMVD and cardiomegaly. Materials and Methods Prospective, blinded study with dogs randomized (ratio 1:1) to pimobendan (0.4–0.6 mg/kg/d) or placebo. Clinical, laboratory, and heart‐size variables in both groups were measured and compared at different time points (day 35 and onset of CHF) and over the study duration. Relationships between short‐term changes in echocardiographic variables and time to CHF or CRD were explored. Results At day 35, heart size had reduced in the pimobendan group: median change in (Δ) LVIDDN −0.06 (IQR: −0.15 to +0.02), P < 0.0001, and LA:Ao −0.08 (IQR: −0.23 to +0.03), P < 0.0001. Reduction in heart size was associated with increased time to CHF or CRD. Hazard ratio for a 0.1 increase in ΔLVIDDN was 1.26, P = 0.0003. Hazard ratio for a 0.1 increase in ΔLA:Ao was 1.14, P = 0.0002. At onset of CHF, groups were similar. Conclusions and Clinical Importance Pimobendan treatment reduces heart size. Reduced heart size is associated with improved outcome. At the onset of CHF, dogs treated with pimobendan were indistinguishable from those receiving placebo.

ABSTRACT Pulmonary hypertension (PH) carries a poor prognosis and a high mortality. Loss of pulmonary arterial compliance (PAC) plays a significant role in the development of PH and is an early predictor of mortality. Currently, there are no therapeutic options to overcome the loss of PAC. Aria CV (Saint Paul, MN) has developed a device to augment PAC. The device consists of a 20‐cc balloon and anchor that can be implanted in the pulmonary artery using a minimally invasive procedure, a catheter, and a gas reservoir. Computed tomography imaging of 46 patients from the ASPIRE database and cadaver studies (n = 7) were used to ascertain device fit and optimize surgical procedure. Aria CV devices (n = 6) were tested for simulated use, durability, and PAC augmentation. Animal studies were conducted to demonstrate device safety in the deflated state (n = 9), and gas embolism due to simulated balloon rupture (n = 5). A chronic bovine model of PH was used to demonstrate PAC augmentation (n = 3). Chronic animal studies (n = 8, 30‐days) were conducted to demonstrate long‐term device safety and biocompatibility per ISO 10993 standards. In‐silico fit and cadaver studies demonstrated that the device could be successfully implanted in the PA for a wide range of patients. In vitro and bovine models of PH demonstrated that the chronic Aria CV device enhanced PAC by > 0.4 ml/mmHg, which matched the PAC enhancement observed in 28 human patients with a short‐term Aria CV device. The device passed all required durability, safety, and biocompatibility testing and is enrolling patients in a Food and Drug Administration (FDA) approved clinical trial (ASPIRE PH, NCT04555161).

The surface of Mars has been well mapped and characterized, yet the subsurface — the most likely place to find signs of extant or extinct life and a repository of useful resources for human exploration — remains unexplored. In the near future this is set to change.

There is currently a need for a review of the definition and methodology of determining sustainable yield. The reasons are: (1) current definitions and concepts are ambiguous and non-physically based so cannot be used for quantitative application, (2) there is a need to eliminate varying interpretations and misinterpretations and provide a sound basis for application, (3) the notion that all groundwater systems either are or can be made to be sustainable is invalid, (4) often there are an excessive number of factors bound up in the definition that are not easily quantifiable, (5) there is often confusion between production facility optimal yield and basin sustainable yield, (6) in many semi-arid and arid environments groundwater systems cannot be sensibly developed using a sustained yield policy particularly where ecological constraints are applied. Derivation of sustainable yield using conservation of mass principles leads to expressions for basin sustainable, partial (non-sustainable) mining and total (non-sustainable) mining yields that can be readily determined using numerical modelling methods and selected on the basis of applied constraints. For some cases there has to be recognition that the groundwater resource is not renewable and its use cannot therefore be sustainable. In these cases, its destiny should be the best equitable use.

Although complex interactions between hosts and microbial associates are increasingly well documented, we still know little about how and why hosts shape microbial communities in nature. In addition, host genetic effects on microbial communities vary widely depending on the environment, obscuring conclusions about which microbes are impacted and which plant functions are important. We characterized the leaf microbiota of 200 Arabidopsis thaliana genotypes in eight field experiments and detected consistent host effects on specific, broadly distributed microbial species (operational taxonomic unit [OTUs]). Host genetic effects disproportionately influenced central ecological hubs, with heritability of particular OTUs declining with their distance from the nearest hub within the microbial network. These host effects could reflect either OTUs preferentially associating with specific genotypes or differential microbial success within them. Host genetics associated with microbial hubs explained over 10% of the variation in lifetime seed production among host genotypes across sites and years. We successfully cultured one of these microbial hubs and demonstrated its growth-promoting effects on plants in sterile conditions. Finally, genome-wide association mapping identified many putatively causal genes with small effects on the relative abundance of microbial hubs across sites and years, and these genes were enriched for those involved in the synthesis of specialized metabolites, auxins, and the immune system. Using untargeted metabolomics, we corroborate the consistent association between variation in specialized metabolites and microbial hubs across field sites. Together, our results reveal that host genetic variation impacts the microbial communities in consistent ways across environments and that these effects contribute to fitness variation among host genotypes.

Functional exercise capacity has been shownto be a strong predictor of survival following pulmonaryrehabilitation. This study evaluated whether questionnaire-ratedfunctional status is also predictive of survival. Following pulmonary rehabilitation, patients withadvanced chronic lung disease were evaluated for survival, 6-min walkdistance, and questionnaire-rated functional status. The latter wasmeasured using the pulmonary functional status scale, which hassubscores of functional activities, psychological status, and dyspnea. Information on survival was available on 149 patients. The mean age was 69 years, and 45% of patientswere male. Eighty-nine percent had a diagnosis of COPD, and their, FEV1 was 37 ± 18% of predicted. Ninety-one (61%) weremarried. The 3-year survival for the group was 85%. Age, gender, bodymass index, and primary diagnosis were not related to survival. Variables strongly associated with increased survival followingpulmonary rehabilitation included a higher postrehabilitation, Functional Activities score, a longer postrehabilitation 6-min walkdistance, and being married (vs widowed, single, or divorced). Diseaseseverity variables associated with survival included an initialreferral to outpatient pulmonary rehabilitation, no supplemental oxygenrequirement, and a higher percent-predicted FEV1. Indicators of functional status are strongpredictors of survival in patients with advanced lungdisease.

Long-read sequencing technologies such as isoform sequencing can generate highly accurate sequences of full-length mRNA transcript isoforms. Such long-read transcriptomics may be especially useful in investigations of lymphocyte functional plasticity as it relates to human health and disease. However, no long-read isoform-aware reference transcriptomes of human circulating lymphocytes are readily available despite being valuable as benchmarks in a variety of transcriptomic studies. To begin to fill this gap, we purified 4 lymphocyte populations (CD4+ T, CD8+ T, NK, and Pan B cells) from the peripheral blood of a healthy male donor and obtained high-quality RNA (RIN > 8) for isoform sequencing and parallel RNA-Seq analyses. Many novel polyadenylated transcript isoforms, supported by both isoform sequencing and RNA-Seq data, were identified within each sample. The datasets met several metrics of high quality and have been deposited to the Gene Expression Omnibus database (GSE202327, GSE202328, GSE202329) as both raw and processed files to serve as long-read reference transcriptomes for future studies of human circulating lymphocytes.

A novel Hamiltonian scheme for non-relativistic quantum electrodynamics in which the gauge arbitrariness of the field potential is kept explicit is used to study the gauge-dependence properties of various versions of perturbation theory when resonance and line-broadening effects are admitted. Time-dependent perturbation theory is shown to have severe gauge-dependence problems unless ad hoc modifications are made. A time-independent formulation of S-matrix theory is then studied. Far from resonance, the S-matrix is gauge invariant in all orders of perturbation theory due to a very precise cancellation of gauge-dependent terms which requires, among other things, complete sets of intermediate states; energy conservation also has a crucial role. However, an obvious separation of the S-matrix into a resonant (pole) and non-resonant background leads to incomplete cancellation of the gauge-dependent terms. The introduction of the Heitler damping matrix into an integral equation for the T-matrix leads to a gauge-invariant result. This provides the basis for a gauge invariant S-matrix theory of atoms and molecules interacting with electromagnetic radiation that encompasses resonance and damping effects.