Search

BRCA1 mutations are associated with increased breast and ovarian cancer risk. BRCA1-mutant tumors are high-grade, recurrent, and often become resistant to standard therapies. Herein, we performed a targeted CRISPR-Cas9 screen and identified MEPCE, a methylphosphate capping enzyme, as a synthetic lethal interactor of BRCA1. Mechanistically, we demonstrate that depletion of MEPCE in a BRCA1-deficient setting led to dysregulated RNA polymerase II (RNAPII) promoter-proximal pausing, R-loop accumulation, and replication stress, contributing to transcription-replication collisions. These collisions compromise genomic integrity resulting in loss of viability of BRCA1-deficient cells. We also extend these findings to another RNAPII-regulating factor, PAF1. This study identifies a new class of synthetic lethal partners of BRCA1 that exploit the RNAPII pausing regulation and highlight the untapped potential of transcription-replication collision-inducing factors as unique potential therapeutic targets for treating cancers associated with BRCA1 mutations.

Gas-liquid foams are important in applications ranging from oil recovery and mineral flotation to food science and microfluidics. Beyond their practical use, they represent an intriguing prototype of a soft material with a complex, viscoelastic rheological response. Crucially, foams allow detailed access to fluid-dynamical processes on the mesoscale of bubbles underlying the large-scale material behavior. This review emphasizes the importance of the geometry and interaction of mesoscale structural elements for the description of the dynamics of entire foams. Using examples including bulk flow of foam under steady shear, interfacial instabilities, and foam fracture through bubble rupture, this article highlights the wide variety of available theoretical descriptions, ranging from network modeling approaches coupling structural element equations of motion to full continuum models with elastoviscoplastic constitutive relations. Foams offer the opportunity to develop rigorous links between such disparate descriptions, providing a blueprint for physical modeling of dynamical multiscale systems with complex structure.

Squamous cell carcinomas are triggered by marked elevation of RAS–MAPK signalling and progression from benign papilloma to invasive malignancy1–4. At tumour–stromal interfaces, a subset of tumour-initiating progenitors, the cancer stem cells, obtain increased resistance to chemotherapy and immunotherapy along this pathway5,6. The distribution and changes in cancer stem cells during progression from a benign state to invasive squamous cell carcinoma remain unclear. Here we show in mice that, after oncogenic RAS activation, cancer stem cells rewire their gene expression program and trigger self-propelling, aberrant signalling crosstalk with their tissue microenvironment that drives their malignant progression. The non-genetic, dynamic cascade of intercellular exchanges involves downstream pathways that are often mutated in advanced metastatic squamous cell carcinomas with high mutational burden7. Coupling our clonal skin HRASG12V mouse model with single-cell transcriptomics, chromatin landscaping, lentiviral reporters and lineage tracing, we show that aberrant crosstalk between cancer stem cells and their microenvironment triggers angiogenesis and TGFβ signalling, creating conditions that are conducive for hijacking leptin and leptin receptor signalling, which in turn launches downstream phosphoinositide 3-kinase (PI3K)–AKT–mTOR signalling during the benign-to-malignant transition. By functionally examining each step in this pathway, we reveal how dynamic temporal crosstalk with the microenvironment orchestrated by the stem cells profoundly fuels this path to malignancy. These insights suggest broad implications for cancer therapeutics.

Whether wild herbivores confer biotic resistance to invasion by exotic plants remains a key question in ecology. There is evidence that wild herbivores can impede invasion by exotic plants, but it is unclear whether and how this generalises across ecosystems with varying wild herbivore diversity and functional groups of plants, particularly over long-term (decadal) time frames. Using data from three long-term (13- to 26-year) exclosure experiments in central Kenya, we tested the effects of wild herbivores on the density of exotic invasive cacti, Opuntia stricta and O. ficus-indica (collectively, Opuntia), which are among the worst invasive species globally. We also examined relationships between wild herbivore richness and elephant occurrence probability with the probability of O. stricta presence at the landscape level (6150 km2). Opuntia densities were 74% to 99% lower in almost all plots accessible to wild herbivores compared to exclosure plots. Opuntia densities also increased more rapidly across time in plots excluding wild herbivores. These effects were largely driven by megaherbivores (≥1000 kg), particularly elephants. At the landscape level, modelled Opuntia stricta occurrence probability was negatively correlated with estimated species richness of wild herbivores and elephant occurrence probability. On average, O. stricta occurrence probability fell from ~0.56 to ~0.45 as wild herbivore richness increased from 6 to 10 species and fell from ~0.57 to ~0.40 as elephant occurrence probability increased from ~0.41 to ~0.84. These multi-scale results suggest that any facilitative effects of Opuntia by wild herbivores (e.g. seed/vegetative dispersal) are overridden by suppression (e.g. consumption, uprooting, trampling). Synthesis. Our experimental and observational findings that wild herbivores confer resistance to invasion by exotic cacti add to evidence that conserving and restoring native herbivore assemblages (particularly megaherbivores) can increase community resistance to plant invasions.

The impact on the clinical training and education of healthcare students by COVID-19 has been documented. However, the thoughts and experiences of clinical tutors (CTs) about radiography students attending for clinical training and education during this now elongated period beyond first recognition of the virus has not been explored. This paper will discuss data collected from CTs in the UK Devolved Nations (UKDN) and the United Arab Emirates (UAE) who were compared because of their similarities in delivery based on individual 'rules of engagement' devised by their various health departments.The purpose of this study was to examine the clinical tutors' thoughts and experiences of supervising radiography students attending clinical placement during the COVID-19 pandemic.The UK Devolved Nations (UKDN) and the United Arab Emirates (UAE) were selected for comparison on an international level as they are geographically distinct with a comparable population and education accredited/acknowledged by the Society and College of Radiographers (SCoR). Data was collected data from CTs across the UKDN and the UAE. The study used an online questionnaire (Google Forms) with closed questions in four themes including: students' experiences, impact on students' clinical placement, attitude of the clinical staff and the potential effects of COVID-19 on future graduates' skills and competencies. Further data was gathered on the experience of CTs mentoring students during the COVID-19 pandemic.Data were collected from 59 CTs (81%, n = 48) from UKDN and (19%, n = 11) UAE. Twenty-seven (46%) respondents reported that COVID-19 had a negative impact on clinical practical experience. However, 32 (54%) identified that COVID-19 had no impact on student supervision/feedback or on clinical achievements. Eleven (19%) respondents thought that students should not have been on clinical placement during the pandemic but a further 51% (n = 30) were happy with the students on placement and expressed willingness to delegate work to students. Interestingly, 58% (n = 34) of CTs suggested that future graduates may need a longer preceptorship after they graduate due to receiving decreased clinical experience during the pandemic. Overall, 78% (n = 46) of respondents thought that students improved their clinical confidence by working directly with COVID-19 positive patients.The current study has identified conflicting opinions across CTs in different clinical departments. Whilst some felt that students should not be in the hospital during the pandemic, others reported that working directly with COVID-19 patients had a positive impact on students as it improved their clinical confidence. Despite the challenges presented by COVID-19, CTs were able to provide direct clinical supervision and feedback to students on clinical placement throughout the pandemic. Nevertheless, future graduates may need a longer preceptorship period due to decreased clinical experience during the pandemic.Clinical placements should continue during subsequent COVID-19 waves of infection or future pandemics to ensure development of skills in resilience and adaptability. Underdeveloped skills due to a decreased range of examinations can be rectified when any wave of the infection subsides by providing tailored training based on individual student's needs.

The overnight change in hospital practice and service delivery during the COVID-19 pandemic raises the question whether undergraduate radiography students received an adequate clinical experience. Many students had their clinical placements cancelled, deferred or replaced with simulated learning. As a way of dealing with the pandemic some hospitals were dedicated to COVID-19 patients only resulting in many elective procedures being cancelled. Many patients also chose to stay away from the hospital out of fear of infection or the desire to reduce the burden on staff. This resulted in a limited range of examinations and clinical experience for those students who were able to complete their clinical placement.This study aims to investigate the impact of COVID-19 on the education and training of radiography students internationally in the United Kingdom Devolved Nations (UKDN) and the United Arab Emirates (UAE), to determine any possible impact on their future careers.Ethical permission was sought and granted from the Research Ethics Committees (ID: 21-04-12-02 and ID:21/0032). An online survey was developed using Google Forms and link was shared with students via email.262 students participated in the study [UAE (n = 60, 23%) and UKDN (n = 202, 77%)]. 72% stated that their clinical skills have improved and 82% were confident in the choice of radiography as a career. Participants from UAE displayed a higher tendency towards anxiety (p = 0.009). Students who were on clinical placements during the COVID-19 pandemic and worked with COVID-19 positive patients displayed less ongoing concern relating to COVID-19 (p = 0.004). 78% of the participants did not require wellbeing advice or request any type of wellbeing support from the higher education institutions (HEIs). Nevertheless, the study found that wellbeing of students was found to be negatively affected during the pandemic.Completing clinical placement during the COVID-19 pandemic allowed the continuation of education as students were allowed to improve their skills, confidence and resilience in coping with uncertainties and challenges. Undergraduate students should not be excluded from the clinical department during subsequent waves of COVID-19 or future pandemics to ensure continued workforce planning is possible.HEIs should find solutions to compensate students for the loss of practical experience and skills due to the decreased number of patients in some areas of radiography practice. Providing academic and career counselling can assist students achieve their professional objectives and decrease the risk of attrition and problems upon qualification.

Non-technical summary. As we consider a transition to a low-carbon future, there is a need to examine the mineral needs for this transformation at a scale reminiscent of the Green Revolution. The efficiency gains of the agrarian transition came at ecological and social costs that should provide important lessons about future metal sourcing. We present three options for a Mineral Revolution: status quo, incremental adaption and revolutionary change. We argue that a sustainable Mineral Revolution requires a paradigm shift that considers wellbeing as a purpose and focuses on preserving natural capital. Technical summary. As we consider a transition to a low-carbon future, there is a need to examine the mineral needs for this transformation at a scale reminiscent of the Green Revolution. The efficiency gains of the agrarian transition came at ecological and social costs that can also provide important lessons about the Mineral Revolution. We lay out some of the key ways in which such a mineral revolution can be delineated over temporal scales in a paradigm shift that considers wellbeing as a purpose and focuses on preserving natural capital. These prospects are conceptually presented as three pathways that consider the status quo, incremental adaption and revolutionary change as a means of planning more effectively for a lowcarbon transition. Social media summary. Sourcing metals sustainably will require to consider wellbeing as a purpose and to preserve natural capital.

Bacterial biofilms are often defined as communities of surface-attached bacteria and are typically depicted with a classic mushroom-shaped structure characteristic of Pseudomonas aeruginosa. However, it has become evident that this is not how all biofilms develop, especially in vivo, in clinical and industrial settings, and in the environment, where biofilms often are observed as non-surface-attached aggregates. In this Review, we describe the origin of the current five-step biofilm development model and why it fails to capture many aspects of bacterial biofilm physiology. We aim to present a simplistic developmental model for biofilm formation that is flexible enough to include all the diverse scenarios and microenvironments where biofilms are formed. With this new expanded, inclusive model, we hereby introduce a common platform for developing an understanding of biofilms and anti-biofilm strategies that can be tailored to the microenvironment under investigation.

A recent systematic review recommended time-varying methods for minimizing bias when estimating the excess length of stay (LOS) for healthcare-associated infections (HAIs); however, little evidence exists concerning which time-varying method is best used for HAI incidence studies.To undertake a retrospective analysis of data from a one-year prospective incidence study of HAIs, in one teaching hospital and one general hospital in NHS Scotland.Three time-varying methods - multistate model, multivariable adjusted survival regression, and matched case-control approach - were applied to the data to estimate excess LOS and compared.The unadjusted excess LOS estimated from the multistate model was 7.8 (95% confidence interval: 5.7-9.9) days, being shorter than the excess LOS estimated from survival regression adjusting for the admission characteristics (9.9; 8.4-11.7) days, and the adjusted estimates from matched case-control approach (10; 8.5-11.5) days. All estimates from the time-varying methods were much lower than the crude time-fixed estimates of 27 days.Studies examining LOS associated with HAI should consider a design which addresses time-dependent bias as a minimum. If there is an imbalance in patient characteristics between the HAI and non-HAI groups, then adjustment for patient characteristics is also important, where survival regression with time-dependent covariates is likely to provide the most flexible approach. Matched design is more likely to result in data loss, whereas a multistate model is limited by the challenge in adjusting for covariates. These findings have important implications for future cost-effectiveness studies of infection prevention and control programmes.

COVID-19 disproportionately impacted patients with cancer as a result of direct infection, and delays in diagnosis and therapy. Oncological clinical trials are resource-intensive endeavors that could be particularly susceptible to disruption by the pandemic, but few studies have evaluated the impact of the pandemic on clinical trial conduct.This prospective, multicenter study assesses the impact of the pandemic on therapeutic clinical trials at two large academic centers in the Northeastern United States between December 2019 and June 2021. The primary objective was to assess the enrollment on, accrual to, and activation of oncology therapeutic clinical trials during the pandemic using an institution-wide cohort of (i) new patient accruals to oncological trials, (ii) a manually curated cohort of patients with cancer, and (ii) a dataset of new trial activations.The institution-wide cohort included 4756 new patients enrolled to clinical trials from December 2019 to June 2021. A major decrease in the numbers of new patient accruals (-46%) was seen early in the pandemic, followed by a progressive recovery and return to higher-than-normal levels (+2.6%). A similar pattern (from -23.6% to +30.4%) was observed among 467 newly activated trials from June 2019 to June 2021. A more pronounced decline in new accruals was seen among academically sponsored trials (versus industry sponsored trials) (P0.05). In the manually curated cohort, which included 2361 patients with cancer, non-white patients tended to be more likely taken off trial in the early pandemic period (adjusted odds ratio: 2.60; 95% confidence interval 1.00-6.63), and substantial pandemic-related deviations were recorded.Substantial disruptions in clinical trial activities were observed early during the pandemic, with a gradual recovery during ensuing time periods, both from an enrollment and an activation standpoint. The observed decline was more prominent among academically sponsored trials, and racial disparities were seen among people taken off trial.

Summary ParagraphMacrophages and dendritic cells have long been appreciated for their ability to migrate to and engulf dying cells and debris, including some of the billions of cells that are naturally eliminated from our body daily. However, a substantial number of these dying cells are cleared by ‘non-professional phagocytes’, local epithelial cells that are critical to organismal fitness. How non-professional phagocytes sense and digest nearby apoptotic corpses while still performing their normal tissue functions is unclear. Here, we explore the molecular mechanisms underlying their multifunctionality. Exploiting the cyclical bouts of tissue regeneration and degeneration during the hair cycle, we show that stem cells can transiently become non-professional phagocytes when confronted with dying cells. Adoption of this phagocytic state requires both local lipids produced by apoptotic corpses to activate RXRα, and tissue-specific retinoids for RARγ activation. This dual factor dependency enables tight regulation of the genes requisite to activate phagocytic apoptotic clearance. The tunable phagocytic program we describe here offers an effective mechanism to offset phagocytic duties against the primary stem cell function of replenishing differentiated cells to preserve tissue integrity during homeostasis. Our findings have broad implications for other non-motile stem or progenitor cells which experience cell death in an immune-privileged niche.

BACKGROUND: Estimates of rotavirus vaccine effectiveness (VE) in the United States appear higher in years with more rotavirus activity. We hypothesized rotavirus VE is constant over time but appears to vary as a function of temporal variation in local rotavirus cases and/or misclassified diagnoses. METHODS: We analyzed 6 years of data from eight US surveillance sites on 8- to 59-month olds with acute gastroenteritis symptoms. Children’s stool samples were tested via enzyme immunoassay (EIA); rotavirus-positive results were confirmed with molecular testing at the US Centers for Disease Control and Prevention. We defined rotavirus gastroenteritis cases by either positive on-site EIA results alone or positive EIA with Centers for Disease Control and Prevention confirmation. For each case definition, we estimated VE against any rotavirus gastroenteritis, moderate-to-severe disease, and hospitalization using two mixed-effect regression models: the first including year plus a year–vaccination interaction, and the second including the annual percent of rotavirus-positive tests plus a percent positive–vaccination interaction. We used multiple overimputation to bias-adjust for misclassification of cases defined by positive EIA alone. RESULTS: Estimates of annual rotavirus VE against all outcomes fluctuated temporally, particularly when we defined cases by on-site EIA alone and used a year–vaccination interaction. Use of confirmatory testing to define cases reduced, but did not eliminate, fluctuations. Temporal fluctuations in VE estimates further attenuated when we used a percent positive–vaccination interaction. Fluctuations persisted until bias-adjustment for diagnostic misclassification. CONCLUSIONS: Both controlling for time-varying rotavirus activity and bias-adjusting for diagnostic misclassification are critical for estimating the most valid annual rotavirus VE.