Nutrient-rich spatial refuges buffer against extinction and promote evolutionary rescue in evolving microbial populations.

Microbial populations are often exposed to long-term abiotic disturbances, which can reduce population viability and cause local extinction. Eco-evolutionary theory suggests that spatial refuges can facilitate persistence and evolutionary rescue. However, one drawback of spatial refuges is reduced exposure to nutrients such as carbon and oxygen, suggesting the protective effect of refuges depends on the interplay between environmental conditions and the degree of stress.

Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state.

The discovery of oncogene addiction in cancer has led to the development of over a dozen FDA-approved biomarker-driven therapies in lung adenocarcinoma. Somatic mutations of the "Ras-like in all tissues" (RIT1) gene are non-canonical driver events in lung cancer, occurring in ~2% of lung adenocarcinomas in a mutually exclusive fashion with and mutations. Patients with -mutant lung cancer lack targeted therapy treatment options, and a lack of pre-clinical models has hindered the development of therapeutic strategies for -mutant lung cancer.

Parallel ecological and evolutionary responses to selection in a natural bacterial community.

Evolution can occur over ecological timescales, suggesting a potentially important role for rapid evolution in shaping community trait distributions. However, evidence of concordant eco-evolutionary dynamics often comes from in vitro studies of highly simplified communities, and measures of ecological and evolutionary dynamics are rarely directly comparable. Here, we quantified how ecological species sorting and rapid evolution simultaneously shape community trait distributions by tracking within- and between-species changes in a key trait in a complex bacterial community.

Proximity-driven site-specific cyclization of phage-displayed peptides.

Cyclization provides a general strategy for improving the proteolytic stability, cell membrane permeability and target binding affinity of peptides. Insertion of a stable, non-reducible linker into a disulphide bond is a commonly used approach for cyclizing phage-displayed peptides. However, among the vast collection of cysteine reactive linkers available, few provide the selectivity required to target specific cysteine residues within the peptide in the phage display system, whilst sparing those on the phage capsid.

Secondary messenger signalling influences Pseudomonas aeruginosa adaptation to sinus and lung environments.

Pseudomonas aeruginosa is a cause of chronic respiratory tract infections in people with cystic fibrosis (CF), non-CF bronchiectasis, and chronic obstructive pulmonary disease. Prolonged infection allows the accumulation of mutations and horizontal gene transfer, increasing the likelihood of adaptive phenotypic traits. Adaptation is proposed to arise first in bacterial populations colonizing upper airway environments.

Ecological dependencies and the illusion of cooperation in microbial communities.

Ecological dependencies - where organisms rely on other organisms for survival - are a ubiquitous feature of life on earth. Multicellular hosts rely on symbionts to provide essential vitamins and amino acids. Legume plants similarly rely on nitrogen-fixing rhizobia to convert atmospheric nitrogen to ammonia.

CRISPR Screening in Tandem with Targeted mtDNA Damage Reveals WRNIP1 Essentiality.

A major impediment to the characterization of mtDNA repair mechanisms in comparison to nuclear DNA repair mechanisms is the difficulty of specifically addressing mitochondrial damage. Using a mitochondria-penetrating peptide, we can deliver DNA-damaging agents directly to mitochondria, bypassing the nuclear compartment. Here, we describe the use of an mtDNA-damaging agent in tandem with CRISPR/Cas9 screening for the genome-wide discovery of factors essential for mtDNA damage response.

FBXW7-loss Sensitizes Cells to ATR Inhibition Through Induced Mitotic Catastrophe.

Unlabelled: FBXW7 is a commonly mutated tumor suppressor gene that functions to regulate numerous oncogenes involved in cell-cycle regulation. Genome-wide CRISPR fitness screens identified a signature of DNA repair and DNA damage response genes as required for the growth of FBXW7-knockout cells. Guided by these findings, we show that FBXW7-mutant cells have high levels of replication stress, which results in a genotype-specific vulnerability to inhibition of the ATR signaling pathway, as these mutant cells become heavily reliant on a robust S-G2 checkpoint.

CRISPR Screening in Tandem with Targeted mtDNA Damage Reveals WRNIP1 Essentiality.

A major impediment to the characterization of mtDNA repair mechanisms, in comparison to nuclear DNA repair mechanisms, is the difficulty of specifically addressing mitochondrial damage. Using a mitochondria-penetrating peptide, we can deliver DNA-damaging agents directly to mitochondria, bypassing the nuclear compartment. Here, we describe the use of a mtDNA-damaging agent in tandem with CRISPR/Cas9 screening for the genome-wide discovery of factors essential for mtDNA damage response.

Chromosome-level genome editing uncovers aneuploidy addiction in cancer.

Publishing in Science, Girish and colleagues achieve chromosome-level genome editing to reveal a requirement for aneuploidy in breast and melanoma cancers. Authors developed and leveraged ReDACT (restoring disomy in aneuploid cells using CRISPR targeting) to generate isogenic models of aneuploidy and demonstrate that some cancers are addicted to increased copy number of specific chromosome arms.

Community composition drives siderophore dynamics in multispecies bacterial communities.

Background: Intraspecific public goods are commonly shared within microbial populations, where the benefits of public goods are largely limited to closely related conspecifics. One example is the production of iron-scavenging siderophores that deliver iron to cells via specific cell envelope receptor and transport systems. Intraspecific social exploitation of siderophore producers is common, since non-producers avoid the costs of production but retain the cell envelope machinery for siderophore uptake.

Cultivating antimicrobial resistance: how intensive agriculture ploughs the way for antibiotic resistance.

Antimicrobial resistance (AMR) is a growing threat to public health, global food security and animal welfare. Despite efforts in antibiotic stewardship, AMR continues to rise worldwide. Anthropogenic activities, particularly intensive agriculture, play an integral role in the dissemination of AMR genes within natural microbial communities - which current antibiotic stewardship typically overlooks.

Relative Biological Effectiveness (RBE) of [Cu]Cu and [Lu]Lu-NOTA-panitumumab F (ab') radioimmunotherapeutic agents vs. γ-radiation for decreasing the clonogenic survival in vitro of human pancreatic ductal adenocarcinoma (PDAC) cells.

Introduction: Our objective was to compare [Cu]Cu-NOTA-panitumumab F(ab') and [Lu]Lu-NOTA-panitumumab F(ab') radioimmunotherapy (RIT) agents for decreasing the clonogenic survival fraction (SF) in vitro of EGFR-positive human pancreatic ductal adenocarcinoma (PDAC) cell lines and estimate the relative biological effectiveness (RBE) vs. γ-radiation (XRT).

Methods: EGFR-positive PDAC cell lines (AsPC-1, PANC-1, MIAPaCa-2, Capan-1) and EGFR-knockout PANC-1 EGFR KO cells were treated in vitro for 18 h with (0-19.

Lessons learnt during COVID-19: making sense of Australian and Swedish university lecturers' experience.

This article reports on a study analysing changes in the use of digital technologies and working from home during the COVID-19 crisis and the impact of these changes on the wellbeing of five female university lecturers from Australia and Sweden. Applying collaborative autoethnographical methods, this study employed Weick's sensemaking framework to explore how the academics made sense of these sudden changes. The Positive emotion, Engagement, Relationships, Meaning, and Accomplishment (PERMA) wellbeing framework was also employed to explore the effect of these changes on the academics' wellbeing.

Modulation of Wnt-β-catenin signaling with antibodies: therapeutic opportunities and challenges.

Since the recognition that mutations in components of the Wnt-β-catenin pathway underlie some human cancers, considerable attention has been dedicated to developing therapeutic modalities to block its activity. Despite numerous efforts, no drug directly inhibiting Wnt signaling is currently clinically available. Conversely, activating the Wnt pathway in a specific manner has recently been made possible with new molecules mimicking the activity of Wnt proteins, thus offering new possibilities for controlling tissue stem cell activity and for the rational treatment of various degenerative conditions.

Crystal structure of the CDK11 kinase domain bound to the small-molecule inhibitor OTS964.

CDK11 is a cyclin-dependent kinase that controls proliferation by regulating transcription, RNA splicing, and the cell cycle. As its activity is increasingly associated with cancer, CDK11 is an attractive target for the development of small-molecule inhibitors. However, the development of CDK11 inhibitors with limited off-target effects against other CDKs poses a challenge based on the high conservation of sequence across family members.

SCF regulates G2-M progression through control of CCNL1 ubiquitination.

FBXW7, which encodes a substrate-specific receptor of an SCF E3 ligase complex, is a frequently mutated human tumor suppressor gene known to regulate the post-translational stability of various proteins involved in cellular proliferation. Here, using genome-wide CRISPR screens, we report a novel synthetic lethal genetic interaction between FBXW7 and CCNL1 and describe CCNL1 as a new substrate of the SCF-FBXW7 E3 ligase. Further analysis showed that the CCNL1-CDK11 complex is critical at the G2-M phase of the cell cycle since defective CCNL1 accumulation, resulting from FBXW7 mutation, leads to shorter mitotic time.

Peptide-YY/glucagon-like peptide-1 combination treatment of obese diabetic mice improves insulin sensitivity associated with recovered pancreatic β-cell function and synergistic activation of discrete hypothalamic and brainstem neuronal circuitries.

Objective: Obesity-linked type 2 diabetes (T2D) is a worldwide health concern and many novel approaches are being considered for its treatment and subsequent prevention of serious comorbidities. Co-administration of glucagon like peptide 1 (GLP-1) and peptide YY (PYY) renders a synergistic decrease in energy intake in obese men. However, mechanistic details of the synergy between these peptide agonists and their effects on metabolic homeostasis remain relatively scarce.

Species interactions drive the spread of ampicillin resistance in human-associated gut microbiota.

Background And Objectives: Slowing the spread of antimicrobial resistance is urgent if we are to continue treating infectious diseases successfully. There is increasing evidence microbial interactions between and within species are significant drivers of resistance. On one hand, cross-protection by resistant genotypes can shelter susceptible microbes from the adverse effects of antibiotics, reducing the advantage of resistance.

The Unmet Rehabilitation Needs in an Inclusion Health Integrated Care Programme for Homeless Adults in Dublin, Ireland.

Background: People who become homeless have higher morbidity and mortality, use a disproportionate amount of healthcare resources, and generate a large volume of potentially preventable healthcare and other costs compared to more privileged individuals. Although access to rehabilitation is a human right under article 26 of the United Nations Convention on the Rights of Persons with Disabilities, the rehabilitation needs of individuals with homelessness have not been explored, and this project's purpose was to establish a baseline of need for this cohort.

Methods: A prospective audit of case discussions at an inclusion health service over a 2-month period in 2018.

Stress causes interspecific facilitation within a compost community.

Ecological theory predicts interactions between species to become more positive under abiotic stress, while competition should prevail in more benign environments. However, experimental tests of this stress gradient hypothesis in natural microbial communities are lacking. We test this hypothesis by measuring interactions between 10 different members of a bacterial community inhabiting potting compost in the presence or absence of toxic copper stress.

Dynamic chromatin accessibility landscape changes following interleukin-1 stimulation.

Dynamic modifications of chromatin allow rapid access of the gene regulatory machinery to condensed genomic regions facilitating subsequent gene expression. Inflammatory cytokine stimulation of cells can cause rapid gene expression changes through direct signalling pathway-mediated transcription factor activation and regulatory element binding. Here we used the Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) to assess regions of the genome that are differentially accessible following treatment of cells with interleukin-1 (IL-1).

Resource heterogeneity and the evolution of public goods cooperation.

Heterogeneity in resources is a ubiquitous feature of natural landscapes affecting many aspects of biology. However, the effect of environmental heterogeneity on the evolution of cooperation has been less well studied. Here, using a mixture of theory and experiments measuring siderophore production by the bacterium as a model for public goods based cooperation, we explore the effect of heterogeneity in resource availability.

IPO11 mediates βcatenin nuclear import in a subset of colorectal cancers.

Activation of Wnt signaling entails βcatenin protein stabilization and translocation to the nucleus to regulate context-specific transcriptional programs. The majority of colorectal cancers (CRCs) initiate following APC mutations, resulting in Wnt ligand-independent stabilization and nuclear accumulation of βcatenin. The mechanisms underlying βcatenin nucleocytoplasmic shuttling remain incompletely defined.