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Development of resistance and tolerance to antifungal drugs in Candida albicans can compromise treatment of infections caused by this pathogenic yeast species. The uniquely expanded C. albicans TLO gene family is comprised of 14 paralogous genes which encode Med2, a subunit of the multiprotein Mediator complex which is involved in the global control of transcription. This study investigates the acquisition of fluconazole tolerance in a mutant in which the entire TLO gene family has been deleted. This phenotype was reversed to varying degrees upon reintroduction of representative members of the alpha- and beta-TLO clades (i.e. TLO1 and TLO2), but not by TLO11, a gamma-clade representative. Comparative RNA sequencing analysis revealed changes in the expression of genes involved in a range of cellular functions, including ergosterol biosynthesis, mitochondrial function, and redox homeostasis. This was supported by the results of mass spectrometry analysis, which revealed alterations in sterol composition of the mutant cell membrane. Our data suggest that members of the C. albicans TLO gene family are involved in the control of ergosterol biosynthesis and mitochondrial function and may play a role in the responses of C. albicans to azole antifungal agents.

The Candida albicans genome contains between ten and fifteen distinct TLO genes that all encode a Med2 subunit of Mediator. In order to investigate the biological role of Med2/Tlo in C. albicans we deleted all fourteen TLO genes using CRISPR-Cas9 mutagenesis. ChIP-seq analysis showed that RNAP II localized to 55% fewer genes in the tloΔ mutant strain compared to the parent, while RNA-seq analysis showed that the tloΔ mutant exhibited differential expression of genes required for carbohydrate metabolism, stress responses, white-opaque switching and filamentous growth. Consequently, the tloΔ mutant grows poorly in glucose- and galactose-containing media, is unable to grow as true hyphae, is more sensitive to oxidative stress and is less virulent in the wax worm infection model. Reintegration of genes representative of the α-, β- and γ-TLO clades resulted in the complementation of the mutant phenotypes, but to different degrees. TLOα1 could restore phenotypes and gene expression patterns similar to wild-type and was the strongest activator of glycolytic and Tye7-regulated gene expression. In contrast, the two γ-TLO genes examined (i.e., TLOγ5 and TLOγ11) had a far lower impact on complementing phenotypic and transcriptomic changes. Uniquely, expression of TLOβ2 in the tloΔ mutant stimulated filamentous growth in YEPD medium and this phenotype was enhanced when Tloβ2 expression was increased to levels far in excess of Med3. In contrast, expression of reintegrated TLO genes in a tloΔ/med3Δ double mutant background failed to restore any of the phenotypes tested, suggesting that complementation of these Tlo-regulated processes requires a functional Mediator tail module. Together, these data confirm the importance of Med2/Tlo in a wide range of C. albicans cellular activities and demonstrate functional diversity within the gene family which may contribute to the success of this yeast as a coloniser and pathogen of humans.

Published models inconsistently associate glioblastoma size with overall survival (OS). This study aimed to investigate the prognostic effect of tumour size in a large cohort of patients diagnosed with GBM and interrogate how sample size and non-linear transformations may impact on the likelihood of finding a prognostic effect. In total, 279 patients with a IDH-wildtype unifocal WHO grade 4 GBM between 2014 and 2020 from a retrospective cohort were included. Uni-/multivariable association between core volume, whole volume (CV and WV), and diameter with OS was assessed with (1) Cox proportional hazard models +/− log transformation and (2) resampling with 1,000,000 repetitions and varying sample size to identify the percentage of models, which showed a significant effect of tumour size. Models adjusted for operation type and a diameter model adjusted for all clinical variables remained significant (p = 0.03). Multivariable resampling increased the significant effects (p < 0.05) of all size variables as sample size increased. Log transformation also had a large effect on the chances of a prognostic effect of WV. For models adjusted for operation type, 19.5% of WV vs. 26.3% log-WV (n = 50) and 69.9% WV and 89.9% log-WV (n = 279) were significant. In this large well-curated cohort, multivariable modelling and resampling suggest tumour volume is prognostic at larger sample sizes and with log transformation for WV.

Glioblastoma is a high-grade aggressive neoplasm characterised by significant intra-tumoral spatial heterogeneity. Personalising therapy for this tumour requires non-invasive tools to visualise its heterogeneity to monitor treatment response on a regional level. To date, efforts to characterise glioblastoma’s imaging features and heterogeneity have focussed on individual imaging biomarkers, or high-throughput radiomic approaches that consider a vast number of imaging variables across the tumour as a whole. Habitat imaging is a novel approach to cancer imaging that identifies tumour regions or ‘habitats’ based on shared imaging characteristics, usually defined using multiple imaging biomarkers. Habitat imaging reflects the evolution of imaging biomarkers and offers spatially preserved assessment of tumour physiological processes such perfusion and cellularity. This allows for regional assessment of treatment response to facilitate personalised therapy. In this review, we explore different methodologies to derive imaging habitats in glioblastoma, strategies to overcome its technical challenges, contrast experiences to other cancers, and describe potential clinical applications.

Abstract Background Childhood obesity is influenced by myriad individual, societal and environmental factors that are not typically reflected in current interventions. Socio-ecological conditions evolve and require ongoing monitoring in terms of assessing their influence on child health. The aim of this study was to identify and prioritise indicators deemed relevant by public health authorities for monitoring and evaluating childhood obesity interventions. Method A three-round Delphi Panel composed of experts from regions across Europe, with a remit in childhood obesity intervention, were asked to identify indicators that were a priority in their efforts to address childhood obesity in their respective jurisdictions. In Round 1, 16 panellists answered a series of open-ended questions to identify the most relevant indicators concerning the evaluation and subsequent monitoring of interventions addressing childhood obesity, focusing on three main domains: built environments, dietary environments, and health inequalities. In Rounds 2 and 3, panellists rated the importance of each of the identified indicators within these domains, and the responses were then analysed quantitatively. Results Twenty-seven expert panellists were invited to participate in the study. Of these, 16/27 completed round 1 (5 9% response rate), 14/16 completed round 2 (87.5% response rate), and 8/14 completed the third and final round (57% response rate). Consensus (defined as > 70% agreement) was reached on a total of 45 of the 87 indicators (49%) across three primary domains (built and dietary environments and health inequalities), with 100% consensus reached for 5 of these indicators (6%). Conclusion Forty-five potential indicators were identified, pertaining primarily to the dietary environment, built environment and health inequalities. These results have important implications more widely for evaluating interventions aimed at childhood obesity reduction and prevention.

Abstract Observer-driven pattern recognition is the standard for interpretation of medical images. To achieve global parity in interpretation, semi-quantitative scoring systems have been developed based on observer assessments; these are widely used in scoring coronary artery disease, the arthritides and neurological conditions and for indicating the likelihood of malignancy. However, in an era of machine learning and artificial intelligence, it is increasingly desirable that we extract quantitative biomarkers from medical images that inform on disease detection, characterisation, monitoring and assessment of response to treatment. Quantitation has the potential to provide objective decision-support tools in the management pathway of patients. Despite this, the quantitative potential of imaging remains under-exploited because of variability of the measurement, lack of harmonised systems for data acquisition and analysis, and crucially, a paucity of evidence on how such quantitation potentially affects clinical decision-making and patient outcome. This article reviews the current evidence for the use of semi-quantitative and quantitative biomarkers in clinical settings at various stages of the disease pathway including diagnosis, staging and prognosis, as well as predicting and detecting treatment response. It critically appraises current practice and sets out recommendations for using imaging objectively to drive patient management decisions.

Abstract Quantifying species population trends is crucial for monitoring progress towards global conservation targets, justifying investments, planning targeted responses and raising awareness about threatened species. Many global indicators are slow in response and report on common species, not on those at greatest risk of extinction. Here we develop a Threatened Species Index as a dynamic tool for tracking annual changes in Australia's imperiled birds. Based on the Living Planet Index method and containing more than 17,000 time series for 65 bird taxa surveyed systematically, the index at its second iteration shows an average reduction of 59% between 1985 and 2016, and 44% between 2000 and 2016. Decreases seem most severe for shorebirds and terrestrial birds and least severe for seabirds. The index provides a potential means for measuring performance against the Convention on Biological Diversity's Aichi Target 12, enabling governments, agencies and the public to observe changes in threatened species.

After a tissue is wounded, cells surrounding the wound adopt distinct wound-healing behaviors to repair the tissue. Considerable effort has been spent on understanding the signaling pathways that regulate immune and tissue-resident cells as they respond to wounds, but these signals must ultimately originate from the physical damage inflicted by the wound. Tissue wounds comprise several types of cellular damage, and recent work indicates that different types of cellular damage initiate different types of signaling. Hence to understand wound signaling, it is important to identify and localize the types of wound-induced cellular damage. Laser ablation is widely used by researchers to create reproducible, aseptic wounds in a tissue that can be live-imaged. Because laser wounding involves a combination of photochemical, photothermal and photomechanical mechanisms, each with distinct spatial dependencies, cells around a pulsed-laser wound will experience a gradient of damage. Here we exploit this gradient to create a map of wound-induced cellular damage. Using genetically-encoded fluorescent proteins, we monitor damaged cellular and sub-cellular components of epithelial cells in living Drosophila pupae in the seconds to minutes following wounding. We hypothesized that the regions of damage would be predictably arrayed around wounds of varying sizes, and subsequent analysis found that all damage radii are linearly related over a 3-fold range of wound size. Thus, around laser wounds, the distinct regions of damage can be estimated after measuring any one. This report identifies several different types of cellular damage within a wounded epithelial tissue in a living animal. By quantitatively mapping the size and placement of these different types of damage, we set the foundation for tracing wound-induced signaling back to the damage that initiates it.

Abstract Well‐designed citizen science projects can improve the capacity of the scientific community to detect and understand declines in threatened species, and with the emergence of frameworks to guide good design, there is an opportunity to test whether projects are aligned with best practice. We assessed the current landscape of citizen science projects for threatened species conservation via a content analysis of the online communique of citizen science projects across Australia. Only 2% of projects stated clear research questions, although approximately 86% had implied project objectives aimed at threatened species conservation. Most projects were focused on field‐based monitoring activities with half using structured ecological survey methods. Most reviewed projects (65%) shared data with open access biodiversity databases and the vast majority use at least one social media platform to communicate with potential and existing participants (up to 81%). Approximately 50% present citizen‐sourced data summaries or publications on their websites. Our study shows there is a very strong foundation for public participation in threatened species conservation activities in Australia, yet there is scope to further integrate the principles of citizen science best practice. Improved integration of these principles will likely yield better outcomes for threatened species as well as for the citizen scientists themselves.

Prostate cancer (PCa) remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of more than 26,000 in 2016 alone. Aggressive and metastatic tumors are treated with androgen deprivation therapies (ADT); however, the tumors acquire resistance and develop into lethal castration resistant prostate cancer (CRPC). With the advent of better therapeutics, the incidences of a more aggressive neuroendocrine prostate cancer (NEPC) variant continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% of the therapy-resistant patients on highly potent new-generation anti-androgen therapies end up with NEPC. This, along with previous observations of an increase in the number of such NE cells in aggressive tumors, has been suggested as a mechanism of resistance development during prostate cancer progression. Dovitinib (TKI-258/CHIR-258) is a pan receptor tyrosine kinase (RTK) inhibitor that targets VEGFR, FGFR, PDGFR, and KIT. It has shown efficacy in mouse-model of PCa bone metastasis, and is presently in clinical trials for several cancers. We observed that both androgen receptor (AR) positive and AR-negative PCa cells differentiate into a NE phenotype upon treatment with Dovitinib. The NE differentiation was also observed when mice harboring PC3-xenografted tumors were systemically treated with Dovitinib. The mechanistic underpinnings of this differentiation are unclear, but seem to be supported through MAPK-, PI3K-, and Wnt-signaling pathways. Further elucidation of the differentiation process will enable the identification of alternative salvage or combination therapies to overcome the potential resistance development.

Conserving species biodiversity demands decisive and effective action. Effective action requires an understanding of species population dynamics. Therefore, robust measures which track temporal changes in species populations are needed. This need, however, must be balanced against the scale at which population change is being assessed. Advances in citizen science and remote sensing technology have heralded an era of “big unstructured data” for biodiversity conservation. However, the value of big unstructured data for assessing changes in species populations, and effectively guiding conservation management has not been rigorously assessed. This can be achieved only by benchmarking big unstructured data against high-quality structured datasets, and ensuring the latter are not lost through an over-emphasis on “big data.” Here, we illustrate the current trend to disproportionately prioritize data quantity over data quality and highlight the discrepancy in global availability between both data types. We propose a research agenda to test whether this trend will result in a net decrease of useful knowledge for biodiversity conservation. We exemplify this by examining the availability of big unstructured data vs. standardized data using data from global repositories on birds as an example. We share experiences from the data collation exercise needed to develop the Australian Threatened Species Index. We argue there is an urgent need to validate and enhance the utility of big unstructured data by: (1) maintaining existing well-designed, standardized long-term species population studies; (2) strengthening data quality control, management, and curation of any type of dataset; and (3) developing purpose-specific rankings to assess data quality.

Las formas de desarrollo desigual y combinado impactan directamente en los procesos de contaminación y agotamiento de los recursos naturales en la sociedad globalizada. Los países del Sur no poseen instituciones capaces de ofrecer resistencia a los procesos socioeconómicos de acumulación del capital, tanto a escala regional como global, y padecen los grandes efectos de la crisis ecológica contemporánea.The forms of combined and unequal development directly impact on the processes of contamination and exhaustion of natural resources in the globalized society. The countries in the South do not have institutions capable of resisting the socio-economic processes of capital accumulation, both at regional and global scale, and suffer the great effects of contemporary ecologic crisis.

What limits on what can be done to individuals in pursuit of some “greater good” are morally permissible, and under what sorts of circumstances? This depends largely on one’s approach to interpersonal aggregation — that is, summing different goods (or harms) affecting different persons and weighing them against other similarly attained aggregates. I outline four approaches: non-aggregationism (e.g. John Taurek, 1977); asymmetric aggregationism (e.g. Peter Singer in many specialist writings, Alistair Norcross); symmetric aggregationism (e.g. Singer in popular writings); and weak aggregationism (e.g. T.M Scanlon). I conclude by briefly suggesting that the weak approach is the “least worst” one.