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High‐resolution climate change projections are increasingly necessary to inform climate policy and adaptation planning. Downscaling of global climate models (GCMs) is required to simulate the climate at the spatial scale relevant for local impacts. Here, we dynamically downscaled 15 CMIP6 GCMs to a 10 km resolution over Australia using the Conformal Cubic Atmospheric model (CCAM), creating the largest ensemble of high‐resolution downscaled CMIP6 projections for Australia. We compared the host CMIP6 models and downscaled simulations to the Australian Gridded Climate Data (AGCD) observational data and evaluated performance using the Kling‐Gupta efficiency and Perkins skill score. Downscaling improved performance over host GCMs for seasonal temperature and precipitation (10% and 43% respectively), and for annual cycles of temperature and precipitation (6% and 13% respectively). Downscaling also improved the fraction of dry days, reducing the bias for too many low‐rain days. The largest improvements were found in climate extremes, with enhancements to extreme minimum temperatures in all seasons varying from 142% to 201%, and to extreme precipitation of 52% in Austral winter and 47% in summer. The ensemble average integrated skill score improved by 16%. Temperature and precipitation biases were reduced in mountainous and coastal areas. CCAM downscaling outperformed host CMIP6 GCMs at multiple spatial scales and regions—continental Australia, Australian IPCC regions and Queensland's regions—with integrated added value ranging from 9% to 150% and higher over densely populated regions more exposed to climate impacts. This data set will be a valuable resource for understanding future climate changes in Australia. Plain Language Summary High‐resolution climate models are used for producing climate change projections for assessing regional and local climate change impacts and for adaptation and policy formulation. We completed 15 high‐resolution climate simulations using the Conformal Cubic Atmospheric Model at a 10 km spatial resolution over the Australian continent and surrounds based on global climate models (GCMs) used in the Intergovernmental Panel on Climate Change Assessment Report 6. We evaluated the new high‐resolution data set by comparing it to observations and to their host global model across several regions within Australia. The high‐resolution simulations improved the representation of topography, seasonal temperature and annual cycles of temperature, precipitation, as well as the number of dry days, extreme precipitation and extreme minimum temperatures. The high‐resolution projections show improvement compared to GCMs consistently across spatial scales and regions, being particularly high (150%) over urban areas with high exposure to impacts. This new 10 km data set is the highest resolution, and largest ensemble of the latest climate projections for the Australian continent and surrounds and will be a valuable tool for evaluating future climate change impacts. Key Points We dynamically downscaled 15 CMIP6 global climate model simulations over Australia to a 10 km spatial resolution using the Conformal Cubic Atmospheric model Two new assessment metrics are proposed to assess model performance and added value of downscaling The integrated added value of downscaling can be as high as 150% over highly populated areas

The capacity to coordinate environmental sensing with initiation of cellular responses underpins microbial survival and is crucial for virulence and stress responses in microbial pathogens. Here we define circuitry that enables the fungal pathogen Candida albicans to couple cell cycle dynamics with responses to cell wall stress induced by echinocandins, a front-line class of antifungal drugs. We discover that the C. albicans transcription factor Cas5 is crucial for proper cell cycle dynamics and responses to echinocandins, which inhibit β-1,3-glucan synthesis. Cas5 has distinct transcriptional targets under basal and stress conditions, is activated by the phosphatase Glc7, and can regulate the expression of target genes in concert with the transcriptional regulators Swi4 and Swi6. Thus, we illuminate a mechanism of transcriptional control that couples cell wall integrity with cell cycle regulation, and uncover circuitry governing antifungal drug resistance. Cas5 is a transcriptional regulator of responses to cell wall stress in the fungal pathogen Candida albicans . Here, Xie et al. show that Cas5 also modulates cell cycle dynamics and responses to antifungal drugs.

Deforestation exacerbates climate change through greenhouse gas emissions, but other climatic alterations linked to the local biophysical changes from deforestation remain poorly understood. Here, we assess the impact of tropical deforestation on fire weather risk—defined as the climate conditions conducive to wildfires—using high-resolution convection-permitting climate simulations. We consider two land cover scenarios for the island of Borneo: land cover in 1980 ( forest scenario ) and land cover in 2050 ( deforestation scenario ) to force a convection-permitting climate model, using boundary conditions from ERA-Interim reanalysis for the 2002–2016 period. Our findings revealed significant alterations in post-deforestation fire precursors such as increased temperature, wind speed and potential evapotranspiration and decreased humidity, cloud cover and precipitation. As a result, fire weather events that would occur once a year in the forested scenario, are likely to occur four times a year following deforestation. Likewise, for extreme conditions, such as those occurring on longer time-horizons than 20 years, the magnitude of extreme fire weather is likely to double following deforestation. These increases in extreme fire weather conditions demonstrate the key role of tropical forests in regulating regional climate processes, including reduced fire weather risk.

Background Globally, temperatures are increasing due to the effects of climate change. Extreme heat is a public health threat, increasing the burden on health systems during heatwaves, and the days following. Australia is susceptible to extreme heat and must plan accordingly to ensure health systems can respond as heatwave conditions increase in frequency, severity, and duration. This study investigates the impact of heatwaves on Emergency Department (ED) presentations in the state of Queensland, Australia, considering key demographic, clinical, and temporal factors. Methods Warm-season (November-March) ED presentations (2010-19) obtained from Queensland Health at the postcode level were analysed in relation to heatwaves. Heatwaves were defined using the Excess Heat Factor, a metric designed by the Australian Bureau of Meteorology. Quasi-Poisson regression models produced incidence rate ratios (IRRs) with 95% confidence intervals (CIs) to quantify differences in ED demand between heatwave and non-heatwave days. Subgroup analyses were conducted by heatwave severity, rurality, sex, age, primary diagnosis, triage category and financial year. Results There was a 10.47% (IRR adj : 1.10; 95% CI: 1.10, 1.11) increase in ED presentations on heatwave days. The effect was greatest during extreme heatwaves (IRR adj : 1.23; 95% CI: 1.20, 1.26). There was a direct relationship between increasing impact and rurality, with those living in very remote areas most impacted, experiencing a 54.26% increase in ED presentations in comparison to non-heatwave days (IRR adj : 1.54; 95% CI: 1.50, 1.59). There was no clear age-related trend, and no significant variation by sex. Presentations increased on heatwave days for most primary diagnoses, with the most notable increase observed in cases classified under ‘endocrine, nutritional, and metabolic disorders’ (IRR adj : 1.27; 95% CI: 1.24, 1.29). The least urgent triage category (category 5) exhibited the most significant increase in ED incidence on heatwave days (IRR adj : 1.27; 95% CI: 1.25, 1.29). Temporal trends showed that the 2015-16 financial year (IRR: 1.13; 95% CI: 1.12, 1.15) demonstrated the greatest increase in ED incidence on heatwave days. Conclusions Emergency departments must prepare for higher numbers of people presenting during heatwaves. The variability in impact across different demographic, clinical, and temporal factors underscores the complex relationship between heatwaves and health system demand. As climate change intensifies heatwaves, future research, including prospective studies, will be needed to provide essential evidence to inform public health planning.

Microbicidal persistence refers to the phenomenon whereby a subpopulation of microbial cells enters a dormant state to evade drug killing. This phenomenon is associated with antibiotic treatment failure in bacterial infections, and thus, the characteristics and mechanisms of bacterial persistence have been extensively studied. Despite significant evolutionary divergence, microbicidal persistence has also been observed in fungi. Notably, recent studies have demonstrated that fungal persistence can occur within the host and significantly impair the efficacy of fungicidal drugs. Given the extremely limited range of first-line fungicidal agents currently in use, improving our understanding of the shared and unique mechanisms of antifungal persistence in various fungal pathogens is of great clinical importance. This review summarizes recent advances in the study of antifungal persistence, covering conceptual definitions, measurement methods, and molecular mechanisms. It also discusses future research directions in this field.

Cancer growth is usually accompanied by metastasis which kills most cancer patients. Here we aim to study the effect of cisplatin at different doses on breast cancer growth and metastasis. We used cisplatin to treat breast cancer cells, then detected the migration of cells and the changes of epithelial-mesenchymal transition (EMT) markers by migration assay, Western blot, and immunofluorescent staining. Next, we analyzed the changes of RNA expression of genes by RNA-seq and confirmed the binding of activating transcription factor 3 (ATF3) to cytoskeleton related genes by ChIP-seq. Thereafter, we combined cisplatin and paclitaxel in a neoadjuvant setting to treat xenograft mouse models. Furthermore, we analyzed the association of disease prognosis with cytoskeletal genes and ATF3 by clinical data analysis. When administered at a higher dose (6 mg/kg), cisplatin inhibits both cancer growth and metastasis, yet with strong side effects, whereas a lower dose (2 mg/kg) cisplatin blocks cancer metastasis without obvious killing effects. Cisplatin inhibits cancer metastasis through blocking early steps of EMT. It antagonizes transforming growth factor beta (TGFβ) signaling through suppressing transcription of many genes involved in cytoskeleton reorganization and filopodia formation which occur early in EMT and are responsible for cancer metastasis. Mechanistically, TGFβ and fibronectin-1 (FN1) constitute a positive reciprocal regulation loop that is critical for activating TGFβ/SMAD3 signaling, which is repressed by cisplatin induced expression of ATF3. Furthermore, neoadjuvant administration of cisplatin at 2 mg/kg in conjunction with paclitaxel inhibits cancer growth and blocks metastasis without causing obvious side effects by inhibiting colonization of cancer cells in the target organs. Thus, cisplatin prevents breast cancer metastasis through blocking early EMT, and the combination of cisplatin and paclitaxel represents a promising therapy for killing breast cancer and blocking tumor metastasis.

The fabrications of circularly polarized luminescent (CPL) material are mainly based on the chemical and physical strategies. Controlled biosynthesis of CPL-active materials is beset with difficulties due to the lack of bioactive luminescent precursors and bio-reactors. Enlighted by microbe-assisted asymmetric biosynthesis, herein, we show the in situ bacterial fermentation of Komagataeibacter sucrofermentants to fabricate a series of bacterial cellulosic biofilms with CPL of green, orange, red, and near-infrared colors. This process can trigger CPL emission for CPL-silent glycosylated luminophores and amplify the g lum of weak CPL-active luminophores up to a 10 −2 scale. To confirm glycosidic bonds formation during the bacterial copolymerization process, we develop an assay utilizing the cellulase-catalyzed biodegradation of BC hybrids. More importantly, we achieve the information encryption and Fe 3+ dual-channel detection based on hybrid bacterial cellulosic biofilms. Therefore, this study not only provides another vision for CPL materials preparation but also broadens the application of bacterial cellulosic hybrids. The fabrication of circularly polarized luminescent (CPL) materials mostly rely on chemical and physical strategies. Here, authors demonstrate microbe-assisted biosynthesis to fabricate a series of multi-coloured bacterial cellulosic biofilms with enhanced CPL.

Fungal pathogens pose a serious threat to public health. Candida auris is an emerging fungal pathogen that is often resistant to commonly used antifungal drugs. However, the mechanisms governing drug resistance and virulence in this organism remain largely unexplored. In this study, we adapted a conditional expression system to modulate the transcription of an essential gene, HSP90 , which regulates antifungal resistance and virulence in diverse fungal pathogens. We showed that Hsp90 is essential for growth in C. auris and is important for tolerance of the clinically important azole antifungals, which block ergosterol biosynthesis. Further, we established that the Cdr1 efflux transporter regulates azole resistance. Finally, we discovered that C. auris transitions from yeast to filamentous growth in response to Hsp90 inhibition, accompanied by global transcriptional remodeling. Overall, this work provides a novel insight into mechanisms regulating azole resistance in C. auris and uncovers a distinct developmental program regulated by Hsp90. Candida auris is an emerging fungal pathogen and a serious global health threat as the majority of clinical isolates display elevated resistance to currently available antifungal drugs. Despite the increased prevalence of C. auris infections, the mechanisms governing drug resistance remain largely elusive. In diverse fungi, the evolution of drug resistance is enabled by the essential molecular chaperone Hsp90, which stabilizes key regulators of cellular responses to drug-induced stress. Hsp90 also orchestrates temperature-dependent morphogenesis in Candida albicans , a key virulence trait. However, the role of Hsp90 in the pathobiology of C. auris remains unknown. In order to study regulatory functions of Hsp90 in C. auris , we placed HSP90 under the control of a doxycycline-repressible promoter to enable transcriptional repression. We found that Hsp90 is essential for growth in C. auris and that it enables tolerance of clinical isolates with respect to the azoles, which inhibit biosynthesis of the membrane sterol ergosterol. High-level azole resistance was independent of Hsp90 but dependent on the ABC transporter CDR1 , deletion of which resulted in abrogated resistance. Strikingly, we discovered that C. auris undergoes a morphogenetic transition from yeast to filamentous growth in response to HSP90 depletion or cell cycle arrest but not in response to other cues that induce C. albicans filamentation. Finally, we observed that this developmental transition is associated with global transcriptional changes, including the induction of cell wall-related genes. Overall, this report provides a novel insight into mechanisms of drug tolerance and resistance in C. auris and describes a developmental transition in response to perturbation of a core regulator of protein homeostasis. IMPORTANCE Fungal pathogens pose a serious threat to public health. Candida auris is an emerging fungal pathogen that is often resistant to commonly used antifungal drugs. However, the mechanisms governing drug resistance and virulence in this organism remain largely unexplored. In this study, we adapted a conditional expression system to modulate the transcription of an essential gene, HSP90 , which regulates antifungal resistance and virulence in diverse fungal pathogens. We showed that Hsp90 is essential for growth in C. auris and is important for tolerance of the clinically important azole antifungals, which block ergosterol biosynthesis. Further, we established that the Cdr1 efflux transporter regulates azole resistance. Finally, we discovered that C. auris transitions from yeast to filamentous growth in response to Hsp90 inhibition, accompanied by global transcriptional remodeling. Overall, this work provides a novel insight into mechanisms regulating azole resistance in C. auris and uncovers a distinct developmental program regulated by Hsp90.

This paper investigates the application of fault attacks to the authenticated encryption stream cipher algorithm MORUS. We propose fault attacks on MORUS with two different goals: one to breach the confidentiality component, and the other to breach the integrity component. For the fault attack on the confidentiality component of MORUS, we propose two different types of key recovery. The first type is a partial key recovery using a permanent fault model, except for one of the variants of MORUS where the full key is recovered with this model. The second type is a full key recovery using a transient fault model, at the cost of a higher number of faults compared to the permanent fault model. Finally, we describe a fault attack on the integrity component of MORUS, which performs a forgery using the bit-flipping fault model.

BRCA1 mutation carriers have a higher risk of developing triple-negative breast cancer (TNBC), which is a refractory disease due to its non-responsiveness to current clinical targeted therapies. Using the Sleeping Beauty transposon system in Brca1-deficient mice, we identified 169 putative cancer drivers, among which Notch1 is a top candidate for accelerating TNBC by promoting the epithelial-mesenchymal transition (EMT) and regulating the cell cycle. Activation of NOTCH1 suppresses mitotic catastrophe caused by BRCA1 deficiency by restoring S/G2 and G2/M cell cycle checkpoints, which may through activation of ATR-CHK1 signalling pathway. Consistently, analysis of human breast cancer tissue demonstrates NOTCH1 is highly expressed in TNBCs, and the activated form of NOTCH1 correlates positively with increased phosphorylation of ATR. Additionally, we demonstrate that inhibition of the NOTCH1-ATR-CHK1 cascade together with cisplatin synergistically kills TNBC by targeting the cell cycle checkpoint, DNA damage and EMT, providing a potent clinical option for this fatal disease. BRCA1 mutation carriers have higher chances of developing triple-negative breast cancer (TNBC). Here, the authors use the Sleeping Beauty mutagenesis system in Brca1 deficient mice and identify 169 putative driver genes, of which NOTCH1 accelerates TNBC formation through promoting epithelial-mesenchymal transition and cell cycle progression.