A GATA Transcription Factor Recruits Hda1 in Response to Reduced Tor1 Signaling to Establish a Hyphal Chromatin State in Candida albicans

Candida albicans is an important opportunistic fungal pathogen of immunocompromised individuals. One critical virulence attribute is its morphogenetic plasticity. Hyphal development requires two temporally linked changes in promoter chromatin, which is sequentially regulated by temporarily clearing the transcription inhibitor Nrg1 upon activation of the cAMP/PKA pathway and promoter recruitment of the histone deacetylase Hda1 under reduced Tor1 signaling. Molecular mechanisms for the temporal connection and the link to Tor1 signaling are not clear. Here, through a forward genetic screen, we report the identification of the GATA family transcription factor Brg1 as the factor that recruits Hda1 to promoters of hypha-specific genes during hyphal elongation. BRG1 expression requires both the removal of Nrg1 and a sub-growth inhibitory level of rapamycin; therefore, it is a sensitive readout of Tor1 signaling. Interestingly, promoters of hypha-specific genes are not accessible to Brg1 in yeast cells. Furthermore, ectopic expression of Brg1 cannot induce hyphae, but can sustain hyphal development. Nucleosome mapping of a hypha-specific promoter shows that Nrg1 binding sites are in nucleosome free regions in yeast cells, whereas Brg1 binding sites are occupied by nucleosomes. Nucleosome disassembly during hyphal initiation exposes the binding sites for both regulators. During hyphal elongation, Brg1-mediated Hda1 recruitment causes nucleosome repositioning and occlusion of Nrg1 binding sites. We suggest that nucleosome repositioning is the underlying mechanism for the yeast-hyphal transition. The hypha-specific regulator Ume6 is a key downstream target of Brg1 and functions after Brg1 as a built-in positive feedback regulator of the hyphal transcriptional program to sustain hyphal development. With the levels of Nrg1 and Brg1 dynamically and sensitively controlled by the two major cellular growth pathways, temporal changes in nucleosome positioning during the yeast-to-hypha transition provide a mechanism for signal integration and cell fate specification. This mechanism is likely used broadly in development

ORGANA: A Robotic Assistant for Automated Chemistry Experimentation and Characterization

Chemistry experimentation is often resource- and labor-intensive. Despite the many benefits incurred by the integration of advanced and special-purpose lab equipment, many aspects of experimentation are still manually conducted by chemists, for example, polishing an electrode in electrochemistry experiments. Traditional lab automation infrastructure faces challenges when it comes to flexibly adapting to new chemistry experiments. To address this issue, we propose a human-friendly and flexible robotic system, ORGANA, that automates a diverse set of chemistry experiments. It is capable of interacting with chemists in the lab through natural language, using Large Language Models (LLMs). ORGANA keeps scientists informed by providing timely reports that incorporate statistical analyses. Additionally, it actively engages with users when necessary for disambiguation or troubleshooting. ORGANA can reason over user input to derive experiment goals, and plan long sequences of both high-level tasks and low-level robot actions while using feedback from the visual perception of the environment. It also supports scheduling and parallel execution for experiments that require resource allocation and coordination between multiple robots and experiment stations. We show that ORGANA successfully conducts a diverse set of chemistry experiments, including solubility assessment, pH measurement, recrystallization, and electrochemistry experiments. For the latter, we show that ORGANA robustly executes a long-horizon plan, comprising 19 steps executed in parallel, to characterize the electrochemical properties of quinone derivatives, a class of molecules used in rechargeable flow batteries. Our user study indicates that ORGANA significantly improves many aspects of user experience while reducing their physical workload. More details about ORGANA can be found at https://ac-rad.github.io/organa/

VeCLIP: Improving CLIP Training via Visual-enriched Captions

Large-scale web-crawled datasets are fundamental for the success of pre-training vision-language models, such as CLIP. However, the inherent noise and potential irrelevance of web-crawled AltTexts pose challenges in achieving precise image-text alignment. Existing methods utilizing large language models (LLMs) for caption rewriting have shown promise on small, curated datasets like CC3M and CC12M. This study introduces a scalable pipeline for noisy caption rewriting. Unlike recent LLM rewriting techniques, we emphasize the incorporation of visual concepts into captions, termed as Visual-enriched Captions (VeCap). To ensure data diversity, we propose a novel mixed training scheme that optimizes the utilization of AltTexts alongside newly generated VeCap. We showcase the adaptation of this method for training CLIP on large-scale web-crawled datasets, termed VeCLIP. Employing this cost-effective pipeline, we effortlessly scale our dataset up to 300 million samples named VeCap dataset. Our results show significant advantages in image-text alignment and overall model performance. For example, VeCLIP achieves up to +25.2% gain in COCO and Flickr30k retrieval tasks under the 12M setting. For data efficiency, VeCLIP achieves +3% gain while only using 14% of the data employed in the vanilla CLIP and 11% in ALIGN. We also note the VeCap data is complementary with other well curated datasets good for zero-shot classification tasks. When combining VeCap and DFN, our model can achieve strong performance on both of image-text retrieval and zero-shot classification tasks, e.g. 83.1% accuracy@1 on ImageNet zero-shot for a H/14 model. We release the pre-trained models at https://github.com/apple/ml-veclip.Comment: CV/M

Hyphal Development in Candida albicans Requires Two Temporally Linked Changes in Promoter Chromatin for Initiation and Maintenance

Phenotypic plasticity is common in development. For Candida albicans, the most common cause of invasive fungal infections in humans, morphological plasticity is its defining feature and is critical for its pathogenesis. Unlike other fungal pathogens that exist primarily in either yeast or hyphal forms, C. albicans is able to switch reversibly between yeast and hyphal growth forms in response to environmental cues. Although many regulators have been found involved in hyphal development, the mechanisms of regulating hyphal development and plasticity of dimorphism remain unclear. Here we show that hyphal development involves two sequential regulations of the promoter chromatin of hypha-specific genes. Initiation requires a rapid but temporary disappearance of the Nrg1 transcriptional repressor of hyphal morphogenesis via activation of the cAMP-PKA pathway. Maintenance requires promoter recruitment of Hda1 histone deacetylase under reduced Tor1 (target of rapamycin) signaling. Hda1 deacetylates a subunit of the NuA4 histone acetyltransferase module, leading to eviction of the NuA4 acetyltransferase module and blockage of Nrg1 access to promoters of hypha-specific genes. Promoter recruitment of Hda1 for hyphal maintenance happens only during the period when Nrg1 is gone. The sequential regulation of hyphal development by the activation of the cAMP-PKA pathway and reduced Tor1 signaling provides a molecular mechanism for plasticity of dimorphism and how C. albicans adapts to the varied host environments in pathogenesis. Such temporally linked regulation of promoter chromatin by different signaling pathways provides a unique mechanism for integrating multiple signals during development and cell fate specification

Reduced TOR signaling sustains hyphal development in Candida albicans by lowering Hog1 basal activity.

Candida albicans is able to undergo reversible morphological changes between yeast and hyphal forms in response to environmental cues. This morphological plasticity is essential for its pathogenesis. Hyphal development requires two temporally linked changes in promoter chromatin, which is sequentially regulated by temporarily clearing the transcription inhibitor Nrg1 upon activation of cAMP/protein kinase A and promoter recruitment of the histone deacetylase Hda1 under reduced target of rapamycin (Tor1) signaling. The GATA family transcription factor Brg1 recruits Hda1 to promoters for sustained hyphal development, and BRG1 expression is a readout of reduced Tor1 signaling. How Tor1 regulates BRG1 expression is not clear. Using a forward genetic screen for mutants that can sustain hyphal elongation in rich media, we found hog1, ssk2, and pbs2 mutants of the HOG mitogen-activated protein kinase pathway to express BRG1 irrespective of rapamycin. Furthermore, rapamycin lowers the basal activity of Hog1 through the functions of the two Hog1 tyrosine phosphatases Ptp2 and Ptp3. Active Hog1 represses the expression of BRG1 via the transcriptional repressor Sko1 as Sko1 disassociates from the promoter of BRG1 in the hog1 mutant or in rapamycin. Our data suggest that reduced Tor1 signaling lowers Hog1 basal activity via Hog1 phosphatases to activate BRG1 expression for hyphal elongation

Candida albicans hyphal initiation and elongation

The fungus Candida albicans is a benign member of the mucosal microbiota, but can cause mucosal infections and life-threatening disseminated invasive infections in susceptible individuals. The ability to switch between yeast, pseudohyphal, and hyphal growth forms (polymorphism) is one of the most investigated virulence attributes of C. albicans. Recent studies suggest that hyphal development in C. albicans requires two temporally linked regulations for initiation and maintenance of the hyphal transcriptional program. Hyphal initiation requires a rapid but temporary disappearance of the Nrg1 transcriptional repressor of hyphal morphogenesis. Hyphal maintenance requires active sensing of the surrounding environment, leading to exclusion of Nrg1 binding to promoters of hypha-specific genes or reduced NRG1 expression. We discuss recent advances in understanding the complex transcriptional regulation of hyphal gene expression. These provide molecular mechanisms underpinning the phenotypic plasticity of C. albicans polymorphism

Sand transport and deposition behaviour in subsea pipelines for flow assurance

Sand transport through tubing and pipeline could cause a series of problems to flow assurance, if not properly managed or controlled. The most serious problem is the accumulation and erosion in multiphase flow pipelines and the surface equipment. Therefore, the importance of understanding the transport and deposition behaviour of sands through multiphase flow pipelines cannot be overemphasized. This study presents the sand transport and deposition characteristics in the complicated multiphase flow pipeline. The numerical result shows that the slurry velocity presents a uniform distribution in the multiphase flow pipeline at the sand concentration of 5% and the sand diameter of 50 µm. However, the slurry velocity at the bottom of the pipeline is significantly smaller than that at the top when the sand concentration and diameter reach 30% and 300 µm, respectively. It indicates that the sand deposition at the bottom of the pipe declines the slurry velocity and transport capacity. The deposition thickness is approximately 10% of the pipe diameter even at the low concentration of 5% sand with a small sand diameter of 50 µm and a high slurry velocity of 1.8 m/s. The sand deposition reaches about 30% of the pipe diameter at the same low concentration and high slurry velocity when the sand diameter increases to 300 μm