Projecting Uncertainty in Ecosystem Persistence Under Climate Change.

Global projections of ecosystem responses to increasing climatic and anthropogenic pressures are needed to inform adaptation planning. However, data of appropriate spatiotemporal resolution are often not available to parameterize complex environmental processes at the global scale. Modeling approaches that can project the probability of ecosystem persistence when parameter uncertainty is high may offer a way forward.

Isoindolinone-Based PET Tracers for Imaging Mutant Huntingtin Aggregates.

Huntington's disease (HD) is caused by the repeat expansion of the CAG trinucleotide in the mutant Huntingtin gene (m) within the exon1 region, resulting in an expanded polyglutamine-containing mHTT exon1 protein that serves as the source of the hallmark mHTT aggregates in people with HD (PwHD). To better understand aggregation formation during disease progression and its utility as a pharmacodynamic biomarker, we have been targeting mHTT aggregates for developing PET imaging tracers and have identified a series of isoindolinones that show significantly higher binding potential (BP, a ratio of Bmax over ) in HD mouse models as well as increased binding in HD post-mortem brains, compared to first generation ligands. We present the structure-activity relationship (SAR) work leading to three candidate tracers progressed for human studies: [C]CHDI-009 (), [F]CHDI-385 () and [F]CHDI-386 ().

A universal language for finding mass spectrometry data patterns.

Despite being information rich, the vast majority of untargeted mass spectrometry data are underutilized; most analytes are not used for downstream interpretation or reanalysis after publication. The inability to dive into these rich raw mass spectrometry datasets is due to the limited flexibility and scalability of existing software tools. Here we introduce a new language, the Mass Spectrometry Query Language (MassQL), and an accompanying software ecosystem that addresses these issues by enabling the community to directly query mass spectrometry data with an expressive set of user-defined mass spectrometry patterns.

MS-RT: A Method for Evaluating MS/MS Clustering Performance for Metabolomics Data.

The clustering of tandem mass spectra (MS/MS) is a crucial computational step to deduplicate repeated acquisitions in data-dependent experiments. This technique is essential in untargeted metabolomics, particularly with high-throughput mass spectrometers capable of generating hundreds of MS/MS spectra per second. Despite advancements in MS/MS clustering algorithms in proteomics, their performance in metabolomics has not been extensively evaluated due to the lack of database search tools with false discovery rate control for molecule identification.

Incorporating cyclone risk in the design of marine protected and conserved areas as an ecosystem-based adaptation approach.

Marine protected and conserved areas (MPCAs) are promoted as an ecosystem-based adaptation (EbA) approach to increase community and ecosystem resilience to climate change. However, traditional approaches to MPCA design typically do not consider climate risk or habitat condition under a climate threat. We used the Great Sea Reef (GSR) in Fiji as a case study to develop a land-sea prioritization framework that links modeled sediment runoff from rainfall during extreme cyclone events to the probability of coral reefs being in good condition.

Structure and function of MDM2 and MDM4 in health and disease.

Both mouse double-minute 2 (MDM2), an E3 ubiquitin ligase, and its closely related paralog, MDM4, which lacks E3 activity, play central roles in cellular homeostasis. MDM-linked dysfunction is associated with an increased risk of oncogenesis, primarily through targeting the tumor suppressor protein p53 for ubiquitination and degradation. Recent studies have revealed multifaceted roles of MDM proteins that are p53 independent with implications for their oncogenic properties.

Incorporating stressor interactions into spatially explicit cumulative impact assessments.

Human-induced stressors are impacting the oceans and reducing the biodiversity of marine ecosystems. The many stressors affecting marine environments do not act in isolation. However, their cumulative impact is difficult to predict.

Stock assessment models overstate sustainability of the world's fisheries.

Effective fisheries management requires accurate estimates of stock biomass and trends; yet, assumptions in stock assessment models generate high levels of uncertainty and error. For 230 fisheries worldwide, we contrasted stock biomass estimates at the time of assessment with updated hindcast estimates modeled for the same year in later assessments to evaluate systematic over- or underestimation. For stocks that were overfished, low value, or located in regions with rising temperatures, historical biomass estimates were generally overstated compared with updated assessments.

Network Topology Evaluation and Transitive Alignments for Molecular Networking.

Untargeted tandem mass spectrometry (MS/MS) is an essential technique in modern analytical chemistry, providing a comprehensive snapshot of chemical entities in complex samples and identifying unknowns through their fragmentation patterns. This high-throughput approach generates large data sets that can be challenging to interpret. Molecular Networks (MNs) have been developed as a computational tool to aid in the organization and visualization of complex chemical space in untargeted mass spectrometry data, thereby supporting comprehensive data analysis and interpretation.

Speeding up the recovery of coastal habitats through management interventions that address constraints on dispersal and recruitment.

Plans for habitat restoration will benefit from predictions of timescales for recovery. Theoretical models have been a powerful tool for informing practical guidelines in planning marine protected areas, suggesting restoration planning could also benefit from a theoretical framework. We developed a model that can predict recovery times following restoration action, under dispersal, recruitment and connectivity constraints.

Integrating socioeconomic and ecological data into restoration practice.

Driven by the United Nations Decade on Restoration and international funding initiatives, such as the Mangrove Breakthrough, investment in mangrove restoration is expected to increase. Yet, mangrove restoration efforts frequently fail, usually because of ad hoc site-selection processes that do not consider mangrove ecology and the socioeconomic context. Using decision analysis, we developed an approach that accounts for socioeconomic and ecological data to identify sites with the highest likelihood of mangrove restoration success.

Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists.

Although stapled α-helical peptides can address challenging targets, their advancement is impeded by poor understandings for making them cell permeable while avoiding off-target toxicities. By synthesizing >350 molecules, we present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects. Key insights include a clear correlation between lipophilicity and permeability, removal of positive charge to avoid off-target toxicities, judicious anionic residue placement to enhance solubility/behavior, optimization of C-terminal length/helicity to enhance potency, and optimization of staple type/number to avoid polypharmacology.

Delivery to, and Reactivation of, the p53 Pathway in Cancer Cells Using a Grafted Cyclotide Conjugated with a Cell-Penetrating Peptide.

Peptides are promising drug modalities that can modulate protein-protein interactions, but their application is hampered by their limited ability to reach intracellular targets. Here, we improved the cytosolic delivery of a peptide blocking p53:MDM2/X interactions using a cyclotide as a stabilizing scaffold. We applied several design strategies to improve intracellular delivery and found that the conjugation of the lead cyclotide to the cyclic cell-penetrating peptide cR10 was the most effective.

Stitched peptides as potential cell permeable inhibitors of oncogenic DAXX protein.

DAXX (Death Domain Associated Protein 6) is frequently upregulated in various common cancers, and its suppression has been linked to reduced tumor progression. Consequently, DAXX has gained significant interest as a therapeutic target in such cancers. DAXX is known to function in several critical biological pathways including chromatin remodelling, transcription regulation, and DNA repair.

A high-throughput microfluidic mechanoporation platform to enable intracellular delivery of cyclic peptides in cell-based assays.

Cyclic peptides are poised to target historically difficult to drug intracellular protein-protein interactions, however, their general cell impermeability poses a challenge for characterizing function. Recent advances in microfluidics have enabled permeabilization of the cytoplasmic membrane by physical cell deformation (i.e.

A data-driven approach to multiple-stressor impact assessment for a marine protected area.

The coastal environment is not managed in a way that considers the impact of cumulative threats, despite being subject to threats from all realms (marine, land, and atmosphere). Relationships between threats and species are often nonlinear; thus, current (linear) approaches to estimating the impact of threats may be misleading. We developed a data-driven approach to assessing cumulative impacts on ecosystems and applied it to explore nonlinear relationships between threats and a temperate reef fish community.

Co-occurrence of biodiversity, carbon storage, coastal protection, and fish and invertebrate production to inform global mangrove conservation planning.

Mangrove forests support unique biodiversity and provide a suite of ecosystem services (ES) that benefit people. Decades of continual mangrove loss and degradation have necessitated global efforts to protect and restore this important ecosystem. Generating and evaluating asset maps of biodiversity and ES is an important precursor to identifying locations that can deliver conservation outcomes across varying scales, such as maximising the co-occurrence of specific ES.

Stressor fluctuations alter mechanisms of seagrass community responses relative to static stressors.

Ecosystems are increasingly affected by multiple anthropogenic stressors that contribute to habitat degradation and loss. Natural ecosystems are highly dynamic, yet multiple stressor experiments often ignore variability in stressor intensity and do not consider how effects could be mediated across trophic levels, with implications for models that underpin stressor management. Here, we investigated the in situ effects of changes in stressor intensity (i.

Further Characterization of Fungal Halogenase RadH and Its Homologs.

RadH is one of the flavin-dependent halogenases that has previously exhibited promising catalytic activity towards hydroxycoumarin, hydroxyisoquinoline, and phenolic derivatives. Here, we evaluated new functional homologs of RadH and expanded its specificities for the halogenation of non-tryptophan-derived, heterocyclic scaffolds. Our investigation revealed that RadH could effectively halogenate hydroxyquinoline and hydroxybenzothiophene.