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29 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Ultra-high Information-content Chemical Imaging with Broadband Coherent Anti-Stokes Raman and Two-photon Fluorescence Lifetime Microscopy

Raman fingerprint spectroscopy and fluorescence lifetime imaging are emerging tools for studying metabolic profiles of biological specimens. While Raman fingerprint spectroscopy detects intrinsic molecular vibrations that reflect the molecular composition and chemical environment of a sample, fluorescence lifetime imaging measures changes in the excited-state lifetime of fluorophores that are sensitive to their microenvironments. Here, we present a multimodal imaging platform combining broadband coherent anti-Stokes Raman scattering (BCARS) and two-photon fluorescence lifetime imaging (2p-FLIM) microscopy that can acquire biologically relevant Raman fingerprint spectra and fluorescence lifetime signals in vivo and simultaneously. The tremendous chemical information obtained from spatially co-registered BCARS and 2p-FLIM images allows us to characterize the subtle differences between sub-cellular compartments and verify the potential false-positive results generated by fluorescence imaging alone. This is demonstrated by directly comparing the BCARS, 2p-FLIM, and two-photon excitation fluorescence(TPEF) signals simultaneously obtained from the same dye-stained organelle in the live, intact C. elegans expressing a green fluorescent protein (GFP) marker. In this work, we introduce the BCARS/2p-FLIM/TPEF setup scheme, the image acquisition steps, data processing, and representative results showing that the cross-modality imaging method enables rigorous characterization and in vivo detection at sub-cellular resolution. Furthermore, this protocol provides a framework for simultaneous chemical and fluorescence lifetime imaging to improve the accuracy of biological interpretation in complex living systems.

Xu, Haoyu [Georgia Institute of Technology, Atlant↗
DOE OSTI2023

Recruitment of Polo-like kinase couples synapsis to meiotic progression via inactivation of CHK-2

Meiotic chromosome segregation relies on synapsis and crossover (CO) recombination between homologous chromosomes. These processes require multiple steps that are coordinated by the meiotic cell cycle and monitored by surveillance mechanisms. In diverse species, failures in chromosome synapsis can trigger a cell cycle delay and/or lead to apoptosis. How this key step in ‘homolog engagement’ is sensed and transduced by meiotic cells is unknown. Here we report that in C. elegans , recruitment of the Polo-like kinase PLK-2 to the synaptonemal complex triggers phosphorylation and inactivation of CHK-2, an early meiotic kinase required for pairing, synapsis, and double-strand break (DSB) induction. Inactivation of CHK-2 terminates DSB formation and enables CO designation and cell cycle progression. These findings illuminate how meiotic cells ensure CO formation and accurate chromosome segregation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Geometrically Matched Multi-source Microscopic Image Synthesis Using Bidirectional Adversarial Networks

Microscopic images from multiple modalities can produce plentiful experimental information. In practice, biological or physical constraints under a given observation period may prevent researchers from acquiring enough microscopic scanning. Recent studies demonstrate that image synthesis is one of the popular approaches to release such constraints. Nonetheless, most existing synthesis approaches only translate images from the source domain to the target domain without solid geometric associations. To embrace this challenge, we propose an innovative model architecture, BANIS, to synthesize diversified microscopic images from multi-source domains with distinct geometric features. The experimental outcomes indicate that BANIS successfully synthesizes favorable image pairs on C. elegans microscopy embryonic images. To the best of our knowledge, BANIS is the first application to synthesize microscopic images that associate distinct spatial geometric features from multi-source domains.

Wang, Dali↗
DOE OSTI2022

A versatile enhanced freeze-substitution protocol for volume electron microscopy

Volume electron microscopy, a powerful approach to generate large three-dimensional cell and tissue volumes at electron microscopy resolutions, is rapidly becoming a routine tool for understanding fundamental and applied biological questions. One of the enabling factors for its adoption has been the development of conventional fixation protocols with improved heavy metal staining. However, freeze-substitution with organic solvent-based fixation and staining has not realized the same level of benefit. Here, we report a straightforward approach including osmium tetroxide, acetone and up to 3% water substitution fluid (compatible with traditional or fast freeze-substitution protocols), warm-up and transition from organic solvent to aqueous 2% osmium tetroxide. Once fully hydrated, samples were processed in aqueous based potassium ferrocyanide, thiocarbohydrazide, osmium tetroxide, uranyl acetate and lead acetate before resin infiltration and polymerization. We observed a consistent and substantial increase in heavy metal staining across diverse and difficult-to-fix test organisms and tissue types, including plant tissues ( Hordeum vulgare ), nematode ( Caenorhabditis elegans ) and yeast ( Saccharomyces cerevisiae ). Our approach opens new possibilities to combine the benefits of cryo-preservation with enhanced contrast for volume electron microscopy in diverse organisms.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes

Mutations that cause familial Alzheimer’s disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid β-peptide (Aβ). Nevertheless, whether Aβ is the primary disease driver remains controversial. We report here that FAD mutations disrupt initial proteolytic events in the multistep processing of APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals that a substrate mimetic traps γ-secretase during the transition state, and this structure aligns with activated enzyme-substrate complex captured by molecular dynamics simulations. In silico simulations and in cellulo fluorescence microscopy support stabilization of enzyme-substrate complexes by FAD mutations. Neuronal expression of C99 and/or presenilin-1 in Caenorhabditis elegans leads to synaptic loss only with FAD-mutant transgenes. Designed mutations that stabilize the enzyme-substrate complex and block Aβ production likewise led to synaptic loss. Collectively, these findings implicate the stalled process—not the products—of γ-secretase cleavage of substrates in FAD pathogenesis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Intra- and inter-molecular regulation by intrinsically-disordered regions governs PUF protein RNA binding

PUF proteins are characterized by globular RNA-binding domains. They also interact with partner proteins that modulate their RNA-binding activities. Caenorhabditis elegans PUF protein fem-3 binding factor-2 (FBF-2) partners with intrinsically disordered Lateral Signaling Target-1 (LST-1) to regulate target mRNAs in germline stem cells. Here, we report that an intrinsically disordered region (IDR) at the C-terminus of FBF-2 autoinhibits its RNA-binding affinity by increasing the off rate for RNA binding. Moreover, the FBF-2 C-terminal region interacts with its globular RNA-binding domain at the same site where LST-1 binds. This intramolecular interaction restrains an electronegative cluster of amino acid residues near the 5' end of the bound RNA to inhibit RNA binding. LST-1 binding in place of the FBF-2 C-terminus therefore releases autoinhibition and increases RNA-binding affinity. This regulatory mechanism, driven by IDRs, provides a biochemical and biophysical explanation for the interdependence of FBF-2 and LST-1 in germline stem cell self-renewal.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Memsensing by surface ion migration within Debye length

Integration between electronics and biology is often facilitated by iontronics, where ion migration in aqueous media governs sensing and memory. However, the Debye screening effect limits electric fields to the Debye length, the distance over which mobile ions screen electrostatic interactions, necessitating external voltages that constrain the operation speed and device design. Here we report a high-speed in-memory sensor based on vanadium dioxide (VO2) that operates without an external voltage by leveraging built-in electric fields within the Debye length. When VO2 contacts a low-work-function metal (for example, indium) in a salt solution, electrochemical reactions generate indium ions that migrate into the VO2 surface under the native electric field, inducing a surface insulator-to-metal phase transition of VO2. The VO2 conductance increase rate reflects the salt concentration, enabling in-memory sensing, or memsensing of the solution. The memsensor mimics Caenorhabditis elegans chemosensory plasticity to guide a miniature boat for adaptive chemotaxis, illustrating low-power aquatic neurorobotics with fewer memory units.

Guo, Ruihan↗
DOE OSTI2023

Expanded diversity of novel hemoplasmas in rare and undersampled Neotropical bats

Hemotropic mycoplasmas are emerging as a model system for studying bacterial pathogens in bats, but taxonomic coverage of sampled host species remains biased. We leveraged a long-term field study in Belize to uncover novel hemoplasma diversity in bats by analyzing 80 samples from 19 species, most of which are infrequently encountered. PCR targeting the partial 16S rRNA gene found 41% of bats positive for hemoplasmas. Phylogenetic analyses found two novel host shifts of hemoplasmas, four entirely new hemoplasma genotypes, and the first hemoplasma detections in four bat species. One of these novel hemoplasmas (from Neoeptesicus furinalis) shared 97.6% identity in the partial 16S rRNA gene to a human hemoplasma (Candidatus Mycoplasma haemohominis). Additional analysis of the partial 23S rRNA gene allowed us to also designate two novel hemoplasma species, in Myotis elegans and Phyllostomus discolor, with the proposed names Candidatus Mycoplasma haematomyotis sp. nov. and Candidatus Mycoplasma haematophyllostomi sp. nov., respectively. Our analyses show that additional hemoplasma diversity in bats can be uncovered by targeting rare or undersampled host species.

16S rRNA gene↗
DOE OSTI2026

Magnetic resonance control of spin-correlated radical pair dynamics in vivo

Magnetic fields can influence reactions involving spin-correlated radical pairs (SCRPs). This provides a mechanism by which both static and time-varying magnetic fields can affect living systems at the biomolecular level. However, an engineered SCRP system conferring magnetic sensitivity to a non-native biochemical process in a multicellular organism has not yet been demonstrated. Here, in this study, we demonstrate control of SCRP dynamics using magnetic resonance in a live transgenic animal. We show that the emission of various red fluorescent proteins (RFPs), in the presence of a flavin cofactor, can be modified by a combination of static and radiofrequency magnetic fields applied near the electron spin resonance frequency. This effect was measured at room temperature both in vitro and in the nematode Caenorhabditis elegans, genetically modified to express the RFP mScarlet. These observations suggest that the magnetic field effects measured in RFP-flavin systems are due to quantum-correlated radical pairs with a coherence time larger than 4 ns. Our experiments demonstrate that radiofrequency magnetic fields can influence dynamics of reactions involving SCRPs in vivo, potentially enabling new methods for remotely controlling biomolecular processes, such as gene expression, and suggest broader potential for quantum tools in biology.

Burd, Shaun C. [Stanford Univ., CA (United States)↗
DOE OSTI2024

Updates to the Alliance of Genome Resources central infrastructure

The Alliance of Genome Resources (Alliance) is an extensible coalition of knowledgebases focused on the genetics and genomics of intensively studied model organisms. The Alliance is organized as individual knowledge centers with strong connections to their research communities and a centralized software infrastructure, discussed here. Model organisms currently represented in the Alliance are budding yeast, Caenorhabditis elegans, Drosophila, zebrafish, frog, laboratory mouse, laboratory rat, and the Gene Ontology Consortium. The project is in a rapid development phase to harmonize knowledge, store it, analyze it, and present it to the community through a web portal, direct downloads, and application programming interfaces (APIs). Here, we focus on developments over the last 2 years. Specifically, we added and enhanced tools for browsing the genome (JBrowse), downloading sequences, mining complex data (AllianceMine), visualizing pathways, full-text searching of the literature (Textpresso), and sequence similarity searching (SequenceServer). We enhanced existing interactive data tables and added an interactive table of paralogs to complement our representation of orthology. To support individual model organism communities, we implemented species-specific “landing pages” and will add disease-specific portals soon; in addition, we support a common community forum implemented in Discourse software. We describe our progress toward a central persistent database to support curation, the data modeling that underpins harmonization, and progress toward a state-of-the-art literature curation system with integrated artificial intelligence and machine learning (AI/ML).

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Harmonizing model organism data in the Alliance of Genome Resources

The Alliance of Genome Resources (the Alliance) is a combined effort of 7 knowledgebase projects: Saccharomyces Genome Database, WormBase, FlyBase, Mouse Genome Database, the Zebrafish Information Network, Rat Genome Database, and the Gene Ontology Resource. The Alliance seeks to provide several benefits: better service to the various communities served by these projects; a harmonized view of data for all biomedical researchers, bioinformaticians, clinicians, and students; and a more sustainable infrastructure. The Alliance has harmonized cross-organism data to provide useful comparative views of gene function, gene expression, and human disease relevance. The basis of the comparative views is shared calls of orthology relationships and the use of common ontologies. The key types of data are alleles and variants, gene function based on gene ontology annotations, phenotypes, association to human disease, gene expression, protein–protein and genetic interactions, and participation in pathways. The information is presented on uniform gene pages that allow facile summarization of information about each gene in each of the 7 organisms covered (budding yeast, roundworm Caenorhabditis elegans, fruit fly, house mouse, zebrafish, brown rat, and human). The harmonized knowledge is freely available on the alliancegenome.org portal, as downloadable files, and by APIs. We expect other existing and emerging knowledge bases to join in the effort to provide the union of useful data and features that each knowledge base currently provides.

59 BASIC BIOLOGICAL SCIENCES↗