bluuebunny/crossref_metadata_2025 huggingface dataset:
Sub-functionalization and epigenetic regulation of a biosynthetic gene cluster inSolanaceae
Authors: Priego-Cubero Santiago , Knoch Eva , Wang Zhidan , Alseekh Saleh , Braun Karl-Heinz , Chapman Philipp , Fernie Alisdair , Liu Chang , Becker Claude
Published: October 2024

Biosynthetic gene clusters (BGCs) are sets of often heterologous genes that are genetically and functionally linked. Among eukaryotes, BGCs are most common in plants and fungi, where they ensure the co-expression of the different enzymes coordinating the biosynthesis of specialised metabolites. Here, we report on a newly identified withanolide BGC inPhysalis grisea(ground-cherry), a member of the nightshade family (Solanaceae). A combination of transcriptomic, epigenomic and metabolic analyses, revealed that, following a duplication event, this BGC evolved two tissue-specifically expressed sub-clusters, containing eight pairs of paralogs that contribute to related but distinct biochemical processes; this sub- functionalisation is tightly associated with epigenetic features and the local chromatin environment. The two sub-clusters appear strictly isolated from each other at the chromatin structural level, each forming a highly self-interacting chromatin domain with tissue-dependent levels of condensation. This correlates with gene expression exclusively in either above- or below-ground tissue, thus spatially separating the production of different withanolide compounds. By comparative phylogenomic analysis, we show that the withanolide BGC most likely evolved before the diversification of theSolanaceaefamily and underwent lineage- specific diversifications and losses. The tissue-specific sub-functionalisation is common to species of thePhysalideaetribe but distinct from other, independent duplication events outside of this clade. In sum, our study reports on the first instance of an epigenetically modulated sub-functionalisation within a BGC and sheds light on the biosynthesis of withanolides, a highly diverse group of steroidal triterpenoids important in plant defence and amenable to pharmaceutical applications due to their anti-inflammatory, antibiotic and anti- cancer properties.
Determining sex differences in drug combinations targeting aortic valve myofibroblast activation using an artificial intelligence derived platform
Authors: Vogt Brandon J. , Wang Peter , Chavez Megan , Guo Peng , Chow Edward Kai-Hua , Ho Dean , Aguado Brian A.
Published: October 2024

Aortic valve stenosis (AVS) is a sexually dimorphic disease where aortic valve leaflets develop fibrosis and calcification, leading to heart failure if untreated. Sex differences in AVS progression depend on valvular interstitial cells (VICs) activating to myofibroblasts that drive aberrant extracellular matrix remodeling. To date, no treatment strategies have leveraged cellular sex differences to determine drug combinations that effectively target VIC myofibroblast activation. Here, we harnessed IDentif.AI, an artificial intelligence (AI)-derived drug optimization platform, to optimize sex-specific synergistic drug combinations that may prevent and reverse VIC myofibroblast activation on hydrogel biomaterials. The results reveal that anti-fibrotic drug efficacy and combinatorial interactions are dependent on cell sex. This study provides a framework for developing clinically relevant AVS treatment strategies through the integration of high-throughput hydrogel cell culture platforms and AI-driven drug optimization. The workflow towards designing targeted AVS drug combinations may help accelerate AVS drug development for male and female patients and address health disparities in AVS treatment outcomes.
Butterfly brains change in morphology and in gene splicing patterns after brief pheromone exposure
Authors: Dion Emilie , Toh YiPeng , Zhu Dantong , Monteiro Antónia
Published: October 2024

How insect brains differ between the sexes and respond to sex-specific pheromones is still not well understood. Here we briefly exposed femaleBicyclus anynanabutterflies to wild type (Wt) and modified male sex pheromone blends, previously shown to modify females’ sexual preferences, and examined how their brains were modified at the morphological and molecular levels, three days later. First, we 3D-reconstructed male and female brains of this species and documented sexual dimorphism in the size of seven of 67 glomeruli present in the olfactory lobe. Then we showed that several glomeruli changed in volume after blend exposures, implicating them in sex pheromone perception. Finally, we found that a few genes were differentially expressed but many more were differentially spliced between male and female naïve brains, and between naive and pheromone blend-exposed brains. These are primarily calcium-binding channels and RNA-binding genes, respectively. A learned preference for changed levels in a single pheromone component was linked to variants of proteins involved in synaptic transmission. Our work shows that naïve male and female brains differ primarily in gene splicing patterns and that a brief, 3-minute, exposure to pheromones produces slight changes in brain volume and large changes in the splicing of genes involved in neural development, that correlate with changes in sexual preferences in females.

Significance statement

How brains differ between the sexes and respond to sex-specific cues is a hot research topic. Here we investigate how the brains of female butterflies differ from those of males and respond to male sex pheromones. We find that the sexes differ in the volume of a sub-set of olfactory lobe glomeruli, and the volume of some glomeruli also changes after exposure to pheromone blends. In addition, male and female brains differ primarily in hundreds of splice variants, both before and after pheromone exposure. These findings suggest that different proteins (splice variants) characterize male and female brains and that a brief exposure to pheromones can lead to changes in brain structure and in further gene splicing linked to altered sexual preferences in female butterflies.
Baby Open Brains: An Open-Source Repository of Infant Brain Segmentations
Authors: Feczko Eric , Stoyell Sally M , Moore Lucille A. , Alexopoulos Dimitrios , Bagonis Maria , Barrett Kenneth , Bower Brad , Cavender Addison , Chamberlain Taylor A. , Conan Greg , Day Trevor KM , Goradia Dhruman , Graham Alice , Heisler-Roman Lucas , Hendrickson Timothy J. , Houghton Audrey , Kardan Omid , Kiffmeyer Elizabeth A , Lee Erik G , Lundquist Jacob T. , Lucena Carina , Martin Tabitha , Mummaneni Anurima , Myricks Mollie , Narnur Pranav , Perrone Anders J. , Reiners Paul , Rueter Amanda R. , Saw Hteemoo , Styner Martin , Sung Sooyeon , Tiklasky Barry , Wisnowski Jessica L , Yacoub Essa , Zimmermann Brett , Smyser Christopher D. , Rosenberg Monica D. , Fair Damien A. , Elison Jed T.
Published: October 2024

Reproducibility of neuroimaging research on infant brain development remains limited due to highly variable protocols and processing approaches. Progress towards reproducible pipelines is limited by a lack of benchmarks such as gold standard brain segmentations. Addressing this core limitation, we constructed the Baby Open Brains (BOBs) Repository, an open source resource comprising manually curated and expert-reviewed infant brain segmentations. Markers and expert reviewers manually segmented anatomical MRI data from 71 infant imaging visits across 51 participants, using both T1w and T2w images per visit. Anatomical images showed dramatic differences in myelination and intensities across the 1 to 9 month age range, emphasizing the need for densely sampled gold standard manual segmentations in these ages. The BOBs repository is publicly available through the Masonic Institute for the Developing Brain (MIDB) Open Data Initiative, which links S3 storage, Datalad for version control, and BrainBox for visualization. This repository represents an open-source paradigm, where new additions and changes can be added, enabling a community-driven resource that will improve over time and extend into new ages and protocols. These manual segmentations and the ongoing repository provide a benchmark for evaluating and improving pipelines dependent upon segmentations in the youngest populations. As such, this repository provides a vitally needed foundation for early-life large-scale studies such as HBCD.
Internal in-frame translation generates Cas11b, which is important for effective interference in an archaeal CRISPR-Cas system
Authors: Sailer A.-L. , Brendel J. , Chernev A. , König S. , Bischler T. , Gräfenhan T. , Urlaub H. , Gophna U. , Marchfelder A.
Published: October 2024

CRISPR-Cas is a sophisticated defence system used by bacteria and archaea to fend off invaders. CRISPR-Cas systems vary in their Cas protein composition and have therefore been divided into different classes and types. Type I systems of bacteria have been shown to contain the small Cas11 protein as part of the interference complex. Here we show for the first time that an archaeal CRISPR-Cas type I system also contains a Cas11 protein. In addition, we show for the first time an internal in-frame translation of an archaeal protein. The Cas11b protein from theHaloferax volcaniitype I-B system is encoded in thecas8bgene. Translation initiation at an internal methionine of thecas8bopen reading frame results in synthesis of Cas11b. Cas11b is required for an effective interference reaction and without Cas11b fewer Cascade complexes form. Comparison of transcriptomes from wild type and a Cas11b less strain show that the depletion of Cas11b results in differential regulation of many genes. Taken together Cas11b is important for the defence reaction of the type I-B CRISPR-Cas system and seems to play an additional cellular role.
Cryo-EM structural insights into Vγ9Vδ2 TCR activation via multiple butyrophilins
Authors: Zhang Mai , Wang Yiqing , Cai Ningning , Qu Yingying , Ma Xianqiang , Xue Jing , Chen Xiaorui , Zhang Xueguang , Xiao Junyu , Zhang Yonghui
Published: October 2024

Human Vγ9Vδ2 T cells detect cancerous and pathogen-infected cells through an “inside-out” mechanism wherein intracellular domains of butyrophilin (BTN) proteins recognize phosphoantigens (pAgs) to prime BTN ectodomains to engage with the T cell receptor (TCR) to activate Vγ9Vδ2 T cells. Here, we present cryo-electron microscopy (cryo-EM) structures, including the full-length BTN3A1-BTN3A2–BTN2A1 complex stabilized by the pAg HMBPP and an HMBPP-primed BTN multimer complex engaged with the Vγ9Vδ2 TCR. The HMBPP-primed BTN3A1-BTN3A2–BTN2A1 complex confirms that this pAg bridges the intracellular B30.2 domains of BTN3A1 and BTN2A1, while also revealing an association of the ectodomains of BTN3A2 and BTN2A1. Upon TCR engagement, the TCR undergoes a substantial conformational change and BTN3A2–BTN2A1 ectodomain interaction dissociates, allowing BTN2A1 to bind to the lateral surface of the Vγ9 chain, while BTN3A2 binds to the apical surface of the Vδ2 chain. Beyond demonstrating that BTN3A2 as abona fideTCR ligand, this dissociation/binding sequence suggests a “pliers-like gripping” mechanism for TCR activation. We also obtained cryo-EM structures of BTN proteins in complex with functional antibodies, further elucidating the overall Vγ9Vδ2 T cell activation process. Thus, our structural insights into how BTN proteins sense antigens and drive TCR activation lay the groundwork for developing targeted γδ T cell immunotherapies.
Structural basis of SARS-Cov-2 spike recognition by engineered synthetic multivalent VHH antibodies
Authors: Lujan Hernandez Ana G. , Laughlin Zane T. , Patel Anamika , Yuan Tom Z. , Nugent Rebecca L. , Axelrod Fumiko , Ortlund Eric A. , Sato Aaron K.
Published: October 2024

High-throughput technologies such as next-generation sequencing (NGS), microarray-based gene synthesis, and phage display have empowered the discovery and engineering of precisely defined, synthetic antibodies with high avidity and drug-like features. Here, we describe a scalable process for engineering homo- and hetero-hexavalent variable domains of camelid heavy-chain (VHH)-Fc antibodies against the severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein. Overall, we demonstrate that VHH trimerization is an effective and modular approach for increasing the affinity of anti-S1 VHH-Fc antibodies for the highly mutated S proteins of SARS-CoV-2 variants. We show that one specific nanobody (named TB201-1) binds spike trimer protein at the interface of two neighboring RBDs, recognizing one distinct epitope on one RBD but making a set of secondary interactions with the neighboring RBD. From this structure, we determine the epitope-paratope residues responsible for spike-nanobody interaction and how mutations found in the SARS-CoV-2 variants contribute to oblate TB201-1 binding. This approach could be leveraged to improve existing antibody-based diagnostics and therapeutics targeting SARS-CoV-2 as the virus evolves.
Expectation elicits music-evoked chills
Authors: de Fleurian Rémi , Clemente Ana , Benetos Emmanouil , Pearce Marcus T.
Published: October 2024

Music-evoked chills (MECs) are physiological responses to pleasurable events in music. Existing research on properties of music that elicit MECs has focused on low-level acoustic features in small samples of music. We created a large dataset of over 1,000 pieces of music timestamped with MECs and used computational methods to predict MEC onsets from both low-level acoustic features and high-level musical expectations. A machine learning classifier was trained to distinguish MEC onsets from non-MEC passages in the same pieces. The results show that MEC onsets are predicted better than chance and corroborate evidence for acoustic elicitors of chills with a much larger dataset. They also produce new empirical evidence that MECs are elicited by expectation, which is a more effective predictor of MEC onsets than acoustic elicitors, and may generalise to pleasurable experience in other domains such as language comprehension or visual perception.
Cysimiditides: RiPPs with a Zn-tetracysteine motif and aspartimidylation
Authors: Zhu Angela , Cao Li , Do Truc , Link A. James
Published: October 2024

Aspartimidylation is a post-translational modification found in multiple families of ribosomally synthesized and post-translationally modified peptides (RiPPs). We recently reported on the imiditides, a new RiPP family in which aspartimidylation is the class-defining modification. Imiditide biosynthetic gene clusters encode a precursor protein and a methyltransferase that methylates a specific Asp residue, converting it to aspartimide. A subset of imiditides harbor a tetracysteine motif, so we have named these molecules cysimiditides. Here, using genome mining we show that there are 56 putative cysimiditides predicted in publicly available genome sequences, all within actinomycetota. We successfully heterologously expressed two examples of cysimiditides and showed that the major products are aspartimidylated and that the tetracysteine motif is necessary for expression. Cysimiditides bind a Zn2+ion, presumably at the tetracysteine motif. Usingin vitroreconstitution of the aspartimidylation reaction, we show that Zn2+is required for methylation and subsequent aspartimidylation of the precursor protein. An AlphaFold 3 model of the cysimiditide fromThermobifida cellulosilyticashows a hairpin structure anchored by the Zn2+-tetracysteine motif with the aspartimide site in the hairpin loop. An AlphaFold 3 model of this cysimiditide in complex with its cognate methyltransferase suggests that the methyltransferase recognizes the Zn2+-tetracysteine motif to correctly dock the precursor protein. Cysimiditides expand the set of experimentally-confirmed RiPPs harboring aspartimides, and represent the first RiPP class that has an obligate metal ion.

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Neural dynamics of spontaneous memory recall and future thinking in the continuous flow of thoughts
Authors: Su Haowen , Li Xian , Born Savannah , Honey Christopher J. , Chen Janice , Lee Hongmi
Published: October 2024

The human brain constantly recalls past experiences and anticipates future events, generating a continuous flow of thoughts. However, the neural mechanisms underlying the natural transitions and trajectories of thoughts during spontaneous memory recall and future thinking remain underexplored. To address this gap, we conducted a functional magnetic resonance imaging study using a think-aloud paradigm, where participants verbalize their uninterrupted stream of thoughts during rest. We found that transitions between thoughts, particularly those involving significant shifts in semantic content, activate the brain's default and control networks. These neural responses to internally generated thought boundaries produce activation patterns resembling those triggered by external event boundaries. Moreover, interactions within and between these networks shape the overall semantic structure of thought trajectories: stronger functional connectivity within the medial temporal subsystem of the default network predicts greater variability in thoughts, while stronger connectivity between the control and core default networks is associated with reduced variability. Together, our findings highlight how the default and control networks guide the dynamic transitions and structure of naturally arising memory and future thinking.
Automated Tumor and FUS Lesion Quantification on Multi-frequency Harmonic Motion and B-mode Imaging Using a Multi-modality Neural Network
Authors: Hu Shiqi , Liu Yangpei , Li Xiaoyue , Konofagou Elisa E.
Published: October 2024

Harmonic Motion Imaging (HMI) is an ultrasound elasticity imaging method that measures the mechanical properties of tissue using amplitude-modulated acoustic radiation force (AM-ARF). By estimating tissue’s on-axis oscillatory motion, HMI-derived displacement images represent localized relative stiffness and can predict the tumor response to neoadjuvant chemotherapy (NACT) and monitor focused ultrasound (FUS) ablation therapy. Multi-frequency HMI (MF-HMI) excites tissue at various AM frequencies simultaneously, which allows for image optimization without prior knowledge of inclusion size and stiffness. However, challenges remain in size estimation as inconsistent boundary effects result in different perceived sizes across AM frequencies. Herein, we developed an automated tumor and FUS lesion quantification method using a transformer-based multi-modality neural network, HMINet. It was trained on 380 pairs of MF-HMI and B-mode images of phantoms andin vivoorthotopic breast cancer mice (4T1). Test datasets included phantoms (n = 32),in vivo4T1 mice (n = 24), breast cancer patients (n = 16), and a FUS-induced lesion, with average segmentation accuracy (Dice Similarity Score) of 0.95, 0.86, 0.82, and 0.87, respectively. To increase the generalizability of HMINet, we applied a transfer learning strategy, i.e., fine-tuning the model using patient data. For NACT patients, the displacement ratios (DR) between the tumor and surrounding tissue were calculated based on HMINet-segmented boundaries to predict tumor response based on stiffness changes.
Overexpression of Ribosomal Proteins Leads to Zn Resistance inEscherichia coli
Authors: Kosaki Tomoki , Shirakawa Riko , Ishikawa Kazuya , Furuta Kazuyuki , Kaito Chikara
Published: October 2024

Knockout of ribosomal protein bL36 (RpmJ) leads to Zn resistance inEscherichia coli, and the expression of ribosomal protein genes other than RpmJ increase in therpmJ-knockout strain. In this study, we examined whether the overexpression of ribosomal proteins causes Zn resistance using anE. colioverexpression gene library (ASKA clone library). The overexpression of 48 of the 54 ribosomal proteins led to Zn resistance. However, the overexpression of proteins other than ribosomal proteins did not lead to Zn resistance, suggesting that Zn resistance is a phenomenon specific to the overexpression of ribosomal proteins. In addition, the overexpression of ribosomal proteins did not lead to resistance to metal ions other than Zn (Cu2+, Ni2+, Mn2+, and Ag+), suggesting a Zn-specific resistance mechanism. Deletion of ZntA, a Zn efflux pump, resulted in the loss of Zn resistance in a ribosomal protein-overexpressing strain. Deletion of Lon protease, which is responsible for degrading misfolded proteins, in a ribosomal protein-overexpressing strain resulted in the accumulation of overexpressed ribosomal proteins and loss of Zn resistance. These results suggest that the overexpression of ribosomal proteins leads to Zn resistance inE. coli viaZntA and Lon protease.

Importance

The ribosome is a complex comprising ribosomal RNAs and more than 50 types of ribosomal proteins. Ribosomal proteins play an important role in ribosomal function responsible for protein translation; however, their involvement in other cellular processes is not fully understood. Based on the finding that ribosomal protein expression increases in a Zn-resistantE. colimutant, we analyzed 54 ribosomal proteins and found that the overexpression of 48 ribosomal proteins led to Zn resistance. This finding suggests a role for ribosomal proteins in resistance to zinc stress.
Protein–protein interactions shapetrans-regulatory impact of genetic variation on protein expression and complex traits
Authors: Li Jinghui , Li Yang I. , Liu Xuanyao
Published: October 2024

Most genetic variants influence complex traits by affecting gene regulation. Yet, despite comprehensive catalogs of molecular QTLs, linking trait-associated variants to biological functions remains difficult. In this study, we re-analyzed large maps of protein QTLs (pQTLs) to show that genes withtrans-pQTLs but withoutcis-pQTLs are under strong selective constraints and are highly enriched in GWAS loci. We found thattrans-pQTLs and theirtranstargets are highly enriched in interacting protein pairs, andtrans-pQTLs in coding regions are significantly enriched at protein-protein interactions (PPI) interfaces. By leveraging existing PPI annotations fortrans-pQTL mapping, we identified 26,028trans-pQTLs influencing 1,061 PPI clusters. Thetrans-pQTLs of PPIs colocalized with 66% GWAS loci per trait on average for 50 complex traits, helping in many cases to link GWAS loci to cellular function. Finally, we identifiedtrans-pQTL effects at multiple autoimmune GWAS loci that converge on the same PPIs, pinpointing protein complexes and signaling pathways that show promising therapeutic target potential.
Growth compensation upon changes in tissue size in theDrosophilaabdomen
Authors: Ferreira Ana , Cairoli Andrea , Mangione Federica , Holder Maxine V. , Ainslie Anna , Aerne Birgit L. , Salbreux Guillaume , Tapon Nicolas
Published: October 2024

Attaining the appropriate size during development is essential for the function of animal tissues and organs. Robust tissue size control implies the existence of compensatory mechanisms that allow developing systems to recover from growth perturbations. However, the difficulty of directly observing normal or compensatory developmental growth means we have little understanding of the cellular behaviours that confer robustness to tissue size control. Here, we study how growth perturbations affect proliferation kinetics and the timing of growth termination ofDrosophilahistoblasts, the progenitors that give rise to the adult abdominal epidermis. Histoblasts undergo extensive growth and proliferation during the pupal stage, which is accessible for long-term live-imaging and precise quantitative analysis. By manipulating cell number or volume prior to the pupal growth phase, we changed the starting size of the abdomen primordium, then observed how the histoblasts adapted to these changes by altering their growth dynamics. We show that, upon a decrease in starting tissue size, the histoblasts compensate by extending their temporal proliferative window, undergoing additional cell cycles, as well as increasing their apical area to maximise coverage of the abdominal surface. When initial tissue size is increased, the histoblasts undergo fewer division cycles and arrest proliferation earlier than normal. Thus, the proliferative window of this tissue is flexible enough to buffer for changes in tissue size. Our data also suggest that the histoblasts sense both spatial and temporal cues to arrest their growth at the appropriate time and ensure accurate tissue size control.
The Platinum Pedigree: A long-read benchmark for genetic variants
Authors: Kronenberg Zev , Nolan Cillian , Mokveld Tom , Rowell William J , Lee Sangjin , Dolzhenko Egor , Chang Pi-Chuan , Holt James Matthew , Saunders Christopher T , Olson Nathanael D. , McGee Sean , Guarracino Andrea , Koundinya Nidhi , Harvey William T , Watkins W. Scott , Munson Katherine M , Hoekzema Kendra , Chua Khi Pin , Fanslow Cairbre , Lambert Christine , Dashnow Harriet , Garrison Erik , Smith Josh , Lansdorp Peter , Zook Justin M , Carroll Andrew , Jorde Lynn B. , Neklason Deborah W , Quinlan Aaron , Eichler Evan , Eberle Michael A
Published: October 2024

Recent advances in genome sequencing have improved variant calling in complex regions of the human genome. However, it is difficult to quantify variant calling performance since existing standards often focus on specificity, neglecting completeness in difficult to analyze regions. To create a more comprehensive truth set, we used Mendelian inheritance in a large pedigree (CEPH-1463) to filter variants across Illumina, PacBio high-fidelity (HiFi), and Oxford Nanopore Technologies platforms. This generated a variant map with over 4.7 million single-nucleotide variants, 767,795 indels, 537,486 tandem repeats, and 24,315 structural variants, covering 2.77 Gb of the GRCh38 genome. This work adds ~200 Mb of high-confidence regions, including 8% more small variants, and introduces the first tandem repeat and structural variant truth sets for NA12878. As an example of the value of this improved benchmark, we retrained DeepVariant using this data to reduce genotyping errors by ~34%.
Expression of endogenousAnopheles gambiaemicroRNAs using anAnopheles gambiaedensovirus (AgDNV) intronic expression system
Authors: Johnson Rebecca M. , Metz Hillery C. , Suzuki Yasutsugu , McLean Kyle J. , Rasgon Jason L.
Published: October 2024

Anopheles gambiaedensovirus (AgDNV) is a highly species-specific parvovirus that reaches high titers in adultAnopheles gambiaemosquitoes with few transcriptomic effects and no significant fitness effects. Given these characteristics, AgDNV has been proposed as a viral vector for basic research and mosquito control. Previous work created an AgDNV co-expression system with a wild-type AgDNV helper plasmid and a transducing enhanced green fluorescent protein (EGFP) expressing plasmid that can be used to co-transfect cells to generate infectious recombinant transducing AgDNV virions. Generated virions infect theAn. gambiaemidgut, fat body, and ovaries, yet this viral vector system is limited in the size of transgenes that can be expressed due to capsid packaging limitations. Considering these size constraints, we created an artificial intron within the EGFP gene of the transducing construct that can express small pieces of genetic material such as microRNAs (miRNAs), microRNA sponges, or other small sequences. Placement of this intron in EGFP created a fluorescent reporter such that incorrect splicing produces a frameshift mutation in EGFP and an early stop codon whereas correct splicing results in normal EGFP expression and co-transcription of the intronic genetic cargo. A selection of miRNAs with predicted or demonstrated importance in mosquito immunity and reproduction with expression localized to the fat body or ovaries were chosen as intronic cargo, construct expression and splicing evaluated, and the impact of miRNA expression on putative miRNA targets was measuredin vitroandin vivo. While the intron was correctly spliced in cells and mosquitoes, miRNA delivery resulted in inconsistent changes to miRNA and target gene transcript levels—possibly due to organ-specific miRNA expression or miRNA-target gene sequence mismatch. However, with optimization this viral vector and developed intron have potential as an expression tool withinAn. gambiaemosquitoes or cells.
PPARγ downregulation in colonic CD8+ T cells results in epithelial barrier disruption in people with HIV on antiretroviral therapy
Authors: Das Adhikari Upasana , Froehle Leah M. , Pipkin Alexandra N. , Baharlou Heeva , Linder Alice H. , Shah Palak , Hussey Amanda , Zhang Qiming , Nyquist Sarah , Khwaled Saleh , Chi Fangtao , Goswami Swagata , Dieffenbach Thomas J. , Read Benjamin J. , Kim Byungji , Irvine Darrell , Asowata Osaretin , Ladinsky Mark , Bjorkman Pamela , Madela Fusi , Khader Shakeel , Shalek Alex , Ghebremichael Musie , Kloverpris Hendrik , Ringel Alison E , Yilmaz Ömer H. , Kwon Douglas S.
Published: October 2024

A hallmark of HIV infection is disruption of intestinal barrier integrity that persists in people with HIV (PWH) despite treatment with antiretroviral therapy (ART). This disruption is central to HIV disease progression, yet the causes remain incompletely understood. We report a novel mechanism by which immunometabolic defects in colon resident CD8+ T cells in PWH lead to intestinal epithelial apoptosis and disruption of intestinal barrier integrity. We show that in PWH, these cells downregulate the lipid sensor peroxisome proliferator-activated receptor-γ (PPARγ), which results in reduced intracellular lipid droplets, impaired fatty acid oxidation, and acquisition of lipids by CD8+ T cells from intestinal epithelial cells, which then contributes to epithelial cell death. Our findings indicate that HIV-associated immunometabolic dysregulation of colon CD8+ T cell leads to loss of intestinal epithelial homeostasis. These results identify potential new strategies to reduce comorbidities in PWH and other disorders with disrupted intestinal barrier integrity.
Building a community-driven bioinformatics platform to facilitateCannabis sativamulti-omics research
Authors: Mansueto Locedie , Kretzschmar Tobias , Mauleon Ramil , King Graham J.
Published: October 2024

Global changes in Cannabis legislation after decades of stringent regulation, and heightened demand for its industrial and medicinal applications have spurred recent genetic and genomics research. An international research community emerged and identified the need for a web portal to host Cannabis-specific datasets that seamlessly integrates multiple data sources and serves omics-type analyses, fostering information sharing.

The Tripal platform was used to host public genome assemblies, gene annotations, QTL and genetic maps, gene and protein expression, metabolic profile and their sample attributes. SNPs were called using public resequencing datasets on three genomes. Additional applications, such as SNP-Seek and MapManJS, were embedded into Tripal. A multi-omics data integration web-service API, developed on top of existing Tripal modules, returns generic tables of sample, property, and values. Use-cases demonstrate the API’s utility for various -omics analyses, enabling researchers to perform multi- omics analyses efficiently.
Genomic diversity and global distribution of four new prasinoviruses from the tropical North Pacific
Authors: Bedi de Silva Anamica , Polson Shawn W. , Schvarcz Christopher R. , Steward Grieg F , Edwards Kyle
Published: October 2024

Viruses that infect phytoplankton are an integral part of marine ecosystems, but the vast majority of viral diversity remains uncultivated. Here we introduce four near-complete genomic assemblies of viruses that infect the widespread marine picoeukaryote Micromonas commoda, doubling the number of published genomes of Micromonas dsDNA viruses. All host and virus isolates were obtained from tropical waters of the North Pacific, a first for viruses infecting green algae in the order Mamiellales. Genome length of the new isolates ranges from 205-212 kb, and phylogenetic analysis shows that all four are members of the genus Prasinovirus. Three of the viruses form a clade that is adjacent to previously sequenced Micromonas viruses, while the fourth virus is relatively divergent from previously sequenced prasinoviruses. We identified 61 putative genes not previously found in prasinoviruses, including a phosphate transporter from a family novel to viruses, and a potential apoptosis inhibitor novel to marine viruses. Forty-eight genes in the new viruses are also found in host genome(s) and may have been acquired through horizontal gene transfer. By analyzing the coding sequences of all published prasinoviruses we found that ~25% of prasinovirus gene content is significantly correlated with host genus identity (i.e., Micromonas, Ostreococcus, or Bathycoccus), and the functions of these genes suggest that much of the viral life cycle is differentially adapted to the three host genera. Mapping of metagenomic reads from global survey data indicates that one of the new isolates, McV-SA1, is relatively common in multiple ocean basins.
Decoding biology with massively parallel reporter assays and machine learning
Authors: La Fleur Alyssa , Shi Yongsheng , Seelig Georg
Published: October 2024

Massively parallel reporter assays (MPRAs) are powerful tools for quantifying the impacts of sequence variation on gene expression. Reading out molecular phenotypes with sequencing enables interrogating the impact of sequence variation beyond genome scale. Machine learning models integrate and codify information learned from MPRAs and enable generalization by predicting sequences outside the training data set. Models can provide a quantitative understanding ofcis-regulatory codes controlling gene expression, enable variant stratification, and guide the design of synthetic regulatory elements for applications from synthetic biology to mRNA and gene therapy. This review focuses oncis-regulatory MPRAs, particularly those that interrogate cotranscriptional and post-transcriptional processes: alternative splicing, cleavage and polyadenylation, translation, and mRNA decay.
Deciphering visceral instincts: a scientific quest to unravel food choices from molecules to mind
Authors: Alway Emily , Reicher Naama , Bohórquez Diego V.
Published: October 2024

The study of biological mechanisms, while crucial, cannot fully explain complex phenomena like the instinct to eat. The mind–body connection, as exemplified by the concept of “voodoo death,” highlights the profound influence of belief and cultural context on physiology. Indigenous knowledge systems further emphasize the interconnectedness of humans with their environment. Recent discoveries in gut–brain communication reveal the intricate neural circuits that drive our visceral desires, but a holistic approach that integrates both physiological mechanisms and the subjective experience of life, informed by diverse cultural perspectives, will be essential to truly understand what it means to be alive.
Consolidating roles of neuroimmune reflexes: specificity of afferent, central, and efferent signals in homeostatic immune networks
Authors: Tracey Kevin J.
Published: October 2024

Neural reflexes occupy a central role in physiological homeostasis. The vagus nerve is a major conduit for transmitting afferent and efferent signals in homeostatic reflex arcs between the body and the brain. Recent advances in neuroscience, immunology, and physiology have revealed important vagus nerve mechanisms in suppressing inflammation and treating rheumatoid arthritis and other autoimmune conditions. Numerous clinical trials indicate that there is significant benefit to vagus nerve stimulation therapy. Although many questions are still unanswered, it will be important, even necessary, to pursue answers that will be useful in guiding interventions to modulate immunological and physiological homeostasis.
Cancer neuroscience at the brain–body interface
Authors: Borniger Jeremy C.
Published: October 2024

Our approaches toward understanding cancer have evolved beyond cell-intrinsic and local microenvironmental changes within the tumor to encompass how the cancer interfaces with the entire host organism. The nervous system is uniquely situated at the interface between the brain and body, constantly receiving and sending signals back and forth to maintain homeostasis and respond to salient stimuli. It is becoming clear that various cancers disrupt this dialog between the brain and body via both neuronal and humoral routes, leading to aberrant brain activity and accelerated disease. In this outlook, I discuss this view of cancer as a homeostatic challenge, emphasize cutting-edge work, and provide outstanding questions that need to be answered to move the field forward.
Interoceptive inference and prediction in food-related disorders
Authors: Subramanian Madhav , Thaiss Christoph A.
Published: October 2024

The brain's capacity to predict and anticipate changes in internal and external environments is fundamental to initiating efficient adaptive responses, behaviors, and reflexes that minimize disruptions to physiology. In the context of feeding control, the brain predicts and anticipates responses to the consumption of dietary substances, thus driving adaptive behaviors in the form of food choices, physiological preparation for meals, and engagement of defensive mechanisms. Here, we provide an integrative perspective on the multisensory computation between exteroceptive and interoceptive cues that guides feeding strategy and may result in food-related disorders.
Collective coordinate models for 2-vortex shape mode dynamics
Authors: Alonso Izquierdo A. , Manton N. S. , Mateos Guilarte J. , Wereszczynski A.
Published: October 2024

Models are developed for the motion of charge-2 Abelian Higgs vortices through the 2-vortex moduli space M, with the vortices excited by their shape mode oscillations. The models simplify to the well-known geodesic flow on M, modified by a potential, when the mode oscillations are fast relative to the moduli space motion and their amplitudes are small. When the lowest-frequency mode is excited with a large amplitude, the geodesic flow is not a correct description. Instead, a chaotic, or even fractal, multibounce structure in vortex-vortex collisions is predicted.

Published by the American Physical Society
2024
The artisanal underground: gold, subsistence, and subsurface materiality in Colombia
Authors: Jonkman Jesse
Published: October 2024

This article focuses on subsurface materiality to explore how small‐scale gold miners in Colombia navigate formal politics. In much critical research, the underground appears as a space of great developmentalist ambition, whose resources enable corporate expansion and bureaucratic rule. Here I take a slightly different route, as I demonstrate that subterranean matter makes possible ways of knowing and working that are anathema to a pro‐corporate legal regime. More specifically, I maintain that Colombian small‐scale miners experience the underground as invisible and unruly matter, and I show that this experience mediates their everyday criticism of, and resistance to, state governance.
An experimental test on the hypothesis of strategic uncertainty
Authors: Li Bin , Wang Meng , Xu Tingyu
Published: October 2024

This study tests the influential hypothesis of strategic uncertainty (HSU) on the topic of bubble formation. We argue that if HSU holds, it shall apply to a stricter situation in which subjects in the market are rational, but none of them know the rationality distribution of others. The research strategies of exclusion and analogy are adopted to create a market that satisfies the two prerequisites of HSU. Briefly, a cohort of 24 participants in the same group is separated equally into three small groups using a pre‐determined rule within a 20‐period treatment. Group #1 is our primary concern, and its members comprise participants whose units of assets are zero with an auxiliary criterion by subjects' performance at the end of Period 5. Across sessions, we determine whether the regrouping criteria and group tags are displayed to subjects to control how hard it is for a trader to judge the distribution of others in his/her group. We observe that mispricing generally vanishes in both the experimental and control groups. This result delivers a negative judgement of HSU at the aggregate level. Observations at the individual level and the robustness experiments deliver the same judgement.
Morphological and functional characterization of circulating hemocytes in Tribolium castaneum larvae
Authors: Wang Suisui , Miao Shiyuan , Li Yusi , Wang Jianhui , Li Chengjun , Lu Yujie , Li Bin
Published: October 2024

Hemocytes are pivotal in the immune response of insects against invasive pathogens. However, our knowledge of hemocyte types and their specific function in Tribolium castaneum, an increasingly important Coleoptera model insect in various research fields, remains limited. Presently, a combination of morphological criteria and dye‐staining properties were used to characterize hemocyte types from T. castaneum larvae, and 4 distinct types were identified: granulocytes, oenocytoids, plasmatocytes and prohemocytes. Following different immune challenges, the total hemocyte counts declined rapidly in the initial phase (at 2 h), then increased over time (at 4 and 6 h) and eventually returned to the naive state by 24 h post‐injection. Notably, the morphology of granulocytes underwent dramatic changes, characterized by an expansion of the surface area and an increased production of pseudopods, and with the number of granulocytes rising significantly through mitotic division. Granulocytes and plasmatocytes, the main hemocyte types in T. castaneum larvae, can phagocytose bacteria or latex beads injected into the larval hemolymph in vivo. Furthermore, these hemocytes participate in the encapsulation and melanization processes in vitro, forming capsules to encapsulate and melanize nickel–nitrilotriacetic acid (Ni–NTA) beads. This study provides the first comprehensive characterization of circulating hemocytes in T. castaneum larvae, offering valuable insights into cell‐mediated immunity in response to bacterial infection and the injection of latex beads. These results deepen our understanding of the cellular response mechanisms in T. castaneum larvae and lay a solid foundation for subsequent investigations of the involvement of T. castaneum hemocytes in combating pathogens.
Biomass consumption, foraging activity and harvesting patterns in two sympatric leaf‐cutting ant species in a Salicaceae plantation in Argentina
Authors: Jiménez Nadia L. , Sánchez‐Restrepo Andrés F. , Guala Mariel E. , Battagliotti Cristian , Farji‐Brener Alejandro G. , Calcaterra Luis A.
Published: October 2024

Leaf‐cutting ants (LCA) are one of the most important pests in the Neotropics region. To estimate the potential biomass consumption by LCA on Salicaceae plantations in the lower delta of the Paraná River, we studied the foraging activity and harvesting patterns of Acromyrmex lundii (Guérin‐Méneville, 1838) and Acromyrmex ambiguus (Emery, 1888) (Hymenoptera: Formicidae) in a 14‐year‐old poplar plantation in Argentina.

Foraging activity (workers/time), harvested vegetal biomass (dry weight/time) and climatic conditions (temperature and relative humidity) were monitored daily and seasonally in nests from autumn 2016 to summer 2017.

The two sympatric species harvested a similar quantity of dry biomass throughout the year (4.9–6.0 kg/colony). Although both species were active in all seasons, their foraging activity was higher in spring and summer, but they avoided extreme temperatures. The accumulated biomass harvested for both species was higher in summer (28.8 and 25.7 g/colony/day, for Ac. ambiguus and Ac. lundii, respectively). However, Ac. lundii harvested three times more biomass than Ac. ambiguus in spring (30.3 and 13.1 g/colony/day, respectively).

Although the highest consumption on the vegetation occurred in summer, control tasks should be started during spring (sprouting phase), the most vulnerable period for Salicaceaes. The consumption of new leaves in spring is critical for tree growth, survival and wood production, especially by Ac. lundii, the most detrimental species during this season.
Trophic Structure and Dietary Overlap in the Sympatric Skinks Trachylepis punctatissima and Trachylepis varia From Central South Africa
Authors: Heideman Neil , Bates Michael , Zhao Zhongning
Published: October 2024

Diet diversity and overlap was investigated in the sympatric skinks Trachylepis punctatissima and Trachylepis varia from central South Africa using stomach and intestinal contents of museum specimens. Simpson's Index and the Shannon–Wiener Index were used to determine their food niche breadths and Pianka's Index to determine the extent to which they shared the food resource. Food items were identified from head capsules, mouthparts and appendages to order level. The two species contained similar prey types with T. varia having the wider niche breadth. Females also had wider niche breadths than males and isopterans were present in significantly higher quantities than the rest of the food items in both species. Larvae were found in both, but arachnids only in T. varia. Trophic niche overlap between the two was fairly high (Pianka's Index, 0.6915) and therefore did not support the hypothesis that similar species sharing a food resource should have well differentiated diets to reduce competition. This finding however requires further verification as the two species may consume different species of the corresponding orders identified. Intraspecifically trophic niche overlap between the sexes was low (T. punctatissima, 0.3889; T. varia, 0.4633) suggesting strong competition for the food resource. Notably lower niche breadth in males compared to females may be due to morphological and behavioural differences and should be further investigated.
Interleukin‐5 as a pleiotropic cytokine orchestrating airway type 2 inflammation: Effects on and beyond eosinophils
Authors: Buchheit Kathleen M. , Shaw Dominick , Chupp Geoffrey , Lehtimaki Lauri , Heffler Enrico , Finney‐Hayward Tricia , Zangrilli James , Kwiatek Justin , Siddiqui Salman , Roufosse Florence , Thamboo Andrew , West Nicholas , Vichiendilokkul Anna , Hellings Peter W. , Peters Anju , Howarth Peter H.
Published: October 2024

Interleukin (IL)‐5 is the key cytokine in the maturation, activation, proliferation, migration and survival of eosinophils, which are key effector cells in many upper and lower airway diseases. Through its effects on eosinophils, IL‐5 indirectly contributes to various pathophysiological processes including tissue damage, repair and remodelling. Understanding the importance of IL‐5 in eosinophil‐associated diseases led to the development of anti‐IL‐5 therapies, which provide clinical benefits across a range of conditions. However, recent evidence suggests that eosinophil‐depletion alone may not account for all of the therapeutic effects of anti‐IL‐5 therapy and that IL‐5 may also contribute to disease independently of its effects on eosinophils. Indeed, evidence from ex vivo studies and targeted therapy in vivo demonstrates that IL‐5 and its inhibition affects a much broader range of cells beyond eosinophils, including epithelial cells, plasma cells, mast cells, basophils, neutrophils, type 2 innate lymphoid cells, T regulatory cells and fibroblasts. This review will provide an update on the evidence supporting the breadth of IL‐5 biology relevant to disease pathogenesis beyond eosinophil‐associated inflammation, where there is a need for additional insight, and the clinical implications of a more central role of IL‐5 in type 2 inflammation.