bluuebunny/crossref_metadata_2025 huggingface dataset:
VC2regulates baseline vicine content in faba bean
Authors: Ugwuanyi Samson , Makhoul Manar , Golicz Agnieszka A. , Obermeier Christian , Snowdon Rod J.
Published: August 2024

Faba bean (Vicia faba) is a valuable legume crop desired globally for its high nutritional composition. However, the seed vicine and convicine (v-c) content reduces the nutritional quality of faba bean protein and can induce favism in individuals with glucose-6-phosphate dehydrogenase deficiency. Recently,VC1gene, encoding a bi-functional riboflavin protein, was reported to be responsible for initiating the biosynthetic pathway inV. faba. In low v-c cultivars, a 2 bp insertion in this gene results in a loss of function, but the mutation only partially eliminates v-c biosynthesis, indicating the involvement of other genes. Here, we demonstrate that a novelV. fabariboflavin gene,VC2, is responsible for the residual v-c contents in faba bean.VC2shares nearly identical functional domains withVC1and has GTP cyclohydrolase II activity, catalyzing the conversion of GTP into an intermediate molecule in the biosynthetic pathway. Gene expression analysis reveals thatVC2contributes a minor effect to the trait, accounting for approximately 5-10% of total riboflavin gene transcripts which significantly correlates with the baseline contents in low v-c cultivars. Our results illustrate that cultivars carrying the 2 bp inactivating insertion inVC1still have residual v-c levels due toVC2activity. Furthermore, we find thatVC1has multiple alleles and exhibits copy number variations, complicating molecular marker development. Conversely, single nucleotide polymorphisms withinVC2provide a reliable alternative for marker-assisted selection in faba bean breeding. In conclusion, our study elucidates the complex genetic regulation of v-c biosynthesis and provides valuable insights to facilitate its elimination in faba bean.
Diabetic liver-enriched secretory dipeptidyl peptidase 4 (DPP4) fuels gut inflammation via attenuation of autophagy
Authors: Athar Mohammad , Bhadury Ratulananda , Gogoi Chayanika , Mishra Pooja , Kumari Prity , Yadav Manisha , Maras Jaswinder Singh , Ghorpade Devram S.
Published: August 2024

The recurrent pathological inflammation of the gut is a major concern in diabetic patients. With the failure of anti-inflammatory or diabetic drugs to limit relapse of colon inflammation demands the unearthing of mechanistic details underlying higher incidences of colitis in diabetic patients. Here we report the enrichment of DPP4 in the livers and blood samples of diabetic humans and mice models of diabesity that is in parallel to the development of colitis. Overexpression of DPP4 exacerbates or hepatic silencing of DPP4 impairs experimental colitis induced by DSS and STM. Mechanistically, we identified liver DPP4 attenuates gut-autophagic response to trigger enteric cell apoptosis, reduced mucin secretion, and compromised gut barrier leading to high infiltration of immune cells secreting inflammatory cytokines establishing pathological gut inflammation. Thus, liver-DPP4-mediated gut autophagy inhibition is a key pathway in diabesitic colitis.
p-IgGen: A Paired Antibody Generative Language Model
Authors: Turnbull Oliver M. , Oglic Dino , Croasdale-Wood Rebecca , Deane Charlotte M.
Published: August 2024

A key challenge in antibody drug discovery is designing novel sequences that are free from developability issues - such as aggregation, polyspecificity, poor expression, or low solubility. Here, we present p-IgGen, a protein language model for paired heavylight chain antibody generation. The model generates diverse, antibody-like sequences with pairing properties found in natural antibodies. We also create a finetuned version of p-IgGen that biases the model to generate antibodies with 3D biophysical properties that fall within distributions seen in clinical-stage therapeutic antibodies.
Microglia initially seed and later reshape amyloid plaques in Alzheimer’s disease
Authors: Baligács Nóra , Albertini Giulia , Borrie Sarah C. , Serneels Lutgarde , Pridans Clare , Balusu Sriram , De Strooper Bart
Published: August 2024

We demonstrate the dual role of microglia in Alzheimer’s disease (AD), initially harmful, by seeding amyloid plaques, and protective in later stages by compacting amyloid plaques. Early microglial depletion using pharmacological or genetic blockage of CSF1R reduces plaque load and associated neuritic dystrophy, while human microglia transplantation restores plaque formation, confirming their seeding role. TransplantedTREM2R47H/R47Hmicroglia exacerbate plaque pathology, highlighting microglia as key initiators of the amyloid pathology cascade.
Sexual receptivity increases in synchrony with the ovulatory cycle in female medaka
Authors: Tomihara Soma , Shimomai Rinko , Nakajo Mikoto , Oka Yoshitaka , Umatani Chie
Published: August 2024

Successful reproduction requires coordinated regulation of gonadal function and sexual behavior. However, the mechanisms of such a regulation remain elusive. Here, we used a teleost medaka to find out possible involvement of ovulation in the control of female sexual behaviors by analyzing the sexual behaviors of the female gene-knockout medaka that do not ovulate and found that ovulation is essential for the facilitation of female sexual receptivity. Behavioral recordings and anatomical examinations showed that the sexual behavior of medaka occurs only after the ovulation. Furthermore, progesterone administration partially reinstated the sexual receptivity of the anovulatory knockout females. Taken together with the result that progesterone receptor is expressed in the brain regions that are considered strong candidate for regulation of sexual behavior, we propose that female sexual receptivity is facilitated in synchrony with the ovulatory cycle via progesterone receptor signaling in specific brain regions that occurs around the timing of ovulation.
Elucidating the Hierarchical Nature of Behavior with Masked Autoencoders
Authors: Stoffl Lucas , Bonnetto Andy , d’Ascoli Stéphane , Mathis Alexander
Published: August 2024

Natural behavior is hierarchical. Yet, there is a paucity of benchmarks addressing this aspect. Recognizing the scarcity of large-scale hierarchical behavioral benchmarks, we create a novel synthetic basketball playing benchmark (Shot7M2). Beyond synthetic data, we extend BABEL into a hierarchical action segmentation benchmark (hBABEL). Then, we develop a masked autoencoder framework (hBehaveMAE) to elucidate the hierarchical nature of motion capture data in an unsupervised fashion. We find that hBehaveMAE learns interpretable latents on Shot7M2 and hBABEL, where lower encoder levels show a superior ability to represent fine-grained movements, while higher encoder levels capture complex actions and activities. Additionally, we evaluate hBehaveMAE on MABe22, a representation learning benchmark with short and long-term behavioral states. hBehaveMAE achieves state-of-the-art performance without domain-specific feature extraction. Together, these components synergistically contribute towards unveiling the hierarchical organization of natural behavior. Models and benchmarks are available athttps://github.com/amathislab/BehaveMAE.
Integrin blocking peptide reverses immunosuppression in experimental gliomas and improves anti-PD-1 therapy outcome
Authors: Ellert-Miklaszewska Aleksandra , Pilanc-Kudlek Paulina , Poleszak Katarzyna , Roura Adria-Jaume , Cyranowski Salwador , Ghosh Mitrajit , Baluszek Szymon , Pasierbinska Maria , Gielniewski Bartłomiej , Swatler Julian , Hovorova Yuliana , Wojnicki Kamil , Kaminska Bozena
Published: August 2024

Immune checkpoint inhibitors (ICI) presented clinical benefits in many cancer patients but invariably fail in glioblastoma (GBM), the most common and deadly primary brain tumor. Lack of ICI efficacy in GBM is attributed to the accumulation of immunosuppressive myeloid cells that create the “cold” tumor microenvironment (TME) impeding infiltration and activation of effector T cells. We developed a designer RGD peptide that hindered glioma-instigated, integrin-mediated pro-tumoral reprogramming of myeloid cells and blocked microglia-dependent invasion of human and mouse glioma cells in co-culturesin vitro. Intratumorally-delivered RGD alone did not reduce glioma growth in syngeneic mice but prevented the emergence of immunosuppressive myeloid cells and led to peritumoral blood vessels normalization. Furthermore, combining RGD with immunotherapy using PD-1 blockade reduced tumor growth, led to upsurge of proliferating, interferon-ɣ producing CD8+T cells and depleted regulatory T cells. Transcriptomic profiles of myeloid cells were altered by the combined treatment, consistently with the restored “hot” inflammatory TME and boosted immunotherapy responses. RGD modified the phenotypes of myeloid cells in human gliomas in nude mice. Thus, combining the integrin blockade with ICI reinvigorates antitumor immunity and paves the way to improve immunotherapy outcomes in GBM.
Patient-specific gene networks reveal novel subtypes and predictive biomarkers in lung cancer
Authors: Lopez-Sanchez Patricio , Avila-Moreno Federico , Hernandez-Lemus Enrqiue , Kuijjer Marieke L. , Espinal-Enriquez Jesus
Published: August 2024

Lung adenocarcinoma (LUAD) is an aggressive form of non-small cell lung cancer. Genome-wide gene co-expression networks (GCNs) has been paramount to describe changes in the transcriptional regulatory programs found between diseased and healthy states of LUAD. Multiple cancerous phenotypes share a distinct GCN architecture, suggesting that network topology holds promise for understanding disease pathology. However, conventional GCN inference methods struggle to capture specificity within a patient population, thus flattening its heterogeneity. To address this issue, the use of single-sample networks (SSN) has emerged as a promising solution. Here, we reconstructed patient-specific GCNs (n=334) using the LIONESS equation. Unsupervised analysis revealed six novel LUAD subtypes based on inter-patient network similarity, reflecting unique biological programs. Supervised analysis, employing regularized Cox regression, identified 12 genes (CHRDL2, SPP2, VAC14, IRF5, GUCY1B1, NCS1, RRM2B, EIF5A2, CCDC62, CTCFL, XG, and TP53INP2) whose weighted degree in SSNs is predictive of patient survival in LUAD. These findings suggest that topological features of SSNs offer insights into the context-specific nature of LUAD, highlighting the potential of SSN-based approaches for further research.
Improved vectors for retron-mediated CRISPR-Cas9 genome editing inSaccharomyces cerevisiae
Authors: Stuecker Tara N. , Hood Stephanie E. , Pineda Julio Molina , Lenaduwe Sonali , Winter Joshua , Sadhu Meru J. , Lewis Jeffrey A.
Published: August 2024

In vivosite-directed mutagenesis is a powerful genetic tool for testing the effects of specific alleles in their normal genomic context. While the budding yeastSaccharomyces cerevisiaepossesses classical tools for site-directed mutagenesis, more efficient recent CRISPR-based approaches use Cas ‘cutting’ combined with homologous recombination of a ‘repair’ template that introduces the desired edit. However, current approaches are limited for fully prototrophic yeast strains, and rely on relatively low efficiency cloning of short gRNAs. We were thus motivated to simplify the process by combining the gRNA and its cognate repair template incison a single oligonucleotide. Moreover, we wished to take advantage of a new approach that uses anE. coliretron (EcRT) to amplify repair templates as multi-copy single-stranded (ms)DNAin vivo, which are more efficient templates for homologous recombination. To this end, we have created a set of plasmids that express Cas9-EcRT, allowing for co-transformation with the gRNA-repair template plasmid in a single step. Our suite of plasmids contains different antibiotic (Nat, Hyg, Kan) or auxotrophic (HIS3, URA3) selectable markers, allowing for editing of fully prototrophic wild yeast strains. In addition to classic galactose induction, we generated a β-estradiol-inducible version of each plasmid to facilitate editing in yeast strains that grow poorly on galactose. The plasmid-based system results in >95% editing efficiencies for point mutations and >50% efficiencies for markerless deletions, in a minimum number of steps and time. We provide a detailed step-by-step guide for how to use this system.
Genomic data reveal a north-south split and introgression history of blood fluke (Schistosoma haematobium) populations from across Africa
Authors: Platt Roy N , Enabulele Egie E. , Adeyemi Ehizogie , Agbugui Marian O , Ajakaye Oluwaremilekun G , Amaechi Ebube C , Ejikeugwu Chika E , Igbeneghu Christopher , Njom Victor S , Dlamini Precious , Arya Grace A. , Diaz Robbie , Rabone Muriel , Allan Fiona , Webster Bonnie , Emery Aidan , Rollinson David , Anderson Timothy J.C.
Published: August 2024

The human parasitic fluke,Schistosoma haematobiumhybridizes with the livestock parasiteS. bovisin the laboratory, but the frequency of hybridization in nature is unclear. We analyzed 34.6 million single nucleotide variants in 162 samples from 18 African countries, revealing a sharp genetic discontinuity between northern and southernS. haematobium. We found no evidence for recent hybridization. Instead the data reveal admixture events that occurred 257-879 generations ago in northernS. haematobiumpopulations. Fifteen introgressedS. bovisgenes are approaching fixation in northernS. haematobiumwith four genes potentially driving adaptation. We identified 19 regions that were resistant to introgression; these were enriched on the sex chromosomes. These results (i) suggest strong barriers to gene flow between these species, (ii) indicate that hybridization may be less common than currently envisaged, but (iii) reveal profound genomic consequences of rare interspecific hybridization between schistosomes of medical and veterinary importance.
Neolithic introgression ofIL23R-related protection against chronic inflammatory bowel diseases in modern Europeans
Authors: Krause-Kyora Ben , da Silva Nicolas Antonio , Kaplan Elif , Kolbe Daniel ,   Archaeological Civilization Disease Consortium (ACDC), Wohlers Inken , Busch Hauke , Ellinghaus David , Caliebe Amke , Sezgin Efe , Nebel Almut , Schreiber Stefan
Published: August 2024

Background

The hypomorphic variant rs11209026-A in theIL23Rgene provides significant protection against immune-related diseases in Europeans, notably inflammatory bowel disease (IBD). Today, the A-allele occurs with an average frequency of 5% in Europe.

Methods

This study comprised 251 ancient genomes from Europe spanning over 14,000 years. In these samples, the investigation focused on admixture informed analyses and selection scans of rs11209026-A and its haplotypes.

Findings

rs11209026-A was found at high frequencies in Anatolian Farmers (AF, 18%) where it was likely under weak positive selection. AF later introduced the allele into the ancient European gene-pool. Subsequent admixture caused its frequency to decrease and formed the current southwest-to-northeast allele frequency cline in Europe. The geographic distribution of rs11209026-A may influence the gradient in IBD incidence rates that are highest in northern and eastern Europe.

Interpretation

Given the dramatic changes from hunting and gathering to agriculture during the Neolithic, AF might have been exposed to selective pressures from a pro-inflammatory lifestyle and diet. Therefore, the protective A-allele may have increased survival by reducing intestinal inflammation and microbiome dysbiosis. The adaptively evolved function of the variant likely contributes to the high efficacy and low side-effects of modern IL-23 neutralization therapies for chronic inflammatory diseases. This study highlights how evolutionary informed research can provide promising targets for new therapeutic strategies.

Funding

Deutsche Forschungsgemeinschaft (DFG German Research Foundation) under Germany’s Excellence Strategy – EXC 2167 390884018 and EXC 2150 390870439.
Integrative spatiotemporal modeling of biomolecular processes: application to the assembly of the Nuclear Pore Complex
Authors: Latham Andrew P. , Tempkin Jeremy O. B. , Otsuka Shotaro , Zhang Wanlu , Ellenberg Jan , Sali Andrej
Published: August 2024

Dynamic processes involving biomolecules are essential for the function of the cell. Here, we introduce an integrative method for computing models of these processes based on multiple heterogeneous sources of information, including time-resolved experimental data and physical models of dynamic processes. We first compute integrative structure models at fixed time points and then optimally select and connect these snapshots into a series of trajectories that optimize the likelihood of both the snapshots and transitions between them. The method is demonstrated by application to the assembly process of the human Nuclear Pore Complex in the context of the reforming nuclear envelope during mitotic cell division, based on live-cell correlated electron tomography, bulk fluorescence correlation spectroscopy-calibrated quantitative live imaging, and a structural model of the fully-assembled Nuclear Pore Complex. Modeling of the assembly process improves the model precision over static integrative structure modeling alone. The method is applicable to a wide range of time-dependent systems in cell biology, and is available to the broader scientific community through an implementation in the open sourceIntegrative Modeling Platformsoftware.
Genomic Loci Associated with Grain Protein and Mineral Nutrients concentrations in Eragrostis tef under Contrasting Water Regimes
Authors: Alemu Muluken Demelie , Ben-Zeev Shiran , Barak Vered , Tutus Yusuf , Cakmak Ismail , Saranga Yehoshua
Published: August 2024

Climate change is becoming a global concern, threating agricultures capacity to meet the food and nutritional requirements of the growing population. Underutilized crops present an opportunity to address resilience to climate change and nutritional deficiencies. Tef is a stress resilient cereal crop, producing gluten free grain of high nutritional quality. However, knowledge is lacking on tef diversity of grain nutritional properties, their interaction with environmental conditions (e.g., water availability) and the underlying genomic loci. We assessed the effect of water availability on tef grain nutrient concentrations and identify the associated genomic loci. A collection of 223 tef genotypes, a subset of tef diversity panel 300, were grown in the field under well watered and water limited conditions in 2021, and phenotyped for grain protein and mineral concentrations and seed color. A genome wide association study was conducted using 28,837 single nucleotide polymorphisms (SNPs) and phenotypic data to identify marker trait associations (MTAs). Tef grain nutrient concentrations exhibited wide genetic diversity with a significant influence of environment. Protein and most micronutrients were more concentrated under water limited conditions, whereas most macronutrients were higher in the well watered environment. A total of 59 SNPs were associated with one or more of the studied traits, resulting in 65 MTAs detected under both water treatments, and providing insights into the genetic basis of grain nutrients. Five SNPs reflected multiple associations, with four detecting the same trait under both treatments (multiple environment effect), and one associated with both Zn and K (pleiotropic effect). In addition, two pairs of closely linked SNPs reflected multiple environment effects. While multiple environment associations provide greater support for the integrity of these MTAs, the pleiotropic locus hints at a common mechanism controlling two mineral ions. The identified MTAs shed new light on the genomic architecture of tefs nutritional properties and provide the basis to enhance tef grain nutritional quality alongside drought resilience.
Alternative Conformations of lncRNAs Identified Through Structural Deconvolution of SHAPE- and DMS-MaP Datasets
Authors: Fallon Lucy , Jones Alisha N
Published: August 2024

The biological function of many classes of RNAs depend on their structures, which can exist as structural ensembles, rather than a single minimum free energy fold. In the past decade, long noncoding RNAs (lncRNAs) have emerged as functional transcripts in gene regulation that behave through their primary sequences and the structures they adopt. Chemical probing experiments, like selective 2’-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP), and dimethyl sulfate-MaP (DMS-MaP), facilitate the characterization of RNA secondary structure both inside and outside the cell. But chemical probing experiments yield anaveragereactivity profile, representative of all the structures a particular RNA transcript adopts at the time of chemical probing, weighted by their relative populations. Chemical probing experiments often struggle to identify coexisting conformations a lncRNA might sample. Computational methods (DRACO, DREEM, DANCE-MaP) have been developed to identify alternate conformations of RNAs by deconvoluting chemical probing data. In this work, we investigate the propensity for lncRNAs to sample multiple structured states, and find each of the studied lncRNAs possess coexisting folds. We discuss the implications of lncRNAs harboring multiple structures and how it may contribute to their multifunctionality in regulating biological processes.
The heme-scavenger, hemopexin, protects against fungal lung injury by mitigating NETosis: an experimental and computational study
Authors: Qu Ganlin , Ribeiro Henrique A. L. , Solomon Angelica L. , Vieira Luis Sordo , Goddard Yana , Diodati Nickolas G. , Lazarte Arantxa V , Wheeler Matthew , Laubenbacher Reinhard , Mehrad Borna
Published: August 2024

Invasive aspergillosis is characterized by lung hemorrhage and release of extracellular heme, which promotes fungal growth. Heme can also mediate tissue injury directly, and both fungal growth and lung injury may induce hemorrhage. To assimilate these interdependent processes, we hypothesized that, during aspergillosis, heme mediates direct lung injury independent of fungal growth, leading to worse infection outcomes, and the scavenger protein, hemopexin, mitigates these effects. Mice with neutropenic aspergillosis were found to have a time-dependent increase in lung extracellular heme and a corresponding hemopexin induction. Hemopexin deficiency resulted in markedly increased lung injury, fungal growth, and lung hemorrhage. Using a computational model of the interactions ofAspergillus, heme, and the host, we predicted a critical role for heme-mediated generation of neutrophil-extracellular traps in this infection. We tested this prediction using a fungal strain unable to grow at body temperature, and found that extracellular heme and fungal exposure synergize to induce lung injury by promoting NET release, and disruption of NETs was sufficient to attenuate lung injury and fungal burden. These data implicate heme-mediated NETosis in both lung injury and fungal growth during aspergillosis, resulting in a detrimental positive feedback cycle that can be interrupted by scavenging heme or disrupting NETs.
A cytochromebdrepressed by a MarR family regulator confers resistance to metals, nitric oxide, sulfide, and cyanide inChromobacterium violaceum
Authors: Batista Bianca B. , Will W. Ryan , de Lima Vinicius M. , Fang Ferric C. , da Silva Neto José F.
Published: August 2024

Chromobacterium violaceumis a ubiquitous environmental pathogen. Despite its remarkable adaptability, little is known about the mechanisms of stress resistance in this bacterium. Here, in a screen for iron-susceptible transposon mutants, we identified a cytochromebdthat protectsC. violaceumagainst multiple stresses. The two subunits of this cytochromebd(CioAB) are encoded by thecioRABoperon, which also encodes a GbsR-type MarR family transcription factor (CioR). A ΔcioABmutant strain was sensitive to iron and the iron-requiring antibiotic streptonigrin and showed a decrease in siderophore production. Growth curves and survival assays revealed that the ΔcioABstrain was also sensitive to zinc, hydrogen peroxide, nitric oxide, sulfide, and cyanide. Expression analysis showed that the promoter activity of thecioRABoperon and the transcript levels of thecioABgenes were increased in a ΔcioRmutant. CioR bound the promoter region of theciooperonin vitro, indicating that CioR is a direct repressor of its own operon. Expression of theciooperon increased at high cell density and was dependent on the quorum-sensing regulator CviR. As cyanide is also a signal forcioexpression, and production of endogenous cyanide is known to be a quorum sensing-regulated trait inC. violaceum, we suggest that CioAB is a cyanide-insensitive terminal oxidase that allow respiration under cyanogenic growth conditions. Our findings indicate that the cytochromebdCioAB protectsC. violaceumagainst multiple stress agents that are potentially produced endogenously or during interactions with a host.

IMPORTANCE

The terminal oxidases of bacterial respiratory chains rely on heme-copper (heme-copper oxidases) or heme (cytochromebd) to catalyze reduction of molecular oxygen to water.Chromobacterium violaceumis a facultative anaerobic bacterium that uses oxygen and other electron acceptors for respiration under conditions of varying oxygen availability. TheC. violaceumgenome encodes multiple respiratory terminal oxidases, but their role and regulation remain unexplored. Here, we demonstrate that CioAB, the single cytochromebdfromC. violaceum, protects this bacterium against multiple stressors that are inhibitors of heme-copper oxidases, including nitric oxide, sulfide, and cyanide. CioAB also confersC. violaceumresistance to iron, zinc, and hydrogen peroxide. This cytochromebdis encoded by thecioRABoperon, which is under direct repression by the MarR-type regulator CioR. In addition, thecioRABoperon responds to quorum sensing and to cyanide, suggesting a protective mechanism of increasing CioAB in the setting of high endogenous cyanide production.
Histone demethylase LSD1 regulates lipid homeostasis duringCryptococcus neoformansinfection
Authors: Lohia Gaurav Kumar , Shah Awantika , Balaji Kithiganahalli Narayanaswamy
Published: August 2024

An opportunistic fungal pathogen,Cryptococcus neoformans (C. neoformans), causes cryptococcal meningitis and is frequently associated with high mortality in immunocompromised individuals, particularly in HIV patients. Formation of metabolically altered lipid-rich foamy macrophages has been reported as a successful strategy employed by various intracellular pathogens to secure a nutrient source and niche within the host. Herein, we elucidate the involvement of macroautophagy, specifically lipophagy, in lipid dysregulation duringC. neoformansinfection. Our study highlights a pivotal role of lipophagy during infection, showing thatC. neoformansdriven activation of WNT-signaling leads to an aberrant lipid accumulation in host macrophages under the regulatory role of a histone modifier, Lysine Specific Demethylase 1 (LSD1). In a murine model of pulmonary infection, targeting host LSD1 led to a significant reduction in lung fungal burden, accompanied by amelioration of lung pathology and reduction of lipid content in the lungs. The study highlights the significance of host epigenetic regulation in modulating foamy macrophage formation through the regulation of lipophagy duringC. neoformanspathogenesis.
Prefrontal Cortex subregions provide distinct visual and behavioral feedback modulation to the Primary Visual Cortex
Authors: Ährlund-Richter S. , Osako Y. , Jenks K.R. , Odom E. , Huang H. , Arnold D.B. , Sur M.
Published: August 2024

The mammalian Prefrontal Cortex (PFC) has been suggested to modulate sensory information processing across multiple cortical regions via long-range axonal projections. These axonal projections arise from PFC subregions with unique brain-wide connectivity and functional repertoires, which may provide the architecture for modular feedback intended to shape sensory processing. Here, we used axonal tracing, axonal and somatic 2-photon calcium imaging, and chemogenetic manipulations in mice to delineate how projections from the Anterior Cingulate Cortex (ACA) and ventrolateral Orbitofrontal Cortex (ORB) of the PFC modulate sensory processing in the primary Visual Cortex (VISp) across behavioral states. Structurally, we found that ACA and ORB have distinct patterning of projections across both cortical regions and layers. ACA axons in VISp had a stronger representation of visual stimulus information than ORB axons, but both projections showed non-visual, behavior-dependent activity. ACA input to VISp enhanced the encoding of visual stimuli by VISp neurons, and modulation of visual responses scaled with arousal. On the other hand, ORB input shaped movement and arousal related modulation of VISp visual responses, but specifically reduced the encoding of high-contrast visual stimuli. Thus, ACA and ORB feedback have separable projection patterns and encode distinct visual and behavioral information, putatively providing the substrate for their unique effects on visual representations and behavioral modulation in VISp. Our results offer a refined model of cortical hierarchy and its impact on sensory information processing, whereby distinct as opposed to generalized properties of PFC projections contribute to VISp activity during discrete behavioral states.
SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma
Authors: Elaimy Ameer L. , El-Derany Marwa O. , James Jadyn , Wang Zhuwen , Pearson Ashley N. , Holcomb Erin A. , Huber Amanda K. , Gijón Miguel , Bell Hannah N. , Sanghvi Viraj R. , Frankel Timothy L. , Su Grace L. , Tapper Elliot B. , Tai Andrew W. , Ramnath Nithya , Centonze Christopher P. , Dobrosotskaya Irina , Moeller Julie A. , Bryant Alex K. , Elliott David A. , Choi Enid , Evans Joseph R. , Cuneo Kyle C. , Fitzgerald Thomas J. , Wahl Daniel R. , Morgan Meredith A. , Chang Daniel T. , Wicha Max S. , Lawrence Theodore S. , Shah Yatrik M. , Green Michael D.
Published: August 2024

End stage liver disease is marked by portal hypertension, systemic elevations in ammonia, and development of hepatocellular carcinoma (HCC). While these clinical consequences of cirrhosis are well described, it remains poorly understood whether hepatic insufficiency and the accompanying elevations in ammonia contribute to HCC carcinogenesis. Using preclinical models, we discovered that ammonia entered the cell through the transporter SLC4A11 and served as a nitrogen source for amino acid and nucleotide biosynthesis. Elevated ammonia promoted cancer stem cell propertiesin vitroand tumor initiationin vivo. Enhancing ammonia clearance reduced HCC stemness and tumor growth. In patients, elevations in serum ammonia were associated with an increased incidence of HCC. Taken together, this study forms the foundation for clinical investigations using ammonia lowering agents as potential therapies to mitigate HCC incidence and aggressiveness.
Phylogenomic prediction of interaction networks in the presence of gene duplication
Authors: Forsythe Evan S , Gatts Tony C , Lane Linnea E , deRoux Chris , Berggren Monica , Rehmann Elizabeth A , Zak Emily N , Bartel Trinity , L’Argent Luna , Sloan Daniel B
Published: August 2024

Assigning gene function from genome sequences is a rate-limiting step in molecular biology research. A protein’s position within an interaction network can potentially provide insights into its molecular mechanisms. Phylogenetic analysis of evolutionary rate covariation (ERC) in protein sequence has been shown to be effective for large-scale prediction of functional relationships and interactions. However, gene duplication, gene loss, and other sources of phylogenetic incongruence are barriers for analyzing ERC on a genome-wide basis. Here, we developedERCnet, a bioinformatic program designed to overcome these challenges, facilitating efficient all- vs-all ERC analyses for large protein sequence datasets. We simulated proteome datasets and found thatERCnetachieves combined false positive and negative error rates well below 10% and that our novel ‘branch-by-branch’ length measurements outperforms ‘root-to-tip’ approaches in most cases, offering a valuable new strategy for performing ERC. We also compiled a sample set of 35 angiosperm genomes to test the performance ofERCneton empirical data, including its sensitivity to user-defined analysis parameters such as input dataset size and branch-length measurement strategy. We investigated the overlap betweenERCnetruns with different species samples to understand how species number and composition affect predicted interactions and to identify the protein sets that consistently exhibit ERC across angiosperms. Our systematic exploration of the performance ofERCnetprovides a roadmap for design of future ERC analyses to predict functional interactions in a wide array of genomic datasets.ERCnetcode is freely available athttps://github.com/EvanForsythe/ERCnet.
Trioxane-based MS-cleavable Cross-linking Mass Spectrometry for Profiling Multimeric Interactions of Cellular Networks
Authors: Yu Clinton , Novitsky Eric , Wang Xiaorong , Echeverria Ignacia , Rychnovsky Scott , Huang Lan
Published: August 2024

Cross-linking mass spectrometry (XL-MS) is a powerful technology for mapping protein-protein interactions (PPIs) at the systems-level. By covalently connecting pairs of proximal residues, cross-linking reagents provide distance restraints to infer protein conformations and interaction interfaces. While binary cross-links have been remarkably informative, multimeric cross-links can offer enhanced spatial resolution to facilitate the characterization of dynamic and heterogeneous protein complexes. However, the identification of multimeric cross-links remains extremely challenging due to fragmentation complexity and the vast expansion of database search space. Here, we present a novel trioxane-based MS-cleavable homotrifunctional cross-linker TSTO, which can target three proximal lysine residues simultaneously. Owing to its unique structure and MS-cleavability, TSTO enables fast and unambiguous identification of cross-linked peptides using LC-MSnanalysis. Importantly, we have demonstrated that the TSTO-based XL-MS platform is effective for mapping PPIs of protein complexes and cellular networks. The trimeric interactions captured by TSTO have uncovered new structural details that cannot be easily revealed by existing reagents, allowing in-depth description of PPIs to facilitate structural modeling. This development not only advances XL-MS technologies for global PPI profiling from living cells, but also offers a new direction for creating multifunctional MS-cleavable cross-linkers to further push structural systems biology forward in the future.
Thermally-induced neuronal plasticity that mediates heat tolerance
Authors: Ambroziak Wojciech , Nencini Sara , Pohle Jörg , Zuza Kristina , Pino Gabriela , Lundh Sofia , Araujo-Sousa Carolina , Goetz Larissa I. L. , Schrenk-Siemens Katrin , Manoj Gokul , Herrera Mildred A. , Acuna Claudio , Siemens Jan
Published: August 2024

Heat acclimation is an adaptive process that improves physiological performance and supports survival in the face of increasing environmental temperatures. Understanding the underlying mechanisms holds potential to mitigate health risks and reduces the steadily increasing number of heat-related casualties associated with global warming. Here we report the identification of a discrete group of hypothalamic preoptic neurons that transform to rheostatically increase their activity over the course of heat acclimation, a property required for mice to become heat tolerant. Peripheral thermo-afferent pathways via the parabrachial nucleus activate preoptic neurons and mediate acute heat-defense mechanisms in non-acclimated animals. However, long-term heat exposure promotes the preoptic neurons to gain intrinsically warm-sensitive activity, independent of thermo-afferent parabrachial input. Our data shows that their newly gained cell-autonomous warm-sensitivity is required to recruit peripheral heat tolerance mechanisms in acclimated animals. Mechanistically, we find a combination of increased sodium leak current and enhanced utilization of the Nav1.3 ion channel to drive their pacemaker-like, warm-sensitive activity. We propose a salient neuronal plasticity mechanism, adaptively driving acclimation to promote heat tolerance.

Highlights

Heat acclimation induces tonic, warm-sensitive firing in hypothalamic VMPO neurons

Tonic activity in VMPO neurons primes peripheral organs to gain heat tolerance capacity

Warm-sensitive tonic firing recruits heat tolerance mechanisms in acclimated animals

NaV1.3 persistent sodium currents drive tonic, warm-sensitive firing in VMPO neurons
Repurposed medicines: a scan of the non-commercial clinical research landscape
Authors: Akinbolade Sola , Fairbairn Ross , Inskip Alex , Potter Rhiannon , Oliver Aoife , Craig Dawn
Published: August 2024

Medicine repurposing is a strategy to identify new uses for existing medicines for the purpose of addressing areas of unmet medical need. This paper aims to provide horizon scanning intelligence on repurposed medicines that are evaluated by non-commercial organisations such as academia, and highlights opportunities for further research to improve patient health outcomes. A scan of the clinical landscape of non-commercially sponsored repurposed medicines is routinely conducted by the NIHR Innovation Observatory (IO). This ongoing project involves a horizon scan of clinical trial registries and the internal horizon scanning Medicines Innovation Database (MInD) of the NIHR IO to identify potential candidate medicines used as monotherapy or in combination to treat new indications outside the scope of their licensed indication. In addition to making these data publicly available, the output also supports the NHS England Medicines Repurposing Programme (MRP). The snapshot scan reported here (trials completing April 2020 to March 2023) identified a total of 528 technologies (meaning, a single product or combination of medicinal products targeting a specific indication in one or more related trials). The technologies were classified according to their characteristics and targeted therapeutic indications as well as revealing the least treated disease conditions. The candidate medicines identified in this scan could potentially receive tailored support towards adoption into practice and policy. The NIHR IO regularly provides this scan as a source of intelligence on repurposed medicines. This provides valuable insights into innovation trends, gaps, and areas of unmet clinical need.
Improving Clarity and Interpretability of Items in a Bilingual Index of Propensity to Integrate Research Evidence into Clinical Decision-Making in Rehabilitation
Authors: Roberge-Dao Jacqueline , Mayo Nancy , Rochette Annie , Shikako Keiko , Thomas Aliki
Published: August 2024

Purpose

To contribute evidence for the clarity and interpretability of a new five-item bilingual multidimensional index of a rehabilitation clinician’s propensity to integrate research evidence into clinical decision-making.

Methods

This study was conducted in three sequential steps: (1) We conducted a focus group with occupational therapists, physical therapists, and researchers to review the items and response options for clarity, consistency, and interval properties and agree on equivalency in English and French. (2) We conducted cognitive interviews whereby clinicians elaborated on their interpretation of the item, comprehensibility of items, and appropriateness of response options. Accepted modifications were integrated and tested with subsequent participants. (3) We conducted an online survey to validate the English and French equivalency of response options on a 0 to 100 scale.

Results

During the qualitative revision process (one focus group with 7 participants followed by 27 interviews), the index was revised 12 times with substantial modifications to theuse of research evidenceandattitudesitems.

Conclusion

This research increases the clinical relevance and reduces measurement error of this brief index which can inform on individual or organizational factors influencing a clinician’s propensity of integrating research evidence into decision-making and ultimately, improve rehabilitation outcomes.
Predicting Cerebrospinal Fluid Alpha-Synuclein Seed Amplification Assay Status from Demographics and Clinical Data
Authors: Venuto Charles S. , Herbst Konnor , Chahine Lana M. , Kieburtz Karl
Published: August 2024

Objective

To develop and externally validate models to predict probabilities of alpha-synuclein (a-syn) positive or negative status in vivo in a mixture of people with and without Parkinson’s disease (PD) using easily accessible clinical predictors.

Methods

Uni- and multi-variable logistic regression models were developed in a cohort of participants from the Parkinson Progression Marker Initiative (PPMI) study to predict cerebrospinal fluid (CSF) a-syn status as measured by seeding amplification assay (SAA). Models were externally validated in a cohort of participants from the Systemic Synuclein Sampling Study (S4) that had also measured CSF a-syn status using SAA.

Results

The PPMI model training/testing cohort consisted of 1260 participants, of which 76% had manifest PD with a mean (± standard deviation) disease duration of 1.2 (±1.6) years. Overall, 68.7% of the overall PPMI cohort (and 88.0% with PD of those with manifest PD) had positive CSF a-syn SAA status results. Variables from the full multivariable model to predict CSF a-syn SAA status included age-and sex-specific University of Pennsylvania Smell Identification Test (UPSIT) percentile values, sex, self-reported presence of constipation problems, leucine-rich repeat kinase 2 (LRRK2) genetic status and pathogenic variant, andGBAstatus. Internal performance of the model on PPMI data to predict CSF a-syn SAA status had an area under the receiver operating characteristic curve (AUROC) of 0.920, and sensitivity/specificity of 0.881/0.845. When this model was applied to the external S4 cohort, which included 71 participants (70.4% with manifest PD for a mean 5.1 (±4.8) years), it performed well, achieving an AUROC of 0.976, and sensitivity/specificity of 0.958/0.870. Models using only UPSIT percentile performed similarly well upon internal and external testing.

Conclusion

Data-driven models using non-invasive clinical features can accurately predict CSF a-syn SAA positive and negative status in cohorts enriched for people living with PD. Scores from the UPSIT were highly significant in predicting a-syn SAA status.
ENCoDE – a skin tone and clinical dataset from a prospective trial on acute care patients
Authors: Hao Sicheng , Matos Joao , Dempsey Katelyn , Alwakeel Mahmoud , Houghtaling Jared , Hong Chuan , Gichoya Judy , Kibbe Warren , Pencina Michael , Cox Christopher E. , Ian Wong A.
Published: August 2024

Background

Although hypothesized to be the root cause of the pulse oximetry disparities, skin tone and its use for improving medical therapies have yet to be extensively studied. Studies previously used self-reported race as a proxy variable for skin tone. However, this approach cannot account for skin tone variability within race groups and also risks the potential to be confounded by other non-biological factors when modeling data. Therefore, to better evaluate health disparities associated with pulse oximetry, this study aimed to create a unique baseline dataset that included skin tone and electronic health record (EHR) data.

Methods

Patients admitted to Duke University Hospital were eligible if they had at least one pulse oximetry value recorded within 5 minutes before an arterial blood gas (ABG) value. We collected skin tone data at 16 different body locations using multiple devices, including administered visual scales, colorimetric, spectrophotometric, and photography via mobile phone cameras. All patients’ data were linked in Duke’s Protected Analytics Computational Environment (PACE), converted into a common data model, and then de-identified before publication in PhysioNet.

Results

Skin tone data were collected from 128 patients. We assessed 167 features per skin location on each patient. We also collected over 2000 images from mobile phones measured in the same controlled environment. Skin tone data are linked with patients’ EHR data, such as laboratory data, vital sign recordings, and demographic information.

Conclusions

Measuring different aspects of skin tone for each of the sixteen body locations and linking them with patients’ EHR data could assist in the development of a more equitable AI model to combat disparities in healthcare associated with skin tone. A common data model format enables easy data federation with similar data from other sources, facilitating multicenter research on skin tone in healthcare.

Description

A prospectively collected EHR-linked skin tone measurements database in a common data model with emphasis on pulse oximetry disparities.
Transferability of polygenic risk scores depending on demography and dominance coefficients
Authors: Fohler Leonie , Mayr Andreas , Maj Carlo , Staerk Christian , Klinkhammer Hannah , Krawitz Peter M.
Published: August 2024

The genetic liability to a complex phenotype is calculated as the sum of genotypes, weighted by effect size estimates derived from summary statistics of genome-wide association study (GWAS) data. Due to different allele frequencies (AF) and linkage disequilibrium (LD) patterns across populations, polygenic risk scores (PRS) that were developed on one population drop drastically in predictive performance when transferred to another. One of the major factors contributing to AF and LD heterogeneity is genetic drift, which acts strongly during population bottlenecks and is influenced by the dominance of certain alleles. In particular, since the causal variants on empirical data are typically not known, the presence of population specific LD-patterns will strongly affect transferability of PRS models. In this work, we therefore conducted demographic simulations to investigate the influence of the dominance coefficient on the transferability of PRS among European, African and Asian populations. By modifying the length and size of the bottleneck leading to the split of Eurasian and African populations, we gain a deeper understanding of the underlying dynamics. Finally, we illustrate that PRS models that are adapted to the underlying dominance coefficient can substantially increase their prediction performance in out-of-target populations.

Significance Statement

Polygenic risk scores (PRS) are increasingly used in clinical care for the management of many complex disorders such as breast cancer or cardiovascular diseases. Since heritability should be independent of ancestry so should be the predictability of the models. This is, however, currently not the case and the missing transferability of PRS is favoring individuals from European descent, who represent the largest population to train PRS. In this work we study on simulated populations what degree of transferability is theoretically achievable under different demographic models and dominance coefficients of the pathogenic variants. The results of our work are twofold: the effect of genetic drift and selection on the transferability can be quantified in simulations and recessive traits are more conserved.