bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive Analysis of177Lu-lilotomab Satetraxetan in Lymphoma Cell Lines: Implications for Precision Radioimmunotherapy and Combination Schemes
Authors: Patzke Sebastian , Cascione Luciano , Melhus Katrine B , Munz Nicolas , Arribas Alberto J. , Gaudio Eugenio , Generalov Roman , Repetto-Llamazares Ada HV , Dahle Jostein , Bertoni Francesco
Published: June 2024

177Lu-lilotomab satetraxetan (Betalutin) is an anti-CD37 radioimmunoconjugate evaluated as single administration therapy for the treatment of patients with relapsed/refractory follicular lymphoma or diffuse large B-cell lymphoma (DLBCL).177Lu-lilotomab satetraxetan treatment is well-tolerated and shows consistent activity in most of the patients evaluated so far. Herein, we investigated the activity of177Lu-lilotomab satetraxetan in a panel of 55 lymphoma cell lines of B and T cell origin. CD37-targeted radioimmunotherapy was more effective in CD37-positive B-cell lymphomas (n=46) than negative CD37 negative T-cell lymphomas (n=9). Focusing on DLBCL cell lines, mutations such asBCL2orMYCtranslocations were not correlated to sensitivity. However,BCL2expression was higher in resistant than sensitive GCB-DLBCL cell lines, and the addition of the BCL2 inhibitor venetoclax showed synergism when added to the radioimmunoconjugate. Finally, the pattern of activity of177Lu-lilotomab satetraxetan differed from what was achieved with a CD37-targeting antibody-drug conjugate or with R-CHOP, indicating the potential benefit of the beta-emitter payload. In conclusion, this systematic analysis of the responsiveness of lymphoma cell lines to CD37-targeting radioimmunotherapy consolidated177Lu-lilotomab satetraxetan as a promising compound for the treatment of CD37 positive malignancies and identified candidate biomarkers and co-targets to detect and overcome cancer cell-intrinsic resistance mechanisms.
Parallel Analyses by Mass Spectrometry (MS) and Reverse Phase Protein Array (RPPA) Reveal Complementary Proteomic Profiles in Triple-Negative Breast Cancer (TNBC) Patient Tissues and Cell Cultures
Authors: Wang Nan , Zhu Yiying , Wang Lianshui , Dai Wenshuang , Hu Taobo , Song Zhentao , Li Xia , Zhang Qi , Ma Jianfei , Xia Qianghua , Li Jin , Liu Yiqiang , Long Mengping , Ding Zhiyong
Published: June 2024

High-plex proteomic technologies have made substantial contributions to mechanism studies and biomarker discovery in complex diseases, particularly cancer. Despite technological advancements, inherent limitations in individual proteomic approaches persist, impeding the achievement of comprehensive quantitative insights into the proteome. In this study, we employed two widely used proteomic technologies, Mass Spectrometry (MS) and Reverse Phase Protein Array (RPPA) to analyze identical samples, aiming to systematically assess the outcomes and performance of the different technologies. Additionally, we sought to establish an integrated workflow by combining these two proteomic approaches to augment the coverage of protein targets for discovery purposes. We used fresh frozen tissue samples from triple-negative breast cancer (TNBC) and cell line samples to evaluate both technologies and implement this dual-proteomic strategy. Using a single-step protein denaturation and extraction protocol, protein samples were subjected to reverse phase chromatography (LC) followed by electrospray ionization (ESI)-mediated MS/MS for proteomic profiling. Concurrently, identical sample aliquots were analyzed by RPPA for profiling of over 300 proteins and phosphoproteins that are in key signaling pathways or druggable targets in cancer. Both proteomic methods demonstrated the expected ability to differentiate samples by groups, revealing distinct proteomic patterns under various experimental conditions, albeit with minimal overlap in identified targets. Mechanism-based analysis uncovered divergent biological processes identified with the two proteomic technologies, capitalizing on their complementary exploratory potential.
An agent-based modelling framework for tumour growth incorporating mechanical and evolutionary aspects of cell dynamics
Authors: Macnamara Cicely K , Ramis-Conde I. , Lorenzi Tommaso , Caiazzo Alfonso
Published: June 2024

We develop an agent-based modelling framework for tumour growth that in-corporates both mechanical and evolutionary aspects of the spatio-temporal dynamics of cancer cells. In this framework, cells are regarded as viscoelastic spheres that interact with other neighbouring cells through mechanical forces. The phenotypic state of each cell is described by the level of expression of an hypoxia-inducible factor that regulates the cellular response to available oxygen. The rules that govern proliferation and death of cells in different phenotypic states are then defined by integrating mechanical constraints and evolutionary principles. Computational simulations of the model are carried out under a variety of scenarios corresponding to different intra-tumoural distributions of oxygen. The results obtained, which indicate excellent agreement between simulation outputs and the results of formal analysis of phenotypic selection, recapitulate the emergence of stable phenotypic heterogeneity among cancer cells driven by inhomogeneities in the intra-tumoural distribution of oxygen. This article is intended to present a proof of concept for the ideas underlying the proposed modelling framework, with the aim to apply the related modelling methods to elucidate specific aspects of cancer progression in the future.
Latitudinal clines in the phenology of floral display associated with adaptive evolution during a biological invasion
Authors: Akbar Mia N. , Moskoff Dale R. , Barrett Spencer C.H. , Colautti Robert I.
Published: June 2024

Premise

Flowering phenology strongly influences reproductive success in plants. Days to first flower is easy to quantify and widely used to characterize phenology, but reproductive fitness depends on the full schedule of flower production over time.

Methods

We examined floral display traits associated with rapid adaptive evolution and range expansion among thirteen populations ofLythrum salicaria, sampled along a 10-degree latitudinal gradient in eastern North America. We grew these collections in a common garden field experiment at a mid-latitude site and quantified variation in flowering schedule shape using Principal Coordinates Analysis (PCoA) and quantitative metrics analogous to central moments of probability distributions (i.e., mean, variance, skew, and kurtosis).

Key Results

Consistent with earlier evidence for adaptation to shorter growing seasons, we found that populations from higher latitudes had earlier start and mean flowering day, on average, when compared to populations from southern latitudes. Flowering skew increased with latitude whereas kurtosis decreased, consistent with a bet-hedging strategy in biotic environments with more herbivores and greater competition for pollinators.

Conclusions

Heritable clines in flowering schedules are consistent with adaptive evolution in response to a predicted shift toward weaker biotic interactions and less variable but more stressful abiotic environments at higher latitudes, potentially contributing to rapid evolution and range expansion of this invasive species.
DeepMASS: Unknown Compound Annotation using Semantic Similarity of Mass Spectral Language and Chemical Space Localization
Authors: Ji Hongchao , Du Ran , Dai Qinliang , Su Meifeng , Lyu Yaqing , Peng Yanchun , Yan Jianbin
Published: June 2024

Untargeted analysis using liquid chromatography□mass spectrometry (LC-MS) allows quantification of known and unknown compounds within biological systems. However, in practical analysis of complex biological system, the majority of compounds often remain unidentified. Here, we developed a novel deep learning-based compound annotation approach via semantic similarity analysis of mass spectral language. This approach enables the prediction of structurally related compounds for unknowns. By considering the chemical space, these structurally related compounds provide valuable information about the potential location of the unknown compounds and assist in ranking candidates obtained from molecular structure databases. Validated with two independent benchmark datasets obtained by chemical standards, our method has consistently demonstrated superior performance compared to existing compound annotation methods. A case study of the tomato ripening process indicates that DeepMASS has significant potential for metabolic biomarker identification in real biological systems. Overall, the presented method shows considerable promise in annotating metabolites, particularly in revealing the “dark matter” in untargeted analysis.
Global increase in the endemism of birds from north to south
Authors: Dehling D. Matthias , Chown Steven L.
Published: June 2024

Endemism is a highly valuable metric for conservation because it identifies areas with irreplaceable species, ecological functions, or evolutionary lineages1–6. Global analyses of endemism currently fail to identify the most irreplaceable areas because the commonly used endemism metrics are correlated with richness, and entire regions, especially in the southern hemisphere, are regularly excluded7–11. Global patterns of endemism are therefore still insufficiently known. Here, using metrics representing irreplaceability, we unveil global patterns of avian taxonomic, functional, and phylogenetic endemism that show striking differences between hemispheres. Across all facets of diversity, endemism decreases poleward in the northern, but increases poleward in the southern, hemisphere, resulting in a global north-south increase in endemism. The pattern is driven by increasingly smaller and discontinuous landmasses towards the south leading to increasingly smaller ranges and reduced overlap in community composition, and, unexpectedly, to peaks of diversity relative to available area in the southern hemisphere. The current misapprehension of global endemism potentially compromises urgent conservation actions, drawing attention away from key areas of irreplaceability. Highly endemic southern-hemisphere communities might be especially vulnerable to the climate crisis because discontinuous landmasses impede range shifts.
Under pressure: integrated endothelial cell response to hydrostatic and shear stresses
Authors: Mandrycky Christian J. , Ishida Takashi , Rayner Samuel G. , Heck Adam , Hadland Brandon , Zheng Ying
Published: June 2024

Blood flow within the vasculature is a critical determinant of endothelial cell (EC) identity and functionality, yet the intricate interplay of various hemodynamic forces and their collective impact on endothelial and vascular responses are not fully understood. Specifically, the role of hydrostatic pressure in the EC flow response is understudied, despite its known significance in vascular development and disease. To address this gap, we developed in vitro models to investigate how pressure influences EC responses to flow. Our study demonstrates that elevated pressure conditions significantly modify shear-induced flow alignment and increase endothelial cell density. Bulk and single-cell RNA sequencing analyses revealed that, while shear stress remains the primary driver of flow-induced transcriptional changes, pressure modulates shear- induced signaling in a dose-dependent manner. These pressure-responsive transcriptional signatures identified in human ECs were conserved during the onset of circulation in early mouse embryonic vascular development, where pressure was notably associated with transcriptional programs essential to arterial and hemogenic EC fates. Our findings suggest that pressure plays a synergistic role with shear stress on ECs and emphasizes the need for an integrative approach to endothelial cell mechanotransduction, one that encompasses the effects induced by pressure alongside other hemodynamic forces.
Low abundant intestinal commensals modulate immune control of chronic myeloid leukemia stem cells
Authors: Hinterbrandner Magdalena , Ronchi Francesca , Rubino Viviana , Römmele Michaela , Chiorazzo Tanja , Mooser Catherine , Ganal-Vonarburg Stephanie C. , McCoy Kathy D. , Macpherson Andrew J. , Ochsenbein Adrian F. , Riether Carsten
Published: June 2024

Leukemia stem cells (LSCs) are resistant to therapy and immune control. The reason for their resistance to elimination by cytotoxic T cells (CTLs) remains unclear. This study shows that specific low abundant Gram-negative intestinal commensals of the genusSutterellasuppress the anti-leukemia immune response in chronic myeloid leukemia (CML). We found that germ-free and specific opportunistic pathogen-free (SOPF) mice are protected from CML development and that colonization of SOPF mice withSutterella wadsworthensis, but not other related and unrelated bacterial strains, rescues CML development. A higher prevalence of this microbe resulted in Myd88/TRIF-mediated CTL exhaustion in SPF compared to SOPF CML mice as evidenced by higher surface expression of exhaustion markers on CTLs, a reduced capacity to produce interferon-gamma and granzyme B and to kill LSCsin vitro. These findings provide new insights into the immune control of LSCs and identifySutterellaspecies as regulators of anti-leukemic immunity in CML.
Versatile roles of Annexin A4 in ccRCC: impact on membrane repair, transcriptional signatures, and composition of the tumor microenvironment
Authors: Wess Maximilian , Rogg Manuel , Gueib-Picard Constance , Merz Annika , Koessinger Anna L. , Feilen Tobias , Andreev Grigor , Werner Martin , Frew Ian J. , Grabbert Markus , Schilling Oliver , Schell Christoph
Published: June 2024

Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of renal malignant disease and is characterized by dismal prognosis in the metastasized setting. Invasive growth of cancer cells relates to high levels of compressive forces translating to relevant damage of the plasma membrane. However, functional implications of protein machineries required for plasma membrane repair in ccRCC are not yet completely elucidated. Given the membrane-associated localization of the large family of annexin proteins, we aimed for a global annotation of annexin proteins, which led to the identification of ANXA4 selectively expressed in cancer cells of ccRCC. Interestingly, ANXA4 showed context-dependent distinct localization patterns including the plasma membrane as well as the nuclear compartment/nuclear membrane. We investigated the functional role of ANXA4 in ccRCC employing genetic titration studies (knockdown, CRISPR/Cas9 knockout and overexpression) and identified impaired acute plasma membrane repair as well as invasive capability in conditions of reduced ANXA4 expression. Utilizing computational segmentation of the tumor microenvironment (TME) of ccRCC samples revealed that ANXA4 low tumors exhibited a distinct TME composition compared to ANXA4 high cases. ANXA4 low tumors showed higher levels of tumor infiltrating lymphocytes accompanied by increased deposition of acellular extracellular matrix. Further transcriptomic analysis demonstrated major alterations in transcriptional signatures related to epithelial-mesenchymal transition (EMT) and immune signaling. Transcription factor enrichment analysis and further functional validation identified ELF3 as one central regulator of invasive properties. Our integrative approach including molecular analyses with advanced histopathological segmentation uncovered novel roles for ANXA4 in modulating acute membrane repair, transcriptional regulation, and shaping cellular composition of the ccRCC tumor microenvironment.
The proteotranscriptomic characterization of venom in the white seafanEunicella singulariselucidates the evolution of Octocorallia arsenal
Authors: Modica Maria Vittoria , Leone Serena , Gerdol Marco , Greco Samuele , Aurelle Didier , Oliverio Marco , Fassio Giulia , El Koulali Khadija , Barrachina Célia , Dutertre Sebastien
Published: June 2024

All the members of the phylum Cnidaria are characterized by the production of venom in specialized structures, the nematocysts. Venom of jellyfish (Medusozoa) and sea anemones (Anthozoa) has been investigated since the 1970s, revealing a remarkable molecular diversity. Specifically, sea anemones harbour a rich repertoire of neurotoxic peptides, some of which have been developed in drug leads. However, venoms of the vast majority of Anthozoa species remain uncharacterized, particularly in the class Octocorallia. To fill this gap, we applied a proteo-transcriptomic approach to investigate the venom composition inEunicella singularis, a gorgonian species common in Mediterranean hard-bottom benthic communities. Our results highlighted the peculiarities of the venom ofE. singulariswith respect to sea anemones, which is reflected in the presence of several toxins with novel folds, worthy of functional characterization. A comparative genomic survey across the octocoral radiation allowed us to generalize these findings and provided insights into the evolutionary history, molecular diversification patterns and putative adaptive roles of venom toxins. A comparison of whole-body and nematocyst proteomes revealed the presence of different cytolytic toxins inside and outside the nematocysts. Two instances of differential maturation patterns of toxin precursors were also identified, highlighting the intricate regulatory pathways underlying toxin expression.
Chemical and Sensory Analyses of Cultivated Pork Fat Tissue as a Flavor Enhancer for Meat Alternatives
Authors: Lew Emily T. , Yuen John S.K. , Zhang Kevin L. , Fuller Katherine , Frost Scott C. , Kaplan David L.
Published: June 2024

The emerging field of cellular agriculture has accelerated the development of cell-cultivated adipose tissue as an additive to enhance the flavor of alternative meat products. However, there has been limited research to evaluate the sensory profile ofinvitro-grown tissues compared to conventionally obtained animal fat. This study aimed to investigate the aromatic characteristics of cell-cultivated fat tissue as a flavor enhancer for meat alternatives. Porcine dedifferentiated fat cells were clonally isolated and differentiated into adipocytes. This cultured adipose tissue was then analyzed alongside native porcine fat using gas chromatography-mass spectrometry (GC/MS) coupled with descriptive sensory analysis by human panelists. This evaluation enabled quantitative and qualitative assessments of volatile compounds released during cooking for both in vitro and in vivo porcine fats. The volatile profiles generated during the cooking process and fatty aroma characteristics reported by sensory panelists were largely similar between the two fat sources, with some differences in the concentration of select compounds and aroma attributes. Ultimately, the panelists found comparable overall liking scores reported between the conventional and cultured porcine fats. These findings provide valuable sensory evidence supporting the viability of cell-cultivated adipose tissue as a flavor component of meat alternatives, substituting for conventional animal fat.
Microarray Integrated Spatial Transcriptomics (MIST) for Affordable, Robust, and Comprehensive Digital Pathology
Authors: Juwayria  , Shrivastava Priyansh , Yadav Kaustar , Das Sourabh , Mittal Shubham , Kumar Sunil , Jain Deepali , Malik Prabhat Singh , Gupta Ishaan
Published: June 2024

10X Visium, a popular Spatial transcriptomics (ST) method, faces limited adoption due to its high cost and restricted sample usage per slide. To address these issues, we propose Microarray Integrated Spatial Transcriptomics (MIST), combining conventional tissue microarray (TMA) with Visium, using laser-cutting and 3D printing to enhance slide throughput. Our design facilitates independent replication and customization in individual labs to suit specific experimental needs. We provide a step-by-step guide from designing TMAs to the library preparation step. We demonstrate MIST’s cost-effectiveness and technical benefits over Visium and GeoMx Nanostring. We also introduce ‘AnnotateMap’, a novel computational tool for efficient analysis of multiple ROIs processed through MIST.
Low-dimensional representations of genome-scale metabolism
Authors: Cain Samuel , Merzbacher Charlotte , Oyarzún Diego A.
Published: June 2024

Cellular metabolism is a highly interconnected network with thousands of reactions that convert nutrients into the molecular building blocks of life. Metabolic connectivity varies greatly with cellular context and environmental conditions, and it remains a challenge to compare genome-scale metabolism across cell types because of the high dimensionality of the reaction flux space. Here, we employ self-supervised learning and genome-scale metabolic models to compress the flux space into low-dimensional representations that preserve structure across cell types. We trained variational autoencoders (VAEs) on large fluxomic data (N= 800, 000) sampled from patient-derived models for various cancer cell types. The VAE embeddings have an improved ability to distinguish cell types than the uncompressed fluxomic data, and sufficient predictive power to classify cell types with high accuracy. We tested the ability of these classifiers to assign cell type identities to unlabelled patient-derived metabolic models not employed during VAE training. We further employed the pre-trained VAE to embed another 38 cell types and trained multilabel classifiers that display promising generalization performance. Our approach distils the metabolic space into a semantically rich vector that can be used as a foundation for predictive modelling, clustering or comparing metabolic capabilities across organisms.
Circumventing glioblastoma resistance to temozolomide through optimal drug combinations designed by quantitative systems pharmacology and machine learning
Authors: Corridore Sergio , Verreault Maïté , Martin Hugo , Delobel Thibault , Carrère Cécile , Idbaih Ahmed , Ballesta Annabelle
Published: June 2024

Glioblastoma is currently associated to a dismal prognosis despite intensive treatment involving maximal-safe surgery, radiotherapy and temozolomide (TMZ)-based chemotherapy. Disease progression or relapse is often due to initial or acquired resistance to temozolomide, which may be mediated by the over-expression of the repair enzyme MGMT. To design TMZ-based drug combinations circumventing the initial resistance of MGMT-overexpressing cells, a quantitative systems pharmacology (QSP) model representing TMZ cellular pharmacokinetics-pharmacodynamics and their connection to the most altered pathways in GBM was developed. This digital network representation of TMZ cellular pharmacology successfully integrates, in a mechanistic fashion, multi-type time- and dose-resolved datasets, available in control or MGMT-overexpressing cells.In silicotarget inhibition screening identified an optimal antitumor strategy consisting in priming cancer cells with inhibitors of the base excision repair and of the homologous recombination pathway prior to TMZ exposure. This drug combination was validated in dedicated experiments, thus allowing to re-sensitize cells which were initially resistant to TMZ. Using machine learning, functional signatures of response to such optimal multiagent therapy were derived to assist decision making about administering it to other cancer cell lines or patients. The developed framework can be extended to account for additional patientspecific altered pathways and may be translated towards the clinics by representing the tumor micro-environment and drug whole-body pharmacokinetics. Overall, we successfully demonstrated the relevance of combined QSP and machine learning to design multi-agent pharmacotherapies circumventing initial tumor resistance.

One Sentence Summary

An integratedin vitro-in silicoapproach allowed to design optimal drug combinations re-sensitizing temozolomide-resistant glioblastoma cells.
Higher functional resilience of temperate forests at intermediate latitudes of a large latitudinal gradient in South America
Authors: Deng Xiongjie , Carvajal Danny E. , Urrutia-Jalabert Rocío , Machida Waira S. , Rosen Alice , Zhang-Zheng Huanyuan , Galbraith David , Díaz Sandra , Malhi Yadvinder , Aguirre-Gutiérrez Jesús
Published: June 2024

Accurately mapping and assessing plant functional composition across space and time is pivotal for understanding environmental change impacts on the biodiversity and functioning of forests. Here, we test the capabilities of a combination ofin-situand remote sensing approaches to deliver accurate estimates of the functional composition of temperate forest ecosystems considering leaf and stem morphological, nutrient, hydraulic, and photosynthetic traits. We identify hydrological stress, soil, and topography as key drivers of plant functional traits. Further, hydrological stress and soil are key determinants of functional dispersion and redundancy in temperate forests distributed across a large latitudinal (30°S to 53°S) gradient in Chile. Functional dispersion peaks across Mediterranean forests, woodlands, and scrub, occupying between 30°S to 35°S. Conversely, functional redundancy peaks between 42°S and 53°S, corresponding to Magellanic subpolar forests. Although functional dispersion and redundancy peak at different latitudes corresponding to distinct forest types; they are both high at latitudes between 35°S and 42°S, coinciding with Valdivian temperate rainforests. Our results highlight areas in temperate forests in South America where both tree functional dispersion and redundancy are high, and hence could potentially be more resilient to environmental changes.
A conserved fungal Knr4/Smi1 protein is vital for maintaining cell wall integrity and host plant pathogenesis
Authors: Kroll Erika , Bayon Carlos , Rudd Jason , Armer Victoria , Umashankar Anjana Magaji- , Ames Ryan , Urban Martin , Brown Neil A. , Hammond-Kosack Kim
Published: June 2024

Filamentous plant pathogenic fungi pose significant threats to global food security, particularly through diseases like Fusarium Head Blight (FHB) and Septoria Tritici Blotch (STB) which affects cereals. With mounting challenges in fungal control and increasing restrictions on fungicide use due to environmental concerns, there is an urgent need for innovative control strategies. Here, we present a comprehensive analysis of the stage-specific infection process ofFusarium graminearumin wheat spikes by generating a dual weighted gene co-expression network (WGCN). Notably, the network contained a mycotoxin-enriched fungal module that exhibited a significant correlation with a detoxification gene-enriched wheat module. This correlation in gene expression was validated through quantitative PCR.

By examining a fungal module with genes highly expressed during early symptomless infection, we identified a gene encoding FgKnr4, a protein containing a Knr4/Smi1 disordered domain. Through comprehensive analysis, we confirmed the pivotal role of FgKnr4 in various biological processes, including morphogenesis, growth, cell wall stress tolerance, and pathogenicity. Further studies confirmed the observed phenotypes are partially due to the involvement of FgKnr4 in regulating the fungal cell wall integrity pathway by modulating the phosphorylation of the MAP-kinase MGV1. Orthologues ofFgKnr4are widespread across the fungal kingdom but are absent in other Eukaryotes, suggesting the protein has potential as a promising intervention target. Encouragingly, the restricted growth and highly reduced virulence phenotypes observed forΔFgknr4were replicated upon deletion of the orthologous gene in the wheat fungal pathogenZymoseptoria tritici. Overall, this study demonstrates the utility of an integrated network-level analytical approach to pinpoint genes of high interest to pathogenesis and disease control.
Transcription factor binding site divergence across maize inbred lines drives transcriptional and phenotypic variation
Authors: Galli Mary , Chen Zongliang , Ghandour Tara , Chaudhry Amina , Gregory Jason , Li Miaomiao , Zhang Xuan , Dong Yinxin , Song Gaoyuan , Walley Justin W. , Chuck George , Whipple Clinton , Kaeppler Heidi F. , Huang Shao-shan Carol , Gallavotti Andrea
Published: June 2024

Regulatory elements are important constituents of plant genomes that have shaped ancient and modern crops. Their identification, function, and diversity in crop genomes however are poorly characterized, thus limiting our ability to harness their power for further agricultural advances using induced or natural variation. Here, we use DNA affinity purification-sequencing (DAP-seq) to map transcription factor (TF) binding events for 200 maize TFs belonging to 30 distinct families and heterodimer pairs in two distinct inbred lines historically used for maize hybrid plant production, providing empirical binding site annotation for 5.3% of the maize genome. TF binding site comparison in B73 and Mo17 inbreds reveals widespread differences, driven largely by structural variation, that correlate with gene expression changes. TF binding site presence-absence variation helps clarify complex QTL such asvgt1, an important determinant of maize flowering time, and DICE, a distal enhancer involved in herbivore resistance. Modification of TF binding regions via CRISPR-Cas9 mediated editing alters target gene expression and phenotype. Our functional catalog of maize TF binding events enables collective and comparative TF binding analysis, and highlights its value for agricultural improvement.
Genomic and Genetic Insights into Mendel’s Pea Genes
Authors: Feng Cong , Chen Baizhi , Hofer Julie , Shi Yan , Jiang Mei , Song Bo , Cheng Hong , Lu Lu , Wang Luyao , Howard Alex , Bendahmane Abdel , Fouchal Anissa , Moreau Carol , Sawada Chie , LeSignor Christine , Vikeli Eleni , Tsanakas Georgios , Zhao Hang , Cheema Jitender , Barclay J. Elaine , Sayers Liz , Wingen Luzie , Vigouroux Marielle , Vickers Martin , Ambrose Mike , Dalmais Marion , Higuera-Poveda Paola , Spanner Rebecca , Horler Richard , Wouters Roland , Chundakkad Smitha , Zhao Xiaoxiao , Li Xiuli , Sun Yuchen , Huang Zejian , Deng Xing Wang , Steuernagel Burkhard , Domoney Claire , Ellis Noel , Chayut Noam , Cheng Shifeng
Published: June 2024

Pea,Pisum sativum, is an excellent model system through which Gregor Mendel established the foundational principles of inheritance. Surprisingly, till today, the molecular nature of the genetic differences underlying the seven pairs of contrasting traits that Mendel studied in detail remains partially understood. Here, we present a genomic and phenotypic variation map, coupled with haplotype-phenotype association analyses across a wide range of traits in a globalPisumdiversity panel. We focus on a genomics-enabled genetic dissection of each of the seven traits Mendel studied, revealing many previously undescribed alleles for the four characterized genes,R,Le,IandA, and elucidating the gene identities and mutations for the remaining three uncharacterized traits. Notably, we identify: (1) a ca. 100kb deletion upstream of theChlorophyll synthase(ChlG) gene, which generates aberrant transcripts and confers the yellow pod phenotype ofgpmutants; (2) an in-frame premature stop codon mutation in a Dodeca-CLE41/44 signalling peptide which explains the parchmentless mutant phenotype corresponding top; and (3) a 5bp in-frame deletion in aCIK-likereceptor kinase gene corresponding to the fasciated stem phenotypefa, which Mendel described in terms of flower position, and we postulate the existence of aModifier of fa(Mfa) locus that masks this meristem defect. Mendel noted the pleiotropy of theamutation, including inhibition of axil ring anthocyanin pigmentation, a trait we found to be controlled by allelic variants of the geneDwithin anR2R3-MYBgene cluster. Furthermore, we characterize and validate natural variation of a quantitative genetic locus governing both pod width and seed weight, characters that Mendel deemed were not sufficiently demarcated for his analyses. This study establishes a cornerstone for fundamental research, education in biology and genetics, and pea breeding practices.
Tendon Inversion Improves Tendon-to-Bone Healing in a Rat Bicep Tenodesis Model
Authors: Cong Ting , Li Thomas M. , Buller Dustin C. , Arvind Varun , Nasser Philip , Laudier Damien M. , Ferlauto Harrison R. , Hall Arielle J. , Li Deborah M. , Huang Alice H. , Cagle Paul J. , Galatz Leesa M. , Hausman Michael R.
Published: June 2024

Purpose

Tendon- or ligament-to-bone repair remains a surgical challenge. While bone tunnel fixation is a common surgical technique whereby soft tissue is expected to heal against a bone tunnel interface, contemporary methods have yet to recapitulate biomechanical similarity to the native enthesis. In this study, we aim to demonstrate that inside-out longitudinal tendon inversion may improve bone tunnel healing with the hypothesis that inversion removes the gliding epitenon surface from the healing interface thereby improving tunnel interface healing.

Methods

40 male Sprague-Dawley rats underwent either native tendon tenodesis (control group) or tendon inversion tenodesis (experimental group). Interface tissue was harvested 8 weeks post-operatively. Biomechanical testing was performed to assess tensile strength and modes of failure. Histology was performed to assess tissue architecture, and immunohistochemistry was used confirmed abrogation of epitendinous lubricin from interface tissue.

Results

Neither surgical intervention led to discernible adverse effects on animal health. Maximum tensile strength increased after tendon inversion compared to control surgery. The extracellular matrix protein lubricin was reduced with tendon inversion, and specimens with tendon inversion had greater healing scores and collagen fibril alignment at the healing interface.

Conclusions

Tendon inversion improves bone tunnel healing in rats.

Clinical Relevance

Our findings suggest that longitudinal tendon inversion, or inverse tubularization, in a rat biceps tenodesis model improves tendon-to-bone healing in part due to disruption of the epitendinous surface at the bone healing interface. This work provides molecular insight into future improvements for tendon-to-bone repair surgical techniques.
Comparative population genomics unveils congruent secondary suture zone in Southwest Pacific Hydrothermal Vents
Authors: Tran Lu Y Adrien , Ruault Stéphanie , Daguin-Thiébaut Claire , Le Port Anne-Sophie , Ballenghien Marion , Castel Jade , Gagnaire Pierre-Alexandre , Bierne Nicolas , Arnaud-Haond Sophie , Poitrimol Camille , Thiébaut Eric , Lallier François H , Broquet Thomas , Jollivet Didier , Bonhomme François , Hourdez Stéphane
Published: June 2024

How the interplay of biotic and abiotic factors shapes current genetic diversity at the community level remains an open question, particularly in the deep sea. Comparative phylogeography of multiple species can reveal the influence of past climatic events, geographic barriers, and species life history traits on spatial patterns of genetic structure across lineages.

To shed light on the factors that shape community-level genetic variation and to improve our understanding of deep-sea biogeographic patterns, we conducted a comparative population genomics study on seven hydrothermal vent species co-distributed in the Back-Arc Basins (BABs) of the Southwest Pacific region. Using ddRAD-seq, we compared the range-wide distribution of genomic diversity across species and discovered a shared phylogeographic break. Demogenetic inference revealed shared histories of lineage divergence and a secondary contact. Low levels of asymmetric gene flow probably occurred in most species between the Woodlark and North Fiji basins, but the exact location of contact zones varied from species to species. For two species, we found individuals from the two lineages co-occurring in sympatry in Woodlark Basin. Although species exhibit congruent patterns of spatial structure (Eastern vs Western sites), they also show variation in the degree of divergence among lineages across the suture zone. Our results also show heterogeneous gene flow across the genome, indicating possible partial reproductive isolation between lineages and early speciation.

Our comparative study highlights the pivotal role of historical and contemporary factors, underscoring the need for a comprehensive approach—especially in addressing knowledge gaps on the life history traits of deep-sea species.
MAPK13 controls structural remodeling and disease after epithelial injury
Authors: Wu Kangyun , Zhang Yong , Mao Dailing , Iberg Courtney A. , Yin-Declue Huiqing , Sun Kelly , Keeler Shamus P. , Wikfors Hallie A. , Young Deanna , Yantis Jennifer , Austin Stephen R. , Byers Derek E , Brody Steven L. , Crouch Erika C. , Romero Arthur G. , Holtzman Michael J.
Published: June 2024

All living organisms are charged with repair after injury particularly at epithelial barrier sites, but in some cases this response leads instead to structural remodeling and long-term disease. Identifying the molecular and cellular control of this divergence is key to disease modification. In that regard, stress kinase control of epithelial stem cells is a rational entry point for study. Here we examine the potential for mitogen-activated protein kinase 13 (MAPK13) regulation of epithelial stem cells using models of respiratory viral injury and post-viral lung disease. We show thatMapk13gene-knockout mice handle acute infectious illness as expected but are protected against structural remodeling manifest as basal-epithelial stem cell (basal-ESC) hyperplasia-metaplasia, immune activation, and mucinous differentiation. In corresponding cell models,Mapk13-deficiency directly attenuates basal-ESC growth and organoid formation. Extension to human studies shows marked induction/activation of basal-cell MAPK13 in clinical samples of comparable remodeling found in asthma and COPD. Here again,MAPK13gene-knockdown inhibits human basal-ESC growth in culture. Together, the data identify MAPK13 as a control for structural remodeling and disease after epithelial injury and as a suitable target for down-regulation as a disease-modifying strategy.

New and noteworthy

This study identifies a distinct role for stress kinase MAPK13 in controlling the epithelial stem cell response to injury and the consequent development of tissue remodeling. The present model has direct implications for lung injury and subsequent disease triggered by respiratory viruses and other inhaled toxins, but the tissue distribution of MAPK13 implies related actions at other barrier sites. The findings also refine a hypothesis for therapeutic intervention based on proper scaling of MAPK13 function including down-regulation with selective kinase inhibitors.
Nitrate reductase activity is required inMedicago truncatula-Sinorhizobium melilotinitrogen-fixing symbiosis
Authors: Marc Bosseno , Alexandre Demba , Natasha Horta Araújo , Dominique Colinet , Marie Pacoud , Yassine El Fazaa , Marc Lepetit , Gilles Clément , Renaud Brouquisse , Alexandre Boscari
Published: June 2024

Nitrate reductase (NR) is a key enzyme in higher land plants, catalyzing the rate-limiting reduction of nitrate to nitrite in the nitrate assimilation pathway. Phylogenetic analysis of NR protein sequences indicates that duplication events responsible for the existence of two NR branches, corresponding to NR1 and NR2 genes, occurred after the divergence of the different orders within the Rosids clade. A third NR sequence branch, named NR3-type, emerged in the inverted repeat-lacking clade of the Fabales order. An intriguing feature of the NR3-type sequences is the absence of conserved phosphorylation sites in the two hinge regions, in contrast to all other NRs. To investigate the respective roles ofMtNR1,MtNR2andMtNR3inM. truncatula, three singleTnt1retrotransposon-taggednrmutants and onenr1/nr2double mutant were analyzed on plants growing either on nitrate, or during the nodulation process. Overall, the absence of phenotypes observed inM. truncatulasingle mutants suggests a significant functional redundancy between the different NRs inM. truncatula. The most striking outcome of this work is the almost complete impairment of nodulation capacity observed in thenr1/nr2double mutant, demonstrating that NR activity is required for the functioning of the N2-fixing symbiosis.
Isolation and characterisation of serine proteases and metalloproteases from the venom of African puff adders
Authors: Wilkinson Mark C. , Modahl Cassandra M. , Saviola Anthony , Albulescu Laura-Oana , Tianyi Frank-Leonel , Casewell Nicholas R.
Published: June 2024

The puff adder (Bitis arietans) is a highly venomous viperid snake responsible for many fatalities in Africa, yet despite this there have been few comprehensive analyses of its venom proteins, particularly of the proteases that play a key role in envenoming. This study set out to isolate and characterise the most abundant serine proteases and metalloproteases found in venoms of puff adders obtained from Nigeria, Tanzania and Kenya. All three contained both classes of protease, but there were clear regional differences in the types of protease and their activities. Prominent in all three venoms was an SVMP PII-a. This protease varied in degree of glycosylation between the three sources, and also in its activity. The protease isolated from Tanzanian venoms, which was non-glycosylated, proved to be highly potent, and very destructive towards laminin in particular. The SVMP PIII content of the three venoms was quite low, but in some Kenyan venoms a prominent 68 kDa SVMP PIII was found which has a novel non-covalent dimeric structure and was strongly gelatinolytic, an activity that was not observed in any of the other SVMPs identified here. The Nigerian venoms were rich in an interesting set of serine proteases (SVSPs), the main forms of which were isolated and characterised. Two distinct groups were identified: trypsin-like acidic SVSPs and chymotrypsin-like basic SVSPs, each with different activities. The acidic SVSP is responsible for the gelatinase activity observed in the Nigerian venom, which is a novel form of activity for SVSPs. This regional diversity in venom protease activities is discussed with reference to the implications it will have in the development of therapeutic interventions.
Translation and Validation of an Epilepsy Screening Instrument in Two Ghanaian Languages
Authors: Darkwa Emmanuel Kwame , Asiamah Sabina , Awini Elizabeth , Sottie Cynthia , Godi Anthony , Williams John E , Akpalu Albert , Cross J Helen , Sander Josemir W. , Sen Arjune , Newton Charles R. , Danso-Appiah Anthony , Adjei Patrick
Published: June 2024

Introduction

The prevalence of epilepsy in sub-Saharan Africa varies considerably, and the exact estimate in Ghana is unknown, with few data available from peri-urban areas. More community-based studies are required to understand the tangible burden of epilepsy in these areas and the difficulties in healthcare access.

Objective

To validate a household survey epilepsy-screening instrument in Shai-Osudoku and Ningo-Prampram District of Greater Accra Region, Ghana.

Methods

We developed a 17-item epilepsy screening instrument by modifying validated English language questionnaires. We included questions that could identify convulsive and non-convulsive seizures. Language experts translated and back-translated the survey instrument into the two languages in this region: Asante Twi and Dangme. Cases were people with epilepsy attending healthcare facilities where these languages are used. Controls were unaffected relatives of cases or people attending the healthcare centres for other medical conditions. We matched cases and controls for geographical location and ethnicity. An affirmative response to one of the seventeen questions was deemed as a positive screen.

Results

One hundred and Forty Dangme Twi speakers (70 cases and 70 controls) and 100 Twi speakers (50 cases and 50 controls) were recruited. The sensitivity and specificity for Dangme were: Stage 1;100% (95% CI: 88.6, 94.9) and 80% (95% CI: 68.7, 88.6) and Stage 2, 98.6% (95% CI: 92.3, 100.0) and 85.7% (95% CI: 75.3, 92.9). The Dangme version reliably identified epilepsy with positive predictive values of 83.3% (95% CI: 73.6, 90.6) and 87.3% (95% CI: 78.6, 90.6) at stages 1 and 2. The questionnaire excluded epilepsy with negative predictive values of 100% (95% CI: 93.6, 100.0) and 98.4% (95% CI: 91.2, 100.0). For the Twi version, the sensitivity and specificity were: 98% (95% CI: 89.4, 99.9) and 92% (95% CI: 80.8, 97.8) at Stage 1, and for Stage 2, 96% (95% CI: 86.3, 99.5) and 94% (95% CI 83.5, 98.7). The Twi questionnaire reliably specified epilepsy with positive predictive values of 92.5% (95% CI: 81.8%, 97.9) and 94.1% (95% CI: 83.8, 98.8) at stages 1 and 2. It excluded epilepsy with negative predictive values of 97.9% (95% CI: 88.7, 99.9) and 95.9% (95% CI: 86.0, 99.5) for the two-stages

Conclusions

Our questionnaire is valid for the two tested languages and is usable for community-based epilepsy surveys in Ghana. The questionnaire can be adapted for other resource-poor settings, although there will need to be translation and iterative in-country testing to ensure its validity is maintained.
Human motion data expansion from arbitrary sparse sensors with shallow recurrent decoders
Authors: Ebers Megan R. , Pitts Mackenzie , Kutz J. Nathan , Steele Katherine M.
Published: June 2024

Advances in deep learning and sparse sensing have emerged as powerful tools for monitoring human motion in natural environments. We develop a deep learning architecture, constructed from a shallow recurrent decoder network, that expands human motion data by mapping a limited (sparse) number of sensors to a comprehensive (dense) configuration, thereby inferring the motion of unmonitored body segments. Even with a single sensor, we reconstruct the comprehensive set of time series measurements, which are important for tracking and informing movement-related health and performance outcomes. Notably, this mapping leverages sensor time histories to inform the transformation from sparse to dense sensor configurations. We apply this mapping architecture to a variety of datasets, including controlled movement tasks, gait pattern exploration, and free-moving environments. Additionally, this mapping can be subject-specific (based on an individual’s unique data for deployment at home and in the community) or group-based (where data from a large group are used to learn a general movement model and predict outcomes for unknown subjects). By expanding our datasets to unmeasured or unavailable quantities, this work can impact clinical trials, robotic/device control, and human performance by improving the accuracy and availability of digital biomarker estimates.