bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fitness advantage of sequential metabolic strategies emerges from community interactions in strongly fluctuating environments
Authors: Wang Zihan , Fu Yu , Goyal Akshit , Maslov Sergei 
Published: June 2024

AbstractMicrobes growing in fluctuating environments employ two key metabolic strategies: sequential (diauxic) utilization and co-utilization of nutrients. Most work has focused on understanding and comparing these strategies physiologically for the growth of single species, rather than ecologically for the assembly of complex natural communities. This is in part because of the lack of good metrics quantifying the fitness of different metabolic strategies in ecological contexts. Here, we present a new consumer-resource framework that incorporates dynamic proteome reallocation, and use it to compare the fitness of metabolic strategies during community assembly. We introduce two notions of fitness of a strategy in fluctuating environments: the time-averaged growth rate and the biomass-weighted prevalence of microbes using a given strategy. We find that sequential utilizers, although disadvantaged in pairwise competitions, gain a significant edge during community assembly — an advantage that becomes more pronounced with increasing community diversity and the size of the species pool from which they are assembled. Low diversity communities resemble pairwise competitions and are dominated by co-utilizers, whereas high diversity, mature communities are dominated by the sequential utilizers. This shift is driven by two factors: the difference in lag times and the increased structural stability conferred by sequential strategies. Overall, our work provides several testable predictions about the co-occurrence patterns of microbes using different metabolic strategies.
Coordinated function of paired NLRs confersYr84-mediated stripe rust resistance in wheat
Authors: Klymiuk Valentyna , Wiebe Krystalee , Chawla Harmeet Singh , Ens Jennifer , Subramaniam Rajagopal , Pozniak Curtis J. 
Published: June 2024

AbstractCloning of resistance genes expands our understanding of their function and facilitates their deployment in breeding. Here, we report the cloning of two genes from wild emmer wheat (Triticum turgidumssp.dicoccoides) underlyingYr84-mediated stripe rust resistance using a combination of fine mapping, long read-sequencing and mutation-induced functional validation. In contrast to all previously cloned stripe rust genes, the incompletely dominantYr84phenotype is conferred through the coordinated function of paired nucleotide-binding leucine-rich repeats (NLR) genesCNLandNL. We hypothesize that based on their genomic organization, annotation, expression profiles and predicted protein structure, CNL functions as a sensor NLR (sNLR) responsible for effector recognition, and NL acts as a helper NLR (hNLR) initiating downstream resistance cascades. The CNL and NL lack an integrated domain(s) previously implicated in effector recognition by paired NLRs, therefore these findings contribute new insights into plant paired NLRs structure and molecular mechanisms of function.
NaBC1 boron transporter enables myoblast response to substrate rigidity via fibronectin-binding integrins
Authors: Gonzalez-Valdivieso Juan , Ciccone Giuseppe , Barcelona-Estaje Eva , Rodrigo-Navarro Aleixandre , Castillo Rafael , Rico Patricia , Salmeron-Sanchez Manuel 
Published: June 2024

SummaryCells are sensitive to the physical properties of their microenvironment and transduce them into biochemical cues that trigger gene expression and alter cell behavior. Numerous proteins, including integrins, are involved in these mechanotransductive events. Here, we identify a novel role for the boron transporter NaBC1 as a mechanotransducer. We demonstrate that soluble boron ions activate NaBC1 to enhance cell adhesion and intracellular tension in C2C12 myoblasts seeded on fibronectin-functionalised polyacrylamide (PAAm) hydrogels. Retrograde actin flow and traction forces exerted by these cells are significantly increasedin vitroin response to both increased boron concentration and hydrogel stiffness. These effects are fibronectin and NaBC1-mediated as they are abrogated in hydrogels coated with laminin-111 in place of fibronectin and in esiRNA NaBC1-silenced cells. Our findings thus demonstrate that NaBC1 controls boron homeostasis and also functions as a mechanosensor.
Highly Repeatable Tissue Proteomics for Kidney Transplant Pathology: Technical and Biological Validation of Protein Analysis using LC-MS/MS
Authors: Hofstraat Rianne , Marx Kristina , Blatnik Renata , Claessen Nike , Chojnacka Aleksandra , Peters-Sengers Hessel , Florquin Sandrine , Kers Jesper , Corthals Garry 
Published: June 2024

AbstractAccurate pathological assessment of tissue samples is key for diagnosis and optimal treatment decisions. Traditional pathology techniques suffer from subjectivity resulting in inter-observer variability, and limitations in identifying subtle molecular changes. Omics approaches provide both molecular evidence and unbiased classification, which increases the quality and reliability of final tissue assessment. Here, we focus on mass spectrometry (MS)-based proteomics as a method to reveal biopsy tissue differences. For MS data to be useful, molecular information collected from formalin fixed paraffin embedding (FFPE) biopsy tissues needs to be consistent and quantitatively accurate and contain sufficient clinically relevant molecular information. Therefore, we developed an MS-based workflow and assessed the analytical repeatability on 36 kidney biopsies, ultimately analysing molecular differences and similarities of over 5000 proteins per biopsy. Additional 301 transplant biopsies were analysed to understand other physical parameters including effects of tissue size, standing time in autosampler, and the effect on clinical validation. MS data were acquired using Data-Independent Acquisition (DIA) which provides gigabytes of data per sample in the form of high proteome (and genome) representation, at exquisitely high quantitative accuracy. The FFPE-based method optimised here provides a coefficient of variation below 20%, analysing more than 5000 proteins per sample in parallel. We also observed that tissue thickness does affect the outcome of the data quality: 5 μm sections show more variation in the same sample than 10 μm sections. Notably, our data reveals an excellent agreement for the relative abundance of known protein biomarkers with kidney transplantation lesion scores used in clinical pathological diagnostics. The findings presented here demonstrate the ease, speed, and robustness of the MS-based method, where a wealth of molecular data from minute tissue sections can be used to assist and expand pathology, and possibly reduce the inter-observer variability.
Digital pathology assessment of kidney glomerular filtration barrier ultrastructure in an animal model of podocytopathy
Authors: Laudon Aksel , Wang Zhaoze , Zou Anqi , Sharma Richa , Ji Jiayi , Kim Connor , Qian Yingzhe , Ye Qin , Chen Hui , Henderson Joel M , Zhang Chao , Kolachalama Vijaya B , Lu Weining 
Published: June 2024

AbstractBackgroundTransmission electron microscopy (TEM) images can visualize kidney glomerular filtration barrier ultrastructure, including the glomerular basement membrane (GBM) and podocyte foot processes (PFP). Podocytopathy is associated with glomerular filtration barrier morphological changes observed experimentally and clinically by measuring GBM or PFP width. However, these measurements are currently performed manually. This limits research on podocytopathy disease mechanisms and therapeutics due to labor intensiveness and inter-operator variability.MethodsWe developed a deep learning-based digital pathology computational method to measure GBM and PFP width in TEM images from the kidneys of Integrin-Linked Kinase (ILK) podocyte-specific conditional knockout (cKO) mouse, an animal model of podocytopathy, compared to wild-type (WT) control mouse. We obtained TEM images from WT and ILK cKO littermate mice at 4 weeks old. Our automated method was composed of two stages: a U-Net model for GBM segmentation, followed by an image processing algorithm for GBM and PFP width measurement. We evaluated its performance with a 4-fold cross-validation study on WT and ILK cKO mouse kidney pairs.ResultsMean (95% confidence interval) GBM segmentation accuracy, calculated as Jaccard index, was 0.73 (0.70-0.76) for WT and 0.85 (0.83-0.87) for ILK cKO TEM images. Automated and manual GBM width measurements were similar for both WT (p=0.49) and ILK cKO (p=0.06) specimens. While automated and manual PFP width measurements were similar for WT (p=0.89), they differed for ILK cKO (p<0.05) specimens. WT and ILK cKO specimens were morphologically distinguishable by manual GBM (p<0.05) and PFP (p<0.05) width measurements. This phenotypic difference was reflected in the automated GBM (p<0.05) more than PFP (p=0.06) widths.ConclusionsThese results suggest that certain automated measurements enabled via deep learning-based digital pathology tools could distinguish healthy kidneys from those with podocytopathy. Our proposed method provides high-throughput, objective morphological analysis and could facilitate podocytopathy research and translate into clinical diagnosis.Key pointsWe leveraged U-Net architecture in an algorithm to measure the widths of glomerular basement membrane and podocyte foot processes.Deep learning-based automated measurement of glomerular filtration barrier morphology has promise in podocytopathy research and diagnosis.
De novo design of alpha-beta repeat proteins
Authors: Zorine Dmitri , Baker David 
Published: June 2024

AbstractProteins composed of a single structural unit tandemly repeated multiple times carry out a wide range of functions in biology. There has hence been considerable interest in designing such repeat proteins; previous approaches have employed strict constraints on secondary structure types and relative geometries, and most characterized designs either mimic a known natural topology, adhere closely to a parametric helical bundle architecture, or exploit very short repetitive sequences. Here, we describe Rosetta-based and deep learning hallucination methods for generating novel repeat protein architectures featuring mixed alpha-helix and beta-strand topologies, and 25 new highly stable alpha-beta proteins designed using these methods. We find that incorporation of terminal caps which prevent beta strand mediated intermolecular interactions increases the solubility and monomericity of individual designs as well as overall design success rate.
New mitochondrial gene order arrangements and evolutionary implications in the subclass Octocorallia
Authors: Poliseno Angelo , Quattrini Andrea M. , Lau Yee Wah , Pirro Stacy , Reimer James D. , McFadden Catherine S. 
Published: June 2024

AbstractThe complete mitochondrial genomes of octocorals typically range from 18.5 kb to 20.5 kb in length, and include 14 protein coding genes (PCGs), two ribosomal RNA genes and one tRNA. To date seven different gene orders (A-G) have been described, yet comprehensive investigations of the actual number of arrangements, as well as comparative analyses and evolutionary reconstructions of mitochondrial genome evolution within the whole subclass Octocorallia have been often overlooked. Here we considered the complete mitochondrial genomes available for octocorals and explored their structure and gene order variability. Our results updated the actual number of mitochondrial gene order arrangements so far known for octocorals from seven to twelve, and allowed us to explore and preliminarily discuss the role of some of the structural and functional factors in the mitogenomes. We performed comparative mitogenomic analyses on the existing and novel octocoral gene orders, considering different mitogenomic structural features such as genome size, GC percentage, AT- and GC-skewness. The mitochondrial gene order history mapped on a recently published nuclear loci phylogeny showed that the most common rearrangement events in octocorals are inversions, and that the mitochondrial genome evolution in the subclass is discontinuous, with rearranged gene orders restricted only to some regions of the tree. We believe that different rearrangement events arose independently and most likely that new gene orders, instead of being derived from other rearranged orders, came from the ancestral and most common gene order. Finally, our data demonstrate how the study of mitochondrial gene orders can be used to explore the evolution of octocorals and in some cases can be used to assess the phylogenetic placement of certain taxa.
Probing the glioma micro-environment: analysis using biopsy in combination with ultra-fast cyclic immunolabeling
Authors: van Solinge Thomas S. , Oh Juhyun , Abels Erik , Koch Peter , Breakefield Xandra O. , Weissleder Ralph , Broekman Marike L.D. 
Published: June 2024

AbstractThe interaction between gliomas and the immune system is poorly understood and thus hindering development of effective immunotherapies for glioma patients. The immune response is highly variable during tumor development, and affected by therapies such as surgery, radiation, and chemotherapy. Currently, analysis of these local changes is difficult due to poor accessibility of the tumor and high-morbidity of sampling. In this study, we developed a model for repeat-biopsy in mice to study these local immunological changes over time. Using fine needle biopsy we were able to safely and repeatedly collect cells from intracranial tumors in mice. Ultra-fast cycling technology (FAST) was used for multi-cycle immunofluorescence of retrieved cells, and provided insights in the changing immune response over time. The combination of these techniques can be utilized to study changes in the immune response in glioma or other intracranial diseases over time, and in response to treatment within the same animal.TeaserFine-needle biopsy and ultra-fast cycling technology techniques were developed to allow for repeat sampling and analysis of glial tumors in mice.
Directed Micro-Ecology Application System: On-site One-step Fermentation Facilitating Microbial Application Through Theoretical and Equipment Innovation
Authors: Ma Rui-qiang , Luo Yun-feng , Zhao Wei-min , Guo Jian-feng , Li Yanjie , Cui Wen-jing 
Published: June 2024

AbstractFunctional microbial agents play a crucial role in various fields such as agriculture, feed fermentation, aquaculture, and environmental protection. However, traditional microbial agents were confronted with critical challenges such as limited shelf-life, reduced activity, and inconsistent efficacy. In this case, we innovatively proposed the concept of Directed Micro-Ecology (DME) and developed its application system, including a core module named DME intelligent fermentor (DME25). Over 40 functional strains, including bacterial strains and fungus strains, were successfully cultured to 10∼50 ×108CFU/mL within 20∼48 h and maintained a relatively low contamination rate (<2.5%). Finally, the stability and effectiveness of these DME-fermented strains were validated in different application areas, all of which exhibited perfect functional characteristics. Firstly, the bacillus strains inhibited the progression of wilt disease and significantly improved the growth of tomatoes. Secondly, all tested lactobacillus strains improved the nutrition and quality of fermented feed, complying with feed industry standards. Lastly, the ammonia nitrogen concentration, nitrite concentration of aquaculture water and phosphate concentration, COD of aquaculture tail water were significantly reduced within 1∼4 d. The successful application of the DME intelligent fermentor in different fields marks a pivotal breakthrough in technological innovation of microbial agents on-site one-step fermentation. This technological advancement opens new avenues for enhancing the stability and effectiveness of microbial agents, infusing powerful impetus to the development of microbial application.
Conditional frequency spectra as a tool for studying selection on complex traits in biobanks
Authors: Patel Roshni A. , Weiß Clemens L. , Zhu Huisheng , Mostafavi Hakhamanesh , Simons Yuval B. , Spence Jeffrey P. , Pritchard Jonathan K. 
Published: June 2024

AbstractNatural selection on complex traits is difficult to study in part due to the ascertainment inherent to genome-wide association studies (GWAS). The power to detect a trait-associated variant in GWAS is a function of frequency and effect size — but for traits under selection, the effect size of a variant determines the strength of selection against it, constraining its frequency. To account for GWAS ascertainment, we propose studying the joint distribution of allele frequencies across populations, conditional on the frequencies in the GWAS cohort. Before considering these conditional frequency spectra, we first characterized the impact of selection and non-equilibrium demography on allele frequency dynamics forwards and backwards in time. We then used these results to understand conditional frequency spectra under realistic human demography. Finally, we investigated empirical conditional frequency spectra for GWAS variants associated with 106 complex traits, finding compelling evidence for either stabilizing or purifying selection. Our results provide insight into polygenic score portability and other properties of variants ascertained with GWAS, highlighting the utility of conditional frequency spectra.
DR3E-Net: Drug Repurposing Network Framework Based on Deep Embedding, Differentially Expressed Genes, and Drug Side Effects
Authors: Bhak YoungMin , Park Joon Ho , Han Hyun Wook 
Published: June 2024

AbstractIn contrast to traditional de-novo drug discovery, which involves high costs and lengthy development times alongside a high failure rate, drug repurposing (DR) offers a potential solution to these challenges. This study introduces DR3E-Net, an in-silico DR framework that integrates embedded vectors of genetic expression influenced by drugs, differentially expressed genes (DEGs) associated with diseases, and information about drug side effects. The DR3E-Net utilized LINCS L1000 datasets, which comprised 680,909 samples, 3,820 drugs, and 977 genes after preprocessing. The deep-embedding model within DR3E-Net was trained on this dataset, facilitating the transformation of 977-dimensional vectors into 32-dimensional unit-hypersphere embeddings. Subsequently, cosine similarity (CS) was computed among them (Step 1). To further elaborate, agonistic drugs against DEG linked to a disease (Alzheimer’s disease (AD) in this study) were merged with outcomes from Step 1 (Step 2). Finally, the SIDER and SAEDR/DRIP databases were combined with the integrated results from Step 2 (Step 3).The DR3E-Net was utilized to predict potential alternative drug candidates for three AD medications: donepezil, galantamine, and memantine. The drugs predicted by the deep-embedding model (Step 1) were combined with agonistic drugs against CRTAP gene, resulting in 111, 86, and 96 drugs, respectively (Step 2). Lastly, drug side effect information was incorporated with the aforementioned drug outcomes, yielding 21, 15, and 18 drugs (Step 3). DR3E-Net was developed to predict functionally similar drugs while considering disease-associated DEGs of patients and drug side effect information.
Bioprinting of aptamer-based programmable bioinks to modulate multiscale microvascular morphogenesis in 4D
Authors: Rana Deepti , Rangel Vincent R. , Padmanaban Prasanna , Trikalitis Vasileios D. , Kandar Ajoy , Kim Hae-Won , Rouwkema Jeroen 
Published: June 2024

AbstractDynamic growth factor presentation influences how individual endothelial cells assemble into complex vascular networks. Here, we developed programmable bioinks that facilitate dynamic VEGF presentation to guide vascular morphogenesis within 3D-bioprinted constructs. We leveraged aptamer’s high affinity for rapid VEGF sequestration in spatially confined regions and utilized aptamer-complementary sequence (CS) hybridization to tune VEGF release kinetics temporally, days after bioprinting. We show that spatial resolution of programmable bioink, combined with CS-triggered VEGF release, significantly influences alignment, organization, and morphogenesis of microvascular networks in bioprinted constructs. The presence of aptamer-tethered VEGF and the generation of instantaneous VEGF gradients upon CS-triggering restricted hierarchical network formation to the printed aptamer regions at all spatial resolutions. Network properties improved as the spatial resolution decreased, with low-resolution designs yielding the highest network properties. Specifically, CS-treated low-resolution designs exhibited significant vascular network remodeling, with increase in vessel density(1.35-fold), branching density(1.54-fold), and average vessel length(2.19-fold) compared to non-treated samples. Our results suggests that CS acts as an external trigger capable of inducing time-controlled changes in network organization and alignment on-demand within spatially localized regions of a bioprinted construct. We envision that these programmable bioinks will open new opportunities for bioengineering functional, hierarchically self-organized vascular networks within engineered tissues.
An ALK1-governed monocytic lineage shapes an immunosuppressive landscape in breast cancer metastases
Authors: Talkhoncheh Mehrnaz Safaee , Sjölund Jonas , Bolivar Paulina , Kurzejamska Ewa , Cordero Eugenia , Pagès Teia Vallès , Larsson Sara , Lehn Sophie , Frimannsson Gustav , Ingesson Viktor , Braun Sebastian , Pantaleo Jessica , Oudenaarden Clara , Lauss Martin , Pearsall R. Scott , Jönsson Göran B. , Rolny Charlotte , Bocci Matteo , Pietras Kristian 
Published: June 2024

AbstractThe biology centered around the TGF-β type I receptor ALK1 (encoded byACVRL1)has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipatedAcvrl1expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+monocytes into circulation, and their eventual extravasation. Notably,ACVRL1+TAMs coincided with an immunosuppressive phenotype, and were over-represented in human cancers progressing on therapy. Accordingly, breast cancer patients with a prominentACVRL1hiTAM signature exhibited a significantly shorter survival. In conclusion, we shed light on an unexpected multimodal regulation of tumorigenic phenotypes by ALK1 and demonstrate its utility as a target for anti-angiogenic immunotherapy.Graphical abstractSee submitted file