bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering topologically associating domains from three-dimensional genome maps with TADGATE
Authors: Dang Dachang , Zhang Shao-Wu , Dong Kangning , Duan Ran , Zhang Shihua 
Published: June 2024

AbstractTopologically associating domains (TADs) emerge as indispensable units in three-dimensional (3D) genome organization, playing a critical role in gene regulation. However, accurately identifying TADs from sparse chromatin contact maps and exploring the structural and functional elements within TADs remain challenging. To this end, we develop a graph attention auto-encoder, TADGATE, to accurately identify TADs even from ultra-sparse contact maps and generate the imputed maps while preserving or enhancing the underlying topological structures. TADGATE can capture specific attention patterns, pointing to two types of units with different characteristics in TADs. Moreover, we find that the organization of TADs is closely associated with chromatin compartmentalization, and TAD boundaries in different compartmental environments exhibit distinct biological properties. We also utilize a two-layer Hidden Markov Model to functionally annotate the TADs and their internal regions, revealing the overall properties of TADs and the distribution of the structural and functional elements within TADs. At last, we apply TADGATE to highly sparse and noisy Hi-C contact maps from 21 human tissues or cell lines, enhancing the clarity of TAD structures, investigating the nature of conserved and cell type-specific boundaries, and unveiling the cell type-specific transcriptional regulatory mechanisms associated with topological domains.
Promoting Human Intestinal Organoid Formation and Stimulation Using Piezoelectric Nanofiber Matrices
Authors: Poling Holly M. , Singh Akaljot , Krutko Maksym , Reza Abid A. , Srivastava Kalpana , Wells James M. , Helmrath Michael A. , Esfandiari Leyla 
Published: June 2024

AbstractHuman organoid model systems have changed the landscape of developmental biology and basic science. They serve as a great tool for human specific interrogation. In order to advance our organoid technology, we aimed to test the compatibility of a piezoelectric material with organoid generation, because it will create a new platform with the potential for sensing and actuating organoids in physiologically relevant ways. We differentiated human pluripotent stem cells into spheroids following the traditional human intestinal organoid (HIO) protocol atop a piezoelectric nanofiber scaffold. We observed that exposure to the biocompatible piezoelectric nanofibers promoted spheroid morphology three days sooner than with the conventional methodology. At day 28 of culture, HIOs grown on the scaffold appeared similar. Both groups were readily transplantable and developed well-organized laminated structures. Graft sizes between groups were similar. Upon characterizing the tissue further, we found no detrimental effects of the piezoelectric nanofibers on intestinal patterning or maturation. Furthermore, to test the practical feasibility of the material, HIOs were also matured on the nanofiber scaffolds and treated with ultrasound, which lead to increased cellular proliferation which is critical for organoid development and tissue maintenance. This study establishes a proof of concept for integrating piezoelectric materials as a customizable platform for on-demand electrical stimulation of cells using remote ultrasonic waveforms in regenerative medicine.
Synergy Between TNFα and Proteostatic Stress Drives Cell Death and Guard Immunity
Authors: Sonnett Matthew , Centofanti Edoardo , Boersma Sanne , Brambach Max , Peshkin Leon , Tatavosian Roubina , Oyler-Yaniv Alon , Oyler-Yaniv Jennifer 
Published: June 2024

AbstractThe production and sensing of type I interferons (IFN-I) are critical for antiviral defense, yet most virus-infected cells do not produce IFN-I or upregulate IFN-stimulated genes. Using quantitative proteomics and global protein synthesis measurements, we show that productive viral infection globally down-regulates protein synthesis, restricting the IFN response. Guard immunity, which responds to disruptions in essential cellular processes, might compensate for the lack of IFN-I response by rapidly killing infected cells. However, non-pathological stressors can also disrupt proteostasis, making it unclear how cells decide to trigger guard immunity. We hypothesized that TNFα, produced by macrophages, provides a contextual signal allowing specificity. Using live-cell fluorescence microscopy and mathematical modeling, we showed that TNFα synergizes with the rapid decay of the anti-apoptotic protein c-FLIP to induce cell death and prevent viral spread. Our findings demonstrate that TNFα contextualizes proteostasis loss as non-sterile, enabling the activation of guard immunity to counteract viral infection.
An unbiased comparison of immunoglobulin sequence aligners
Authors: Konstantinovsky Thomas , Peres Ayelet , Polak Pazit , Yaari Gur 
Published: June 2024

AbstractAdaptive Immune Receptor Repertoire sequencing (AIRR-seq) is critical for our under-standing of the adaptive immune system’s dynamics in health and disease. Reliable analysis of AIRR-seq data depends on accurate Immunoglobulin (Ig) sequence alignment. Various Ig sequence aligners exist, but there is no unified benchmarking standard representing the complexities of AIRR-seq data, obscuring objective comparisons of aligners across tasks. Here, we introduce GenAIRR, an efficient simulation framework for generating Ig sequences alongside their ground truths. GenAIRR realistically simulates the intricacies of V(D)J recombination, somatic hypermutation, and an array of sequence corruptions. We comprehensively assessed prominent Ig sequence aligners across various metrics, unveiling unique performance characteristics for each aligner. The GenAIRR-produced datasets, combined with the proposed rigorous evaluation criteria, establish a solid basis for unbiased benchmarking of immunogenetics computational tools. It sets up the ground for further improving the crucial task of Ig sequence alignment, ultimately enhancing our understanding of adaptive immunity.
Transcriptome-wide analysis of circRNA and RBP profiles and their molecular and clinical relevance for GBM
Authors: Latowska-Łysiak J , Zarębska Ż , Sajek MP , Grabowska A , Buratin A , Misiorek JO , Kuczyński K , Bortoluzzi S , Żywicki M , Kosiński JG , Rybak-Wolf A , Piestrzeniewicz R , Barciszewska AM , Rolle K 
Published: June 2024

ABSTRACTGlioblastoma (GBM) is the most aggressive and lethal type of glioma, characterized by aberrant expression of non-coding RNAs including circular RNAs (circRNAs). They might impact cellular processes by interacting with other molecules – like microRNAs or RNA-binding proteins (RBPs). The diagnostic value of circRNAs and circRNAs/RBPs complexes is still largely unknown. To explore circRNAs and RBPs transcripts expression in GBM, we performed and further analyzed RNA-seq data from GBM patients’ primary and recurrent tumor samples. We identified circRNAs differentially expressed in primary tumors, the circRNA progression markers in recurrent GBM samples as well as the expression profile of RBP transcripts. Subsequent analysis allowed us to generate a comprehensive catalog of circRNA-RBP interactions regarding both the RBPs sequestration by circRNA as well as the RBPs involvement in circRNA biogenesis. Furthermore, we demonstrated the clinical potential of circRNAs and RBPs in GBM and proposed them as the stratification markers in the de novo assembled tumor subtypes. Therefore, our transcriptome-wide study specified circRNA-RBP interactions that could play a significant regulatory role in gliomagenesis and GBM progression.
Accelerated phenology fails to buffer fitness loss from delayed rain onset in a clade of wildflowers
Authors: Worthy Samantha J. , Ashlock Sarah R. , Miller Arquel , Maloof Julin N. , Strauss Sharon Y. , Gremer Jennifer R. , Schmitt Johanna 
Published: June 2024

AbstractThe timing of early life cycle events has cascading effects on phenology and fitness. These effects may be critical for climate resilience of plant populations, especially in Mediterranean environments, where delayed rainfall onset causes delayed germination. To examine impacts of germination timing on ten species of theStreptanthus/Caulanthusclade, we induced germination across a range of dates in ambient seasonal conditions and recorded phenological and fitness traits. Later germination cohorts accelerated flowering, partially stabilizing flowering date, but the degree of this compensatory plasticity differed across species. Fitness declined with later germination; the magnitude of this decline depended on the balance between direct negative effects of later germination and compensatory positive effects of accelerated flowering. The resulting species’ differences in fitness responses suggest differential vulnerability to climate change. Species from wetter, cooler, less variable habitats accelerated flowering more and declined less in seed set with later germination, suggesting climate adaptation. However, other fitness responses to germination timing, like first year fitness, were evolutionarily labile across the clade and unrelated to climate. Although compensatory phenological plasticity may buffer the impacts of delayed germination, it cannot prevent long term declines in population fitness as fall rains come later with climate change.
A humoral immune response to parasitoid wasps inDrosophilais regulated by JAK/STAT, NF-κB and GATA
Authors: Zhou Shuyu Olivia , Day Jonathan P. , Deplancke Bart , Leitão Alexandre B. , Jiggins Francis M. 
Published: June 2024

AbstractThe two arms of innate immunity consist of the cell-mediated cellular defenses and the systemic humoral immune responses.Drosophilahumoral immune defenses in the context of antimicrobial immunity, particularly the regulation and activation of antimicrobial peptide secretion from the fat body, have been studied extensively. HowDrosophilaregulates humoral immunity against another major natural enemy, the parasitoid wasp, is less well-characterized. In this study, we focused on a gene crucial in anti-parasitoid immunity,lectin-24A, which is specifically induced following parasitization. We found that a fluorescent reporter driven by the region upstream oflectin-24Ashowed localized posterior expression in the larval fat body, theDrosophilatissue mediating humoral immunity. Furthermore, with RNA sequencing of the anterior and posterior fat body sections, we found that components of JAK/STAT, GATA, and Toll pathways were regulated differentially in the anterior-posterior axis of the fat body and/or by infection. Predicted binding motifs for transcription factors in all three of these pathways were identified in the 444bp upstream region of thelectin-24Agene, where scrambling these motifs leads to reduced basal or induced expression of the fluorescent reporter. Investigating each of these pathways, we found that JAK/STAT, the GATA factor Pannier, and the NF-κB factor dorsal all modulate the expression oflectin-24A. The binding motifs associated with these transcription factors were also enriched in the upstream sequences of parasitism-induced genes in the fat body. Taken together, these results indicate that JAK/STAT, Pannier, and NF-κB signaling are involved in the regulation oflectin-24Aand, more generally,Drosophilahumoral anti-parasitoid immunity after infection.
Interplay between phosphorylation and oligomerization tunes the conformational ensemble of SWEET transporters
Authors: Weigle Austin T. , Shukla Diwakar 
Published: June 2024

ABSTRACTSWEET sugar transporters are desirable biotechnological targets for improving plant growth. One engineering strategy includes modulating how SWEET transporters are regulated. Phosphorylation and oligomerization have been shown to positively regulate SWEET function, leading to increased sugar transport activity. However, constitutive phosphorylation may not be beneficial to plant health under basal conditions. Structural and mechanistic understanding of the interplay between phosphorylation and oligomerization in functional regulation of SWEETs remains limited. Using extensive molecular dynamics simulations coupled with Markov state models, we demonstrate the thermodynamic and kinetic effects of SWEET phosphorylation and oligomerization using OsSWEET2b as a model. We report that the beneficial effects of these SWEET regulatory mechanisms bias outward-facing states and improved extracellular gating, which complement published experimental findings. Our results offer molecular insights to SWEET regulation and may guide engineering strategies throughout the SWEET transport family.
Regeneration-specific promoter switching facilitates Mest expression in the mouse digit tip to modulate neutrophil response
Authors: Jou Vivian , Peña Sophia M. , Lehoczky Jessica A. 
Published: June 2024

ABSTRACTThe mouse digit tip regenerates following amputation, a process mediated by a cellularly heterogeneous blastema. We previously found the gene Mest to be highly expressed in mesenchymal cells of the blastema and a strong candidate pro-regenerative gene. We now show Mest digit expression is regeneration-specific and not upregulated in post-amputation fibrosing proximal digits. Mest homozygous knockout mice exhibit delayed bone regeneration though no phenotype is found in paternal knockout mice, inconsistent with the defined maternal genomic imprinting of Mest. We demonstrate that promoter switching, not loss of imprinting, regulates biallelic Mest expression in the blastema and does not occur during embryogenesis, indicating a regeneration-specific mechanism. Requirement for Mest expression is tied to modulating neutrophil response, as revealed by scRNAseq and FACS comparing wildtype and knockout blastemas. Collectively, the imprinted gene Mest is required for proper digit tip regeneration and its blastema expression is facilitated by promoter switching for biallelic expression.
Escalation of genome defense capacity enables control of an expanding meiotic driver
Authors: Chen Peiwei , Pan Katherine C. , Park Eunice H. , Luo Yicheng , Lee Yuh Chwen G. , Aravin Alexei A. 
Published: June 2024

SummaryFrom RNA interference to chromatin silencing, diverse genome defense pathways silence selfish genetic elements to safeguard genome integrity1,2. Despite their diversity, different defense pathways share a modular organization, where numerous specificity factors identify diverse targets and common effectors silence them. In the PIWI-interacting RNA (piRNA) pathway, which controls selfish elements in the metazoan germline, diverse target RNAs are first identified by complementary base pairing with piRNAs and then silenced by PIWI-clade nucleases via enzymatic cleavage1,3. Such a binary architecture allows the defense systems to be readily adaptable, where new targets can be captured via the innovation of new specificity factors4,5. Thus, our current understanding of genome defense against lineage-specific selfish genes has been largely limited to the evolution of specificity factors, while it remains poorly understood whether other types of innovations are required. Here, we describe a new type of innovation, which escalates the defense capacity of the piRNA pathway to control a recently expanded selfish gene inDrosophila melanogaster. Through anin vivoRNAi screen for repressors ofStellate—a recently evolved and expanded selfish meiotic driver6–8—we discovered a novel defense factor, Trailblazer. Trailblazer is a transcription factor that promotes the expression of two PIWI-clade nucleases, Aub and AGO3, to matchStellatein abundance. Recent innovation in the DNA-binding domain of Trailblazer enabled it to drastically elevate Aub and AGO3 expression in theD. melanogasterlineage, thereby escalating the silencing capacity of the piRNA pathway to control expandedStellateand safeguard fertility. As copy-number expansion is a recurrent feature of diverse selfish genes across the tree of life9–12, we envision that augmenting the defense capacity to quantitatively match selfish genes is likely a repeatedly employed defense strategy in evolution.
Understanding the heterogeneous performance of variant effect predictors across human protein-coding genes
Authors: Fawzy Mohamed , Marsh Joseph A. 
Published: June 2024

AbstractVariant effect predictors (VEPs) are computational tools developed to assess the impacts of genetic mutations, often in terms of likely pathogenicity, employing diverse algorithms and training data. Here, we investigate the performance of 35 VEPs in the discrimination between pathogenic and putatively benign missense variants across 963 human protein-coding genes, revealing considerable gene-level heterogeneity as measured by the widely used area under the receiver operating characteristic curve (AUROC) metric. To investigate the origins of this heterogeneity and the extent to which gene-level VEP performance is predictable, we train random forest models to predict the gene-level AUROC for each VEP. We find that performance as measured by AUROC is related to factors such as gene function, protein structure, and evolutionary conservation. Notably, intrinsic disorder in proteins emerged as a significant factor influencing apparent VEP performance, often leading to inflated AUROC values due to their enrichment in weakly conserved putatively benign variants. While our results suggest that gene-level features may be useful for identifying genes where VEP predictions are likely to be more or less reliable, they also highlight the limitations of AUROC for comparing VEP performance across different genes.
Mechanisms of sustaining oxygen extraction efficiency in dragonfly nymphs during aquatic hypoxia
Authors: Lee Daniel J. , Matthews Philip G.D. 
Published: June 2024

AbstractDespite breathing water using their tidally ventilated rectal gills, dragonfly nymphs show a surprising ability to maintain oxygen (O2) extraction from the water during hypoxia. However, an increase in convective O2transfer is insufficient to sustain aerobic demands by itself, which suggests that diffusive mechanisms must also be involved. This study examines the contributions of changing the O2partial pressure gradient (PO2) and/or O2conductance across the rectal gill in maintaining O2extraction efficiency (OEE) of dragonfly nymphs during hypoxia. Data were collected using the same custom-designed respiro-spirometer described in a previous study with the addition of an implanted O2sensor to measure hemolymph PO2. Results show that the implantation of the O2sensor does not affect the respiratory and ventilatory response of nymphs to hypoxia. Hemolymph PO2fell from 6.3 ± 1.6 kPa at normoxia to 2.5 ± 0.6 kPa at 16.0 kPa, which resulted in the PO2diffusion gradient remaining statistically constant at these two water PO2s (17.5 ± 1.7 and 15.4 ± 0.7 kPa during normoxia and 16.0 kPa respectively). Beyond 16.0 kPa, a progressive reduction in hemolymph PO2was unable to sustain the diffusion gradient. Mathematical modeling revealed that while the addition of hemolymph PO2in tandem with ventilation frequency was able to elevate OEE during 16.0 kPa to that of normoxia, both were still insufficient during severe hypoxia and required an increase in O2conductance. Estimating the change in whole-gill conductance showed that nymphs are indeed increasing their conductance as the water becomes hypoxic, demonstrating a reliance on both diffusion gradient and O2conductance to enhance diffusive O2transfer in conjunction with convective mechanisms to maintain O2extraction during hypoxia.
Seasonal analysis of leaf antioxidant activity in Colombian eliteHevea brasiliensisgenotypes as a breeding strategy to enhance water deficit tolerance under Amazonian environmental conditions
Authors: Guaca-Cruz Lised , Sterling Armando , Clavijo Andrés , Suárez-Salazar Juan Carlos 
Published: June 2024

AbstractThis study evaluated the foliar antioxidant activity in nineHevea brasiliensisgenotypes from the ECC-1 (Élite Caquetá Colombia) selection and the IAN 873 cultivar (control) in trees in the growth stage in two large-scale clonal trials in response to different climatic (semi-humid warm and humid warm sites) and seasonal (dry and rainy periods) conditions in the Colombian Amazon. The results indicated that ROS production increased under conditions of lower water availability (dry period), leading to lipid peroxidation, high defense of photosynthetic pigments, and development of better osmotic adjustment capacity in the ECC 64, IAN 873, ECC 90, and ECC 35 genotypes due to high concentrations of carotenoids (0.40 mg g-1), reducing sugars (65.83 µg mg-1), and MDA (2.44 nmol ml-1). In contrast, during the rainy period, a post-stress action was observed due to high contents of proline and total sugars (39.43 µg g-1and 173.03 µg g-1, respectively). At the site level, with high PAR values (1143 moles photons m-2s-1), temperature (32.11 °C), and lower precipitation (135 mm), higher antioxidant activity (chlorophylls a, b and total, carotenoids, and proline) was recorded at the humid warm site, demonstrating that the ECC 90, ECC 64, and ECC 66 genotypes are tolerant to water deficit compared to IAN 873. The ECC 64 genotype, independent of seasonal changes and site conditions, presented the highest contents in Chl a, total Chl, reducing sugars, total sugars, and MDA, showing a tendency to adapt to fluctuating conditions. This study showed that water fluctuations do not cause the same metabolic responses, and these vary intraspecifically, depending on their developmental stage and the climatic and seasonal variations characteristic of the Colombian Amazon.
Continuous exposure to 60 Hz extremely low frequency electromagnetic field at 10 to 16 mT promotes various human cell proliferation by activating extracellular-signal-regulated kinase
Authors: Goh Jaeseong , Suh Donghwa , Um Dae Yong , Chae Seung Ahn , Park Gwan Soo , Song Kiwon 
Published: June 2024

AbstractWe previously showed that continuous exposure to 60 Hz extremely low-frequency electromagnetic fields (ELF-EMF) at 6 mT promotes cell proliferation. Here, we investigated the cellular effect of 60 Hz ELF-EMF at over 10 mT. We revised the ELF-EMF-generating device to increase the magnetic flux density of the ELF-EMF stably without thermal effect. We investigated the cellular effect of 10-16 mT ELF-EMF on various mammalian cells including human cervical carcinoma HeLa, rat neuroblastoma B103, liver cancer stem cells Huh7 and Hep3B, immortalized normal hepatic cell MIHA, and normal fibroblast IMR-90. Cell proliferation was promoted around 20% or more in all cells through continuous ELF-EMF exposure at 10 and 14 mT for 72 h, compared with the sham exposure group. In the cells whose proliferation was activated by 14 mT ELF-EMF, the MEK-ERK pathway and NF-κB were activated but not Akt. These cells showed a slight increase in the S phase population in BrdU incorporation and Ki-67 expression. In these cells, intracellular and mitochondrial ROS levels were not changed, and the proliferation-activating cellular effects of ELF-EMF were maintained even when oxidative phosphorylation was interrupted by CCCP. Additionally, no changes in intracellular calcium levels were observed in ELF-EMF-exposed cells and the proliferation-activating cellular effects of ELF-EMF were maintained in the presence of a calcium chelator, BAPTA-AM. These observations suggested that ROS and intracellular calcium do not mediate ELF-EMF’s proliferation-activating physiological effect. Altogether, we demonstrated that 60 Hz ELF-EMF at 10 to 14 mT promotes cell proliferation by activating ERK1/2 and does not affect intracellular ROS and calcium levels.