bluuebunny/crossref_metadata_2025_split huggingface dataset:
RBP4 functions as an antagonistic ligand of orphan DR6
Authors: Kim Taeyun , Lee Wonhee John , Nguyen Thy N. C. , Jang Juhee , Kim Kiwook , Kim Min-Sik , Seo Daeha , Lee Young-Sam , Lee Yun-Il 
Published: October 2024

SummaryDeath receptor (DR) is a unique transmembrane receptor mediating extrinsic factor-induced programmed cell death pathways. For most DRs, the regulatory mechanism has been revealed to involve agonistic death ligand (e.g., TRAIL, TNF-α)-driven receptor clustering and activation, offering an in-depth understanding of the mechanistic basis for cell death regulation and therapeutic strategies. However, only death receptor 6 (DR6) remains orphan, and its molecular mechanism is poorly understood. Here, we identified retinol binding protein 4 (RBP4), a major vitamin-A carrier protein, as an antagonistic ligand of DR6. Single-molecule photobleaching and single-receptor tracking analyses revealed that RBP4 drives DR6 dimerization on the plasma membrane to prevent DR6 prodegenerative heterointeractions and consequent neurodegenerative processes. DR6 homodimerization predominantly depends on an extracellular intrinsically disordered region, allowing the agonistic propensity of increasing Ca2+levels. Collectively, our study establishes the distinct molecular mechanism of DR6 and highlights the non-canonical role of RBP4 as a cell death regulator.
Conserved sites on the influenza H1 and H3 hemagglutinin recognized by human antibodies
Authors: Maurer Daniel P. , Vu Mya , Ramos Ana Sofia Ferreira , Dugan Haley L. , Khalife Paul , Geoghegan James C. , Walker Laura M. , Bajic Goran , Schmidt Aaron G. 
Published: October 2024

ABSTRACTMonoclonal antibodies (mAbs) targeting the influenza hemagglutinin (HA) have the potential to be used as prophylactics or templates for next-generation vaccines that provide broad protection. Here, we isolated broad, subtype-neutralizing mAbs from human B cells targeting the H1 or H3 HA head as well as a unique mAb targeting the stem. The H1 mAbs target the previously defined lateral patch epitope on H1 HAs and recognize HAs from 1933 to 2021 in addition to a swine H1N1 virus with pandemic potential. Using directed evolution, we improved the neutralization potency of these H1 mAbs towards a contemporary H1 strain. Using deep mutational scanning of four antigenically distinct H1N1 viruses, we identified potential viral escape pathways. For the H3 mAbs we used cryo-EM to define the targeted epitopes: one mAb recognizes the side of the H3 head, accommodating the N133 glycan and a pocket underneath the receptor binding site. The other H3 mAb recognizes an epitope in the HA stem that overlaps with previously characterized mAbs, but with distinct antibody variable genes and mode of recognition. Collectively, these mAbs identify common sites recognized by broad, subtype-specific mAbs that may be elicited by next-generation vaccines.
Genomes ofWiebesiafig wasps reveal the adaptation and codiversification in fig-fig wasp mutualism
Authors: Lo Bai-Wei , Lin Hsin-Fu , Kong Siu-Wah , Wu Wen-Jer , Wang Selina Cai-Ling , Lu Xuemei , Wang Hurng-Yi 
Published: October 2024

AbstractFigs and fig wasps represent one of the most intimate examples of plant-pollinator coevolution. As figs diversified into geographically isolated populations, both figs and fig wasps underwent selective pressures driven by local adaptation and coevolution.Ficus pumilacomprises two ecologically distinct varieties: the creeping fig (F. pumilavar.pumila), which is widely distributed across the lowlands of East Asia, and the jelly fig (F. pumilavar.awkeotsang), endemic to Taiwan and found at mid-elevations. To elucidate how codiversification with fig hosts influences the evolutionary trajectories of fig wasps, we analyzed the genomes ofWiebesiasp. 2 and sp. 3, the respective pollinators of creeping fig and jelly fig. Our demographic analysis indicates that vicariance during the Last Glacial Period facilitated ecological differentiation between these two fig-fig wasp pairs. Through comparative and population genomic analyses, we identified selection signals linked to habitat adaptation, with evolutionary rates corresponding to the life history traits of their host figs. Variations in host preference behavior, chemosensory gene expression, and adaptive duplications in olfactory receptors highlight potential mechanisms for adaptation to host floral scents. These findings collectively underscore how the obligate mutualism between figs and their pollinating wasps allows the ecological traits and habitat preferences of fig hosts to shape the evolutionary pathways of their pollinators, leaving distinct molecular imprints in the fig wasp genomes. This study demonstrates the capacity of tightly intertwined life cycles between plants and pollinators to drive adaptation and diversification.
Degradation of fish food webs in the anthropocene
Authors: Carvajal-Quintero Juan D. , Dornelas Maria , Comte Lise , Herrrera-Pérez Juliana , Tedesco Pablo A. , Giam Xingli , Brose Ulrich , Chase Jonathan M. 
Published: October 2024

AbstractThe Anthropocene is marked by profound changes in biodiversity and the ecosystems in which species live1–4. A primary signature of this change is the often rapid change in species composition through time (i.e., species turnover) rather than changes in the numbers of species per se5–7. Less well known, however, is which types of species are ‘winning’ and which are ‘losing’ as ecosystems change through time8,9, as well as whether and how these changes influence higher-level processes in the food webs in which species are embedded10,11. Here, we combine a compilation of long-term observations of ∼15,000 freshwater and marine fish communities surveyed for 1949-2019 years, together with information about their diets and trophic status in order to evaluate how the food webs in which these fish communities are embedded are changing through time. We found widespread alteration to fish food web topology and functioning. This includes an increase in connectance and generalism in food webs, which has led to greater predation pressure, as indicated by higher diet overlap and increased prey vulnerability. We also identified a decrease in modularity, which has reduced the compartmentalization within local networks. These changes extend across the trophic structure of food webs, causing a cascading shift in the proportion of species across trophic levels. Our study highlights the complex responses of biodiversity change of fish food webs in the Anthropocene, which can ultimately influence the functions of these ecosystems and human well-being12,13.
Changes in the cellular composition of the endometrium during the implantation window are associated with recurrent pregnancy loss
Authors: Reddin Ian G. , Pearson-Farr Jennifer E. , Turaj Anna H. , Lim Sean H. , Lewis Rohan M. , Cheong Ying C , Cleal Jane K. 
Published: October 2024

AbstractRecurrent pregnancy loss (RPL) affects 1-2% of women trying to conceive, yet in many cases the causes remain unclear. Endometrial function is central to the establishment and maintenance of pregnancy, and endometrial dysfunction may underlie RPL. A greater understanding of the endometrial cell populations and their interactions in women with and without RPL may identify markers of endometrial receptivity and the likelihood of pregnancy success. Single cell RNA sequencing was performed on RPL (n = 3) and control (n = 4) endometrial biopsies collected at days 21-24 of the menstrual cycle, the window of implantation. 10,022 cells were clustered and nine major individual cell types were characterised. Further analysis identified six distinct endometrial stromal cell (EnSCs) and three natural killer (NK) cell sub-populations. In RPL, there were changes in the abundance of specific endometrial stromal and NK cell subpopulations with associated differences in cellular communication between the cell types related to the Wnt pathway and angiogenesis. This is consistent with NK cell signalling orchestrating the difference in abundance of stromal cells and regulating processes needed for successful implantation. These changes in RPL endometrium provide further evidence for an endometrial cause of RPL and identify specific mechanisms for future study.
CRB2 Depletion Induces YAP Signaling and Disrupts Mechanosensing in Podocytes
Authors: Sun Yingyu , Kronenberg Nils M. , Sethi Sidharth K. , Dash Surjya N. , Kovalik Maria E. , Sempowski Benjamin , Strickland Shelby , Raina Rupresh , John Sperati C. , Tian Xuefei , Ishibe Shuta , Hall Gentzon , Gather Malte C. 
Published: October 2024

AbstractFocal Segmental Glomerulosclerosis (FSGS) is a histologic lesion caused by a variety of injurious stimuli that lead to dysfunction/loss of glomerular visceral epithelial cells (i.e. podocytes). Pathogenic mutations in CRB2, encoding the type 1 transmembrane protein Crumb 2 Homolog Protein, have been shown to cause early-onset corticosteroid-resistant nephrotic syndrome (SRNS)/FSGS. Here, we identified a 2-generation East Asian kindred (DUK40595) with biopsy-proven SRNS/FSGS caused by a compound heterozygous mutation in CRB2 comprised of the previously described truncating mutation p.Gly1036_Alafs*43 and a rare 9-bp deletion mutation p.Leu1074_Asp1076del. Because compound heterozygous mutations involving the truncating p.Gly1036_Alafs*43 variant have been associated with reduced CRB2 expression in podocytes and autosomal recessive SRNS/FSGS, we sought to define the pathogenic effects of CRB2 deficiency in podocytes. We show that CRB2 knockdown induces YAP activity and target gene expression in podocytes. It upregulates YAP-mediated mechanosignaling and increases the density of focal adhesion and F-actin. Using Elastic Resonator Interference Stress Microscopy (ERISM), we demonstrate that CRB2 knockdown also enhances podocyte contractility in a substrate stiffness-dependent manner. The knockdown effect decreases with increasing substrate stiffness, indicating impaired mechanosensing in CRB2 knockdown cells at low substrate stiffness. While the mechanical activation of CRB2 knockdown cells is associated with increased YAP activity, the enhanced cell contractility is not significantly reduced by the selective YAP inhibitors K-975 and verteporfin, suggesting that multiple pathways may be involved in mechanosignaling downstream of CRB2. Taken together, these studies provide the first evidence that CRB2 deficiency may impair podocyte mechanotransduction via disruption of YAP signaling in podocytes.
In siliconanoscope to study the interplay of genome organization and transcription regulation
Authors: Gopi Soundhararajan , Brandani Giovanni B , Tan Cheng , Jung Jaewoon , Gu Chenyang , Mizutani Azuki , Ochiai Hiroshi , Sugita Yuji , Takada Shoji 
Published: October 2024

ABSTRACTIn eukaryotic genomes, regulated access and communication between cis-regulatory elements (CREs) are necessary for enhancer-mediated transcription of genes. The molecular framework of the chromatin organization underlying such communication remains poorly understood. To better understand it, we develop a multiscale modeling pipeline to build near-atomistic models of the 200 kbNanoggene locus in mouse embryonic stem cells comprising nucleosomes, transcription factors, co-activators, and RNA polymerase II-Mediator complexes. By integrating diverse experimental data, including protein localization, genomic interaction frequencies, cryo-electron microscopy, and single-molecule fluorescence studies, our model offers novel insights into chromatin organization and its role in enhancer-promoter communication. The models equilibrated by high-performance molecular dynamics simulations span a scale of ∼350 nm, revealing an experimentally consistent local and global organization of chromatin and transcriptional machinery. Our models elucidate that the sequence-regulated chromatin accessibility facilitates the recruitment of transcription regulatory proteins exclusively at CREs, guided by the contrasting nucleosome organization compared to other regions. By constructing an experimentally consistent near-atomic model of chromatin in the cellular environment, our approach provides a robust framework for future studies on nuclear compartmentalization, chromatin organization, and transcription regulation.
Efficient Inference, Training, and Fine-tuning of Protein Language Models
Authors: Çelik Muhammed Hasan , Xie Xiaohui 
Published: October 2024

AbstractProtein language models have shown great promise in predicting protein structure, function, and the effects of missense variants on protein fitness. However, their use has been limited by the substantial computational resources required. In this work, we focus on improving the computational efficiency of protein language models (PLMs), specifically the Evolutionary Scale Modeling (ESM) family, to increase the accessibility of PLMs. By implementing optimizations such as FlashAttention and Partition-Attention, a novel technique designed to handle proteins of variable length, we achieved a 16-fold speedup in inference time and reduced memory usage by 3 to 14 times for long proteins. Additionally, 4-bit quantization applied to billion-parameter models led to a 2 to 3 times reduction in memory consumption with minimal performance loss in the missense variant effect prediction task. Training efficiency was also improved, with a 6-fold reduction in runtime achieved through activation checkpointing and the DeepSpeed Zero-Offload strategy. For fine-tuning, we employed parameter-efficient methods, enabling state-of-the-art predictions of protein properties and functions by training only the model head or a small fraction of adapter weights. For instance, we achieved a Spearman’s correlation coefficient of 70% in melting point prediction and an 87% area under the precision-recall curve (AU-PRC) for transcription factor prediction. Our efficient ESM (ESME) implementation significantly lowers the barrier to using these powerful models, making them accessible to academic laboratories with limited computational resources. The ESME implementation is available on PyPI (pypi.org/project/esm-efficient) and GitHub (github.com/uci-cbcl/esm-efficient).
Divergent biosynthesis of monoterpene indole alkaloids from geissoschizine
Authors: Kamileen Mohamed O. , Hong Benke , Gase Klaus , Kunert Maritta , Caputi Lorenzo , Lichman Benjamin R. , O’Connor Sarah E. 
Published: October 2024

AbstractPlants can generate structural diversity by enzymatic rearrangement of a central intermediate. 19E-geisssochizine is one such chemically versatile intermediate that plays a central role in the biosynthesis of monoterpene indole alkaloids such as strychnine, ibogaine and vinblastine. Here we report how 19E-geissoschizine undergoes oxidative transformations to generate four distinct alkaloid scaffolds through the action of three biosynthetic enzymes. Using in vitro enzymatic assays and gene silencing, we demonstrate how these three cytochrome P450 enzymes in the medicinal plantCatharanthus roseustransform 19E-geisssochzine intostrychnos, sarpagan, akuammiline-type, andmavacurane-type alkaloids. We use mutational analysis to show how minimal changes to the active site of these similar enzymes modulate product specificity. This work highlights how substrate reactivity and enzyme mutations work synergistically to generate chemical diversity.
The population structure of invasiveLantana camarais shaped by its mating system
Authors: Praveen P. , Gopal Rajesh , Ramakrishnan Uma 
Published: October 2024

AbstractOver the last century, invasive species have emerged as an important driver of global biodiversity loss. Many invasive species have low genetic diversity in the invaded habitats, owing to the demographic bottleneck during introduction.Lantana camarais one of the hundred most problematic invasive species globally. Despite its ecological importance in many countries, our understanding of the genetic diversity patterns of this plant remains poor. Previous studies hypothesize that invasiveL. camarais a species complex with a hybrid origin, but this remains untested. We investigated the population genetic patterns of this invasive species by sampling 359 plants that represented a spectrum of flower colour variants across 36 locations, spanning most of the biogeographic regions across India. Analyses of the population structure using 19,008 SNPs revealed thatL. camarain India exhibits a strong genetic structure. Interestingly, the structuring pattern does not exhibit a strong correlation with geography. In the structure analysis, individuals with similar flower colours clustered together regardless of their location of origin. The genetic distance between most of the individuals was low, indicating the absence of multiple species. A high inbreeding coefficient and a low proportion of heterozygous sites observed suggested that the strong structure could be due to self-fertilization. Thus we infer thatL. camaraexists as homozygous inbred lines formed by self-fertilization and that these inbred lines could be associated with distinct flower colours. Together, this would explain the correlation between flower colour and genetic structure, and the lack of geographic structure. These results refute the argument thatL. camarais a species complex and emphasize the importance of the mating system in shaping the patterns of diversity in this invasive species. Our findings highlight a hitherto unknown role for mating systems in invasive species, furthering our understanding of evolution in invasive species.
Phylogenetic Study of Long Non-Coding RNANEAT1andMALAT1to Infer Structural-Functional Connection
Authors: Arkhipova Ksenia , Drukker Micha 
Published: October 2024

AbstractNEAT1andMALAT1are the only two lncRNAs that utilise the tRNA-processing machinery for their maturation, coded very close to each other yet differing in function and evolutionary conservation. Here, we identifiedNEAT1andMALAT1orthologs in 545 mammals and studied their conservation patterns to gain functional insights. In the functional basis ofNEAT1Long, we found G-quadruplexes and short sequence motifs that interact with the DSHS family of proteins and TDP-43, as well as gene length and self-complementary regions that further stabilise paraspeckle integrity. We found that transposable elements play a crucial role inNEAT1evolution by contributing structures recognised by DSHS proteins. We identified theNEAT1Shortisoform in allNEAT1orthologs, and our results suggest its distinct functional role. Our findings also support the conservation of the isoform switch mechanism mediated by TDP-43. The function ofMALAT1is likely based on its highly conserved primary sequence, and we demonstrated the gene regions under stronger purifying selection. This is the first large-scale phylogenetic study ofNEAT1– a lncRNAs that lack sequence similarity between orthologs while maintaining functional and syntenic conservation.
Quantitative light element (sodium and potassium) profiling in plant tissues using monochromatic X-ray fluorescence analysis
Authors: Kahlon Parvinderdeep S. , Kokkinopoulou Pinelopi , Alfageme Silvia Bugallo , Leong Cheuk Ka , Chen Zewu , Testerink Christa , van der Ent Antony 
Published: October 2024

ABSTRACTAccurately determining the elemental composition of plant tissues is essential for physiological studies on plant stress, including salinity tolerance. However, high-throughput routine analysis of light elements (range of sodium to calcium) in plant samples is challenging due to the need for complete sample dissolution and expensive inductively coupled plasma-mass-spectrometry (ICP-MS) analysis. Lower costs method (ion chromatography, ion selective electrodes) exists, but also require sample dissolution and lack sensitivity for very small samples (<10 mg). This study reports on a new method for the quantitative analysis of light elements in plant tissues using monochromatic X-ray fluorescence (XRF) instrumentation and innovative sample preparation and mounting. We used this approach to assess elemental uptake, distribution, and accumulation inArabidopsis thalianaandOryza sativaplants subjected to salt stress. The method can be used on samples as small as 1 mg making it suitable for smallArabidopsis thalianaplants. We systematically evaluated different sample preparations methods, repeatability, and measurement times to confirm the robustness of the technique. The results show that the monochromatic XRF method delivers rapid, non-destructive, and extraction-free analysis, strongly correlating with ICP-MS acquired data. As such, the monochromatic XRF method is a reliable and efficient alternative for studying salinity tolerance ideally suited for investigating elemental composition of early plant developmental stages, offering new possibilities for research into early stimuli sensing, perception and nutrient efficiency.
Uncovering pre-sensitizing agents to FLT3 inhibitors in acute myeloid leukemia with ReSisTrace lineage tracing
Authors: Eriksson Johanna , Zheng Shuyu , Bao Jie , Dai Jun , Wang Wenyu , Vähärautio Anna , Tang Jing 
Published: October 2024

AbstractWhile FLT3 inhibitors have significantly improved the treatment of aggressive FLT3-mutated acute myeloid leukemia (AML), the emergence of resistance remains as a major challenge. Here, we applied our recently developed single-cell lineage-tracing method ReSisTrace to identify cells that are pre-resistant or pre-sensitive to FLT3 inhibitors midostaurin and quizartinib in FLT3-ITD-positive AML. By comparing the gene expression profiles of these cells, we unraveled the transcriptional pre-resistance signatures, including G1 to S phase transition 1 (GSPT1) gene. Targeting GSPT1 with the small molecule CC-90009 exhibited strong synergistic effect when combined with FLT3 inhibitors in the FLT3-ITD-mutated MOLM-13 and MV4-11 cell lines and primary AML patient samples. Further, we identified novel compounds that induced transcriptomic changes opposite to the pre-resistance signatures, thereby driving cells to FLT3 inhibitor-sensitive states. Vistusertib (mTOR inhibitor), linsitinib (IGF1R and insulin receptor inhibitor), and meisoindigo (IGF1R and Src family kinase inhibitor), all inhibiting pathways parallel to or downstream of oncogenic FLT3 signaling, were predicted and validated to pre-sensitize the FLT3-ITD-mutated cell lines and primary cells to FLT3 inhibitors. Collectively, these findings demonstrate the validity of our lineage-tracing method in unveiling pre-existing transcriptional features of treatment vulnerability in hematological cancers, and elucidate novel strategies for enhancing FLT3 inhibitor treatment efficacy in FLT3-ITD-positive AML by preventing the emergence of treatment resistance.