bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deletion of FNDC5/Irisin modifies murine osteocyte function in a sex-specific manner
Authors: Shimonty Anika , Pin Fabrizio , Prideaux Matt , Peng Gang , Huot Joshua R , Kim Hyeonwoo , Rosen Clifford J , Spiegelman Bruce M , Bonewald Lynda F 
Published: November 2023

AbstractIrisin, released from exercised muscle, has been shown to have beneficial effects on numerous tissues but its effects on bone are unclear. We found significant sex and genotype differences in bone from wildtype (WT) mice compared to mice lackingFndc5(KO), with and without calcium deficiency. Despite their bone being indistinguishable from WT females, KO female mice were partially protected from osteocytic osteolysis and osteoclastic bone resorption when allowed to lactate or when placed on a low-calcium diet. Male KO mice have more but weaker bone compared to WT males, and when challenged with a low-calcium diet lost more bone than WT males. To begin to understand responsible molecular mechanisms, osteocyte transcriptomics was performed. Osteocytes from WT females had greater expression of genes associated with osteocytic osteolysis and osteoclastic bone resorption compared to WT males which had greater expression of genes associated with steroid and fatty acid metabolism. Few differences were observed between female KO and WT osteocytes, but with a low calcium diet, the KO females had lower expression of genes responsible for osteocytic osteolysis and osteoclastic resorption than the WT females. Male KO osteocytes had lower expression of genes associated with steroid and fatty acid metabolism, but higher expression of genes associated with bone resorption compared to male WT. In conclusion, irisin plays a critical role in the development of the male but not the female skeleton and protects male but not female bone from calcium deficiency. We propose irisin ensures the survival of offspring by targeting the osteocyte to provide calcium in lactating females, a novel function for this myokine.
A method for evaluating hunger and thirst in monkeys by measuring blood ghrelin and osmolality levels
Authors: Suwa Yuki , Kunimatsu Jun , Kamata Akua , Matsumoto Masayuki , Yamada Hiroshi 
Published: November 2023

AbstractHunger and thirst drive animals’ consumption behavior and regulate their decision-making regarding rewards. We previously assessed the thirst states of monkeys by measuring blood osmolality under controlled water access and related the thirst states to risky decisions for fluid rewards. However, hunger assessments in monkeys have been poorly performed. Moreover, the lack of precise measures for hunger states leads to another issue regarding how hunger and thirst states interact with each other in each individual. Thus, when controlling food access to motivate subject performances, how these two physiological needs are satisfied in captive monkeys remains unclear. Here, we measured blood ghrelin levels and osmolality for hunger and thirst, respectively, in four captive macaques. Using enzyme-linked immunosorbent assay, we found that the levels of blood ghrelin, a widely measured hunger-related peptide hormone in humans, were high after 20 h of no food access (withad libitumwater), which is a typical controlled food access condition. One hour after consuming the regular dry meal, the value decreased in three out of four monkeys to within the range of individual blood ghrelin levels. Additionally, blood osmolality measured from the same blood sample, the standard hematological index of hydration status, increased after consuming regular dry meals with no water access. Thus, ghrelin and osmolality may provide a precise reflection of the physiological states of individual monkeys for hunger and thirst, suggesting that these indices can be used as a tool for monitoring hunger and thirst levels that mediate the animal’s decision-making for consuming rewards.
Using natural language processing to extract plant functional traits from unstructured text
Authors: Domazetoski Viktor , Kreft Holger , Bestova Helena , Wieder Philipp , Koynov Radoslav , Zarei Alireza , Weigelt Patrick 
Published: November 2023

AbstractFunctional plant ecology aims to understand how functional traits govern the distribution of species along environmental gradients, the assembly of communities, and ecosystem functions and services. The rapid rise of functional plant ecology has been fostered by the mobilization and integration of global trait datasets, but significant knowledge gaps remain about the functional traits of the ∼380,000 vascular plant species worldwide. The acquisition of urgently needed information through field campaigns remains challenging, time-consuming and costly. An alternative and so far largely untapped resource for trait information is represented by texts in books, research articles and on the internet which can be mobilized by modern machine learning techniques.Here, we propose a natural language processing (NLP) pipeline that automatically extracts trait information from an unstructured textual description of a species and provides a confidence score. To achieve this, we employ textual classification models for categorical traits and question answering models for numerical traits. We demonstrate the proposed pipeline on five categorical traits (growth form, life cycle, epiphytism, climbing habit and life form), and three numerical traits (plant height, leaf length, and leaf width). We evaluate the performance of our new NLP pipeline by comparing results obtained using different alternative modeling approaches ranging from a simple keyword search to large language models, on two extensive databases, each containing more than 50,000 species descriptions.The final optimized pipeline utilized a transformer architecture to obtain a mean precision of 90.8% (range 81.6-97%) and a mean recall of 88.6% (77.4-97%) on the categorical traits, which is an average increase of 21.4% in precision and 57.4% in recall compared to a standard approach using regular expressions. The question answering model for numerical traits obtained a normalized mean absolute error of 10.3% averaged across all traits.The NLP pipeline we propose has the potential to facilitate the digitalization and extraction of large amounts of plant functional trait information residing in scattered textual descriptions. Additionally, our study adds to an emerging body of NLP applications in an ecological context, opening up new opportunities for further research at the intersection of these fields.
Engineering Modular and Tunable Single Molecule Sensors by Decoupling Sensing from Signal Output
Authors: Grabenhorst Lennart , Pfeiffer Martina , Schinkel Thea , Kümmerlin Mirjam , Maglic Jasmin B. , Brüggenthies Gereon A. , Selbach Florian , Murr Alexander T. , Tinnefeld Philip , Glembockyte Viktorija 
Published: November 2023

AbstractBiosensors play key roles in medical research and diagnostics, but there currently is a lack of sensing platforms that combine easy adaptation to new targets, strategies to tune the response window to relevant analyte concentration ranges and allow for the incorporation of multiple sensing elements to benefit from multivalency. Utilizing a DNA origami nanostructure as a scaffold for arranging the different sensor components, we here propose an approach for the development of modular and tunable single-molecule sensors capable of detecting a variety of biomolecular targets such as nucleic acids, antibodies and restriction enzymes while offering mechanisms to tune the dynamic window, the specificity, and the cooperativity of the sensor.
Novel tri-segmented rhabdoviruses: A data mining expedition unveils the cryptic diversity of cytorhabdoviruses
Authors: Bejerman Nicolás , Dietzgen Ralf Georg , Debat Humberto 
Published: November 2023

AbstractCytorhabdoviruses (genusCytorhabdovirus, familyRhabdoviridae) are plant-infecting viruses with enveloped, bacilliform virions. Established members of the genusCytorhabdovirushave unsegmented single-stranded negative-sense RNA genomes (ca. 10-16 kb) which encode four to ten proteins. Here, by exploring large publicly available metatranscriptomics datasets, we report the identification and genomic characterization of 93 novel viruses with genetic and evolutionary cues of cytorhabdoviruses. Strikingly, five unprecedented cytorhabdoviruses with tri-segmented genomes were also identified. This finding represents the first tri-segmented viruses in the familyRhabdoviridae. Interestingly, the nucleocapsid and polymerase were the only typical rhabdoviral proteins encoded by those tri-segmented viruses, whereas in three of them, a protein similar to the emaravirus (familyFimoviridae) silencing suppressor was found, while the other predicted proteins had no matches in any sequence databases. Genetic distance and evolutionary insights suggest that all these novel viruses may represent members of novel species. Phylogenetic analyses, of both novel and previously classified plant rhabdoviruses, provide compelling support for the division of the genusCytorhabdovirusinto three distinct genera. This proposed reclassification not only enhances our understanding of the evolutionary dynamics within this group of plant rhabdoviruses but also illuminates the remarkable genomic diversity they encompass. This study not only represents a significant expansion of genomics of cytorhabdoviruses that will enable future research on the evolutionary peculiarity of this genus, but also shows the plasticity in the rhabdovirus genome organization with the discovery of tri-segmented members with a unique evolutionary trajectory.
Sphingosine induction of thePseudomonas aeruginosahemolytic phospholipase C/sphingomyelinase, PlcH
Authors: Mackinder Jacob R. , Hinkel Lauren A. , Schutz Kristin , Eckstrom Korin , Fisher Kira , Wargo Matthew J. 
Published: November 2023

AbstractThe hemolytic phospholipase C, PlcH, is an important virulence factor forPseudomonas aeruginosa. PlcH preferentially hydrolyzes sphingomyelin and phosphatidylcholine and this hydrolysis activity can drives tissue damage, inflammation, and interferes with the oxidative burst of immune cells. Among other contributors, transcription ofplcHwas previously shown to be induced by phosphate starvation via PhoB and by the choline metabolite, glycine betaine, via GbdR. Here, we show that sphingosine can induceplcHtranscription and resultant secreted PlcH enzyme activity. This induction is dependent on the sphingosine-sensing transcription regulator SphR. The SphR induction ofplcHoccurs from the promoter for the gene upstream ofplcHthat encodes the neutral ceramidase, CerN, and transcriptional read-through of thecerNtranscription terminator. Evidence for these conclusions come from mutation of the SphR binding site in thecerNpromoter, mutation of thecerNterminator, enhancement ofcerNtermination by adding therrnBterminator, and RT-PCR showing that the intergenic region betweencerNandplcHis made as RNA during sphingosine, but not choline, induction. We also observe that, like glycine betaine induction, sphingosine induction ofplcHis under catabolite repression control, which likely explains why such induction was not seen in other studies using sphingosine in rich media. The addition of sphingosine as a novel inducer for PlcH points to regulation ofplcHtranscription as a site for integration of multiple host-derived signals.
Covalent 14-3-3 Molecular Glues and Heterobifunctional Molecules Against Nuclear Transcription Factors and Regulators
Authors: Shao Qian , Duong Tuong Nghi , Park Inji , Nomura Daniel K. 
Published: November 2023

Abstract14-3-3 proteins have the unique ability to bind and sequester a multitude of diverse phosphorylated signaling proteins and transcription factors. Many previous studies have shown that 14-3-3 interactions with specific phosphorylated substrate proteins can be enhanced through small-molecule natural product or fully synthetic molecular glue interactions. However, enhancing 14-3-3 interactions with both therapeutically intractable transcription factor substrates as well as potential neo-substrates to sequester and inhibit their function has remained elusive. One of the 14-3-3 proteins, 14-3-3σ or SFN, has a cysteine C38 at the substrate binding interface near sites where previous 14-3-3 molecular glues have been found to bind. In this study, we screened a fully synthetic cysteine-reactive covalent ligand library to identify molecular glues that enhance interaction of 14-3-3σ with not only druggable transcription factors such as estrogen receptor (ERα), but also challenging oncogenic transcription factors such as YAP and TAZ that are part of the Hippo transducer pathway. We identified a hit EN171 that covalently targets 14-3-3 to enhance 14-3-3 interactions with ERα, YAP, and TAZ leading to impaired estrogen receptor and Hippo pathway transcriptional activity. We further demonstrate that EN171 could not only be used as a molecular glue to enhance native protein interactions, but also could be used as a covalent 14-3-3 recruiter in heterobifunctional molecules to sequester nuclear neo-substrates such as BRD4 into the cytosol. Overall, our study reveals a covalent ligand that acts as a novel 14-3-3 molecular glue for challenging transcription factors such as YAP and TAZ and also demonstrates that these glues can be potentially utilized in heterobifunctional molecules to sequester nuclear neo-substrates out of the nucleus and into the cytosol to enable targeted protein localization.
ContactBlot: Microfluidic Control and Measurement of Cell-Cell Contact State to Assess Contact-Inhibited ERK Signaling
Authors: Zhang Yizhe , Naguro Isao , Ryuno Hiroki , Herr Amy E. 
Published: November 2023

ABSTRACTExtracellular signal-regulated kinase (ERK) signaling is essential to regulated cell behaviors, including cell proliferation, differentiation, and apoptosis. The influence of cell-cell contacts on ERK signaling is central to epithelial cells, yet few studies have sought to understand the same in cancer cells, particularly with single-cell resolution. To acquire same-cell measurements of both phenotypic (cell-contact state) and targeted-protein profile (ERK phosphorylation), we prepend high-content, whole-cell imaging prior to endpoint cellular-resolution western blot analyses for each of hundreds of individual HeLa cancer cells cultured on that same chip, which we callcontactBlot. By indexing the phosphorylation level of ERK in each cell or cell-cluster to the imaged cell-contact state, we compare ERK signaling between isolated and in-contact cells. We observe attenuated (∼2×) ERK signaling in HeLa cells which are in-contactversusisolated. Attenuation is sustained when the HeLa cells are challenged with hyperosmotic stress. Our findings show the impact of cell-cell contacts on ERK activation with isolated and in-contact cells, while introducing a multi omics tool for control and scrutiny of cell-cell interactions.
Targeting Rab-RILPL Interactions as a Strategy to Downregulate Pathogenic LRRK2 in Parkinson’s Disease
Authors: Alexander Krista K. , Naaldijk Yahaira , Fasiczka Rachel , Brahmia Besma , Chen Tiancheng , Hilfiker Sabine , Kennedy Eileen J. 
Published: November 2023

ABSTRACTFamilial Parkinson’s disease (PD) is frequently linked to multiple disease-causing mutations within Leucine-Rich Repeat Protein Kinase 2 (LRRK2), leading to aberrant kinase activity. Multiple pathogenic effects of enhanced LRRK2 activity have been identified including loss of cilia and centrosomal cohesion defects. When phosphorylated by LRRK2, Rab8a and Rab10 bind to phospho-specific RILPL effector proteins. RILPL-mediated accumulation of pRabs proximal to the mother centriole is critical for initiating deficits in ciliogenesis and centrosome cohesion mediated by LRRK2. We hypothesized that Rab-derived phospho-mimics may serve to block phosphorylated Rab proteins from docking with RILPL in the context of hyperactive LRRK2 mutants. This would serve as an alternative strategy to downregulate pathogenic signaling mediated by LRRK2, rather than targeting LRRK2 kinase activity itself. To test this theory, we designed a series of constrained peptides mimicking phosphorylated Switch II derived from Rab8. These RILPL interacting peptides, termed RIP, were further shown to permeate cells. Further, several peptides were found to bind RILPL2 and restore ciliogenesis and centrosomal cohesion defects in cells expressing PD-associated mutant LRRK2. This research demonstrates the utility of constrained peptides as downstream inhibitors to target pathogenic LRRK2 activity and may provide an alternative approach to target specific pathways activated by LRRK2.
Heritability within groups is uninformative about differences among groups: cases from behavioral, evolutionary, and statistical genetics
Authors: Schraiber Joshua G. , Edge Michael D. 
Published: November 2023

AbstractWithout the ability to control or randomize environments (or genotypes), it is difficult to determine the degree to which observed phenotypic differences between two groups of individuals are due to genetic vs. environmental differences. However, some have suggested that these concerns may be limited to pathological cases, and methods have appeared that seem to give—directly or indirectly—some support to claims that aggregate heritable variation within groups can be related to heritable variation among groups. We consider three families of approaches: the “between-group heritability” sometimes invoked in behavior genetics, the statisticPSTused in empirical work in evolutionary quantitative genetics, and methods based on variation in ancestry in an admixed population, used in anthropological and statistical genetics. We take up these examples to show mathematically that information on within-group genetic and phenotypic information in the aggregate cannot separate among-group differences into genetic and environmental components, and we provide simulation results that support our claims. We discuss these results in terms of the long-running debate on this topic.
Outer layer of Vb neurons in medial entorhinal cortex project to hippocampal dentate gyrus in mice
Authors: Yamamoto Naoki , Yokose Jun , Ramesh Kritika , Kitamura Takashi , Ogawa Sachie K. 
Published: November 2023

AbstractEntorhinal cortical (EC)-hippocampal (HPC) circuits are crucial for learning and memory. Although it was traditionally believed that superficial layers (II/III) of the EC mainly project to the HPC and deep layers (V/VI) receive input from the HPC, recent studies have highlighted the significant projections from layers Va and VI of the EC into the HPC. However, it still remains unknown whether Vb neurons in the EC provide projections to the hippocampus. In this study, using a molecular marker for Vb and retrograde tracers, we identified that the outer layer of Vb in the medial EC (MEC) neurons directly project to both dorsal and ventral hippocampal DG, with a significant preference for the ventral DG. In contrast to the distribution of DG-projecting Vb cells, anterior thalamus-projecting Vb cells are distributed through the outer to the inner layer of Vb. Furthermore, dual tracer injections revealed that DG-projecting Vb cells and anterior thalamus-projecting Vb cells are distinct populations. These results suggest that the roles of MEC Vb neurons are not merely limited to the formation of EC-HPC loop circuits, but rather contribute to multiple neural processes for learning and memory.
Phylogenetic diversity of flowering plants declines throughout the growing season across a subalpine elevational gradient
Authors: Veldhuisen Leah N , Enquist Brian J , Dlugosch Katrina M 
Published: November 2023

AbstractCo-flowering is a potential facilitative mechanism for plants to overcome pollinator declines and phenological mismatches by attracting more pollinators to a multi-species patch. Due to associated competition, facilitation is expected to be more beneficial among more distantly related plants that compete less, and more prevalent in stressful conditions where benefits outweigh potential costs. We test a novel set of predictions that follow from these hypotheses, including that modules of co-flowering species in montane plant communities will be associated with i) increased fitness, ii) phylogenetic overdispersion, and ii) higher elevations. We quantified flowering phenology and fitness of plants across an elevational gradient in the Colorado Rocky Mountains, identified co-flowering modules using a network approach, and analyzed the phylogenetic distribution of co-flowering modules. We found that fitness correlated positively with co-flowering across elevations, but the correlation was strongest at high-elevation sites. Phylogenetic dispersion increased with elevation but declined throughout the growing season. Late-season modules were more underdispersed at all elevations than early-season modules. By combining analyses of phenological timing, network structure, environmental stress, fitness, and phylogenetic patterns, our results reveal that plant communities may lose phylogenetic diversity as conditions become hotter and drier and climate change alters flowering phenology and pollination networks.
Tree-structured topic modelling of single-cell gene expression data uncovers hierarchical relationships between immune cell types
Authors: Ye Patricia E. , Zhang Yichen , Klein Geltink Ramon I. , Park Yongjin P. 
Published: November 2023

AbstractImmune cells undergo a series of differentiation steps following a lineage-tree structure stemming from hematopoietic stem cells. During differentiation of immune cells in both homeostasis and pathological processes, many gene regulatory mechanisms are shared by fully differentiated immune cell sub-types. In order to characterize these features quantitatively, we proposeLaRCH, a tree-structured embedded topic model. In this model, single-cell gene expression profiles are represented by a mixture of topics consisting of latent features that follow an underlying tree structure, mirroring that of cellular differentiation–nested cluster structures. We present findings of our model trained on simulated single-cell RNA sequencing (scRNA-seq) based on cell-sorted bulk RNA-seq data as well as on a scRNA-seq dataset of over 1.2 million cells from healthy individuals and individuals diagnosed with systemic lupus erythematosus (SLE). The cellular topic profiles estimated by our model markedly improve clustering accuracy over traditional latent variable models and illustrate transcriptomic differences between SLE phenotypes, revealing a pivotal role of multiple immune cell types in disease progression and relapse. Ultimately,LaRCHcaptures the hierarchical context between cellular subtypes by simultaneously identifying shared and distinct latent features amongst subsets of heterogeneous samples of cells.