bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plk3 Regulates Bacteremia and Supports Sepsis
Authors: Kostyak John C , Sarojini Sharath S , Naik Meghna U , Dai Wei , Michael James V , McKenzie Steven E , Naik Ulhas P 
Published: February 2024

AbstractObjectiveSepsis, which is the body’s response to overwhelming infection, can lead to septic shock, characterized by thrombocytopenia, hypotension, and organ damage. Polo-like kinase 3 (Plk3) is a ubiquitously expressed serine/threonine kinase, but its exact role in immune function is unknown.Approach and ResultsWe usedPlk3−/−and WT mice to evaluate the function of Plk3 in several models of severe sepsis. We found that WT mice die within 48 hours of 100% cecal ligation and puncture (CLP), whilePlk3−/−mice survive. Survival following cecal slurry (CS) injection mirrored that of CLP as recipient WT mice succumbed, while recipientPlk3−/−mice survived. Analysis of bacterial load 24 hours after CLP revealed that WT blood and peritonea were loaded with bacteria, but bacteria were virtually undetectable in the peritonea or blood ofPlk3−/−mice. To determine if bacteria infiltrate the blood ofPlk3−/−mice shortly after infection, we measured bacteria 1 and 3 hours after CS injection. We found a time-dependent increase in bacteria in the blood of WT mice that was not observed inPlk3−/−mice. To determine if the lack of bacteria in the blood ofPlk3−/−mice is due to enhanced clearance, we injectedE. coliIV into WT andPlk3−/−mice. We found 75% mortality for both WT andPlk3−/−mice within 72 hours following IV injection suggesting that survival ofPlk3−/−mice following enteric infection is likely due to reduced bacteremia.ConclusionCollectively our data suggest that Plk3 supports the systemic dissemination of bacteria and subsequent sepsis following enteric infection.
Sucrose-responsive osmoregulation of plant cell size by a long non-coding RNA
Authors: Hajný Jakub , Trávníčková Tereza , Rony R. M. Imtiaz Karim , Sacharowski Sebastian , Krzyszton Michal , Zalabák David , Hardtke Christian S. , Pečinka Aleš , Swiezewski Szymon , van Norman Jaimie M. , Novák Ondřej 
Published: February 2024

AbstractThe shoot of green plants is the primary site of carbon assimilation into sugars, the key source of energy and metabolic building blocks. The systemic transport of sugars is essential for plant growth and morphogenesis. Plants evolved intricate networks of molecular players to effectively orchestrate the subcellular partitioning of sugars. Dynamic distribution of these osmotically active compounds is a handy tool to regulate cell turgor pressure. Pressure-induced mechanical forces play an instructive role in developmental biology across kingdoms. Here, we functionally characterized a long non-coding RNA,CARMA,as a negative regulator of a receptor-like kinase, CANAR. Sugar-responsiveCARMAspecifically fine-tunesCANARexpression in the phloem, the route of sugar transport. By controlling sugar distribution, the CARMA-CANAR module allows cells to flexibly adapt to the external osmolality and adjust the size of vascular cell types during organ growth and development. We identify a nexus of plant vascular tissue formation with cell internal pressure monitoring and reveal a novel functional aspect of long non-coding RNAs in developmental biology.
Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism
Authors: Profaci CP , Harvey SS , Bajc K , Zhang TZ , Zhang AZ , Nemec KM , McKinsey GL , Longworth A , McMullen TP , Arnold TD , Lawson DA , Bennett FC , Davalos D , Daneman R 
Published: February 2024

SummaryMicroglia are resident immune cells of the central nervous system, yet their functions far exceed those related to immunology. From pruning neural synapses during development to preventing excessive neural activity throughout life, microglia are intimately involved in the brain’s most basic processes. Studies have reported a close interaction between microglia and endothelial cells, as well as both helpful and harmful roles for microglia at the blood-brain barrier (BBB) in the context of disease. However, much less work has been done to understand microglia-endothelial cell interactions in the healthy brain. Here, we aim to determine the role of microglia at the healthy BBB. We used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia and analyzed BBB ultrastructure, permeability, and transcriptome. Interestingly, we found that, despite their direct contact with endothelial cells, microglia are not necessary for maintenance of BBB structure, function, or gene expression in the healthy brain. However, we found that PLX5622 treatment alters brain endothelial cholesterol metabolism, and this effect was independent from microglial depletion, suggesting PLX5622 has off-target effects on brain vasculature.
Lipid membrane topographies are regulators for the spatial distribution of liquid protein condensates
Authors: Kang Chae Yeon , Chang Yoohyun , Zieske Katja 
Published: February 2024

ABSTRACTLiquid protein condensates play important roles in orchestrating subcellular organization and in serving as hubs for biochemical reactions. Recent studies have established associations between lipid membranes and proteins capable of forming liquid condensates, and shown that liquid protein condensates can remodel lipid membranes. However, little is known about how the topography of membranes affects liquid condensates. Here, we devised a cell-free system to reconstitute liquid condensates on lipid membranes with microstructured topographies and demonstrated an important role of lipid membranes topography as a biophysical regulator. By employing membrane surfaces designed with microwells, we found that liquid condensates assemble into orderly patterns. Furthermore, we demonstrated that membrane topographies influence the shape of liquid condensates. Finally, we showed that capillary forces, mediated by membrane topographies, led to the directed fusion of liquid condensates. Our results demonstrate that membrane topography is a potent biophysical regulator for the localization and shape of mesoscale liquid protein condensates.
Algorithmic construction of topologically complex biomineral lattices via cellular syncytia
Authors: Vyas Pranav , Brannon Charlotte , Formery Laurent , Lowe Christopher J. , Prakash Manu 
Published: February 2024

AbstractBiomineralization is ubiquitous in both unicellular and multicellular living systems [1, 2] and has remained elusive due to a limited understanding of physicochemical and biomolecular processes [3]. Echinoderms, identified with diverse architectures of calcite-based structures in the dermis[4], present an enigma of how cellular processes control shape and form of individual structures. Specifically, in holothurians (sea cucumbers), multi-cellular clusters construct discrete single-crystal calcite ‘ossicles’ (∼100µm length scale), with diverse morphologies both across species and even within an individual animal [5]. The local rules that might encode these unique morphologies in calcite ossicles in holothurians remain largely unknown. Here we show how transport processes in a cellular syncytium impart a top-down control on ossicle geometry via symmetry breaking, branching, and fusion in finite cellular clusters. As a unique example of cellular masonary, we show how coordination within a small cluster of cells builds calcite structures about an order of magnitude larger than any individual participating cell. We establish live imaging of ossicle growth inApostichopus parvimensisjuveniles revealing how individual crystalline seeds (∼1−2µm) grow inside a multi-cellular syncytial complex with the biomineral completely wrapped within a membrane-bound cytoplasmic sheath. Constructing a topological description of ossicle geometries from 3D micro-CT (computational tomography) data reveals the hidden growth history and conserved patterns across ossicle types. We further demonstrate vesicle transport on the surface of the ossicle, rather than cell motility, regulates material transport to the ossicle tips via a unique cytoskeletal architecture. Finally, using reduced order models of conserved transport on self-closing active branching networks, we highlight the hidden universality in the growth process of distinct ossicles. The system presented here serves as a unique playground merging top-down cellular physiology and classical branching morphogenesis [6] with bottom-up non-equilibrium mineralization [7] processes at the interface of living and non-living matter [8].
Time-restricted feeding leads to sex- and organ-specific responses in the murine digestive system
Authors: Oparija-Rogenmozere Lalita , Di Natale Madeleine R. , Hunne Billie , Koo Ada , Ringuet Mitchell , Fazio Coles Therese E. , Fothergill Linda J. , McQuade Rachel , Furness John B. 
Published: February 2024

AbstractFood intake is one of the main zeitgebers in the digestive system; however, little is known about organ- and sex-specific differences in food-driven regulation. We placed male and female C57Bl/6 mice on time-restricted feeding (TRF), limiting the food intake period to 8 hours. Food was added either at dark (ZT12) or light (ZT0) onset for 14 days. Afterwards, an additional 4-hour delay in the feeding period was introduced for half of the mice, and the TRF regime continued for another 14 days.TRF from ZT12 to ZT20 led to the highest weight gain in females but the lowest in males while improving intestinal transepithelial resistance (TEER) in both sexes. However, it also led to the disappearance of food-anticipatory response in several hepatic genes. Delaying the start of TRF until ZT16 led to an increase in weight gain and a decrease in fasting plasma glucose levels in male mice, as well as to strong entrainment of metabolism-related hepatic and duodenal genes in both sexes.The alignment of food intake with the early lights-on phase (ZT0-ZT8) caused only minor changes in physiological responses. However, it did lead to an overall downregulation of hepatic and an upregulation of duodenal and gastric genes, with additional loss of food-anticipatory gene expression in both sexes. Delaying the start of food intake until ZT4 was highly detrimental, causing an increase in fasting blood glucose levels, a decrease in TEER, and further disruptions in gene expression patterns in the stomach and liver. In contrast, the duodenum was able to restore its food-driven gene expression.These results demonstrate that the adjustment to food intake time in mice is highly sex- and organ-specific. Our chosen TRF regimes were not able to synchronize food-anticipatory responses between the liver and gut. Instead, we observed that organs entrain to food intake at different rates.
Effects of head-only exposure to 900 MHz GSM electromagnetic fields in rats : changes in neuronal activity as revealed by c-Fos imaging without concomitant cognitive impairments
Authors: Bontempi Bruno , Lévêque Philippe , Dubreuil Diane , Jay Thérèse M. , Edeline Jean-Marc 
Published: February 2024

AbstractOver the last decade, animal models have been used to evaluate the physiological and cognitive effects of mobile phone exposures. Here, we used a head-only exposure system in rats to determine whether exposure to 900MHz GSM electromagnetic fields (EMF) induces regional changes in neuronal activation as revealed by c-Fos imaging. In a first study, rats were exposed for 2h to brain average specific absorption rates (BASARs) ranging from 0.5 to 6W/kg. Changes in neuronal activation were found to be dose-dependent with significant increases in c-Fos expression occurring at BASAR of 1W/kg in prelimbic, infralimbic, frontal and cingulate cortices. In a second study, animals were submitted to either a spatial working memory (WM) task in a radial maze or a spatial reference memory (RM) task in an open field arena. Exposures (45min) were conducted before each training session (BASARs of 1 and 3.5W/kg). Control groups included sham-exposed and control cage animals. In both tasks, behavioral performance evolved similarly in the four groups over testing days. However, c-Fos staining was significantly reduced in cortical areas (prelimbic, infralimbic, frontal, cingulate and visual cortices) and in hippocampus of animals engaged in the WM task (BASARs of 1 and 3.5W/kg). In the RM task, EMF exposure-induced decreases were limited to temporal and visual cortices (BASAR of 1W/kg). These results demonstrate that both acute and subchronic exposures to 900MHz EMFs can produce biological effects, but these effects were not sufficient to induce detectable cognitive deficits in the tasks used here.
NR4A3 deficiency ameliorates contact hypersensitivity and exacerbates psoriasis by regulating gene expression in dendritic cells
Authors: Katagiri Mayuka , Ito Naoto , Nagata Kazuki , Nakano Shiori , Minamikawa Natsuki , Yamashita Niya , Takahashi Miki , Kurihara Masami , Nagaoka Masanori , Ando Miki , Ito Tomoka , Yashiro Takuya , Yoshimura Akihiko , Nishiyama Chiharu 
Published: February 2024

AbstractNR4A3 is a transcription factor that belongs to the nuclear receptor superfamily. To reveal the roles of NR4A3 in skin diseases, we constructed contact hypersensitivity (CHS)- and imiquimod-induced psoriasis models inNr4a3-/-mice. In the CHS inducedNr4a3-/-mice, ear swelling was significantly reduced, accompanied by suppressed migration of dendritic cells (DCs), in which CCR7 expression was reduced. In contrast, ear swelling in psoriasis modelNr4a3-/-mice was enhanced. The expression levels of inflammatory cytokines in psoriasis skin lesions and in TLR7-ligand-stimulated DCs were increased by NR4A3 deficiency. Subcutaneous (s.c.) injection of hapten-treatedNr4a3+/+DCs induced ear swelling inNr4a3-/-mice, and s.c. injection of TLR7-ligand-stimulatedNr4a3-/-DCs caused significant ear swelling. Compared withNr4a3+/+DCs,Nr4a3-/-DCs expressed lower levels of CCR7 and IRF4, and higher levels of TLR7, IRF7, IFN-β, and PU.1. Taken together, NR4A3 deficiency ameliorates CHS and exacerbates psoriasis by regulating the expression of CCR7, TLR7, and related transcription factors in DCs.
The Alexander Disease Protein GFAP Drives Mitochondrial Fission
Authors: Xiong Ding , Kong Linghai , Tan Ye Sing , Yuan Fang , Sun Zijun , Li Xueyan , Abella Emily , Messing Albee , Zhang Su-Chun 
Published: February 2024

AbstractMitochondrial plasticity, coordinated by fission and fusion, is crucial to ensure cellular functions. Mitochondrial fission is mediated by the GTPase Drp1 at the constriction site, which is proposed to be driven by the actin-myosin contractile force. However, the mechanism that propels constriction remains unclear, and the potential involvement of additional mechanisms in this process remains an open question. Here, using structured illumination microscopy and electron microscopy, we show that the type-III intermediate filament glial fibrillary acidic protein (GFAP) closely surrounds mitochondria fission sites and associates with accumulated Drp1 molecules. Remarkably, loss of GFAP results in hyperfused mitochondria under physiological condition and even Ca2+-induced mitochondrial fission. Additionally, mutations of GFAP, the cause of Alexander disease, result in an elevated recruitment of Drp1 to GFAP, leading to significantly increased mitochondrial fissions. Taking together, these findings suggest a novel mechanism of mitochondrial division mediated by type-III intermediate filaments.
Purging viral latency by a bifunctional HSV-vectored therapeutic vaccine in chronically SIV-infected macaques
Authors: Wen Ziyu , Li Pingchao , Yuan Yue , Wang Congcong , Li Minchao , Wang Haohang , Shi Minjuan , He Yizi , Cui Mingting , Chen Ling , Sun Caijun 
Published: February 2024

AbstractThe persistence of latent viral reservoirs remains the major obstacle to eradicating human immunodeficiency virus (HIV). We herein found that ICP34.5 can act as an antagonistic factor for the reactivation of HIV latency by herpes simplex virus type I (HSV-1), and thus recombinant HSV-1 with ICP34.5 deletion could more effectively reactivate HIV latency than its wild-type counterpart. Mechanistically, HSV-ΔICP34.5 promoted the phosphorylation of HSF1 by decreasing the recruitment of protein phosphatase 1 (PP1α), thus effectively binding to the HIV LTR to reactivate the latent reservoirs. In addition, HSV-ΔICP34.5 enhanced the phosphorylation of IKKα/β through the degradation of IκBα, leading to p65 accumulation in the nucleus to elicit NF-κB pathway-dependent reactivation of HIV latency. Then, we constructed the recombinant HSV-ΔICP34.5 expressing simian immunodeficiency virus (SIV) env, gag, or the fusion antigen sPD1-SIVgag as a therapeutic vaccine, aiming to achieve a functional cure by simultaneously reactivating viral latency and eliciting antigen-specific immune responses. Results showed that these constructs effectively elicited SIV-specific immune responses, reactivated SIV latency, and delayed viral rebound after the interruption of antiretroviral therapy (ART) in chronically SIV-infected rhesus macaques. Collectively, these findings provide insights into the rational design of HSV-vectored therapeutic strategies for pursuing an HIV functional cure.
Trapped in translocation – Stalling of XPD on a crosslinked DNA substrate
Authors: Kuper Jochen , Hove Tamsanqa , Maidl Sarah , Sauer Florian , Kempf Maximilian , Greiter Elke , Neitz Hermann , Höbartner Claudia , Kisker Caroline 
Published: February 2024

AbstractThe super family 2 (SF2) helicase XPD is a central component of the general transcription factor II H (TFIIH) which is essential for transcription and nucleotide excision DNA repair (NER)1. Within these two processes XPDs helicase function is vital for NER but not for transcription initiation, where XPD only acts as a scaffold for other factors2. We deciphered one of the most enigmatic steps in XPD helicase action: the active separation of dsDNA and its stalling upon approaching an interstrand crosslink, one of the most severe DNA damages in the cell, using cryo EM. Furthermore, the structure clearly shows how dsDNA is separated and reveals a highly unusual involvement of the Arch domain in active dsDNA separation. Combined with mutagenesis and biochemical analyses, we identify distinct functional residues important for helicase activity. Surprisingly, those areas also affect core TFIIH translocase activity, revealing a yet unencountered function of XPD within the TFIIH scaffold. Importantly, our structure provides a basis for XPD damage recognition and further suggests how the NER bubble could be formed, leading to a model for the location of the XPG nuclease relative to the excised damage.
Design and optimization of novel succinate dehydrogenase inhibitors against agricultural fungi based on Transformer model
Authors: Zhang Yuan , Chai Jianqi , Li Ling , Zhao Wenqian , Chen Yuanyuan , Zhang Liangyun , Xu Zhihui , Yang Chunlong , Pian Cong 
Published: February 2024

AbstractSuccinate dehydrogenase inhibitors (SDHIs) are a promising class of fungicides targeting the energy production pathway of pathogenic fungi. However, overuse has led to resistance, necessitating the development of new and effective SDHIs. This study takes the Transformer model to generate a customized virtual library of potential SDHIs. These candidates were then meticulously screened based on expert knowledge and synthetic feasibility, ultimately yielding several pyrazole carboxamide derivatives as the promising leads. Subsequent synthesis, antifungal activity testing, and structural optimization further refined these leads into potent SDHI candidates. This work marks the first application of a generative model to SDHI design, establishing a robust workflow for virtual library generation, screening, activity evaluation, and structure optimization. This provides one way for the rational design of future SDHIs, not only against fungi, but potentially other agricultural pathogens as well.
Spatiotemporal observation reveals metastatic tumor-driven vascular remodeling as a potential route to polyclonal colonization
Authors: Ikeda Yukinori , Oshima Hiroko , Kok Sau Yee , Oshima Masanobu , Matsunaga Yukiko T. 
Published: February 2024

AbstractPolyclonal metastasis, which arises from clusters of circulating tumor cells, promotes metastasis development and has become a major target of metastasis inhibition. Mouse experiments have clearly verified that nonmetastatic and metastatic tumors coexist and form metastatic nests, but the detailed mechanism of extravasation remains unclear. We established a three-dimensional tumor microvessel model to investigate extravasation between nonmetastatic tumors, metastatic tumors, and mosaic tumor organoids in a mixed state by time-lapse imaging and to determine the sequential steps of the extravasation of tumor cells via vascular remodeling. This comparison revealed a new concept of extravascular invasion via vascular remodeling in metastatic carcinoma. Furthermore, the involvement of liver host cells, the hepatic stellate cells, demonstrated an interaction with metastatic cells to facilitate metastatic foci formation. Moreover,Adam28was highly expressed exclusively in metastatic tumor cells, suggesting its involvement in vascular remodeling. These results demonstrate the ability of metastatic tumor cells for extravasation in polyclonal metastasis, which may lead to the development of new therapeutic targets.
Automated high-throughput biological sex identification from archaeological human dental enamel using targeted proteomics
Authors: Koenig Claire , Bortel Patricia , Paterson Ryan S. , Rendl Barbara , Madupe Palesa P. , Troché Gaudry B. , Hermann Nuno Vibe , Martínez de Pinillos Marina , Martinón-Torres María , Mularczyk Sandra , Jørkov Marie Louise Schjellerup , Gerner Christopher , Kanz Fabian , Martinez-Val Ana , Cappellini Enrico , Olsen Jesper V. 
Published: February 2024

AbstractBiological sex is key information for archaeological and forensic studies, which can be determined by proteomics. However, lack of a standardised approach for fast and accurate sex identification currently limits the reach of proteomics applications. Here, we introduce a streamlined mass spectrometry (MS)-based workflow for determination of biological sex using human dental enamel. Our approach builds on a minimally invasive sampling strategy by acid etching, a rapid online liquid chromatography (LC) gradient coupled to high-resolution parallel reaction monitoring assay allowing for a throughput of 200 samples-per-day with high quantitative performance enabling confident identification of both males and females. Additionally, we have developed a streamlined data analysis pipeline and integrated it into an R-Shiny interface for ease-of-use. The method was first developed and optimised using modern teeth and then validated in an independent set of deciduous teeth of known sex. Finally, the assay was successfully applied to archaeological material, enabling the analysis of over 300 individuals. We demonstrate unprecedented performance and scalability, speeding up MS analysis by tenfold compared to conventional proteomics-based sex identification methods. This work paves the way for large-scale archaeological or forensic studies enabling the investigation of entire populations rather than focusing on individual high-profile specimens.