bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transport among protocells via tunneling nanotubes
Authors: Schanke Ingrid Jin , Xue Lin , Spustova Karolina , Gözen Irep 
Published: September 2021

AbstractWe employ model protocell networks for evaluation of molecular transport through lipid nanotubes as potential means of communication among primitive cells on the early Earth. Network formation is initiated by deposition of multilamellar lipid reservoirs onto a silicon oxide surface in an aqueous environment. These reservoirs autonomously develop into surface-adhered protocells interconnected via lipid nanotubes, and encapsulate solutes from the ambient buffer in the process. We prepare networks in the presence of DNA and RNA and observe encapsulation of these molecules, and their diffusive transport between the lipid compartments via the interconnecting nanotubes. By means of an analytical model we determine key physical parameters affecting the transport, such as nanotube diameter and compartment size. We conclude that nanotube-mediated transport in self-organized nanotube-vesicle networks could have been a possible pathway of chemical communication between primitive, self-assembled protocells under early earth conditions, circumventing the necessity for crossing the membrane barrier. We suggest this transport within a closed protocell network as a feasible means of RNA and DNA exchange under primitive prebiotic conditions, possibly facilitating early replication.
Multimodal Detection of Dopamine by Sniffer Cells Expressing Genetically Encoded Fluorescence Sensors
Authors: Herenbrink Carmen Klein , Støier Jonatan Fullerton , Reith William Dalseg , Dagra Abeer , Cuadrado Gregorek Miguel Alejandro , Li Yulong , Tian Lin , Gether Ulrik , Herborg Freja 
Published: September 2021

AbstractDopamine serves an important role in supporting both locomotor control and higher brain functions such as motivation and learning. Dopaminergic dysfunction is implicated in an equally multidimensional spectrum of neurological and neuropsychiatric diseases. Extracellular dopamine levels are known to be tightly controlled by presynaptic dopamine transporters (DAT), which is also a main target of psychostimulants. Still, detailed data on dopamine dynamics in space and time is needed to fully understand how dopamine signals are encoded and translated into cellular and behavioral responses, and to uncover the pathological effects of dopamine-related diseases. The recently developed genetically encoded fluorescent dopamine sensors enable unprecedented monitoring of dopamine dynamics and have changed the field of in vivo dopamine recording. However, the potential of these sensors to be used for in vitro and ex vivo assays remains unexplored. Here, we demonstrate a generalizable blueprint for making “sniffer” dopamine cells for multimodal detection of dopamine in vitro and ex vivo. We generated sniffer cell lines with inducible expression of six different dopamine sensors and performed a head-to-head comparison of sensor properties to guide users in sensor selection. In proof-of-principle experiments, we show how the sniffer cells can be applied to measure release of endogenous dopamine from cultured neurons and striatal slices, and for determining total dopamine content in striatal tissue. Furthermore, we use the sniffer cells to quantify DAT-mediated dopamine uptake, and AMPH-induced and constitutive dopamine efflux as a radiotracer free, high-throughput alternative to electrochemical- and radiotracer-based assays. Importantly, the sniffer cells framework can readily be applied to other transmitter systems for which the list of genetically encoded fluorescent sensors is rapidly growing.
Development of infants’ neural speech processing and its relation to later language skills: an MEG study
Authors: Zhao T. Christina , Kuhl Patricia K. 
Published: September 2021

AbstractThe ‘sensitive period’ for phonetic learning (∼6-12 months) is one of the earliest milestones in language acquisition where infants start to become specialized in processing speech sounds in their native language. In the last decade, advancements in neuroimaging technologies for infants are starting to shed light on the underlying neural mechanisms supporting this important learning period. The current study reports on the largest longitudinal dataset to date with the aim to replicate and extend on two important questions: 1) what are the developmental changes during the ‘sensitive period’ for native and nonnative speech processing? 2) how does native and nonnative speech processing in infants predict later language outcomes? Fifty-four infants were recruited at 7 months of age and their neural processing of speech was measured using Magnetoencephalography (MEG). Specifically, the neural sensitivity to a native and a nonnative speech contrast was indexed by the mismatch response (MMR). They repeated the measurement again at 11 months of age and their language development was further tracked from 12 months to 30 months of age using the MacArthur-Bates Communicative Development Inventory (CDI). Using an a prior Region-of-Interest (ROI) approach, we observed significant increases for the Native MMR in the left inferior frontal region (IF) and superior temporal region (ST) from 7 to 11 months, but not for the Nonnative MMR. Complementary whole brain comparison revealed more widespread developmental changes for both contrasts. However, only individual differences in the left IF and ST for the Nonnative MMR at 11 months of age were significant predictors of individual vocabulary growth up to 30 months of age. An exploratory machine-learning based analysis further revealed that whole brain MMR for both Native and Nonnative contrasts can robustly predict later outcomes, but with very different underlying spatial-temporal patterns. The current study extends our current knowledge and suggests that native and nonnative speech processing may follow different developmental trajectories and utilize different mechanisms that are relevant for later language skills.
Developing selective FPR2 agonists can be a potential approach to treat moderate to severe asthma
Authors: Visaga Senthil A. , Kalonia Harikesh , Verma Vinay , Sinha Sandeep , Singh Shashi Kant , Upadhyay Swati , Sahdev Sudhir , Pansari Amita , Kumar Rajesh , Bandgar Mahadev , Karanjule Narayan , Shirumalla Raj Kumar , Morishita Kaoru , Tandon Ruchi 
Published: September 2021

AbstractFormyl peptide receptor (FPR) family members have been reported to play important role in the resolution of inflammation. A few FPR2/FPR1 dual agonists are reported in the public domain for their anti-inflammatory properties. None of these molecules, however, have been successful as a therapy yet. Recent reports bring forward the ambiguous role of FPR1 in inflammation. These include both positive and negative outcomes. We, therefore, aimed to develop selective FPR2 agonists and evaluated their potential in mitigating the non-resolving inflammation in mouse models of moderate to severe asthma. Extensive structure-activity-relationship (SAR) studies were conducted on the imidazole and benzimidazole chemotype series to identify potent and selective FPR2 agonists. A few molecules were shortlisted based on their in vitro profile and absorption, distribution, metabolism and excretion (ADME) properties and were further evaluated in mouse models of asthma. We report herewith identification of 3 RCI compounds with low nanomolar potency for FPR2 agonism and >10,000 fold selectivity over FPR1 in Ca2+ release assay. These molecules also showed potency in other in vitro assays and potent efficacy in three distinct animal models of asthma. Our data suggest that FPR2 agonism can be a potential therapeutic approach to treat asthma. Our findings also propose that FPR1 can be spared to achieve the desired pharmacological activity.
Deletion of serine palmitoyl transferase 2 in hepatocytes impairs ceramide/sphingomyelin balance, prevents obesity and leads to liver damage in mice
Authors: Lallement Justine , Raho Ilyès , Merlen Grégory , Rainteau Dominique , Croyal Mikael , Schiffano Melody , Kassis Nadim , Doignon Isabelle , Soty Maud , Lachkar Floriane , Krempf Michel , Foufelle Fabienne , Amouyal Chloé , Le Stunff Hervé , Magnan Christophe , Tordjmann Thierry , Cruciani-Guglielmacci Céline 
Published: September 2021

AbstractCeramides (Cer) have been shown as lipotoxic inducers, which disturb numerous cell signalling pathways especially insulin signalling pathway leading to metabolic disorders such as type 2 diabetes. In this study, we aimed to determine the role of de novo hepatic Cer synthesis on energy and liver homeostasis in mice. We generated mice lacking serine palmitoyltransferase 2 (Sptlc2), the rate limiting enzyme of Cer de novo synthesis, in hepatocytes.Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic Cer, especially C16:0-Cer and C18:0-Cer associated with an increased neutral sphingomyelinase 2 expression, and a decreased sphingomyelin content in the liver. Sptlc2ΔHep mice were protected against obesity induced by high fat diet. Bile acid (BA) hydrophobicity was drastically decreased in KO mice, and was associated with a defect in lipid absorption. In addition, an important increase of tauro-muricholic acid in BA pool composition was associated with a downregulation of the nuclear BA receptor FXR target genes. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production. Finally, Sptlc2 disruption promoted apoptosis, inflammation and progressive development of hepatic fibrosis worsening with age.Our data suggest a compensatory mechanism to regulate hepatic Cer content from sphingomyelin hydrolysis, with deleterious impact on liver homeostasis. In addition, our results show the implication of hepatic sphingolipid modulation on BA metabolism and hepatic glucose production in an insulinin-dependent manner, which demonstrates the role of Cer in many metabolic functions still under-researched.
Acoustic array biochip combined with allele-specific PCR for multiple cancer mutation analysis in tissue and liquid biopsy
Authors: Naoumi Nikoletta , Michaelidou Kleita , Papadakis George , Simaiaki Agapi E. , Fernández Román , Calero Maria , Arnau Antonio , Tsortos Achilleas , Agelaki Sofia , Gizeli Electra 
Published: September 2021

ABSTRACTRegular screening of cancerous point mutations is of importance to cancer management and treatment selection. Although excellent techniques like next generation sequencing and droplet digital PCR are available, these are still lacking in speed, simplicity and cost-effectiveness. Here a new approach is presented where allele-specific PCR (AS-PCR) is combined with a novel High Fundamental Frequency Quartz Crystal Microbalance (HFF-QCM) array biosensor for the amplification and detection, respectively, of cancer point mutations. For the proof-of-concept, the method was applied to the screening of the BRAF V600E and KRAS G12D mutations in spiked-in and clinical samples. Regarding the BRAF target, an analytical sensitivity of 0.01%, i.e., detection of 1 mutant copy of genomic DNA in an excess of 104 wild type molecules, was demonstrated; moreover, quantitative results during KRAS detection were obtained when an optimized assay was employed with a sensitivity of 0.05%. The assays were validated using tissue and plasma samples obtained from melanoma, colorectal and lung cancer patients. Results are in full agreement with Sanger sequencing and droplet digital PCR, demonstrating efficient detection of BRAF and KRAS mutations in samples having an allele frequency below 1%. The high sensitivity and technology-readiness level of the methodology, together with the ability for multiple sample analysis (24 array biochip), cost-effectiveness and compatibility with routine work-flow, hold promise for the implementation of this AS-PCR/acoustic methodology in clinical oncology as a tool for tissue and liquid biopsy.
3D virtual Histopathology of Cardiac Tissue from Covid-19 Patients based on Phase-Contrast X-ray Tomography
Authors: Reichardt Marius , Jensen Patrick Møller , Dahl Vedrana Andersen , Dahl Anders Bjorholm , Ackermann Maximilian , Shah Harshit , Länger Florian , Werlein Christopher , Kühnel Mark , Jonigk Danny , Salditt Tim 
Published: September 2021

AbstractFor the first time, we have used phase-contrast x-ray tomography to characterize the three-dimensional (3d) structure of cardiac tissue from patients who succumbed to Covid-19. By extending conventional histopatholocigal examination by a third dimension, the delicate pathological changes of the vascular system of severe Covid-19 progressions can be analyzed, fully quantified and compared to other types of viral myocarditis and controls. To this end, cardiac samples with a cross section of 3.5mm were scanned at the synchrotron in a parallel beam configuration. The vascular network was segmented by a deep learning architecture suitable for 3d datasets (V-net), trained by sparse manual annotations. Pathological alterations of vessels, concerning the variation of diameters and the amount of small holes, were observed, indicative of elevated occurrence of intussusceptive angiogenesis, also confirmed by scanning electron microscopy. Further, we implemented a fully automated analysis of the tissue structure in form of shape measures based on the structure tensor. The corresponding distributions show that the histopathology of Covid-19 differs from both influenza and typical coxsackie virus myocarditis.
Androglobin, a chimeric mammalian globin, is required for male fertility
Authors: Keppner Anna , Correia Miguel , Santambrogio Sara , Koay Teng Wei , Maric Darko , Osterhof Carina , Winter Denise V , Clerc Angèle , Stumpe Michael , Chalmel Frédéric , Dewilde Sylvia , Odermatt Alex , Kressler Dieter , Hankeln Thomas , Wenger Roland H. , Hoogewijs David 
Published: September 2021

AbstractSpermatogenesis is a highly specialised process, involving multiple dedicated pathways and regulatory check-points. Defects ultimately lead to male sub-fertility or sterility, and numerous aspects of mammalian sperm formation remain unknown. The predominant expression of the latest globin family member, androglobin (Adgb) in mammalian testis tissue prompted us to assess its physiological function in spermatogenesis. Adgb knockout mice display male infertility, reduced testis weight, impaired maturation of elongating spermatids, abnormal sperm shape and ultrastructural defects in microtubule and mitochondrial organisation. Epididymal sperm from Adgb knockout animals display multiple flagellar malformations including coiled, bifide or shortened flagella, and erratic acrosomal development. Following immunoprecipitation and mass spectrometry, we could identify septin 10 (Sept10) as interactor of Adgb. The Sept10-Adgb interaction was confirmed both in vivo using testis lysates, and in vitro by reciprocal co-immunoprecipitation experiments. Furthermore, absence of Adgb leads to mislocalisation of Sept10 in sperm, indicating defective manchette and sperm annulus formation. Finally, in vitro data suggest that Adgb contributes to Sept10 proteolysis in a calmodulin (CaM)-dependent manner. Collectively, our results provide evidence that Adgb is essential for murine spermatogenesis and further suggest that interdependence between Adgb and Sept10 is required for sperm head shaping via the manchette and proper flagellum formation.
Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice
Authors: Balasubramanian Priya , Schaar Anne E. , Gustafson Grace E. , Smith Alex B. , Howell Porsha R. , Greenman Angela , Baum Scott , Colman Ricki J. , Lamming Dudley W. , Diffee Gary , Anderson Rozalyn M. 
Published: September 2021

AbstractThe loss of skeletal muscle function with age, known as sarcopenia, significantly reduces independence and quality of life and can have significant metabolic consequences. Although exercise is effective in treating sarcopenia it is not always a viable option clinically, and currently there are no pharmacological therapeutic interventions for sarcopenia. Here we show that chronic treatment with pan-adiponectin receptor agonist AdipoRon improved muscle function in male mice by a mechanism linked to skeletal muscle metabolism and tissue remodeling. In aged mice, 6 weeks of AdipoRon treatment improved skeletal muscle functional measures in vivo and ex vivo. Improvements were linked to changes in fiber type, including an enrichment of oxidative fibers, and an increase in mitochondrial activity. In young mice, 6 weeks of AdipoRon treatment improved contractile force and activated the energy sensing kinase AMPK and the mitochondrial regulator PGC-1a (peroxisome proliferator activated receptor gamma coactivator 1 alpha). In cultured cells, the AdipoRon induced stimulation of AMPK and PGC-1a was associated with increased mitochondrial membrane potential, reorganization of mitochondrial architecture, increased respiration, and increased ATP production. Furthermore, the ability of AdipoRon to stimulate AMPK and PGC1a was conserved in nonhuman primate cultured cells. These data show that AdipoRon is an effective agent for the prevention of sarcopenia in mice and indicate that its effects translate to primates, suggesting it may also be a suitable therapeutic for sarcopenia in clinical application.
The Barley HvSTP13GR mutant triggers resistance against biotrophic fungi
Authors: Skoppek Ines Caroline , Punt Wilko , Heinrichs Marleen , Ordon Frank , Wehner Gwendolin , Boch Jens , Streubel Jana 
Published: September 2021

AbstractHigh-yielding and stress resistant crops are essential to ensure future food supply. Barley is an important crop to feed livestock and to produce malt, but the annual yield is threatened by pathogen infections. Pathogens can trigger an altered sugar partitioning in the host plant, that possibly leads to an advantage for the pathogen. Hampering these processes represents a promising strategy to potentially increase resistance. We analyzed the response of the barley monosaccharide transporter HvSTP13 towards biotic stress and its potential use for plant protection. The expression of HvSTP13 increased upon bacterial and fungal PAMP application, suggesting a PAMP-triggered signaling that converged on the transcriptional induction of the gene. Promoter studies indicate a region that is likely targeted by transcription factors downstream of PAMP-triggered immunity pathways. We confirmed that the non-functional HvSTP13GR variant confers resistance against an economically relevant biotrophic rust fungus, in barley. In addition, we established targeted CRISPR/Cas9 cytosine base editing in barley protoplasts to generate alternative HvSTP13 mutants and characterized the sugar transport activity and subcellular localization of the proteins. These mutants represent promising variants for future resistance analysis. Our experimental setup provides basal prerequisites to further decode the role of HvSTP13 in response to biological stress. Moreover, in line with other studies, our experiments indicate that the alteration of sugar partitioning pathways, in a host pathogen interaction, is a promising approach to achieve broad and durable resistance in plants.
Molecular Basis for the Interaction of Catalase with D-Penicillamine : Rationalization of some of its Deleterious Effects
Authors: Padovani Dominique , Galardon Erwan 
Published: September 2021

AbstractD-penicillamine (D-Pen) is a sulfur compound used in the management of rheumatoid arthritis, Wilson’s disease (WD), and alcohol dependence. Many side effects are associated with its use, particularly after long-term treatment. However, the molecular bases for such side effects are poorly understood. Based on the well-known oxidase activity of hemoproteins, and the participation of catalase in cellular H2O2redox signaling, we posit that D-Pen could inactivate catalase, thus disturbing H2O2levels. Herein, we report on the molecular bases that could partly explain the side effects associated with this drug compound, and we demonstrate that it induces the formation of compound II, a temporarily inactive state of the enzyme, through two distinct mechanisms. Initially, D-Pen reacts with native catalase and/or iron metal ions, used to mimic non heme iron overload observed in long-term treated WD patients, to generate thiyl radicals. These partake into a futile redox cycling, thus producing superoxide radical anions O2•-and hydrogen peroxide H2O2. Then, either H2O2unexpectedly reacts with native CAT-Fe(II) to produce compound II, or both aforementioned reactive oxygen species intervene into compound II generation through compound I formation then reduction. These findings support evidence that D-Pen could perturb H2O2redox homeostasis through transient but recurring catalase inactivation, which may in part rationalize some deleterious effects observed with this therapeutic agent, as discussed.Graphical abstract
AHK5 mediates ETR1-initiated multistep phosphorelay in Arabidopsis
Authors: Szmitkowska Agnieszka , Cuyacot Abigail Rubiato , Pekárová Blanka , Žd’árská Markéta , Houser Josef , Komárek Jan , Jaseňáková Zuzana , Jayasree Aswathy , Heunemann Michael , Ubogoeva Elena , Spyroglou Ioannis , Trtilek Martin , Mironova Victoria , Harter Klaus , Zemlyanskaya Elena , Žídek Lukáš , Wimmerová Michaela , Hejátko Jan 
Published: September 2021

SummaryPlants, like other sessile organisms, need to sense many different signals, and in response to them, modify their developmental programs to be able to survive in a highly changing environment. The multistep phosphorelay (MSP) in plants is a good candidate for a response mechanism that integrates multiple signal types both environmental and intrinsic in origin. Recently, ethylene was shown to control MSP activity via the histidine kinase (HK) activity of ETHYLENE RESPONSE 1 (ETR1)1,2, but the underlying molecular mechanism still remains unclear.Here we show that although ETR1 is an active HK, its receiver domain (ETR1RD) is structurally and functionally unable to accept the phosphate from the phosphorylated His in the ETR1 HK domain (ETR1HK) to initiate the phosphorelay to ARABIDOPSIS HISTIDINE-CONTAINING PHOSPHOTRANSMITTERs (AHPs), the next link downstream members in MSP signaling. Instead, ETR1 interacts with another HK ARABIDOPSIS HISTIDINE KINASE 5 (AHK5) and transfers the phosphate from ETR1HK through the receiver domain of AHK5 (AHK5RD), and subsequently to AHP1, AHP2 and AHP3, independently of the HK activity of AHK5. We show that AHK5 is necessary for ethylene-initiated, but not cytokinin-initiated, MSP signaling in planta and that it thus mediates hormonal control of root growth.