bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct but cooperating brain networks supporting semantic cognition
Authors: Jung JeYoung , Lambon Ralph Matthew A. 
Published: July 2021

AbstractSemantic cognition is a complex brain function involving multiple processes from sensory systems, semantic systems, to domain-general cognitive systems, reflecting its multifaceted nature. However, it remain unclear how these systems cooperate with each other to achieve effective semantic cognition. Here, we investigated the neural networks involved in semantic cognition using independent component analysis (ICA). We used a semantic judgement task and a pattern matching task as a control task with two levels of difficulty to disentangle task-specific networks from domain-general networks and to delineate task-specific involvement of these networks. ICA revealed that semantic processing recruited two task-specific networks (semantic network [SN] and extended semantic network [ESN]) as well as domain general networks including the frontoparietal network (FPN) and default mode network (DMN). Specifically, two distinct semantic networks were differently modulated by task difficulty. The SN was coupled with the extended semantic network and FPN but decoupled with the DMN, whereas the ESN was synchronised with the FPN and DMN. Furthermore, the degree of decoupling between the SN and DMN was associated with semantic performance. Our findings suggest that human higher cognition is achieved by the neural dynamics of brain networks, serving distinct and shared cognitive functions depending on task demands.
Paninvasion severity assessment of a U.S. grape pest to disrupt the global wine market
Authors: Huron Nicholas A. , Behm Jocelyn E. , Helmus Matthew R. 
Published: July 2021

AbstractEconomic impacts from plant pests are often felt at the regional scale, yet some impacts expand to the global scale through the alignment of a pest’s invasion potentials. Such globally invasive species (i.e., paninvasives) are like the human pathogens that cause pandemics. Like pandemics, assessing paninvasion risk for an emerging regional pest is key for stakeholders to take early actions that avoid market disruption. Here, we develop the paninvasion severity assessment framework and use it to assess a rapidly spreading regional U.S. grape pest, the spotted lanternfly planthopper(Lycorma delicatula;SLF), to spread and disrupt the global wine market. We found that SLF invasion potentials are aligned globally because important viticultural regions with suitable environments for SLF establishment also heavily trade with invaded U.S. states. If the U.S. acts as an invasive bridgehead, Italy, France, Spain, and other important wine exporters are likely to experience the next SLF introductions. Risk to the global wine market is high unless stakeholders work to reduce SLF invasion potentials in the U.S. and globally.
Comparison of Neutralizing Antibody Titers Elicited by mRNA and Adenoviral Vector Vaccine against SARS-CoV-2 Variants
Authors: Tada Takuya , Zhou Hao , Samanovic Marie I. , Dcosta Belinda M. , Cornelius Amber , Mulligan Mark J. , Landau Nathaniel R. 
Published: July 2021

AbstractThe increasing prevalence of SARS-CoV-2 variants has raised concerns regarding possible decreases in vaccine efficacy. Here, neutralizing antibody titers elicited by mRNA-based and an adenoviral vector-based vaccine against variant pseudotyped viruses were compared. BNT162b2 and mRNA-1273-elicited antibodies showed modest neutralization resistance against Beta, Delta, Delta plus and Lambda variants whereas Ad26.COV2.S-elicited antibodies from a significant fraction of vaccinated individuals were of low neutralizing titer (IC50 <50). The data underscore the importance of surveillance for breakthrough infections that result in severe COVID-19 and suggest the benefit of a second immunization following Ad26.COV2.S to increase protection against the variants.
Emergence and fragmentation of the alpha-band driven by neuronal network dynamics
Authors: Zonca Lou , Holcman David 
Published: July 2021

AbstractRhythmic neuronal network activity underlies brain oscillations. To investigate how connected neuronal networks contribute to the emergence of the α-band and the regulation of Up and Down states, we study a model based on synaptic short-term depression-facilitation with afterhyperpolarization (AHP). We found that the α-band is generated by the network behavior near the attractor of the Up-state. Coupling inhibitory and excitatory networks by reciprocal connections leads to the emergence of a stable α-band during the Up states, as reflected in the spectrogram. To better characterize the emergence and stability of thalamocortical oscillations containing α and δ rhythms during anesthesia, we model the interaction of two excitatory with one inhibitory networks, showing that this minimal network topology leads to a persistent α-band in the neuronal voltage characterized by dominant Up over Down states. Finally, we show that the emergence of the α-band appears when external inputs are suppressed, while the fragmentation occurs at small synaptic noise or with increasing inhibitory inputs. To conclude, interaction between excitatory neuronal networks with and without AHP seems to be a general principle underlying changes in network oscillations that could apply to other rhythms.Author summaryBrain oscillations recorded from electroencephalograms characterize behaviors such as sleep, wakefulness, brain evoked responses, coma or anesthesia. The underlying rhythms for these oscillations are associated at a neuronal population level to fluctuations of the membrane potential between Up (depolarized) and Down (hyperpolarized) states. During anesthesia with propofol, a dominant alpha-band (8-12Hz) can emerge or disappear, but the underlying mechanisms remain unclear. Using modeling, we report that the alpha-band appears during Up states in neuronal populations driven by short-term synaptic plasticity and noise. Moreover, we show that three connected networks representing the thalamocortical loop reproduce the dynamics of the alpha-band, which emerges following the arrest of excitatory stimulations, but can disappear by increasing inhibitory inputs. To conclude, short-term plasticity in well connected neuronal networks can explain the emergence and fragmentation of the alpha-band.
Small-molecule cocktails induce the differentiation of human adipose-derived mesenchymal stem cells into hepatocyte-like cells
Authors: Yin Kan , Xu Yang , Wu Di , Yang Weiyan , Dong Naijun , Li Ning , Zhao Robert Chunhua 
Published: July 2021

AbstractAt present, liver transplantation and hepatocyte therapy are common methods for the treatment of end-stage liver diseases, but they are restricted due to the shortage of liver donors and the safety and effectiveness of hepatocyte sources. Human adipose-derived mesenchymal stem cells (HAD-MSCs) have been applied to efficiently and stably induce phenotypic and functional liver cells or tissues in vitro due to their advantages such as wide sources and easy access to materials. In this study, the HAD-MSCs liver differentiation induction system was established and optimized based on the “cocktail method” of chemical small molecule compounds. We used HAD-MSCs as seed cells and gradually obtained mature hepatoid cells with normal phenotype and function after induction with small molecule compounds and growth factor system in vitro. The hepatoid cells induced by the two groups showed high similarity in phenotype and functional characteristics of mature hepatocytes. The differentiation system of human adipose mesenchymal stem cells into hepatocytes induced by small-molecule compounds in vitro was successfully constructed. This study will lay a foundation for the optimization of liver differentiation strategies and provide a reliable source of functional liver cells for clinical studies of liver diseases.
Structural model of PORCN illuminates disease-associated variants and drug binding sites
Authors: Yu Jia , Liao Pei Ju , Xu Weijun , Jones Julie R. , Everman David B. , Flanagan-Steet Heather , Keller Thomas H. , Virshup David M. 
Published: July 2021

ABSTRACTWnt signaling is essential for normal development and is a therapeutic target in cancer. The enzyme PORCN, or porcupine, is a membrane-bound O-acyltransferase (MBOAT) that is required for the post-translational modification of all Wnts, adding an essential mono-unsaturated palmitoleic acid to a serine on the tip of Wnt hairpin 2. Inherited mutations in PORCN cause focal dermal hypoplasia, and therapeutic inhibition of PORCN slows the growth of Wnt-dependent cancers. Here, based on homology to mammalian MBOAT proteins we develop and validate a molecular structural model of PORCN. The model accommodates palmitoleoyl-CoA and Wnt hairpin 2 in two tunnels in the conserved catalytic core, shedding light on the catalytic mechanism. The model predicts how previously uncharacterized human variants of uncertain significance can alter PORCN function. Drugs including ETC-159, IWP-L6 and LGK-974 dock in the PORCN catalytic site, providing insights into PORCN pharmacologic inhibition. This structural model provides mechanistic insights into PORCN substrate recognition and catalysis as well as the inhibition of its enzymatic activity and can facilitate the development of improved inhibitors and the understanding of disease relevant PORCN mutants.
A novel nanoluciferase transgenic reporter to measure proteinuria in zebrafish
Authors: Naylor Richard W. , Lemarie Emmanuel , Jackson-Crawford Anthony , Bernard Davenport J. , Mironov Aleksandr , Lowe Martin , Lennon Rachel 
Published: July 2021

AbstractThe zebrafish is an important animal system for modelling human diseases. This includes kidney dysfunction as the embryonic kidney (pronephros) shares considerable molecular and morphological homology with the human nephron. Zebrafish also have a high fecundity, with females capable of laying 200-300 eggs per week, thereby facilitating chemical and mutation screening. A key clinical indicator of kidney disease is proteinuria, but a high-throughput readout of proteinuria in the zebrafish is lacking. Coupling the advantages of the zebrafish system with a tool to measure proteinuria will advance the scope for testing the efficacy of drugs to treat kidney diseases. Here, we generated a stable transgenic zebrafish line using the l-fabp10 liver-specific promoter to over-express a nanoluciferase molecule fused with the D3 domain of Receptor-Associated-Protein (RAP) to create NL-D3. In the healthy state, NL-D3 is excreted, but when embryos were treated with chemicals that affected either proximal tubular reabsorption (cisplatin, gentamicin) or glomerular filtration (angiotensin II, Hanks Balanced Salt Solution, Bovine Serum Albumin), NL-D3 presence in the urine increased. Similarly, depletion of several gene products associated with kidney disease (nphs1, nphs2, lrp2a, ocrl, col4a3, col4a4, and col4a5) also induced NL-D3 proteinuria. Furthermore, we found that treating col4a4 depleted zebrafish larvae (a model of Alport syndrome) with captopril reduced proteinuria. Our findings confirm the use of the NL-D3 transgenic zebrafish as a robust and quantifiable proteinuria reporter. Given the feasibility of high-throughput assays in zebrafish, this novel reporter will permit screening for drugs that ameliorate proteinuria and thereby prioritise candidates for further translational studies.Significance StatementThe zebrafish has become an important system for modelling kidney disease. However, proteinuria, an important clinical indicator of kidney dysfunction, is not easily detected in zebrafish. Here, we describe a transgenic line that uses a nanoluciferase reporter to enable detection of proteinuria in multiple models of glomerular and proximal tubular kidney disease in the zebrafish. In this system proteinuria can be accurately measured in a high-throughput manner and will enable the screening of drugs that affect glomerular filtration or protein re-uptake in the proximal tubule.
Differences between intrinsic and acquired nucleoside analogue resistance in acute myeloid leukaemia cells
Authors: Rothenburger Tamara , Thomas Dominique , Schreiber Yannick , Wratil Paul R. , Pflantz Tamara , Knecht Kirsten , Digianantonio Katie , Temple Joshua , Schneider Constanze , Baldauf Hanna-Mari , McLaughlin Katie-May , Rothweiler Florian , Bilen Berna , Farmand Samira , Bojkova Denisa , Costa Rui , Ferreirós Nerea , Geisslinger Gerd , Oellerich Thomas , Xiong Yong , Keppler Oliver T. , Wass Mark N. , Michaelis Martin , Cinatl Jindrich 
Published: July 2021

SummaryBackgroundSAMHD1 mediates resistance to anti-cancer nucleoside analogues, including cytarabine, decitabine, and nelarabine that are commonly used for the treatment of leukaemia, through cleavage of their triphosphorylated forms. Hence, SAMHD1 inhibitors are promising candidates for the sensitisation of leukaemia cells to nucleoside analogue-based therapy. Here, we investigated the effects of the cytosine analogue CNDAC, which has been proposed to be a SAMHD1 substrate, in the context of SAMHD1.MethodsCNDAC was tested in 13 acute myeloid leukaemia (AML cell lines), in 26 acute lymphoblastic leukaemia cell lines, ten AML sublines adapted to various antileukaemic drugs, 24 single cell-derived clonal AML sublines, and primary leukaemic blasts from 24 AML patients. Moreover, 24 CNDAC-resistant sublines of the AML cell lines HL-60 and PL-21 were established. The SAMHD1 gene was disrupted using CRISPR/Cas9 and SAMHD1 depleted using RNAi, and the viral Vpx protein. Forced DCK expression was achieved by lentiviral transduction. SAMHD1 promoter methylation was determined by PCR after treatment of genomic DNA with the methylation-sensitive HpaII endonuclease. Nucleoside (analogue) triphosphate levels were determined by LC-MS/MS. CNDAC interaction with SAMHD1 was analysed by an enzymatic assay and by crystallisation.ResultsAlthough the cytosine analogue CNDAC was anticipated to inhibit SAMHD1, SAMHD1 mediated intrinsic CNDAC resistance in leukaemia cells. Accordingly, SAMHD1 depletion increased CNDAC triphosphate (CNDAC-TP) levels and CNDAC toxicity. Enzymatic assays and crystallisation studies confirmed CNDAC-TP to be a SAMHD1 substrate. In 24 CNDAC-adapted acute myeloid leukaemia (AML) sublines, resistance was driven by DCK (catalyses initial nucleoside phosphorylation) loss. CNDAC-adapted sublines displayed cross-resistance only to other DCK substrates (e.g. cytarabine, decitabine). Cell lines adapted to drugs not affected by DCK or SAMHD1 remained CNDAC sensitive. In cytarabine-adapted AML cells, increased SAMHD1 and reduced DCK levels contributed to cytarabine and CNDAC resistance.ConclusionIntrinsic and acquired resistance to CNDAC and related nucleoside analogues are driven by different mechanisms. The lack of cross-resistance between SAMHD1/ DCK substrates and non-substrates provides scope for next-line therapies after treatment failure.
Ultra-lightweight living structural material for enhanced stiffness and environmental sensing
Authors: Park Heechul , Schwartzman Alan F. , Tang Tzu-Chieh , Wang Lei , Lu Timothy K. 
Published: July 2021

AbstractNatural materials such as bone, wood, and bamboo can inspire the fabrication of stiff, lightweight structural materials. Biofilms are one of the most dominant forms of life in nature. However, little is known about their physical properties as a structural material. Here we report an Escherichia coli biofilm having a Young’s modulus close to 10 GPa with ultra-low density, indicating a high-performance structural material. The mechanical and structural characterization of the biofilm and its components illuminates its adaptable bottom-up design, consisting of lightweight microscale cells covered by a dense network of amyloid nanofibrils on the surface. We engineered E. coli such that 1) carbon nanotubes assembled on the biofilm, enhancing its stiffness to over 30 GPa, or that 2) the biofilm sensitively detected heavy metal as an example of an environmental toxin. These demonstrations offer new opportunities for developing responsive living structural materials to serve many real-world applications.
Profiling of human neural crest chemoattractant activity as replacement of fetal bovine serum for in vitro chemotaxis assays
Authors: Dolde Xenia , Karreman Christiaan , Wiechers Marianne , Schildknecht Stefan , Leist Marcel 
Published: July 2021

AbstractFetal bovine serum (FBS) is the only known stimulus for migration of human neural crest cells (NCCs). Non-animal chemoattractants are desirable for the optimization of chemotaxis assays to be incorporated in a test battery for reproductive and developmental toxicity. We confirmed here in an optimized transwell assay that FBS triggers directed migration along a concentration gradient. The responsible factor was found to be a protein in the 30-100 kDa size range. In a targeted approach, we tested a large panel of serum constituents known to be chemotactic for NCCs in animal models (e.g. VEGF, PDGF, FGF, SDF-1/CXCL12, ephrins, endothelin, Wnt, BMPs). None of the corresponding human proteins showed any effect in our chemotaxis assays based on human NCCs. We then examined, whether human cells would produce any factor able to trigger NCC migration in a broad screening approach. We found that HepG2 hepatoma cells produced chemotaxis-triggering activity (CTA). Using chromatographic methods and by employing the NCC chemotaxis test as bioassay, the responsible protein was enriched by up to 5000-fold. We also explored human serum and platelets as direct source, independent of any cell culture manipulations. A CTA was enriched from platelet lysates several thousand-fold. Its temperature and protease- sensitivity suggested also a protein component. The capacity of this factor to trigger chemotaxis was confirmed by single-cell video-tracking analysis of migrating NCCs. The human CTA characterized here may be employed in the future for the setup of assays testing for the disturbance of directed NCC migration by toxicants.
Megasatellite formation and evolution in vertebrates
Authors: Descorps-Declère Stéphane , Richard Guy-Franck 
Published: July 2021

AbstractSince the formation of the first proto-eukaryotes, more than 1.5 billion years ago, eukaryotic gene repertoire as well as genome complexity has significantly increased. Among genetic elements that are responsible for this increase in genome coding capacity and plasticity are tandem repeats such as microsatellites, minisatellites and their bigger brothers, megasatellites. Although microsatellites have been thoroughly studied in many organisms for the last 20 years, little is known about the distribution and evolution of mini- and megasatellites. Here, we describe the first genome-wide analysis of megasatellites in 58 vertebrate genomes, belonging to 12 monophyletic groups. We show that two bursts of megasatellite formation occurred, one after the radiation between agnatha et gnathostomata fishes and the second one later, in therian mammals. Megasatellites are frequently encoded in genes involved in transcription regulation (zinc-finger proteins) and intracellular trafficking, but also in cell membrane metabolism, reminiscent of what was observed in fungi genomes. The presence of many introns within young megasatellites suggests a model in which an exon-intron DNA segment is first duplicated and amplified before the accumulation of mutations in intronic parts partially erase the tandem repeat in such a way that it becomes detectable only in exonic regions. In addition, evidence for the genetic transfer of megasatellites between unrelated genes suggests that megasatellite formation and evolution is a very dynamic and still ongoing process in vertebrate genomes.
Plasticity of the dopaminergic phenotype and of locomotion in larval zebrafish induced by changes in brain excitability during the embryonic period
Authors: Bataille Sandrine , Jalaber Hadrien , Colin Ingrid , Remy Damien , Affaticati Pierre , Froc Cynthia , Vernier Philippe , Demarque Michaël 
Published: July 2021

AbstractDuring the embryonic period, neuronal communication starts before the establishment of the synapses with alternative forms of neuronal excitability, called here Embryonic Neuronal Excitability (ENE). ENE has been shown to modulate the unfolding of development transcriptional programs but the global consequences for the developing organisms are not all understood. Here we monitored calcium transients in zebrafish embryos as a proxy for ENE to assess the efficacy of transient pharmacological treatments to either increase or decrease ENE. Increasing or decreasing ENE for 24 hours at 2 days post fertilization (dpf), at the end of the embryonic period, promoted respectively an increase or a decrease in the numbers of dopamine (DA) neurons in the telencephalon and in the olfactory bulb of zebrafish larvæ at 6 dpf. This plasticity of dopaminergic specification occurs within a stable population of vMAT2-positive cells, hence identifying an unanticipated biological marker for this reserve pool of of DA neurons that can be recruited by increasing ENE.Modulating ENE also affected larval locomotion several days after the end of the treatments. In particular, the increase of ENE from 2 to 3 dpf promoted hyperlocomotion of larvæ at 6 dpf, reminiscent of endophenotypes reported for Attention Deficit with Hyperactivity Disorders and schizophrenia in zebrafish. These results provide a convenient framework to identify environmental factors that could disturb ENE as well as to study the molecular mechanisms linking ENE to neurotransmitter specification, with relevance to the pathogenesis of neurodevelopmental disorders.Significance Statement- Spontaneous calcium transients, used as a proxy for Embryonic Neuronal Excitability (ENE), are detected in the forebrain of embryonic zebrafish.- Short-term pharmacological treatments by bath application could increase or decrease ENE.- The post-mitotic differentiation of the dopaminergic phenotype is modulated by ENE in the zebrafish forebrain.- The plasticity of the dopaminergic specification occurs within a reserve pool of vMAT2-positive cells.- Transient increase of ENE at the end of the embryonic period induces hyperlocomotion, a phenotype associated with ADHD and schizophrenia in this model.- Our results open clinically relevant perspectives to study the pathogenesis of neurodevelopmental disorders in zebrafish.