bluuebunny/crossref_metadata_2025_split huggingface dataset:
Self-supervised neural network improves tri-exponential intravoxel incoherent motion model fitting in non-alcoholic fatty liver disease
Authors: Troelstra Marian A. , van Dijk Anne-Marieke , Witjes Julia J. , Mak Anne Linde , Zwirs Diona , Runge Jurgen H. , Verheij Joanne , Beuers Ulrich H. , Nieuwdorp Max , Holleboom Adriaan G. , Nederveen Aart J. , Gurney-Champion Oliver J. 
Published: April 2022

AbstractNeural network generated intravoxel incoherent motion (IVIM) parameter maps are visually more detailed, less noisy and have a higher test-retest repeatability than conventional least-squares (LSQ) generated images. Recent literature suggests that tri-exponential models may fit liver IVIM data more accurately than conventional bi-exponential models, warranting investigation into the use of a neural network (NN) to estimate tri-exponential IVIM parameters. Here, we developed a tri-exponential IVIM unsupervised physics-informed deep neural network (IVIM3-NET), assessed its performance in non-alcoholic fatty liver disease (NAFLD) and compared outcomes with bi-exponential LSQ and NN fits and tri-exponential LSQ fits. Scanning was performed using a 3.0T free-breathing multi-slice diffusion-weighted single-shot echo-planar imaging sequence with 18 b-values. Images were analysed for visual quality, comparing the bi- and tri-exponential IVIM models for LSQ fits and NN fits using parameter-map signal-to-noise ratios (SNR) and adjusted R2. IVIM parameters were compared to histological fibrosis, disease activity and steatosis grades. Parameter map quality improved with bi- and tri-exponential NN approaches, with average parameter-map SNR increasing from 3.38 to 5.59 and 2.45 to 4.01 for bi- and tri-exponential LSQ and NN models respectively. In 33 out of 36 patients, the tri-exponential model exhibited higher adjusted R2 values than the bi-exponential model. Correlating IVIM data to liver histology showed that the bi- and tri-exponential NN outperformed both LSQ models for the majority of IVIM parameters (10 out of 15 significant correlations). Overall, our results support the use of a tri-exponential IVIM model in NAFLD. We show that the IVIM3-NET can be used to improve image quality compared to a tri-exponential LSQ fit and provides promising correlations with histopathology.
Overactive mitochondrial DNA replisome causes neonatal heart failure via ferroptosis
Authors: Landoni Juan C. , Laalo Tuomas , Goffart Steffi , Kivelä Riikka , Skube Karlo , Nieminen Anni I. , Wickström Sara A. , Stewart James , Suomalainen Anu 
Published: April 2022

SummaryIncreasing mitochondrial DNA (mtDNA) replication and amount have been proposed as therapeutic approaches for mitochondrial dysfunction, but also as a mechanism of premature aging. We addressed this fascinating paradox by enhancing mtDNA replication via two mechanisms: increasing both mtDNA replication licensing and processivity. We crossed mice overexpressing Twinkle helicase (boosting mtDNA replication initiation) with mtDNA mutator mice (exonuclease-deficient mtDNA replicase, increasing mtDNA mutagenesis and replication processivity). The former model is asymptomatic by two years of age, whereas the latter manifests with progeroid symptoms at six months. Surprisingly, the double transgenics demonstrate postnatally halted growth and devastating cardiomyopathy, fatal within weeks. The mice show high mtDNA replication preventing cardiac maturation and the postnatal shift to oxidative metabolism, causing ferroptotic cardiomyocyte death. Our findings emphasize the critical importance of mtDNA replisome regulation for perinatal cardiac maturation. Furthermore, the data implicate ferroptosis as a cell death mechanism for neonatal mitochondrial cardiomyopathies.
Colouring coral larvae for tracking dispersal
Authors: Doropoulos Christopher , Roff George 
Published: April 2022

ABSTRACTEcologists have long sought to understand larval dispersal characteristics of benthic marine invertebrates. Direct quantification of coral larvae dispersal has proven challenging, in part due to their complex life-history, minute size, and widespread dispersal at the scale of kilometres. Instead, indirect methods such as particle modelling, chemical signatures, and genetic correlation are often used in dispersal studies.Here, we develop a direct method of quantifying larval dispersal by applying vital stains to coral larvae, allowing differentiation and direct tracking of millions of larvae from the pelagic dispersal stage through to the sedentary stages of attachment and metamorphosis on coral reefs.Neutral red and Nile blue stains were extremely effective at staining coral larvae, while alizarin red and calcein blue showed no visible results. Differences in toxicity to vital stains was noted among species, withAcroporaspp. exhibiting decreased larval survival and settlement, while Merulinidae spp. were unaffected. By experimenting with different incubation times and concentrations, our results indicate that neutral red can be effectively applied for short periods (<20 minutes) at low concentrations (1-100 mg l-1), whereas Nile blue requires longer stain times (>60 minutes) at higher concentrations (100-1000 mg l-1).The strong colour of both neutral red and Nile blue stains was retained by newly settled larvae in lab settings upwards of five days following settlement, providing a direct method of differentiating between newly settled larvae on reefs. Field-validation of Nile blue applied to coral larvae from wild-captured coral slicks demonstrates the efficacy of staining across a diverse range of coral taxa.Vital staining provides a simple, rapid (<60 mins), and low cost (<AUD$0.00001 per larva) method of colouring coral larvae that allows for direct tracking of dispersal and recruitment in studies of reef connectivity and restoration.
Effect of LSD and music on the time-varying brain dynamics
Authors: Adamska Iga , Finc Karolina 
Published: April 2022

AbstractRationalePsychedelics are getting closer to being widely used in clinical treatment. Music is known as a key element of psychedelic-assisted therapy due to its psychological effects, specifically on the emotion, meaning-making and sensory processing. However, there is still a lack of understanding in how psychedelics influence brain activity in experimental settings involving music listening.ObjectivesThe main goal of our research is to investigate the effect of music, as a part of “setting”, on the brain states dynamics after lysergic acid diethylamide (LSD) intake.MethodsWe used an open dataset, where a group of 15 participants underwent two functional MRI scanning sessions under LSD and placebo influence. Every scanning session contained three runs: two resting-state runs separated by one run with music listening. We applied K-Means clustering to identify the repetitive patterns of brain activity, so-calledbrain states. For further analysis, we calculated states’ dwell time, fractional occupancy and transition probability.ResultsThe interaction effect of music and psychedelics led to change in the time-varying brain activity of the task-positive state. LSD, regardless of the music, affected the dynamics of the state of combined activity of DMN, SOM and VIS networks. Crucially, we observed that the music itself could potentially have a long-term influence on the resting-state, in particular on states involving task-positive networks.ConclusionsThis study indicates that music, as a crucial element of “setting”, can potentially have an influence on the subject’s resting-state during psychedelic experience. Further studies should replicate these results on a larger sample size.
A Self-Purifying Microfluidic System for Identifying Drugs Acting Against Adult Schistosomes
Authors: Girod Vincent , Ghoris Marie-José , Caby Stéphanie , Melnyk Oleg , Dissous Colette , Senez Vincent , Vicogne Jérôme 
Published: April 2022

AbstractThe discovery of novel antihelminthic molecules to combat the development and spread of schistosomiasis, a disease caused by several Schistosoma flatworm species, mobilizes significant research efforts worldwide. In the absence of reliable and practical biochemical assays for measuring the viability of adult worms, the antischistosomicidal activity of molecules is usually evaluated by a detailed microscopic observation of worm mobility and/or integrity upon drug exposure. These assays have the disadvantage of being inacurate, subjective, biased by the limited in vitro worm viability and difficult to integrate at high density. We describe here a self-purifiying microfluidic system enabling the selection of healthy adult worms and the identification of molecules acting on the parasite. The worms are assayed in a dynamic environment that eliminates unhealthy worms that cannot attach firmly to the chip walls prior to being exposed to the drug. The detachment of the worms is also used as second step readout for identifying active compounds. We have validated this new fluidic screening approach using the two major antihelmintic drugs, Praziquantel and Artemisinin. The reported dynamic system is simple to produce and to parallelize. Importantly, it enables a quick, sensitive and reliable detection of antischistosomal compounds in no more than one day. This system can potentially be modified in the future to better mimic the natural habitat of the parasite.
Cognitive dysfunction and anxiety resulting from synaptic downscaling, hippocampal atrophy and ventricular enlargement with intracerebroventricular streptozotocin injection in male Wistar rats
Authors: Roy Avishek , Sharma Sakshi , Nag Tapas Chandra , Katyal Jatinder , Gupta Yogendra Kumar , Jain Suman 
Published: April 2022

AbstractInsulin-resistant brain state is proposed to be the early sign of Alzheimer’s disease(AD), which can be studied in intracerebroventricular streptozotocin (ICV-STZ) rodent model. ICV-STZ is reported to induce sporadic AD with the majority of the disease hallmarks as phenotype. On the other hand, Available experimental evidence has used varying doses of STZ (<1 to 3mg/kg) and studied its effect for different study durations, ranging from 14-270 days. Though these studies suggest 3mg/kg of ICV-STZ to be the optimum dose for progressive pathogenesis, the reason for such is elusive.Here we sought to investigate the mechanism of action of 3mg/kg ICV-STZ on cognitive and non-cognitive aspects at a follow-up interval of two weeks for two months. On 60th day, we examined layer thickness, cell density, ventricular volume, spine density, protein expression related to brain metabolism and mitochondrial function by histological examination. Findings suggest progressive loss of spatial, episodic, avoidance memory with increase in anxiety in a span of two month. Furthermore, hippocampal neurodegeneration, ventricular enlargement, diffused amyloid plaque deposition, loss of spine in dentate gyrus and imbalance in energy homeostasis was found on 60th day post injection. Interestingly, AD rats showed a uniform fraction of time spent in four quadrants of water maze with change in strategy when they were exposed to height. Our findings reveal that ICV-STZ injection at a dose of 3mg/kg can cause cognitive and neuropsychiatric abnormalities due to structural loss both at neuronal as well as synaptic level, which is tightly associated with change in neuronal metabolism.
The genetic architectures of vine and skin maturity in tetraploid potato
Authors: Caraza-Harter Maria V. , Endelman Jeffrey B. 
Published: April 2022

ABSTRACTPotato vine and skin maturity, which refer to foliar senescence and adherence of the tuber periderm, respectively, are both important to production and therefore breeding. Our objective was to investigate the genetic architectures of these traits in a genome-wide association panel of 586 genotypes, and through joint linkage mapping in a half-diallel subset (N = 397). Skin maturity was measured by image analysis after mechanized harvest 120 days after planting. To correct for the influence of vine maturity on skin maturity under these conditions, the former was used as a covariate in the analysis. The genomic heritability based on a 10K SNP array was 0.33 for skin maturity vs. 0.46 for vine maturity. Only minor QTL were detected for skin maturity, the largest being on chromosome 9 and explaining 8% of the variation. As in many previous studies, S. tuberosum Cycling DOF Factor 1 (CDF1) had a large influence on vine maturity, explaining 33% of the variation in the panel as a bi-allelic SNP and 44% in the half-diallel as a multi-allelic QTL. From the estimated effects of the parental haplotypes in the half-diallel and prior knowledge of the allelic series for CDF1, the CDF1 allele for each haplotype was predicted and ultimately confirmed through whole-genome sequencing. The ability to connect statistical alleles from QTL models with biological alleles based on DNA sequencing represents a new milestone in genomics-assisted breeding for tetraploid species.
All-optical visualization of specific molecules in the ultrastructural context of brain tissue
Authors: M’Saad Ons , Kasula Ravikiran , Kondratiuk Ilona , Kidd Phylicia , Falahati Hanieh , Gentile Juliana E. , Niescier Robert F. , Watters Katherine , Sterner Robert C. , Lee Seong , Liu Xinran , De Camilli Pietro , Rothman James E. , Koleske Anthony J. , Biederer Thomas , Bewersdorf Joerg 
Published: April 2022

SummaryUnderstanding the molecular anatomy and neural connectivity of the brain requires imaging technologies that can map the 3D nanoscale distribution of specific proteins in the context of brain ultrastructure. Light and electron microscopy (EM) enable visualization of either specific labels or anatomical ultrastructure, but combining molecular specificity with anatomical context is challenging. Here, we present pan-Expansion Microscopy of tissue (pan-ExM-t), an all-optical mouse brain imaging method that combines ∼24-fold linear expansion of biological samples with fluorescent pan-staining of protein densities (providing EM-like ultrastructural context), and immunolabeling of protein targets (for molecular imaging). We demonstrate the versatility of this approach by imaging the established synaptic markers Homer1, Bassoon, PSD-95, Synaptophysin, the astrocytic protein GFAP, myelin basic protein (MBP), and anti-GFP antibodies in dissociated neuron cultures and mouse brain tissue sections. pan-ExM-t reveals these markers in the context of ultrastructural features such as pre and postsynaptic densities, 3D nanoarchitecture of neuropil, and the fine structures of cellular organelles. pan-ExM-t is adoptable in any neurobiological laboratory with access to a confocal microscope and has therefore broad applicability in the research community.Highlightspan-ExM-t visualizes proteins in the context of synaptic ultrastructureLipid labeling in pan-ExM-t reveals organellar and cellular membranesAll-optical, easily accessible alternative to correlative light/electron microscopyHigh potential for high throughput connectomics studies
Breast cancer stem cell-derived tumors escape from γδ T cell immunosurveillance in vivo by modulating γδ T cell ligands
Authors: Raute Katrin , Strietz Juliane , Andrieux Geoffroy , Thomas Oliver S. , Kistner Klaus M. , Zintchenko Marina , Aichele Peter , Zhou Houjiang , Weber Wilfried , Boerries Melanie , Swamy Mahima , Maurer Jochen , Minguet Susana 
Published: April 2022

AbstractTriple negative breast cancer (TNBC) lacks targeted therapy options. TNBC is enriched in breast cancer stem cells (BCSCs), which play a key role in metastasis, chemoresistance, relapse and mortality. γδ T cells hold great potential in immunotherapy against cancer, and might be an alternative to target TNBC. γδ T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor sensing, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. We show that patient-derived triple negative BCSCs are efficiently recognized and killed by ex vivo expanded γδ T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to γδ T cell immunotherapy. Mechanistically, we unraveled concerted differentiation and immune escape: xenografted BCSCs lost stemness, expression of γδ T cell ligands, adhesion molecules and pAgs, thereby evading immune recognition by γδ T cells. Indeed, neither pro-migratory engineered γδ T cells, nor anti-PD-1 checkpoint blockade significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the γδ T cells, and could be pharmacologically reverted by Zoledronate or IFN-α treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.
Kidins220 regulates the development of B cells bearing the λ light chain
Authors: Schaffer Anna-Maria , Fiala Gina J. , Hils Miriam , Natali Eriberto Noel , Babrak Lmar , Herr Laurenz A. , Rizzi Marta , Miho Enkelejda , Schamel Wolfgang , Minguet Susana 
Published: April 2022

AbstractThe ratio between Igκ and Igλ light chain (LC)-expressing B cells varies considerably between species. We recently identified Kinase D-interacting substrate of 220 kDa (Kidins220) as an interaction partner of the BCR. In vivo ablation of Kidins220 in B cells resulted in a marked reduction of λLC-expressing B cells. Kidins220 knockout B cells fail to open and recombine the genes of the λLC locus, even in genetic scenarios where the κLC genes cannot be rearranged or where the κLC confers autoreactivity. κLC gene recombination and expression in Kidins220-deficient B cells is normal. Kidins220 regulates the development of λLC B cells by enhancing the survival of developing B cells and thereby extending the time-window in which the λLC locus opens and the genes are rearranged and transcribed. Further, our data suggest that Kidins220 guarantees optimal pre-BCR and BCR signaling to induce λLC locus opening and gene recombination during B cell development and receptor editing.One Sentence SummaryWe demonstrate that the scaffold protein Kidins220 regulates the development of λLC B cells by supporting B cell precursor survival and optimizing pre-BCR and BCR signaling to open, recombine, and transcribe the genes of the λLC locus.
Socially learned arbitrary call use in a wild primate
Authors: Deshpande Adwait , Zuberbuhler Klaus 
Published: April 2022

AbstractHuman speech is an unusually flexible form of primate communication. A limited repertoire of phonemes is assembled into morphemes whose combinations are linked to referents by social learning in culturally specific ways. Non-human primate vocal utterances, in contrast, are drastically less flexible at every level, i.e., acoustic diversity, combinatoriality and referential function. Here, we were interested in whether primate vocal behaviour, despite its inflexible nature, is still amenable to social learning, a well-documented, powerful mechanism in many other aspects of primate behaviour. We provided wild vervet monkeys with social learning opportunities to operate a food dispensing apparatus by uttering specific vocalisations, ‘move-grunts’, that were contextually inappropriate. In two separate experiments, subjects witnessed how another group member produced move-grunts whilst operating a food dispenser. In experiment 1, subjects only heard playbacks of the calls, followed by food release; in experiment 2, they witnessed a complete demonstration video of conspecific including the calls, followed by food release. None of the subjects learned the task in experiment 1, but 1 of 39 subjects, a juvenile female, succeeded in experiment 2 by producing move-grunts at the food dispenser to obtain food rewards. We discuss our results and behavioural observations in relation to the current theory and its eventual implications for reconstructing the evolutionary pathway to human speech.
Re-engineering ofCUP1promoter and Cup2/Ace1 transactivator to convertSaccharomyces cerevisiaeinto a whole-cell eukaryotic biosensor capable of detecting 10 nM of bioavailable copper
Authors: Žunar Bojan , Mosrin Christine , Bénédetti Héléne , Vallée Béatrice 
Published: April 2022

AbstractWhile copper is an essential micronutrient and a technologically indispensable heavy metal, it is toxic at high concentrations, harming the environment and human health. Currently, copper is monitored with costly and low-throughput analytical techniques that do not evaluate bioavailability, a crucial parameter which can be measured only with living cells. We overcame these limitations by building upon yeastS. cerevisiae’s native copper response and constructed a promising next-generation eukaryotic whole-cell copper biosensor. We combined a dual-reporter fluorescent system with an engineeredCUP1promoter and overexpressed Cup2 transactivator, constructing through four iterations a total of 16 variants of the biosensor, with the best one exhibiting a linear range of 10-8to 10-3M of bioavailable copper. Moreover, this variant distinguishes itself by superior specificity, detection limit, and linear range, compared to other currently reported eukaryotic and prokaryotic whole-cell copper biosensors. By re-engineering the transactivator, we altered the system’s sensitivity and growth rate, while assessing the performance of Cup2 with heterologous activation domains. Thus, in addition to presenting the next-generation whole-cell copper biosensor, this work urges for an iterative design of eukaryotic biosensors and paves the way toward higher sensitivity through transactivator engineering.Graphical abstract
Chromatin regulates genome-wide transcription factor binding affinities
Authors: Neikes Hannah K. , Lindeboom Rik G.H. , Gräwe Cathrin , Lamers Lieke A. , Baltissen Marijke P. , Jansen Pascal W.T.C. , van Heeringen Simon J. , Logie Colin , Teichmann Sarah A. , Vermeulen Michiel 
Published: April 2022

AbstractTranscription factor binding across the genome is regulated by DNA sequence and chromatin features. However, it is not yet possible to quantify the impact of chromatin context on genome-wide transcription factor binding affinities. Here we report the establishment of a method to determine genome-wide absolute apparent binding affinities of transcription factors to native, chromatinized DNA. Our experiments revealed that DNA accessibility is the main determinant of transcription factor binding in the genome, which largely restricts nanomolar affinity binding of YY1, SP1 and MYC/MAX to promoters, while FOXA1 also interacts with non-promoter elements with high affinity. Furthermore, whereas consensus DNA binding motifs for transcription factors are important to establish very high-affinity binding sites, these motifs are not always strictly required to generate nanomolar affinity interactions in the genome. Finally, we uncovered transcription factor concentration dependent binding to specific gene classes, suggesting transcription factor concentration dependent effects on gene expression and cell fate. Importantly, our method adds a quantitative dimension to transcription factor biology which enables stratification of genomic targets based on transcription factor concentration and prediction of transcription factor binding sites under non-physiological conditions, such as disease associated overexpression of (onco)genes.