bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pseudo-craniotomy of a whole-brain model reveals tumor-induced alterations to neuronal dynamics in glioma patients
Authors: Alexandersen Christoffer G. , Douw Linda , Zimmermann Mona L.M. , Bick Christian , Goriely Alain 
Published: December 2023

AbstractBrain tumors can induce pathological changes in neuronal dynamics both on a local and global level. Here, we use a whole-brain modeling approach to investigate these pathological alterations in neuronal activity. By fitting a Hopf whole-brain model to empirical functional connectivity, we demonstrate that phase correlations are largely determined by the ratio of interregional coupling strength and intraregional excitability. Furthermore, we observe considerable differences in interregional-versus-intraregional dynamics between glioma patients and healthy controls, both on an individual and population-based level. In particular, we show that local tumor pathology induces shifts in the global brain dynamics by promoting the contribution of interregional interactions. Our approach demonstrates that whole-brain models provide valuable insights for understanding glioma-associated alterations in functional connectivity.
Diet-induced miRNAs regulate adult neurogenesis and functional activity of nascent neurons in the hypothalamus
Authors: Srinivasan Balakumar , Samaddar Sarbani , Roy Dipanjan , Banerjee Sourav 
Published: December 2023

AbstractNeurogenesis in the hypothalamus upon high fat diet (HFD) feeding regulates the feeding circuit. HFD induces the neurogenesis of β2 tanycytes in young-adult mice. However molecular mechanisms of tanycytic neurogenesis; and their functional integration into the feeding circuitry are poorly understood. We investigated the role of miRNAs in the regulation of HFD-induced tanycytic neurogenesis. miRNA arrays identified a cohort of HFD-induced, differentially-regulated miRNAs in BrdU+β2-tanycytes. These miRNAs arise from different chromosomes, rather than a single cluster.In siliconetwork analysis on the predicted targets of all five HFD-induced miRNAs and reporter assays identified a subset of targets that influence neurogenesis and neuronal differentiation. HFD-induced miRNAs drive a molecular program leading to the functional integration of nascent neurons; introduction of a miRNA sponge sequestering all five miRNAs abolishes it. Diet-regulated newborn neurons preferentially differentiate into AgRP+ neurons that functionally integrate into the feeding circuit.
Integrative genomics reveals the polygenic basis of seedlessness in grapevine
Authors: Wang Xu , Liu Zhongjie , Zhang Fan , Xiao Hua , Cao Shuo , Xue Hui , Liu Wenwen , Su Ying , Liu Zhenya , Zhong Haixia , Zhang Fuchun , Ahmad Bilal , Long Qiming , Zhang Yingchun , Liu Yuting , Gan Yu , Hou Ting , Jin Zhongxin , Wu Xinyu , Wang Yiwen , Peng Yanling , Zhou Yongfeng 
Published: December 2023

AbstractSeedlessness is a crucial quality trait in table grape (Vitis viniferaL.) breeding. However, the development of seeds involved intricate regulations, while the polygenic basis of seed abortion remains unclear. Here, we combine comparative genomics, population genetics, quantitative genetics, and integrative genomics to unravel the evolution and polygenic basis of seedlessness in grapes. We generated four haplotype-resolved telomere-to-telomere (T2T) genomes for two seedless grape cultivars, ‘Thompson Seedless’ (TS, syn. ‘Sultania’) and ‘Black Monukka’ (BM). Comparative genomics identified a ∼4.25 Mb hemizygous inversion on Chr10 specific in seedless cultivars, with seedless-associated genesVvTT16andVvSUS2located at breakpoints. Population genomic analyses of 548 grapevine accessions revealed two distinct clusters of seedless cultivars, tracing the origin of the seedlessness trait back to ‘Sultania’. Introgression, rather than convergent selection, shaped the evolutionary history of seedlessness in grape improvement. Genome-wide association study (GWAS) analysis identified 110 quantitative trait loci (QTLs) associated with 634 candidate genes, including novel candidate genes, such as three11S GLOBULIN SEED STORAGE PROTEINand twoCYTOCHROME P450genes, and well-known genes likeVviAGL11. Integrative genomic analyses resulted in 339 core candidate genes categorized into 13 groups related to seed development. Machine learning based genomic selection achieved a remarkable 99% precision in predicting grapevine seedlessness. Our findings highlight the polygenic nature of seedless and provide novel candidate genes for molecular genetics and an effective prediction for seedlessness in grape genomic breeding.
Error-corrected deep targeted sequencing of circulating cell-free DNA from colorectal cancer patients for sensitive detection of circulating tumor DNA
Authors: Frydendahl Amanda , Rasmussen Mads Heilskov , Jensen Sarah Østrup , Henriksen Tenna Vesterman , Demuth Christina , Diekema Mathilde , Ditzel Henrik J. , Wen Sara Witting Christensen , Pedersen Jakob Skou , Dyrskjøt Lars , Andersen Claus Lindbjerg 
Published: December 2023

ABSTRACTIntroductionCirculating tumor DNA (ctDNA) is a promising biomarker, reflecting the presence of tumor cells. Sequencing-based detection of ctDNA at low tumor fractions is challenging due to the crude error rate of sequencing. To mitigate this challenge, we developed UMIseq, a fixed-panel deep-targeted sequencing approach, which is universally applicable to all colorectal cancer (CRC) patients.MethodsUMIseq features UMI-mediated error correction, exclusion of mutations related to clonal hematopoiesis, a panel of normals for error modeling, and signal integration from single-nucleotide variations, insertions, deletions, and phased mutations. UMIseq was trained and independently validated on pre-operative (pre-OP) plasma from CRC patients (n=364) and healthy individuals (n=61).ResultsUMIseq displayed an area under the curve surpassing 0.95 for allele frequencies (AF) down to 0.05%. In the training cohort, the pre-OP detection rate reached 80% at 95% specificity, while in the validation cohort, it was 70%. UMIseq enabled the detection of AFs down to 0.004%. To assess the potential for detection of residual disease, 26 post-operative plasma samples from stage III CRC patients were analyzed. Detection of ctDNA was associated with recurrence (p =0.08).ConclusionUMIseq demonstrated robust performance with high sensitivity and specificity, enabling the detection of ctDNA at low allele frequencies.
Angiotensin-II drives changes in microglia-vascular interactions in rats with heart failure
Authors: Althammer Ferdinand , Roy Ranjan K. , Kirchner Matthew K. , McGrath Shaina , Lira Elba Campos , Stern Javier E. 
Published: December 2023

AbstractActivation of microglia, the resident immune cells of the central nervous system, leading to the subsequent release of pro-inflammatory cytokines, has been linked to cardiac remodeling, autonomic disbalance, and cognitive deficits in heart failure (HF). While previous studies emphasized the role of hippocampal Angiotensin II (AngII) signaling in HF-induced microglial activation, unanswered mechanistic questions persist. Evidence suggests significant interactions between microglia and local microvasculature, potentially affecting blood-brain barrier integrity and cerebral blood flow regulation. Still, whether the microglial-vascular interface is affected in the brain during HF remains unknow. Using a well-established ischemic HF rat model, we demonstrate increased vessel-associated microglia (VAM) in HF rat hippocampi, which showed heightened expression of AngII AT1a receptors. Acute AngII administration to sham rats induced microglia recruitment to the perivascular space, along with increased expression of TNFa. Conversely, administering an AT1aR blocker to HF rats prevented the recruitment of microglia to the perivascular space, normalizing their levels to those in healthy rats. These results highlight the critical importance of a rather understudied phenomenon (i.e., microglia-vascular interactions in the brain) in the context of the pathophysiology of a highly prevalent cardiovascular disease, and unveil novel potential therapeutic avenues aimed at mitigating neuroinflammation in cardiovascular diseases.
Conditions for successful nitrogen removal from source-separated urine by partial nitritation/anammox
Authors: Faust Valentin , Markus Philipp , Schielke-Jenni Sarina , Timmer Marijn J. , Paepe Jolien De , Ganigué Ramon , Vlaeminck Siegfried E. , Udert Kai M. 
Published: December 2023

AbstractPartial nitritation/anammox (PN/A) of source-separated urine is less energy-intensive and potentially cheaper and more environmentally friendly than conventional nitrogen removal from mixed sewage. However, PN/A of undiluted source-separated urine has not yet been established. In this study, the feasibility of PN/A for source-separated urine (total nitrogen ≈ 2 to 3 g-N L-1). To evaluate the influence of different factors, one- and two-stage configurations were operated using different influents, i.e. source-separated urine, synthetic urine, and urine with additional divalent cations. While partial nitritation was successfully achieved in both configurations with digester supernatant and urine, anammox activity was lost shortly after switching from digester supernatant to the urine influents. Toxic organic compounds or pharmaceuticals and the high monovalent to divalent cation ratio were suspected as causes of anammox failure, but were ruled out due to the different reactor configurations and influent compositions tested. Other suspected factors such as COD/N ratio, phosphate and sulfate inhibition, nitrogen compound inhibition, metal inhibition, pH and dissolved oxygen were also systematically excluded. Instead, the high salt concentration in urine compared to the digester supernatant most likely caused the reactor to fail due to the disintegration of large flocs, and the resulting challenge of biomass retention. The shortcomings of the floccular sludge system were overcome by using biofilm carriers, resulting in successful PN/A. This hybrid system ran for 140 days with nitrogen removal rates of up to 1000 mg-N L-1d-1with an average of 410 ± 220 mg-N L-1d-1, and a nitrogen removal efficiency of 93 ± 3% at 30°C.
Trans-synaptic molecular context of NMDA receptor nanodomains
Authors: Anderson Michael C , Dharmasri Poorna A , Damenti Martina , Metzbower Sarah R , Laghaei Rozita , Blanpied Thomas A , Levy Aaron D 
Published: December 2023

ABSTRACTTight coordination of the spatial relationships between protein complexes is required for cellular function. In neuronal synapses, many proteins responsible for neurotransmission organize into subsynaptic nanoclusters whose trans-cellular alignment modulates synaptic signal propagation. However, the spatial relationships between these proteins and NMDA receptors (NMDARs), which are required for learning and memory, remain undefined. Here, we mapped the relationship of key NMDAR subunits to reference proteins in the active zone and postsynaptic density using multiplexed super-resolution DNA-PAINT microscopy. GluN2A and GluN2B subunits formed nanoclusters with diverse configurations that, surprisingly, were not localized near presynaptic vesicle release sites marked by Munc13-1. Despite this, we found asubsetof release sites was enriched with NMDARs, and modeling of glutamate release and receptor activation in measured synapses indicated this nanotopography promotes NMDAR activation. This subset of release sites was internally denser with Munc13-1, aligned with abundant PSD-95, and associated closely with specific NMDAR nanodomains. Further, NMDAR activation drove rapid reorganization of this release site/receptor relationship, suggesting a structural mechanism for tuning NMDAR-mediated synaptic transmission. This work reveals a new principle regulating NMDAR signaling and suggests that synaptic functional architecture depends on the assembly of and trans-cellular spatial relationships between multiprotein nanodomains.
Learning a conserved mechanism for early neuroectoderm morphogenesis
Authors: Lefebvre Matthew , Colen Jonathan , Claussen Nikolas , Brauns Fridtjof , Raich Marion , Mitchell Noah , Fruchart Michel , Vitelli Vincenzo , Streichan Sebastian J 
Published: December 2023

AbstractMorphogenesis is the process whereby the body of an organism develops its target shape. The morphogen BMP is known to play a conserved role across bilaterian organisms in determining the dorsoventral (DV) axis. Yet, how BMP governs the spatio-temporal dynamics of cytoskeletal proteins driving morphogenetic flow remains an open question. Here, we use machine learning to mine a morphodynamic atlas of Drosophila development, and construct a mathematical model capable of predicting the coupled dynamics of myosin, E-cadherin, and morphogenetic flow. Mutant analysis shows that BMP sets the initial condition of this dynamical system according to the following signaling cascade: BMP establishes DV pair-rule-gene patterns that set-up an E-cadherin gradient which in turn creates a myosin gradient in the opposite direction through mechanochemical feedbacks. Using neural tube organoids, we argue that BMP, and the signaling cascade it triggers, prime the conserved dynamics of neuroectoderm morphogenesis from fly to humans.
Evidence of the ability of endocrine disrupting compounds to induce testicular germ cell cancer in humans
Authors: Nicolas Nour , Moison Delphine , Jampy Amandine , Masson Quentin , Dechamps Nathalie , Messiaen Sébastien , Abdallah Sonia , Pozzi-Gaudin Stéphanie , Benachi Alexandra , Ulveling Damien , Francastel Claire , Rouiller-Fabre Virginie , Livera Gabriel , Guerquin Marie-Justine 
Published: December 2023

ABSTRACTTesticular cancer is an increasing burden in modern societies and the most common malignancy among young adult males. Environment contaminants, especially endocrine disrupting compounds (EDC), may play a significant role in the development of these cancers through epigenetic alterations occurring during fetal and neonatal development. As long-term studies in humans and suitable experimental models with the potential to develop testicular cancer are lacking, no causal link can be established between endocrine disruptor exposure and testicular cancer incidence. Therefore, we developed an experimental model that recapitulates the differentiation of germ cells from primordial germ cells (pluripotency) into spermatocytes (meiosis) by using xenografted human fetal testis combined with germ cell transplantation into adult testis compartments. Using this model, we demonstrate that long-term fetal exposure (until 12 weeks) to a mixture of Di-2-ethylhexylphthalate (DEHP) and Bisphenol A (BPA), two most prevalent plasticizers, could interfere with fetal germ cell differentiation, leading to carcinogenesis and seminomas. Transcriptome, methylome, and histological analyses reveal that BPA/DEHP exposure induced some significant hallmarks of germ cell tumors to occur: persistent pluripotent and proliferative germ cells, global hypomethylation of CpGs in germ cells, abnormal expression of meiotic markers and fibrotic signatures in fetal testis. Additionally, we found that EDC-exposed fetal germ cells were more likely to develop seminoma in a context that allows spermatogenesis to begin. This study proposes the first experimental evidence that EDC exposure can cause long-term, irreversible lesions in fetal germ cells, which then lead to testicular tumorigenesis in adults.
Intensive task-switching training and single-task training differentially affect behavioral and neural manifestations of cognitive control in children
Authors: Schwarze Sina A. , Laube Corinna , Khosravani Neda , Lindenberger Ulman , Bunge Silvia A. , Fandakova Yana 
Published: December 2023

AbstractThe ability to flexibly switch between tasks develops during childhood. Children’s task-switching performance improves with practice, but the underlying processes remain unclear. We used functional magnetic resonance imaging to examine how nine weeks of task-switching training affect performance and task-related activation and functional connectivity. Children (8–11 years) were assigned to one of three groups: intensive task switching (SW; n = 72), intensive single tasking (SI; n = 74), and passive control (n = 41). While mixing costs decreased in both training groups initially, only the SW group maintained these training-related improvements at the end of training. Activation in dorsolateral prefrontal cortex decreased with training, but again only the SW group maintained these activation decreases at the end of training. Condition-specific connectivity increases with task switching became less pronounced with training, especially in the SI group. Lower costs of task switching along with decreased task-related activations suggest increased processing efficiency in frontoparietal regions with training. Intensive task-switching training was associated with sustained changes, possibly facilitated by a greater mismatch between processing supplies and environmental demands. Our findings suggest that experience-dependent changes with intensive task-switching training do not mirror maturational processes but rather facilitate performance via more efficient task processing.
Variation in hemolymph content and properties among three Mediterranean bee species
Authors: Elfar Salma A. , Bahgat Iman M. , Shebl Mohamed A. , Lihoreau Mathieu , Tawfik Mohamed M. 
Published: December 2023

AbstractHemolymph, as mediator of immune responses and nutrient circulation, can be used as physiological marker of an insect’s health, environmental quality or ecological adaptations. Recent studies reported intraspecific variation in protein contents and biological activities of the hemolymph of honey bees related to their diet. Here we measured interspecific variation in three common bee species in the Mediterranean Basin with contrasting ecologies:Apis mellifera,Chalicodoma siculum,andXylocopa pubescens. Despite all the bees were collected in the same area, we found important quantitative and qualitative variations of hemolymph extracts across species. Samples ofA. melliferaandC. siculumhad much higher protein concentration, anticancer, antimicrobial and antoxidant activities than samples ofX. pubescens.This first descriptive study suggests life history traits of bee species have strong influences on their hemolymph properties and call for future large scale comparative analyses across more species and geographical areas.
Discovery of novel brain permeable human ACSS2 inhibitors for blocking breast cancer brain metastatic growth
Authors: Esquea Emily , Ciraku Lorela , Young Riley G. , Merzy Jessica , Talarico Alexandra N. , Rashad Adel Ahmed , Cocklin Simon , Simone Nicole L. , Beld Joris , Reginato Mauricio J. , Dick Alexej 
Published: December 2023

AbstractBreast-cancer brain metastasis (BCBM) poses a significant clinical challenge, resulting in an end-stage diagnosis and hindered by limited therapeutic options. The blood-brain barrier (BBB) acts as an anatomical and physiological hurdle for therapeutic compounds, restricting the effective delivery of therapies to the brain. In order to grow and survive in a nutrient-poor environment, tumors in the brain must adapt to their metabolic needs, becoming highly dependent on acetate. These tumors rely on the conversion of acetate to acetyl-CoA by the enzyme Acetyl-CoA synthetase 2 (ACSS2), a key metabolic enzyme involved in regulating fatty acid synthesis and protein acetylation in tumor cells. ACSS2 has emerged as a crucial enzyme required for the growth of tumors in the brain. Here, we utilized a computational pipeline, combining pharmacophore-based shape screen methodology with ADME property predictions to identify novel brain-permeable ACSS2 inhibitors. From a small molecule library, this approach identified 30 potential ACSS2 binders, from which two candidates, AD-5584 and AD-8007, were validated for their binding affinity, predicted metabolic stability, and, notably, their ability to traverse the BBB. We show that treatment of BCBM cells, MDA-MB-231BR, with AD-5584 and AD-8007 leads to a significant reduction in lipid storage, reduction in colony formation, and increase in cell deathin vitro. Utilizing anex vivoorthotopic brain-slice tumor model, we show that treatment with AD-8007 and AD-5584 significantly reduces tumor size and synergizes with radiation in blocking BCBM tumor growthex vivo.Importantly, we show that following intraperitoneal injections with AD-5584 and AD-8007, we can detect these compounds in the brain, confirming their BBB permeability. Thus, we have identified and validated novel ACSS2 inhibitor candidates for further drug development and optimization as agents for treating patients with breast cancer brain metastasis.
Conserved cold tolerance ofRhagoletisspecies from different host fruits, elevations in Colorado, USA
Authors: Lemay Katelyn , Moore Mackenzie , Brown Paige , Gadey Lahari , Ragland Gregory J. , Toxopeus Jantina 
Published: December 2023

AbstractUnderstanding and characterizing how insects tolerate low temperatures is important for predicting their overwintering survival and subsequent geographic spread. This study characterized the cold tolerance of two members of theRhagoletisgenus in Colorado, U.S.A. Pupae were collected from infested fruit in late summer and early fall. For the first time, we show that the rosehip flyRhagoletis basiolais freeze-avoidant; overwintering pupae could supercool to temperatures as low as −26°C and survive. Interestingly, the temperature at which ice forms (supercooling point; SCP) did not vary betweenR. basiolaat high (c. 2900 m above sea level) and lower (c. 1650 m a.s.l.) elevations. We also report the apple maggotRhagoletis pomonellainfesting an unusual host fruit, the Dolgo crabapple, in close proximity to infested hawthorn trees.R. pomonellainfesting hawthorn fruits and crabapples had similar SCPs, and survived temperatures as low as −21°C. Pupae from both host fruits also survived prolonged exposure (2 weeks or more) to mild low temperatures (0 to −5°C). Further study into the mechanisms underlying the impressive and conserved cold tolerance ofR. pomonellaandR. basiolais an interesting avenue for future research.
The LH receptor regulates hippocampal spatial memory and restores dendritic spine density in ovariectomized APP/PS1 AD mice
Authors: Mey Megan , Bhatta Sabina , Suresh Sneha , Montero Labrador Luis , Piontkivska Helen , Casadesus Gemma 
Published: December 2023

AbstractActivation of the luteinizing hormone receptor (LHCGR) rescues spatial memory function and spine density losses associated with gonadectomy and high circulating gonadotropin levels in females. However, whether this extends to the AD brain or the mechanisms that underlie these benefits remain unknown. To address this question, we delivered the LHCGR agonist human chorionic gonadotropin (hCG) intracerebroventricularly (ICV), under reproductively intact and ovariectomized conditions to mimic the post-menopausal state in the APP/PS1mouse brain. Cognitive function was tested using the Morris water maze task, and hippocampal dendritic spine density, Aβ pathology, and signaling changes associated with these endpoints were determined to address mechanisms. Here we show that central LHCGR activation restored function in ovariectomized APP/PS1 female mice to wild-type levels without altering Aβ pathology. LHCGR activation increased hippocampal dendritic spine density regardless of reproductive status, and this was mediated by BDNF-dependent and independent signaling. We also show that ovariectomy in the APP/PS1 brain elicits an increase in peripherally derived pro-inflammatory genes which are inhibited by LHCGR activation. This may mediate reproductive status specific effects of LHCGR agonism on cognitive function and BDNF expression. Together, this work highlights the relevance of the LHCGR on cognition and its therapeutic potential in the “menopausal” AD brain.