bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive Whole Genome Sequencing Reveals Origins of Mutational Signatures Associated with Aging and Temozolomide Chemotherapy
Authors: Hwang Taejoo , Sitko Lukasz Karol , Khoirunnisa Ratih , Aguad Fernanda Navarro , Samuel David M , Park Hajoong , Cheon Banyoon , Mutsnaini Luthfiyyah , Lee Jaewoong , Takeda Shunichi , Lee Semin , Ivanov Dmitri , Gartner Anton 
Published: April 2024

AbstractIn a comprehensive study to decipher the multi-layered response to the chemotherapeutic agent temozolomide (TMZ), we analyzed 427 genomes and determined mutational patterns in a collection of ∼40 isogenic DNA repair-deficient human TK6 lymphoblast cell lines. We demonstrate that the spontaneous mutational background is very similar to the aging-associated mutational signature SBS40 and mainly caused by polymerase zeta-mediated translesion synthesis (TLS).MSH2-/-mismatch repair knockout in conjunction with additional repair deficiencies uncovers cryptic mutational patterns. We report how distinct mutational signatures are induced by TMZ upon sequential inactivation of DNA repair pathways, mirroring the acquisition of chemotherapy resistance by glioblastomas. The most toxic adduct induced by TMZ,O6-meG, is directly repaired by theO6-methylguanine-DNA methyltransferase (MGMT). InMGMT-/-cells, mismatch repair (MMR) leads to cell death and limits mutagenesis. MMR deficiency results in TMZ resistance, allowing the accumulation of ∼105C>T substitutions corresponding to signature SBS11. Under these conditions, N-alkylated bases, processed by base excision repair (BER), limit cell survival. Without BER, 3-meA is read through via error-prone TLS, causing T>A substitutions but not affecting survival. Blocking BER after abasic site formation results in large deletions and TMZ hypersensitization. Our findings reveal potential vulnerabilities of TMZ-resistant tumors.
How to deal with internal fragment ions?
Authors: Grimaud Arthur , Babović Maša , Haugaard Holck Frederik , Jensen Ole N. , Schwämmle Veit 
Published: April 2024

1AbstractTandem mass spectrometry of peptides and proteins generates mass spectra of their gas-phase fragmentation product ions, including N-terminal, C-terminal, and internal fragment ions. Whereas N- and C-terminal ions are routinely assigned and identified using computational methods, internal fragment ions are often difficult to annotate correctly. They become particularly relevant for long peptides and full proteoforms where the peptide backbone is more likely to be fragmented multiple times. Internal fragment ions potentially offer tremendous information regarding amino acid sequences and positions of post-translational modifications of peptides and intact proteins. However, their practical application is challenged by the vast number of theoretical internal fragments that exist for long amino acid sequences, leading to a high risk of false-positive annotations. We analyze the mass spectral contributions of internal fragment ions in spectra from middle-down and top-down experiments and introduce a novel graph-based annotation approach designed to manage the complexity of internal fragments. Our graph-based representation allows us to compare multiple candidate proteoforms in a single graph, and to assess different candidate annotations in a fragment ion spectrum. We demonstrate cases from middle-down and top-down data where internal ions enhance amino acid sequence coverage of polypeptides and proteins and accurate localization of post-translational modifications. We conclude that our graph-based method provides a general approach to process complex tandem mass spectra, enhance annotation of internal fragment ions, and improve proteoform sequencing and characterization by mass spectrometry.
Iron transport pathways in the human malaria parasitePlasmodium falciparumrevealed by RNA-sequencing
Authors: Wunderlich Juliane , Kotov Vadim , Votborg-Novél Lasse , Ntalla Christina , Geffken Maria , Peine Sven , Portugal Silvia , Strauss Jan 
Published: April 2024

ABSTRACTHost iron deficiency is protective against severe malaria as the human malaria parasitePlasmodium falciparumdepends on bioavailable iron from its host to proliferate. The essential pathways of iron acquisition, storage, export, and detoxification in the parasite differ from those in humans, as orthologs of the mammalian transferrin receptor, ferritin, or ferroportin, and a functional heme oxygenase are absent inP. falciparum. Thus, the proteins involved in these processes may be excellent targets for therapeutic development, yet remain largely unknown. Here, we show that parasites cultured in erythrocytes from an iron-deficient donor displayed significantly reduced growth rates compared to those grown in red blood cells from healthy controls. Sequencing of parasite RNA revealed diminished expression of genes involved in overall metabolism, hemoglobin digestion, and metabolite transport under low-iron versus control conditions. Supplementation with hepcidin, a specific ferroportin inhibitor, resulted in increased labile iron levels in erythrocytes, enhanced parasite replication, and transcriptional upregulation of genes responsible for merozoite motility and host cell invasion. Through endogenous GFP tagging of differentially expressed putative transporter genes followed by confocal live-cell imaging, proliferation assays with knockout and knockdown lines, and protein structure predictions, we identified six proteins that are likely required for ferrous iron transport inP. falciparum. Of these, we localizedPfVIT andPfZIPCO to cytoplasmic vesicles,PfMRS3 to the mitochondrion, and the novel putative iron transporterPfE140 to the plasma membrane for the first time inP. falciparum.PfNRAMP/PfDMT1 andPfCRT were previously reported to efflux Fe2+from the digestive vacuole. Our data support a new model for parasite iron homeostasis, in whichPfE140 is involved in iron uptake across the plasma membrane,PfMRS3 ensures non-redundant Fe2+supply to the mitochondrion as the main site of iron utilization,PfVIT transports excess iron into cytoplasmic vesicles, andPfZIPCO exports Fe2+from these organelles in case of iron scarcity. These results provide new insights into the parasite’s response to differential iron availability in its environment and into the mechanisms of iron transport inP. falciparumas promising candidate targets for future antimalarial drugs.
SON-dependent nuclear speckle rejuvenation alleviates proteinopathies
Authors: Dion William , Tao Yuren , Chambers Maci , Zhao Shanshan , Arbuckle Riley K. , Sun Michelle , Kubra Syeda , Jamal Imran , Nie Yuhang , Ye Megan , Larsen Mads B. , Camarco Daniel , Ickes Eleanor , DuPont Claire , Wang Haokun , Wang Bingjie , Liu Silvia , Pi Shaohua , Chen Bill B , Chen Yuanyuan , Chen Xu , Zhu Bokai 
Published: April 2024

AbstractCurrent treatments targeting individual protein quality control have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common upstream druggable target capable of global proteostasis modulation. Building on our prior research establishing nuclear speckles as a pivotal membrane-less organelle responsible for global proteostasis transcriptional control, we aim to alleviate proteinopathies through nuclear speckle rejuvenation. We identified pyrvinium pamoate as a small-molecule nuclear speckle rejuvenator that enhances protein quality control while suppressing YAP1 signaling via decreasing the surface/interfacial tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, nanomolar pyrvinium pamoate alleviated retina degeneration and reduced tauopathy by promoting autophagy and ubiquitin-proteasome system in a SON-dependent manner without causing cellular stress. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity were also observed in human tauopathies. Our study uncovers novel therapeutic targets for tackling protein misfolding disorders within an expanded proteostasis framework encompassing nuclear speckles and YAP1.
Characterization of a novel zebrafish model ofMTMR5-associated CMT4B3
Authors: Lindzon Jordan , List Maia , Geissah Salma , Zhao Mo , Dowling James J. 
Published: April 2024

AbstractBiallelic loss of expression/function variants inMTMR5cause the inherited peripheral neuropathy Charcot-Marie-Tooth (CMT) Type 4B3. There is an incomplete understanding of the disease pathomechanism(s) underlying CMT4B3, and despite its severe clinical presentation, currently no disease modifying therapies. A key barrier to the study of CMT4B3 is the lack of pre-clinical models that recapitulate the clinical and pathologic features of the disease. To address this barrier, we generated a zebrafish CRISPR/Cas9 mutant line with a full gene deletion ofmtmr5.Resulting homozygous deletion zebrafish are born at normal Mendelian ratios and have preserved motor function. However, starting by 14 day-post-fertilization, mutant zebrafish develop obvious morphometric changes in head size and brain volume. These changes are accompanied at the pathological level by abnormal axon outgrowths and by the presence of dysmyelination, changes reminiscent of the nerve pathology in human CMT4B3. Overall, ourmtmr5zebrafish mirror genetic, clinical, and pathologic features of human CMT4B3. As such, it represents a first pre-clinical model to phenocopy the disease, and an ideal tool for future studies on disease pathomechanism(s) and therapy development.Summary StatementWe created a novel zebrafishmtmr5/sbf1mutant model of Charcot-Marie-Tooth Type 4B3 that recapitulates key features of the human disorder and provides the firstin vivomodel for therapy development.
Intracortical microstimulation of human somatosensory cortex is sufficient to induce perceptual biases
Authors: Greenspon Charles M. , Shelchkova Natalya D. , Hobbs Taylor G. , Bensmaia Sliman J. , Gaunt Robert A. 
Published: April 2024

AbstractTime-order error, a psychophysical phenomenon in which the duration in between successive stimuli alters perception, has been studied for decades by neuroscientists and psychologists. To date, however, the locus of these effects is unknown. We use intracortical microstimulation of somatosensory cortex in humans as a tool to bypass initial stages of processing and restrict the possible locations that signals could be modified. We find that, using both amplitude discrimination and magnitude estimation paradigms, intracortical microstimulation reliably evoked time-order errors across all participants. Points of subjective equality were symmetrically shifted during amplitude discrimination experiments and the intensity of a successive stimulus was perceived as being more intense when compared to single stimulus trials in magnitude estimation experiments. The error was reduced for both paradigms at longer inter-stimulus intervals. These results show that direct activation of primary somatosensory cortex is sufficient to induce time-order errors.
A 10-Year Longitudinal Study of Brain Cortical Thickness in People with First-Episode Psychosis using Normative Models
Authors: Berthet Pierre , Haatveit Beathe C. , Kjelkenes Rikka , Worker Amanda , Kia Seyed Mostafa , Wolfers Thomas , Rutherford Saige , Alnaes Dag , Dinga Richard , Pedersen Mads L. , Dahl Andreas , Fernandez-Cabello Sara , Dazzan Paola , Agartz Ingrid , Nesvåg Ragnar , Ueland Torill , Andreassen Ole A. , Simonsen Carmen , Westlye Lars T. , Melle Ingrid , Marquand Andre 
Published: April 2024

ABSTRACTBackgroundClinical forecasting models have potential to optimize treatment and improve outcomes in psychosis, but predicting long-term outcomes is challenging and long-term follow up data are scarce. In this 10-year longitudinal study we aimed to characterize the temporal evolution of cortical correlates of psychosis and their associations with symptoms.DesignStructural MRI from people with first-episode psychosis and controls (n=79 and 218) were obtained at enrollment, after 12 months (n=67 and 197), and 10 years (n=23 and 77), within the Thematically Organized Psychosis (TOP) study. Normative models for cortical thickness estimated on public MRI datasets (n=42983) were applied to TOP data to obtain deviation scores for each region and timepoint. Positive And Negative Syndrome Scale (PANSS) scores were acquired at each timepoint along with registry data. Linear mixed effects (LME) models assessed effects of diagnosis, time and their interactions on cortical deviations plus associations with symptoms.ResultsLMEs revealed conditional main effects of diagnosis and time x diagnosis interactions in a distributed cortical network, where negative deviations in patients attenuate over time. In patients, symptoms also attenuate over time. LMEs revealed effects of anterior cingulate on PANSS total, and insular and orbitofrontal regions on PANSS negative scores.ConclusionsThis long-term longitudinal study revealed a distributed pattern of cortical differences which attenuated over time together with a reduction in symptoms. These findings are not in line with a simple neurodegenerative account of schizophrenia, and deviations from normative models offer a promising avenue to develop biomarkers to track clinical trajectories over time.
Postoperative Karnofsky performance status prediction in patients withIDHwild-type glioblastoma: a multimodal approach integrating clinical and deep imaging features
Authors: Sasagasako Tomoki , Ueda Akihiko , Mineharu Yohei , Mochizuki Yusuke , Doi Souichiro , Park Silsu , Terada Yukinori , Sano Noritaka , Tanji Masahiro , Arakawa Yoshiki , Okuno Yasushi 
Published: April 2024

ABSTRACTBackground and PurposeGlioblastoma is a highly aggressive brain tumor with limited survival that poses challenges in predicting patient outcomes. The Karnofsky Performance Status (KPS) score is a valuable tool for assessing patient functionality and contributes to the stratification of patients with poor prognoses. This study aimed to develop a 6-month postoperative KPS prediction model by combining clinical data with deep learning-based image features from pre- and postoperative MRI scans, offering enhanced personalized care for glioblastoma patients.Materials and MethodsUsing 1,476 MRI datasets from the Brain Tumor Segmentation Challenge 2020 public database, we pretrained two variational autoencoders (VAEs). Imaging features from the latent spaces of the VAEs were used for KPS prediction. Neural network-based KPS prediction models were developed to predict scores below 70 at 6 months postoperatively. In this retrospective single-center analysis, we incorporated clinical parameters and pre- and postoperative MRI images from 150 newly diagnosed IDH wild-type glioblastoma, divided into training (100 patients) and test (50 patients) sets. In training set, the performance of these models was evaluated using the area under the curve (AUC), calculated through fivefold cross-validation repeated 10 times. The final evaluation of the developed models assessed in the test set.ResultsAmong the 150 patients, 61 had 6-month postoperative KPS scores below 70 and 89 scored 70 or higher. We developed three models: a clinical-based model, an MRI-based model, and a multimodal model that incorporated both clinical parameters and MRI features. In the training set, the mean AUC was 0.785±0.051 for the multimodal model, which was significantly higher than the clinical-based model (0.716±0.059, P=0.038) using only clinical parameters and MRI-based model (0.651±0.028, P<0.001) using only MRI features. In the test set, the multimodal model achieved an AUC of 0.810, outperforming the clinical-based (0.670) and MRI-based (0.650) models.ConclusionThe integration of MRI features extracted from VAEs with clinical parameters in the multimodal model substantially enhanced KPS prediction performance. This approach has the potential to improve prognostic prediction, paving the way for more personalized and effective treatments for patients with glioblastoma.
Functional network organization is locally atypical in children and adolescents with congenital heart disease
Authors: Roy Joy , Reynolds William , Panigrahy Ashok , Ceschin Rafael 
Published: April 2024

AbstractChildren and adolescents with congenital heart disease (CHD) frequently experience neurodevelopmental impairments that can impact academic performance, memory, attention, and behavioral function, ultimately affecting overall quality of life. This study aims to investigate the impact of CHD on functional brain network connectivity and cognitive function. Using resting-state fMRI data, we examined several network metrics across various brain regions utilizing weighted networks and binarized networks with both absolute and proportional thresholds. Regression models were fitted to patient neurocognitive exam scores using various metrics obtained from all three methods. Our results unveil significant differences in network connectivity patterns, particularly in temporal, occipital, and subcortical regions, across both weighted and binarized networks. Furthermore, we identified distinct correlations between network metrics and cognitive performance, suggesting potential compensatory mechanisms within specific brain regions.
Neurochemical and Neurophysiological Effects of Intravenous Administration ofN,N-Dimethyltryptamine in Rats
Authors: Glynos Nicolas G. , Huels Emma R. , Nelson Amanda , Kim Youngsoo , Kennedy Robert T. , Mashour George A. , Pal Dinesh 
Published: April 2024

AbstractN,N-dimethyltryptamine (DMT) is a serotonergic psychedelic that is being investigated clinically for the treatment of psychiatric disorders. Although the neurophysiological effects of DMT in humans are well-characterized, similar studies in animal models as well as data on the neurochemical effects of DMT are generally lacking, which are critical for mechanistic understanding. In the current study, we combined behavioral analysis, high-density (32-channel) electroencephalography, and ultra-high-performance liquid chromatography-tandem mass spectrometry to simultaneously quantify changes in behavior, cortical neural dynamics, and levels of 17 neurochemicals in medial prefrontal and somatosensory cortices before, during, and after intravenous administration of three different doses of DMT (0.75 mg/kg, 3.75 mg/kg, 7.5 mg/kg) in male and female adult rats. All three doses of DMT produced head twitch response with most twitches observed after the low dose. DMT caused dose-dependent increases in serotonin and dopamine levels in both cortical sites along with a reduction in EEG spectral power in theta (4-10 Hz) and low gamma (25-55 Hz), and increase in power in delta (1-4 Hz), medium gamma (65-115 ), and high gamma (125-155 Hz) bands. Functional connectivity decreased in the delta band and increased across the gamma bands. In addition, we provide the first measurements of endogenous DMT in these cortical sites at levels comparable to serotonin and dopamine, which together with a previous study in occipital cortex, suggests a physiological role for endogenous DMT. This study represents one of the most comprehensive characterizations of psychedelic drug action in rats and the first to be conducted with DMT.Significance StatementN,N-dimethyltryptamine (DMT) is a serotonergic psychedelic with potential as a tool for probing the neurobiology of consciousness and as a therapeutic agent for psychiatric disorders. However, the neurochemical and neurophysiological effects of DMT in rat, a preferred animal model for mechanistic studies, are unclear. We demonstrate that intravenous DMT caused a dose-dependent increase in serotonin and dopamine in medial prefrontal and somatosensory cortices, and simultaneously increased gamma functional connectivity. Similar effects have been shown for other serotonergic and atypical psychedelics, suggesting a shared mechanism of drug action. Additionally, we report DMT during normal wakefulness in two spatially and functionally distinct cortical sites — prefrontal, somatosensory — at levels comparable to those of serotonin and dopamine, supporting a physiological role for endogenous DMT.
A Role for Cross-linking Proteins in Actin Filament Network Organization and Force Generation
Authors: Hill Jennifer M. , Cai Songlin , Carver Michael D. , Drubin David G. 
Published: April 2024

AbstractThe high turgor pressure across the plasma membrane of yeasts creates a requirement for substantial force production by actin polymerization and myosin motor activity for clathrin-mediated endocytosis (CME). Endocytic internalization is severely impeded in the absence of fimbrin, an actin filament crosslinking protein called Sac6 in budding yeast. Here, we combine live-cell imaging and mathematical modeling to gain new insights into the role of actin filament crosslinking proteins in force generation. Genetic manipulation showed that CME sites with more crosslinking proteins are more effective at internalization under high load. Simulations of an experimentally constrained, agent- based mathematical model recapitulate the result that endocytic networks with more double-bound fimbrin molecules internalize the plasma membrane against elevated turgor pressure more effectively. Networks with large numbers of crosslinks also have more growing actin filament barbed ends at the plasma membrane, where the addition of new actin monomers contributes to force generation and vesicle internalization. Our results provide a richer understanding of the crucial role played by actin filament crosslinking proteins during actin network force generation, highlighting the contribution of these proteins to the self-organization of the actin filament network and force generation under increased load.
Differential α-Synuclein-induced Autophagy Dysfunction in Neuronal and Microglial Cells drives Tunneling Nanotubes and Aggregate Spread to Microglia
Authors: Chakraborty Ranabir , Samella Philippa , Nonaka Takashi , Hasegawa Masato , Zurzolo Chiara 
Published: April 2024

AbstractTunneling nanotubes (TNTs) represent a major form of intercellular communication, enabling material exchange of different kinds over long distances between the connected cells. Previous investigations have demonstrated the efficient directional transfer of α-Synuclein (α-Syn) aggregates from neuronal cells to microglia. However, the mechanisms underlying this directional specificity have remained elusive. Here, we investigate the localization, dynamics, and impacts of α-Syn aggregates on the lysosome and autophagic pathways in neuronal and microglial cells. Our findings reveal differential localization of aggregates with lysosomes of neuronal and microglial cells alongside a disparity in lysosomal dynamics. Microglia exhibit a high propensity for lysosomal turnover, particularly through lysophagy, while neuronal lysosomes display compromised degradative capacity and impaired autophagic flux. Consequently, aggregates in neuronal cells are less efficiently targeted for degradation. Furthermore, perturbation of autophagy in neuronal cells elevates TNT-mediated aggregate transfer to microglia. Thus, while revealing distinct effects of α-Syn aggregates in neuronal and microglial cells, our study identifies dysfunctional autophagy as a pivotal determinant driving the preferential directional transfer of aggregates from neurons to microglia.TeaserCompromised lysosome functionality and autophagy in neuronal cells leads to α-Synuclein dissipation to microglia via Tunneling Nanotubes.Graphical Abstract