bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Angular Resolution Susceptibility Imaging and Estimation of Fiber Orientation Distribution Functions in Primate Brain
Authors: Gkotsoulias Dimitrios G. , Müller Roland , Jäger Carsten , Schlumm Torsten , Mildner Toralf , Eichner Cornelius , Pampel André , Jaffe Jennifer , Gräßle Tobias , Alsleben Niklas , Chen Jingjia , Crockford Catherine , Wittig Roman , Liu Chunlei , Möller Harald E. 
Published: October 2022

AbstractUncovering brain-tissue microstructure including axonal characteristics is a major neuroimaging research focus. Within this scope, anisotropic properties of magnetic susceptibility in white matter have been successfully employed to estimate primary axonal trajectories using mono-tensorial models. However, anisotropic susceptibility has not yet been considered for modeling more complex fiber structures within a voxel, such as intersecting bundles, or an estimation of orientation distribution functions (ODFs). This information is routinely obtained by high angular resolutiondiffusionimaging (HARDI) techniques. In applications to fixed tissue, however, diffusion-weighted imaging suffers from an inherently low signal-to-noise ratio and limited spatial resolution, leading to high demands on the performance of the gradient system in order to mitigate these limitations. In the current work, high angular resolutionsusceptibilityimaging (HARSI) is proposed as a novel, phase-based methodology to estimate ODFs. A multiple gradient-echo dataset was acquired in an entire fixed chimpanzee brain at 61 orientations by reorienting the specimen in the magnetic field. The constant solid angle method was adapted for estimating phase-based ODFs. HARDI data were also acquired for comparison. HARSI yielded information on whole-brain fiber architecture, including identification of peaks of multiple bundles that resembled features of the HARDI results. Distinct differences between both methods suggest that susceptibility properties may offer complementary microstructural information. These proof-of-concept results indicate a potential to study the axonal organization inpost-mortemprimate and human brain at high resolution.HighlightsIntroduction of High Angular Resolution Susceptibility Imaging (HARSI) for advancing Quantitative Susceptibility Mapping (QSM).HARSI-derived fiber orientation distributions in fixed chimpanzee brain.HARSI-based visualization of complex fiber configurations.Comparisons between HARSI and High Angular Resolution Diffusion Imaging.Potential for high-resolutionpost-mortemimaging of fiber architecture.
Dynamic hippocampal-cortical interactions during event boundaries support retention of complex narrative events
Authors: Barnett Alexander J. , Nguyen Mitchell , Spargo James , Yadav Reesha , Cohn-Sheehy Brendan I. , Ranganath Charan 
Published: October 2022

AbstractAccording to most memory theories, encoding involves continuous communication between the hippocampus and neocortex leaving the temporal dynamics of hippocampal-neocortical interactions often overlooked. Recent work has shown that we perceive complex events in our lives as dynamic, with relatively distinct starting and stopping points known as event boundaries. Event boundaries may be important for memory, as they are associated with increased activity in the hippocampus, and extended neocortical regions (the posterior cingulate cortex, lateral parietal cortex, and parahippocampal cortex). Our objective was to determine how functional connectivity between the hippocampus and neocortical regions during the encoding of naturalistic events (movies) related to subsequent retrieval and retention of those events. Participants encoded two 16-minute cartoon movies during fMRI scanning. After encoding, participants freely recalled one of the movies immediately, and the other after a 2-day delay. We quantified hippocampal-neocortical functional connectivity (FC) at time windows around each event onset, middle, and offset, and compared these FC measures with subsequent recall. These analyses revealed that higher FC between the hippocampus and the posterior medial network (PMN) at an event’s offset related to whether that event was subsequently recalled. In contrast, mid-event connectivity between the hippocampus and PMN was associated with poorer memory. Furthermore, hippocampal-PMN offset connectivity predicted not only whether events were retained in memory, but also the degree to which these events could be recalled in detail after a 2-day delay. These data demonstrate that the relationship between memory encoding and hippocampal-neocortical interaction is more dynamic than suggested by most memory theories, and they converge with recent modeling work suggesting that event offset is an optimal time for encoding.
Structural basis for the Rad6 activation by the Bre1 N-terminal domain
Authors: Shi Meng , Zhao Jiaqi , Li Mengfei , Huang Wei , Bai Xue , Zhang Wenxue , Zhang Kai , Chen Xuefeng , Xiang Song 
Published: October 2022

AbstractThe mono-ubiquitination of the histone protein H2B (H2Bub1) is a highly conserved histone post-translational modification that plays critical roles in many fundamental processes. In yeast, this modification is catalyzed by the conserved Bre1-Rad6 complex. Bre1 contains a unique N-terminal Rad6 binding domain (RBD), how it interacts with Rad6 and contributes to the H2Bub1 catalysis is unclear. Here, we present crystal structure of the Bre1 RBD-Rad6 complex and structure-guided functional studies. Our structure provides a detailed picture of the interaction between the dimeric Bre1 RBD and a single Rad6 molecule. We further found that the interaction stimulates Rad6’s enzymatic activity by allosterically increasing its active site accessibility and likely contribute to the H2Bub1 catalysis through additional mechanisms. In line with these important functions, we found that the interaction is crucial for multiple H2Bub1-regulated processes. Our study provides molecular insights into the H2Bub1 catalysis.
Mechanotransduction events at the physiological site of touch detection
Authors: Ziolkowski Luke H. , Gracheva Elena O. , Bagriantsev Sviatoslav N. 
Published: October 2022

AbstractAfferents of peripheral mechanoreceptors innervate the skin of vertebrates, where they detect physical touch via mechanically gated ion channels (mechanotransducers). While the afferent terminal is generally understood to be the primary site of mechanotransduction, the functional properties of mechanically activated (MA) ionic current generated by mechanotransducers at this location remain obscure. Here, we report patch-clamp recordings from the afferent terminal innervating Grandry (Meissner) corpuscles in the bill skin of a tactile specialist duck. We show that mechanical stimulation evokes MA current in the afferent with fast kinetics of activation and inactivation during the dynamic phases of the mechanical stimulus. These responses trigger rapidly adapting firing in the afferent detected at the terminal and in the afferent fiber outside of the corpuscle. Our findings elucidate the initial electrogenic events of touch detection in the mechanoreceptor nerve terminal.
Gene expression profiling in trigeminal ganglia from Cntnap2-/-and Shank3b-/-mouse models of autism spectrum disorder
Authors: Ciancone-Chama Alessandra G. , Bozzi Yuri , Balasco Luigi 
Published: October 2022

AbstractSensory difficulties represent a crucial issue in the life of autistic individuals. The diagnostic and statistical manual of mental disorders describes both hyper- and hypo-responsiveness to sensory stimulation as a criterion for the diagnosis autism spectrum disorders (ASD). Among the sensory domain affected in ASD, altered responses to tactile stimulation represent the most commonly reported sensory deficits. Although tactile abnormalities have been reported in monogenic cohorts of patients and genetic mouse models of ASD, the underlying mechanisms are still unknown. Traditionally, autism research has focused on the central nervous system as the target to infer the neurobiological bases of such tactile abnormalities. Nonetheless, the peripheral nervous system represents the initial site of processing of sensory information and a potential site of dysfunction in the sensory cascade. Here we investigated the gene expression deregulation in the trigeminal ganglion (which directly receives tactile information from whiskers) in two genetic models of syndromic autism (Shank3b and Cntnap2 mutant mice) at both adult and juvenile ages. We found several neuronal and non-neuronal markers involved in inhibitory, excitatory, neuroinflammatory and sensory neurotransmission to be differentially regulated within the trigeminal ganglia of both adult and juvenile Shank3b and Cntnap2 mutant mice. These results may help in entangling the multifaced complexity of sensory abnormalities in autism and open avenues for the development of peripherally targeted treatments for tactile sensory deficits exhibited in ASD.
Epigenetic Priming Enhances Chondrogenic Potential of Expanded Chondrocytes for Cartilage Repair
Authors: Scott Adrienne K. , Gallagher Katie M. , Schneider Stephanie E. , Kurse Abhijit , Neu Corey P. 
Published: October 2022

ABSTRACTExpansion of chondrocytes presents a major obstacle in the cartilage regeneration procedure matrix-induced autologous chondrocyte implantation (MACI). Dedifferentiation of chondrocytes during the expansion process leads to the emergence of a fibrotic (chondrofibrotic) phenotype that decreases the chondrogenic potential of the implanted cells. We aim to 1) determine the extent that chromatin architecture of H3K27me3 and H3K9me3 remodels during dedifferentiation and persists when expanded chondrocytes are transferred to a 3D culture; and 2) to prevent this persistent remodeling to enhance the chondrogenic potential of expanded chondrocytes. Chromatin architecture remodeling of H3K27me3 and H3K9me3 was observed at 0, 8 and 16 population doublings in a two-dimensional (2D) culture and after encapsulation of the expanded chondrocytes in a three-dimensional (3D) hydrogel culture. Chondrocytes were treated with inhibitors of epigenetic modifiers (epigenetic priming) for 16 population doublings and then encapsulated in 3D hydrogels. Chromatin architecture of chondrocytes and gene expression were evaluated before and after encapsulation. We observed a change in chromatin architecture of epigenetic modifications H3K27me3 and H3K9me3 during chondrocyte dedifferentiation. Although inhibiting enzymes that modify H3K27me3 and H3K9me3 did not alter the dedifferentiation process in 2D culture, applying these treatments during the 2D expansion did increase the expression of select chondrogenic genes and protein deposition of type II collagen when transferred to a 3D environment. Overall, we found that epigenetic priming of expanded chondrocytes alters the cell fate when chondrocytes are later encapsulated into a 3D environment, providing a potential method to enhance the success of cartilage regeneration procedures.
COVID-19 prognostic model using Bayesian networks learnt on patient data
Authors: Bernaola Nikolas , Bielza Concha , Larrañaga Pedro 
Published: October 2022

AbstractThe response to the ongoing second wave of the COVID-19 pandemic can be helped by giving medical professionals access to models learned on patient data. To achieve this, we learned a Bayesian network model to predict risk of ICU admission, death and time of stay in the hospital from patient history, initial vital signs, initial laboratory tests and medication. Data were obtained from patients that were admitted to an HM hospital with suspicion of COVID-19 until 24/04/2020, excluding unconfirmed diagnosis, those who were admitted before the epidemic started in Madrid, had an outcome that was not discharge or death or died within 24 hours of presentation. Relevant variables for the model were selected with help from medical professionals. We learned the model using Bayesian search as implemented in GeNIe. Of 2,307 patients in the dataset, 679 were excluded. With the remaining 1,645 patients, we learned a model that predicted death with 86.4% accuracy. Some of the initial variables were discarded because they were independent of the outcomes of interest conditioned on some of the other variables. This high redundancy might be useful to build simpler tests for the severity of COVID-19. We show how the model can be used at different stages of patient admission and even with only partial information about the patient. This can be done by clinicians that want a fast second opinion or a summary of the available data from previous patients similar to the one at hand. We then include how we plan to improve the model with extra patient data and how it could be expanded to other contexts, like for example, an epidemiological one.
Cell-free urine- and plasma DNA mutational analysis predicts neoadjuvant chemotherapy response and outcome in patients with muscle invasive bladder cancer
Authors: Christensen Emil , Nordentoft Iver , Elbæk Sara K. , Birkenkamp-Demtröder Karin , Taber Ann , Andreasen Tine G. , Strandgaard Trine , Knudsen Michael , Lamy Philippe , Agerbæk Mads , Jensen Jørgen B. , Dyrskjøt Lars 
Published: October 2022

AbstractPurposeInvestigate and compare the use of plasma- and urine DNA mutation analysis for predicting neoadjuvant chemotherapy (NAC) response and long-term oncological outcome in patients with muscle invasive bladder cancer.Experimental DesignWhole exome sequencing of tumor and germline DNA was performed for 92 patients treated with NAC followed by radical cystectomy (RC). A custom NGS panel capturing approx. 50 mutations per patient was designed and utilized to track tumor-derived DNA (tdDNA) in liquid biopsies. A total of 447 plasma samples, 281 urine supernatants and 123 urine pellets collected before, during and after treatment were analyzed. Patients were enrolled from 2013-2019 with a median follow-up time of 41.3 months after RC.ResultsWe identified tdDNA before initiation of NAC in 89% of urine supernatants, 85% of urine pellets and 43% of plasma samples. tdDNA levels were higher in urine supernatants and urine pellets compared to plasma samples (p<0.001). In plasma, detection of tdDNA before NAC was associated with a lower NAC response rate (p<0.001). Detection of tdDNA after NAC was associated with lower response rates in plasma, urine supernatant and urine pellet (p<0.001, p=0.03, p=0.002). tdDNA dynamics during NAC was predictive of NAC response and outcome in urine supernatant and plasma (p=0.006,p=0.002). A combined measure from plasma and urine supernatant tdDNA dynamics stratified patients by outcome (p=0.003).ConclusionsAnalysis of tdDNA in plasma and urine samples both separately and combined has potential to predict treatment response and outcome.
Impact of COVID-19 on the national development of countries: implications for the public health
Authors: Kuzmenko Olha , Lyeonov Serhiy , Letunovska Nataliia , Kashcha Mariya , Strielkowski Wadim 
Published: October 2022

AbstractThe article focuses on measuring the fluctuations in countries’ development as a result of the COVID-19 pandemic. The obtained measures make it possible to predict the extent of the impact of risks to public health on the economy, financial-budgetary, political-institutional development of states in the future, as well as the social determinants of public health. This assessment represents a new paradigm that makes it possible to effectively evaluate the manifestations of the consequences of COVID-19 and to identify the relevant determinants of the lack of resilience of the medical and social security systems to the coronavirus pandemic around the world. We picked the determinant of national development indicators of the 59 countries in order to measure the fluctuations in their economic development. In addition, we applied the binary response model for identifying the economic, financial-budgetary, and political-institutional development change with the happiness index of the countries being the dependent variable. The analysis of our empirical model made it possible for us to conclude that economic and financial-budgetary components have significantly increased the influence on well-being during the COVID-19 pandemic. In contrast, we observed the decrease in the impact of political and institutional indicators during the same period.
A genetic risk score improves risk stratification for anticoagulation-related intracerebral hemorrhage
Authors: Mayerhofer Ernst , Parodi Livia , Prapiadou Savvina , Malik Rainer , Rosand Jonathan , Georgakis Marios K , Anderson Christopher D 
Published: October 2022

AbstractBackgroundIntracerebral hemorrhage (ICH) is the most devastating adverse outcome for patients on anticoagulants. Clinical risk scores (CRS) that quantify bleeding risk can guide decision making in situations when indication or duration for anticoagulation is uncertain. We investigated whether integration of a genetic risk score (GRS) into an existing risk factor-based CRS could improve risk stratification for anticoagulation-related ICH.MethodsWe constructed 153 GRS from genome-wide association data of 1,545 ICH cases and 1,481 controls and validated them in 431 ICH cases and 431 matched controls from the population-based UK Biobank. The score that explained the largest variance in ICH risk was selected and tested for prediction of incident ICH in an independent cohort of 5,530 anticoagulant users. A CRS for major anticoagulation-related hemorrhage, based on 8/9 components of the HAS-BLED score, was compared with an enhanced score incorporating an additional point for high genetic risk for ICH (CRS+G).ResultsAmong anticoagulated individuals, 94 ICH occurred over a mean follow-up of 11.9 years. Compared to the lowest GRS tertile, being in the highest tertile was associated with a two-fold increased risk for incident ICH (HR: 2.08 [95% CI 1.22, 3.56]). While the CRS predicted incident ICH with a HR of 1.24 per one point increase (95% CI [1.01, 1.53]), adding a point for high genetic ICH risk led to a stronger association (HR of 1.33 per one point increase, 95% CI [1.11, 1.59]) with improved risk stratification (C-index 0.58 vs. 0.53) and maintained calibration (integrated calibration index 0.001 for both). The new score (CRS+G) showed 20% improvement of high-risk classification among individuals with ICH and a net reclassification improvement of 0.10.ConclusionsAmong anticoagulant users, a prediction score incorporating genomic information is superior to a clinical risk score alone for ICH risk stratification and could serve in clinicaldecision making.
The pervasive association between political ideology and COVID-19 vaccine uptake in Brazil: an ecologic study
Authors: Seara-Morais Gabriel J. , Avelino-Silva Thiago J. , Couto Marcia , Avelino-Silva Vivian I. 
Published: October 2022

AbstractBackgroundStudies suggest vaccine hesitancy is an increasingly significant phenomenon in Brazil and other countries. Moreover, political ideologies have emerged as an influencing factor for vaccine hesitancy during the COVID-19 pandemic.MethodsIn this study, we use information from publicly available databases to investigate the association between political alignment, depicted by the percentage of Bolsonaro voters in the presidential elections of 2018 and 2022, and COVID-19 vaccination in Brazilian municipalities, adjusted for human development index (HDI) scores and basic sociodemographic characteristics of voters.FindingsFor both the 2018 and 2022 elections, higher percentages of Bolsonaro voters were significantly associated with a lower vaccination index after adjustment for voters’ sociodemographic characteristics. We also found a statistically significant interaction between the percentage of Bolsonaro voters and HDI, with a more significantly detrimental effect of the right-wing political stance in municipalities in the lower HDI quartile.InterpretationOur study highlights what may be the beginning of a new scenario with unforeseen challenges for vaccine programs: the politicization of vaccines. Strategies to face these challenges should include joint efforts from governments and civil society for a common public health goal.FundingThis manuscript received no specific funding
Lipid Droplets Fuel Small Extracellular Vesicle Biogenesis
Authors: Genard Géraldine C. , Tirinato Luca , Pagliari Francesca , Da Silva Jessica , Giammona Alessandro , Alquraish Fatema , Bordas Marie , Marafioti Maria Grazia , Di Franco Simone , Janssen Jeannette , Garcia-Calderón Daniel , Hanley Rachel , Nistico Clelia , Fukasawa Yoshinori , Müller Torsten , Krijgsveld Jeroen , Todaro Matilde , Costanzo Francesco Saverio , Stassi Giorgio , Nessling Michelle , Richter Karsten , Maass Kendra K. , Liberale Carlo , Seco Joao 
Published: October 2022

AbstractDespite an increasing gain of knowledge regarding small extracellular vesicle (sEV) composition and functions in cell-cell communication, the mechanism behind their biogenesis remains unclear. Here, we revealed for the first time that the sEV biogenesis and release into the microenvironment are tightly connected with another important organelle: Lipid Droplets (LD). We have observed this correlation using different human cancer cell lines as well as patient-derived colorectal cancer stem cells (CR-CSCs). Our results showed that the use of external stimuli such as radiation, pH, hypoxia, or lipid interfering drugs, known to affect the LD content, had a similar effect in terms of sEV secretion. Additional validations were brought using multiple omics data, at the mRNA and protein levels. Altogether, the possibility to fine-tune sEV biogenesis by targeting LDs, could have a massive impact on the amount, the cargos and the properties of those sEVs, paving the way for new clinical perspectives.Significance Statement
Validation of ligand tetramers for the detection of antigen-specific lymphocytes
Authors: Fitzpatrick Kristin S. , Degefu Hanna N. , Poljakov Katrina , Bibby Madeleine G. , Remington Allison J. , Searles Tyler G. , Gray Matthew D. , Boonyaratanakornkit Jim , Rosato Pamela C. , Taylor Justin J. 
Published: October 2022

ABSTRACTThe study of antigen-specific lymphocytes has been a key advancement in immunology the past few decades. The development of multimerized probes containing antigens, peptide:MHC complexes, or other ligands was one innovation allowing the direct study antigen-specific lymphocytes by flow cytometry. While these types of studies are now common and performed by thousands of laboratories, quality control and assessment of probe quality is often minimal. In fact, many of these types of probes are made in-house and protocols vary between labs. While peptide:MHC multimers can often be obtained from commercial sources or core facilities, few such services exist for antigen multimers. To ensure high quality and consistency with ligand probes, we have developed an easy and robust multiplexed approach using commercially available beads able to bind antibodies specific for the ligand of interest. Using this assay, we have sensitively assessed the performance of peptide:MHC and antigen tetramers and find considerable batch-to-batch variability in performance and stability over time. This assay can also reveal common production errors such as miscalculation of antigen concentration. Unexpectedly, probes including the fluorochrome allophycocyanin exhibited more rapid performance decline compared to probes including the fluorochrome R-phycoerythrin when both were stored at 4°C. This performance decline was reduced for most, but not all, batches when antigen tetramers were instead stored at −20°C in 50% glycerol. This work could set the stage for the development of standardized assays for all commonly used ligand probes to limit lab-to-lab technical variation, and experimental failure due to probe underperformance.