bluuebunny/crossref_metadata_2025_split huggingface dataset:
scROSHI - robust supervised hierarchical identification of single cells
Authors: Prummer Michael , Bertolini Anne , Bosshard Lars , Barkmann Florian , Yates Josephine , Boeva Valentina ,   The TumorProfiler Consortium, Stekhoven Daniel , Singer Franziska 
Published: April 2022

AbstractIdentifying cell types based on expression profiles is a pillar of single cell analysis. Existing machine-learning methods identify predictive features from annotated training data, which are often not available in early-stage studies. This can lead to overfitting and inferior performance when applied to new data. To address these challenges we present scROSHI, which utilizes previously obtained cell type-specific gene sets and does not require training or the existence of annotated data. By respecting the hierarchical nature of cell type relationships and assigning cells consecutively to more specialized identities, excellent prediction performance is achieved. In a benchmark based on publicly available PBMC data sets, scROSHI outperforms competing methods when training data are limited or the diversity between experiments is large.
Speech Production in Intracranial Electroencephalography: iBIDS Dataset
Authors: Verwoert Maxime , Ottenhoff Maarten C. , Goulis Sophocles , Colon Albert J. , Wagner Louis , Tousseyn Simon , van Dijk Johannes P. , Kubben Pieter L. , Herff Christian 
Published: April 2022

ABSTRACTSpeech production is an intricate process involving a large number of muscles and cognitive processes. The neural processes underlying speech production are not completely understood. As speech is a uniquely human ability, it can not be investigated in animal models. High-fidelity human data can only be obtained in clinical settings and is therefore not easily available to all researchers. Here, we provide a dataset of 10 participants reading out individual words while we measured intracranial EEG from a total of 1103 electrodes. The data, with its high temporal resolution and coverage of a large variety of cortical and sub-cortical brain regions, can help in understanding the speech production process better. Simultaneously, the data can be used to test speech decoding and synthesis approaches from neural data to develop speech Brain-Computer Interfaces and speech neuroprostheses.
High frequency spike inference with particle Gibbs sampling
Authors: Diana Giovanni , Sermet B. Semihcan , DiGregorio David A. 
Published: April 2022

AbstractFluorescent calcium indicators are indispensable tools for monitoring the spiking activity of large neuronal populations in animal models. However, despite the plethora of algorithms developed over the last decades, accurate spike time inference methods for spike rates greater than 20 Hz are lacking. More importantly, little attention has been devoted to the quantification of statistical uncertainties in spike time estimation, which is essential for assigning confidence levels to inferred spike patterns. To address these challenges, we introduce (1) a statistical model that accounts for bursting neuronal activity and baseline fluorescence modulation and (2) apply a Monte Carlo strategy (particle Gibbs with ancestor sampling) to estimate the joint posterior distribution of spike times and model parameters. Our method is competitive with state-of-the-art supervised and unsupervised algorithms by analyzing the CASCADE benchmark datasets. The analysis of fluorescence transients recorded using an ultrafast genetically encoded calcium indicator, GCaMP8f, demonstrates the ability of our method to infer spike time intervals as short as five milliseconds. Overall, our study describes a Bayesian inference method to detect neuronal spiking patterns and their uncertainty. The use of particle Gibbs samplers allows for unbiased estimates of spike times and all model parameters, and it provides a flexible statistical framework to test more specific models of calcium indicators.
Paired Associates Learning is Disrupted After Unilateral Parietal Lobe Controlled Cortical Impact in Rats: A Trial-by-Trial Behavioral Analysis
Authors: Smith Samantha M. , Garcia Elena L. , Davidson Caroline , Thompson John , Lovett Sarah , Ferekides Nedi , Federico Quinten , Bumanglag Argyle V. , Hernandez Abbi R. , Abisambra Jose F. , Burke Sara N. 
Published: April 2022

ABSTRACTApproximately 60-70 million people suffer from a traumatic brain injury (TBI) each year. As animal models continue to be paramount in understanding and treating cognitive impairment following TBI, the necessity of testing intervention strategies in clinically relevant settings cannot be ignored. This study used a unilateral parietal lobe controlled cortical impact (CCI) model of TBI and tested rats on a touchscreen-based associative learning task, Paired Associates Learning (PAL). In humans, PAL has been used to assess cognitive deficits in stimulus-location association in a multitude of disease states, including TBI. To date, the extent to which a rat model of TBI produces deficits in PAL has not yet been reported, although the usage of PAL will be important for understanding the clinical consequences of cognitive impairment post-injury and throughout intervention treatment. This study details the behavioral and histological consequences of the CCI injury model and closes a translational research gap between basic and clinical TBI research.HIGHLIGHTSPAL performance declines in a rat model of TBI.Response-driven bias in PAL becomes elevated after TBI.Inflammatory microglial response in the thalamus correlates with PAL deficit.
Microphysiological Drug-Testing Platform for Identifying Responses to Prodrug Treatment in Primary Leukemia
Authors: Gökçe Furkan , Kaestli Alicia , Lohasz Christian , de Geus Martina , Kaltenbach Hans-Michael , Renggli Kasper , Bornhauser Beat , Hierlemann Andreas , Modena Mario 
Published: April 2022

AbstractDespite increasing survival rates of pediatric leukemia patients over the past decades, the outcome of some leukemia subtypes has remained dismal. Drug sensitivity and resistance testing on patient-derived leukemia samples provide important information to tailor treatments for high-risk patients. However, currently used well-based drug screening platforms have imitations in predicting the effects of prodrugs, a class of therapeutics that require metabolic activation to become effective. To address this issue, we developed a microphysiological drug-testing platform that enables co-culturing of patient-derived leukemia cells, human bone marrow mesenchymal stromal cells, and human liver microtissues within the same microfluidic platform. This platform also enables to control the physical interaction between the diverse cell types. We were able to recapitulate hepatic prodrug activation of ifosfamide in our platform, which is very difficult in traditional well-based assays. By testing the susceptibility of primary patient-derived leukemia samples to the prodrug ifosfamide, we identified sample-specific sensitivities to ifosfamide in primary leukemia samples. We found that our microfluidic platform enabled the recapitulation of physiologically relevant conditions and the testing of prodrugs including short-lived and unstable metabolites. The platform holds great potential for clinical translation and precision chemotherapy selection.
Cataloging the potential functional diversity of Cacna1e splice variants using long-read sequencing
Authors: Bhuiyan Shamsuddin , Tyson John R. , Belmadani Manuel , Sicherman Jordan , Snutch Terrance P. , Pavlidis Paul 
Published: April 2022

ABSTRACTVoltage gated calcium channels (VGCCs) regulate the influx of calcium ions in many cell types, but our lack of knowledge about the plethora of VGCC splice variants remains a gap in our understanding of calcium channel function. A recent advance in profiling gene splice variation is to use long-read RNA-sequencing technology. We sequenced Cacna1e transcripts from the rat thalamus using Oxford Nanopore sequencing, yielding the full structure of 2,110 Cacna1e splice variants. However, we observed that only 154 Cacna1e splice variants were likely to encode for a functional VGCC based on predicted amino acid sequences. We then computationally prioritized these 154 splice variants using expression and evolutionary conservation and found that four splice variants are candidate functionally distinct splice isoforms. Our work not only provides long-read sequencing of Cacna1e for the first time, but also the first computational evaluation of which Cacna1e splice variants are the best candidates for future follow-up.SIGNIFICANCE STATEMENTVoltage gated calcium channels (Cacna1x genes) are implicated in many neurological disorders and their encoding genes are predicted to have complex patterns of alternative splicing. Previous approaches relied on short-read RNA-seq to characterize calcium channel splice variants. Here, we use long-read nanopore sequencing to establish a set of Cacna1e transcripts in the rat thalamus and use computational methods to prioritize four transcripts as functionally distinct splice isoforms. Our work to provide the field with prioritized transcripts will not only improve our understanding of Cacna1e function but its role in disease as well.
Brain-wide sensory aberrations in a Parkinson’s Disease mouse model revealed by functional MRI
Authors: Lungu Ruxanda , Fernandes Francisca F. , Outeiro Tiago F. , Shemesh Noam 
Published: April 2022

AbstractParkinson’s disease (PD) is associated with irreparable damage to dopaminergic neurons in brain areas involved in movement. Frequently, a very early symptom of PD involves an impaired sense of smell, while other studies suggest a broader impairment of other sensory modalities. Still, the associated brain-wide mechanisms underlying this phenomenon remain unclear. Here, we harness in vivo functional Magnetic Resonance Imaging (fMRI) at 9.4T to investigate how the olfactory and visual systems are affected in an α-Synuclein (αSyn) mouse model of PD. We find significant aberrations in fMRI responses along both sensory pathways including decreases in activation extent and in activation amplitude. Deficits in the olfactory system were larger than in the visual pathway, but nevertheless both sensory systems were clearly impacted, suggesting a more overarching mechanism may be involved. To further ensure that the aberrations observed in the fMRI signals were not driven solely by putative vascular deficiency, we quantified c-FOS expression in the olfactory system and found statistically significant decreases in the PD group when compared to age-matched controls. Hence, our findings indicate a neural origin for the observed fMRI aberrations. Our findings thus demonstrate a more global deficiency in sensory systems in the (αSyn) mouse model.One Sentence SummaryParkinson’s disease (PD) is associated with an impaired sense of smell and more generally sensory deficits, but the associated brain-wide mechanisms remain unclear; here, we investigate aberrations in BOLD-fMRI responses along sensory pathways in an αSYN PD mouse model.
Design of an Integrated Microvascularised Human Skin-on-a-Chip Tissue Equivalent Model
Authors: Jones Christian F. E. , di Ciò Stefania , Connelly John , Gautrot Julien 
Published: April 2022

AbstractTissue engineered skin constructs have been under development since the 1980s as a replacement for human skin tissues and animal models for therapeutics and cosmetic testing. These have evolved from simple single cell-assays to increasingly complex models with integrated dermal equivalents and multiple cell types including a dermis, epidermis and vasculature. The development of micro-engineered platforms and biomaterials has enabled scientists to better recreate and capture the tissue microenvironment in vitro, including the vascularization of tissue models and their integration into microfluidic chips. However, to date, microvascularised human skin equivalents in a microfluidic context have not been reported. Here we present the design of a novel skin-on-a-chip model integrating human derived primary and immortalized cells in a full thickness skin equivalent. The model is housed in a microfluidic device, in which a microvasculature was previously established. We characterize the impact of our chip design on the quality of the microvascular networks formed and evidence that this enables the formation of more homogenous networks. We developed a methodology to harvest tissues from embedded chips, after 14 days of culture, and characterize the impact of culture conditions and vascularization (including with pericyte co-cultures) on the stratification of the epidermis in the resulting skin equivalents. Our results indicate that vascularization enhances stratification and differentiation (thickness, architecture and expression of terminal differentiation markers such as involucrin and transglutaminase 1), allowing formation of more mature skin equivalents in microfluidic chips. The skin-on-a-chip tissue equivalents developed, thanks to their realistic microvasculature, may find application for the testing efficacy and safety of therapeutics delivered systemically, in a human context.
The presynaptic active zone protein Bassoon as a marker for synapses between Type lll cells and afferent nerve fibers in taste buds
Authors: Ikuta Rio , Hamada Shun 
Published: April 2022

AbstractTaste buds are receptor organs for gustation. Two types of taste receptor cells have been identified in taste buds: Type II and Type III cells. Type III cells connect with afferent fibers through conventional chemical synapses. In the present study on taste buds, we used immunocytochemistry to examine the distribution pattern of Bassoon, a scaffolding protein of the cytomatrix at the active zones of conventional synapses. Bassoon was predominantly detected as small puncta in Type III cells. Bassoon-immunoreactive puncta were observed in proximity to or partially overlapping with intragemmal nerve fibers. Immunoelectron microscopy showed Bassoon at the active zones of the conventional synapses of Type III cells. The present results demonstrated that Bassoon is a marker for synapses between Type III cells and afferent fibers in taste buds.
DeepParcellation: a novel deep learning method for robust brain magnetic resonance imaging parcellation in older East Asians
Authors: Lim Eun-Cheon , Choi Uk-Su , Choi Kyu Yeong , Lee Jang Jae , Sung Yul-Wan , Ogawa Seiji , Kim Byeong Chae , Lee Kun Ho , Gim Jungsoo ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: April 2022

AbstractAccurate parcellation of cortical regions is crucial for distinguishing morphometric changes in aged brains, particularly in degenerative brain diseases. Normal aging and neurodegeneration precipitate brain structural changes, leading to distinct tissue contrast and shape in people aged > 60 years. Manual parcellation by trained radiologists can yield a highly accurate outline of the brain; however, analyzing large datasets is laborious and expensive. Alternatively, newly-developed computational models can quickly and accurately conduct brain parcellation, although thus far only for the brains of Caucasian individuals. DeepParcellation, our novel deep learning model for 3D magnetic resonance imaging (MRI) parcellation, was trained on 5,035 brains of older East Asians (Gwangju Alzheimer’s & Related Dementia) and 2,535 brains of Caucasians. We trained full 3D models for N-way individual regions of interest using memory reduction techniques. Our method showed the highest similarity and robust reliability among age-ethnicity groups, especially when parcellating the brains of older East Asians.
Ketamine and its metabolite 2R,6R-hydroxynorketamine promote ocular dominance plasticity and release TRKB from inhibitory control without changing perineuronal nets enwrapping parvalbumin interneurons
Authors: Cannarozzo Cecilia , Rubiolo Anna , Casarotto Plinio , Castrén Eero 
Published: April 2022

AbstractKetamine has been described as a fast-acting antidepressant, exerting effects in depressed patients and in preclinical models with a rapid onset of action. The typical antidepressant fluoxetine is known to induce plasticity in the adult rodent visual cortex, as assessed by a shift in ocular dominance, a classical model of brain plasticity, and a similar effect has been described for ketamine and its metabolite 2R,6R-hydroxynorketamine (R,R-HNK). Here, we demonstrate that ketamine (at 3 or 20 mg/kg) and R,R-HNK facilitated the shift in ocular dominance in monocularly deprived mice, after 3 injections, throughout the 8-days regimen. Notably, the comparison between the treatments indicates a higher effect size of R,R-HNK compared to ketamine. Treatment with ketamine or R,R-HNK failed to influence the levels of perineuronal nets (PNNs) surrounding parvalbumin-positive interneurons. However, we observed in vitro that both ketamine and R,R-HNK are able to disrupt the tropomyosin-related kinase B (TRKB) interaction with the protein tyrosine phosphatase sigma (PTPσ), which upon binding to PNNs dephosphorylates TRKB. These results support a model where diverse drugs promote the reinstatement of juvenile-like plasticity by directly binding TRKB and releasing it from PTPσ regulation, without necessarily affecting PNNs deposits.
Studying meiosis in mitosis: Activating the meiosis-specific Red1-Hop1-Mek1 complex in mitotic budding yeast cells
Authors: Nivsarkar Vaishnavi N. , Chen Linda , Funk Saskia K. , Weir John R. , Vader Gerben 
Published: April 2022

AbstractIn mitosis, sequences on sister chromatids are preferred as DNA repair templates, whereas in meiosis interhomolog-based repair is promoted. The switch of template preference during homologous recombinational (HR) repair of DNA breaks is a defining event in sexual reproduction. This preference is needed to establish linkages between homologous chromosomes that support meiotic chromosome segregation. In budding yeast, a central activity that enforces meiotic interhomolog bias is encoded in a meiosis-specific protein kinase complex, consisting of Red1, Hop1 and Mek1 (i.e., the RHM complex). Activation of Mek1 kinase in meiosis – dictated by complex formation and upstream DNA break-dependent signaling – leads to modification of HR factors and the establishment of interhomolog HR repair bias. How meiotic repair bias is established is a central question with implications for sexual reproduction, genetic diversity and genome stability. Studying the role of the RHM complex in DNA repair is complicated by the fact that Red1 and Hop1 are required for efficient meiotic DNA break formation. Here, we conditionally express RHM components in mitotically-dividing cells to show that these factors can autonomously establish the RHM complex outside of its physiological environment. In vivo analysis is complemented with in vitro biochemical reconstitution to analyze the composition of a Red1-Hop1 subcomplex. The RHM complex can be activated under DNA damaging conditions in mitotically-dividing cells, and activation depends on upstream Mec1 kinase function. We use this system to perform a structure-function analysis of RHM complex formation and Mek1 activation. Finally, we demonstrate that expressing active Mek1 in mitosis leads to rad51Δ-like DNA break sensitivity, suggesting that activation of the RHM complex is sufficient to reconstitute (parts of) its physiological function in mediating HR-based repair. This system should enable querying downstream effects of RHM complex action on DNA repair dynamics and template bias. Human homologs of Red1 and Hop1 are often aberrantly re-expressed in cancer cells. Our system has the potential to inform on (dys)functional effects of these genes on genome stability during human tumorigenesis.
Genomic analyses identify key molecules and significant biological processes in LOC441461 treated gastric cancer cells
Authors: Zhang Liang , Chang Tingxiang , Wang Mengshan 
Published: April 2022

AbstractGastric cancer (GC) remains one of the leading cancers globally with a high prevalence and high mortality rate. Currently, Long noncoding RNAs (lncRNAs) LOC441461 have been found to be related to cancer that regulates cell growth, apoptosis, and metastasis. However, the mechanisms of LOC441461 treated gastric cancer are still unknown. In this study, we aim to identify the key molecules and signaling pathways by analyzing the RNA-seq data. The GSE193700 was created by the Illumina NovaSeq 6000 (Homo sapiens). The KEGG and GO analyses indicated that Human papillomavirus infection and Epstein-Barr virus infection were the main biological processes during the knockdown of LOC441461 in gastric cancer. Moreover, we figured out several interactive genes including STAT1, IFIH1, ISG15, IRF7, IRF1, MX1, DDX58, IFIT1, RSAD2, and IFIT3. Our study may provide new knowledge on the treatment of gastric cancer.
Chitin oligomers directly promote lymphoid innate and adaptive immune cell activation
Authors: Gloria Yamel Cardona , Fuchs Katharina , Chang Tzu-Hsuan , Engels Pujan , Rusch Elisa , Gouttefangeas Cécile , Weber Alexander N.R. 
Published: April 2022

AbstractBackgroundChitin is a highly abundant N-acetyl-glucosamine (GlcNAc) polysaccharide which has been linked to immune responses in the context of fungal infections and allergic asthma, especially T helper 2 (Th2) immune responses. Unfortunately, due to the frequent use of crude chitin preparations of unknown purity and degree of polymerization there is still great uncertainty how chitin activates different parts of the human immune system.ObjectiveWe recently identified chitin oligomers of six GlcNAc units as the smallest immunologically active chitin motif and the innate immune receptor TLR2 as primary chitin sensor on human and murine myeloid cells, but the response of lymphoid cells to oligomeric chitin has not been investigated and was addressed here.MethodsFlow cytometric analysis of primary human immune cells upon stimulation with oligomeric chitin. For detailed Methods, please see the Methods section in this article’s Online Repository at www.jacionline.org.ResultHere we report that chitin oligomers also activate immune responses by both primary lymphoid innate and adaptive immune cells: Notably, chitin oligomers activated Natural Killer (NK) cells and B lymphocytes. Moreover, the maturation of dendritic cells enabled CD8 T cell recall responses.ConclusionsOur results suggest that chitin oligomers not only trigger immediate innate responses in limited range of myeloid cells but exert critical activities across the entire human immune system.Key messagesChitin oligomers are microbe-associated molecular patterns involved in TLR2-dependent fungal recognition by myeloid immune cells.Here we show that lymphoid cells, most notably Natural Killer (NK) cells and B cells, are activated by oligomeric chitin.Oligomeric chitin also promotes antigen-presenting cell (APC) maturation and CD8 T cell recall responses.Capsule summaryOligomeric chitin is a novel microbe-associated molecular patterns involved in TLR2-dependent fungal recognition by myeloid innate immune cells. Here we show that lymphoid innate and adaptive immune responses are also promoted by oligomeric chitin.