bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analytical performance of a highly sensitive system to detect gene variants using next-generation sequencing for lung cancer companion diagnostics
Authors: Kato Kikuya , Okami Jiro , Nakamura Harumi , Honma Keiichiro , Sato Yoshiharu , Nakamura Seiji , Kukita Yoji , Nakatsuka Shin-ichi , Higashiyama Masahiko 
Published: October 2021

AbstractThe recent increase in the number of molecular-targeted agents for non-small cell lung carcinoma and the corresponding target genes has led to the demand for the simultaneous testing of multiple genes. Although gene panels that use next-generation sequencing (NGS) are ideal for this purpose, conventional panels require a high tumor content, and biopsy samples often do not meet this requirement. We developed a new NGS panel, called a compact panel, to accommodate biopsy samples without restricting tumor content. The panel was characterized by high sensitivity, with detection limits for mutations of 0.14%, 0.20%, 0.48%, 0.24%, and 0.20% forEGFRexon 19 deletion, L858R, T790M,BRAFV600E, andKRASG12C, respectively. Mutation detection also had a high quantitative ability, with correlation coefficients ranging from 0.966 to 0.992. The threshold for fusion detection was 1%. The panel exhibited good concordance with the approved tests. Identity rates are as follows:EGFRpositive, 100% (95% confidence interval, 95.5-100);EGFRnegative, 90.9 (82.2-96.3);BRAFpositive, 100 (59.0-100);BRAFnegative, 100 (94.9-100);KRASG12C positive, 100 (92.7-100);KRASG12C negative, 100 (93.0-100);ALKpositive, 96.7 (83.8-99.9);ALKnegative, 98.4 (97.2-99.2);ROS1positive, 100 (66.4-100);ROS1negative, 99.0 (94.6-100);METpositive, 98.0 (89.0-99.9);METnegative 100 (92.8-100);RETpositive, 93.8 (69.8-100);RETnegative, 99.8 (94.9-100). The analytical performance showed that the compact panel could handle various types of biopsy samples obtained by routine clinical practice without requiring strict pathological monitoring, as in the case of conventional NGS panels.
ConTreeDP: A consensus method of tumor trees based on maximum directed partition support problem
Authors: Fu Xuecong , Schwartz Russell 
Published: October 2021

AbstractPhylogenetic inference has become a crucial tool for interpreting cancer genomic data, but continuing advances in our understanding of somatic mutability in cancer, genomic technologies for profiling it, and the scale of data available have created a persistent need for new algorithms able to deal with these challenges. One particular need has been for new forms of consensus tree algorithms, which present special challenges in the cancer space for dealing with heterogeneous data, short evolutionary time scales, and rapid mutation by a wide variety of somatic mutability mechanisms. We develop a new consensus tree method for clonal phylogenetics, ConTreeDP, based on a formulation of the Maximum Directed Partition Support Consensus Tree (MDPSCT) problem. We demonstrate theoretically and empirically that our approach can efficiently and accurately compute clonal consensus trees from cancer genomic data.Availability: https://github.com/CMUSchwartzLab/ConTreeDP
Tagging active neurons by soma-targeted Cal-Light
Authors: Hyun Jung Ho , Nagahama Kenichiro , Namkung Ho , Mignocchi Neymi , Hannan Patrick , Krüssel Sarah , Kwak Chuljung , McElroy Abigail , Liu Bian , Cui Mingguang , Lee Seunghwan , Lee Dongmin , Huganir Richard L. , Sawa Akira , Kwon Hyung-Bae 
Published: October 2021

AbstractVerifying causal effects of neural circuits is essential for proving direct a circuit-behavior relationship. However, techniques for tagging only active neurons with high spatiotemporal precision remain at the beginning stages. Here we developed the soma-targeted Cal-Light (ST-Cal-Light) which selectively converts somatic calcium rise triggered by action potentials into gene expression. Such modification simultaneously increases the signal-to-noise ratio (SNR) of reporter gene expression and reduces the light requirement for successful labeling. Because of the enhanced efficacy, the ST-Cal-Light enables the tagging of functionally engaged neurons in various forms of behaviors, including context-dependent fear conditioning, leverpressing choice behavior, and social interaction behaviors. We also targeted kainic acid-sensitive neuronal populations in the hippocampus which subsequently suppressed seizure symptoms, suggesting ST-Cal-Light’s applicability in controlling disease-related neurons. Furthermore, the generation of a conditional ST-Cal-Light knock-in (KI) mouse provides an opportunity to tag active neurons in a region- or cell-type specific manner via crossing with other Cre-driver lines. Thus, the versatile ST-Cal-Light system links somatic action potentials to behaviors with high temporal precision, and ultimately allows functional circuit dissection at a single cell resolution.
Feature distribution learning by passive exposure
Authors: Pascucci David , Ceylan Gizay , Kristjánsson Árni 
Published: October 2021

AbstractHumans can rapidly estimate the statistical properties of groups of stimuli, including their average and variability. But recent studies of so-called Feature Distribution Learning (FDL) have shown that observers can quickly learn even more complex aspects of feature distributions. In FDL, observers learn the full shape of a distribution of features in a set of distractor stimuli and use this information to improve visual search: response times (RT) are slowed if the target feature lies inside the previous distractor distribution, and the RT patterns closely reflect the distribution shape. FDL requires only a few trials and is markedly sensitive to different distribution types. It is unknown, however, whether our perceptual system encodes feature distributions automatically and by passive exposure, or whether this learning requires active engagement with the stimuli. In two experiments, we sought to answer this question. During an initial exposure stage, participants passively viewed a display of 36 lines that included one orientation singleton or no singletons. In the following search display, they had to find an oddly oriented target. The orientations of the lines were determined either by a Gaussian or a uniform distribution. We found evidence for FDL only when the passive trials contained an orientation singleton. Under these conditions, RT’s decreased as a function of the orientation distance between the target and the exposed distractor distribution. These results suggest that FDL can occur by passive exposure, but only if an orientation singleton appears during exposure to the distribution.
Neuronal hemoglobin induces loss of dopaminergic neurons in mouse Substantia nigra, cognitive deficits and cleavage of endogenous α-synuclein
Authors: Chiara Santulli , Carlotta Bon , Elena De Cecco , Marta Codrich , Joanna Narkiewicz , Pietro Parisse , Fabio Perissinotto , Claudio Santoro , Francesca Persichetti , Giuseppe Legname , Stefano Espinoza , Stefano Gustincich 
Published: October 2021

ABSTRACTBackgroudParkinson’s disease (PD) presents the selective loss of A9 dopaminergic (DA) neurons of Substantia Nigrapars compacta(SNpc) and the presence of intracellular aggregates called Lewy bodies. α-synuclein (α-syn) species truncated at the carboxy terminal (C-terminal) accumulate in pathological inclusions and promote α-syn aggregation and toxicity.Hemoglobin (Hb) is the major oxygen carrier protein in erythrocytes. In addition, Hb is expressed in A9 DA neurons where it influences mitochondrial activity. Hb overexpression increases cells’ vulnerability in a neurochemical model of PDin vitroand forms cytoplasmic and nucleolar aggregates upon short-term overexpression in mouse SNpc.Methodsα and β-globin chains were co-expressed in DA cells of SNpcin vivoupon stereotaxic injections of an Adeno-Associated Virus isotype 9 (AAV9) and in DA iMN9D cellsin vitro.ResultsLong-term Hb over-expression in SNpc induced the loss of about 50% of DA neurons, a mild motor impairment and deficits in recognition and spatial working memory. Hb triggered the formation of endogenous α-synuclein C-terminal truncated species. Similar α-syn fragments were foundin vitroin DA iMN9D cells over-expressing α and β-globins when treated with pre-formed α-syn fibrils.ConclusionOur study positions Hb as a relevant player in PD pathogenesis for its ability to trigger DA cells’ lossin vivoand the formation of C-terminal α-synuclein fragments.
Whole genome sequences of Treponema pallidum subsp. endemicum isolated from Cuban patients: the non-clonal character of isolates suggests a persistent human infection rather than a single outbreak
Authors: Vrbová Eliška , Noda Angel A. , Grillová Linda , Rodríguez Islay , Forsyth Allyn , Oppelt Jan , Šmajs David 
Published: October 2021

AbstractBejel (endemic syphilis) is a neglected non-venereal disease caused by Treponema pallidum subsp. endemicum (TEN). Although it is mostly present in hot, dry climates, a few cases have been found outside of these areas. The aim of this work was the sequencing and analysis of TEN isolates obtained from “syphilis patients” in Cuba, which is not considered an endemic area for bejel.Genomes were obtained by pool segment genome sequencing or direct sequencing methods, and the bioinformatics analysis was performed according to an established pipeline.We obtained four genomes with 100%, 81.7%, 52.6%, and 21.1% of broad coverage, respectively. The sequenced genomes revealed a non-clonal character, with nucleotide variability ranging between 0.2–10.3 nucleotide substitutions per 100 kbp among the TEN isolates. Nucleotide changes affected 27 genes, and the analysis of the completely sequenced genome also showed a recombination event between tprC and tprI, in TP0488 as well as in the intergenic region between TP0127–TP0129.Despite limitations in the quality of samples affecting broad sequencing coverage, the determined non-clonal character of the isolates suggests a persistent infection in the Cuban population rather than a single outbreak caused by imported case.Author summaryThe incidence of venereal syphilis has greatly increased in the last years, however endemic syphilis (bejel) which have been considered as a disease restricted to dry arid areas such as the Sahel and the Middle East, remain as a neglected disease. In Cuba, which is a tropical country, several bejel cases were unexpectedly detected few years ago in “syphilis” patients with no records of travel abroad or sex with foreign partners. In this study, we explored the whole genome sequences from four of the Cuban Treponema pallidum subsp. endemicum (TEN) isolates and the substantial genetic diversity detected among them suggests a persistent infection of TEN within the human population rather than a single outbreak of a TEN isolate introduced from an area where it is typically endemic. This finding has significant implications on this neglected and also possibly tropical disease in terms of geographical/temporal distribution, and highlights the importance of keeping in mind neglected diseases in apparently non-endemic areas.
Rapid brain development and reduced neuromodulator titres correlate with host shifts in Rhagoletis pomonella
Authors: Kharva Hinal , Feder Jeffrey L. , Hahn Daniel A , Olsson Shannon B. 
Published: October 2021

AbstractHost shifts are considered a key generator of insect biodiversity. For insects, adaptation to new host plants often requires changes in larval/pupal development and behavioural preference towards new hosts. Neurochemicals play key roles in both development and behaviour, and therefore provide a potential source for such synchronization. Here, we correlated life history timing, brain development, and corresponding levels of 14 neurochemicals in Rhagoletis pomonella (Diptera: Tephritidae), a species undergoing ecological speciation through an ongoing host shift from hawthorn to apple fruit. These races exhibit differences in pupal diapause timing as well as adult behavioural preference with respect to their hosts. This difference in behavioral preference is coupled with differences in neurophysiological response to host volatiles. We found that apple race pupae exhibited adult brain morphogenesis three weeks faster after an identical simulated winter than the hawthorn race, which correlated with significantly lower titres of several neurochemicals. In some cases, particularly biogenic amines, differences in titres were reflected in the mature adult stage, when host preference is exhibited. In summary, life history timing, neurochemical titre, and brain development can be coupled in this speciating system, providing new hypotheses for the origins of new species through host shifts.
Repetition-attenuation of auditory N1 is modulated by the phonological representations of spoken word-forms
Authors: Yue Jinxing , Wang Peng , Li Jiayin , Li Zhipeng , Liang Xia , He Yifei 
Published: October 2021

AbstractRepeated auditory stimuli are usually found to elicit attenuated peak amplitude of the N1 component of the event related brain potential (ERP). While the repetition-attenuation of the auditory N1 has been found sensitive to some cognitive factors, less is known whether and how the representational properties of stimuli influence this physiological phenomenon. To further address this issue, we focus on the phonological representations of spoken word-forms, and hypothesise modulatory roles of two phonological features: the lexicality and its usage frequency of a word-form. To test this, we used a short-term habituation design with a factorial combination of the two features at two levels each (i.e., lexicality (real versus pseudo word-form) × frequency (high versus low frequency)). EEG was recorded from 30 native Mandarin-speaking participants while they were passively delivered with stimulations trains. Each train consisted of five presentation positions (S1 ∼ S5), on which one word-form is presented repeatedly, separated by a brief, constant interstimulus interval. At the fourth presentation position (S4), we found greater N1 attenuation in low-frequency pseudo word-forms than in low-frequency real and high-frequency pseudo word-forms, respectively. The results support our representational modulation hypothesis, and provides the first evidence that representations of different phonological features interactively modulate the N1 repetition-attenuation. The brain function that underlies the phonological effects of the representational modulation on N1 repetition-attenuation might be sensory filtering.
Dynamic Instability of Dendrite Tips Generates the Highly Branched Morphologies of Sensory Neurons
Authors: Shree Sonal , Sutradhar Sabyasachi , Trottier Olivier , Tu Yuhai , Liang Xin , Howard Jonathon 
Published: October 2021

AbstractThe highly ramified arbors of neuronal dendrites provide the substrate for the high connectivity and computational power of the brain. Altered dendritic morphology is associated with neuronal diseases. Many molecules have been shown to play crucial roles in shaping and maintaining dendrite morphology. Yet, the underlying principles by which molecular interactions generate branched morphologies are not understood. To elucidate these principles, we visualized the growth of dendrites throughout larval development ofDrosophilasensory neurons and discovered that the tips of dendrites undergo dynamic instability, transitioning rapidly and stochastically between growing, shrinking, and paused states. By incorporating these measured dynamics into a novel, agent-based computational model, we showed that the complex and highly variable dendritic morphologies of these cells are a consequence of the stochastic dynamics of their dendrite tips. These principles may generalize to branching of other neuronal cell-types, as well as to branching at the subcellular and tissue levels.
Composite receptive fields in the mouse auditory cortex
Authors: Lu Sihao , Steadman Mark , Ang Grace W. Y. , Kozlov Andrei S. 
Published: October 2021

AbstractA central question in sensory neuroscience is how neurons represent complex natural stimuli. This process involves multiple steps of feature extraction to obtain a condensed, categorical representation useful for classification and behavior. It has previously been shown that central auditory neurons in the starling have composite receptive fields composed of multiple features when probed with conspecific songs. Whether this property is an idiosyncratic characteristic of songbirds, a group of highly specialized vocal learners, or a generic characteristic of central auditory systems in different animals is, however, unknown. To address this question, we have recorded responses from auditory cortical neurons in mice, and characterized their receptive fields using mouse ultrasonic vocalizations (USVs) as a natural and ethologically relevant stimulus and pitch-shifted starling songs as a natural but ethologically irrelevant control stimulus. We have found that auditory cortical neurons in the mouse display composite receptive fields with multiple excitatory and inhibitory subunits. Moreover, this was the case with either the conspecific or the heterospecific vocalizations. We then trained the sparse filtering algorithm on both classes of natural stimuli to obtain statistically optimal features, and compared the natural and artificial features using UMAP, a dimensionality-reduction algorithm previously used to analyze mouse USVs and birdsongs. We have found that the receptive-field features obtained with the mouse USVs and those obtained with the pitch-shifted starling songs clustered together, as did the sparse-filtering features. However, the natural and artificial receptive-field features clustered mostly separately. These results indicate that composite receptive fields are likely a generic property of central auditory systems in different classes of animals. They further suggest that the quadratic receptive-field features of the mouse auditory cortical neurons are natural-stimulus invariant.
Variable inhibition of unwinding rates of DNA catalyzed by the SARS-Cov-2 (COV19) helicase nsp13 by structurally distinct single DNA lesions
Authors: Sales A.H. , Ciervo S. , Lupoli T. , Shafirovich V. , Geacintov N.E. 
Published: October 2021

AbstractThe SARS 2 (Covid 19) helicase nsp13 plays a critically important role in the replication of the Corona virus by unwinding double-stranded RNA (and DNA) with a 5’⟶3’ strand polarity. Here we explored the impact of single, structurally defined covalent DNA lesions on the helicase activity of nsp13 in aqueous solutions, The objectives were to derive mechanistic insights into the relationships between the structures of DNA lesions, the DNA distortions that they engender, and the inhibition of helicase activity. The lesions included two bulky stereoisomeric N2-guanine adducts derived from the reactions of benzo[a]pyrene diol epoxide with DNA. The trans-adduct assumes a minor groove conformation, while the cis-product adopts a base-displaced intercalated conformation. The non-bulky DNA lesions included the intra-strand cross-linked thymine dimers, the cis-syn-cyclobutane pyrimidine dimer, and the pyrimidine (6−4) pyrimidone photoproduct. All four lesions strongly inhibit the helicase activity of nsp13, The UV photolesions feature a 2 - 5-fold smaller inhibition of the nsp13 unwinding activity than the bulky DNA adducts, and the kinetics of these two pairs of DNA lesions are also different. The connections between the structural features of these four DNA lesions and their impact on nsp13 unwinding efficiencies are discussed.
SWI/SNF chromatin remodeler complex within the reward pathway is required for behavioral adaptations to stress
Authors: Zayed Abdallah , Baranowski Camille , Compagnion Anne Claire , Vernochet Cécile , Karaki Samah , de Cuttoli Romain Durand , Saint-Jour Estefani , Bhattacharya Soumee , Marti Fabio , Vanhoutte Peter , Yaniv Moshe , Faure Philippe , Barik Jacques , Amar Laurence , Tronche François , Parnaudeau Sebastien 
Published: October 2021

AbstractStress exposure is a cardinal risk factor for most psychiatric diseases. Preclinical and clinical studies point to changes in gene expression involving epigenetic modifications within mesocorticolimbic brain circuits. Brahma (BRM) and Brahma-Related-Gene-1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that repeated social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons Brg1 gene inactivation reduces the expression of stress- and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges.
pVHL regulates protein stability of TCF/LEF transcription factor family via ubiquitin-independent proteasomal degradation
Authors: Wang Caixia , Rong Xiaozhi , Zhang Haifeng , Wang Bo , Bai Yan , Liu Yunzhang , Lu Ling , Li Yun , Sun Yonghua , Zhao Chengtian , Zhou Jianfeng 
Published: October 2021

AbstractThe Wnt/β-catenin signaling pathway plays key roles in development and adult tissue homeostasis by controlling cell proliferation and cell fate decisions. In this pathway, transcription factors TCF/LEFs are the key components to repress target gene expression by recruiting co-repressors or to activate target gene expression by recruiting β-catenin when the Wnt signals are absent or present, respectively. While progress has been made in our understanding of Wnt signaling regulation, the underlying mechanism that regulates the protein stability of the TCF/LEF family is far less clear. Here, we show that von Hippel-Lindau protein (pVHL), which is the substrate recognition component in an E3 ubiquitin ligase complex, controls TCF/LEF protein stability. Unexpectedly, pVHL directly binds to TCF/LEFs and promotes their proteasomal degradation independent of E3 ubiquitin ligase activity. Knockout of vhl in zebrafish embryos leads to a reduction of dorsal habenular neurons and this effect is upstream of dorsal habenular neurons phenotype in tcf7l2-null mutants. Our study uncovers a previously unknown mechanism for the protein stability regulation of the TCF/LEF transcription factors and demonstrates that pVHL contains a 26S proteasome binding domain that drives ubiquitin-independent proteasomal degradation. These findings provide new insights into the ubiquitin-independent actions of pVHL and uncover novel mechanistical regulation of Wnt/β-catenin signaling.