bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neural evidence for the successor representation in choice evaluation
Authors: Russek Evan M. , Momennejad Ida , Botvinick Matthew M. , Gershman Samuel J. , Daw Nathaniel D. 
Published: August 2021

AbstractEvaluating choices in multi-step tasks is thought to involve mentally simulating trajectories. Recent theories propose that the brain simplifies these laborious computations using temporal abstraction: storing actions’ consequences, collapsed over multiple timesteps (the Successor Representation; SR). Although predictive neural representations and, separately, behavioral errors (“slips of action”) consistent with this mechanism have been reported, it is unknown whether these neural representations support choices in a manner consistent with the SR. We addressed this question by using fMRI to measure predictive representations in a setting where the SR implies specific errors in multi-step expectancies and corresponding behavioral errors. By decoding measures of state predictions from sensory cortex during choice evaluation, we identified evidence that behavioral errors predicted by the SR are accompanied by predictive representations of upcoming task states reflecting SR predicted erroneous multi-step expectancies. These results provide neural evidence for the SR in choice evaluation and contribute toward a mechanistic understanding of flexible and inflexible decision making.
Adaptation of anammox bacteria to low temperature via gradual acclimation and cold shocks: distinctions in protein expression, membrane composition and activities
Authors: Kouba V. , Vejmelkova D. , Zwolsman E. , Hurkova K. , Navratilova K. , Laureni M. , Vodickova P. , Podzimek T. , Hajslova J. , Pabst M. , van Loosdrecht M.C.M. , Bartacek J. , Lipovova P. , Weissbrodt D.G. 
Published: August 2021

AbstractAnammox bacteria enable an efficient removal of nitrogen from sewage in processes involving partial nitritation and anammox (PN/A) or nitrification, partial denitrification, and anammox (N-PdN/A). In mild climates, anammox bacteria must be adapted to ≤15 °C, typically by gradual temperature decrease; however, this takes months or years. To reduce the time necessary for the adaptation, an unconventional method of ‘cold shocks’ is promising, involving hours-long exposure of anammox biomass to extremely low temperatures. We compared the efficacies of gradual temperature decrease and cold shocks to increase the metabolic activity of anammox (fed batch reactor, planktonic “Ca. Kuenenia”). We assessed the cold shock mechanism on the level of protein expression (quantitative shot-gun proteomics, LC-HRMS/MS) and structure of membrane lipids (UPLC-HRMS/MS). The shocked culture was more active (0.66±0.06 vs 0.48±0.06 kg-N/kg-VSS/d) and maintained the relative content of N-respiration proteins at levels consistent levels with the initial state, whereas the content of these proteins decreased in gradually acclimated culture. Cold shocks also induced a more efficient up-regulation of cold shock proteins (e.g. CspB, TypA, ppiD). Ladderane lipids characteristic for anammox evolved to a similar end-point in both cultures which confirms their role in anammox bacteria adaptation to cold and indicates a three-pronged adaptation mechanism involving ladderane lipids (ladderane alkyl length, introduction of shorter non-ladderane alkyls, polar headgroup). Overall, we show the outstanding potential of cold shocks for low-temperature adaptation of anammox bacteria and provide yet unreported detailed mechanisms of anammox adaptation to low temperatures.HighlightsAnammox bacteria were adapted to low T by gradual acclimation and cold shocksThe shocked culture was more active (0.66±0.06 vs 0.48±0.06 kg-N/kg-VSS/d)N-respiration proteins content decreased in gradually acclimated bacteriaSeveral cold shock proteins were upregulated more efficiently by cold shocksAt ↓T, anammox adjusted ladderane membrane lipid composition in three aspectsGraphical abstract
NBI-921352, a First-in-Class, NaV1.6 Selective, Sodium Channel Inhibitor That Prevents Seizures inScn8aGain-of-Function Mice, and Wild-Type Mice and Rats
Authors: Johnson JP , Focken Thilo , Khakh Kuldip , Tari Parisa Karimi , Dube Celine , Williams Aaron , Andrez Jean-Christophe , Bankar Girish , Bogucki David , Burford Kristen , Chang Elaine , Chowdhury Sultan , Dean Richard , de Boer Gina , Decker Shannon , Dehnhardt Christoph , Feng Mandy , Gong Wei , Goodchild Samuel J , Grimwood Michael , Hasan Abid , Hussainkhel Angela , Jia Qi , Lee Stephanie , Li Jenny , Lin Sophia , Lindgren Andrea , Lofstrand Verner , Mezeyova Janette , Namdari Rostam , Nelkenbrecher Karen , Shuart Noah Gregory , Sojo Luis , Sun Shaoyi , Taron Matthew , Waldbrook Matthew , Weeratunge Diana , Wesolowski Steven , Wilson Michael , Xie Zhiwei , Yoo Rhena , Young Clint , Zenova Alla , Zhang Wei , Cutts Alison J , Sherrington Robin P , Pimstone Simon N , Winquist Raymond , Cohen Charles J , Empfield James R 
Published: August 2021

AbstractNBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target NaV1.6 channels. Such a molecule provides a precision-medicine approach to targetSCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess NaV1.6 sodium current, or other indications where NaV1.6 mediated hyper-excitability contributes to disease (Gardella and Moller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC500.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756X for NaV1.1, 134X for NaV1.2, 276X for NaV1.7, and >583X for NaV1.3, NaV1.4, and NaV1.5). NBI-921352 is a state-dependent inhibitor, preferentially inhibiting activated (inactivated or open) channels. The state dependence leads to potent stabilization of inactivation, inhibiting NaV1.6 currents, including resurgent and persistent NaV1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where NaV1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in aScn8aGoF mouse, as well as in wild-type mouse and rat seizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor antiseizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 was well tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment ofSCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.
Novel System to Monitor In Vivo Neural Graft Activity After Spinal Cord Injury
Authors: Ago Kentaro , Nagoshi Narihito , Imaizumi Kent , Kitagawa Takahiro , Kawai Momotaro , Kajikawa Keita , Shibata Reo , Kamata Yasuhiro , Kojima Kota , Shinozaki Munehisa , Kondo Takahiro , Iwano Satoshi , Miyawaki Atsushi , Ohtsuka Masanari , Bito Haruhiko , Kobayashi Kenta , Shibata Shinsuke , Shindo Tomoko , Kohyama Jun , Matsumoto Morio , Nakamura Masaya , Okano Hideyuki 
Published: August 2021

AbstractExpectations for neural stem/progenitor cell (NS/PC) transplantation as a treatment for spinal cord injury (SCI) are increasing. However, whether and how grafted cells are incorporated into the host neural circuit and contribute to motor function recovery remain unknown. The aim of this project was to establish a novel non-invasive in vivo imaging system to visualize the activity of neural grafts by which we can simultaneously demonstrate the circuit-level integration between the graft and host, and the contribution of graft neuronal activity to host behaviour. We introduced Akaluc, a newly engineered luciferase, under control of a potent neuronal activity-dependent synthetic promoter, E-SARE, into NS/PCs and engrafted the cells into SCI model mice. Through the use of this system, we reveal that the activity of grafted cells was integrated with host behaviour and driven by host neural circuit inputs. This non-invasive system is expected to help elucidate the therapeutic mechanism of cell transplantation treatment for SCI and determine better therapy techniques that maximize the function of cells in the host circuit.
Dissecting errors made in response to externally- and internally-driven visual tasks in the common marmosets and humans
Authors: Amly Wajd , Chen Chih-Yang , Onoe Hirotaka , Isa Tadashi 
Published: August 2021

ABSTRACTVarious visual paradigms in oculomotor research have been used for studying the neural processes of eye movement, cognitive control, attention and neurological disorders. However, we usually analyse data collected from humans or over-trained non-human primates (NHPs), focusing only on successful trials, whereas error trials are usually excluded. These errors may repetitively show up in diseases, but their interpretation would be difficult due to the absence of records taken from healthy controls. In the current study, we aimed to analyse both correctly and incorrectly performed trials in both marmosets and humans. We trained marmosets to perform the gap saccade task and the oculomotor delayed response task. We also collected data from human subjects who performed identical tasks. We categorised error trials into three different groups, based on the time when an incorrect response occurred. We also interpreted possible causes by analysing saccade reaction time, saccade landing position and task history. Despite the rareness of human error, we found that marmosets and humans showed remarkably similar behaviour in error and success. We also found that successful saccades in the gap saccade task had always the highest peak velocity in both species, reflecting faster sensorimotor processing for correct responses. Our results suggest that marmosets and humans might share similar neural processing for successful and unsuccessful oculomotor behaviour, making them a suitable model for studying human behaviour. More importantly, analysing error trials in sync with successful ones will provide further insights into the cognitive and sensorimotor processes.NEW AND NOTEWORTHYThis is the first detailed report focusing on analysing both error and successful trials in oculomotor tasks. We proposed nomenclatures and a generalizable way of grouping and analysing error trials. Our results also indicate that marmosets can be a promising experimental candidate for oculomotor research because they replicate the saccade properties of error and success seen in humans. This will help set the baseline measurements to study brain disorders using NHP and understand the neural mechanisms from a different perspective.
BiomeHorizon: visualizing microbiome time series data in R
Authors: Fink Isaac , Abdill Richard J. , Blekhman Ran , Grieneisen Laura 
Published: August 2021

AbstractSummaryA key aspect of microbiome research is analysis of longitudinal dynamics using time series data. A method to visualize both the proportional and absolute change in the abundance of multiple taxa across multiple subjects over time is needed. We developed BiomeHorizon, an open-source R package that visualizes longitudinal compositional microbiome data using horizon plots.Availability and ImplementationBiomeHorizon is available at https://github.com/blekhmanlab/biomehorizon/ and released under the MIT license. A guide with step-by-step instructions for using the package is provided at https://blekhmanlab.github.io/biomehorizon/. The guide also provides code to reproduce all plots in this manuscript.Contactlgrienei@umn.edu, blekhman@umn.edu, iafink@uchicago.eduSupplementary informationNone
Exploiting flow cytometry for the unbiased quantification of protein inclusions inCaenorhabditis elegans
Authors: Claesson Kristian , Chew Yee Lian , Ecroyd Heath 
Published: August 2021

AbstractThe aggregation of proteins into inclusions or plaques is a prominent hallmark of a diverse range of pathologies including neurodegenerative diseases. The quantification of such inclusions inCaenorhabditis elegansmodels of aggregation is usually achieved by fluorescence microscopy or other techniques involving biochemical fractionation of worm lysates. Here, we describe a simple and rapid flow cytometry-based approach that allows fluorescently-tagged inclusions to be enumerated in whole worm lysate in a quantitative and unbiased fashion. We demonstrate that this technique is applicable to multipleC. elegansmodels of aggregation and importantly, can be used to monitor the dynamics of inclusion formation in response to heat shock and during aging. This includes the characterisation of physicochemical properties of inclusions, such as their size, which may reveal how aggregate formation is distinct in different tissues or at different stages of pathology or aging. This new method can be used as a powerful technique for the medium- to high-throughput quantification of inclusions in future studies of genetic or chemical modulators of aggregation inC. elegans.
AZD7442 demonstrates prophylactic and therapeutic efficacy in non-human primates and extended half-life in humans
Authors: Loo Yueh-Ming , McTamney Patrick M. , Arends Rosalinda H. , Gasser Robert A. , Abram Michael E. , Aksyuk Anastasia , Diallo Seme , Flores Daniel J. , Kelly Elizabeth J. , Ren Kuishu , Roque Richard , Rosenthal Kim , Streicher Katie , Tuffy Kevin M. , Bond Nicholas J. , Cornwell Owen , Bouquet Jerome , Cheng Lily I. , Dunyak James , Huang Yue , Rosenbaum Anton I. , Andersen Hanne , Carnahan Robert H. , Crowe James E. , Kuehne Ana I. , Herbert Andrew S. , Dye John M. , Bright Helen , Kallewaard Nicole L. , Pangalos Menelas N. , Esser Mark T. 
Published: August 2021

AbstractDespite the success of SARS-CoV-2 vaccines, there remains a need for more prevention and treatment options for individuals remaining at risk of COVID-19. Monoclonal antibodies (mAbs) against the viral spike protein have potential to both prevent and treat COVID-19, and reduce the risk of severe disease and death. Here, we describe AZD7442, a combination of two mAbs, AZD8895 (tixagevimab) and AZD1061 (cilgavimab), that simultaneously bind to distinct non-overlapping epitopes on the spike protein receptor binding domain to potently neutralize SARS-CoV-2. Initially isolated from individuals with prior SARS-CoV-2 infection, the two mAbs were designed to extend their half-lives and abrogate effector functions. The AZD7442 mAbs individually prevent the spike protein from binding to angiotensin-converting enzyme 2 receptor, blocking virus cell entry. Together, these two mAbs create a higher barrier to viral escape and a wider breadth of coverage, neutralizing all known SARS-CoV-2 variants of concern. In a non-human primate model of SARS-CoV-2 infection, prophylactic AZD7442 administration prevented infection, while therapeutic administration accelerated virus clearance from lung. In an ongoing Phase I study in healthy participants (NCT04507256), 300 mg intramuscular AZD7442 provided SARS-CoV-2 serum geometric mean neutralizing titers >10-fold above those of convalescent sera for ≥3 months, which remained 3-fold above those of convalescent sera 9 months post-AZD7442 administration. Approximately 1–2% of serum AZD7442 levels were detected in nasal mucosa, a site of SARS-CoV-2 infection. Extrapolation of the time course of serum AZD7442 concentrations suggests AZD7442 may provide up to 12 months of protection and benefit individuals at high-risk of COVID-19.
Single-cell transcriptomic atlas of individuals receiving inactivated COVID-19 vaccines reveals distinct immunological responses between vaccine and natural SARS-CoV-2 infection
Authors: Wang Yi , Wang Xiaoxia , Luu Laurence Don Wai , Li Jieqiong , Cui Xiaodai , Yao Hailan , Zhang Xin , Chen Shaojin , Fu Jin , Wang Licheng , Wang Chongzhen , Yuan Rui , Cai Qingguo , Huang Xiaolan , Huang Junfei , Xu Wenjian , Li Shijun , Zhu Xiong , Tai Jun 
Published: August 2021

AbstractTo control the ongoing COVID-19 pandemic, CoronaVac (Sinovac), an inactivated vaccine, has been granted emergency use authorization by many countries. However, the underlying mechanisms of the inactivated COVID-19 vaccine-induced immune response remain unclear, and little is known about its features compared to SARS-CoV-2 infection. Here, we implemented single-cell RNA sequencing (scRNA-seq) to profile longitudinally collected PBMCs (peripheral blood mononuclear cells) in six individuals immunized with CoronaVac and compared these to the profiles of COVID-19 infected patients from a Single Cell Consortium. Both inactivated vaccines and SARS-CoV-2 infection drove changes in immune cell type proportions, caused B cell activation and differentiation, and induced the expression of genes associated with antibody production in the plasma. The inactivated vaccine and SARS-COV-2 infection also caused alterations in peripheral immune activity such as interferon response, inflammatory cytokine expression, innate immune cell apoptosis and migration, effector T cell exhaustion and cytotoxicity, however, the magnitude of change was greater in COVID-19 patients, especially those with severe disease, than in immunized individuals. Further analyses revealed a distinct peripheral immune cell phenotype associated with CoronaVac immunization (HLA class II upregulation and IL21R upregulation in naïve B cells) versus SARS-CoV-2 infection (HLA class II downregulation and IL21R downregulation in naïve B cells severe disease). There were also differences in the expression of important genes associated with proinflammatory cytokines and thrombosis. In conclusion, this study provides a single-cell atlas of the systemic immune response to CoronaVac immunization and reveals distinct immune responses between inactivated vaccines and SARS-CoV-2 infection.
Total Infectomes Characterization of Respiratory Infections in pre-COVID-19 Wuhan, China
Authors: Shi Mang , Zhao Su , Yu Bin , Wu Wei-Chen , Hu Yi , Tian Jun-Hua , Yin Wen , Ni Fang , Hu Hong-Ling , Geng Shuang , Tan Li , Peng Ying , Song Zhi-Gang , Wang Wen , Chen Yan-Mei , Holmes Edward C. , Zhang Yong-Zhen 
Published: August 2021

AbstractAt the end of 2019 Wuhan witnessed an outbreak of “atypical pneumonia” that later developed into a global pandemic. Metagenomic sequencing rapidly revealed the causative agent of this outbreak to be a novel coronavirus - SARS-CoV-2. Herein, to provide a snapshot of the pathogens in pneumonia-associated respiratory samples from Wuhan prior to the emergence of SARS-CoV-2, we collected bronchoalveolar lavage fluid samples from 408 patients presenting with pneumonia and acute respiratory infections at the Central Hospital of Wuhan between 2016 and 2017. Unbiased total RNA sequencing was performed to reveal their “total infectome”, including viruses, bacteria and fungi. Consequently, we identified 37 pathogen species, comprising 15 RNA viruses, 3 DNA viruses, 16 bacteria and 3 fungi, often at high abundance and including multiple co-infections (12.8%). However, SARS-CoV-2 was not present. These data depict a stable core infectome comprising common respiratory pathogens such as rhinoviruses and influenza viruses, an atypical respiratory virus (EV-D68), and a single case of a sporadic zoonotic pathogen –Chlamydia psittaci. Samples from patients experiencing respiratory disease on average had higher pathogen abundance than healthy controls. Phylogenetic analyses of individual pathogens revealed multiple origins and global transmission histories, highlighting the connectedness of the Wuhan population. This study provides a comprehensive overview of the pathogens associated with acute respiratory infections and pneumonia, which were more diverse and complex than obtained using targeted PCR or qPCR approaches. These data also suggest that SARS-CoV-2 or closely related viruses were absent from Wuhan in 2016-2017.
A gap-free tomato genome built from complementary PacBio and Nanopore long DNA sequences reveals extensive linkage drag during breeding
Authors: van Rengs Willem M. J. , Schmidt Maximilian H.-W. , Effgen Sieglinde , Wang Yazhong , Zaidan Mohd Waznul Adly Mohd , Huettel Bruno , Schouten Henk J. , Usadel Björn , Underwood Charles J. 
Published: August 2021

AbstractThe assembly and scaffolding of plant crop genomes facilitates the characterization of genetically diverse cultivated and wild germplasm. The cultivated tomato has been improved through the introgression of genetic material from related wild species, including resistance to pandemic strains of Tobacco Mosaic virus (TMV) from Solanum peruvianum. Here we applied PacBio HiFi and ONT nanopore sequencing to develop independent, highly contiguous and complementary assemblies of an inbred TMV-resistant tomato variety. We merged the HiFi and ONT assemblies to generate a long-read-only assembly where all twelve chromosomes were represented as twelve contiguous sequences (N50=68.5 Mbp). The merged assembly was validated by chromosome conformation capture data and is highly consistent with previous tomato assemblies that made use of genetic maps and HiC for scaffolding. Our long-read-only assembly reveals that a complex series of structural variants linked to the TMV resistance gene likely contributed to linkage drag of a 64.1 Mbp region of the S. peruvianum genome during tomato breeding. We show that this minimal introgression region is present in six cultivated tomato hybrid varieties developed in three commercial breeding programs. Our results suggest that complementary long read technologies can facilitate the rapid generation of near complete genome sequences.
Recurrent Integration of Human Papillomavirus Genomes at Transcriptional Regulatory Hubs
Authors: Warburton Alix , Markowitz Tovah E. , Katz Joshua P. , Pipas James M. , McBride Alison A. 
Published: August 2021

ABSTRACTOncogenic human papillomavirus (HPV) genomes are often integrated into host chromosomes in HPV-associated cancers. HPV genomes are integrated either as a single copy, or as tandem repeats of viral DNA interspersed with, or without, host DNA. Integration occurs frequently in common fragile sites susceptible to tandem repeat formation, and the flanking or interspersed host DNA often contains transcriptional enhancer elements. When co-amplified with the viral genome, these enhancers can form super-enhancer-like elements that drive high viral oncogene expression. Here, we compiled highly curated datasets of HPV integration sites in cervical (CESC) and head and neck squamous cell carcinoma (HNSCC) cancers and assessed the number of breakpoints, viral transcriptional activity, and host genome copy number at each insertion site. Tumors frequently contained multiple distinct HPV integration sites, but often only one “driver” site that expressed viral RNA. Since common fragile sites and active enhancer elements are cell-type specific, we mapped these regions in cervical cell lines using FANCD2 and Brd4/H3K27ac ChIP-seq, respectively. Large enhancer clusters, or super-enhancers, were also defined using the Brd4/H3K27ac ChIP-seq dataset. HPV integration breakpoints were enriched at both FANCD2-associated fragile sites, and enhancer-rich regions, and frequently showed adjacent focal DNA amplification in CESC samples. We identified recurrent integration “hotspots” that were enriched for super-enhancers, some of which function as regulatory hubs for cell-identity genes. We propose that during persistent infection, extrachromosomal HPV minichromosomes associate with these transcriptional epicenters, and accidental integration could promote viral oncogene expression and carcinogenesis.