bluuebunny/crossref_metadata_2025_split huggingface dataset:
Divisive Normalization Circuits Faithfully Represent Auditory and Visual Sensory Stimuli
Authors: Lazar Aurel A. , Liu Tingkai , Zhou Yiyin 
Published: September 2022

AbstractDivisive normalization is a canonical neural computation employed for sensory adaptation in vision, olfaction and attention modulation. While Divisive Normalization has been proposed to be an efficient coding algorithm, it remains unclear whether such transformation results in information loss in a dynamic setting. Leveraging a previously proposed general mathematical framework called the Divisive Normalization Processor (DNP), we first show that the DNP circuit describes a wide class of neural circuits as well as phenomenological models including the Linear-Nonlinear cascade model. We then demonstrate both theoretically and computationally that the DNP is an invertible operator that could faithfully represent input information given sufficient output samples.
Abnormal intrinsic neural timescale and reduced grey matter volume in Parkinson’s disease
Authors: Wei Yarui , Zhang Chunyan , Peng Yuanyuan , Chen Chen , Han Shaoqiang , Wang Weijian , Zhang Yong , Lu Hong , Cheng Jingliang 
Published: September 2022

AbstractBACKGROUND: Numerous studies indicate altered peak latency of event-related potential and altered time variability of brain function network in Parkinson’s disease (PD), and the intrinsic neural timescale estimated how long neural information stored in a local brain area has been specialized. However, it was unclear whether PD patients exhibited abnormal intrinsic timescales and accompanied with abnormal grey matter and whether PD patients exhibited different temporal feature at different stages. STUDY TYPE: Prospective. POPULATION: 74 PD patients, including 44 patients in the early stage (PD-ES) and 30 patients in the late stage (PD-LS), and 73 healthy controls (HC). SEQUENCE: 3.0T MRI scanner; prototypic T1 magnetization prepared rapid acquisition gradient echo (MPRAGE); resting-state fMRI. ASSESSMENT: the intrinsic timescales were estimated by using the magnitude of the autocorrelation of intrinsic neural signals. Voxel-based morphometry (VBM) was performed to calculate the grey matter volume (GMV) in the whole brain. STATISTICAL TEST: Analysis of variance (ANOVA); two-samplet-tests; Spearman rank correlation analysis; Mann-Whitney U test; Kruskal-Wallis’ H test. RESULTS: We identified that the PD group had abnormal intrinsic timescales in bilateral lingual and calcarine gyri, bilateral postcentral and precentral gyri, and the right middle cingulum gyrus, which correlated with the symptom severity and the GMV. Moreover, longer timescale in the right middle frontal gyrus were also found in the PD group. Increasingly, the PD-ES group had longer timescales in the anterior cortical regions, whereas the PD-LS group had shorter timescales in the posterior cortical regions. DATA CONCLUSION: Our findings suggest that PD patients exhibit abnormal intrinsic timescales in visual, sensorimotor, and cognitive systems and distinct patterns of intrinsic timescales and GMV in cerebral cortex at different stages, which might provide new insights for the neural substrate of PD.
Coupling machine learning and epidemiological modelling to characterise optimal fungicide doses when fungicide resistance is partial or quantitative
Authors: Taylor Nick P , Cunniffe Nik J 
Published: September 2022

AbstractIncreasing fungicide dose tends to lead to better short-term control of plant diseases. However, high doses select more rapidly for fungicide resistant strains, reducing long-term disease control. When resistance is qualitative and complete – i.e. resistant strains are unaffected by the chemical and resistance requires only a single genetic change – using the lowest possible dose ensuring sufficient control is well-known as the optimal resistance management strategy. However, partial resistance (where resistant strains are still partially suppressed by the fungicide) and quantitative resistance (where a range of resistant strains are present) remain ill-understood. Here we use a model of quantitative fungicide resistance (parameterised for the economically-important fungal pathogen Zymoseptoria tritici) which handles qualitative partial resistance as a special case. We show that – for both qualitative partial resistance and quantitative resistance – although low doses are optimal for resistance management, for some model parameterisations the benefit does not outweigh the improvement in control from increasing doses. Via a machine learning approach (a gradient-boosted trees model combined with Shapley values to facilitate interpretability) we interpret the effect of parameters controlling pathogen mutation and characterising the fungicide, in addition to the timescale of interest.
A family of novel immune systems targets early infection of nucleus-forming jumbo phages
Authors: Li Yuping , Guan Jingwen , Hareendranath Surabhi , Crawford Emily , Agard David A. , Makarova Kira S. , Koonin Eugene V. , Bondy-Denomy Joseph 
Published: September 2022

AbstractJumbo bacteriophages of the ⌽KZ-like family are characterized by large genomes (>200 kb) and the remarkable ability to assemble a proteinaceous nucleus-like structure. The nucleus protects the phage genome from canonical DNA-targeting immune systems, such as CRISPR-Cas and restriction-modification. We hypothesized that the failure of common bacterial defenses creates selective pressure for immune systems that target the unique jumbo phage biology. Here, we identify the “jumbo phage killer” (Juk) immune system that is deployed by a clinical isolate of Pseudomonas aeruginosa to resist ⌽KZ. Juk immunity rescues the cell by preventing early phage transcription, DNA replication, and nucleus assembly. Phage infection is first sensed by JukA (formerly YaaW), which localizes rapidly to the site of phage infection at the cell pole, triggered by ejected phage factors. The effector protein JukB is recruited by JukA, which is required to enable immunity and the subsequent degradation of the phage DNA. JukA homologs are found in several bacterial phyla and are associated with numerous other putative effectors, many of which provided specific anti-⌽KZ activity when expressed in P. aeruginosa. Together, these data reveal a novel strategy for immunity whereby immune factors are recruited to the site of phage protein and DNA ejection to prevent phage progression and save the cell.
Synthesis of Long RNA with a Site-Specific Modification by Enzymatic Splint Ligation
Authors: Gamper Howard , McCormick Caroline , Tavakoli Sepideh , Wanunu Meni , Rouhanifard Sara H. , Hou Ya-Ming 
Published: September 2022

ABSTRACTSynthesis of RNA molecules that contain an internal site-specific modification is important for RNA research and therapeutics. While solid-state synthesis is attainable for such RNA in the range of 100 nucleotides (nts), it is currently impossible with kilobase (kb)-long RNA. Instead, long RNA with an internal modification is usually assembled in an enzymatic 3-part splint ligation to join a short RNA oligonucleotide, containing the site-specific modification, with both a left-arm and a right-arm long RNA that are synthesized by in vitro transcription. However, long RNAs have structural heterogeneity and those synthesized by in vitro transcription have 3’-end sequence heterogeneity, which together substantially reduce the yield of 3-part splint ligation. Here we describe a method of 3-part splint ligation with an enhanced efficiency utilizing a ribozyme cleavage reaction to address the 3’-end sequence heterogeneity and involving DNA disruptors proximal to the ligation sites to address the structural heterogeneity. The yields of the synthesized kb-long RNA are sufficiently high to afford purification to homogeneity for practical RNA research. We also verify the sequence accuracy at each ligation junction by nanopore sequencing.
The ClpX protease is essential for removing the CI master repressor and completing prophage induction in Staphylococcus aureus
Authors: Thabet Mohammed A. , Penadés José R. , Haag Andreas F. 
Published: September 2022

AbstractBacteriophages (phages) are the predominant biological entities on the planet and play an important role in the spread of bacterial virulence, pathogenicity, and antimicrobial resistance. After infection, temperate phages can integrate in the bacterial chromosome thanks to the expression of the prophage-encoded CI master repressor. Upon SOS induction, and promoted by RecA*, CI auto-cleaves generating two fragments, one containing the N-terminal domain (NTD), which retains strong DNA-binding capacity, and other corresponding to the C-terminal part of the protein. However, it is unknown how the CI NTD is removed, a process that is essential to allow prophage induction. Here we identify for the first time that the specific interaction of the ClpX protease with the CI NTD repressor fragment is essential and sufficient for prophage activation after SOS-mediated CI autocleavage, defining the final stage in the prophage induction cascade. Our results provide unexpected roles for the bacterial protease ClpX in phage biology.
Functional identification of cis-regulatory long noncoding RNAs at controlled false-discovery rates
Authors: Dhaka Bhavya , Zimmerli Marc , Hanhart Daniel , Moser Mario , Guillen-Ramirez Hugo , Mishra Sanat , Esposito Roberta , Polidori Taisia , Widmer Maro , García-Pérez Raquel , Kruithof-de Julio Marianna , Pervouchine Dmitri , Melé Marta , Chouvardas Panagiotis , Johnson Rory 
Published: September 2022

ABSTRACTA key attribute of some long noncoding RNAs (lncRNAs) is their ability to regulate expression of neighbouring genes in cis. However, such ‘cis-lncRNAs’ are presently defined using ad hoc criteria that, we show, are prone to false-positive predictions. The resulting lack of cis-lncRNA catalogues hinders our understanding of their extent, characteristics and mechanisms. Here, we introduce TransCistor, a framework for defining and identifying cis-lncRNAs based on enrichment of targets amongst proximal genes. TransCistor’s simple and conservative statistical models are compatible with functionally-defined target gene maps generated by existing and future technologies. Using transcriptome-wide perturbation experiments for 268 human and 134 mouse lncRNAs, we provide the first large-scale survey of cis-lncRNAs. Known cis-lncRNAs are correctly identified, including XIST, LINC00240 and UMLILO, and predictions are consistent across analysis methods, perturbation types and independent experiments. Our results indicate that cis-activity is detected in a minority of lncRNAs, primarily involving activators over repressors. Cis-lncRNAs are detected by both RNA interference and antisense oligonucleotide perturbations. Mechanistically, cis-lncRNA transcripts are observed to physically associate with their target-genes, and are weakly enriched with enhancer-elements. In summary, TransCistor establishes a quantitative foundation for cis-lncRNAs, opening a path to elucidating their molecular mechanisms and biological significance.
Photocycle characterization of a blue-orange cyanobacteriochrome fromSynechococcussp. PCC 7002
Authors: Mihnev Aleksandar , Forbes Liam , McKenzie J. Douglas , Cogdell Richard J. , Amtmann Anna 
Published: September 2022

ABSTRACTCyanobacteria employ photoreceptors called cyanobacteriochromes (CBCRs) to sense the colour and intensity of light. The information extracted from the solar spectrum is used for adaptive responses such as optimizing photosynthesis, phototaxis and cell aggregation. cGMP-phosphodiesterase/adenlylate cyclase/FhlA (GAF) domains are the principal light sensors in cyanobacteriochromes. They contain a conjugated bilin chromophore and boast an impressive spectral diversity. Characterizing the spectral characteristics of GAF domains in model strains, such asSynechococcussp. PCC 7002, can open new avenues for optogenetics and biotechnology. Based on sequence analysis we predicted several different GAF domains in this strain. TheSynPCC7002_a0852gene encodes a single GAF domain with two cysteine residues: one in the conserved α3 helix and one in the conserved DXCF motif. Spectral analysis of recombinantSynPCC7002_A0852with phycocyanobilin (PCB) showed that the protein cycles between two states, Po and Pb, which absorb orange and blue light, respectively. Measurements of kinetics identified Po as the dark state of the protein. Acid-denaturation analysis suggested that the 15E isomer of PCB is bound in the (dark) Po state, whereas 15Z is bound the (photoproduct) Pb state. Site-directed mutagenesis and iodoacetamide treatments showed that Cys73 in the DXCF motif is essential for the conversion from Po to Pb. Future experiments dark-purified protein/chromophore versions are required to establish the sequence of events in the photocycle. In summary,SynPCC7002_A0852enables orange/blue colour perception inSynechococcussp. PCC 7002 as other CBRCs of this protein family but might contain the energetically higher chromophore isoform in its dark state. Such photocycle has previously been found in ‘bathy’ bacteriophytochromes but not in CBCRs.
Genome engineering by RNA-guided transposition forAnabaenaPCC 7120
Authors: Arévalo Sergio , Rico Daniel Pérez , Abarca Dolores , Dijkhuizen Laura W. , Sarasa-Buisan Cristina , Lindblad Peter , Flores Enrique , Nierzwicki-Bauer Sandra , Schluepmann Henriette 
Published: September 2022

AbstractIn genome engineering, integration of incoming DNA has been dependent on enzymes produced by dividing cells which has been a bottle neck towards increasing DNA-insertion frequencies and accuracy. Recently, RNA-guided transposition with CRISPR-associated transposase (CAST) was reported as highly effective and specific inEscherichia coli. Here we developed Golden-Gate vectors to test CAST in filamentous cyanobacteria and show that it is effective inAnabaenasp. strain PCC 7120. The comparatively large plasmids containing the CAST and the engineered transposon were successfully transferred intoAnabaenavia conjugation using either suicide or replicative plasmids. Single guide(sg)-RNA encoding the leading, but not the reverse complement strand of the target were effective with the protospacer associated motif (PAM) sequence included in the sgRNA. In four out of six cases analyzed over two distinct target loci, the insertion site was exactly 63 bases after the PAM. CAST on a replicating plasmid was toxic which could be used to cure the plasmid. In all six cases analyzed, only the transposon cargo defined by the sequence ranging from left and right elements was inserted at the target loci, therefore, RNA-guided transposition resulted from cut and paste. No endogenous transposons were remobilized by exposure to CAST enzymes. This work is foundational for genome editing by RNA-guided transposition in filamentous cyanobacteria, whether in culture or in complex communities.
Quercetin reduces APP expression, oxidative stress and mitochondrial dysfunction in the N2a/APPswe cells via ERK1/2 and AKT pathways
Authors: Tang Zhi , Guo Min , Peng Yaqian , Zhang Ting , Xiao Yan , Ni Ruiqing , Qi Xiaolan 
Published: September 2022

ABSTRACTAbnormal amyloid-β (Aβ) abnormal accumulation and oxidative stress play important roles in Alzheimer’s disease (AD). Quercetin has been reported to possess antioxidant and anti-inflammatory properties, and thus of therapeutic interests for neurodegenerative disorders. In the present study, we aimed to characterize the mechanisms by which quercetin exerts neuroprotective effects in murine neuroblastoma N2a cells stably expressing human Swedishh mutant amyloid precursor protein (APP). Quercetin treatment exhibited low cytoxicity, attenuated APP expression and APP-induced oxidative neurotoxicity in N2a/APP cells. We found that quercetin effected via the down-regulation of phospho-extracellular signal□regulated protein kinase (p-ERK1/2) pathway and up-regulation of phospho-protein kinase B (p-AKT) pathway in N2a/APP cells. In addition, quercetin ameliorated the elevated levels of reactive oxygen species using DCFH-DA flow-cytometry in N2a/APP cells, lipid peroxidation using (4-HNE), and DNA oxidation (8-OHdG assays). Quercetin ameliorated the loss of mitochondrial membrane potential using JC-1 fluorescence assay in N2a/APP cells in a dose-dependent mannor. In conclusion, we domenstrated the neuroprotective effects of quercetin against the APP expression induced oxidative neurotoxicity, impairment of mitochondrial function and oxidative stress through inactivation of the ERK1/2 signaling pathway and activation of AKT signaling pathways.
Guild-level microbiome signature associated with COVID-19 severity and prognosis
Authors: Guo Mingquan , Wu Guojun , Tan Yun , Li Yan , Jin Xin , Qi Weiqiang , Guo XiaoKui , Zhang Chenhong , Zhu Zhaoqin , Zhao Liping 
Published: September 2022

AbstractCOVID-19 severity has been associated with alterations of the gut microbiota. However, the relationship between gut microbiome alterations and COVID-19 prognosis remains elusive. Here, we performed a genome-resolved metagenomic analysis on fecal samples collected from 300 in-hospital COVID-19 patients at time of admission. Among the 2,568 high quality metagenome-assembled genomes (HQMAGs), Redundancy Analysis identified 33 HQMAGs which showed differential distribution among mild, moderate, and severe/critical severity groups. Random Forest model based on these 33 HQMAGs classified patients from different severity groups (average AUC = 0.79). Co-abundance network analysis found that the 33 HQMAGs were organized as two competing guilds. Guild 1 harbored more genes for short-chain fatty acid biosynthesis, and fewer genes for virulence and antibiotic resistance, compared with Guild 2. Random Forest regression showed that these 33 HQMAGs at admission had the capacity to predict 8 clinical parameters, which are predictors for COVID-19 prognosis, at Day 7 in hospital. Moreover, the dominance of Guild 1 over Guild 2 at admission predicted the death/discharge outcome of the critical patients (AUC = 0.92). Random Forest models based on these 33 HQMAGs classified patients with different COVID-19 symptom severity, and differentiated COVID-19 patients from healthy subjects, non-COVID-19, and pneumonia controls in three independent datasets. Thus, this genome-based guild-level signature may facilitate early identification of hospitalized COVID-19 patients with high risk of more severe outcomes at time of admission.
A spatiotemporal map of the aging mouse brain reveals white matter tracts as vulnerable foci
Authors: Hahn Oliver , Foltz Aulden G , Atkins Micaiah , Kedir Blen , Moran-Losada Patricia , Guldner Ian H , Munson Christy , Kern Fabian , Pálovics Róbert , Lu Nannan , Zhang Hui , Kaur Achint , Hull Jacob , Huguenard John R , Grönke Sebastian , Lehallier Benoit , Partridge Linda , Keller Andreas , Wyss-Coray Tony 
Published: September 2022

SummaryAging is the key risk factor for cognitive decline, yet the molecular changes underlying brain aging remain poorly understood. Here, we conducted spatiotemporal RNA-seq of the mouse brain, profiling 1,076 samples from 15 regions across 7 ages and 2 rejuvenation interventions. Our analysis identified a brain-wide gene signature of aging in glial cells, which exhibited spatially defined changes in magnitude. By integrating spatial and single-nucleus transcriptomics, we found that glia aging was particularly accelerated in white matter compared to cortical regions, while specialized neuronal populations showed region-specific expression changes. Rejuvenation interventions, including young plasma injection and dietary restriction, exhibited distinct effects on gene expression in specific brain regions. Furthermore, we discovered differential gene expression patterns associated with three human neurodegenerative diseases, highlighting the importance of regional aging as a potential modulator of disease. Our findings identify molecular foci of brain aging, providing a foundation to target age-related cognitive decline.
Multi-modal Efficacy of a Chimeric Vesiculovirus Expressing the Morreton Glycoprotein in Sarcoma
Authors: Dumbauld Chelsae , Barro Oumar , Elliott Natalie M. , Zhou Yumei , Gabere Musa , Raupach Elizabeth , Baker Alexander T. , Barrett Michael T. , Buetow Kenneth H. , Jacobs Bertram , Seetharam Mahesh , Borad Mitesh J. , Nagalo Bolni Marius 
Published: September 2022

AbstractVesiculoviruses are attractive oncolytic virus (OV) platforms due to their rapid replication, genome with appreciable transgene capacity, broad tropism, limited pre-existing immunity, and type I interferon response gradient between malignant and normal cells. We developed a synthetic chimeric virus (VMG) expressing the glycoprotein (G) from Morreton virus (MorV) with remaining genes from vesicular stomatitis virus (VSV). VMG exhibited in vitro efficacy in cell proliferation and cell death assays across a broad range of sarcoma subtypes and across multiple species. Notably, all cell lines tested showed ability of VMG to yield productive infections with rapid replication kinetics. Pilot safety evaluations of VMG in immunocompetent, non-tumor bearing mice showed absence of toxicity with intranasal doses as high as 1e10 TCID50. VMG resulted in tumor reduction in vivo in an immunodeficient subcutaneous Ewing sarcoma model at doses as low as 2e5 TCID50. In the immune competent murine syngeneic fibrosarcoma model, while no tumor inhibition was achieved with VMG, there was a robust induction of CD8+ T cells suggestive of potential for combination approaches with immunomodulatory agents such as immune checkpoint inhibitors. The studies described herein establish the potential for VMG as a novel oncolytic virotherapy platform with multi-modal anti-tumor effects in sarcoma.
HCR Lateral Flow Assays for Amplified Instrument-Free At-Home SARS-CoV-2 Testing
Authors: Schulte Samuel J. , Huang Jining , Pierce Niles A. 
Published: September 2022

ABSTRACTThe lateral flow assay format enables rapid, instrument-free, at-home testing for SARS-CoV-2. Due to the absence of signal amplification, this simplicity comes at a cost in sensitivity. Here, we enhance sensitivity by developing an amplified lateral flow assay that incorporates isothermal, enzyme-free signal amplification based on the mechanism of hybridization chain reaction (HCR). The simplicity of the user experience is maintained using a disposable 3-channel lateral flow device to automatically deliver reagents to the test region in three successive stages without user interaction. To perform a test, the user loads the sample, closes the device, and reads the result by eye after 60 minutes. Detecting gamma-irradiated SARS-CoV-2 virions in a mixture of saliva and extraction buffer, the current amplified HCR lateral flow assay achieves a limit of detection of 200 copies/μL using available antibodies to target the SARS-CoV-2 nucleocapsid protein. By comparison, five commercial unamplified lateral flow assays that use proprietary antibodies exhibit limits of detection of 500 copies/μL, 1000 copies/μL, 2000 copies/μL, 2000 copies/μL, and 20,000 copies/μL. By swapping out antibody probes to target different pathogens, amplified HCR lateral flow assays offer a platform for simple, rapid, and sensitive at-home testing for infectious disease. As an alternative to viral protein detection, we further introduce an HCR lateral flow assay for viral RNA detection.HCR lateral flow assayAmplifiedInstrument-freeAt-home60 minNaked eyeSARS-CoV-2200 copies/μL