bluuebunny/crossref_metadata_2025 huggingface dataset:
Nodular Regenerative Hyperplasia Is Not a Rare Condition After Liver Transplantation: Incidence, Predictive Factors, and Impact on Survival
Authors: Kounis Ilias , Sebagh Mylène , Evain Manon , Cailliez Valérie , Roche Bruno , De Martin Eleonora , Sobesky Rodolphe , Guettier Catherine , Allard Marc Antoine , Golse Nicolas , Azoulay Daniel , Vibert Eric , Duclos Vallee Jean Charles , Feray Cyrille , Samuel Didier , Coilly Audrey
Published: September 2022

Background.

The objectives of this study were to evaluate incidence and to identify the risk factors of occurrence and the predictive factors of symptomatic forms of nodular regenerative hyperplasia (NRH) after liver transplantation (LT).

Methods.

To identify risk factors of NRH following LT, we included 1648 patients transplanted from 2004 to 2018 and compared the patients developing NRH after LT to those who did not. To identify predictive factors of symptomatic NRH, we selected 115 biopsies displaying NRH and compared symptomatic to asymptomatic forms. Symptomatic NRH was defined as the presence of ascites, esophageal varices, hepatic encephalopathy, portal thrombosis, retransplantation, or death related to NRH.

Results.

The incidence of NRH following LT was 5.1%. In multivariate analysis, the independent factor of developing NRH after LT was the donor’s age (odds ratio [OR] = 1.02; confidence interval, 1.01-1.03; P = 0.02). Symptomatic forms occurred in 29 (25.2%) patients: 19 (16.5%) patients presented with ascites, 13 (11.3%) with esophageal varices, 4 (3.5%) with hepatic encephalopathy, and 8 (7%) with portal thrombosis. The median period before the onset of symptoms was 8.4 (1.5–11.3) y after LT. The spleen size at diagnosis/before LT ratio (OR = 12.5; 114.17-1.37; P = 0.0252) and thrombectomy during transplantation (OR = 11.17; 1.48-84.11; P = 0.0192) were associated with symptomatic NRH in multivariate analysis.

Conclusions.

NRH following LT is frequent (5.1%) and leads to symptomatic portal hypertension in 25.2% of patients. Using older grafts increases the risk of developing NRH after LT. Clinicians should screen for signs of portal hypertension, particularly in measuring spleen size.
Accounting for assay performance when estimating the temporal dynamics in SARS-CoV-2 seroprevalence in the U.S
Authors: García-Carreras Bernardo , Hitchings Matt D. T. , Johansson Michael A. , Biggerstaff Matthew , Slayton Rachel B. , Healy Jessica M. , Lessler Justin , Quandelacy Talia , Salje Henrik , Huang Angkana T. , Cummings Derek A. T.
Published: September 2022

Estimating the incidence of SARS-CoV-2 infection is central to understanding the state of the pandemic. Seroprevalence studies are often used to assess cumulative infections as they can identify asymptomatic infection. Since July 2020, commercial laboratories have conducted nationwide serosurveys for the U.S. CDC. They employed three assays, with different sensitivities and specificities, potentially introducing biases in seroprevalence estimates. Using mechanistic models, we show that accounting for assays explains some of the observed state-to-state variation in seroprevalence, and when integrating case and death surveillance data, we show that when using the Abbott assay, estimates of proportions infected can differ substantially from seroprevalence estimates. We also found that states with higher proportions infected (before or after vaccination) had lower vaccination coverages, a pattern corroborated using a separate dataset. Finally, to understand vaccination rates relative to the increase in cases, we estimated the proportions of the population that received a vaccine prior to infection.
Quotidian Profile of Vergence Angle in Ambulatory Subjects Monitored with Wearable Eye Tracking Glasses
Authors: Dilbeck Mikayla D. , Gentry Thomas N. , Economides John R. , Horton Jonathan C.
Published: September 2022

PURPOSE

Wearable tracking glasses record eye movements and fixations as ambulatory subjects navigate their environment. We tested the performance of eye tracking glasses under laboratory and real world conditions, to characterize the vergence behavior of normal individuals engaged in their customary daily pursuits.

METHODS

To define the accuracy and variability of the eye tracking glasses, 4 subjects fixated with the head stabilized at a series of distances corresponding to vergence demands of: 0.25, 0.50, 1, 2, 4, 8, 16, and 32°. Then, 10 subjects wore the eye tracking glasses for prolonged periods while carrying out their normal activities. Vergence profiles were compiled for each subject and compared with interpupillary distance.

RESULTS

In the laboratory the eye tracking glasses were comparable in accuracy to remote video eye trackers, outputting a mean vergence value within 1° of demand at all angles except 32°. In ambulatory subjects the glasses were less accurate, due to tracking interruptions and measurement errors, only partly mitigated by application of data filters. Nonetheless, a useful record of vergence behavior was obtained in every subject. Vergence angle often had a bimodal distribution, reflecting a preponderance of activities at near (mobile phone, computer) or far (driving, walking). Vergence angle was highly correlated with interpupillary distance.

CONCLUSIONS

Wearable eye tracking glasses provide a history of vergence angle and the corresponding scene witnessed by ambulatory subjects. They offer insight into the diversity of human ocular motor behavior and may become useful for diagnosis of disorders that affect vergence, such as convergence insufficiency, Parkinson disease, and strabismus.
SARS-CoV-2 mRNA vaccination elicits broad and potent Fc effector functions to VOCs in vulnerable populations
Authors: Hederman Andrew P. , Natarajan Harini , Wiener Joshua A. , Wright Peter F. , Bloch Evan M. , Tobian Aaron A.R. , Redd Andrew D. , Blankson Joel N. , Rottenstreich Amihai , Zarbiv Gila , Wolf Dana , Goetghebuer Tessa , Marchant Arnaud , Ackerman Margaret E.
Published: September 2022

SARS-CoV-2 variants have continuously emerged even as highly effective vaccines have been widely deployed. Reduced neutralization observed against variants of concern (VOC) raises the question as to whether other antiviral antibody activities are similarly compromised, or if they might compensate for lost neutralization activity. In this study, the breadth and potency of antibody recognition and effector function was surveyed in both healthy individuals as well as immunologically vulnerable subjects following either natural infection or receipt of an mRNA vaccine. Considering pregnant women as a model cohort with higher risk of severe illness and death, we observed similar binding and functional breadth for healthy and immunologically vulnerable populations. In contrast, considerably greater functional antibody breadth and potency across VOC was associated with vaccination than prior infection. However, greater antibody functional activity targeting the endemic coronavirus OC43 was noted among convalescent individuals, illustrating a dichotomy in recognition between close and distant human coronavirus strains that was associated with exposure history. Probing the full-length spike and receptor binding domain (RBD) revealed that antibody-mediated Fc effector functions were better maintained against full-length spike as compared to RBD. This analysis of antibody functions in healthy and vulnerable populations across a panel of SARS-CoV-2 VOC and extending through endemic alphacoronavirus strains suggests the differential potential for antibody effector functions to contribute to protecting vaccinated and convalescent subjects as the pandemic progresses and novel variants continue to evolve.

One Sentence Summary

As compared to natural infection with SARS-CoV-2, vaccination drives superior functional antibody breadth raising hopes for candidate universal CoV vaccines.
Systemic and intrinsic functions of ATRX in glial cell fate and CNS myelination
Authors: Rowland Megan E. , Jiang Yan , Shafiq Sarfraz , Ghahramani Alireza , Pena-Ortiz Miguel A. , Dumeaux Vanessa , Bérubé Nathalie G.
Published: September 2022

Neurodevelopmental disorders are often characterized by abnormal production of myelin, an extension of the oligodendrocyte plasma membrane wrapped around axons to facilitate nerve conduction. However, the molecular mechanisms that control myelination during brain development are incompletely resolved. Here, we provide evidence that loss of ATRX, encoded by the gene mutated in the ATR-X intellectual disability syndrome, leads to myelin deficits in the mouse CNS. While postnatal systemic thyroxine administration can improve myelination, the rescue is incomplete, pointing to additional roles of ATRX in this process. We show that targeted inactivation of ATRX in postnatal oligodendrocyte progenitor cells (OPCs), but not in neurons, also leads to myelination deficits, demonstrating cell-intrinsic effects of ATRX deficiency. A subset of ATRX-null OPCs express lower levels of oligodendrocyte specification and differentiation markers, including the basic helix-loop-helix Olig2 transcription factor. Mechanistically, we provide evidence that ATRX occupies genomic sites in OPCs marked by H3K27Ac, CHD7 and CHD8 and demonstrate that reduced Olig2 expression is associated with decreased H3K27Ac. Finally, our data suggest that ATRX-null OPCs acquire a more plastic state and can exhibit astrocyte-like features in vitro and in vivo, supporting a model in which ATRX regulates the onset of myelination by promoting OPC identity and suppressing astrogliogenesis. These previously unrecognized functions of ATRX might explain white matter pathogenesis in ATR-X syndrome patients.
Exploring problematic internet use and gaming in young adults with autism spectrum disorder
Authors: Normand Claude L. , Fisher Marisa H. , Fecteau Stéphanie-M. , Tremblay Kelly , Roy Evelyne , Poulin Marie-Hélène
Published: September 2022

Characteristics of autism spectrum disorder (ASD) could lead individuals with ASD to spend large amounts of time on internet and potentially becoming addicted. Sixty-five individuals with ASD (mean age = 23.77, SD = 4.3) completed an online survey measuring compulsive internet use and gaming disorder. Six participants (9.3%) had problematic internet use, while only two (3%) scored above cut-off for gaming disorder. Exploratory analyses found no differences according to gender, age, employment or co-occurring diagnoses of anxiety, ADHD or depression. Our data suggest that problematic internet could be more frequent than gaming disorder in Canadian young adults with autism and that these issues should be investigated further.
Re-exploiting multiple RNA-seq data to identify transcript variations in Podospora anserina
Authors: Lelandais Gaëlle , Remy Damien , Malagnac Fabienne , Pierre Grognet
Published: September 2022

Background

Publicly available RNA-seq datasets are often underused although being helpful to improve functional annotation of eukaryotic genomes. This is especially true for filamentous fungi genomes which structure differs from most well annotated yeast genomes. Podospora anserina is a filamentous fungal model, which genome has been sequenced and annotated in 2008. Still, the current annotation lacks information about cis-regulatory elements, including promoters, transcription starting sites and terminators, which are instrumental to integrate epigenomic features into global gene regulation strategies.

Results

Here we took advantage of 37 RNA-seq experiments that were obtained in contrasted developmental and physiological conditions, to complete the functional annotation of P. anserina genome. Out of the 10,800 previously annotated genes, 5’UTR and 3’UTR were defined for 7,554, among which, 3,328 showed differential transcriptional signal starts and/or transcriptional end sites. In addition, alternative splicing events were detected for 2350 genes, mostly due alternative 3’splice site and 1,958 novel transcriptionally active regions (nTARs) in unannotated regions were identified.

Conclusions

Our study provides a comprehensive genome-wide functional annotation release of P. anserina genome, including chromatin features, cis-acting elements such as UTRs, alternative splicing events and transcription of non-coding regions. These new findings will likely improve our understanding of gene regulation strategies in compact genomes, such as those of filamentous fungi. Characterization of alternative transcripts and nTARs paves the way to the discovery of putative new genes, alternative peptides or regulatory non-coding RNAs.
IRescue: uncertainty-aware quantification of transposable elements expression at single cell level
Authors: Benedetto Polimeni , Federica Marasca , Valeria Ranzani , Beatrice Bodega
Published: September 2022

Transposable elements (TEs) are mobile DNA repeats that contribute to the evolution of eukaryotic genomes. In complex organisms, TE expression is tissue specific. However, their contribution to cellular heterogeneity is still unknown and challenging to investigate in single-cell RNA sequencing (scRNA-seq), due to the ubiquity and homology of TEs in the genome. We introduce IRescue (Interspersed Repeats single-cell quantifier), the first software that accurately estimates the expression of TE subfamilies at single-cell level, implementing a UMI deduplication algorithm to allocate reads ambiguously mapped on TEs, while correcting for UMI sequencing errors. Applying IRescue on simulated datasets and real scRNA-seq of colorectal cancers, we could precisely estimate TE subfamilies expression. We show that IRescue improves the definition of cellular heterogeneity, detecting TE expression signatures and specific TE-containing splicing isoforms.
Change in functional trait diversity mediates the effects of nutrient addition on grassland stability
Authors: Chen Qingqing , Wang Shaopeng , Seabloom Eric W. , Isbell Forest , Borer Elizabeth T. , Bakker Jonathan D. , Bharath Siddharth , Roscher Christiane , Peri Pablo Luis , Power Sally A. , Donohue Ian , Stevens Carly , Ebeling Anne , Nogueira Carla , Caldeira Maria C , MacDougall Andrew S. , Moore Joslin L. , Bagchi Sumanta , Jentsch Anke , Tedder Michelle , Kirkman Kevin , Alberti Juan , Hautier Yann
Published: September 2022

Nutrient enrichment impacts grassland plant diversity such as species richness, functional trait composition and diversity, but whether and how these changes affect ecosystem stability in the face of increasing climate extremes remains largely unknown.

We quantified the direct and diversity-mediated effects of nutrient addition (by nitrogen, phosphorus, and potassium) on the stability of aboveground biomass production in 10 long-term grassland experimental sites. We measured five facets of stability as the temporal invariability, resistance during and recovery after extreme dry and wet growing seasons.

Leaf traits (leaf carbon, nitrogen, phosphorus, potassium, and specific leaf area) were measured under ambient and nutrient addition conditions in the field and were used to construct the leaf economic spectrum (LES). We calculated functional trait composition and diversity of LES and of single leaf traits. We quantified the contribution of intraspecific trait shifts and species replacement to change in functional trait composition as responses to nutrient addition and its implications for ecosystem stability.

Nutrient addition decreased functional trait diversity and drove grassland communities to the faster end of the LES primarily through intraspecific trait shifts, suggesting that intraspecific trait shifts should be included for accurately predicting ecosystem stability. Moreover, the change in functional trait diversity of the LES in turn influenced different facets of stability. That said, these diversity-mediated effects were overall weak and/or overwhelmed by the direct effects of nutrient addition on stability. As a result, nutrient addition did not strongly impact any of the stability facets. These results were generally consistent using individual leaf traits but the dominant pathways differed. Importantly, major influencing pathways differed using average trait values extracted from global trait databases (e.g. TRY).

Synthesis. Investigating changes in multiple facets of plant diversity and their impacts on multidimensional stability under global changes such as nutrient enrichment can improve our understanding of the processes and mechanisms maintaining ecosystem stability.
Age and micronutrient effects on the microbiome in a mouse model of zinc depletion and supplementation
Authors: Davis Edward W. , Wong Carmen P. , Arnold Holly K. , Kasschau Kristin , Gaulke Christopher A. , Sharpton Thomas J. , Ho Emily
Published: September 2022

Older adult populations are at risk for elevated zinc deficiency, which may predispose them to immune dysfunction and age-related chronic inflammation that drives myriad diseases and disorders. Recent work also implicates the gut microbiome in the onset and severity of age-related inflammation, indicating that dietary zinc status and the gut microbiome may interact to impact age-related host immunity. We hypothesize that age-related alterations in the gut microbiome contribute to the demonstrated zinc deficits in host zinc levels and increased inflammation. We tested this hypothesis with a multifactor two-part study design in a C57BL/6 mouse model. The two studies included young (2 month old) and aged (24 month old) mice fed either (1) a zinc adequate or zinc supplemented diet, or (2) a zinc adequate or marginal zinc deficient diet, respectively. Overall microbiome composition did not significantly change with zinc status; beta diversity was driven almost exclusively by age effects. Microbiome differences due to age are evident at all taxonomic levels, with more than half of all taxonomic units significantly different at each. Furthermore, we found 150 out of 186 genera were significantly different between the two age groups, with Bacteriodes and Parabacteroides being the primary components of young and old mice, respectively. These data suggest that modulating individual micronutrient concentrations does not lead to comprehensive microbiome shifts, but rather affects specific components of the gut microbiome. However, a phylogenetic agglomeration technique (ClaaTU) revealed phylogenetic clades of microbiota that respond to modulation of dietary zinc status in an age-dependent manner. Collectively, these results suggest that there exists a complex interplay between host age, gut microbiome composition, and dietary zinc status.
Compressed Data Structures for Population-Scale Positional Burrows–Wheeler Transforms
Authors: Bonizzoni Paola , Boucher Christina , Cozzi Davide , Gagie Travis , Kashgouli Sana , Köppl Dominik , Rossi Massimiliano
Published: September 2022

Abstract

The positional Burrows–Wheeler Transform (PBWT) was presented in 2014 by Durbin as a means to find all maximal haplotype matches inhsequences containingwvariation sites in 𝒪(hw)-time. This time complexity of finding maximal haplotype matches using the PBWT is a significant improvement over the naïve pattern-matching algorithm that requires 𝒪(h2w)-time. Compared to the more famous Burrows-Wheeler Transform (BWT), however, a relatively little amount of attention has been paid to the PBWT. This has resulted in less space-efficient data structures for building and storing the PBWT. Given the increasing size of available haplotype datasets, and the applicability of the PBWT to pangenomics, the time is ripe for identifying efficient data structures that can be constructed for large datasets. Here, we present a comprehensive study of the memory footprint of data structures supporting maximal haplotype matching in conjunction with the PBWT. In particular, we present several data structure components that act as building blocks for constructing six different data structures that store the PBWT in a manner that supports efficiently finding the maximal haplotype matches. We estimate the memory usage of the data structures by bounding the space usage with respect to the input size. In light of this experimental analysis, we implement the solutions that are deemed to be superior with respect to the memory usage and show the performance on haplotype datasets taken from the 1000 Genomes Project data.
Using pressure-driven flow systems to evaluate laser speckle contrast imaging
Authors: Sullender Colin T. , Santorelli Adam , Richards Lisa M. , Mannava Pawan K. , Smith Christopher , Dunn Andrew K.
Published: September 2022

Significance

Microfluidic flow phantom studies are commonly used for characterizing the performance of laser speckle contrast imaging (LSCI) instruments. The selection of the flow control system is critical for the reliable generation of flow during testing. The majority of recent LSCI studies using microfluidics used syringe pumps for flow control.

Aim

We quantified the uncertainty in flow generation for a syringe pump and a pressure-regulated flow system. We then assessed the performance of both LSCI and multi-exposure speckle imaging (MESI) using the pressure-regulated flow system across a range of flow speeds.

Approach

The syringe pump and pressure-regulated flow systems were evaluated during stepped flow profile experiments in a microfluidic device using an inline flow sensor. The uncertainty associated with each flow system was calculated and used to determine the reliability for instrument testing. The pressure-regulated flow system was then used to characterize the relative performance of LSCI and MESI during stepped flow profile experiments while using the inline flow sensor as reference.

Results

The pressure-regulated flow system produced much more stable and reproducible flow outputs compared to the syringe pump. The expanded uncertainty for the syringe pump was 8–20× higher than that of the pressure-regulated flow system across the tested flow speeds. Using the pressure-regulated flow system, MESI outperformed single-exposure LSCI at all flow speeds and closely mirrored the flow sensor measurements, with average errors of 4.6 ± 2.6% and 15.7 ± 4.6%, respectively.

Conclusions

Pressure-regulated flow systems should be used instead of syringe pumps when assessing the performance of flow measurement techniques with microfluidic studies. MESI offers more accurate relative flow measurements than traditional LSCI across a wide range of flow speeds.
The balance N1 and the ERN correlate in amplitude across individuals in small samples of younger and older adults
Authors: Payne Aiden M. , Ting Lena H. , Hajcak Greg
Published: September 2022

The error-related negativity (ERN) is a neural correlate of error monitoring often used to investigate individual differences in developmental, mental health, and adaptive contexts. However, limited experimental control over errors presents several confounds to its measurement. An experimentally controlled disturbance to standing balance evokes the balance N1, which we previously suggested may share underlying mechanisms with the ERN based on a number of shared features and factors. We now measure whether the balance N1 and ERN are correlated across individuals within two small groups (N=21 young adults and N=20 older adults). ERNs were measured in arrow flanker tasks using hand and foot response modalities (ERN-hand and ERN-foot). The balance N1 was evoked by sudden slip-like movements of the floor while standing. The ERNs and the balance N1 showed good and excellent internal consistency, respectively, and were correlated in amplitude in both groups. One principal component strongly loaded on all three evoked potentials, suggesting that the majority of individual differences are shared across the three ERPs. However, there remains a significant component of variance shared between the ERN-hand and ERN-foot beyond what they share with the balance N1. It is unclear whether this component of variance is specific to the arrow flanker task, or something fundamentally related to error processing that is not evoked by a sudden balance disturbance. If the balance N1 were to reflect error processing mechanisms indexed by the ERN, balance paradigms offer several advantages in terms of experimental control over errors.
Historical biogeography of Cannabis in the Iberian Peninsula: palynological evidence
Authors: Rull V. , Burjachs F. , Carrión J.S. , Ejarque A. , Fernández S. , López-Sáez J.A. , Luelmo-Lautenschlaeger R. , Ochando J. , Pérez-Díaz S. , Revelles J. , Riera S. , Rodríguez S.
Published: September 2022

The tempo and mode of colonization of the Iberian Peninsula (IP) by Cannabis sativa, its further internal spreading and the potential cultural and environmental factors involved remain unknown. The available continental-wide European meta-analyses using pollen and archaeological evidence account for only a few IP sites, insufficient for a sound assessment. This paper presents a nearly comprehensive database of almost 60 IP sites with palynological evidence of Cannabis and analyzes the corresponding spatiotemporal patterns. The first scattered records of this pollen type, likely corresponding to wild Cannabis, date from the Middle and Upper Paleolithic (150 to 12 ky BP) and would have entered the IP by maritime Mediterranean or terrestrial continental pathways, or both. A first burst of introductions, probably in a cultivated form, would have occurred during the Neolithic (7-5 ky BP) using similar paths. Human participation in this Neolithic acceleration remains unclear but cannot be dismissed. A period of reduced Cannabis arrivals (mostly via MP) occurred between the Chalcolithic and the Roman Epoch (4.5-2 ky BP), when the innermost parts of the IP were colonized (Late Bronze). A second, likely anthropogenic, introduction acceleration took place in the Middle Ages (1.5 ky BP onward) using the MP and CP. Maximum cultivation and hemp retting activity was recorded during the Modern Ages (16th-19th centuries), coinciding with the increased demand of hemp fiber to supply the Spanish royal navy for imperial expansion and commerce. A potential link between Cannabis colonization/introduction bursts and climatic warmings has been observed that should be tested with future studies. Regional moisture variations seem to be less influential. Further efforts to enhance and improve the database used in this study are encouraged. The results of this paper should be compared with archaeological and historical evidence to clarify the role of human migrations and cultural changes in the historical biogeography of Cannabis in the IP.
Microbial interactions impact the growth response ofClostridioides difficileto antibiotics
Authors: Hromada Susan , Venturelli Ophelia
Published: September 2022

In the human gut, the growth ofClostridioides difficileis impacted by a complex web of inter-species interactions with members of human gut microbiota. We investigate the contribution of inter-species interactions on the antibiotic response ofC. difficileto clinically relevant antibiotics using bottom-up assembly of human gut communities. We discover two classes of microbial interactions that alterC.difficile’s antibiotic susceptibility: infrequent increases in tolerance at high antibiotic concentrations and frequent growth enhancements at low antibiotic concentrations. Based on genome-wide transcriptional profiling data, we demonstrate that metal sequestration due to hydrogen sulfide production by the prevalent gut speciesDesulfovibrio pigerincreases metronidazole tolerance ofC. difficile. Competition with species that display higher sensitivity to the antibiotic thanC. difficileleads to enhanced growth ofC. difficileat low antibiotic concentrations. A dynamic computational model identifies the ecological design principles driving this effect. Our results provide a deeper understanding of ecological and molecular principles shapingC. difficile’s response to antibiotics, which could inform therapeutic interventions.
A Computational Model of Learning Flexible Navigation in a Maze by Layout-Conforming Replay of Place Cells
Authors: Gao Yuanxiang
Published: September 2022

Recent experimental observations have shown that the reactivation of hippocampal place cells (PC) during sleep or immobility depicts trajectories that can go around barriers and can flexibly adapt to a changing maze layout. Such layout-conforming replay sheds a light on how the activity of place cells supports the learning of flexible navigation in a dynamically changing maze. However, existing computational models of replay fall short of generating layout-conforming replay, restricting their usage to simple environments, like linear tracks or open fields. In this paper, we propose a computational model that generates layout-conforming replay and explains how such replay drives the learning of flexible navigation in a maze. First, we propose a Hebbian-like rule to learn the inter-PC synaptic strength during exploring a maze. Then we use a continuous attractor network (CAN) with feedback inhibition to model the interaction among place cells and hippocampal interneurons. The activity bump of place cells drifts along a path in the maze, which models layout-conforming replay. During replay in rest, the synaptic strengths from place cells to striatal medium spiny neurons (MSN) are learned by a novel dopamine-modulated three-factor rule to store place-reward associations. During goal-directed navigation, the CAN periodically generates replay trajectories from the animal’s location for path planning, and the trajectory leading to a maximal MSN activity is followed by the animal. We have implemented our model into a high-fidelity virtual rat in the MuJoCo physics simulator. Extensive experiments have demonstrated that its superior flexibility during navigation in a maze is due to a continuous re-learning of inter-PC and PC-MSN synaptic strength.
Impact of airline travel network on the global importation risk of monkeypox, 2022
Authors: Kinoshita Ryo , Sassa Miho , Otake Shogo , Yoshimatsu Fumi , Shi Shoi , Ueno Ryo , Suzuki Motoi , Yoneoka Daisuke
Published: September 2022

Background

As of 4 September 2020, a total of 53,996 monkeypox cases were confirmed globally. Currently, most monkeypox cases are concentrated in Europe and the Americas, while many countries outside these regions are also continuously observing imported cases. We aimed to estimate the potential global risk of monkeypox importation and consider hypothetical scenarios of travel restrictions by varying passenger volumes via airline travel network.

Method

Passenger volume data for the airline network, and the time of first confirmed monkeypox case for a total of 1680 airports in 176 countries (and territories) were extracted from publicly available data sources. A survival analysis technique in which the hazard function was a function of effective distance was utilized to estimate the importation risk. Scenarios which selectively reduced the passenger volume from/to countries with detected monkeypox cases and increased/decreased the global passenger volume to the level of 2019 (high volume) or 2021 (low volume) regardless of monkeypox detection were considered for travel restrictions.

Results

The arrival time ranged from 9 to 48 days since the first case was identified in the UK on 6 May 2022. The estimated risk of importation showed that regardless of the geographic region, most locations will have an intensified importation risk by 31 December 2022. Travel restrictions had a minor impact on the global airline importation risk against monkeypox.

Conclusions

Instead of preventing the importation of monkeypox cases via airline networks, high risk countries should enhance local capacities for the identification of monkeypox and prepare to carry out contact tracing and isolation.
Divisive Normalization Circuits Faithfully Represent Auditory and Visual Sensory Stimuli
Authors: Lazar Aurel A. , Liu Tingkai , Zhou Yiyin
Published: September 2022

Divisive 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

BACKGROUND: 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

Increasing 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

Jumbo 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

Synthesis 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

Bacteriophages (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

A 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

Cyanobacteria 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

In 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

Abnormal 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.