bluuebunny/crossref_metadata_2025 huggingface dataset:
Disentangling the role of poultry farms and wild birds in the spread of highly pathogenic avian influenza virus H5N8 in Europe
Authors: Guinat Claire , Agui Cecilia Valenzuela , Vaughan Timothy G. , Scire Jérémie , Pohlmann Anne , Staubach Christoph , King Jacqueline , Swieton Edyta , Dan Adam , Cernikova Lenka , Ducatez Mariette F. , Stadler Tanja
Published: October 2021

Recent outbreaks of highly pathogenic avian influenza H5N8 virus in Europe have caused severe damage to animal health, wildlife conservation and livestock economic sustainability. While epidemiological and phylogenetic studies have generated important clues about the virus spread in Europe, they remained opaque to the specific role of poultry farms and wild birds. Using a phylodynamic framework, we inferred the H5N8 virus transmission dynamics among poultry farms and wild birds in four severely affected countries and investigated drivers of spread between farms across borders during the 2016-17 epidemic. Based on existing genetic data, we showed that the virus was likely introduced into poultry farms during the autumn, in line with the timing of arrival of migratory wild birds. Then, transmission was mainly driven by farm-to-farm transmission in Germany, Hungary and Poland, suggesting that better understanding of how infected farms are connected in those countries would greatly help control efforts. In contrast, the epidemic was dominated by wild bird-to-farm transmission in Czech Republic, meaning that more sustainable prevention strategies should be developed to reduce virus exposure from wild birds. We inferred effective reproduction number Re estimates among poultry farms and wild birds. We expect those estimates being useful to parameterize predictive models of virus spread aiming at optimising control strategies. None of the investigated predictors related to live poultry trade, poultry census and geographic proximity were identified as supportive predictors of the viral spread between farms across borders, suggesting that other drivers should be considered in future studies.

Significance statement

In winter 2016-17, Europe was severely hit by an unprecedented epidemic of highly pathogenic avian influenza (HPAI) H5N8 virus, causing significant impact on animal health, wildlife conservation and livestock economic sustainability. By applying phylodynamic tools to H5N8 sequence data collected from poultry farms and wild birds during the epidemic, we quantified how effectively the first infections were detected, how fast the virus spread, how many infections were missed and how many transmission events occurred at the wildlife-domestic interface. Also, we investigated predictors of the virus spread between farms across borders. These results are crucial to better understand the virus transmission dynamics, with the view to inform policy decision-making and reduce the impact of future epidemics of HPAI viruses.
Wiring multiple microenvironment proteomes uncovers the biology in head and neck cancer
Authors: Busso-Lopes Ariane Fidelis , Rivera César , Neves Leandro Xavier , Granato Daniela Campos , Patroni Fábio Malta de Sá , Mazo Tatiane de Rossi , Normando Ana Gabriela Costa , Domingues Romênia Ramos , Heberle Henry , Pretti Marco Antônio , de Mello Barbara Pereira , Rodrigues Andre Nimtz , Lacerda Pammela Araujo , Galdino Nayane Alves de Lima , Gollob Kenneth John , Medina Tiago da Silva , Cervigne Nilva de Karla , Prado-Ribeiro Ana Carolina , Brandão Thaís Bianca , Villa Luisa Lina , Uno Miyuki , Boroni Mariana , Kowalski Luiz Paulo , González-Arriagada Wilfredo , Paes Leme Adriana Franco
Published: October 2021

The poor prognosis of head and neck cancer (HNC) is associated with the presence of metastasis within the lymph nodes (LNs). Herein, the proteome of 140 multisite samples from a 59-HNC patient cohort, including primary and matched LN-negative or -positive tissues, saliva, and blood cells, reveals insights into the biology and potential metastasis biomarkers that may assist in clinical decision making. Protein profiles are strictly associated with immune modulation across datasets, and this provides the basis for investigating immune markers associated with metastasis. The proteome of LN metastatic cells recapitulates the proteome of the primary tumor sites. Conversely, the LN microenvironment proteome highlights the candidate prognostic markers. By integrating prioritized peptide, protein, and transcript levels with machine learning models, we identified a nodal metastasis signature in the blood and saliva. In summary, we present the deepest proteome characterization wiring multiple sampling sites in HNC, thus providing a promising basis for understanding tumoral biology and identifying metastasis-associated signatures.
Loss of epigenetic regulation disrupts lineage integrity, reactivates multipotency and promotes breast cancer
Authors: Langille Ellen R. , Al-Zahrani Khalid N. , Ma Zhibo , Malik Ahmad , Loganathan Sampath K. , Trcka Dan , Liu Jeff , Kozma Katelyn , Tsai Ricky , Teng Katie , Espin Roderic , Barutcu Seda , Nguyen Thomas , Bremner Rod , Jackson Hartland W. , Knudsen Erik S. , Bader Gary , Egan Sean E. , Pujana Miquel Angel , Wrana Jeff , Wahl Geoffrey M. , Schramek Daniel
Published: October 2021

Systematically investigating the scores of genes mutated in cancer and discerning real drivers from inconsequential bystanders is a prerequisite for Precision Medicine, but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent ‘long-tail’ breast cancer genes, which revealed epigenetic regulation as major tumor suppressive mechanism. We report that core or accessory components of the COMPASS histone methylase complex including KMT2C, KDM6A, BAP1 and ASXL2 (“EpiDrivers”) cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells. Mechanistically, we find that Cre-mediated activation of PIK3CAH1047R elicited an aberrant alveolar lactation program in luminal cells, which was exacerbated upon loss of EpiDrivers. Remarkably, EpiDriver loss in basal cells also triggered an alveolar-like lineage conversion and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. As EpiDrivers are mutated in 39% of human breast cancers, lineage infidelity and lactation mimicry may significantly contribute to early steps of breast cancer progression.

Statement of significance

Infrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. In-vivo CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of lactation genes as potential early events in tumorigenesis.
Oxytocin reduces interoceptive influences on empathy-for-pain in the anterior insula
Authors: Betka Sophie , Van Praag Cassandra Gould , Rae Charlotte L , Pfeifer Gaby , Sequeira Henrique , Duka Theodora , Critchley Hugo
Published: October 2021

Empathy-for-pain states are underpinned byinteroception, i.e the central representation of internal states. Cardiac signals occur in a phasic manner; baroreceptor discharges at systole communicate the heartbeats’ strength. These signals modulate pain and emotion processing. We tested whether these phasic interoceptive signals modulate empathy-for-pain. As oxytocin (OT) enhances empathy and modulates interoceptive signals’ precision, we also tested if OT administration impacts empathy-for-pain via interoceptive mechanisms.

Male subjects (N=32) attended three sessions to perform psychometric tests and an fMRI empathy-for-pain task, after intranasal administration of OT or placebo (40IU). Pictures of hands in painful or non-painful context were presented at systole or diastole. Effects of drug, emotion and cardiac timing on behaviour and brain activity was tested using general and mixed-effects linear models.

Across conditions, activation was observed within regions implicated in pain and empathy-for-pain, with insula activation greater in the right than left hemisphere. OT administration, compared to placebo, attenuated the reactivity of some regions, including anterior cingulate cortex, but presentation of stimuli at systole blocked the OT attenuating effect.

Our data suggest that OT alters the processing of motivationally-salient social cues, interacting with interoceptive signals. Our findings may inform targeted use of OT in psychiatric conditions linked to aberrant interoceptive processing.
Safb1 regulates cell fate determination in adult neural stem cells by enhancing Drosha cleavage of NFIB mRNA
Authors: Iffländer Niklas , Rolando Chiara , Balta Elli-Anna , Forcella Pascal , Mukhtar Tanzila , Bock Thomas , Taylor Verdon
Published: October 2021

During brain homeostasis, stem cell fate determination is crucial to guarantee function, adaptation and regeneration while preventing neurodegeneration and cognitive impairment. How neural stem cells (NSCs) are instructed to generate neurons or glia is not well understood. Here we addressed how fate is resolved in multipotent adult hippocampal NSCs, and identify Scaffold Attachment Factor B1 (Safb1) as a determinant of neuron production by blocking glial commitment. Safb1 is sufficient to block oligodendrocytic differentiation of NSCs by preventing expression of the transcription factor NFIB at the post-transcriptional level. Detailed interrogation of the Drosha interactome and functional validation revealed that Safb1 enhances NFIB mRNA cleavage in a Drosha-dependent fashion. Thus, our study provides a cellular mechanism for selective NSC fate regulation by post-transcriptional destabilization of mRNAs. Given the importance of NSC maintenance and fate determination in the adult brain, our findings have major implications for cell-specific gene expression, brain disease and aging.
Visual occipito-temporal sensitivity to digits through elementary school
Authors: Fraga-González Gorka , Di Pietro Sarah V. , Pleisch Georgette , Neuenschwander Jasmin , Walitza Susanne , Brandeis Daniel , Karipidis Iliana I. , Brem Silvia
Published: October 2021

Number processing abilities are important for academic and personal development. The course of initial specialization of ventral occipito-temporal cortex (vOTC) for visual number processing is crucial for the development of numeric and arithmetic skills. We examined the visual N1, the electrophysiological correlate of vOTC activations across five time points in kindergarten (T1), middle and end of first grade (T2, T3), second (T4) and fifth grade (T5). 62 children (35 female) performed a target detection task which included visual presentation of digits, false fonts, and letters. Arithmetic skills were measured at T4 and T5 with standardized math tests. Stronger N1 amplitudes for digits than false fonts were found across all 5 measurements. Arithmetic skills correlated negatively with visual N1 sensitivity to digits at T4 (2nd grade, mean age 8.3 yrs) over the left hemisphere, possibly reflecting allocation of more attentional or cognitive resources with poorer arithmetic skills. Our main result shows persistent visual N1 sensitivity to digits that is already present early on in pre-school and remains stable until fifth grade. This differs from the relatively sharp rise and fall of the visual N1 sensitivity to words or letters between kindergarten and middle of elementary school. The present study thus indicates different trajectories in the development of visual processing for written characters that are relevant to numeracy and literacy.
Decoding personalized motor cortical excitability states from human electroencephalography
Authors: Hussain Sara J , Quentin Romain
Published: October 2021

Brain state-dependent transcranial magnetic stimulation (TMS) requires real-time identification of cortical excitability states. Current approaches deliver TMS during brain states that correlate with motor cortex (M1) excitability at the group level. Here, we hypothesized that machine learning classifiers could successfully discriminate between high and low M1 excitability states in individual participants using information obtained from low-density electroencephalography (EEG) signals. To test this, we analyzed a publicly available dataset that delivered 600 single TMS pulses to the right M1 during EEG and electromyography (EMG) recordings in 20 healthy adults. Multivariate pattern classification was used to discriminate between brain states during which TMS evoked small and large motor-evoked potentials (MEPs). Results show that personalized classifiers successfully discriminated between low and high M1 excitability states in 80% of tested participants. MEPs elicited during classifier-predicted high excitability states were significantly larger than those elicited during classifier-predicted low excitability states in 90% of tested participants. Personalized classifiers did not generalize across participants. Overall, results show that individual participants exhibit unique brain activity patterns which predict low and high M1 excitability states and that these patterns can be efficiently captured using low-density EEG signals. Our findings suggest that deploying individualized classifiers during brain state-dependent TMS may enable fully personalized neuromodulation in the future.
Polar lipids are linked to nanoparticles in xylem sap of temperate angiosperm species
Authors: Guan Xinyi , Schenk H. Jochen , Roth Mary R. , Welti Ruth , Werner Julia , Kaack Lucian , Trabi Christophe L. , Jansen Steven
Published: October 2021

Xylem sap of angiosperm species has been found to include low concentrations of polar lipids and nanoparticles, including surfactant-coated nanobubbles. Although the nanoparticles have been suggested to consist of polar lipids, no attempt has been made to determine if nanoparticle and lipid concentrations are related. Here, we examined concentrations of nanoparticles and lipids in xylem sap and contamination control samples of six temperate angiosperm species with a NanoSight device and based on mass spectrometry. We found (1) that the concentration of nanoparticles and lipids were both diluted when an increasing amount of sap was extracted, (2) that their concentrations were significantly correlated in three species, (3) that their concentrations were affected by vessel anatomy, and (4) that concentrations of nanoparticles and lipids were very low in contamination-control samples. Moreover, there was little seasonal difference, no freezing-thawing effect on nanoparticles, and little seasonal variation in lipid composition. These findings indicate that lipids and nanoparticles are related to each other, and largely do not pass interconduit pit membranes. Further research is needed to examine the formation and stability of nanoparticles in xylem sap in relation to lipid composition, and the complicated interactions among the gas, liquid, and solid phases in xylem conduits.
PermaPhosSer: autonomous synthesis of functional, permanently phosphorylated proteins
Authors: Zhu Phillip , Franklin Rachel , Vogel Amber , Stanisheuski Stanislau , Reardon Patrick , Sluchanko Nikolai N. , Beckman Joseph S. , Karplus P. Andrew , Mehl Ryan A. , Cooley Richard B.
Published: October 2021

Installing stable, functional mimics of phosphorylated amino acids into proteins offers a powerful strategy to study protein regulation. Previously, a genetic code expansion (GCE) system was developed to translationally install non-hydrolyzable phosphoserine (nhpSer), with the γ-oxygen replaced with carbon, but it has seen limited usage. Here, we achieve a 40-fold improvement in this system by engineering into Escherichia coli a biosynthetic pathway that produces nhpSer from the central metabolite phosphoenolpyruvate. Using this “PermaPhosSer” system – an autonomous 21-amino acid E. coli expression system for incorporating nhpSer into target proteins – we show that nhpSer faithfully mimics the effects of phosphoserine in three stringent test cases: promoting 14-3-3/client complexation, disrupting 14-3-3 dimers, and activating GSK3β phosphorylation of the SARS-CoV-2 nucleocapsid protein. This facile access to nhpSer containing proteins should allow nhpSer to replace Asp and Glu as the go-to pSer phosphomimetic for proteins produced in E. coli.
Versatile Encapsulation and Synthesis of Potent Therapeutic Liposomes by Thermal Equilibration
Authors: Roberts Steven A. , Lee Chaebin , Singh Shrishti , Agrawal Nitin
Published: October 2021

The wide-scale use of liposomal delivery systems is hampered by difficulties in obtaining potent liposomal suspensions. Passive and active loading strategies have been proposed to formulate drug encapsulated liposomes, but are limited by low efficiencies (passive) or high drug specificities (active). Here, we present an efficient and universal loading strategy for synthesizing therapeutic liposomes. Integrating a thermal equilibration technique with our unique liposome synthesis approach, co-loaded targeting liposomes can be engineered in an efficient and scalable manner with potencies 200-fold higher than typical passive encapsulation techniques. We demonstrate this capability through simultaneous co-loading of hydrophilic and hydrophobic small molecules and through targeted delivery of liposomal Doxorubicin to a metastatic breast cancer cell line MDA-MB-231. Molecular dynamic simulations are used to explain interactions between Doxorubicin and liposome membrane during thermal equilibration. By addressing the existing challenges, we have developed an unparalleled approach that will facilitate the formulation of novel theranostic and pharmaceutical strategies.
Genomic insights into variation in thermotolerance between hybridizing swordtail fishes
Authors: Payne Cheyenne , Bovio Stephen , Powell Daniel , Gunn Theresa , Banerjee Shreya , Grant Victoria , Rosenthal Gil , Schumer Molly
Published: October 2021

Understanding how organisms adapt to changing environments is a core focus of research in evolutionary biology. One common mechanism is adaptive introgression, which has received increasing attention as a potential route to rapid adaptation in populations struggling in the face of ecological change, particularly global climate change. However, hybridization can also result in deleterious genetic interactions that may limit the benefits of adaptive introgression. Here, we used a combination of genome-wide quantitative trait locus mapping and differential gene expression analyses between the swordtail fish speciesXiphophorus malincheandX. birchmannito study the consequences of hybridization on thermotolerance. While these two species are adapted to different thermal environments, we document a complicated architecture of thermotolerance in hybrids. We identify a region of the genome that contributes to reduced thermotolerance in individuals heterozygous forX. malincheandX. birchmanniancestry, as well as widespread misexpression in hybrids of genes that respond to thermal stress in the parental species, particularly in the circadian clock pathway. We also show that a previously mapped hybrid incompatibility betweenX. malincheandX. birchmannicontributes to reduced thermotolerance in hybrids. Together, our results highlight the challenges of understanding the impact of hybridization on complex ecological traits and its potential impact on adaptive introgression.
Light-sheet scattering microscopy to visualize long-term interactions between cells and extracellular matrix
Authors: Zhou Xiangda , Zhao Renping , Yanamandra Archana K. , Hoth Markus , Qu Bin
Published: October 2021

Visualizing interactions between cells and the extracellular matrix (ECM) mesh is important to understand cell behavior and regulatory mechanisms by the extracellular environment. However, long term visualization of three-dimensional (3D) matrix structures remains challenging mainly due to photobleaching or blind spots perpendicular to the imaging plane. Here, we combine label-free light-sheet scattering microcopy (LSSM) and fluorescence microscopy to solve these problems. We verified that LSSM can reliably visualize structures of collagen matrices from different origin including bovine, human and rat tail. The quality and intensity of collagen structure images acquired by LSSM did not decline with time. LSSM offers abundant wavelength choice to visualize matrix structures, maximizing combination possibilities with fluorescently-labelled cells, allowing visualizing of long-term ECM-cell interactions in 3D. Interestingly, we observed ultrathin thread-like structures between cells and matrix using LSSM, which were not observed by normal fluorescence microscopy. Transient local alignment of matrix by cell-applied forces can be observed. In summary, LSSM provides a powerful and robust approach to investigate the complex interplay between cells and ECM.
The behavioral effects of gestational and lactational benzo[a]pyrene exposure vary by sex and genotype in mice with differences at the Ahr and Cyp1a2 loci
Authors: Honaker Amanda , Kyntchev Angela , Foster Emma , Clough Katelyn , Asiedu Emmanuella , Feltner Mackenzie , Ferguson Victoria , Forrest Philip Tyler , Mullaguru Jayasree , Niang Mame Diarra , Perry Connor , Sene Yvonne , Curran Christine Perdan
Published: October 2021

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) and known carcinogen in the Top 10 on the United States’ list of priority pollutants. Humans are exposed through a variety of sources including tobacco smoke, grilled foods and fossil fuel combustion. Recent studies of children exposed to higher levels of PAHs during pregnancy and early life have identified numerous adverse effects on the brain and behavior that persist into school age and adolescence. Our studies were designed to look for genotype and sex differences in susceptibility to gestational and lactational exposure to BaP using a mouse model with allelic differences in the aryl hydrocarbon receptor and the xenobiotic metabolizing enzyme CYP1A2. Pregnant dams were exposed to 10 mg/kg/day of BaP in corn oil-soaked cereal or the corn oil vehicle alone from gestational day 10 until weaning at postnatal day 25. Neurobehavioral testing began at P60 using one male and one female per litter. We found main effects of sex, genotype and treatment as well as significant gene x treatment and sex x treatment interactions. BaP-treated female mice had shorter latencies to fall in the Rotarod test. High-affinity AhrbCyp1a2(−/−) mice had greater impairments in Morris water maze. Interestingly, poor-affinity AhrdCyp1a2(−/−) mice also had deficits in spatial learning and memory regardless of treatment. We believe our findings provide future directions in identifying human populations at highest risk of early life BaP exposure, because our model mimics known human variation in our genes of interest. Our studies also highlight the value of testing both males and females in all neurobehavioral studies.

Highlights

Gestational and lactational benzo[a]pyrene (BaP) exposure has sex and genotype-specific neurobehavioral effects in mice.

Female mice were more susceptible to motor deficits following developmental BaP exposure. Males were more susceptible to deficits in reversal learning and memory.

AhrbCyp1a2(−/−) knockout mice were more susceptible to spatial learning and memory deficits following developmental BaP exposure.

Poor-affinity AhrdCyp1a2(−/−) mice had deficits in spatial learning and memory regardless of treatment.
E-Cannula reveals anatomical diversity in sharp-wave ripples as a driver for the recruitment of distinct hippocampal assemblies
Authors: Liu Xin , Terada Satoshi , Kim Jeong-Hoon , Lu Yichen , Ramezani Mehrdad , Grosmark Andres , Losonczy Attila , Kuzum Duygu
Published: October 2021

The hippocampus plays a critical role in spatial navigation and episodic memory. However, research on in vivo hippocampal activity dynamics has mostly relied on single modalities such as electrical recordings or optical imaging, with respectively limited spatial and temporal resolution. This technical difficulty greatly impedes multi-level investigations into network state-related changes in cellular activity. To overcome these limitations, we developed the E-Cannula integrating fully transparent graphene microelectrodes with imaging-cannula. The E-Cannula enables the simultaneous electrical recording and two-photon calcium imaging from the exact same population of neurons across an anatomically extended region of the mouse hippocampal CA1 stably across several days. These large-scale simultaneous optical and electrical recordings showed that local hippocampal sharp wave ripples (SWRs) are associated with synchronous calcium events involving large neural populations in CA1. We show that SWRs exhibit spatiotemporal wave patterns along multiple axes in 2D space with different spatial extents (local or global) and temporal propagation modes (stationary or travelling). Notably, distinct SWR wave patterns were associated with, and decoded from, the selective recruitment of orthogonal CA1 cell assemblies. These results suggest that the diversity in the anatomical progression of SWRs may serve as a mechanism for the selective activation of the unique hippocampal cell assemblies extensively implicated in the encoding of distinct memories. Through these results we demonstrate the utility of the E-Cannula as a versatile neurotechnology with the potential for future integration with other optical components such as green lenses, fibers or prisms enabling the multi-modal investigation of cross-time scale population-level neural dynamics across brain regions.
NetGAM: Using generalized additive models to improve the predictive power of ecological network analyses constructed using time-series data
Authors: Gleich Samantha J. , Cram Jacob A. , Weissman Jake L. , Caron David A.
Published: October 2021

Ecological network analyses are used to identify potential biotic interactions between microorganisms from species abundance data. These analyses are often carried out using time-series data; however, time-series networks have unique statistical challenges. Time-dependent species abundance data can lead to species co-occurrence patterns that are not a result of direct, biotic associations and may therefore result in inaccurate network predictions. Here, we describe a generalize additive model (GAM)-based data transformation that removes time-series signals from species abundance data prior to running network analyses. Validation of the transformation was carried out by generating mock, time-series datasets, with an underlying covariance structure, running network analyses on these datasets with and without our GAM transformation, and comparing the network outputs to the known covariance structure of the simulated data. The results revealed that seasonal abundance patterns substantially decreased the accuracy of the inferred networks. Additionally, the GAM transformation increased the F1 score of inferred ecological networks on average and improved the ability of network inference methods to capture important features of network structure. This study underscores the importance of considering temporal features when carrying out network analyses and describes a simple, effective tool that can be used to improve results.
The Listening Zone of Human Electrocorticographic Field Potential Recordings
Authors: McCarty Meredith J , Woolnough Oscar , Mosher John C. , Seymour John , Tandon Nitin
Published: October 2021

Intracranial electroencephalographic (icEEG) recordings provide invaluable insights into neural dynamics in humans due to their unmatched spatiotemporal resolution. Yet, such recordings reflect the combined activity of multiple underlying generators, confounding the ability to resolve spatially distinct neural sources. To empirically quantify the listening zone of icEEG recordings, we computed the correlations between signals as a function of distance (expressed as full width at half maximum; FWHM) between 8,752 recording sites in 71 patients implanted with either subdural electrodes (SDE), stereo-encephalography electrodes (sEEG), or high-density sEEG electrodes. As expected, for both SDE and sEEG electrodes, higher frequency signals exhibited a sharper fall off relative to lower frequency signals. For broadband high gamma (BHG) activity, the mean FWHM of SDEs (6.6 ± 2.5 mm) and sEEGs in gray matter (7.14 ± 1.7 mm) was not significantly different, however the FWHM for low frequencies recorded by sEEGs was 2.45 mm smaller than SDEs. White matter sEEG electrodes showed much lower power for frequencies 17 to 200 Hz (q < 0.01) and a much broader decay (11.3 ± 3.2 mm) than gray matter electrodes (7.14 ± 1.7 mm). The use of a bipolar referencing scheme significantly lowered FWHM for sEEG electrodes, as compared with a white matter reference or a common average reference. These results outline the influence of array design, spectral bands, and referencing schema on local field potential recordings and source localization in icEEG recordings in humans. The metrics we derive have immediate relevance to the analysis and interpretation of both cognitive and epileptic data.
scGAD: single-cell gene associating domain scores for exploratory analysis of scHi-C data
Authors: Shen Siqi , Zheng Ye , Keleş Sündüz
Published: October 2021

Quantitative tools are needed to leverage the unprecedented resolution of single-cell high-throughput chromatin conformation (scHi-C) data and to integrate it with other single-cell data modalities. We present single-cell gene associating domain (scGAD) scores as a dimension reduction and exploratory analysis tool for scHi-C data. scGAD enables summarization at the gene level while accounting for inherent gene-level genomic biases. Low-dimensional projections with scGAD capture clustering of cells based on their 3D structures. scGAD enables identifying genes with significant chromatin interactions within and between cell types. We further show that scGAD facilitates the integration of scHi-C data with other single-cell data modalities by enabling its projection onto reference low-dimensional embeddings.

Availability

scGAD is part of the BandNorm R package at https://sshen82.github.io/BandNorm/articles/scGAD-tutorial.html.

Contact

keles@stat.wisc.edu, yzheng23@fredhutch.org

Supplementary information

Supplementary data are available at Bioinformatics online.
Coding of latent variables in sensory, parietal, and frontal cortices during closed-loop virtual navigation
Authors: Noel Jean-Paul , Balzani Edoardo , Avila Eric , Lakshminarasimhan Kaushik , Bruni Stefania , Alefantis Panos , Savin Cristina , Angelaki Dora E.
Published: October 2021

We do not understand how neural nodes operate and coordinate within the recurrent action-perception loops that characterize naturalistic self-environment interactions. Here, we record single-unit spiking activity and local field potentials (LFPs) simultaneously from the dorsomedial superior temporal area (MSTd), parietal area 7a, and dorsolateral prefrontal cortex (dlPFC) as monkeys navigate in virtual reality to “catch fireflies.” This task requires animals to actively sample from a closed-loop virtual environment while concurrently computing continuous latent variables: (i) the distance and angle travelled (i.e., path integration) and (ii) the distance and angle to a memorized firefly location (i.e., a hidden spatial goal). We observed a patterned mixed selectivity, with the prefrontal cortex most prominently coding for latent variables, parietal cortex coding for sensorimotor variables, and MSTd most often coding for eye-movements. However, even the traditionally considered sensory area (i.e., MSTd) tracked latent variables, demonstrating path integration and vector-coding of hidden spatial goals. Further, global encoding profiles and unit-to-unit coupling (i.e., noise correlations) suggested a functional subnetwork composed by MSTd and dlPFC, and not between these and 7a, as anatomy would suggest. We show that the greater the unit-to-unit coupling between MSTd and dlPFC, the more the animals’ gaze position was indicative of the ongoing location of the hidden spatial goal. We suggest this MSTd-dlPFC subnetwork reflects the monkeys’ natural and adaptive task strategy wherein they continuously gaze toward the location of the (invisible) target. Together, these results highlight the distributed nature of neural coding during closed action-perception loops and suggest that fine-grain functional subnetworks may be dynamically established to subserve (embodied) task strategies.
Accurate estimation of intrinsic biases for improved analysis of bulk and single-cell chromatin accessibility sequencing data using SELMA
Authors: Hu Shengen Shawn , Liu Lin , Li Qi , Ma Wenjing , Guertin Michael J. , Meyer Clifford A. , Deng Ke , Zhang Tingting , Zang Chongzhi
Published: October 2021

Genome-wide profiling of chromatin accessibility by DNase-seq or ATAC-seq has been widely used to identify regulatory DNA elements and transcription factor binding sites. However, enzymatic DNA cleavage exhibits intrinsic sequence biases that confound chromatin accessibility profiling data analysis. Existing computational tools are limited in their ability to account for such intrinsic biases and not designed for analyzing single-cell data. Here, we present Simplex Encoded Linear Model for Accessible Chromatin (SELMA), a computational method for systematic estimation of intrinsic cleavage biases from genomic chromatin accessibility profiling data. We demonstrate that SELMA yields accurate and robust bias estimation from both bulk and single-cell DNase-seq and ATAC-seq data. SELMA can utilize internal mitochondrial DNA data to improve bias estimation. We show that transcription factor binding inference from DNase footprints can be improved by incorporating estimated biases using SELMA. Furthermore, we show strong effects of intrinsic biases in single-cell ATAC-seq data, and develop the first single-cell ATAC-seq intrinsic bias correction model to improve cell clustering. SELMA can enhance the performance of existing bioinformatics tools and improve the analysis of both bulk and single-cell chromatin accessibility sequencing data.
Structure and dynamics of Odinarchaeota tubulin and the implications for eukaryotic microtubule evolution
Authors: Akıl Caner , Ali Samson , Tran Linh T. , Gaillard Jeremie , Li Wenfei , Hayashida Kenichi , Hirose Mika , Kato Takayuki , Oshima Atsunori , Fujishima Kosuke , Blanchoin Laurent , Narita Akihiro , Robinson Robert C.
Published: October 2021

Tubulins are critical for the internal organization of eukaryotic cells, and understanding their emergence is an important question in eukaryogenesis. Asgard archaea are the closest known prokaryotic relatives to eukaryotes. Here, we elucidated the apo and nucleotide-bound X-ray structures of an Asgard tubulin from hydrothermal-living Odinarchaeota (OdinTubulin). The GTP-bound structure resembles a microtubule protofilament, with GTP bound between subunits, coordinating the “+” end subunit through a network of water molecules and unexpectedly by two cations. A water molecule is located suitable for GTP hydrolysis. Time course crystallography and electron microscopy revealed conformational changes on GTP hydrolysis. OdinTubulin forms tubules at high temperatures, with short curved protofilaments coiling around the tubule circumference, more similar to FtsZ, rather than running parallel to its length, as in microtubules. Thus, OdinTubulin represents an evolution intermediate between prokaryotic FtsZ and eukaryotic microtubule-forming tubulins.
EnterotoxigenicEscherichia colidegrades the host MUC2 mucin barrier to facilitate critical pathogen-enterocyte interactions in human small intestine
Authors: Sheikh Alaullah , Wangdi Tamding , Vickers Tim J , Aaron Bailey , Palmer Margot , Miller Mark J. , Kim Seonyoung , Herring Cassandra , Simoes Rita , Crainic Jennifer A. , Gildersleeve Jeffrey C. , van der Post Sjoerd , Hansson Gunnar C. , Fleckenstein James M.
Published: October 2021

EnterotoxigenicEscherichia coli(ETEC) are a genetically diverse pathologic variant ofE. colidefined by the production of heat-labile (LT) and/or heat-stable (ST) toxins. ETEC are estimated to cause hundreds of millions of cases of diarrheal illness annually. However, it is not clear that all strains are equally equipped to cause disease and asymptomatic colonization with ETEC is common in low-middle income regions lacking basic sanitation and clean water where ETEC are ubiquitous. Recent molecular epidemiology studies have revealed a significant association between strains which produce EatA, a secreted autotransporter protein, and the development of symptomatic infection. Here, we demonstrate that LT stimulates production of MUC2 mucin by goblet cells in human small intestine, enhancing the protective barrier between pathogens and enterocytes. In contrast, using explants of human small intestine as well as small intestinal enteroids, we show that EatA counters this host defense by engaging and degrading the MUC2 mucin barrier to promote bacterial access to target enterocytes and ultimately toxin delivery suggesting that EatA plays a crucial role in the molecular pathogenesis of ETEC. These findings may inform novel approaches to prevention of the acute diarrheal illness as well as the sequelae associated with ETEC and other pathogens that rely on EatA and similar proteases for efficient interaction with their human hosts.
Amplicon Sequencing of Single-copy Protein-coding Genes Reveals Accurate Diversity for Sequence-discrete Microbiome Populations
Authors: Yang Chengfeng , Su Qinzhi , Tang Min , Luo Shiqi , Zheng Hao , Zhang Xue , Zhou Xin
Published: October 2021

An in-depth understanding of microbial function and the division of ecological niches requires accurate delineation and identification of microbes at a fine taxonomic resolution. Microbial phylotypes are typically defined using a 97% small subunit (16S) rRNA threshold. However, increasing evidence has demonstrated the ubiquitous presence of taxonomic units of distinct functions within phylotypes. These so-called sequence-discrete populations (SDPs) have used to be mainly delineated by disjunct sequence similarity at the whole-genome level. However, gene markers that could accurately identify and quantify SDPs are lacking in microbial community studies. Here we developed a pipeline to screen single-copy protein-coding genes that could accurately characterize SDP diversity via amplicon sequencing of microbial communities. Fifteen candidate marker genes were evaluated using three criteria (extent of sequence divergence, phylogenetic accuracy, and conservation of primer regions) and the selected genes were subject to test the efficiency in differentiating SDPs within Gilliamella, a core honeybee gut microbial phylotype, as a proof-of-concept. The results showed that the 16S V4 region failed to report accurate SDP diversities due to low taxonomic resolution and changing copy numbers. In contrast, the single-copy genes recommended by our pipeline were able to successfully quantify Gilliamella SDPs for both mock samples and honeybee guts, with results highly consistent with those of metagenomics. The pipeline developed in this study is expected to identify single-copy protein coding genes capable of accurately quantifying diverse bacterial communities at the SDP level.

IMPORTANCE

Microbial communities can be distinguished by discrete genetic and ecological characteristics. These sequence-discrete populations are foundational for investigating the composition and functional structures of microbial communities at high resolution. In this study, we screened for reliable single-copy protein-coding marker genes to identify sequence-discrete populations through our pipeline. Using marker gene amplicon sequencing, we could accurately and efficiently delineate the population diversity in microbial communities. These results suggest that single copy protein-coding genes can be an accurate, quantitative and economical alternative for characterizing population diversity. Moreover, the feasibility of a gene as marker for any bacterial population identification can be quickly evaluated by the pipeline proposed here.
Transcriptional regulation of photoprotection in dark-to-light transition - more than just a matter of excess light energy
Authors: Redekop Petra , Sanz-Luque Emanuel , Yuan Yizhong , Villain Gaelle , Petroutsos Dimitris , Grossman Arthur R.
Published: October 2021

In nature, photosynthetic organisms are exposed to different light spectra and intensities depending on the time of day and atmospheric and environmental conditions. When photosynthetic cells absorb excess light, they induce non-photochemical quenching to avoid photo-damage and trigger expression of ‘photoprotective’ genes. In this work, we used the green alga Chlamydomonas reinhardtii to assess the impact of light intensity, light quality, wavelength, photosynthetic electron transport and CO2 on induction of the ‘photoprotective’ genes (LHCSR1, LHCSR3 and PSBS) during dark-to-light transitions. Induction (mRNA accumulation) occurred at very low light intensity, was independently modulated by blue and UV-B radiation through specific photoreceptors, and only LHCSR3 was strongly controlled by CO2 levels through a putative enhancer function of CIA5, a transcription factor that controls genes of the carbon concentrating mechanism. We propose a model that integrates inputs of independent signaling pathways and how they may help the cells anticipate diel conditions and survive in a dynamic light environment.
Repeated unilateral handgrip contractions alter functional connectivity and improve contralateral limb response times: A neuroimaging study
Authors: Andrushko Justin W. , Levenstein Jacob M. , Zich Catharina , Edmond Evan C. , Campbell Jon , Clarke William T. , Emir Uzay , Farthing Jonathan P. , Stagg Charlotte J.
Published: October 2021

In humans, motor learning is underpinned by changes in sensorimotor network functional connectivity (FC). Unilateral contractions increase FC in the ipsilateral primary motor cortex (M1) and supplementary motor area (SMA); areas involved in motor planning and execution of the contralateral hand. Therefore, unilateral contractions are a promising approach to augment motor performance in the contralateral hand. In a within-participant, randomized, cross-over design, 15 right-handed adults had two magnetic resonance imaging (MRI) sessions, where functional-MRI and MR-Spectroscopic Imaging were acquired before and after repeated right-hand contractions at either 5% or 50% maximum voluntary contraction (MVC). Before and after scanning, response times (RTs) were determined in both hands. Nine minutes of 50% MVC contractions resulted in decreased handgrip force in the contracting hand, and decreased RTs in the contralateral hand. This improved motor performance in the contralateral hand was supported by significant neural changes: increased FC between SMA-SMA and increased FC between right M1 and right Orbitofrontal Cortex. At a neurochemical level, the degree of GABA decline in left M1, left and right SMA correlated with subsequent behavioural improvements in the left-hand. These results support the use of repeated handgrip contractions as a potential modality for improving motor performance in the contralateral hand.

Significance Statement

Enhanced functional connectivity and decreased inhibition in sensorimotor areas of the brain underpin enhancements in motor performance and learning. In this study we investigated the impact of repeated right handgrip contractions at 50% MVC to improve behaviour, enhance functional connectivity and alter sensorimotor inhibition. We found that after nine minutes of repeated 50% MVC handgrip contractions with the right-hand, left-hand response times were significantly improved. This behavioural improvement was accompanied by altered interhemispheric functional connectivity and neurochemical changes across sensorimotor areas. Repeated unilateral handgrip contractions may be an effective method for enhancing contralateral limb motor performance in rehabilitation settings.
End-to-end learning of multiple sequence alignments with differentiable Smith-Waterman
Authors: Petti Samantha , Bhattacharya Nicholas , Rao Roshan , Dauparas Justas , Thomas Neil , Zhou Juannan , Rush Alexander M. , Koo Peter K. , Ovchinnikov Sergey
Published: October 2021

Multiple Sequence Alignments (MSAs) of homologous sequences contain information on structural and functional constraints and their evolutionary histories. Despite their importance for many downstream tasks, such as structure prediction, MSA generation is often treated as a separate pre-processing step, without any guidance from the application it will be used for. Here, we implement a smooth and differentiable version of the Smith-Waterman pairwise alignment algorithm that enables jointly learning an MSA and a downstream machine learning system in an end-to-end fashion. To demonstrate its utility, we introduce SMURF (Smooth Markov Unaligned Random Field), a new method that jointly learns an alignment and the parameters of a Markov Random Field for unsupervised contact prediction. We find that SMURF learns MSAs that mildly improve contact prediction on a diverse set of protein and RNA families. As a proof of concept, we demonstrate that by connecting our differentiable alignment module to AlphaFold and maximizing predicted confidence, we can learn MSAs that improve structure predictions over the initial MSAs. Interestingly, the alignments that improve AlphaFold predictions are self-inconsistent and can be viewed as adversarial. This work highlights the potential of differentiable dynamic programming to improve neural network pipelines that rely on an alignment and the potential dangers of relying on black-box methods for optimizing predictions of protein sequences.