bluuebunny/crossref_metadata_2025 huggingface dataset:
EEG signatures of contextual influences on visual search with real scenes
Authors: Meghdadi Amir H. , Giesbrecht Barry , Eckstein Miguel P
Published: October 2020

The use of scene context is a powerful way by which biological organisms guide and facilitate visual search. Although many studies have shown enhancements of target-related electroencephalographic activity (EEG) with synthetic cues, there have been fewer studies demonstrating such enhancements during search with scene context and objects in real world scenes. Here, observers covertly searched for a target in images of real scenes while we used EEG to measure the steady state visual evoked response to objects flickering at different frequencies. The target appeared in its typical contextual location or out of context while we controlled for low-level properties of the image including target saliency against the background and retinal eccentricity. A pattern classifier using EEG activity at the relevant modulated frequencies showed target detection accuracy increased when the target was in a contextually appropriate location. A control condition for which observers searched the same images for a different target orthogonal to the contextual manipulation, resulted in no effects of scene context on classifier performance, confirming that image properties cannot explain the contextual modulations of neural activity. Pattern classifier decisions for individual images was also related to the aggregated observer behavioral decisions for individual images. Together, these findings demonstrate target-related neural responses are modulated by scene context during visual search with real world scenes and can be related to behavioral search decisions.

Significance Statement

Contextual relationships among objects are fundamental for humans to find objects in real world scenes. Although there is a larger literature understanding the brain mechanisms when a target appears at a location indicated by a synthetic cue such as an arrow or box, less is known about how the scene context modulates target-related neural activity. Here we show how neural activity predictive of the presence of a searched object in cluttered real scenes increases when the target object appears at a contextual location and diminishes when it appears at a place that is out of context. The results increase our understanding of how the brain processes real scenes and how context modulates object processing.
Common host variation drives malaria parasite fitness in healthy human red cells
Authors: Ebel Emily R , Kuypers Frans A , Lin Carrie , Petrov Dmitri A , Egan Elizabeth S
Published: October 2020

The replication ofPlasmodium falciparumparasites within red blood cells (RBCs) causes severe disease in humans, especially in Africa. The influence of host RBC variation on parasite replication is largely uncharted, aside from a handful of deleterious alleles like sickle cell. Here, we integrated analyses of exome sequencing, RBC phenotyping, and parasite fitness assays on blood from 122 individuals, most with African ancestry. In donors lacking alleles for hemoglobinopathies or G6PD deficiency, RBC phenotypes including size, deformability, and hydration status explained 21-38% of the variation in parasite growth rate. With the addition of non-pathogenic polymorphisms in 14 RBC proteins includingSPTA1, PIEZO1, andATP2B4, our model explained 73-82% of the variation in parasite growth rate. Interestingly, we observed little evidence for divergent selection on this variation between Africans and Europeans. These findings suggest a model in which widespread, non-pathogenic variation in a moderate number of genes strongly modulatesP. falciparumfitness in RBCs.
Humans surviving cholera develop antibodies againstVibrio choleraeO-specific polysaccharide that inhibit pathogen motility
Authors: Charles Richelle C. , Kelly Meagan , Tam Jenny M. , Akter Aklima , Hossain Motaher , Islam Kamrul , Biswas Rajib , Kamruzzaman Mohammad , Chowdhury Fahima , Khan Ashraful I. , Leung Daniel T. , Weil Ana , LaRocque Regina C. , Bhuiyan Taufiqur Rahman , Rahman Atiqur , Mayo-Smith Leslie M. , Becker Rachel L. , Vyas Jatin M. , Faherty Christina S. , Nickerson Kourtney P. , Giffen Samantha , Ritter Alaina S. , Waldor Matthew K. , Xu Peng , Kováč Pavol , Calderwood Stephen B. , Kauffman Robert C. , Wrammert Jens , Qadri Firdausi , Harris Jason B. , Ryan Edward T.
Published: October 2020

The mechanism of protection against cholera afforded by previous illness or vaccination is currently unknown. We have recently shown that antibodies targeting O-specific polysaccharide (OSP) ofVibrio choleraecorrelate highly with protection against cholera.V. choleraeis highly motile and possesses a flagellum sheathed in O-specific polysaccharide (OSP), and motility ofV. choleraecorrelates with virulence. Using high speed video microscopy, and building upon previous animal-related work, we demonstrate that sera, polyclonal antibody fractions, and OSP-specific monoclonal antibodies recovered from humans surviving cholera blockV. choleraemotility at both subagglutinating and agglutinating concentrations. This anti-motility effect is reversed by pre-adsorbing sera and polyclonal antibody fractions with purified OSP; and is associated with OSP-specific but not flagellin-specific monoclonal antibodies. F[ab] fragments of OSP-specific polyclonal antibodies do not inhibit motility, suggesting a requirement for antibody-mediated crosslinking in motility inhibition. We show that OSP-specific antibodies do not directly affectV. choleraeviability, but that OSP-specific monoclonal antibody highly protects against death in the murine cholera model. We usedin vivocompetitive index studies to demonstrate that OSP-specific antibodies impede colonization and survival ofV. choleraein intestinal tissues, and that this impact is motility-dependent. Our findings suggest that the impedance of motility by antibodies targetingV. choleraeOSP contributes to protection against cholera.

IMPORTANCE

Cholera is a severe dehydrating illness of humans caused byVibrio cholerae. V. choleraeis a highly motile bacterium that has a single flagellum covered in lipopolysaccharide (LPS) displaying O-specific polysaccharide (OSP), andV. choleraemotility correlates with its ability to cause disease. The mechanisms of protection against cholera are not well understood; however, sinceV. choleraeis a non-invasive intestinal pathogen, it is likely that antibodies that bind the pathogen or its products in the intestinal lumen contribute to protection from infection. Here, we demonstrate that OSP-specific antibodies isolated from humans surviving cholera in Bangladesh inhibitV. choleraemotility and are associated with protection against challenge in a motility-dependent manner.
Face neurons in human visual cortex
Authors: Decramer Thomas , Premereur Elsie , Zhu Qi , Van Paesschen Wim , van Loon Johannes , Vanduffel Wim , Taubert Jessica , Janssen Peter , Theys Tom
Published: October 2020

The exquisite capacity of primates to detect and recognize faces is crucial for social interactions. Although disentangling the neural basis of human face recognition remains a key goal in neuroscience, direct evidence at the single-neuron level is virtually nonexistent. We recorded from face-selective neurons in human visual cortex, in a region characterized by functional magnetic resonance imaging (fMRI) activations for faces compared to objects (i.e. the occipital face area, OFA). The majority of visually responsive neurons in this fMRI activation showed strong selectivity at short latencies for faces compared to objects. Feature scrambled faces and face-like objects could also drive these neurons, suggesting that the OFA is not tightly-tuned to the visual attributes that typically define whole human faces. These single-cell recordings within the human face processing system provide vital experimental evidence linking previous imaging studies in humans and invasive studies in animal models.
Dopamine D1 receptor activation drives plasticity in the songbird auditory pallium
Authors: Macedo-Lima Matheus , Boyd Hannah M. , Remage-Healey Luke
Published: October 2020

Vocal learning species must form and extensively hone associations between sounds and social contingencies. In songbirds, dopamine signaling guides song motor-production, variability, and motivation, but it is unclear how dopamine regulates fundamental auditory associations for learning new sounds. We hypothesized that dopamine regulates learning in the auditory pallium, in part by interacting with local neuroestradiol signaling. Here, we show that zebra finch auditory neurons frequently coexpress D1 receptor (D1R) protein, neuroestradiol-synthase, GABA, and parvalbumin. Auditory classical conditioning increased neuroplasticity gene induction in D1R-positive neurons.In vitro,D1R pharmacological activation reduced the amplitude of GABAergic and glutamatergic currents, and increased the latter’s frequency.In vivo, D1R activation reduced the firing of putative interneurons, increased the firing of putative excitatory neurons, and made both neuronal types unable to adapt to novel stimuli. Together, these data support the hypothesis that dopamine acting via D1Rs modulates learning and memory in the songbird sensory cortex.
Intercellular telomere transfer extends T cell lifespan
Authors: Vaz Bruno , Vuotto Claudia , Valvo Salvatore , D’Ambra Clara , Esposito Francesco Maria , Chiurchiù Valerio , Devine Oliver , Sanchez Massimo , Borsellino Giovanna , Gilroy Derek , Akbar Arne N. , Dustin Michael L. , Karin Michael , Lanna Alessio
Published: October 2020

The common view is that T-lymphocytes activate telomerase, a DNA polymerase that extends telomeres at chromosome ends, to delay senescence. We show that independently of telomerase, T cells elongate telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs). Upon contact with T cells, APCs degraded shelterin to donate telomeres, which were cleaved by TZAP, and then transferred in extracellular vesicles (EVs) at the immunological synapse. Telomere vesicles retained the Rad51 recombination factor that enabled them to fuse with T cell chromosomal ends causing an average lengthening of ∼3000 base pairs. Thus, we identify a previously unknown telomere transfer program that supports T cell lifespan.
Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-in vivo predictions of hepatic clearance
Authors: Krishnan Preethi , Smith Andrew K. , Ropella Glen E.P. , Dutta Lopamudra , Kennedy Ryan C. , Hunt C. Anthony
Published: October 2020

We explore a virtual experiment strategy to discover plausible mechanism-based explanations for frequently inaccurate predictions of hepatic drug clearance made using established in vitro-in vivo extrapolation methods. We describe a three-protocol plan that uses validated software analogs of real in vitro and in vivo systems constructed using a common set of objects, components, spaces, and methods. Both systems utilize identical quasi-autonomous hepatocyte analogs containing enzyme-like objects. We parameterize concrete mobile objects (virtual compounds) to simulate the referent drug’s disposition and removal characteristics in vitro and in vivo. The goal of Protocol one (Protocol two) is that measures of virtual compound removal using the in vitro analog (in vivo analog) map directly to the measurements used to compute intrinsic clearance (in vivo hepatic clearance). Protocol three, the focus of this work, requires achieving an essential cross-system validation target. For a subset of virtual compounds, measurements of unbound compounds entering hepatocytes (and their subsequent removal) during virtual in vitro experiments will directly predict corresponding measures made during virtual in vivo experiments. We study four highly permeable virtual compounds when their unbound fraction is fixed at one of seven values (0.05-1.0). Results span the range of hepatic extraction ratios. We achieve the cross-system validation target in 15 cases. In the other 13 cases, explanations of the in vitro-in vivo differences in disposition and removal trace to differences in compound-hepatocyte access within the two analogs during execution. The hepato-mimetic structural organization of hepatocytes within the in vivo analog, which is absent within the in vitro analog, is the determining factor. The results taken together support the feasibility of using the three-protocol plan to help explain observed in vitro-in vivo extrapolation discrepancies. We conjecture that, for some cases, the model mechanism-based explanations of discrepancies described herein will have wet-lab counterparts.
Clinical connectome fingerprints of cognitive decline
Authors: Sorrentino Pierpaolo , Rucco Rosaria , Lardone Anna , Liparoti Marianna , Lopez Emahnuel Troisi , Cavaliere Carlo , Soricelli Andrea , Jirsa Viktor , Sorrentino Giuseppe , Amico Enrico
Published: October 2020

Brain connectome fingerprinting is rapidly rising as a novel influential field in brain network analysis. Yet, it is still unclear whether connectivity fingerprints could be effectively used for mapping and predicting disease progression from human brain data. We hypothesize that dysregulation of brain activity in disease would reflect in worse subject identification. Hence, we propose a novel framework,Clinical Connectome Fingerprinting, to detect individual connectome features from clinical populations. We show that “clinical fingerprints” can map individual variations between elderly healthy subjects and patients undergoing cognitive decline in functional connectomes extracted from magnetoencephalography data. We find that identifiability is reduced in patients as compared to controls, and show that these connectivity features are predictive of the individual Mini-Mental State Examination (MMSE) score in patients. We hope that the proposed methodology can help in bridging the gap between connectivity features and biomarkers of brain dysfunction in large-scale brain networks.
PIEZO2 mediates ultrasonic hearing via cochlear outer hair cells in mice
Authors: Li Jie , Liu Shuang , Song Chenmeng , Hu Qun , Zhao Zhikai , Deng Tuantuan , Wang Yi , Zhu Tong , Zou Linzhi , Wang Shufeng , Chen Jiaofeng , Liu Lian , Hou Hanqing , Yuan Kexin , Zheng Hairong , Liu Zhiyong , Chen Xiaowei , Sun Wenzhi , Xiao Bailong , Xiong Wei
Published: October 2020

Ultrasonic hearing is exploited for hunting and navigation as in echolocation by microbats and bottleneck dolphins, and for social communication like ultrasonic vocalization by mice and rats. However, the molecular and cellular basis for ultrasonic hearing is not known yet. Here we show that knockout of the mechanosensitive ion channel PIEZO2 in cochlea disrupts the ultrasonic hearing but not the low-frequency hearing in mice, as shown by audiometry and acoustically-associative freezing behavior. Deletion ofPiezo2in the outer hair cells specifically abolishes the associative learning of the mice upon hearing the ultrasonic frequency.Ex vivocochlear Ca2+imaging revealed that the ultrasonic transduction requires both PIEZO2 and the hair-cell mechanotransduction channel. Together, our study demonstrates that the outer hair cells are the effector cells with PIEZO2 as an essential molecule for ultrasonic hearing in mice.

Significance Statement

Some animals have evolved an incredible ability for vocalizing and hearing ultrasonic frequencies that is inaudible for humans (> 20 kHz). For many years, it has been considered that animals hear ultrasonic frequencies with their cochlear hair cells, using the identical set of mechanotransduction molecules in the hair bundles for hearing audible frequencies. Here, we show that the mice lacking the mechanosensitive ion channel PIEZO2 hardly hear ultrasonic frequencies, while can still be sensitive to audible frequencies. Thus, animals may use a partially different mechanism for sensing physiological ultrasound.
Variant analysis of SARS-CoV-2 genomes in the Middle East
Authors: Bindayna Khalid Mubarak , Crinion Shane
Published: October 2020

Background

Coronavirus (COVID-19) was introduced into society in late 2019 and has now reached over 26 million cases and 850,000 deaths. The Middle East has a death toll of ∼50,000 and over 20,000 of these are in Iran, which has over 350,000 confirmed cases. We expect that Iranian cases caused outbreaks in the neighbouring countries and that variant mapping and phylogenetic analysis can be used to prove this. We also aim to analyse the variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to characterise the common genome variants and provide useful data in the global effort to prevent further spread of COVID-19.

Methods

The approach uses bioinformatics approaches including multiple sequence alignment, variant calling and annotation and phylogenetic analysis to identify the genomic variants found in the region. The approach uses 122 samples from the 13 countries of the Middle East sourced from the Global Initiative on Sharing All Influenza Data (GISAID).

Findings

We identified 2200 distinct genome variants including 129 downstream gene variants, 298 frame shift variants, 789 missense variants, 1 start lost, 13 start gained, 1 stop lost, 249 synonymous variants and 720 upstream gene variants. The most common, high impact variants were 10818delTinsG, 2772delCinsC, 14159delCinsC and 2789delAinsA. Variant alignment and phylogenetic tree generation indicates that samples from Iran likely introduced COVID-19 to the rest of the Middle East.

Interpretation

The phylogenetic and variant analysis provides unique insight into mutation types in genomes. Initial introduction of COVID-19 was most likely due to Iranian transmission. Some countries show evidence of novel mutations and unique strains. Increased time in small populations is likely to contribute to more unique genomes. This study provides more in depth analysis of the variants affecting in the region than any other study.

Funding

None
Bacterial precursors and unsaturated long-chain fatty acids are biomarkers of North-Atlantic demosponges
Authors: de Kluijver Anna , Nierop Klaas G.J. , Morganti Teresa M. , Bart Martijn C. , Slaby Beate M. , Hanz Ulrike , de Goeij Jasper M. , Mienis Furu , Middelburg Jack J.
Published: October 2020

Sponges produce distinct fatty acids (FAs) that (potentially) can be used as chemotaxonomic and ecological biomarkers to study endosymbiont-host interactions and the functional ecology of sponges. Here, we present FA profiles of five common habitat-building deep-sea sponges (class Demospongiae, order Tetractinellida), which are classified as high microbial abundance (HMA) species.Geodia hentscheli, G. parva, G. atlantica, G. barretti, andStelletta rhaphidiophorawere collected from boreal and Arctic sponge grounds in the North-Atlantic Ocean. Bacterial FAs dominated in all five species and particularly isomeric mixtures of mid-chain branched FAs (MBFAs, 8- and 9-Me-C16:0and 10 and 11-Me-C18:0) were found in high abundance (together ≥ 20% of total FAs) aside more common bacterial markers. In addition, the sponges produced long-chain linear, mid- anda(i)-branched unsaturated FAs (LCFAs) with a chain length of 24‒28 C atoms and had predominantly the typical Δ5,9unsaturation, although also Δ9,19and (yet undescribed) Δ11,21unsaturations were identified.G. parvaandS. rhaphidiophoraeach produced distinct LCFAs, whileG. atlantica, G. barretti, andG. hentscheliproduced similar LCFAs, but in different ratios. The different bacterial precursors varied in carbon isotopic composition (δ13C), with MBFAs being more enriched compared to other bacterial (linear anda(i)-branched) FAs. We propose biosynthetic pathways for different LCFAs from their bacterial precursors, that are consistent with small isotopic differences found in LCFAs. Indeed, FA profiles of deep-sea sponges can serve as chemotaxonomic markers and support the conception that sponges acquire building blocks from their endosymbiotic bacteria.
SARS-CoV-2 infection induces mixed M1/M2 phenotype in circulating monocytes and alterations in both dendritic cell and monocyte subsets
Authors: Sanja Matic , Suzana Popovic , Predrag Djurdjevic , Danijela Todorovic , Natasa Djordjevic , Zeljko Mijailovic , Predrag Sazdanovic , Dragan Milovanovic , Dejana Ruzic Zecevic , Marina Petrovic , Maja Sazdanovic , Nenad Zornic , Vladimir Vukicevic , Ivana Petrovic , Snezana Matic , Marina Karic Vukicevic , Dejan Baskic
Published: October 2020

Clinical manifestations of SARS-CoV-2 infection range from mild to critically severe. The aim of the study was to highlight the immunological events associated with the severity of SARS-CoV-2 infection, with an emphasis on cells of innate immunity. Thirty COVID-19 patients with mild/moderate symptoms and 27 patients with severe/critically severe symptoms were recruited from the Clinical Center of Kragujevac during April 2020. Flow cytometric analysis was performed to reveal phenotypic and functional alterations of peripheral blood cells and to correlate them with the severity of the disease. In severe cases, the number of T and B lymphocytes, dendritic cells, NK cells, and HLA-DR-expressing cells was drastically decreased. In the monocyte population proportion between certain subsets was disturbed and cells coexpressing markers of M1 and M2 monocytes were found in intermediate and non-classical subsets. In mild cases decline in lymphocyte number was less pronounced and innate immunity was preserved as indicated by an increased number of myeloid and activated dendritic cells, NK cells that expressed activation marker at the same level as in control and by low expression of M2 marker in monocyte population. In patients with severe disease, both innate and adoptive immunity are devastated, while in patients with mild symptoms decline in lymphocyte number is lesser, and the innate immunity is preserved.
In-stream habitat availability for river dolphins in response to flow: use of ecological integrity to manage river flows
Authors: Paudel Shambhu , Koprowski John L. , Thakuri Usha
Published: October 2020

Population decline and extinction risk of riverine cetaceans are primarily associated with flow alteration. Previous studies predominantly highlighted maintenance of adequate flow for low water seasons when habitats contract and the risk of local extinction escalates. Although riverine cetaceans are sensitive to reduction in river flow, no studies quantify the relationships between flow and ecology of riverine cetaceans to mitigate the potential adverse impacts of flow alteration. We quantify the relationships between flow and the ecology of river cetaceans with reference to Ganges River dolphins (GRD;Platanista gangetica gangetica) usable area availability (AWS) for the low water season at wider flows (50-575 m3/s) at finer spatial and temporal scales. This study reveals that distribution of usable area to GRD highly regulated by the adequate flow level as the interaction of appropriate velocity and depth at particular geomorphic that likely offer energetically efficient modes of locomotion to increase surfacing behavior efficiency, suggesting the hydro-physical environment as a major determinant of river cetaceans distribution and abundance. Flow and AWS relationships indicate that the flow during dry season negatively contributed to AWS, whereas that of pre-monsoon maximized the AWS, suggesting that modifying flow regimes does alter in-stream habitats at varying spatial scales and may influence life-history strategies. Substantial fragmentation in suitable pool availability and loss of longitudinal connectivity exhibited by dry season flow suggested a higher risk of adverse biological effects during the dry season, which may reduce population viability by reducing survivorship and reproduction failure. Owing to riverine cetaceans’ dependence on the attribute of freshwater flow, they can be expected to be more affected by flow regulations as interactive effects. Considering the seasonal effects and changes in the availability of usable areas by flow alteration, adopting effective habitat retention plans by water-based development projects appears critical to avoid further ecological risks in aquatic species conservation. Identifying priority riverscapes for river cetaceans and prioritizing investment opportunities is an essential first step towards effective riverine cetacean conservation.
Forecasting COVID-19 cases at the Amazon region: a comparison of classical and machine learning models
Authors: de Souza Dalton Garcia Borges , Alves Júnior Francisco Tarcísio , Soma Nei Yoshihiro
Published: October 2020

BACKGROUND

Since the first reports of COVID-19, decision-makers have been using traditional epidemiological models to predict the days to come. However, the enhancement of computational power, the demand for adaptable predictive frameworks, the short past of the disease, and uncertainties related to input data and prediction rules, also make other classical and machine learning techniques viable options.

OBJECTIVE

This study investigates the efficiency of six models in forecasting COVID-19 confirmed cases with 17 days ahead. We compare the models autoregressive integrated moving average (ARIMA), Holt-Winters, support vector regression (SVR), k-nearest neighbors regressor (KNN), random trees regressor (RTR), seasonal linear regression with change-points (Prophet), and simple logistic regression (SLR).

MATERIAL AND METHODS

We implement the models to data provided by the health surveillance secretary of Amapáa, a Brazilian state fully carved in the Amazon rainforest, which has been experiencing high infection rates. We evaluate the models according to their capacity to forecast in different historical scenarios of the COVID-19 progression, such as exponential increases, sudden decreases, and stability periods of daily cases. To do so, we use a rolling forward splitting approach for out-of-sample validation. We employ the metrics RMSE, R-squared, and sMAPE in evaluating the model in different cross-validation sections.

FINDINGS

All models outperform SLG, especially Holt-Winters, that performs satisfactorily in all scenarios. SVR and ARIMA have better performances in isolated scenarios. To implement the comparisons, we have created a web application, which is available online.

CONCLUSION

This work represents an effort to assist the decision-makers of Amapá in future decisions to come, especially under scenarios of sudden variations in the number of confirmed cases of Amapá, which would be caused, for instance, by new contamination waves or vaccination. It is also an attempt to highlight alternative models that could be used in future epidemics.
Disentangling the role of surface topography and intrinsic wettability in the prey capture mechanism ofNepenthespitcher plants
Authors: Labonte David , Robinson Adam , Bauer Ulrike , Federle Walter
Published: October 2020

Nepenthespitcher plants capture prey with leaves specialised as pitfall traps. Insects are trapped when they ‘aquaplane’ on the pitcher rim (peristome), a surface structured with macroscopic and microscopic radial ridges. What is the functional significance of this hierarchical surface topography? Here, we use insect pad friction measurements, photolithography, wetting experiments and physical modelling to demonstrate that the ridges enhance the traps’ efficacy by satisfying two functional demands on prey capture: Macroscopic ridges restrict lateral but enhance radial spreading of water, thereby creating continuous slippery tracks which facilitate prey capture when little water is present. Microscopic ridges, in turn, ensure that the water film between insect pad and peristome remains stable, causing insects to aquaplane. In combination, the hierarchical ridge structure hence renders the peristome wettable, and water films continuous, so avoiding the need for a strongly hydrophilic surface chemistry, which would compromise resistance to desiccation and attract detrimental contamination.
Activation of MAP3K DLK and LZK in Purkinje Cells Causes Rapid and Slow Degeneration Depending on Signaling Strength
Authors: Li Yunbo , Ritchie Erin M , Steinke Christopher L. , Qi Cai , Chen Lizhen , Zheng Binhai , Jin Yishi
Published: October 2020

The conserved MAP3K Dual leucine zipper kinases can activate JNK via MKK4 or MKK7. Vertebrate DLK and LZK share similar biochemical activities and undergo auto-activation upon increased expression. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing ofMkk7, strongly attenuates Purkinje cell degeneration induced by activation of LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.
Integrated multivariate analysis of transcriptomic data reveals immunological mechanisms in mice afterLeishmania infantuminfection
Authors: Palacios Génesis , Diaz-Solano Raquel , Valladares Basilio , Dorta-Guerra Roberto , Carmelo Emma
Published: October 2020

Transcriptional analysis of complex biological scenarios has been extensively used, even though sometimes results may prove imprecise or difficult-to interpret due to an overwhelming amount of information. In this study, a large-scale Real-time qPCR experiment was coupled to multivariate statistical analysis to describe the main immunological events underlying the earlyL. infantuminfection in livers of BALB/c mice. High-throughput qPCR was used to evaluate the expression of 223 genes related to immunometabolism 1-, 3-, 5- and 10-days post infection. This integrative analysis showed strikingly different gene signatures at 1- and 10-days post infection, revealing progression of infection in the experimental model based on the upregulation of particular immunological response patterns and mediators. This approach addresses the challenge of integrating large collections of transcriptional data for the identification of candidate biomarkers in experimental models.
RBMX enables productive RNA processing of ultra-long exons important for genome stability
Authors: Luzzi Sara , Hysenaj Gerald , Siachisumo Chileleko , Cheung Kathleen , Gazzara Matthew , James Katherine , Dalgliesh Caroline , Chadegani Mahsa Kheirollahi , Ehrmann Ingrid , Smith Graham R , Cockell Simon J , Munkley Jennifer , Barash Yoseph , Elliott David J
Published: October 2020

Previously we showed that the germline-specific RNA binding protein RBMXL2 is essential for male meiosis where it represses cryptic splicing patterns (1). Here we find that its ubiquitously expressed paralog RBMX helps underpin human genome stability by preventing non-productive splicing. In particular, RBMX blocks selection of aberrant splice and polyadenylation sites within some ultra-long exons that would interfere with genes needed for normal replication fork activity. Target exons include within theETAA1(Ewings Tumour Associated 1) gene, where RBMX collaborates with its interaction partner Tra2β to enable full-length exon inclusion by blocking selection of an aberrant 3’ splice site. Our data reveal a novel group of RNA processing targets potently repressed by RBMX, and help explain why RBMX is associated with gene expression networks in cancer, replication and sensitivity to genotoxic drugs.
The influence of intergenerational transfer of white matter tracts on early reading development
Authors: Vandermosten Maaike , Schevenels Klara , Economou Maria , Hoeft Fumiko
Published: October 2020

Parents have large genetic and environmental influences on their children’s cognition, behavior, and brain. Previous studies have indicated intergenerational transfer of the behavior of reading. Despite a close coupling between brain and behavior however, the intergenerational transfer of reading-related structural brain networks have not been investigated. Therefore, we investigated its parent-child associations for the first time. We examined how white matter tracts i.e., Arcuate Fasciculus (AF) and Inferior Fronto-Occipital Fasciculus (IFOF), are associated with children’s early reading development from Kindergarten to Grade 3 in 33 families. First, we observed in our sample of children -who all had typical reading skills despite half of them having an increased risk for dyslexia- that fractional anisotropy in bilateral IFOF and right AF correlated with reading development. Second, parent-child correlations were observed for bilateral IFOF but not for AF. Finally, we demonstrated that the relation between children’s IFOF and reading development was largely explained by parental IFOF. The findings preliminarily suggest that white matter organization in IFOF represents a pre-existing protective factor in children at risk, as it is mainly determined by biological parental factors. Large-scale intergenerational, multi-level and longitudinal studies are needed to understand the dynamic interrelations between brain, environment and behavior.
Synaptic counts approximate synaptic contact area in Drosophila
Authors: Barnes Christopher L. , Bonnéry Daniel , Cardona Albert
Published: October 2020

The pattern of synaptic connections among neurons defines the circuit structure, which constrains the computations that a circuit can perform. The strength of synaptic connections is costly to measure yet important for accurate circuit modeling. It has been shown that synaptic surface area correlates with synaptic strength, yet in the emerging field of connectomics, most studies rely instead on the counts of synaptic contacts between two neurons. Here we quantified the relationship between synaptic count and synaptic area as measured from volume electron microscopy of the larval Drosophila central nervous system. We found that the total synaptic surface area, summed across all synaptic contacts from one presynaptic neuron to a postsynaptic one, can be accurately predicted solely from the number of synaptic contacts, for a variety of neurotransmitters. Our findings support the use of synaptic counts for approximating synaptic strength when modeling neural circuits.
Distinct roles of nonmuscle myosin II isoforms for establishing tension and elasticity during cell morphodynamics
Authors: Weißenbruch Kai , Grewe Justin , Hippler Marc , Fladung Magdalena , Tremmel Moritz , Stricker Kathrin , Schwarz Ulrich S. , Bastmeyer Martin
Published: October 2020

Nonmuscle myosin II (NM II) is an integral part of essential cellular processes, including adhesion and migration. Mammalian cells express up to three isoforms termed NM IIA, B, and C. We used U2OS cells to create CRISPR/Cas9-based knockouts of all three isoforms and analyzed the phenotypes on homogeneous substrates, in collagen gels, and on micropatterned substrates. We find that NM IIA is essential to build up cellular tension during initial stages of force generation, while NM IIB is necessary to elastically stabilize NM IIA-generated tension. A scale-bridging mathematical model explains our observations by relating actin fiber stability to the molecular rates of the myosin crossbridge cycle. A dynamic cell stretch/release experiment confirms these predictions and in addition reveals a novel role for NM IIC, namely the ability to establish tensional homeostasis.
PRC1 drives Polycomb-mediated gene repression by controlling transcription initiation and burst frequency
Authors: Dobrinić Paula , Szczurek Aleksander T. , Klose Robert J.
Published: October 2020

The Polycomb repressive system plays a fundamental role in controlling gene expression during mammalian development. To achieve this, Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) bind target genes and use histone modification-dependent feedback mechanisms to form Polycomb chromatin domains and repress transcription. The interrelatedness of PRC1 and PRC2 activity at these sites has made it difficult to discover the specific components of Polycomb chromatin domains that drive gene repression and to understand mechanistically how this is achieved. Here, by exploiting rapid degron-based approaches and time-resolved genomics we kinetically dissect Polycomb-mediated repression and discover that PRC1 functions independently of PRC2 to counteract RNA polymerase II binding and transcription initiation. Using single-cell gene expression analysis, we reveal that PRC1 acts uniformly within the cell population, and that repression is achieved by controlling transcriptional burst frequency. These important new discoveries provide a mechanistic and conceptual framework for Polycomb-dependent transcriptional control.
The VCBS superfamily, a diverse group of β-propellers that includes tachylectin and integrins
Authors: Pereira Joana , Lupas Andrei N.
Published: October 2020

β-Propellers are found in great variety across all kingdoms of life. They assume many cellular roles, primarily as scaffolds for macromolecular interactions and catalysis. Despite their diversity, most β-propeller families clearly originated by amplification from the same ancient peptide - the β-propeller blade. In cluster analyses, β-propellers of the WD40 superfamily always formed the largest group, to which some important families, such as the α-integrin, Asp-box, and glycoside hydrolase β-propellers connected weakly. Motivated by the dramatic growth of sequence databases we revisited these connections, with a special focus on VCBS-like β-propellers, which have not been analysed for their evolutionary relationships so far. We found that they form a supercluster with integrin-like β-propellers and tachylectins, clearly delimited from the superclusters formed by WD40 and Asp-Box β-propeller. Connections between the three superclusters are made mainly through PQQ-like β-propeller. Our results present a new, greatly expanded view of the β-propeller classification landscape.
Learning when effort matters: Neural dynamics underlying updating and adaptation to changes in performance efficacy
Authors: Grahek Ivan , Frömer Romy , Fahey Mahalia Prater , Shenhav Amitai
Published: October 2020

To determine how much cognitive control to invest in a task, people need to consider whether exerting controlmattersfor obtaining rewards. In particular, they need to account for the efficacy of their performance – the degree to which rewards are determined by performance or by independent factors. Yet it remains unclear how people learn about theirperformance efficacyin an environment. Here we combined computational modeling with measures of task performance and EEG, to provide a mechanistic account of how people (a) learn and update efficacy expectations in a changing environment, and (b) proactively adjust control allocation based on current efficacy expectations. Across two studies subjects performed an incentivized cognitive control task while their performance efficacy (the likelihood that rewards are performance- contingent or random) varied over time. We show that people update their efficacy beliefs based on prediction errors – leveraging similar neural and computational substrates as those that underpin reward learning – and adjust how much control they allocate according to these beliefs. Using computational modeling, we show that these control adjustments reflect changes in information processing, rather than the speed-accuracy tradeoff. These findings demonstrate the neurocomputational mechanism through which people learn how worthwhile their cognitive control is.
Metabolic dissimilarity determines the establishment of cross-feeding interactions in bacteria
Authors: Giri Samir , Oña Leonardo , Waschina Silvio , Shitut Shraddha , Yousif Ghada , Kaleta Christoph , Kost Christian
Published: October 2020

The exchange of metabolites among different bacterial genotypes profoundly impacts the structure and function of microbial communities. However, the factors governing the establishment of these cross-feeding interactions remain poorly understood. While shared physiological features may facilitate interactions among more closely related individuals, a lower relatedness should reduce competition and thus increase the potential for synergistic interactions. Here we investigate how the relationship between a metabolite donor and recipient affects the propensity of strains to engage in unidirectional cross-feeding interactions. For this, we performed pairwise cocultivation experiments between four auxotrophic recipients and 25 species of potential amino acid donors. Auxotrophic recipients grew in the vast majority of pairs tested (78%), suggesting metabolic cross-feeding interactions are readily established. Strikingly, both the phylogenetic distance between donor and recipient and the dissimilarity of their metabolic networks were positively associated with the growth of auxotrophic recipients. Analysing the co-growth of species from a gut microbial communityin-silicoalso revealed that recipient genotypes benefitted more from interacting with metabolically dissimilar partners, thus corroborating the empirical results. Together, our work identifies the metabolic dissimilarity between bacterial genotypes as key factor determining the establishment of metabolic cross-feeding interactions in microbial communities.

Highlights

The exchange of essential metabolites is common in microbial communities

Metabolic cross-feeding interactions readily establish between auxotrophic and prototrophic bacterial strains

Both the phylogenetic and the metabolic dissimilarity between donors and recipients determines the successful establishment of metabolic cross-feeding interactions
Exploring the variance in complex traits captured by DNA methylation assays
Authors: Battram Thomas , Gaunt Tom R. , Speed Doug , Timpson Nicholas J. , Hemani Gibran
Published: October 2020

Following years of epigenome-wide association studies (EWAS), traits analysed to date tend to yield few associations. Reinforcing this observation, we conducted EWAS on 400 traits and 16 yielded at least one association at the conventional significance threshold (P<1×10−7). To investigate why EWAS yield is low, we formally estimated the proportion of phenotypic variation captured by 421,693 blood derived DNA methylation markers (h2EWAS) across all 400 traits. The mean h2EWASwas zero, with evidence for regular cigarette smoking exhibiting the largest association with all markers (h2EWAS=0.42) and the only one surpassing a false discovery rate < 0.1. Though underpowered to determine the h2EWASvalue for any one trait, h2EWASwas predictive of the number of EWAS hits across the traits analysed (AUC=0.7). Modelling the contributions of the methylome on a per-site versus a per-region basis gave varied h2EWASestimates (r=0.47) but neither approach obtained substantially higher model fits across all traits. Our analysis indicates that most complex traits do not heavily associate with markers commonly measured in EWAS within blood. However, it is likely DNA methylation does capture variation in some traits and h2EWASmay be a reasonable way to prioritise traits that are likely to yield associations.
Age-related differences in network structure and dynamic synchrony of cognitive control
Authors: Hinault T. , Mijalkov M. , Pereira J.B. , Volpe Giovanni. , Bakker A. , Courtney S.M.
Published: October 2020

Cognitive trajectories vary greatly across older individuals, and the neural mechanisms underlying these differences remain poorly understood. Here, we propose a mechanistic framework of cognitive variability in older adults, linking the influence of white matter microstructure on fast and effective communications between brain regions. Using diffusion tensor imaging and electroencephalography, we show that individual differences in white matter network organization are associated with network clustering and efficiency in the alpha and high-gamma bands, and that functional network dynamics partly explain individual cognitive control performance in older adults. We show that older individuals with high versus low structural network clustering differ in task-related network dynamics and cognitive performance. These findings were corroborated by investigating magnetoencephalography networks in an independent dataset. This multimodal brain connectivity framework of individual differences provides a holistic account of how differences in white matter microstructure underlie age-related variability in dynamic network organization and cognitive performance.
Computational Model to Quantify the Growth of Antibiotic Resistant Bacteria in Wastewater
Authors: Sutradhar Indorica , Ching Carly , Desai Darash , Suprenant Mark , Briars Emma , Heins Zachary , Khalil Ahmad S. , Zaman Muhammad H.
Published: October 2020

Although wastewater and sewage systems are known to be significant reservoirs of antibiotic resistant bacterial populations and periodic outbreaks of drug resistant infection, there is little quantitative understanding of the drivers behind resistant population growth in these settings. In order to fill this gap in quantitative understanding of the development of antibiotic resistant infections in wastewater, we have developed a mathematical model synthesizing many known drivers of antibiotic resistance in these settings to help predict the growth of resistant populations in different environmental scenarios. A number of these drivers of drug resistant infection outbreak including antibiotic residue concentration, antibiotic interaction, chromosomal mutation and horizontal gene transfer, have not previously been integrated into a single computational model. We validated the outputs of the model with quantitative studies conducted on the eVOLVER continuous culture platform. Our integrated model shows that low levels of antibiotic residues present in wastewater can lead to increased development of resistant populations, and the dominant mechanism of resistance acquisition in these populations is horizontal gene transfer rather than acquisition of chromosomal mutations. Additionally, we found that synergistic antibiotic interactions lead to increased resistant population growth. These findings, consistent with recent experimental and field studies, provide new quantitative knowledge on the evolution of antibiotic resistant bacterial reservoirs, and the model developed herein can be adapted for use as a prediction tool in public health policy making, particularly in low income settings where water sanitation issues remain widespread and disease outbreaks continue to undermine public health efforts.

Importance

The rate at which antimicrobial resistance (AMR) has developed and spread throughout the world has increased in recent years, and according to the Review on Antimicrobial Resistance in 2014 it is suggested that the current rate will lead several million people AMR-related deaths by 205025. One major reservoir of resistant bacterial populations that has been linked to outbreaks of drug resistant bacterial infections, but is not well understood, is in wastewater settings, where antibiotic pollution is often present. Using ordinary differential equations incorporating several known drivers of resistance in wastewater, we find that interactions between antibiotic residues and horizontal gene transfer significantly affect the growth of resistant bacterial reservoirs.