bluuebunny/crossref_metadata_2025 huggingface dataset:
Lower statistical support with larger datasets: insights from the Ochrophyta radiation
Authors: Di Franco Arnaud , Baurain Denis , Glöckner Gernot , Melkonian Michael , Philippe Hervé
Published: January 2021

It is commonly assumed that increasing the number of characters has the potential to resolving radiations. We studied photosynthetic stramenopiles (Ochrophyta) using alignments of heterogeneous size and origin (6,762 sites for mitochondrion, 21,692 sites for plastid and 209,105 sites for nucleus). While statistical support for the relationships between the six major Ochrophyta lineages increases when comparing the mitochondrion and plastid trees, it decreases in the nuclear tree. Statistical support is not simply related to the dataset size but also to the quantity of phylogenetic signal available at each position and our ability to extract it. Here, we show that proper signal extraction is difficult to attain, as demonstrated by conflicting results obtained when varying taxon sampling. Even though the use of a better fitting model improved signal extraction and reduced the observed conflicts, the plastid dataset provided higher statistical support for the ochrophyte radiation than the larger nucleus dataset. We propose that the higher support observed in the plastid tree is due to an acceleration of the evolutionary rate in one short deep internal branch, implying that more phylogenetic signal per position is available to resolve the Ochrophyta radiation in the plastid than in the nuclear dataset. Our work therefore suggests that, in order to resolve radiations, beyond the obvious use of datasets with more positions, we need to continue developing models of sequence evolution that better extract the phylogenetic signal and design methods to search for genes/characters that contain more signal specifically for short internal branches.
Data proliferation, reconciliation, and synthesis in viral ecology
Authors: Gibb Rory , Albery Gregory F. , Becker Daniel J. , Brierley Liam , Connor Ryan , Dallas Tad A. , Eskew Evan A. , Farrell Maxwell J. , Rasmussen Angela L. , Ryan Sadie J. , Sweeny Amy , Carlson Colin J. , Poisot Timothée
Published: January 2021

The fields of viral ecology and evolution have rapidly expanded in the last two decades, driven by technological improvements, and motivated by efforts to discover potentially zoonotic wildlife viruses under the rubric of pandemic prevention. One consequence has been a massive proliferation of host-virus association data, which comprise the backbone of research in viral macroecology and zoonotic risk prediction. These data remain fragmented across numerous data portals and projects, each with their own scope, structure, and reporting standards. Here, we propose that synthesis of host-virus association data is a central challenge to improve our understanding of the global virome and develop foundational theory in viral ecology. To illustrate this, we build an open reconciled mammal-virus database from four key published datasets, applying a standardized taxonomy and metadata. We show that reconciling these datasets provides a substantially richer view of the mammal virome than that offered by any one individual database. We argue for a shift in best practice towards the incremental development and use of synthetic datasets in viral ecology research, both to improve comparability and replicability across studies, and to facilitate future efforts to use machine learning to predict the structure and dynamics of the global virome.
Geographical variability of bacterial communities of cryoconite holes of Andean glaciers
Authors: Pittino Francesca , Seeger Michael , Azzoni Roberto , Ambrosini Roberto , Franzetti Andrea
Published: January 2021

Cryoconite holes, ponds full of melting water with a sediment on the bottom, are hotspot of biodiversity of glacier surface. They host a metabolically active bacterial community that is involved in different dynamics concerning glacier ecosystems. Indeed, they are responsible of organic matter production and with other microorganisms establish a real microecosystem. Cryoconite holes have been described in different areas of the world (e.g., Arctic, Antarctic, Alps, Himalaya), and with this study we will provide the first description of bacterial communities of cryoconite holes of the Andes in South America. We collected samples on three high elevation glaciers of the Andes (Iver, Iver East and Morado glaciers) and two Patagonian glaciers located at sea level (Exploradores glacier and Perito Moreno). Results show that the most abundant orders are Burkholderiales, Cytophagales, Sphingobacteriales, Actinomycetales, Pseudomonadales, Rhodospiarillales, Rhizobiales, Sphingomonadales and Bacteroidales, which have been reported on glaciers of other areas of the world, Bacterial communities change from one glacier to another and both water pH and O2 concentration affect bacterial communities composition.
Identifying priority areas for research and conservation of the largetooth sawfishPristis pristisin Colombia and Panama
Authors: López-Angarita Juliana , Cubillos-M. Juan Camilo , Villate-Moreno Melany , Del Cid Annissamyd , Díaz Juan M , Cooke Richard , Tilley Alexander
Published: January 2021

Sawfishes are considered one of the most endangered families of fishes in the world. Their diadromous ecology and vulnerability to fishing nets have brought most populations to the brink of collapse. Conservation of the surviving populations is hindered by the paucity of historic and contemporary catch and observational records, and assessments of suitable coastal and riverine habitats. Colombia and Panama are two of 14 countries considered as a high priority for the development of species-specific national legal protection of the critically endangered largetooth sawfish (Pristis pristis). To construct a baseline for the temporal and spatial distribution of the largetooth sawfish in Colombia and Panama, we collected historical records from museum databases and from literature over the past century, analysed available small-scale fisheries landings databases, and conducted interviews with fish workers in 38 locations across both countries. We found 257 records of sawfish occurrences across both countries between 1896 and 2015, with 69% of the records before the year 2000. The declining trend in the frequency of observations was corroborated by fishers, who reported fewer sawfish catches over the last 20 years. Using kernel density estimation of recent encounter locations, we identify potential hotspots that may represent extant populations of sawfish. These locations are broadly characterized by their remoteness and high mangrove forest cover. Given the length and cultural diversity of the Pacific coastlines of Colombia and Panama, and the inaccessibility of many of the communities, our findings provide important guidance to target rapid conservation and fisheries interventions to priority areas. We suggest that the relative success of community-managed fishing areas in the region makes this a valuable platform on which to build local stewardship of marine resources, while raising awareness of the need to safeguard critically endangered largetooth sawfish.
Opioid withdrawal produces sex-specific effects on fentanyl-vs.-food choice and mesolimbic transcription
Authors: Townsend E. Andrew , Kim R. Kijoon , Robinson Hannah L. , Marsh Samuel A. , Banks Matthew L. , Hamilton Peter J.
Published: January 2021

Background

Opioid withdrawal is a key driver of opioid addiction and an obstacle to recovery. However, withdrawal effects on opioid reinforcement and mesolimbic neuroadaptation are understudied and the role of sex is largely unknown.

Methods

Male (n=10) and female (n=9) rats responded under a fentanyl-vs.-food “choice” procedure during daily 2h sessions. In addition to the daily choice sessions, rats were provided extended access to fentanyl during 12h sessions. After two weeks of this self-administration regimen, the nucleus accumbens (NAc) and ventral tegmental area (VTA) of a subset of rats were subjected to RNA sequencing. In the remaining rats, a third week of this self-administration regimen was conducted, during which methadone effects on fentanyl-vs.-food choice were determined.

Results

Prior to opioid dependence, male and female rats similarly allocated responding between fentanyl and food. Abstinence from extended fentanyl access elicited a similar increase in somatic withdrawal signs in both sexes. Despite similar withdrawal signs and extended access fentanyl intake, opioid withdrawal was accompanied by a maladaptive increase in fentanyl choice in males, but not females. Behavioral sex differences corresponded with transcriptional hyperfunction in the NAc and VTA of opioid-withdrawn females relative to males. Methadone blocked withdrawal-associated increases in fentanyl choice in males, but failed to further decrease fentanyl choice in females.

Conclusions

These results provide foundational evidence of sex-specific neuroadaptations to opioid withdrawal, which may be relevant to the female-specific resilience to withdrawal-associated increases in opioid choice and aid in the identification of novel therapeutic targets.
The effect of handrail cross-sectional design and age on applied handrail forces during reach-to-grasp balance reactions
Authors: Gosine Philippa , Komisar Vicki , Novak Alison C.
Published: January 2021

Handrails have been shown to reduce the likelihood of falls. Despite common use, little is known about how handrail shape and size affect the forces that people can apply after balance loss, and how these forces and the corresponding ability to recover balance depend on age. Following rapid platform translations, 16 older adults and 16 sex-matched younger adults recovered their balance using seven handrail cross-sections varying in shape and size. Younger adults were able to withstand higher perturbations, but did not apply higher forces, than older adults. However, younger adults achieved their peak resultant force more quickly, which may reflect slower rates of force generation with older adults. Considering handrail design, the 38mm round handrails allowed participants to successfully recover from the largest perturbations and enabled the highest force generation. Conversely, tapered handrails had the poorest performance, resulting in the lowest force generation and withstood perturbation magnitudes. Our findings suggest that the handrail cross-sectional design affects the magnitude of force generation and may impact the success of recovery. Our findings can inform handrail design recommendations that support effective handrail use in demanding, balance recovery scenarios.
The total mRNA concentration buffering system in yeast is global rather than gene-specific
Authors: García-Martínez José , Medina Daniel A. , Bellvís Pablo , Sun Mai , Cramer Patrick , Chávez Sebastián , Pérez-Ortín José E.
Published: January 2021

Gene expression in eukaryotes does not follow a linear process from transcription to translation and mRNA degradation. Instead it follows a circular process in which cytoplasmic mRNA decay crosstalks with nuclear transcription. In many instances this crosstalk contributes to buffer mRNA at a roughly constant concentration. Whether the mRNA buffering concept operates on the total mRNA concentration or at the gene-specific level, and if the mechanism to do so is a global or a specific one, remain unknown. Here we assessed changes in mRNA concentrations and their synthesis rates along the transcriptome of aneuploid strains of the yeastSaccharomyces cerevisiae. We also assessed mRNA concentrations and their synthesis rates in non sense-mediated decay (NMD) targets in euploid strains. We found that the altered synthesis rates in the genes from the aneuploid chromosome and the changes in their mRNA stabilities were not counterbalanced. In addition, the stability of NMD targets was not specifically compensated by the changes in synthesis rate. We conclude that there is no genetic compensation of NMD mRNA targets in yeast, and total mRNA buffering uses mostly a global system rather than a gene-specific one.
Minimal genetically encoded tags for fluorescent protein labeling in living neurons
Authors: Arsić Aleksandra , Hagemann Cathleen , Stajković Nevena , Schubert Timm , Nikić-Spiegel Ivana
Published: January 2021

Modern light microscopy, including super-resolution techniques, brought about a demand for small labeling tags that bring the fluorophore closer to the target. This challenge can be addressed by labeling unnatural amino acids (UAAs) with click chemistry. UAAs are site-specifically incorporated into a protein of interest by genetic code expansion. If the UAA carries a strained alkene or alkyne moiety it can be conjugated to a tetrazine-bearing fluorophore via a strain-promoted inverse-electron-demand Diels–Alder cycloaddition (SPIEDAC), a variant of bioorthogonal click chemistry. The minimal size of the incorporated tag and the possibility to couple the fluorophores directly to the protein of interest with single-residue precision make SPIEDAC live-cell labeling unique. However, until now, this type of labeling has not been used in complex, non-dividing cells, such as neurons. Using neurofilament light chain as a target protein, we established SPIEDAC labeling in living primary neurons and applied it for fixed-cell, live-cell, dual-color pulse—chase and super-resolution microscopy. We also show that SPIEDAC labeling can be combined with CRISPR/Cas9 genome engineering for tagging endogenous NFL. Due to its versatile nature and compatibility with advanced microscopy techniques, we anticipate that SPIEDAC labeling will contribute to novel discoveries in neurobiology.
Decynium-22 affects behavior in the zebrafish light/dark test
Authors: Maximino Caio
Published: January 2021

Decynium-22 (D-22) is an inhibitor of the uptake2system of monoamine clearance, resulting in increased levels of dopamine, norepinephrine, and serotonin in the nervous system and elsewhere. Uptake2is mediated by low-affinity, high-capacity transporters that are inhibited by glucocorticoids, suggesting a mechanism of fast glugocorticoid-monoamine interaction in the brain. D-22 dose-dependently increased anxiety-like behavior in adult zebrafish exposed to the light/dark test, monotonically increasing scototaxis (dark preference), but affecting risk assessment with an inverted-U-shaped response. These results suggest that the uptake2system has a role in defensive behavior in zebrafish, presenting a novel mechanism by which stress and glucocorticoids could produce fast neurobehavioral adjustments in vertebrates.Data:https://github.com/lanec-unifesspa/decynium22
A triple-negative matrix-producing breast carcinoma is arrested by tumor-targetingSalmonella typhimuriumA1-R in a PDOX model
Authors: Hamada Kazuyuki , Yamamoto Jun , Hozumi Chihiro , Zhao Ming , Murata Takuya , Sugisawa Norihiko , Sun Yu , Aoki Yusuke , Nishino Hiroto , Bouvet Michael , Tsunoda Takuya , Hoffman Robert M.
Published: January 2021

Background/Aim

Matrix-producing breast carcinoma (MPBC), is a rare, recalcitrant and highly aggressive. The present study aimed to determine the efficacy of tumor-targetingSalmonella typhimurium(S. typhimurium) A1-R on a triple-negative MPBC in a patient-derived orthotopic xenograft (PDOX) model.

Methods

The PDOX model was established in the left second mammary gland of a nude mouse by surgical orthotopic implantation (SOI) of the patient triple-negative MPBC PDOX models were randomized into two groups: G1, control group (n=6); G2, tumor-targetingS. typhimuriumA1-R group (n=7, intravenous (i.v.) injection via tail vein, weekly, for two weeks). All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week.

Results

S. typhimuriumA1-R arrested tumor growth compared to the control group (P = 0.016).

Conclusion

The results of the present study suggest thatS. typhimuriumA1-R has future clinical potential in triple-negative MPBC patients.
Discovering hidden brain network responses to naturalistic stimuli via tensor component analysis of multi-subject fMRI data
Authors: Hu Guoqiang , Li Huanjie , Zhao Wei , Hao Yuxing , Bai Zonglei , Nickerson Lisa D. , Cong Fengyu
Published: January 2021

The study of brain network interactions during naturalistic stimuli facilitates a deeper understanding of human brain function. Intersubject correlation (ISC) analysis of functional magnetic resonance imaging (fMRI) data is a widely used method that can measure neural responses to naturalistic stimuli that are consistent across subjects. However, interdependent correlation values in ISC artificially inflated the degrees of freedom, which hinders the investigation of individual differences. Besides, the existing ISC model mainly focus on similarities between subjects but fails to distinguish neural responses to different stimuli features. To estimate large-scale brain networks evoked with naturalistic stimuli, we propose a novel analytic framework to characterize shared spatio-temporal patterns across subjects in a purely data-driven manner. In the framework, a third-order tensor is constructed from the timeseries extracted from all brain regions from a given parcellation, for all participants, with modes of the tensor corresponding to spatial distribution, time series and participants. Tensor component analysis (TCA) will then reveal spatially and temporally shared components, i.e., naturalistic stimuli evoked networks, their temporal courses of activity and subject loadings of each component. To enhance the reproducibility of the estimation with TCA, a novel spectral clustering method, tensor spectral clustering, was proposed and applied to evaluate the stability of TCA algorithm. We demonstrate the effectiveness of the proposed framework via simulations and real fMRI data collected during a motor task with a traditional fMRI study design. We also apply the proposed framework to fMRI data collected during passive movie watching to illustrate how reproducible brain networks are identified evoked by naturalistic movie viewing.
Cladistic hypotheses as degree of equivalence relational structures: implications for three-item statements
Authors: Rineau Valentin , Prin Stéphane
Published: January 2021

Three-item statements, as minimal informative rooted binary phylogenetic trees on three items, are the minimal units of cladistic information. Their importance for phylogenetic reconstruction, consensus and supertree methods relies on both (i) the fact that any cladistic tree can always be decomposed into a set of three-item statements, and (ii) the possibility, at least under some conditions, to build a new cladistic tree by combining all or part of the three-item statements deduced from several prior cladistic trees. In order to formalise such procedures, severalk-adic rules of inference, i.e., rules that allow us to deduce at least one new three-item statement from exactlykother ones, have been identified. However, no axiomatic background has been proposed, and it remains unknown if a particulark-adic rule of inference can be reduced to more basic rules. In order to solve this problem, we propose here to define three-item statements in terms of degree of equivalence relations. Given both the axiomatic definition of the latter and their strong connection to hierarchical classifications, we establish a list of the most basic properties for three-item statements. With such an approach, we show that it is possible to combine five three-item statements from basic rules although they are not combinable only from dyadic rules. Such a result suggests that all higherk-adic rules are well reducible to a finite set of simpler rules.
A Paradoxical Screening Serological Assay for the Diagnosis of Whipple’s Disease (infection with Tropheryma whipplei)
Authors: Liew K.C. , Nguyen Chelsea , Waidyatillake Nilakshi T , Stenos John , Walton Aaron , Athan Eugene , Harris Owen , Graves Stephen
Published: January 2021

Whipple’s disease (WD) is a rare infection due to Tropheryma whipplei. Following in-vitro cultivation of T. whipplei, an indirect-immunofluorescence serological assay (IFA) was developed. We tested the hypothesis that this assay could be used to either identify WD patients, or rule out WD, in patients in whom the diagnosis is being considered, based on the antibody titers of their IgM and IgG antibody responses. In this small study fourteen WD patients and 22 healthy volunteers’ sera were obtained from across Australia. All specimens were coded and de-identified before testing. A patient with an IgG antibody titer of ≤1:16 may have WD [sensitivity 57% (8/14) and specificity close to 100% (22/22)]. High IgM antibody titers (≥1:256) were more common in WD patients [sensitivity 50% (7/14) and specificity 86% (19/22)] than in controls. The area under Receiver-Operator-Characteristic curve for IgG in the IFA assay was 0.84 (95% CI 0.69-1.00). At an IgG antibody titer of ≤1:16 the Youden’s index was 0.57. WD patients’ under-produce IgG antibody to T.whipplei but are more likely to over-produce IgM antibodies. This screening IFA serological assay may be clinically useful in detecting those with a possible diagnosis of WD. Patients with an IgG antibody titer of ≤1:16 and an IgM antibody titer of ≥1:256 may have WD and should proceed to a tissue biopsy and PCR for confirmation. Further validation of this assay, by increasing the sample size, by testing it in patients with non-WD disease and trialing in other countries should be undertaken.
SARS-CoV-2 seropositivity and seroconversion in patients undergoing active cancer-directed therapy
Authors: Sun Lova , Surya Sanjna , Goodman Noah G. , Le Anh N. , Kelly Gregory , Owoyemi Olutosin , Desai Heena , Zheng Cathy , DeLuca Shannon , Good Madeline L. , Hussain Jasmin , Jeffries Seth D. , Kry Yolanda R. , Kugler Emily M. , Mansour Maikel , Ndicu John , Osei-Akoto AnnaClaire , Prior Timothy , Pundock Stacy L. , Varughese Lisa A. , Weaver JoEllen , Doucette Abigail , Dudek Scott , Verma Shefali Setia , Gouma Sigrid , Weirick Madison E. , McAllister Christopher M. , Bange Erin , Gabriel Peter , Ritchie Marylyn , Rader Daniel J. , Vonderheide Robert H. , Schuchter Lynn M , Verma Anurag , Maillard Ivan , Mamtani Ronac , Hensley Scott E. , Gross Robert , Wileyto E. Paul , Huang Alexander C. , Maxwell Kara N. , DeMichele Angela
Published: January 2021

Multiple studies have demonstrated the negative impact of cancer care delays during the COVID-19 pandemic, and transmission mitigation techniques are imperative for continued cancer care delivery. To gauge the effectiveness of these measures at the University of Pennsylvania, we conducted a longitudinal study of SARS-CoV-2 antibody seropositivity and seroconversion in patients presenting to infusion centers for cancer-directed therapy between 5/21/2020 and 10/8/2020. Participants completed questionnaires and had up to five serial blood collections. Of 124 enrolled patients, only two (1.6%) had detectable SARS-CoV-2 antibodies on initial blood draw, and no initially seronegative patients developed newly detectable antibodies on subsequent blood draw(s), corresponding to a seroconversion rate of 0% (95%CI 0.0-4.1%) over 14.8 person-years of follow up, with a median of 13 healthcare visits per patient. These results suggest that cancer patients receiving in-person care at a facility with aggressive mitigation efforts have an extremely low likelihood of COVID-19 infection.
3D Mapping of Neurofibrillary Tangle Burden in the Human Medial Temporal Lobe
Authors: Yushkevich Paul A , Muñoz López Mónica , Iñiguez de Onzoño Martin Maria Mercedes , Ittyerah Ranjit , Lim Sydney , Ravikumar Sadhana , Bedard Madigan L. , Pickup Stephen , Liu Weixia , Wang Jiancong , Hung Ling Yu , Lasserve Jade , Vergnet Nicolas , Xie Long , Dong Mengjin , Cui Salena , McCollum Lauren , Robinson John L. , Schuck Theresa , de Flores Robin , Grossman Murray , Tisdall M. Dylan , Prabhakaran Karthik , Mizsei Gabor , Das Sandhitsu R. , Artacho-Pérula Emilio , Arroyo Jiménez María del Mar , Marcos Rabal María Pilar , Molina Romero Francisco Javier , Cebada Sánchez Sandra , Delgado González José Carlos , de la Rosa-Prieto Carlos , Córcoles Parada Marta , Lee Edward B. , Trojanowski John Q. , Ohm Daniel T. , Wisse Laura E.M. , Wolk David A. , Irwin David J. , Insausti Ricardo
Published: January 2021

Abstract Tau protein neurofibrillary tangles (NFT) are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease (AD) and related dementias. Our knowledge of the pattern of NFT progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in AD, is based on conventional 2D histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe (MTL) specimens were used to construct 3D quantitative maps of NFT burden in the MTL at individual and group levels. These maps reveal significant variation in NFT burden along the anterior-posterior axis. While early NFT pathology is thought to be confined to the transentorhinal region, we find similar levels of NFT burden in this region and other MTL subregions, including amygdala, temporopolar cortex, and subiculum/CA1.
EmptyNN: A neural network based on positive-unlabeled learning to remove cell-free droplets and recover lost cells in single-cell RNA sequencing data
Authors: Yan Fangfang , Zhao Zhongming , Simon Lukas M.
Published: January 2021

Droplet-based single-cell RNA sequencing (scRNA-seq) has significantly increased the number of cells profiled per experiment and revolutionized the study of individual transcriptomes. However, to maximize the biological signal robust computational methods are needed to distinguish cell-free from cell-containing droplets. Here, we introduce a novel cell-calling algorithm called EmptyNN, which trains a neural network based on positive-unlabeled learning for improved filtering of barcodes. We leveraged cell hashing and genetic variation to provide ground-truth. EmptyNN accurately removed cell-free droplets while recovering lost cell clusters, and achieved an Area Under the Receiver Operating Characteristics (AUROC) of 94.73% and 96.30%, respectively. The comparisons to current state-of-the-art cell-calling algorithms demonstrated the superior performance of EmptyNN, as measured by the number of recovered cell-containing droplets and cell types. EmptyNN was further applied to two additional datasets and showed good performance. Therefore, EmptyNN represents a powerful tool to enhance scRNA-seq quality control analyses.
Repurposing of an Antifungal Drug against Gastrointestinal Stromal Tumors
Authors: Arulanandam Charli Deepak , Prathiviraj R , Kaveriyappan Govindarajan Rasiravathanahalli
Published: January 2021

Drug discovery is an important research area to improve human health. Currently, treatment of gastrointestinal stromal tumors (GISTs) is unsuccessful due to drug-resistance, hence, there is a demand for alternatives. Often, there is limited time available for toxicological assessments and a lack of safer drugs. It is possible to identify new drugs from existing approved drugs possessing another purpose in the clinical lines. In this study, virtual screening of some Food and Drug Administration (FDA-USA) approved and available antifungal and antineoplastic drugs were performed against GISTs based on docking affinity of human platelet-derived growth factor receptor alpha (PDGFRA) with these drugs to identify a suitable PDGFRA inhibitor for saving the time required for toxicity screening. The protein and ligand-binding affinity were investigated for five FDA approved antineoplastic and thirty-six antifungal drugs against PDGFRA using the AutoDock (AD) and AutoDock Vina (ADV) software. Based on docking score and inhibition constant (Ki), Itraconazole was predicted as a better PDGFRA inhibitor among all the computationally tested drugs.
Dopamine enhances model-free credit assignment through boosting of retrospective model-based inference
Authors: Deserno Lorenz , Moran Rani , Michely Jochen , Lee Ying , Dayan Peter , Dolan Raymond J.
Published: January 2021

Dopamine is implicated in signalling model-free (MF) reward prediction errors and various aspects of model-based (MB) credit assignment and choice. Recently, we showed that cooperative interactions between MB and MF systems include guidance of MF credit assignment by MB inference. Here, we used a double-blind, placebo-controlled, within-subjects design to test the hypothesis that enhancing dopamine levels, using levodopa, boosts the guidance of MF credit assignment by MB inference. We found that levodopa enhanced retrospective guidance of MF credit assignment by MB inference, without impacting on MF and MB influences per se. This drug effect positively correlated with working memory, but only in a context where reward needed to be recalled for MF credit assignment. The dopaminergic enhancement in MB-MF interactions correlated negatively with a dopamine-dependent change in MB credit assignment, possibly reflecting a potential trade-off between these two components of behavioural control. Thus, our findings demonstrate that dopamine boosts MB inference during guidance of MF learning, supported in part by working memory, but trading-off with a dopaminergic enhancement of MB credit assignment. The findings highlight a novel role for a DA influence on MB-MF interactions.
High-resolution model of Arabidopsis Photosystem II reveals the consequences of digitonin-extraction
Authors: Graça André T. , Hall Michael , Persson Karina , Schröder Wolfgang P.
Published: January 2021

In higher plants, the photosynthetic process is performed and regulated by Photosystem II (PSII).Arabidopsis thalianawas the first higher plant with a fully sequenced genome, conferring it the status of a model organism; nonetheless, a high-resolution structure of its Photosystem II is missing. We present the first Cryo-EM high-resolution structure of Arabidopsis PSII supercomplex with average resolution of 2.79 Å, an important model for future PSII studies. The digitonin extracted PSII complexes demonstrate the importance of: the LHG2630-lipid-headgroup in the trimerization of the light-harvesting complex II; the stabilization of the PsbJ subunit and the CP43-loop E by DGD520-lipid; the choice of detergent for the integrity of membrane protein complexes. Furthermore, our data shows at the anticipated Mn4CaO5-site a single metal ion density as a reminiscent early stage of Photosystem II photoactivation.
How the healthy ageing brain supports semantic binding during language comprehension
Authors: Markiewicz Roksana , Segaert Katrien , Mazaheri Ali
Published: January 2021

Semantic binding refers to constructing complex meaning based on elementary building blocks. Using EEG, we investigated the age-related changes in modulations of oscillatory brain activity supporting lexical retrieval and semantic binding. Young and older adult participants were visually presented two-word phrases, which for the first word revealed a lexical retrieval signature (e.g.swiftvs.swrfeq) and for the second word revealed a semantic binding signature (e.g.horsein a semantic binding “swifthorse” vs. no binding “swrfeqhorse” context). The oscillatory brain activity associated with lexical retrieval as well as semantic binding significantly differed between healthy older and young adults. Specifically for lexical retrieval, we found that different age groups exhibited opposite patterns of theta and alpha modulation, which as a combined picture suggest that lexical retrieval is associated with different and delayed signatures in older compared to young adults. For semantic binding, in young adults we found a signature in the low-beta range centred around the target word onset (i.e. a smaller low-betaincrease for binding relative to no binding), while in healthy older adults we found an opposite binding signature about ~500ms later in the low- and high-beta range (i.e. a smaller low- and high-betadecrease for binding relative to no binding). The novel finding of a different and delayed oscillatory signature for semantic binding in healthy older adults reflects that the integration of word meaning into the semantic context takes longer and relies on different mechanisms in healthy older compared to young adults.
A temporal parcellation of the sensory-evoked responses during the rubber hand illusion reveals manipulation- and illusion-specific correlates
Authors: Sciortino Placido , Kayser Christoph
Published: January 2021

The neurophysiological processes reflecting body illusions such as the rubber hand remain debated. In particular, previous studies investigating neural responses evoked by the illusion-inducing stimuli provide diverging reports as to when these responses reflect the illusory state. To resolve these controversies in previous work we applied multivariate (cross-) classification to EEG responses obtained during the rubber hand illusion and multiple control conditions in human participants. These controls were designed to test for markers of the illusory state that generalize across the spatial arrangements of limbs or the specific nature of the control condition (rubber hand or participant’s real hand) - hence which are independent of the precise experimental conditions used as contrast for the illusion. This revealed a parcellation of evoked responses into a temporal sequence of events that each differentiate the illusion and control conditions along distinct dimensions. Importantly, around 130-150 ms following stimulus onset the neurophysiological signals reliably differentiated the illusory-state from all non-illusion epochs. This neurophysiological signature was not correlated with changes in skin conductance accompanying the illusion, suggesting that neurophysiological and bodily signals reflect distinct illusion-related processes.
The Pentose Phosphate Pathway constitutes a major metabolic hub in pathogenicFrancisella
Authors: Rytter Héloise , Jamet Anne , Ziveri Jason , Ramond Elodie , Coureuil Mathieu , Lagouge-Roussey Pauline , Euphrasie Daniel , Tros Fabiola , Goudin Nicolas , Chhuon Cerina , Nemazanyy Ivan , de Moraes Fabricio Edgar , Labate Carlos , Guerrera Ida Chiara , Charbit Alain
Published: January 2021

Metabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and hence represent potential targets for anti-bacterial strategies. Here, we addressed the role of the pentose phosphate pathway (PPP) and its connections with other metabolic pathways in the pathophysiology ofFrancisella novicida. The involvement of the PPP inFrancisellaintracellular life cycle was first demonstrated with the study of PPP inactivation mutants. Indeed, inactivation oftktA, rpiAorrpegenes, severely impaired intramacrophagic multiplication during the first 24 hours. Time-lapse video microscopy demonstrated thatrpiAandrpemutants were able to resume late intracellular bacterial multiplication. To get further insight into the links between the PPP and other metabolic networks of the bacterium, we next performed a thorough proteo-metabolomic analysis of these mutants. We show that the PPP constitutes a major bacterial metabolic hub with multiple connections with glycolysis, tricarboxylic acid cycle and other pathways, such as fatty acid degradation and sulfur metabolism. Hence, our study highlights how the PPP is instrumental toFrancisellapathogenesis and growth in its intracellular niche.
Genetic nurture effects on education: a systematic review and meta-analysis
Authors: Wang Biyao , Baldwin Jessie R. , Schoeler Tabea , Cheesman Rosa , Barkhuizen Wikus , Dudbridge Frank , Bann David , Morris Tim T. , Pingault Jean-Baptiste
Published: January 2021

Child educational development is associated with major psychological, social, economic and health milestones throughout the life course. Understanding the early origins of educational inequalities and their reproduction across generations is therefore crucial. Recent genomic studies provide novel insights in this regard, uncovering “genetic nurture” effects, whereby parental genotypes influence offspring’s educational development via environmental pathways rather than genetic transmission. These findings have yet to be systematically appraised. We conducted the first systematic review and meta-analysis to quantify genetic nurture effects on educational outcomes and investigate key moderators. Twelve studies comprising 38,654 distinct parent(s)-offspring pairs or trios from eight cohorts were included, from which we derived 22 estimates of genetic nurture effects. Multilevel random effects models showed that the effect of genetic nurture on offspring’s educational outcomes (βgenetic nurture= 0.08, 95% CI [0.07, 0.09]) was about half the size of direct genetic effects (βdirect genetic= 0.17, 95% CI [0.13, 0.20]). Maternal and paternal genetic nurture effects were similar in magnitude, suggesting comparable roles of mothers and fathers in determining their children’s educational outcomes. Genetic nurture effects were largely explained by parental educational level and family socioeconomic status, suggesting that genetically influenced environments play an important role in shaping child educational outcomes. Even after accounting for genetic transmission, we provide evidence that environmentally mediated parental genetic influences contribute to the intergenerational transmission of educational outcomes. Further exploring these downstream environmental pathways may inform educational policies aiming to break the intergenerational cycle of educational underachievement and foster social mobility.

Public Significance Statement

This meta-analysis demonstrates that parents’ genetics influence their children’s educational outcomes through the rearing environments that parents provide. This “genetic nurture” effect is largely explained by family socioeconomic status and parental education level, is similar for mothers and fathers (suggesting that both parents equally shape their children’s educational outcomes) and is about half the size of direct genetic effects on children’s educational outcomes. Interventions targeting such environmental pathways could help to break the intergenerational cycle of educational underachievement and foster social mobility.
Metastatic Single Tumor Cells Evade NK Cell-mediated Killing by Thrombin-mediated Loss of the Activating Ligand CD155/PVR/Necl-5
Authors: Ichise Hiroshi , Tsukamoto Shoko , Hirashima Tsuyoshi , Konishi Yoshinobu , Oki Choji , Tsukiji Shinya , Iwano Satoshi , Miyawaki Atsushi , Sumiyama Kenta , Terai Kenta , Matsuda Michiyuki
Published: January 2021

Natural killer (NK) cells lyse invading tumor cells to limit metastatic growth in the lung, but how some cancers evade this host protective mechanism to establish a growing lesion is not known. Here we have combined ultra-sensitive bioluminescence whole body imaging with intravital two-photon microscopy involving genetically-encoded biosensors to examine this question. NK cells eliminated disseminated tumor cells from the lung within 24 hrs of arrival, but not thereafter. Intravital dynamic imaging revealed that a disseminated tumor cell in a pulmonary capillary interacts with an NK cell every 2 hrs on average. In the first 4 hrs after tumor cell arrival, 50% of such encounters lead to tumor cell death but after 24 hrs of arrival, nearly 100% of the interactions result in the survival of the tumor cell. This evasion of NK cell surveillance is mediated by thrombin-dependent loss of cell surface CD155/PVR/Necl-5, a ligand for the NK cell activating receptor DNAM-1. This loss prevents the NK cell signaling needed for effective killing of tumor targets. By quantitatively visualizing the evasion of NK cell surveillance, we have uncovered a molecular mechanism for cancer evasion and provided an explanation for the anti-metastatic effect of anticoagulants.

Intravital functional two-photon microscopy reveals that metastatic tumor cells lodged in pulmonary capillaries acquire resistance to patrolling NK cells. Protease-mediated loss of the activating ligand CD155/PVR/Necl-5 on tumor cells prevents NK cells from ERK activation and tumor cell killing.
KIT is required for fetal liver erythropoiesis but dispensable for angiogenesis
Authors: Fantin Alessandro , Plein Alice , Tacconi Carlotta , Villa Emanuela , Ceccacci Elena , Denti Laura , Ruhrberg Christiana
Published: January 2021

Blood vessels are fundamental to sustain organ growth and tissue metabolism. In the mouse embryo, endothelial cell (EC) progenitors almost concomitantly give rise to the first blood vessels in the yolk sac and the large vessels of the embryo proper. Thereafter, the vascular network expands by angiogenesis to vascularize developing organs such as the brain. Although the first blood cells form in the yolk sac before blood vessels have assembled, consecutive waves of hematopoietic progenitors subsequently bud from hemogenic endothelium located within the wall of yolk sac and large intraembryonic vessels in a process termed endothelial to hematopoietic transition (endoHT). The receptor tyrosine kinase KIT is required for late embryonic erythropoiesis, but KIT is also expressed earlier in the hemogenic endothelium, in hematopoietic progenitors that arise via endoHT from hemogenic endothelium and non-hemogenic ECs, such as in the brain. However, it remains unclear whether KIT has essential roles in early hematopoiesis or even blood vessel growth. Here, we have combined transcriptomic analysis to delineateKitexpression with the analysis of knockout mice to show that KIT is expressed during but dispensable for yolk sac endoHT or brain angiogenesis but required for transient definitive erythropoiesis in the fetal liver.
Proprotein Convertase Subtilisin/kexin Type 9 Links Inflammation to Vascular Endothelial Cell Dysfunction
Authors: Leucker Thorsten M. , Amat-Codina Nuria , Chelko Stephen , Gerstenblith Gary
Published: January 2021

Vascular endothelial cell (EC) dysfunction is a pathological mediator of he development, progression, and clinical manifestations of atherosclerotic disease. Inflammation is associated with EC dysfunction, but the responsible mechanisms are not well characterized. There is substantial evidence that serum proprotein convertase subtilisin/kexin type 9 (PCSK9) is increased in pro-inflammatory states and that elevated PCSK9 levels are associated with adverse cardiovascular outcomes after controlling for traditional risk factors, including low-density lipoprotein (LDL) cholesterol.

Here we investigate PCSK9 as a novel link between inflammation and vascular EC dysfunction, as assessed by nitric oxide (NO) bioavailability. Tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine, increasedPCSK9mRNA expression and PCSK9 protein levels in isolated human aortic ECs, which were accompanied by reduced total and phosphorylated endothelial nitric oxide synthase (eNOS) protein levels and NO bioavailability. Finally, genetic PCSK9 reduction utilizing a PCSK9 specific siRNA in human aortic ECs resulted in the rescue of phosphorylated eNOS protein levels and NO bioavailability.

Our results demonstrate that PCSK9 is increased in human aortic ECs exposed to a pro-inflammatory stimulus and that this increase is associated with EC dysfunction. Silencing of TNFα-mediated augmentation ofPCSK9expression utilizing a small interfering RNA againstPCSK9rescued the inflammation-induced EC dysfunction. These results indicate that PCSK9 is a causal link between inflammation and EC dysfunction, a potent driver of atherosclerotic cardiovascular disease.
Formation and Spontaneous Long-Term Repatterning of Headless Planarian Flatworms
Authors: Bischof Johanna , LaPalme Jennifer V. , Miller Kelsie A. , Morokuma Junji , Williams Katherine B. , Fields Chris , Levin Michael
Published: January 2021

Regeneration requires the production of large numbers of new cells, and thus cell division regulators, particularly ERK signaling, are critical in regulating this process. In the highly regenerative planarian flatworm, questions remain as to whether ERK signaling controls overall regeneration or plays a head-specific role. Here we show that ERK inhibition in the 3 days following amputation delays regeneration, but that all tissues except the head can overcome this inhibition, resulting in headless regenerates. This prevention of head regeneration happens to a different degree along the anterior-posterior axis, with very anterior wounds regenerating heads even under ERK inhibition. Remarkably, 4 to 18 weeks after injury, the headless animals induced by ERK inhibition remodel to regain single-headed morphology, in the absence of further injury, in a process driven by Wnt/β-catenin signaling. Interestingly, headless animals are likely to exhibit unstable axial polarity, and cutting or fissioning prior to remodeling can result in body-wide reversal of anterior-posterior polarity. Our data reveal new aspects of how ERK signaling regulates regeneration in planaria and show anatomical remodeling on very long timescales.
Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease
Authors: Sánchez-Ceinos Julia , Guzmán-Ruiz Rocío , Rangel-Zúñiga Oriol A. , López-Alcalá Jaime , Moreno-Caño Elena , del Río-Moreno Mercedes , Romero-Cabrera Juan L. , Pérez-Martínez Pablo , Maymo-Masip Elsa , Vendrell Joan , Fernández-Veledo Sonia , Fernández-Real José M. , Laurencikiene Jurga , Rydén Mikael , Membrives Antonio , Luque Raúl M. , López-Miranda José , Malagón María M.
Published: January 2021

Preadipocytes are crucial for healthy adipose tissue expansion. Preadipocyte differentiation is altered in obese individuals, which has been proposed to contribute to obesity-associated metabolic disturbances. Here, we demonstrate that impaired alternative splicing and dysregulated endoplasmic reticulum (ER)- associated protein degradation (ERAD) represent marker pathways of dysfunctional preadipocytes in obese individuals with insulin resistance (IR)/type 2 diabetes (T2D). Down-regulation of a key member of the major spliceosome,PRFP8/PRP8, as observed in IR/T2D preadipocytes from subcutaneous (SC) fat, prevented adipogenesis by altering both the expression and splicing patterns of adipogenic transcription factors and lipid droplet-related proteins, while adipocyte differentiation was restored upon recovery ofPRFP8/PRP8 normal levels. Adipocyte differentiation was also compromised under conditions of ERAD hyperactivation, as occurs in SC and omental (OM) preadipocytes in IR/T2D obesity. Thus, targeting mRNA splicing and ER proteostasis in preadipocytes could improve adipose tissue function and thus contribute to metabolic health in obese individuals.