bluuebunny/crossref_metadata_2025 huggingface dataset:
The genetic architecture of human cortical folding
Authors: van der Meer Dennis , Kaufmann Tobias , Shadrin Alexey A. , Makowski Carolina , Frei Oleksandr , Roelfs Daniel , Sánchez Jennifer Monereo , Linden David E.J. , Rokicki Jaroslav , de Leeuw Christiaan , Thompson Wesley K. , Loughnan Robert , Fan Chun Chieh , Thompson Paul M. , Westlye Lars T. , Andreassen Ole A. , Dale Anders M.
Published: January 2021

The folding of the human cerebral cortex is a highly genetically regulated process that allows for a much larger surface area to fit into the cranial vault and optimizes functional organization. Sulcal depth is a robust, yet understudied measure of localized folding, previously associated with a range of neurodevelopmental disorders. Here, we report the first genome-wide association study of sulcal depth. Through the Multivariate Omnibus Statistical Test (MOSTest) applied to vertexwise measures from 33,748 participants of the UK Biobank (mean age 64.3 years, 52.0% female) we identified 856 genetic loci associated with sulcal depth at genome-wide significance (α=5×10-8). Comparison with two other measures of cortical morphology, cortical thickness and surface area, indicated that sulcal depth has higher yield in terms of loci discovered, higher heritability and higher effective sample size. There was a large amount of genetic overlap between the three traits, with gene-based analyses indicating strong associations with neurodevelopmental processes. Our findings demonstrate sulcal depth is a promising MRI phenotype that may enhance our understanding of human cortical morphology.
Examining the effect of chronic intranasal oxytocin administration on the neuroanatomy and behavior of three autism-related mouse models
Authors: Lindenmaier Zsuzsa , Ellegood Jacob , Stuive Monique , Easson Kaitlyn , Yee Yohan , Fernandes Darren , Foster Jane , Anagnostou Evdokia , Lerch Jason P.
Published: January 2021

1

Although initially showing great potential, oxytocin treatment has encountered a translational hurdle in its promise of treating the social deficits of autism. Some debate surrounds the ability of oxytocin to successfully enter the brain, and therefore modify neuroanatomy. Moreover, given the heterogeneous nature of autism, treatment will only amerliorate symptoms in a subset of patients. Therefore, to determine whether oxytocin changes brain circuitry, and whether it does so variably, depending on genotype, we implemented a large randomized, blinded, placebo-controlled, preclinical study on chronic intranasal oxytocin treatment in three different mouse models related to autism with a focus on using neuroanatomical phenotypes to assess and subset treatment response. Intranasal oxytocin (0.6IU) was administered daily, for 28 days, starting at 5 weeks of age to the16p11.2deletion,Shank3(exon 4-9) knockout, andFmr1knockout mouse models. Given the sensitivity of structural magnetic resonance imaging (MRI) to the neurological effects of interventions like drugs, along with many other advantages, the mice underwentin vivolongitudinal and high-resolutionex vivoimaging with MRI. The scans included threein vivoT1-weighted, 90um isotropic resolution scans and a T2-weighted, 3D fast spin echo with 40um isotropic resolutionex vivoscan to assess the changes in neuroanatomy using established automated image registration and deformation based morphometry approaches in response to oxytocin treatment. The behavior of the mice was assessed in multiple domains, including social behaviours and repetitive behaviours, among others. Treatment effect on the neuroanatomy did not reach significance, although the pattern of trending effects was promising. No significant effect of treatment was found on social behavior in any of the strains, although a significant effect of treatment was found in theFmr1mouse, with treatment normalizing a grooming deficit. No other treatment effect on behavior was observed that survived multiple comparisons correction. Overall, chronic treatment with oxytocin had limited effects on the three mouse models related to autism, and no promising pattern of response susceptibility emerged.
Using image-based haplotype alignments to map global adaptation of SARS-CoV-2
Authors: Ouellette Tom W. , Shaw Jim , Awadalla Philip
Published: January 2021

Quantifying evolutionary change among viral genomes is an important clinical device to track critical adaptations geographically and temporally. We built image-based haplotype-guided evolutionary inference (ImHapE) to quantify adaptations in expanding populations of non-recombining SARS-CoV-2 genomes. By combining classic population genetic summaries with image-based deep learning methods, we show that different rates of positive selection are driving evolutionary fitness and dispersal of SARS-CoV-2 globally. A 1.35-fold increase in evolutionary fitness is observed within the UK, associated with expansion of both the B.1.177 and B.1.1.7 SARS-CoV-2 lineages.
New SHIVs and Improved Design Strategy for Modeling HIV-1 Transmission, Immunopathogenesis, Prevention and Cure
Authors: Li Hui , Wang Shuyi , Lee Fang-Hua , Roark Ryan S. , Murphy Alex I. , Smith Jessica , Zhao Chengyan , Rando Juliette , Chohan Neha , Ding Yu , Kim Eunlim , Lindemuth Emily , Bar Katharine J. , Pandrea Ivona , Apetrei Christian , Keele Brandon F. , Lifson Jeffrey D. , Lewis Mark G. , Denny Thomas N. , Haynes Barton F. , Hahn Beatrice H. , Shaw George M.
Published: January 2021

Simian-human immunodeficiency virus (SHIV) chimeras contain the HIV-1 envelope (env) gene embedded within an SIVmac proviral backbone. Previously, we showed that substitution of Env residue 375-Ser by bulky aromatic residues enhances Env binding to rhesus CD4 and enables primary or transmitted/founder (T/F) HIV-1 Envs to support efficient SHIV replication in rhesus macaques (RMs). Here, we test this design strategy more broadly by constructing and analyzing SHIVs containing ten strategically selected primary or T/F HIV-1 Envs corresponding to subtypes A, B, C, AE and AG, each with six allelic variants at position 375. All ten SHIVs bearing wildtype Env375 residues replicated efficiently in human CD4+T cells, but only one of these replicated efficiently in rhesus CD4+T cells. This was a SHIV whose subtype AE Env naturally contained a bulky aromatic His residue at position 375. Replacement of wildtype Env375 residues by Trp, Tyr, Phe or His in the other nine SHIVs uniformly led to efficient replication in rhesus CD4+ Tin vitroand in RMsin vivo. Env375-Trp – the residue found most frequently among SIV strains infecting Old World monkeys – was favored for SHIV replication in RMs, although some SHIVs preferred Env375-Tyr, -His or -Phe. Nine SHIVs containing optimized Env375 alleles were grown large scale in primary activated rhesus CD4+T cells to serve as challenge stocks in preclinical prevention trials. These virus stocks were genetically homogeneous, native-like in Env antigenicity and tier-2 neutralization sensitivity, transmissible by rectal, vaginal, penile, oral or intravenous inoculation routes, and exhibited acute and early replication kinetics that were indistinguishable from HIV-1 infection in humans. Finally, to expedite future SHIV constructions and eliminate short redundant elements intat1andenvgp41 that were spontaneously deleted in chronically infected monkeys, we engineered a simplified second-generation SHIV design scheme and validated it in RMs. Overall, our findings demonstrate that SHIVs bearing primary or T/F Envs with bulky aromatic amino acid substitutions at position Env375 consistently replicate in RMs, recapitulating many features of HIV-1 infection in humans. We further show that SHIV challenge stocks grown in primary rhesus CD4+T cells are efficiently transmitted by mucosal routes common to HIV-1 infection and can be used effectively to test for vaccine efficacy in preclinical monkey trials.
Induced systemic resistance impacts the phyllosphere microbiome through plant-microbe-microbe interactions
Authors: Sommer Anna , Wenig Marion , Knappe Claudia , Kublik Susanne , Fösel Bärbel , Schloter Michael , Vlot A. Corina
Published: January 2021

Both above- and below-ground parts of plants are constantly confronted with microbes, which are main drivers for the development of plant-microbe interactions. Plant growth-promoting rhizobacteria enhance the immunity of above-ground tissues, which is known as induced systemic resistance (ISR). We show here that ISR also influences the leaf microbiome. We compared ISR triggered by the model strainPseudomonas simiaeWCS417r (WCS417) to that triggered byBacillus thuringiensis israelensis(Bti) inArabidopsis thaliana. In contrast to earlier findings, immunity elicited by both strains depended on salicylic acid. Both strains further relied on MYC2 for signal transduction in the plant, while WCS417-elicited ISR additionally depended on SAR-associated metabolites, including pipecolic acid. A metabarcoding approach applied to the leaf microbiome revealed a significant ISR-associated enrichment of amplicon sequence variants with predicted plant growth-promoting properties. WCS417 caused a particularly dramatic shift in the leaf microbiota with more than 50% of amplicon reads representing two bacterial species: WCS417 andFlavobacteriumsp.. Co-inoculation experiments using WCS417 andAt-LSPHEREFlavobacteriumsp. Leaf82, suggest that the proliferation of these bacteria is influenced by both microbial and plant-derived factors. Together, our data connect systemic immunity with leaf microbiome dynamics and highlight the importance of plant- microbe-microbe interactions for plant health.
Standardized quality control workflow to evaluate the reproducibility and differentiation potential of human iPSCs into neurons
Authors: Chen Carol X.-Q. , Abdian Narges , Maussion Gilles , Thomas Rhalena A. , Demirova Iveta , Cai Eddie , Tabatabaei Mahdieh , Beitel Lenore K. , Karamchandani Jason , Fon Edward A. , Durcan Thomas M.
Published: January 2021

Induced pluripotent stem cells (iPSCs) derived from human somatic cells have created new opportunities to generate disease-relevant cells. Thus, as the use of patient-derived stem cells has become more widespread, having a workflow to monitor each line is critical. This ensures iPSCs pass a suite of quality control measures, promoting reproducibility across experiments and between labs. With this in mind, we established a multistep workflow to assess our newly generated iPSCs for variations and reproducibility relative to each other and iPSCs obtained from external sources. Our benchmarks for evaluating iPSCs include examining iPSC morphology and proliferation in two different media conditions and evaluating their ability to differentiate into each of the three germ layers, with a particular focus on neurons. Genomic integrity in the human iPSCs was analyzed by G-band karyotyping and a qPCR-based test for the detection of hotspot mutations test. Cell-line identity was authenticated by Short Tandem Repeat (STR) analysis. Using standardized dual SMAD inhibition methods, all iPSC lines gave rise to neural progenitors that could subsequently be differentiated into cortical neurons. Neural differentiation was analyzed qualitatively by immunocytochemistry and quantitatively by qPCR for progenitor, neuronal, cortical, and glial markers. Taken together, we present a multistep quality control workflow to evaluate variability and reproducibility across and between iPSCs.
Susceptibility of white-tailed deer (Odocoileus virginianus) to SARS-CoV-2
Authors: Palmer Mitchell V. , Martins Mathias , Falkenberg Shollie , Buckley Alexandra , Caserta Leonardo C. , Mitchell Patrick K. , Cassmann Eric D. , Rollins Alicia , Zylich Nancy C. , Renshaw Rendall W. , Guarino Cassandra , Wagner Bettina , Lager Kelly , Diel Diego G.
Published: January 2021

The origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing the global coronavirus disease 19 (COVID-19) pandemic, remains a mystery. Current evidence suggests a likely spillover into humans from an animal reservoir. Understanding the host range and identifying animal species that are susceptible to SARS-CoV-2 infection may help to elucidate the origin of the virus and the mechanisms underlying cross-species transmission to humans. Here we demonstrated that white-tailed deer (Odocoileus virginianus), an animal species in which the angiotensin converting enzyme 2 (ACE2) – the SARS-CoV-2 receptor – shares a high degree of similarity to humans, are highly susceptible to infection. Intranasal inoculation of deer fawns with SARS-CoV-2 resulted in established subclinical viral infection and shedding of infectious virus in nasal secretions. Notably, infected animals transmitted the virus to non-inoculated contact deer. Viral RNA was detected in multiple tissues 21 days post-inoculation (pi). All inoculated and indirect contact animals seroconverted and developed neutralizing antibodies as early as day 7 pi. The work provides important insights into the animal host range of SARS-CoV-2 and identifies white-tailed deer as a susceptible wild animal species to the virus.

IMPORTANCE

Given the presumed zoonotic origin of SARS-CoV-2, the human-animal-environment interface of COVID-19 pandemic is an area of great scientific and public- and animal-health interest. Identification of animal species that are susceptible to infection by SARS-CoV-2 may help to elucidate the potential origin of the virus, identify potential reservoirs or intermediate hosts, and define the mechanisms underlying cross-species transmission to humans. Additionally, it may also provide information and help to prevent potential reverse zoonosis that could lead to the establishment of a new wildlife hosts. Our data show that upon intranasal inoculation, white-tailed deer became subclinically infected and shed infectious SARS-CoV-2 in nasal secretions and feces. Importantly, indirect contact animals were infected and shed infectious virus, indicating efficient SARS-CoV-2 transmission from inoculated animals. These findings support the inclusion of wild cervid species in investigations conducted to assess potential reservoirs or sources of SARS-CoV-2 of infection.
Real-Time Electronic Health Record Mortality Prediction During the COVID-19 Pandemic: A Prospective Cohort Study
Authors: Sottile Peter D. , Albers David , DeWitt Peter E. , Russell Seth , Stroh J.N. , Kao David P. , Adrian Bonnie , Levine Matthew E. , Mooney Ryan , Larchick Lenny , Kutner Jean S. , Wynia Matthew K. , Glasheen Jeffrey J. , Bennett Tellen D.
Published: January 2021

Background

The SARS-CoV-2 virus has infected millions of people, overwhelming critical care resources in some regions. Many plans for rationing critical care resources during crises are based on the Sequential Organ Failure Assessment (SOFA) score. The COVID-19 pandemic created an emergent need to develop and validate a novel electronic health record (EHR)-computable tool to predict mortality.

Research Questions

To rapidly develop, validate, and implement a novel real-time mortality score for the COVID-19 pandemic that improves upon SOFA.

Study Design and Methods

We conducted a prospective cohort study of a regional health system with 12 hospitals in Colorado between March 2020 and July 2020. All patients >14 years old hospitalized during the study period without a do not resuscitate order were included. Patients were stratified by the diagnosis of COVID-19. From this cohort, we developed and validated a model using stacked generalization to predict mortality using data widely available in the EHR by combining five previously validated scores and additional novel variables reported to be associated with COVID-19-specific mortality. We compared the area under the receiver operator curve (AUROC) for the new model to the SOFA score and the Charlson Comorbidity Index.

Results

We prospectively analyzed 27,296 encounters, of which 1,358 (5.0%) were positive for SARS-CoV-2, 4,494 (16.5%) included intensive care unit (ICU)-level care, 1,480 (5.4%) included invasive mechanical ventilation, and 717 (2.6%) ended in death. The Charlson Comorbidity Index and SOFA scores predicted overall mortality with an AUROC of 0.72 and 0.90, respectively. Our novel score predicted overall mortality with AUROC 0.94. In the subset of patients with COVID-19, we predicted mortality with AUROC 0.90, whereas SOFA had AUROC of 0.85.

Interpretation

We developed and validated an accurate, in-hospital mortality prediction score in a live EHR for automatic and continuous calculation using a novel model, that improved upon SOFA.

Take Home Points

Study Question

Can we improve upon the SOFA score for real-time mortality prediction during the COVID-19 pandemic by leveraging electronic health record (EHR) data?

Results

We rapidly developed and implemented a novel yet SOFA-anchored mortality model across 12 hospitals and conducted a prospective cohort study of 27,296 adult hospitalizations, 1,358 (5.0%) of which were positive for SARS-CoV-2. The Charlson Comorbidity Index and SOFA scores predicted all-cause mortality with AUROCs of 0.72 and 0.90, respectively. Our novel score predicted mortality with AUROC 0.94.

Interpretation

A novel EHR-based mortality score can be rapidly implemented to better predict patient outcomes during an evolving pandemic.
Factor V is an immune inhibitor that is expressed at increased levels in leukocytes of patients with severe Covid-19
Authors: Wang Jun , Kotagiri Prasanti , Lyons Paul A , Mescia Federica , Bergamaschi Laura , Turner Lorinda , Al-Lamki Rafia S , Morgan Michael D , Calero-Nieto Fernando J , Bach Karsten , Mende Nicole , Wilson Nicola K , Watts Emily R ,   Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration, Chinnery Patrick F , Kingston Nathalie , Papadia Sofia , Stirrups Kathleen , Walker Neil , Gupta Ravindra K , Toshner Mark , Weekes Michael P , Nathan James A , Walmsley Sarah R , Ouwehand Willem H , Kasanicki Mary , Göttgens Berthold , Marioni John C , Smith Kenneth GC , Pober Jordan S , Bradley John R
Published: January 2021

Severe Covid-19 is associated with elevated plasma Factor V (FV) and increased risk of thromboembolism. We report that neutrophils, T regulatory cells (Tregs), and monocytes from patients with severe Covid-19 express FV, and expression correlates with T cell lymphopenia.In vitrofull length FV, but not FV activated by thrombin cleavage, suppresses T cell proliferation. Increased and prolonged FV expression by cells of the innate and adaptive immune systems may contribute to lymphopenia in severe Covid-19. Activation by thrombin destroys the immunosuppressive properties of FV. Anticoagulation in Covid-19 patients may have the unintended consequence of suppressing the adaptive immune system.
Direct Simulation of the CoVid-19 epidemic
Authors: Cabrera-Becerril Augusto , Miramontes Pedro , Peralta Raúl
Published: January 2021

Abstract

We introduce an agent-based model to simulate the epidemiological dynamics of COVID-19. Most computational models proposed to study this epidemic do no take into account human mobility. We present a direct simulation model where mobility plays a key role and propose as well four quarantine strategies. The results show that the no-quarantine strategy does lead to a high peak of contagions with no rebound. Quarantined strategies, for their part, show a re-emergence of the epidemic with smaller and softer peaks.
Near-atomic resolution Cryo-EM structure of Mayaro virus identifies key structural determinants of alphavirus particle formation
Authors: Chmielewski David , Kaelber Jason , Jin Jing , Weaver Scott C. , Auguste Albert J. , Chiu Wah
Published: January 2021

Mayaro virus (MAYV) is an arthritis-inducing alphavirus circulating in the Americas, with potential to rapidly emerge in new geographical regions and populated environments. Intraparticle heterogeneity has typically limited atomic resolution structures of alphavirus virions, while imposing icosahedral symmetry in data processing prevents characterization of non-icosahedral features. Here, we report a near-atomic resolution cryo-EM structure of the MAYV E1-E2-E3-CP subunit by addressing deviations from icosahedral symmetry within each virus particle. We identified amino acid contacts at E1 protein interfaces forming the icosahedral lattice and investigated their effect on MAYV growth through site-directed mutagenesis. Further, mutation of a short stretch of conserved residues in E2 subdomain D, near an unidentified “pocket factor” including E2Y358, significantly reduced MAYV growth and provides strong evidence that this unknown factor influences assembly. Further, a symmetry-free reconstruction revealed the MAYV virion is not strictly icosahedral, suggesting defects in global symmetry may be a feature of the virus particle budding process. Our study provides insights into alphavirus assembly and suggests a common path in the formation of spherical, enveloped viruses, leading to particle imperfections.
Epidemiological and evolutionary consequences of CRISPR-Cas reactivity
Authors: Chabas Hélène , Müller Viktor , Bonhoeffer Sebastian , Regoes Roland R.
Published: January 2021

Adaptive immune systems face a control challenge: they should react with enough strength to clear an infection while avoiding to harm their organism. CRISPR-Cas systems are adaptive immune systems of prokaryotes that defend against fast evolving viruses. Here, we explore the CRISPR-Cas control challenge and look how its reactivity, i.e. its probability to acquire a new resistance, impacts the epidemiological outcome of a phage outbreak and the prokaryote’s fitness. We show that in the absence of phage evolution, phage extinction is driven by the probability to acquire at least one resistance. However, when phage evolution is fast, phage extinction is characterised by an epidemiological critical threshold: any reactivity below this critical threshold leads to phage survival whereas any reactivity above it leads to phage extinction. We also show that in the absence of autoimmunity, high levels of reactivity evolve. However, when CRISPR-Cas systems are prone to autoimmune reactions, intermediate levels of reactivity are evolutionarily optimal. These results help explaining why natural CRISPR-Cas systems do not show high levels of reactivity.

Author summary

CRISPR-Cas systems are adaptive immune systems that use a complex 3-step molecular mechanism to defend prokaryotes against phages. Viral infections of populations defending with CRISPR-Cas can result in rapid phage extinction or in medium-term phage maintenance. What controls phage fate? Using mathematical modeling, we show that two parameters control this outcome: the phage escape rate and CRISPR-Cas reactivity (i.e. its probability of resistance acquisition upon infection). Furthermore, CRISPR-Cas reactivity impacts host fitness. From this, we derive that 1) CRISPR-Cas reactivity is a key predictor of the efficiency and of the cost of a CRISPR-Cas system, 2) there is an optimal reactivity balancing the cost of autoimmunity and immune efficiency and 3) high phage escape rate selects for higher CRISPR-Cas reactivities.
Iron acquisition across outer membrane: The role of major outer membrane protein Slr1908 under iron supplemented conditions inSynechocystis6803
Authors: Agarwal Rachna , Choudhury Sharmistha Dutta , Narayana Rao Akipeddi V S S
Published: January 2021

The Ton-B dependent outer membrane (OM) transporters are responsible for active iron (Fe) import inSynechocystissp. strain PCC 6803 (S. 6803 or WT) under Fe depletion. However, the mechanism of Fe acquisition under Fe supplemented conditions remains uncharacterised. In the present study, functional role of OMP Slr1908 inS. 6803 was addressed by insertional mutagenesis. TheΔslr1908cells exhibited slower growth in the first week in comparison to the WT and displayed an absorption and 77K fluorescence spectrum typical of Fe deficiency. Indeed, the mutant had ∼ 80% less Fe as confirmed by atomic absorption spectroscopy and55Fe-radiotracer uptake. The iron deficiency was paralleled with low Mn content. The mutant had low SOD content as well as activity, less cytochromes, less chlorophyll content, less Fv/ Fm, lower ETRII and high oxidative stress in comparison to the WT at the end of first week. Interestingly, the mutant showed transcriptional upregulation of iron stress induced proteinisiAandisiBsignifying intracellular Fe deficiency. Upregulation of OMP Slr0042 was also observed at RNA and protein level. The results indicate that Slr1908 is a major Fe uptake OMP inS. 6803 the deletion of which leads to initial slow growth that gets partially offset by induction of other Fe importing OMPs.
The impact of age and education on phonemic and semantic verbal fluency: Behavioral and fMRI correlates
Authors: Fonseca Rochele Paz , Marcotte Karine , Hubner Lilian C. , Zimmermann Nicolle , Netto Tânia Maria , Bizzo Bernardo , Döring Thomas , Landeira-Fernandez J. , Gasparetto Emerson L. , Joanette Yves , Ansaldo Ana Inés
Published: January 2021

The purpose of this study was to examine the impact of age and education on the neural and behavioral correlates of verbal fluency. Forty-eight healthy adult participants were included: high-educated young and elderly, low-educated young and elderly. Participants performed semantic and phonemic and a control task during fMRI scanning. The phonemic fluency data showed an education effect across age groups. As for the semantic fluency data, there was an education effect only in young participants. The second-level fMRI results showed, in phonemic fluency, a main effect of age in the left posterior cingulate, superior temporal gyrus (STG) and right caudate, whereas the main effect of education involved activation in the right semantic fluency, there were a main effect of age in the left paracentral lobule and posterior cingulate, a main effect of education in the left claustrum and an interaction in the right claustrum and STG and the hippocampus bilaterally.
ApoE4 attenuates cortical neuronal activity and impairs memory in young apoE4 rats
Authors: Har-Paz Ilona , Arieli Elor , Moran Anan
Published: January 2021

The E4 allele of apolipoprotein E (apoE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). However, apoE4 may cause innate brain abnormalities before the appearance of AD related neuropathology. Understanding these primary dysfunctions is vital for early detection of AD and the development of therapeutic strategies for it. Recently we have shown impaired extra-hippocampal memory in young apoE4 mice – a deficit that was correlated with attenuated structural pre-synaptic plasticity in cortical and subcortical regions. Here we test the hypothesis that these early structural deficits impact learningviachanges in basal and stimuli evoked neuronal activity. We recorded extracellular neuronal activity from the gustatory cortex (GC) of three-month-old humanized apoE4 and wildtype rats, before and after conditioned taste aversion (CTA) training. Despite normal sucrose drinking behavior before CTA, young apoE4 rats showed impaired CTA learning, consistent with our previous results in apoE4 mice. This behavioral deficit was correlated with decreased basal and taste-evoked firing rates in both putative excitatory and inhibitory GC neurons. Single neuron and ensemble analyses of taste coding demonstrated that apoE4 neurons could be used to correctly classify tastes, but were unable to undergo plasticity to support learning. Our results suggest that apoE4 impacts brain excitability and plasticity early in life and may act as an initiator for later AD pathologies.

Significant statement

The ApoE4 allele is the strongest genetic risk-factor for late-onset Alzheimer’s disease (AD), yet the link between apoE4 and AD is still unclear. Recent molecular and in-vitro studies suggest that apoE4 interferes with normal brain functions decades before the development of its related AD neuropathology. Here we recorded the activity of cortical neurons from young apoE4 rats during extra-hippocampal learning to study early apoE4 neuronal activity abnormalities, and their effects over coding capacities. We show that apoE4 drastically reduces basal and stimuli-evoked cortical activity in both excitatory and inhibitory neurons. The apoE4-induced activity attenuation did not prevent coding of stimuli identity and valence, but impaired capacity to undergo activity changes to support learning. Our findings support the hypothesis that apoE4 interfere with normal neuronal plasticity early in life; a deficit that may lead to late-onset AD development.
Clinically Relevant Gene Editing in Hematopoietic Stem Cells for the Treatment of Pyruvate Kinase Deficiency Hemolytic Anemia
Authors: Fañanas-Baquero Sara , Quintana-Bustamante Oscar , Dever Daniel P. , Alberquilla Omaira , Sanchez Rebeca , Camarena Joab , Ojeda-Perez Isabel , Dessy-Rodriguez Mercedes , Turk Rolf , Schubert Mollie S. , Lopez-Lorenzo Jose L. , Bianchi Paola , Bueren Juan A. , Behlke Mark A. , Porteus Matthew , Segovia Jose-Carlos
Published: January 2021

Pyruvate Kinase Deficiency (PKD) is an autosomal recessive disorder caused by mutations in the PKLR gene, which constitutes the main cause of chronic non-spherocytic hemolytic anemia. PKD incidence is estimated in 1 in 20,000 people worldwide. The PKLR gene encodes for the erythroid pyruvate kinase protein (RPK) implicated in the last step of the anaerobic glycolysis in red blood cells. The defective enzyme fails to maintain normal erythrocyte ATP levels, producing severe hemolytic anemia, and can be fatal in severe patients. The only curative treatment for PKD is allogeneic hematopoietic stem and progenitor cells (HSPC) transplantation, so far. However, HSPC transplant is associated with a significant morbidity and mortality, especially in PKD patients. Here, we address the correction of PKD through precise gene editing at the PKLR endogenous locus to keep the tight regulation of RPK enzyme during erythropoiesis. We combined CRISPR/Cas9 system and rAAVs for donor matrix delivery to build an efficient and safe system to knock-in a therapeutic donor at the translation start site of the RPK isoform in human hematopoietic progenitors. Edited human hematopoietic progenitors efficiently reconstituted human hematopoiesis in primary and secondary immunodeficient recipient mice. Moreover, erythroid cells derived from edited PKD-HSPCs restored normal levels of ATP, demonstrating the restoration of RPK function in PKD erythropoiesis after gene editing. Our gene editing strategy may represent a lifelong therapy to restore RPK functionality in RBCs of patients and correct PKD.

Single Sentence Summary

Clinically relevant gene editing in hematopoietic stem cells for the treatment of Pyruvate Kinase Deficiency.
Mice in a labyrinth: Rapid learning, sudden insight, and efficient exploration
Authors: Rosenberg Matthew , Zhang Tony , Perona Pietro , Meister Markus
Published: January 2021

Animals learn certain complex tasks remarkably fast, sometimes after a single experience. What behavioral algorithms support this efficiency? Many contemporary studies based on two-alternative-forced-choice (2AFC) tasks observe only slow or incomplete learning. As an alternative, we study the unconstrained behavior of mice in a complex labyrinth and measure the dynamics of learning and the behaviors that enable it. A mouse in the labyrinth makes ~2000 navigation decisions per hour. The animal quickly discovers the location of a reward in the maze and executes correct 10-bit choices after only 10 reward experiences – a learning rate 1000-fold higher than in 2AFC experiments. Many mice improve discontinuously from one minute to the next, suggesting moments of sudden insight about the structure of the labyrinth. The underlying search algorithm does not require a global memory of places visited and is largely explained by purely local turning rules.
Estimating and forecasting the burden and spread of SARS-CoV2 first wave in Colombia
Authors: Vega Jaime E. Cascante , Cordovez Juan M. , Santos-Vega Mauricio
Published: January 2021

Abstract

Following the rapid dissemination of COVID-19 cases in Colombia in 2020, large-scale non-pharmaceutical interventions (NPIs) were implemented as national emergencies in most of the municipalities of the country starting by a lockdown on March 20th of 2020. Using combinations of meta-population models SEAIIRD (Susceptible-Exposed-Asymptomatic-Infected-Recovered-Diseased) which describes the disease dynamics in the different localities, with movement data that accounts for the number of commuters between units and statistical inference algorithms could be an effective approach to both nowcast and forecast the number of cases and deaths in the country. Here we used an iterated filtering (IF) framework to fit the parameters of our model to the reported data across municipalities from march to late October in locations with more than 50 reported deaths and cases historically. Since the model is high dimensional (6 state variable by municipality) inference on those parameters is highly non-trivial, so we used an Ensemble-Adjustment-Kalman-Filter (EAKF) to estimate time variable system states and parameters. Our results show that the model is capable of capturing the evolution of the outbreak in the country and providing estimates of the epidemiological parameters in time. These estimates could become the base for planning future interventions as well as evaluate the impact of NPIs on the effective reproductive number (ℛeff) and the key epidemiological parameters, such as the contact rate or the reporting rate. Our approach demonstrates that real-time, publicly available ensemble forecasts can provide robust short-term predictions of reported COVID-19 deaths in Colombia. This model has the potential to be used as a forecasting and prediction tool to evaluate disease dynamics and to develop a real time surveillance system for management and control.
Patrolling human SLE haematopoietic progenitors demonstrate enhanced extramedullary colonisation; implications for peripheral tissue injury
Authors: Kokkinopoulos Ioannis , Banos Aggelos , Grigoriou Maria , Filia Anastasia , Manolakou Theodora , Alissafi Themis , Malissovas Nikolaos , Mitroulis Ioannis , Verginis Panayotis , Boumpas Dimitrios T.
Published: January 2021

Systemic Lupus erythematosus (SLE) is an autoimmune disease where bone-marrow-derived haematopoietic cells have a key role in its pathogenesis with accumulating evidence suggesting an aberrant function of haematopoietic stem/progenitor cells (HSPCs). By employing next-generation sequencing, we compared the gene transcription signatures of CD34+HSPCs deriving from either the bone marrow or HSPCs patrolling the bloodstream of healthy and individuals with SLE, seeking common transcriptional pathways that may have been modified between steady and disease states. Our findings indicate that circulating and bone marrow-derived HSPCs are distinct in steady and diseased states. Non-mobilised, SLE-derived circulating HSPCs demonstrated enhanced engrafting and altered differentiation capacities. Importantly, xenotransplantation of circulating HSPCs in humanised mice showed that human peripheral blood HSPCs possess the ability for extramedullary organ colonisation to the kidneys. SLE CD34+HSPCs homing and engraftment at extramedullary sites such as the spleen and kidneys may participate in peripheral tissue injury.
Spatiotemporal transcriptional dynamics of the cycling mouse oviduct
Authors: Roberson Elle C. , Battenhouse Anna M. , Garge Riddhiman K. , Tran Ngan Kim , Marcotte Edward M. , Wallingford John B.
Published: January 2021

Female fertility in mammals requires iterative remodeling of the entire adult female reproductive tract across the menstrual/estrous cycle. However, while transcriptome dynamics across the estrous cycle have been reported in human and bovine models, no global analysis of gene expression across the estrous cycle has yet been reported for the mouse. Here, we examined the cellular composition and global transcriptional dynamics of the mouse oviduct along the anteroposterior axis and across the estrous cycle. We observed robust patterns of differential gene expression along the anteroposterior axis, but we found surprisingly few changes in gene expression across the estrous cycle. Notable gene expression differences along the anteroposterior axis included a surprising enrichment for genes related to embryonic development, such as Hox and Wnt genes. The relatively stable transcriptional dynamics across the estrous cycle differ markedly from other mammals, leading us to speculate that this is an evolutionarily derived state that may reflect the extremely rapid five-day mouse estrous cycle. This dataset fills a critical gap by providing an important genomic resource for a highly tractable genetic model of mammalian female reproduction.
Asymmetry in updating long-term memory for time
Authors: Derouet Joffrey , Droit-Volet Sylvie , Doyère Valérie
Published: January 2021

The present study evaluates the updating of long-term memory for duration. After learning a temporal discrimination associating one lever with a standard duration (4 sec) and another lever with both a shorter (1-sec) and a longer (16-sec) duration, rats underwent a single session for learning a new standard duration. The temporal generalization gradient obtained 24 h later showed a modification in long-term memory for durations longer than the standard but only when the new duration was longer than the one initially learned. The effect was confirmed for another set of durations (0.5–2–8 sec). Our study demonstrates asymmetry in updating long-term memory for time.
Risk management in the public sector: a structured literature review
Authors: Bracci Enrico , Tallaki Mouhcine , Gobbo Giorgia , Papi Luca
Published: January 2021

Purpose

Risk management (RM) is receiving increasing academic and practitioner attention in the public sector. Despite this, there is a lack of systematization of this body of knowledge. The purpose of this paper is to analyze the state of art by examining the knowledge gaps and defining the emerging themes of RM in the public sector to guide future research agendas.

Design/methodology/approach

The authors conducted a structured literature review (SLR). They analyzed 63 papers, by using Scopus database, published from 1990 to 2018. All papers were categorized and analyzed according to 11 criteria defined by the literature.

Findings

Results show that there is an increasing attention to RM with a need for more effort to consolidate research knowledge. Findings also established a lack of theorization, with a limited explanatory capacity of most studies. The paper defined four main areas for future developments to increase the body of knowledge. Namely, RM and managerial systems (i.e. MCSs and performance management), integrating RM systems and the building blocks of RM that the authors identify will also play a role in helping the authors to understand the diffusion of RM within public sector organizations.

Originality/value

Despite the increasing attention to RM in the public sector, more research is required. Considering RM in public sector risks to be a “black box”, this paper revealed some new insights that could help to analyze better RM in the public sector, to open the black box and to avoid a symbolic use of the RM. In fact, integration with the managerial systems and the strengthening of the building block could help to exploit the potential of RM in the public sector.
Re-territorialising the policing of cybercrime in the post-COVID-19 era: towards a new vision of local democratic cyber policing
Authors: Horgan Shane , Collier Ben , Jones Richard , Shepherd Lynsay
Published: January 2021

Purpose

The purpose of this study is to develop the theorisation of cybercrime in the context of the pandemic, and to sketch out a vision of how law enforcement might respond to a transformed landscape of online crime and offending.

Design/methodology/approach

This conceptual paper draws on empirical evidence from a range of sources (including official statistics) and the existing research literature, and revisits routine activities theory to illuminate the way that cybercrime patterns are being transformed by the pandemic.

Findings

The pandemic is reshaping the routine activities of societies en masse, leading to changes in the ecology of risk and opportunity for cybercrime. There is evidence of a large increase in the prevalence of cybercrime as a result, yet much of this has a paradoxically “local” character.

Practical implications

The authors identify specific practical implications for law enforcement, namely, that the role of local police in policing cybercrime should be re-envisioned, with a democratic, community-oriented approach at its heart.

Originality/value

The theoretical perspective outlined is a novel and critical development of a well-established framework, opening up new paths to the theorisation of cybercrime and cybercrime policing. The authors’ suggestions for practitioners have the potential for direct impact, both at the level of practice and in terms of broader imaginaries and organisation of police and policing.
A paradigm shift in financial landscape: encouraging collaboration and innovation among Indonesian FinTech lending players
Authors: Utami Ami Fitri , Ekaputra Irwan Adi
Published: January 2021

Purpose

This paper aims to examine about the nature and strategy of current competitive dynamics by FinTech lending Indonesia players.

Design/methodology/approach

This paper uses both primary and secondary data. Interviews of several executives of a FinTech lending firm are done to gain direct insight of how the firms strategize their business operation. On the other hand, secondary data from internet search (e.g., OJK’s Website, FinTech Lending firm’s websites) are used to grasp the overview of the industrial landscape.

Findings

The study confirms that differentiation, collaboration, compliance and strong internal resources (e.g. team and funding) are the most pivotal elements for FinTech lending success. The study also confirmed the FinTech lending industrial landscape as an emerging and fragmented industry.

Research limitations/implications

This paper offers an original and detailed solution about how the FinTech lending company strategies may survive in a dynamic competition. The paper also shows the industrial analysis of the FinTech lending industry, which is rarely discussed in previous research. However, this study only focused on the lending sub-sector of FinTech, and the sample for primary data is highly limited (only three interviews).

Practical implications

This paper proposes a strategy that can be conducted by FinTech lending companies to achieve their business goals, including business growth, profits and improve financial inclusion in Indonesia. This perspective can act as a means to create practical modus operandi for policymakers and practitioners, especially FinTech lending companies in Indonesia.

Originality/value

This paper offers an original and detailed solution about how the FinTech lending company strategies may survive in adynamic competition. This study also provides a theoretical framework for use in further empirical research into the process of resource mobilization from FinTech lending Indonesia companies.
A cross-national diagnosis of infodemics: comparing the topical and temporal features of misinformation around COVID-19 in China, India, the US, Germany and France
Authors: Zeng Jing , Chan Chung-hong
Published: January 2021

Purpose

This study empirically investigates how the COVID-infodemic manifests differently in different languages and in different countries. This paper focuses on the topical and temporal features of misinformation related to COVID-19 in five countries.

Design/methodology/approach

COVID-related misinformation was retrieved from 4,487 fact-checked articles. A novel approach to conducting cross-lingual topic extraction was applied. The rectr algorithm, empowered by aligned word-embedding, was utilised. To examine how the COVID-infodemic interplays with the pandemic, a time series analysis was used to construct and compare their temporal development.

Findings

The cross-lingual topic model findings reveal the topical characteristics of each country. On an aggregated level, health misinformation represents only a small portion of the COVID-infodemic. The time series results indicate that, for most countries, the infodemic curve fluctuates with the epidemic curve. In this study, this form of infodemic is referred to as “point-source infodemic”. The second type of infodemic is continuous infodemic, which is seen in India and the United States (US). In those two countries, the infodemic is predominantly caused by political misinformation; its temporal distribution appears to be largely unrelated to the epidemic development.

Originality/value

Despite the growing attention given to misinformation research, existing scholarship is dominated by single-country or mono-lingual research. This study takes a cross-national and cross-lingual comparative approach to investigate the problem of online misinformation. This paper demonstrates how the technological barrier of cross-lingual topic analysis can be overcome with aligned word-embedding algorithms.

Peer review:

The peer review history for this article is available at: https://publons.com/publon/10.1108/OIR-09-2020-0417
Elevation and aspect determine the differences in soil properties and plant species diversity on Himalayan mountain summits
Authors: Hamid Maroof , Khuroo Anzar Ahmad , Malik Akhtar Hussain , Ahmad Rameez , Singh Chandra Prakash
Published: January 2021

Although vegetation has been the focus of recent studies on mountain summits, little is known about smaller‐scale spatial patterns of soil physico‐chemical properties. Here, we report patterns and drivers of soil physico‐chemical properties and their role in shaping the plant diversity on mountain summits of the Himalaya. Using the globally standardized Multi‐Summit Approach, four summits along an elevation gradient from treeline to nival zone were selected in Kashmir Himalaya. Sampling of the summits was carried out to collect soil samples together with vegetation data and soil temperature. The results revealed that there is a significant effect of elevation and aspect on soil physico‐chemical properties and species richness on the summits. A significant correlation was observed between soil parameters and elevation, indicating that summits with distinct pool of species possess distinct soil properties. Moreover, soil temperature clearly determined the aspect‐wise distribution of soil parameters and species richness. The Canonical Correspondence Analysis revealed that elevation, soil temperature, pH, electrical conductivity and C:N ratio were more prominent in determining the plant diversity on summits. Our results demonstrate that mosaic of micro‐climatic conditions driven by elevation and aspect favor a suite of soil properties, which in turn determine the patterns of species diversity on the mountain summits. The present study, therefore, enhances understanding of the spatial patterns of variation in soil and plant diversity of mountain summits, which will help to monitor, model and predict how these ecologically unique ecosystems will respond to climate warming in the Himalaya, with implications for such environments elsewhere.
Putting the Australian Economy on the Scales
Authors: Leigh Andrew
Published: January 2021

Based on the increasing size of the service sector, some believe that growth in advanced countries has come without much change in the physical weight of output. To investigate the question, I generate rough estimates of the physical weight of Australian output from 1831 to 2018, using data on the weight of traded goods. These ballpark estimates imply that the weight of annual output increased from around 50,000 tonnes to around 800 million tonnes. Over the long term, a 10 per cent increase in real GDP was associated with a 12 per cent increase in the physical weight of output.