bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurally Adjusted Ventilator Assist in Infants With Acute Respiratory Failure: A Literature Scoping Review
Authors: Harris Julia , Tibby Shane M , Endacott Ruth , Latour Jos M.
Published: April 2021

OBJECTIVES:

To map the evidence for neurally adjusted ventilatory assist strategies, outcome measures, and sedation practices in infants less than 12 months with acute respiratory failure using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidance.

DATA SOURCES:

CINAHL, MEDLINE, COCHRANE, JBI, EMBASE, PsycINFO, Google scholar, BNI, AMED. Trial registers included the following: ClinicalTrials.gov, European Union clinical trials register, International Standardized Randomized Controlled Trial Number register. Also included were Ethos, Grey literature, Google, dissertation abstracts, EMBASE conference proceedings.

STUDY SELECTION:

Abstracts were screened followed by review of full text. Articles incorporating a heterogeneous population of both infants and older children were assessed, and where possible, data for infants were extracted. Fifteen articles were included. Ten articles were primary research: randomized controlled trial (n = 3), cohort studies (n = 4), retrospective data analysis (n = 2), case series (n = 1). Other articles are expert opinion (n = 2), neurally adjusted ventilatory assist updates (n = 1), and a literature review (n = 2). Three studies included exclusively infants. We also included 12 studies reporting jointly on infants and children.

DATA EXTRACTION:

A standardized data extraction tool was used.

DATA SYNTHESIS:

Key findings were that evidence related to neurally adjusted ventilatory assist ventilation strategies in infants and related to specific primary conditions is limited. The setting of neurally adjusted ventilatory assist level is not consistent, and how to optimize this mode of ventilation was not documented. Outcome measures varied considerably, most studies focused on improvements in respiratory and physiological variables. Sedation use is variable with regard to medication type and dose. There is an indication that less sedation is required in patients receiving neurally adjusted ventilatory assist, but no conclusive evidence to support this.

CONCLUSIONS:

This review highlights a lack of standardized strategies for neurally adjusted ventilatory assist ventilation and sedation practices among infants with acute respiratory failure. Studies were limited by small sample sizes and a lack of focus on specific patient groups. Robust studies are needed to provide evidence-based clinical recommendations for the use of neurally adjusted ventilatory assist in infants with acute respiratory failure.
Functional Impairments and Rehabilitation Outcomes of Patients With Immunotherapy-Induced Acute Inflammatory Demyelinating Polyradiculoneuropathy, Myasthenia Gravis, and Myositis
Authors: Ng Amy H. , Molinares Diana M. , Guo Ying , Fu Jack , Bruera Eduardo
Published: April 2021

Immunotherapy has led to a higher survival rate among different oncological disease groups but also associated with adverse-related events in multiple organ systems. Immunotherapy-related musculoskeletal weakness often results in a loss of cancer survivors’ physical function, ultimately impacting their independence and quality of life. This is a retrospective study of 24 cancer patients who were treated with immunotherapy either alone or in conjunction with other oncological treatments. Twelve subjects (50%) were found to have acute inflammatory demyelinating polyradiculopathy/Guillain-Barré syndrome, six (25%) myositis, two (8%) myasthenia gravis, two (8%) diagnosis of myositis/myasthenia gravis, and one (4%) Guillain-Barré syndrome/myasthenia gravis combination. Physical therapy was provided in 91.7% of the cases, and physiatrist was involved in 54% of the cases. Almost half (45%) were discharged home, six (25%) to acute inpatient rehabilitation, two (8%) to subacute rehabilitation, three (12.5%) to hospice, and two (8%) died. The average length of hospital stay was 30 days, and eight patients (33%) readmitted within 3 mos. Our findings highlight the severity of functional impairments and the need for early rehabilitation interventions.
Readmission following surgical stabilization of rib fractures: Analysis of incidence, cost, and risk factors using the Nationwide Readmissions Database
Authors: Aalberg Jeffrey J. , Johnson Benjamin P. , Hojman Horacio M. , Rattan Rishi , Arabian Sandra , Mahoney Eric J. , Bugaev Nikolay
Published: April 2021

BACKGROUND

Surgical stabilization of rib fractures (SSRF) has become increasingly common for the treatment of traumatic rib fractures; however, little is known about related postoperative readmissions. The aims of this study were to determine the rate and cost of readmissions and to identify patient, hospital, and injury characteristics that are associated with risk of readmission in patients who underwent SSRF. The null hypotheses were that readmissions following rib fixation were rare and unrelated to the SSRF complications.

METHODS

This is a retrospective analysis of the 2015 to 2017 Nationwide Readmission Database. Adult patients with rib fractures treated by SSRF were included. Univariate and multivariate analyses were used to compare patients readmitted within 30 days with those who were not, based on demographics, comorbidities, and hospital characteristics. Financial information examined included average visit costs and national extrapolations.

RESULTS

A total of 2,522 patients who underwent SSRF were included, of whom 276 (10.9%) were readmitted within 30 days. In 36.2% of patients, the reasons for readmissions were related to complications of rib fractures or SSRF. The rest of the patients (63.8%) were readmitted because of mostly nontrauma reasons (32.2%) and new traumatic injuries (21.1%) among other reasons. Multivariate analysis demonstrated that ventilator use, discharge other than home, hospital size, and medical comorbidities were significantly associated with risk of readmission. Nationally, an estimated 2,498 patients undergo SSRF each year, with costs of US $176 million for initial admissions and US $5.9 million for readmissions.

CONCLUSION

Readmissions after SSRF are rare and mostly attributed to the reasons not directly related to sequelae of rib fractures or SSRF complications. Interventions aimed at optimizing patients’ preexisting medical conditions before discharge should be further investigated as a potential way to decrease rates of readmission after SSRF.

LEVEL OF EVIDENCE

Epidemiological study, level III.
Can social vulnerability indices predict county trauma fatality rates?
Authors: Phelos Heather M. , Deeb Andrew-Paul , Brown Joshua B.
Published: April 2021

BACKGROUND

Social vulnerability indices were created to measure resiliency to environmental disasters based on socioeconomic and population characteristics of discrete geographic regions. They are composed of multiple validated constructs that can also potentially identify geographically vulnerable populations after injury. Our objective was to determine if these indices correlate with injury fatality rates in the US.

METHODS

We evaluated three social vulnerability indices: The Hazards & Vulnerability Research Institute’s Social Vulnerability Index (SoVI), the Center for Disease Control’s Social Vulnerability Index (SVI), and the Economic Innovation Group’s Distressed Community Index (DCI). We analyzed SVI subindices and common individual census variables as indicators of socioeconomic status. Outcomes included age-adjusted county-level overall, firearm, and motor vehicle collision deaths per 100,000 population. Linear regression determined the association of injury fatality rates with the SoVI, SVI, and DCI. Bivariate choropleth mapping identified geographic variation and spatial autocorrelation of overall fatality, SoVI, and DCI.

RESULTS

A total of 3,137 US counties were included. Only 24.6% of counties fell into the same vulnerability quintile for all three indices. Despite this, all indices were associated with increasing fatality rates for overall, firearm, and motor vehicle collision fatality. The DCI performed best by model fit, explanation of variance, and diagnostic performance on overall injury fatality. There is significant geographic variation in SoVI, DCI, and injury fatality rates at the county level across the United States, with moderate spatial autocorrelation of SoVI (Moran’s I, 0.35; p < 0.01) and high autocorrelation of injury fatality rates (Moran’s I, 0.77; p < 0.01) and DCI (Moran’s I, 0.53; p < 0.01).

CONCLUSION

While the indices contribute unique information, higher social vulnerability is associated with higher injury fatality across all indices. These indices may be useful in the epidemiologic and geographic assessment of injury-related fatality rates. Further study is warranted to determine if these indices outperform traditional measures of socioeconomic status and related constructs used in trauma research.

LEVEL OF EVIDENCE

Epidemiological, level IV.
Physician-staffed ambulance and increased in-hospital mortality of hypotensive trauma patients following prolonged prehospital stay: A nationwide study
Authors: Yamamoto Ryo , Suzuki Masaru , Yoshizawa Jo , Nishida Yusho , Junichi Sasaki
Published: April 2021

BACKGROUND

The benefits of physician-staffed emergency medical services (EMS) for trauma patients remain unclear because of the conflicting results on survival. Some studies suggested potential delays in definitive hemostasis due to prolonged prehospital stay when physicians are dispatched to the scene. We examined hypotensive trauma patients who were transported by ambulance, with the hypothesis that physician-staffed ambulances would be associated with increased in-hospital mortality, compared with EMS personnel-staffed ambulances.

METHODS

A retrospective cohort study that included hypotensive trauma patients (systolic blood pressure ≤ 90 mm Hg at the scene) transported by ambulance was conducted using the Japan Trauma Data Bank (2004–2019). Physician-staffed ambulances are capable of resuscitative procedures, such as thoracotomy and surgical airway management, while EMS personnel-staffed ambulances could only provide advanced life support. In-hospital mortality and prehospital time until the hospital arrival were compared between patients who were classified based on the type of ambulance. Inverse probability weighting was conducted to adjust baseline characteristics including age, sex, comorbidities, mechanism of injury, vital signs at the scene, injury severity, and ambulance dispatch time.

RESULTS

Among 14,652 patients eligible for the study, 738 were transported by a physician-staffed ambulance. In-hospital mortality was higher in the physician-staffed ambulance than in the EMS personnel-staffed ambulance (201/699 [28.8%] vs. 2287/13,090 [17.5%]; odds ratio, 1.90 [1.61–2.26]; adjusted odds ratio, 1.22 [1.14–1.30]; p < 0.01), and the physician-staffed ambulance showed longer prehospital time (50 [36–66] vs. 37 [29–48] min, difference = 12 [11–12] min, p < 0.01). Such potential harm of the physician-staffed ambulance was only observed among patients who arrived at the hospital with persistent hypotension (systolic blood pressure < 90 mm Hg on hospital arrival) in subgroup analyses.

CONCLUSION

Physician-staffed ambulances were associated with prolonged prehospital stay and increased in-hospital mortality among hypotensive trauma patients compared with EMS personnel-staffed ambulance.

LEVEL OF EVIDENCE

Therapeutic, level IV.
Evaluating the impact of keeping indoor dining closed on COVID-19 rates among large US cities: a quasi-experimental design
Authors: Schnake-Mahl Alina S. , O’Leary Gabriella , Mullachery Pricila H. , Vaidya Vaishnavi , Connor Gabrielle , Rollins Heather , Kolker Jennifer , Diez Roux Ana V. , Bilal Usama
Published: April 2021

Objective

Indoor dining is one of the potential key drivers of COVID-19 transmission. We leverage the heterogeneity in state government preemption of city indoor dining closures, to estimate the impact of keeping indoor dining closed on COVID-19 incidence.

Methods

We obtained case rates and city/state re-opening dates from March to October 2020 in 11 U.S. cities. We categorized cities as (treatment) cities that were allowed by the state to reopen but kept indoor dining closed; and (comparison) cities that would have kept indoor dining closed but were preempted by their state and had to reopen indoor dining.

Results

Keeping indoor dining closed was associated with a 43% (IRR=0.57, 95% CI 0.46 to 0.69) decline in COVID-19 incidence over 4-weeks compared with cities that reopened indoor dining. These results were consistent after testing alternative modeling strategies.

Conclusions

Keeping indoor dining closed contributes to reductions in COVID-19 spread.

Policy Implications

Evidence of the relationship between indoor dining and COVID-19 incidence can inform state and local decisions to restrict indoor dining as a tailored strategy to reduce COVID-19 incidence.
Establishment of local adaptation in partly self-fertilizing populations
Authors: Trickovic Bogi , Glémin Sylvain
Published: April 2021

Populations often inhabit multiple ecological patches and thus experience divergent selection, which can lead to local adaptation if migration is not strong enough to swamp locally adapted alleles. Conditions for the establishment of a locally advantageous allele have been studied in randomly mating populations. However, many species reproduce, at least partially, through self-fertilization, and how selfing affects local adaptation remains unclear and debated. Using a two-patch branching process formalism, we obtained a closed-form approximation under weak selection for the probability of establishment of a locally advantageous allele (P) for arbitrary selfing rate and dominance level, where selection is allowed to act on viability or fecundity, and migration can occur via seed or pollen dispersal. This solution is compared to diffusion approximation and used to investigate the consequences of a shift in a mating system onP, and the establishment of protected polymorphism. We find that selfing can either increase or decreaseP, depending on the patterns of dominance in the two patches, and has conflicting effects on local adaptation. Globally, selfing favors local adaptation when locally advantageous alleles are (partially) recessive, when selection between patches is asymmetrical and when migration occurs through pollen rather than seed dispersal. These results establish a rigorous theoretical background to study heterogeneous selection and local adaptation in partially selfing species.
Seroprevalence of anti-SARS-CoV-2 antibodies among school and daycare children and personnel: Protocol for a cohort study in Montreal, Canada
Authors: Zinszer K , McKinnon B , Bourque N , Zahreddine M , Charland K , Papenburg J , Fortin G , Hamelin ME , Saucier A , Apostolatos A , Pierce L , Savard-Lamothe A , Carbonneau Julie , Conrod P , Haley N , Laurin I , Boivin G , De Serres G , Quach C
Published: April 2021

Background

Further evidence is needed to understand the contribution of schools and daycares to the spread of COVID-19 in the context of diverse transmission dynamics and continually evolving public health interventions. The Enfants et COVID-19: Étude de séroprévalence (EnCORE) study will estimate the seroprevalence and seroconversion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among school and daycare children and personnel. In addition, the study will examine associations between seroprevalence and socio-demographic characteristics and reported COVID-19 symptoms and tests, and investigates changes in health, lifestyle and well-being outcomes.

Methods

This study includes children and personnel from 62 schools and daycares in four neighbourhoods in Montreal, Canada. All children age 2-17 years attending one of the participating schools or daycares and their parents are invited to participate, as well as a sample of personnel members. Participants respond to brief questionnaires and provide blood samples, collected via dried blood spot (DBS), at baseline (October 2020-March 2021) and follow-up (May-June 2021). Questionnaires include socio-demographic and household characteristics, reported COVID-19 symptoms and tests, potential COVID-19 risk factors and prevention efforts, and health and lifestyle information. Logistic regression using generalized estimating equations will be used to estimate seroprevalence and seroconversion, accounting for school-level clustering.

Discussion

The results of the EnCORE study will contribute to our knowledge about SARS-CoV-2 transmission in schools and daycares, which is critical for decisions regarding school attendance and the management of school outbreaks through the remainder of this school year and beyond.
Stimulation-mediated reverse engineering of silent neural networks
Authors: Ren Xiaoxuan , Hai Aviad
Published: April 2021

Reconstructing connectivity of neuronal networks from single cell activity is essential to understanding brain function, but the challenge of deciphering connections from populations of silent neurons has been largely unmet. We demonstrate a protocol for deriving connectivity of realistic silent neuronal networks using stimulation combined with a supervised learning algorithm, that enables inferring connection weights with high fidelity and predicting spike trains at the single-spike and single-cell level with high accuracy. These testable predictions about the number and protocol of the required stimulations is expected to enhance future efforts for deriving neuronal connectivity and drive new experiments to better understand brain function.
Distinct nociresponsive region in mouse primary somatosensory cortex
Authors: Osaki Hironobu , Kanaya Moeko , Ueta Yoshifumi , Miyata Mariko
Published: April 2021

Nociception, somatic discriminative aspects of pain, is represented in the primary somatosensory cortex (S1), as is touch, but the separation and the interaction of the two modalities within S1 remain unclear. Here, we show the spatially-distinct tactile and nociceptive processing in the granular barrel field (BF) and the adjacent dysgranular region (Dys) in mouse S1. Simultaneous recording of the multiunit activity across subregions reveals that Dys responses are selective to noxious input whereas those of BF are to tactile input. At the single neuron level, nociceptive information is represented separately from the tactile information in Dys layer 2/3. In contrast, both modalities are converged in a layer 5 neuron in each region. Interestingly, the two modalities interfere with each other in both regions. We further demonstrate that Dys, but not BF, activity is critically involved in neuropathic pain and pain behavior, and thus provide evidence that Dys is a center specialized for nociception in S1.
Environmental selection and epistasis in an empirical phenotype-environment-fitness landscape
Authors: Chen J.Z. , Fowler D.M. , Tokuriki N.
Published: April 2021

Fitness landscapes, mappings of genotype/phenotype to their effects on fitness, are invaluable concepts in evolutionary biochemistry. Though widely discussed, measurements of phenotype-fitness landscapes in proteins remain scarce. Here, we quantify all single mutational effects on fitness and phenotype of VIM-2 β-lactamase across a 64-fold range of ampicillin concentrations. We then construct a phenotype-fitness landscape that takes variations in environmental selection pressure into account. We found that a simple, empirical landscape accurately models the ~39,000 mutational data points, suggesting the evolution of VIM-2 can be predicted based on the selection environment. Our landscape provides new quantitative knowledge on the evolution of the β-lactamases and proteins in general, particularly their evolutionary dynamics under sub-inhibitory antibiotic concentrations, as well as the mechanisms and environmental dependence of nonspecific epistasis.

One Sentence Summary

An empirical fitness landscape discloses the environmental dependence of mutational effects in VIM-2 β-lactamase.
Aging alters the metabolic flux signature of the ER unfolded protein responsein vivoin mice
Authors: Schneider Catherine P. , Peng Lucy , Yuen Samuel , Halstead John , Palacios Hector , Nyangau Edna , Mohammed Hussein , Ziari Naveed , Frakes Ashley E. , Dillin Andrew , Hellerstein Marc K.
Published: April 2021

Age is a risk factor for numerous diseases, including neurodegenerative diseases, cancers, and diabetes. Loss of protein homeostasis is a central hallmark of aging. Activation of the endoplasmic reticulum unfolded protein response (UPRER) includes changes in protein translation and membrane lipid synthesis. Using stable isotope labeling, a “signature” of the UPRERin vivoin mouse liver was developed by inducing ER stress and measuring rates of both proteome-wide translation andde novolipogenesis. Several changes in protein synthesis across ontologies were noted with age, including a more dramatic suppression of translation under ER stress in aged mice as compared to young mice. Binding immunoglobulin protein (BiP) synthesis rates and mRNA levels were increased more in aged than young mice.De novolipogenesis rates decreased under ER stress conditions in aged mice, including both triglyceride and phospholipid fractions. In young mice, only a significant reduction was seen in the triglyceride fraction. These data indicate that aged mice have an exaggerated response to ER stress, which may indicate that the aging renders the UPRERless effective in resolving proteotoxic stress.
Learning interpretable cellular responses to complex perturbations in high-throughput screens
Authors: Lotfollahi Mohammad , Susmelj Anna Klimovskaia , De Donno Carlo , Ji Yuge , Ibarra Ignacio L. , Wolf F. Alexander , Yakubova Nafissa , Theis Fabian J. , Lopez-Paz David
Published: April 2021

Recent advances in multiplexed single-cell transcriptomics experiments are facilitating the high-throughput study of drug and genetic perturbations. However, an exhaustive exploration of the combinatorial perturbation space is experimentally unfeasible, so computational methods are needed to predict, interpret, and prioritize perturbations. Here, we present the compositional perturbation autoencoder (CPA), which combines the interpretability of linear models with the flexibility of deep-learning approaches for single-cell response modeling. CPA encodes and learns transcriptional drug responses across different cell type, dose, and drug combinations. The model produces easy-to-interpret embeddings for drugs and cell types, which enables drug similarity analysis and predictions for unseen dosage and drug combinations. We show that CPA accurately models single-cell perturbations across compounds, doses, species, and time. We further demonstrate that CPA predicts combinatorial genetic interactions of several types, implying that it captures features that distinguish different interaction programs. Finally, we demonstrate that CPA can generatein-silico5,329 missing genetic combination perturbations (97.6% of all possibilities) with diverse genetic interactions. We envision our model will facilitate efficient experimental design and hypothesis generation by enablingin-silicoresponse prediction at the single-cell level, and thus accelerate therapeutic applications using single-cell technologies.
A curated collection of human vaccination response signatures
Authors: Smith Kenneth C. , Chawla Daniel G. , Dhillon Bhavjinder K. , Ji Zhou , Vita Randi , van der Leest Eva C. , Weng Jing Yi (Jessica) , Tang Ernest , Abid Amani ,   The Human Immunology Project Consortium (HIPC), Peters Bjoern , Hancock Robert E.W. , Floratos Aris , Kleinstein Steven H.
Published: April 2021

Recent advances in high-throughput experiments and systems biology approaches have resulted in hundreds of publications identifying “immune signatures”. Unfortunately, these are often described within text, figures, or tables in a format not amenable to computational processing, thus severely hampering our ability to fully exploit this information. Here we present a data model to represent immune signatures, along with the Human Immunology Project Consortium (HIPC) Dashboard (www.hipc-dashboard.org), a web-enabled application to facilitate signature access and querying. The data model captures the biological response components (e.g., genes, proteins, cell types or metabolites) and metadata describing the context under which the signature was identified using standardized terms from established resources (e.g., HGNC, Protein Ontology, Cell Ontology). We have manually curated a collection of >600 immune signatures from >60 published studies profiling human vaccination responses for the current release. The system will aid in building a broader understanding of the human immune response to stimuli by enabling researchers to easily access and interrogate published immune signatures.
Profiling the transcallosal response of rat motor cortex evoked by contralateral optogenetic stimulation of glutamatergic cortical neurons
Authors: Skoven Christian Stald , Tomasevic Leo , Kvitsiani Duda , Pakkenberg Bente , Dyrby Tim Bjørn , Siebner Hartwig Roman
Published: April 2021

Background

Efficient interhemispheric integration of neural activity between left and right primary motor cortex (M1) is critical for inter-limb motor control.

Objective

We employed optogenetic stimulation to establish a framework for probing transcallosal M1-M1 interactions in rats.

Methods

In male rats, we optogenetically stimulated glutamatergic neurons in right M1 and recorded the transcallosally evoked potential with chronically implanted electrodes in contralateral left M1 during dexmedetomidine anesthesia. We systematically varied the stimulation intensity and duration to characterize the relationship between stimulation parameters in right M1 and the characteristics of the evoked intracortical potentials in left M1.

Results

Optogenetic stimulation of right M1 consistently evoked a transcallosal response in left M1 with a consistent negative peak (N1) that sometimes was preceded by a smaller positive peak (P1). Higher stimulation intensity or longer stimulation duration gradually increased N1 amplitude and reduced N1 variability across trials. Median N1 latencies remained stable, once stimulation elicited a reliable N1 peak and did not display a systematic shortening with increasing stimulation intensity or duration.

Conclusions

Optogenetically stimulated glutamatergic neurons in M1 can reliably evoke a transcallosal response in anesthetized rats and can be used to characterize the relationship between “stimulation dose” and “response magnitude” (i.e., the gain function) of transcallosal M1-to-M1 glutamatergic connections. Detailed knowledge of the stimulus-response relationship is needed to optimize the efficacy of optogenetic stimulation. Since transcallosal M1-M1 interactions can also be probed non-invasively with transcranial magnetic stimulation in humans, our optogenetic stimulation approach bears translational potential for studying how unilateral M1 stimulation can induce interhemispheric plasticity.
Passive receptor dissociation driven by porin threading establishes active colicin transport throughEscherichia coliOmpF
Authors: Francis Marie-Louise R. , Webby Melissa N. , Housden Nicholas G. , Kaminska Renata , Elliston Emma , Chinthammit Boonyaporn , Lukoyanova Natalya , Kleanthous Colin
Published: April 2021

Bacteria deploy weapons to kill their neighbours during competition for resources and aid survival within microbiomes. Colicins were the first antibacterial system identified yet how these bacteriocins cross the outer membrane of Escherichia coli is unknown. Here, by solving the structures of translocation intermediates and imaging toxin import, we uncover the mechanism by which the Tol-dependent nuclease colicin E9 (ColE9) crosses the outer membrane. We show that threading of ColE9’s disordered domain through two pores of the trimeric porin OmpF causes the colicin to disengage from its primary receptor, BtuB, and reorganise the translocon either side of the membrane. These rearrangements prime the toxin for import through the lumen of a single OmpF subunit, which is driven by the proton motive force-linked TolQ-TolR-TolA-TolB assembly. Our study explains why OmpF is a better translocator than OmpC and reconciles the mechanisms by which Ton- and Tol- dependent bacteriocins cross the bacterial outer membrane.
Hippocampal theta sequences in REM sleep during spatial learning
Authors: Zielinski Mark C. , Shin Justin D. , Jadhav Shantanu P.
Published: April 2021

Rapid eye movement (REM) sleep is known to play a role in hippocampally-dependent memory, yet the activity and development of hippocampal neuronal ensembles during this state is not well understood. Here we investigated patterning of CA1 place cell activity by theta oscillations, a shared electrophysiological hallmark of both waking behavior and REM sleep, in male rats learning a spatial memory task. We report the existence of REM theta sequences, sequential reactivations of place cells in REM theta that parallel waking theta sequences. REM and wake theta sequences develop rapidly with experience, recapitulating behavioral sequences of compressed space in forward and reverse directions throughout learning. REM sleep exhibited a balance of forward and reverse sequences in contrast to predominantly forward wake theta sequences. Finally, we found that a CA1 neuronal population known to shift preferred theta phases in REM exhibited differential participation in wake and REM theta sequences. In particular, this phase-shifting population showed an increased contribution to REM theta sequence representations after behavioral performance asymptotes and the task is learned, supporting a previously hypothesized role in depotentiation. These findings suggest a role for REM associated theta sequences in state dependent memory functions of the hippocampal circuit, providing evidence that REM sleep is associated with sequence reactivation that can support consolidation of representations necessary for memory guided behavior.
Template switching in DNA replication can create and maintain RNA hairpins
Authors: Mönttinen Heli , Löytynoja Ari
Published: April 2021

The evolutionary origin of ribonucleic acid (RNA) stem structures and the preservation of their base-pairing under a spontaneous and random mutation process have puzzled theoretical evolutionary biologists. DNA replication-related template switching is a mutation mechanism that creates reverse-complement copies of sequence regions within a genome by replicating briefly either along the complementary or nascent DNA strand. Depending on the relative positions and context of the four switch points, this process may produce a reverse-complement repeat capable of forming the stem of a perfect DNA hairpin, or fix the base-pairing of an existing stem. Template switching is typically thought to trigger large structural changes and its possible role in the origin and evolution of RNA genes has not been studied. Here we show that the reconstructed ancestral histories of RNA genes contain mutation patterns consistent with the DNA replication-related template switching. In addition to multi-base compensatory mutations, the mechanism can explain complex sequence changes, though mutations breaking the structure rarely get fixed in evolution. Our results suggest a solution for the longstanding dilemma of RNA gene evolution and demonstrate how template switching can both create perfect stems with a single mutation event and help maintaining the stem structure over time. Interestingly, template switching also provides an elegant explanation for the asymmetric base-pair frequencies within RNA stems.
Genome-scale modeling ofPseudomonas aeruginosaPA14 unveils its broad metabolic capabilities and role of metabolism in drug potentiation
Authors: Dahal Sanjeev , Renz Alina , Dräger Andreas , Yang Laurence
Published: April 2021

P. aeruginosais an opportunistic human pathogen that is one of the leading causes of hospital-acquired infections. We have developed an updated genome-scale model (GEM) ofPseudomonas aeruginosaPA14 for systems-study of the pathogen. We used both automated and semi-manual approaches to reconstruct and curate the model. After an extensive literature research, we added organism-specific reactions (e.g., phenazine transport and redox metabolism, cofactor metabolism, carnitine metabolism, oxalate production, etc.) to the model. This effort led to a highly curated, three-compartment, and mass-and-charge balanced BiGG model of PA14 that contains 1509 genes, 1779 metabolic reactions and 1151 unique metabolites. The model (iSD1509) has the largest genome coverage ofP. aeruginosaPA14 to date with 424 more genes than the previous model (iPau1129). It is also the most accurate with prediction accuracies as high as 92.4% (for gene essentiality) and 93.5% (for substrate utilization). The model simulates growth in both aerobic and anaerobic conditions. It predicts the biosynthesis of the virulence factor phenazine as a process for the pathogen to grow in low-oxygen environment. Further, a mechanism for the overproduction of a drug susceptibility biomarker (gluconate) can be elucidated by the principles of optimal growth. Finally, the model also simulates drug activity potentiation and protection by fumarate and glyoxylate, respectively, and provides mechanistic explanations for these processes. Overall,iSD1509 can be utilized to decipher the metabolic mechanisms associated with virulence and antibiotic susceptibility ofP. aeruginosaPA14 to aid in the development of effective intervention strategies.
Opposing roles of the dorsolateral and dorsomedial striatum in the acquisition of skilled action sequencing in rats
Authors: Turner Karly M. , Svegborn Anna , Langguth Mia , McKenzie Colin , Robbins Trevor W.
Published: April 2021

The shift in control from dorsomedial to dorsolateral striatum during skill and habit formation has been well established, but whether striatal subregions orchestrate this shift co-operatively or competitively remains unclear. Cortical inputs have also been implicated in the shift towards automaticity, but it is unknown if they mirror their downstream striatal targets across this transition. We addressed these questions using a five-step heterogeneous action sequencing task in rats that is optimally performed by automated chains of actions. By optimising automatic habitual responding, we discovered that loss of function in the dorsomedial striatum accelerated sequence acquisition. In contrast, loss of function in the dorsolateral striatum impeded acquisition of sequencing, demonstrating functional opposition within the striatum. Unexpectedly the medial prefrontal cortex was not involved, however the lateral orbitofrontal cortex was critical. These results shift current theories about striatal control of behavior to a model of competitive opposition, where the dorsomedial striatum acts in a gating role to inhibit dorsolateral-striatum driven behavior.
The neural bases of program comprehension: a coordinate-based fMRI meta-analysis
Authors: Ikutani Yoshiharu , Itoh Takeshi D. , Kubo Takatomi
Published: April 2021

The understanding of brain activity during program comprehension have advanced thanks to noninvasive neuroimaging techniques, such as functional magnetic resonance imaging (fMRI). However, individual neuroimaging studies of program comprehension often provided inconsistent results and made it difficult to identify the neural bases. To identify the essential brain regions, this study performed a small meta-analysis on recent fMRI studies of program comprehension using multilevel kernel density analysis (MKDA). Our analysis identified a set of brain regions consistently activated in various program comprehension tasks. These regions consisted of three clusters, each of which centered at the left inferior frontal gyrus pars triangularis (IFG Tri), posterior part of middle temporal gyrus (pMTG), and right middle frontal gyrus (MFG). Additionally, subsequent analyses revealed relationships among the activation patterns in the previous studies and multiple cognitive functions. These findings suggest that program comprehension mainly recycles the language-related networks and partially employs other domain-general resources in the human brain.
Vaccinia virus subverts xenophagy through phosphorylation and nuclear targeting of p62
Authors: Krause Melanie , Yakimovich Artur , Kriston-Vizi Janos , Huttunen Moona , Mercer Jason
Published: April 2021

Autophagy is an essential degradation program required to maintain cell homeostasis. Amongst its many functions is the engulfment and destruction of cytosolic pathogens, termed Xenophagy. Not surprisingly, many pathogens have adapted various strategies to circumvent or co-opt autophagic degradation during infection. For poxviruses, it is known that infection activates autophagy, which however is not required for successful replication. Despite the fact that these complex viruses replicate exclusively in the cytoplasm, autophagy-mediated control of poxvirus infection has not been explored. Using the prototypic poxvirus, vaccinia virus (VACV), we show that over-expression of the xenophagy receptors p62, NDP52 and Tax1Bp1 restricts poxvirus infection. While NDP52 and Tax1Bp1 were degraded, p62 was found to initially target cytoplasmic virions before being shunted to the nucleus. Nuclear translocation of p62 during infection was dependent upon p62 NLS2, and VACV kinase mediated phosphorylation of associated p62 residues T269/S272. These results indicate that VACV actively targets the xenophagy receptor p62 during the early stages of infection to avoid destruction, and further suggest that poxviruses exhibit a unique multi-layered control of autophagy in order to facilitate cytoplasmic replication.
Accumulation-depuration data collection in support of toxicokinetic modelling
Authors: Ratier Aude , Charles Sandrine
Published: April 2021

Regulatory bodies requires evaluation of bioaccumulation of chemicals within organisms with the objective to better assess risks linked to the toxicity of active substances. To this end, toxicokinetic (TK) data are particularly useful to relate the chemical exposure concentration to the accumulation and depuration processes happening within organisms. The bioaccumulative property of substances is quantified by bioaccumulation metrics obtained by fitting TK models to data collected from bioaccumulation tests. The internal concentrations of the studied substances are measured within organisms at regular time points during both accumulation and depuration phases, and their time course is captured by TK models thus providing bioaccumulation metrics. Still today, raw TK data remain difficult to access, as most of the time provided within papers in plots only. To increase accessibility to TK data, we present in this paper a wide collection of raw data sets extracted from the scientific literature in support of TK modelling to be performed with the MOSAICbioaccweb application (https://mosaic.univ-lyon1.fr/bioacc/).
Genetic mapping of sex and self-incompatibility determinants in the androdioecious plantPhillyrea angustifolia
Authors: Carré Amélie , Gallina Sophie , Santoni Sylvain , Vernet Philippe , Godé Cécile , Castric Vincent , Saumitou-Laprade Pierre
Published: April 2021

Abstract

The diversity of mating and sexual systems in angiosperms is spectacular, but the factors driving their evolution remain poorly understood. In plants of the Oleaceae family, an unusual self-incompatibility (SI) system has been discovered recently, whereby only two distinct homomorphic SI specificities segregate stably. To understand the role of this peculiar SI system in preventing or promoting the diversity of sexual phenotypes observed across the family, an essential first step is to characterize the genetic architecture of these two traits. Here, we developed a high-density genetic map of the androdioecious shrubP. angustifoliabased on a F1 cross between a hermaphrodite and a male parent with distinct SI genotypes. Using a double restriction-site associated digestion (ddRAD) sequencing approach, we obtained reliable genotypes for 196 offspring and their two parents at 10,388 markers. The resulting map comprises 23 linkage groups totaling 1,855.13 cM on the sex-averaged map. We found strong signals of association for the sex and SI phenotypes, that were each associated with a unique set of markers on linkage group 12 and 18 respectively, demonstrating inheritance of these traits as single, independent, mendelian factors. TheP. angustifolialinkage map shows robust synteny to the olive tree genome overall. Two of the six markers strictly associated with SI inP. angustifoliahave strong similarity with a recently identified 741kb chromosomal region fully linked to the SI phenotype on chromosome 18 of the olive tree genome, providing strong cross-validation support. The SI locus stands out as being markedly rearranged, while the sex locus has remained relatively more collinear between the two species. ThisP. angustifolialinkage map will be a useful resource to investigate the various ways by which the sex and SI determination systems have co-evolved in the broader phylogenetic context of the Oleaceae family.
Studies of Salt and Stress Sensitivity on Arterial Pressure in Renin-b Deficient Mice
Authors: Nakagawa Pablo , Gomez Javier , Lu Ko-Ting , Grobe Justin L. , Sigmund Curt D.
Published: April 2021

Excessive sodium intake is known to increase the risk for hypertension, heart disease, and stroke. Individuals who are more susceptible to the effects of high salt are at higher risk for cardiovascular diseases even independent of their blood pressure status. Local activation of the renin-angiotensin system (RAS) in the brain, among other mechanisms, has been hypothesized to play a key role in contributing to salt balance. We have previously shown that deletion of the alternative renin isoform termed renin-b disinhibits the classical renin-a encoding preprorenin in the brain resulting in elevated brain RAS activity. Thus, we hypothesized that renin-b deficiency results in higher susceptibility to salt-induced elevation in blood pressure. Telemetry implanted Ren-bNulland wildtype littermate mice were first offered a low salt diet for a week and subsequently a high salt diet for another week. A high salt diet induced a mild blood pressure elevation in both Ren-bNulland wildtype mice, but mice lacking renin-b did not exhibit an exaggerated pressor response. When renin-b deficient mice were exposed to a high salt diet for a longer duration (4 weeks), was a trend for increased myocardial enlargement in Ren-bNullmice when compared with control mice. Multiple studies have also demonstrated the association of chronic and acute environmental stress with hypertension. Activation of the RAS in the rostral ventrolateral medulla and the hypothalamus is required for stress-induced hypertension. Thus, we next questioned whether the lack of renin-b would result in exacerbated response to an acute restraint-stress. Wildtype and Ren-bNullmice equally exhibited elevated blood pressure in response to restraint-stress, which was similar in mice fed either a low or high salt diet. These studies highlight a complex mechanism that masks/unmasks roles for renin-b in cardiovascular physiology.
Development and comparison of Loop-Mediated Isothermal Amplification with Quantitative PCR for the specific detection ofSaprolegniaspp
Authors: Ghosh Satyaki , Straus David L. , Good Christopher , Phuntumart Vipaporn
Published: April 2021

Saprolegniasis is an important disease in freshwater aquaculture, and is associated with oomycete pathogens in the genusSaprolegnia. Early detection of significant levels ofSaprolegniaspp. pathogens would allow informed decisions for treatment which could significantly reduce losses. This study is the first to report the development of loop-mediated isothermal amplification (LAMP) for the detection ofSaprolegniaspp. and compares it with quantitative PCR (qPCR). The developed protocols targeted the internal transcribed spacer (ITS) region of ribosomal DNA and the cytochrome C oxidase subunit 1 (CoxI) gene and was shown to be specific only toSaprolegniagenus. This LAMP method can detect as low as 10 fg ofS. salmonisDNA while the qPCR method has a detection limit of 2 pg ofS. salmonisDNA, indicating the superior sensitivity of LAMP compared to qPCR. When applied to detect the pathogen in water samples, both methods could detect the pathogen when only one zoospore ofSaprolegniawas present. We propose LAMP as a quick (about 20-60 minutes) and sensitive molecular diagnostic tool for the detection ofSaprolegniaspp. suitable for on-site applications.
The dopamine circuit as a reward-taxis navigation system
Authors: Karin Omer , Alon Uri
Published: April 2021

Research on certain circuits in simple organisms, such as bacterial chemotaxis, has enabled the formulation of mathematical design principles, leading to ever more precise experimental tests, catalyzing quantitative understanding. It would be important to map these principles to the far more complex case of a vertebrate behavioral circuit. Here, we provide such a mapping for the midbrain dopamine system. Dopamine transmission plays a key role in learning, motivation, and movement, but its systems-level function is not fully understood. We develop a minimal mechanistic model of the dopamine circuit based on physiological and behavioral data, and show that it can be mapped mathematically to the bacterial chemotaxis circuit. Just as chemotaxis robustly climbs attractant gradients, the dopamine circuit performs ‘reward-taxis’ where the attractant is the expected value of reward. The reward-taxis mechanism is based on a circuit feature called fold-change detection, where the circuit outputs the temporal logarithmic derivative of expected reward. The model can explain the general matching law, in which the ratio of responses to concurrent rewards goes as the reward ratio to the power β. It provides an accurate mechanistic value for β as the average gain/baseline ratio of the dopaminergic neurons. Reward-taxis provides testable etiologies for specific dopamine-related disorders.
GeneCodis 4: Expanding the modular enrichment analysis to regulatory elements
Authors: García-Moreno A. , López-Domínguez R. , Ramirez-Mena A. , Pascual-Montano A. , Aparicio-Puerta E. , Hackenberg M. , Carmona-Saez P.
Published: April 2021

GeneCodis is a web-based tool for functional enrichment analysis that allows researchers to integrate different sources of annotations. It extracts sets of significant concurrent annotations and assigns a statistical score to evaluate those that are significantly enriched in the input list. Since its first release in 2007, it has been widely employed to analyze lists of genes in order to interpret the underlying biological mechanisms. Here we present GeneCodis 4, a new release that expands the functional analysis provided by the application, to accept regulatory elements, including lists of, transcription factors, CpG sites and miRNAs. It also incorporates new annotation databases and improved interactive visualizations functionalities to explore results. GeneCodis 4 is freely available athttps://genecodis.genyo.es.