bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of bone morphogenetic protein 2 and thrombopoietin treatment on angiogenic properties of endothelial cells derived from the lung and bone marrow of young and aged, male and female mice
Authors: Dadwal Ushashi C. , Bhatti Fazal Ur Rehman , Awosanya Olatundun D. , Nagaraj Rohit U. , Perugini Anthony J. , Sun Seungyup , Valuch Conner R. , de Andrade Staut Caio , Mendenhall Stephen K. , Tewari Nikhil P. , Mostardo Sarah L. , Nazzal Murad K. , Battina Hanisha L. , Zhou Donghui , Kanagasabapathy Deepa , Blosser Rachel J. , Mulcrone Patrick L. , Li Jiliang , Kacena Melissa A.
Published: August 2021

With an aging world population, there is an increased risk of fracture and impaired healing. One contributing factor may be aging‐associated decreases in vascular function; thus, enhancing angiogenesis could improve fracture healing. Both bone morphogenetic protein 2 (BMP‐2) and thrombopoietin (TPO) have pro‐angiogenic effects. The aim of this study was to investigate the effects of treatment with BMP‐2 or TPO on the in vitro angiogenic and proliferative potential of endothelial cells (ECs) isolated from lungs (LECs) or bone marrow (BMECs) of young (3‐4 months) and old (22‐24 months), male and female, C57BL/6J mice. Cell proliferation, vessel‐like structure formation, migration, and gene expression were used to evaluate angiogenic properties. In vitro characterization of ECs generally showed impaired vessel‐like structure formation and proliferation in old ECs compared to young ECs, but improved migration characteristics in old BMECs. Differential sex‐based angiogenic responses were observed, especially with respect to drug treatments and gene expression. Importantly, these studies suggest that NTN1, ROBO2, and SLIT3, along with angiogenic markers (CD31, FLT‐1, ANGPT1, and ANGP2) differentially regulate EC proliferation and functional outcomes based on treatment, sex, and age. Furthermore, treatment of old ECs with TPO typically improved vessel‐like structure parameters, but impaired migration. Thus, TPO may serve as an alternative treatment to BMP‐2 for fracture healing in aging owing to improved angiogenesis and fracture healing, and the lack of side effects associated with BMP‐2.
Mechanisms linking hypoxia to phosphorylation of insulin‐like growth factor binding protein‐1 in baboon fetuses with intrauterine growth restriction and in cell culture
Authors: Kakadia Jenica , Biggar Kyle , Jain Bhawani , Chen Allan W. , Nygard Karen , Li Cun , Nathanielsz Peter W. , Jansson Thomas , Gupta Madhulika B.
Published: August 2021

Hypoxia increases fetal hepatic insulin‐like growth factor binding protein‐1 (IGFBP‐1) phosphorylation mediated by mechanistic target of rapamycin (mTOR) inhibition. Whether maternal nutrient restriction (MNR) causes fetal hypoxia remains unclear. We used fetal liver from a baboon (Papio sp.) model of intrauterine growth restriction due to MNR (70% global diet of Control) and liver hepatocellular carcinoma (HepG2) cells as a model for human fetal hepatocytes and tested the hypothesis that mTOR‐mediated IGFBP‐1 hyperphosphorylation in response to hypoxia requires hypoxia‐inducible factor‐1α (HIF‐1α) and regulated in development and DNA‐damage responses‐1 (REDD‐1) signaling. Western blotting (n = 6) and immunohistochemistry (n = 3) using fetal liver indicated greater expression of HIF‐1α, REDD‐1 as well as erythropoietin and its receptor, and vascular endothelial growth factor at GD120 (GD185 term) in MNR versus Control. Moreover, treatment of HepG2 cells with hypoxia (1% pO2) (n = 3) induced REDD‐1, inhibited mTOR complex‐1 (mTORC1) activity and increased IGFBP‐1 secretion/phosphorylation (Ser101/Ser119/Ser169). HIF‐1α inhibition by echinomycin or small interfering RNA silencing prevented the hypoxia‐mediated inhibition of mTORC1 and induction of IGFBP‐1 secretion/phosphorylation. dimethyloxaloylglycine (DMOG) induced HIF‐1α and also REDD‐1 expression, inhibited mTORC1 and increased IGFBP‐1 secretion/phosphorylation. Induction of HIF‐1α (DMOG) and REDD‐1 by Compound 3 inhibited mTORC1, increased IGFBP‐1 secretion/ phosphorylation and protein kinase PKCα expression. Together, our data demonstrate that HIF‐1α induction, increased REDD‐1 expression and mTORC1 inhibition represent the mechanistic link between hypoxia and increased IGFBP‐1 secretion/phosphorylation. We propose that maternal undernutrition limits fetal oxygen delivery, as demonstrated by increased fetal liver expression of hypoxia‐responsive proteins in baboon MNR. These findings have important implications for our understanding of the pathophysiology of restricted fetal growth.
Resistance training rejuvenates the mitochondrial methylome in aged human skeletal muscle
Authors: Ruple Bradley A. , Godwin Joshua S. , Mesquita Paulo H. C. , Osburn Shelby C. , Vann Christopher G. , Lamb Donald A. , Sexton Casey L. , Candow Darren G. , Forbes Scott C. , Frugé Andrew D. , Kavazis Andreas N. , Young Kaelin C. , Seaborne Robert A. , Sharples Adam P. , Roberts Michael D.
Published: August 2021

Resistance training (RT) dynamically alters the skeletal muscle nuclear DNA methylome. However, no study has examined if RT affects the mitochondrial DNA (mtDNA) methylome. Herein, ten older, Caucasian untrained males (65 ± 7 y.o.) performed six weeks of full‐body RT (twice weekly). Body composition and knee extensor torque were assessed prior to and 72 h following the last RT session. Vastus lateralis (VL) biopsies were also obtained. VL DNA was subjected to reduced representation bisulfite sequencing providing excellent coverage across the ~16‐kilobase mtDNA methylome (254 CpG sites). Biochemical assays were also performed, and older male data were compared to younger trained males (22 ± 2 y.o., n = 7, n = 6 Caucasian & n = 1 African American). RT increased whole‐body lean tissue mass (p = .017), VL thickness (p = .012), and knee extensor torque (p = .029) in older males. RT also affected the mtDNA methylome, as 63% (159/254) of the CpG sites demonstrated reduced methylation (p < .05). Several mtDNA sites presented a more “youthful” signature in older males after RT in comparison to younger males. The 1.12 kilobase mtDNA D‐loop/control region, which regulates replication and transcription, possessed enriched hypomethylation in older males following RT. Enhanced expression of mitochondrial H‐ and L‐strand genes and complex III/IV protein levels were also observed (p < .05). While limited to a shorter‐term intervention, this is the first evidence showing that RT alters the mtDNA methylome in skeletal muscle. Observed methylome alterations may enhance mitochondrial transcription, and RT evokes mitochondrial methylome profiles to mimic younger men. The significance of these findings relative to broader RT‐induced epigenetic changes needs to be elucidated.
Synchrony and rhythm interaction: from the brain to behavioural ecology
Authors: Greenfield Michael D. , Honing Henkjan , Kotz Sonja A. , Ravignani Andrea
Published: August 2021

This theme issue assembles current studies that ask how and why precise synchronization and related forms of rhythm interaction are expressed in a wide range of behaviour. The studies cover human activity, with an emphasis on music, and social behaviour, reproduction and communication in non-human animals. In most cases, the temporally aligned rhythms have short—from several seconds down to a fraction of a second—periods and are regulated by central nervous system pacemakers, but interactions involving rhythms that are 24 h or longer and originate in biological clocks also occur. Across this spectrum of activities, species and time scales, empirical work and modelling suggest that synchrony arises from a limited number of coupled-oscillator mechanisms with which individuals mutually entrain. Phylogenetic distribution of these common mechanisms points towards convergent evolution. Studies of animal communication indicate that many synchronous interactions between the signals of neighbouring individuals are specifically favoured by selection. However, synchronous displays are often emergent properties of entrainment between signalling individuals, and in some situations, the very signallers who produce a display might not gain any benefit from the collective timing of their production.

This article is part of the theme issue ‘Synchrony and rhythm interaction: from the brain to behavioural ecology’.
Mapping between sound, brain and behaviour: four-level framework for understanding rhythm processing in humans and non-human primates
Authors: Lenc Tomas , Merchant Hugo , Keller Peter E. , Honing Henkjan , Varlet Manuel , Nozaradan Sylvie
Published: August 2021

Humans perceive and spontaneously move to one or several levels of periodic pulses (a meter, for short) when listening to musical rhythm, even when the sensory input does not provide prominent periodic cues to their temporal location. Here, we review a multi-levelled framework to understanding how external rhythmic inputs are mapped onto internally represented metric pulses. This mapping is studied using an approach to quantify and directly compare representations of metric pulses in signals corresponding to sensory inputs, neural activity and behaviour (typically body movement). Based on this approach, recent empirical evidence can be drawn together into a conceptual framework that unpacks the phenomenon of meter into four levels. Each level highlights specific functional processes that critically enable and shape the mapping from sensory input to internal meter. We discuss the nature, constraints and neural substrates of these processes, starting with fundamental mechanisms investigated in macaque monkeys that enable basic forms of mapping between simple rhythmic stimuli and internally represented metric pulse. We propose that human evolution has gradually built a robust and flexible system upon these fundamental processes, allowing more complex levels of mapping to emerge in musical behaviours. This approach opens promising avenues to understand the many facets of rhythmic behaviours across individuals and species.

This article is part of the theme issue ‘Synchrony and rhythm interaction: from the brain to behavioural ecology’.
Vocal learning as a preadaptation for the evolution of human beat perception and synchronization
Authors: Patel Aniruddh D.
Published: August 2021

The human capacity to synchronize movements to an auditory beat is central to musical behaviour and to debates over the evolution of human musicality. Have humans evolved any neural specializations for music processing, or does music rely entirely on brain circuits that evolved for other reasons? The vocal learning and rhythmic synchronization hypothesis proposes that our ability to move in time with an auditory beat in a precise, predictive and tempo-flexible manner originated in the neural circuitry for complex vocal learning. In the 15 years since the hypothesis was proposed a variety of studies have supported it. However, one study has provided a significant challenge to the hypothesis. Furthermore, it is increasingly clear that vocal learning is not a binary trait animals have or lack, but varies more continuously across species. In the light of these developments and of recent progress in the neurobiology of beat processing and of vocal learning, the current paper revises the vocal learning hypothesis. It argues that an advanced form of vocal learning acts as a preadaptation for sporadic beat perception and synchronization (BPS), providing intrinsic rewards for predicting the temporal structure of complex acoustic sequences. It further proposes that in humans, mechanisms of gene-culture coevolution transformed this preadaptation into a genuine neural adaptation for sustained BPS. The larger significance of this proposal is that it outlines a hypothesis of cognitive gene-culture coevolution which makes testable predictions for neuroscience, cross-species studies and genetics.

This article is part of the theme issue ‘Synchrony and rhythm interaction: from the brain to behavioural ecology’.
Rhythmic abilities in humans and non-human animals: a review and recommendations from a methodological perspective
Authors: Bouwer Fleur L. , Nityananda Vivek , Rouse Andrew A. , ten Cate Carel
Published: August 2021

Rhythmic behaviour is ubiquitous in both human and non-human animals, but it is unclear whether the cognitive mechanisms underlying the specific rhythmic behaviours observed in different species are related. Laboratory experiments combined with highly controlled stimuli and tasks can be very effective in probing the cognitive architecture underlying rhythmic abilities. Rhythmic abilities have been examined in the laboratory with explicit and implicit perception tasks, and with production tasks, such as sensorimotor synchronization, with stimuli ranging from isochronous sequences of artificial sounds to human music. Here, we provide an overview of experimental findings on rhythmic abilities in human and non-human animals, while critically considering the wide variety of paradigms used. We identify several gaps in what is known about rhythmic abilities. Many bird species have been tested on rhythm perception, but research on rhythm production abilities in the same birds is lacking. By contrast, research in mammals has primarily focused on rhythm production rather than perception. Many experiments also do not differentiate between possible components of rhythmic abilities, such as processing of single temporal intervals, rhythmic patterns, a regular beat or hierarchical metrical structures. For future research, we suggest a careful choice of paradigm to aid cross-species comparisons, and a critical consideration of the multifaceted abilities that underlie rhythmic behaviour.

This article is part of the theme issue ‘Synchrony and rhythm interaction: from the brain to behavioural ecology’.
Rhythm interaction in animal groups: selective attention in communication networks
Authors: Greenfield Michael D. , Aihara Ikkyu , Amichay Guy , Anichini Marianna , Nityananda Vivek
Published: August 2021

Animals communicating interactively with conspecifics often time their broadcasts to avoid overlapping interference, to emit leading, as opposed to following, signals or to synchronize their signalling rhythms. Each of these adjustments becomes more difficult as the number of interactants increases beyond a pair. Among acoustic species, insects and anurans generally deal with the problem of group signalling by means of ‘selective attention’ in which they focus on several close or conspicuous neighbours and ignore the rest. In these animals, where signalling and receiving are often dictated by sex, the process of selective attention in signallers may have a parallel counterpart in receivers, which also focus on close neighbours. In birds and mammals, local groups tend to be extended families or clans, and group signalling may entail complex timing mechanisms that allow for attention to all individuals. In general, the mechanisms that allow animals to communicate in groups appear to be fully interwoven with the basic process of rhythmic signalling.

This article is part of the theme issue ‘Synchrony and rhythm interaction: from the brain to behavioural ecology’.
Imperfect synchrony in animal displays: why does it occur and what is the true role of leadership?
Authors: Perez Daniela M. , Klunk Cristian L. , Araujo Sabrina B. L.
Published: August 2021

Synchrony can be defined as the precise coordination between independent individuals, and this behaviour is more enigmatic when it is imperfect. The traditional theoretical explanation for imperfect synchronous courtship is that it arises as a by-product of the competition between males to broadcast leading signals to attract female attention. This competition is considered an evolutionary stable strategy maintained through sexual selection. However, previous studies have revealed that leading signals are not honest indicators of male quality. We studied imperfect courtship synchrony in fiddler crabs to mainly test whether (i) signal leadership and rate are defined by male quality and (ii) signal leadership generates synchrony. Fiddler crab males wave their enlarged claws during courtship, and females prefer leading males—displaying ahead of their neighbour(s). We filmed groups of waving males in the field to detect how often individuals were leaders and if they engaged in synchrony. Overall, we found that courtship effort is not directly related to male size, a general proxy for quality. Contrary to the long-standing assumption, we also revealed that leadership is not directly related to group synchrony, but faster wave rate correlates with both leadership and synchrony.

This article is part of the theme issue ‘Synchrony and rhythm interaction: from the brain to behavioural ecology’.
Social synchronization of circadian rhythms with a focus on honeybees
Authors: Siehler Oliver , Wang Shuo , Bloch Guy
Published: August 2021

Many animals benefit from synchronizing their daily activities with conspecifics. In this hybrid paper, we first review recent literature supporting and extending earlier evidence for a lack of clear relationship between the level of sociality and social entrainment of circadian rhythms. Social entrainment is specifically potent in social animals that live in constant environments in which some or all individuals do not experience the ambient day-night cycles. We next focus on highly social honeybees in which there is good evidence that social cues entrain the circadian clocks of nest bees and can override the influence of conflicting light-dark cycles. The current understanding of social synchronization in honeybees is consistent with self-organization models in which surrogates of forager activity, such as substrate-borne vibrations and colony volatiles, entrain the circadian clocks of bees dwelling in the dark cavity of the nest. Finally, we present original findings showing that social synchronization is effective even in an array of individually caged callow bees placed on the same substrate and is improved for bees in connected cages. These findings reveal remarkable sensitivity to social time-giving cues and show that bees with attenuated rhythms (weak oscillators) can nevertheless be socially synchronized to a common phase of activity.

This article is part of the theme issue ‘Synchrony and rhythm interaction: from the brain to behavioural ecology’.
A virulent and pathogenic infectious clone of Senecavirus A
Authors: Fernandes Maureen H. V. , de Lima Marcelo , Joshi Lok R. , Diel Diego G.
Published: August 2021

Senecavirus A (SVA) is a picornavirus that circulates in swine populations worldwide causing vesicular disease (VD) in affected animals. Here we developed a reverse genetics system for SVA based on the well-characterized wild-type SVA strain SD15-26 (wt SVA SD15-26). The full-length cDNA genome of SVA was cloned into a plasmid under a T7 RNA polymerase promoter. Following in vitro transcription, the genomic viral RNA was transfected into BHK-21 cells and rescue of infectious virus (rSVA SD15-26) was shown by inoculation of highly susceptible H1299 cells. In vitro characterization of the rSVA SD15-26 showed similar replication properties and protein expression levels as the wt SVA SD15-26. A pathogenesis study was conducted in 15-week-old finishing pigs to evaluate the pathogenicity and infection dynamics of the rSVA SD15-26 virus in comparison to the wt SVA SD15-26. Animals from both rSVA- and wt SVA SD15-26-inoculated groups presented characteristic SVA clinical signs (lethargy and lameness) followed by the development of vesicular lesions on the snout and/or feet. The clinical outcome of infection, including disease onset, severity and duration was similar in rSVA- and the wt SVA SD15-26-inoculated animals. All animals inoculated with rSVA or with wt SVA SD15-26 presented a short-term viremia, and animals from both groups shed similar amounts of virus in oral and nasal secretion, and faeces. Our data demonstrates that the rSVA SD5-26 clone is fully virulent and pathogenic in pigs, presenting comparable pathogenesis and infection dynamics to the wt SVA SD15-26 strain. The infectious clone generated here is a useful platform to study virulence determinants of SVA, and to dissect other aspects of SVA infection biology, pathogenesis and persistence.
Population genomics of transposable element activation in the highly repressive genome of an agricultural pathogen
Authors: Pereira Danilo , Oggenfuss Ursula , McDonald Bruce A. , Croll Daniel
Published: August 2021

The activity of transposable elements (TEs) can be an important driver of genetic diversity with TE-mediated mutations having a wide range of fitness consequences. To avoid deleterious effects of TE activity, some fungi have evolved highly sophisticated genomic defences to reduce TE proliferation across the genome. Repeat-induced point mutation (RIP) is a fungal-specific TE defence mechanism efficiently targeting duplicated sequences. The rapid accumulation of RIPs is expected to deactivate TEs over the course of a few generations. The evolutionary dynamics of TEs at the population level in a species with highly repressive genome defences is poorly understood. Here, we analyse 366 whole-genome sequences of Parastagonospora nodorum, a fungal pathogen of wheat with efficient RIP. A global population genomics analysis revealed high levels of genetic diversity and signs of frequent sexual recombination. Contrary to expectations for a species with RIP, we identified recent TE activity in multiple populations. The TE composition and copy numbers showed little divergence among global populations regardless of the demographic history. Miniature inverted-repeat transposable elements (MITEs) and terminal repeat retrotransposons in miniature (TRIMs) were largely underlying recent intra-species TE expansions. We inferred RIP footprints in individual TE families and found that recently active, high-copy TEs have possibly evaded genomic defences. We find no evidence that recent positive selection acted on TE-mediated mutations rather that purifying selection maintained new TE insertions at low insertion frequencies in populations. Our findings highlight the complex evolutionary equilibria established by the joint action of TE activity, selection and genomic repression.
Respiratory syncytial virus-specific immunoglobulin G (IgG) concentrations associate with environmental and genetic factors: the Factors Influencing Pediatric Asthma Study
Authors: Erdei Esther , Torgerson Dara , O’Leary Rae , Spear Melissa , Shedden Matias , O’Leary Marcia , Enright Kendra , Best Lyle
Published: August 2021

Exposure to respiratory syncytial virus (RSV) during childhood is nearly ubiquitous by age two, and infants who develop severe RSV bronchiolitis are more likely to develop asthma later in life. In the Factors Influencing Pediatric Asthma (FIPA) study including 319 children from a Northern Plains American Indian community, we found 73% of children to have high concentrations of RSV-specific IgG (>40 IU/mL). High concentration of RSV-specific IgG was associated with increased exposure to second-hand tobacco smoke (p=7.5×10−4), larger household size (p=4.0×10−3), and lower levels of total serum IgE (p=5.1×10−3). Parents of children with asthma more often reported an RSV diagnosis and/or hospitalization due to RSV, and children with asthma had lower concentrations of RSV IgG as compared to those without asthma among RSV-exposed individuals (mean 117 IU/mL vs. 154, p=7.1×10−4). However, lower RSV IgG was surprisingly exclusive to children with asthma recruited during the winter months when RSV is thought to circulate more broadly. Multivariate regression indicated the strongest predictors of RSV-specific IgG concentration included asthma status (p=0.040), per cent eosinophils (p=0.035), and an asthma x RSV season interaction (p=3.7×10−3). Among candidate genes, we identified a genetic association between an intronic variant in IFNL4 and RSV-specific IgG concentration whereby the minor allele (A) was associated with higher concentration (rs12979860, p=4.3×10−3). Overall our findings suggest there are seasonal differences in immunological response to RSV infection in asthma cases vs. controls, and identify both environmental and genetic contributions that warrant further investigation.
Predicting SARS-CoV-2 infections for children and youth with single symptom screening
Authors: Webster Richard J. , Reddy Deepti , Harrison Mary-Ann , Farion Ken J. , Wilmore Jacqueline , Foote Michelle , Thampi Nisha
Published: August 2021

Symptom-based SARS-CoV-2 screening and testing decisions in children have important implications on daycare and school exclusion policies. Single symptoms account for a substantial volume of testing and disruption to in-person learning and childcare, yet their predictive value is unclear, given the clinical overlap with other circulating respiratory viruses and non-infectious etiologies. We aimed to determine the relative frequency and predictive value of single symptoms for paediatric SARS-CoV-2 infections from an Ottawa COVID-19 assessment centre from October 2020 through April 2021.

Overall, 46.3% (n=10,688) of pediatric encounters were for single symptoms, and 2.7% of these tested positive. The most common presenting single symptoms were rhinorrhea (31.8%), cough (17.4%) and fever (14.0%). Among children with high-risk exposures children in each age group, the following single symptoms had a higher proportion of positive SARS-CoV-2 cases compared to no symptoms; fever and fatigue (0-4 years); fever, cough, headache, and rhinorrhea (5-12 years); fever, loss of taste or smell, headache, rhinorrhea, sore throat, and cough (13-17 years). There was no evidence that the single symptom of either rhinorrhea or cough predicted SARS-CoV-2 infections among 0-4 year olds, despite accounting for a large volume (61.1%) of single symptom presentations in the absence of high-risk exposures.

Symptom-based screening needs to be responsive to changes in evidence and local factors, including the expected resurgence of other respiratory viruses following relaxation of social distancing/masking, to reduce infection-related risks in schools and daycare settings.
Pediatric critical COVID-19 and mortality in a multinational cohort
Authors: Gonzalez-Dambrauskas Sebastian , Vasquez-Hoyos Pablo , Camporesi Anna , Cantillano Edwin Mauricio , Dallefeld Samantha , Dominguez-Rojas Jesus , Francoeur Conall , Gurbanov Anar , Vega Liliana Mazzillo , Shein Steven , Yock-Corrales Adriana , Karsies Todd
Published: August 2021

Objectives

To understand the international epidemiology of critical pediatric COVID-19 and compare presentation, treatments, and outcomes of younger (<2 years) and older (>2 years) children.

Design

Prospective, observational study from April 1 to December 31, 2020

Setting

International multicenter study from 55 sites from North America, Latin America, and Europe.

Participants

Patients <19 years old hospitalized with critical COVID-19

Interventions

none

Main outcomes measured

Clinical course, treatments, and outcomes were compared between younger and older children. Multivariable logistic regression was used to calculate adjusted odds ratios (aOR) for hospital mortality.

Results

557 subjects (median age, 8 years; 24% <2 years) were enrolled from 55 sites (63% Latin American). Half had comorbidities. Younger children had more respiratory findings (56% vs 44%), viral pneumonia (45% vs 29%), and treatment with invasive ventilation (50% vs 37). Gastrointestinal (28% vs 69%) or mucocutaneous (16% vs 44%) findings, vasopressor requirement (44% vs 60%), and MIS-C (15% vs 40%) were less common in younger children. Hospital mortality was 10% overall but 15% in younger children (odds ratio 1.89 [95%CI 1.05-3.39]). When adjusted for age, sex, region, and illness severity, mortality-associated factors included cardiac (aOR 2.6; 95%CI 1.07-6.31) or pulmonary comorbidities (aOR 4.4; 95%CI 1.68-11.5), admission hypoxemia (aOR 2.33; 95%CI 1.24-4.37), and lower respiratory symptoms (aOR 2.83; 95%CI 1.49-5.39). Gastrointestinal (aOR 0.49; 95%CI 0.26-0.92) or mucocutaneous symptoms (aOR 0.31; 95%CI 0.15-0.64), treatment with intravenous immune globulin (aOR 0.33; 95%CI 0.17-0.65), and MIS-C (aOR 0.26; 95%CI 0.11-0.64) were associated with lower mortality.

Conclusions

We identified age-related differences in presentation and mortality for critical pediatric COVID-19 that should prompt more attention to improving management in younger children, especially in developing countries.

Table of Contents Summary

This is a multinational study describing critical pediatric COVID-19 clinical spectrum and related mortality in high and low-middle income countries during 2020.

What’s known on this subject

Pediatric critical illness due to COVID-19 is uncommon and have lower mortality compared to adults when hospitalized. While larger cohorts are from high-income countries (HICs), studies including data from low-middle-income countries (LMICs) remain scarce.

What this study adds

In our multinational cohort of critical pediatric COVID-19, we identified higher mortality than previously reported and age-related disease patterns. Children <2 years old had more respiratory disease and higher mortality, and older children had more non-pulmonary disease and better outcomes.
Long-term effects of increased adoption of artemisinin combination therapies in Burkina Faso
Authors: Zupko Robert J. , Nguyen Tran Dang , Somé Anyirékun Fabrice , Tran Thu Nguyen-Anh , Gerardin Jaline , Dudas Patrick , Hoang Giang Dang Duy , Tran Kien Trung , Wesolowski Amy , Ouédraogo Jean-Bosco , Boni Maciej F.
Published: August 2021

Artemisinin combination therapies (ACTs) are the WHO-recommended first-line therapies for uncomplicated Plasmodium falciparum malaria. The emergence and spread of artemisinin-resistant genotypes is a major global public health concern due to the increased rate of treatment failures that result. This is particularly germane for WHO designated ‘high burden to high impact’ (HBHI) countries, such as Burkina Faso, where there is increased emphasis on improving guidance, strategy, and coordination of local malaria response in an effort to reduce the prevalence of P. falciparum malaria. To explore how the increased adoption of ACTs may affect the HBHI malaria setting of Burkina Faso, we added spatial structure to a validated individual-based stochastic model of P. falciparum transmission and evaluated the long-term effects of increased ACT use. We explored how de novo emergence of artemisinin-resistant genotypes, such as pfkelch13 580Y, may occur under scenarios in which private-market drugs are eliminated or multiple first-line therapies (MFT) are deployed. We found that elimination of private market drugs would result in lower treatment failures rates (between 11.98% and 12.90%) when compared to the status quo (13.11%). However, scenarios incorporating MFT with equal deployment of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PPQ) may accelerate near-term drug resistance (580Y frequency ranging between 0.62 to 0.84 in model year 2038) and treatment failure rates (26.69% to 34.00% in 2038), due to early failure and substantially reduced treatment efficacy resulting from piperaquine-resistant genotypes. A rebalanced MFT approach (90% AL, 10% DHA-PPQ) results in approximately equal long-term outcomes to using AL alone but may be difficult to implement in practice.
Shared responsibility decreases the sense of agency in the human brain
Authors: El Zein Marwa , Dolan Ray J. , Bahrami Bahador
Published: August 2021

Sharing responsibility in social decision-making helps individuals use the flexibility of the collective context to benefit themselves by claiming credit for good outcomes or avoiding the blame for bad outcomes. Using magnetoencephalography (MEG), we examined the neuronal basis of the impact that social context has on this flexible sense of responsibility. Participants performed a gambling task in various social contexts and reported feeling less responsibility when playing as a member of a team. A reduced MEG outcome processing effect was observed as a function of decreasing responsibility at 200 ms post outcome onset and was centred over parietal and pre-central brain regions. Prior to outcome revelation in socially made decisions, an attenuated motor preparation signature at 500 ms after stimulus onset was found. A boost in reported responsibility for positive outcomes in social contexts was associated with increased activity in regions related to social and reward processing. Together, these results show that sharing responsibility with others reduces agency, influencing pre-outcome motor preparation and post-outcome processing, and provides opportunities to flexibly claim credit for positive outcomes.
Patient-Derived Three-Dimensional Cortical Neurospheres to Model Parkinson’s Disease
Authors: Raja Waseem K. , Neves Esther , Burke Christopher , Jiang Xin , Xu Ping , Rhodes Kenneth J , Khurana Vikram , Scannevin Robert H , Chung Chee Yeun
Published: August 2021

There are currently no preventive or disease-modifying therapies for Parkinson’s Disease (PD). Failures in clinical trials necessitate a re-evaluation of existing pre-clinical models in order to adopt systems that better recapitulate underlying disease mechanisms and better predict clinical outcomes. In recent years, models utilizing patient-derived induced pluripotent stem cells (iPSCs) have emerged as attractive models to recapitulate disease-relevant neuropathology in vitro without exogenous overexpression of disease-related pathologic proteins. Here, we utilized iPSCs derived from patients with early-onset PD and dementia phenotypes that harbored either a point mutation (A53T) or multiplication at the α-synuclein/SNCA gene locus. We generated a three-dimensional (3D) cortical neurosphere culture model to better mimic the tissue microenvironment of the brain. We extensively characterized the differentiation process using quantitative PCR, Western immunoblotting and immunofluorescence staining. Differentiation and aging of the neurospheres revealed alterations in fatty acid profiles and elevated total and pathogenic phospho-α-synuclein levels in both A53T and the triplication lines compared to their isogenic control lines. Furthermore, treatment of the neurospheres with a small molecule inhibitor of stearoyl CoA desaturase (SCD) attenuated the protein accumulation and aberrant fatty acid profile phenotypes. Our findings suggest that the 3D cortical neurosphere model is a useful tool to interrogate targets for PD and amenable to test small molecule therapeutics.
Bantam regulates the adult sleep circuit in Drosophila
Authors: Hobin Michael , Dorfman Katherine , Adel Mohamed , Rivera-Rodriguez Emmanuel J. , Griffith Leslie C.
Published: August 2021

Sleep is a highly conserved feature of animal life characterized by dramatic changes in behavior, neural physiology and gene expression. The gene regulatory factors responsible for these sleep-dependent changes remain largely unknown. microRNAs are post-transcriptional modulators of gene expression which have been implicated in sleep regulation. Our previous screen identified 25 sleep-regulating microRNAs in Drosophila melanogaster, including the developmental regulator bantam (ban). Here we show that ban promotes early nighttime sleep through a population of glutamatergic neurons- the γ5β′2a/β′2mp/β′2mp_bilateral Mushroom Body Output Neurons (MBONs). We found that knockdown of ban in these neurons led to a reduction in early night sleep. The γ5β′2a/β′2mp/β′2mp_bilateral MBONs were previously shown to be wake-promoting, suggesting that ban acts to inhibit these neurons. GCaMP calcium imaging revealed that bantam inhibits the neural activity of the γ5β′2a/β′2mp/β′2mp_bilateral MBONs during the night but not the day. Blocking synaptic transmission in the γ5β′2a/β′2mp/β′2mp_bilateral MBONs rescued the effect of ban knockdown on sleep. Together these results suggest that ban promotes night sleep via the inhibition of the γ5β′2a/β′2mp/β′2mp_bilateral MBONs. RNAseq further revealed that bantam negatively regulates the wake-promoting mRNAs Kelch and CCHamide-2 receptor in the γ5β′2a/β′2mp/β′2mp_bilateral MBONs. These experiments establish bantam as an active regulator of sleep and neural activity within the fly brain.
Eliminating Aedes aegypti from its southern margin in Australia: insights from genomic data and simulation modeling
Authors: Rašić Gordana , Filipović Igor , Wu Sean L , León Tomás M , Bennett Jared B , Sánchez C Héctor M , Marshall John M , Trewin Brendan J
Published: August 2021

A rare example of a successful long-term elimination of the mosquito Aedes aegypti is in Brisbane, Queensland, where the legislatively-enforced removal of rainwater tanks drove its disappearance by the mid-1950s. However, a decade-long drought led to the mass installation of rainwater tanks throughout the region, re-introducing critical breeding sites for the mosquito’s persistence in this subtropical region. With Ae. aegypti re-invading towns just 150 km north of Brisbane, we examined the potential for their sustained elimination. Through genomic analyses, we estimated historical expansion and current isolation between neighboring populations as close as 15 kilometers. The estimated recent migration rate, entomological and meteorological data were used to calibrate the simulations of elimination campaigns in the two southernmost populations. Our simulations indicate that Ae. aegypti could be eliminated with moderate release numbers of incompatible Wolbachia-infected (IIT) males (sorted with an error rate ≤10-6) if non-compliant rainwater tanks are removed first. With this combined campaign, highly effective suppression (>99%) was predicted in both towns, and complete elimination was predicted in 35% of simulations in one town. Without tank removal, however, IIT led to a moderate suppression (61-93%) even with a 40:1 ratio of released IIT males to local males. Moreover, with a ratio of >20:1, Wolbachia establishment was predicted when the sorting error was >10-7. Our conservative estimates of intervention outcomes inform the planning of Ae. aegypti elimination in the region, and offer insight into the effective combinations of conventional and novel control tools, particularly for vulnerable mosquito populations at range margins.

Significance

After decades of range stagnation in Australia, the Aedes aegypti mosquito is expanding southward, approaching the most-densely-populated areas of Queensland. Using population genomics and simulation modeling of elimination campaigns, we show that Australia’s southernmost populations of this disease vector are genetically isolated and could be eliminated with moderate releases of incompatible Wolbachia-infected males if major larval breeding sites (non-compliant rainwater tanks) are removed first. The risk of Wolbachia establishment for this approach is low, and so is the risk of quick mosquito re-invasion. Our conservative estimates of intervention outcomes inform the planning of Ae. aegypti elimination in the region, and offer new insight into the benefits of combining conventional and novel control tools, particularly for mosquito populations at range margins.
Genome sequencing and molecular characterisation of XDR Acinetobacter baumannii reveal complexities in resistance: Novel combination of Sulbactam-Durlobactam holds promise for therapeutic intervention
Authors: Naha Aniket , Vijayakumar Saranya , Lal Binesh , Shankar Baby Abirami , Chandran Suriya , Ramaiah Sudha , Veeraraghavan Balaji , Anbarasu Anand
Published: August 2021

Acinetobacter baumannii is an emerging nosocomial strain expressing extensive drug resistance (XDR). Whole-genome sequencing and molecular characterisation analysis revealed the presence of carbapenemase in 92.86% of studied Indian isolates having blaOXA-51, blaOXA-23, blaOXA-58, and blaNDM genes, with a few evidences of dual carbapenemase genes. As per the MLST scheme, IC2Oxf/CC2Pas was the predominant clone, with 57.14% isolates belonging to this lineage. The presence of β-lactamases has rendered sulbactam (SUL) resistance (MIC: 16-256µg/ml) in all the studied isolates. The efficacy of novel durlobactam (DUR) in inhibiting β-lactamases and PBP2 was assessed through in-silico inter-molecular interaction analysis. Several non-synonymous single nucleotide polymorphisms (nsSNPs) were identified in PBP2 (G264S, I108V, S259T) and PBP3 (A515V, T526S) sequences. Minimal variations were recorded in the protein-backbone dynamics in active-site motifs of wild-type (WT) and mutants (MT), which correlated with the negligible binding energy fluctuations for PBP3-SUL (−5.85±0.04Kcal/mol) and PBP2-DUR (−5.16±0.66Kcal/mol) complexes. Furthermore, stronger binding affinities and low inhibition constants were noted in DUR complexed with OXA23 (−7.36Kcal/mol; 4.01µM), OXA58 (−6.44Kcal/mol; 19.07µM) and NDM (−6.82Kcal/mol; 10.01µM) when compared with conventional drugs avibactam and aztreonam. Stable interaction profiles of DUR, can possibly restore SUL activity against both PBP3WT and PBP3MTs. The study establishes the efficacy of novel SUL-DUR combination as a successful treatment strategy to combat emerging XDR strains.
Helicity-dependent resonant X-ray scattering in CuB2O4
Authors: Ovchinnikova E. N. , Rogalev A. , Wilhelm F. , de Bergevin F. , Dmitrienko V. E. , Oreshko A. P. , Kozlovskaya K. A. , Bakonin R. D.
Published: August 2021

Exploitation of X-ray circular polarized beams to study forbidden Bragg reflections and new information that could be obtained in these experiments are discussed. It is shown that the intensities of such reflections can be different for the right- and left-circular polarizations (i.e.exhibiting circular dichroism) even for the dipole–dipole resonant transitions involved in the scattering process. This difference can be observed only in crystals having no center of inversion. Here, this approach is used to study helicity-dependent resonant diffraction in copper metaborate CuB2O4single crystal, which is non-centrosymmetric but achiral. Nonetheless, a strong circular dichroism has been observed forhh0 forbidden reflections in the vicinity of the CuK-edge. This effect is shown to originate from dipolar transitions in Cu atoms occupying the 8(d) Wyckoff position only.
Robotic sample changers for macromolecular X-ray crystallography and biological small-angle X-ray scattering at the National Synchrotron Light Source II
Authors: Lazo Edwin O. , Antonelli Stephen , Aishima Jun , Bernstein Herbert J. , Bhogadi Dileep , Fuchs Martin R. , Guichard Nicolas , McSweeney Sean , Myers Stuart , Qian Kun , Schneider Dieter , Shea-McCarthy Grace , Skinner John , Sweet Robert , Yang Lin , Jakoncic Jean
Published: August 2021

Here we present two robotic sample changers integrated into the experimental stations for the macromolecular crystallography (MX) beamlines AMX and FMX, and the biological small-angle scattering (bioSAXS) beamline LiX. They enable fully automated unattended data collection and remote access to the beamlines. The system designs incorporate high-throughput, versatility, high-capacity, resource sharing and robustness. All systems are centered around a six-axis industrial robotic arm coupled with a force torque sensor and in-house end effectors (grippers). They have the same software architecture and the facility standard EPICS-based BEAST alarm system. The MX system is compatible with SPINE bases and Unipucks. It comprises a liquid nitrogen dewar holding 384 samples (24 Unipucks) and a stay-cold gripper, and utilizes machine vision software to track the sample during operations and to calculate the final mount position on the goniometer. The bioSAXS system has an in-house engineered sample storage unit that can hold up to 360 samples (20 sample holders) which keeps samples at a user-set temperature (277 K to 300 K). The MX systems were deployed in early 2017 and the bioSAXS system in early 2019.
Versatile microporous polymer-based supports for serial macromolecular crystallography
Authors: Martiel Isabelle , Beale John H. , Karpik Agnieszka , Huang Chia-Ying , Vera Laura , Olieric Natacha , Wranik Maximilian , Tsai Ching-Ju , Mühle Jonas , Aurelius Oskar , John Juliane , Högbom Martin , Wang Meitian , Marsh May , Padeste Celestino
Published: August 2021

Serial data collection has emerged as a major tool for data collection at state-of-the-art light sources, such as microfocus beamlines at synchrotrons and X-ray free-electron lasers. Challenging targets, characterized by small crystal sizes, weak diffraction and stringent dose limits, benefit most from these methods. Here, the use of a thin support made of a polymer-based membrane for performing serial data collection or screening experiments is demonstrated. It is shown that these supports are suitable for a wide range of protein crystals suspended in liquids. The supports have also proved to be applicable to challenging cases such as membrane proteins growing in the sponge phase. The sample-deposition method is simple and robust, as well as flexible and adaptable to a variety of cases. It results in an optimally thin specimen providing low background while maintaining minute amounts of mother liquor around the crystals. The 2 × 2 mm area enables the deposition of up to several microlitres of liquid. Imaging and visualization of the crystals are straightforward on the highly transparent membrane. Thanks to their affordable fabrication, these supports have the potential to become an attractive option for serial experiments at synchrotrons and free-electron lasers.
Frag4Lead: growing crystallographic fragment hits by catalog using fragment-guided template docking
Authors: Metz Alexander , Wollenhaupt Jan , Glöckner Steffen , Messini Niki , Huber Simon , Barthel Tatjana , Merabet Ahmed , Gerber Hans-Dieter , Heine Andreas , Klebe Gerhard , Weiss Manfred S.
Published: August 2021

In recent years, crystallographic fragment screening has matured into an almost routine experiment at several modern synchrotron sites. The hits of the screening experiment,i.e.small molecules or fragments binding to the target protein, are revealed along with their 3D structural information. Therefore, they can serve as useful starting points for further structure-based hit-to-lead development. However, the progression of fragment hits to tool compounds or even leads is often hampered by a lack of chemical feasibility. As an attractive alternative, compound analogs that embed the fragment hit structurally may be obtained from commercial catalogs. Here, a workflow is reported based on filtering and assessing such potential follow-up compounds by template docking. This means that the crystallographic binding pose was integrated into the docking calculations as a central starting parameter. Subsequently, the candidates are scored on their interactions within the binding pocket. In an initial proof-of-concept study using five starting fragments known to bind to the aspartic protease endothiapepsin, 28 follow-up compounds were selected using the designed workflow and their binding was assessed by crystallography. Ten of these compounds bound to the active site and five of them showed significantly increased affinity in isothermal titration calorimetry of up to single-digit micromolar affinity. Taken together, this strategy is capable of efficiently evolving the initial fragment hits without major synthesis efforts and with full control by X-ray crystallography.