bluuebunny/crossref_metadata_2025 huggingface dataset:
96 The pediatric health app landscape: Results of an environmental scan
Authors: Benoit James , Hartling Lisa , Scott Shannon
Published: October 2021

Primary Subject area

Technology

Background

Providing resources that aid in detection and identification of serious childhood illness helps parents feel better equipped to assess their child’s health and significantly changes parental health-seeking behaviours. Some of these resources are limited by accessibility and scalability. Remote locations and staffing limitations create challenges for parents aiming to access health information about their child. Mobile health (mHealth) apps offer a scalable, accessible solution for improving health literacy by enabling access to health information through mobile devices.

Objectives

To systematically identify all Canadian and US child health apps for parents.

Design/Methods

We used an environmental scan approach – a review designed to summarize information for decision makers. The Android and Apple app marketplaces were used as search platforms. We built a list of search terms and used these platforms to search for apps targeted at parents, related to pediatric illnesses in US and Canada. Then once we determined that the app met the inclusion criteria, each included app was assessed using the Mobile App Rating Scale (MARS), a validated tool for assessing health apps. The MARS examines apps on five domains: engagement, functionality, aesthetics, information quality, and subjective quality.

Results

650 unique apps were screened and 53 apps were included. On a scale of 1-5, the 53 apps assessed had an average Engagement score of 2.82/5 (θ = 0.86), Functionality of 3.98/5 (θ = 0.72), Aesthetics of 3.09/5 (θ = 0.87), Information quality of 2.73/5 (θ = 1.32), and Subjective quality of 2.2 (θ = 0.79). App scores ranged from 2.2/5 to 4.5/5 (µ= 3.2, θ =0.6).The top three apps were Baby and Child First Aid (4.5/5), Ada (4.5/5), and HANDi Paediatric (4.2/5). Taken together, the top three apps covered topics of emergency pediatric first aid, identification of (and appropriate response to) common childhood illnesses, a means of checking symptoms, and a means of responding to emergency situations. There was a lack of Canadian-based app content available to parents in both marketplaces. In addition, published evidence of the included apps’ impact was poor: only 5/53 apps had an evidence base showing the app had been trialed.

Conclusion

There is a need for evidence-based apps of Canadian origin related to childhood illnesses. The results of this scan created a picture of the health app landscape by examining trends in apps related to pediatric health that are readily available to parents, and by identifying gaps in app design that can be addressed.
107 Addition of CRP and Respiratory Viral Testing for Risk-Stratification of Febrile Young Infants
Authors: Poirier Cassandra , Filion-Ouellet Emilie , Anderson Gregory , Burstein Brett
Published: October 2021

Primary Subject area

Emergency Medicine - Paediatric

Background

Febrile young infants are frequently brought for medical attention. Although most have viral illnesses, approximately 10% have serious bacterial infections (SBIs) including urinary tract infections, bacteremia or bacterial meningitis. Risk-stratification must have high sensitivity given the consequences of a missed SBI diagnosis. The most widely used risk-stratification criteria rely upon the serum white blood cell count (WBC) and urinalysis (UA), but predate the widespread use of CRP and respiratory virus testing (RVT), both of which offer enhanced ability to detect high-risk infants. CRP and RVT have never been evaluated together or in combination with traditional biomarkers, particularly for the detection invasive bacterial infections (IBI), bacteremia and meningitis.

Objectives

Compare the diagnostic utility of CRP and RVT in combination with WBC and UA for risk-stratification of febrile young infants.

Design/Methods

This was a retrospective study of healthy term febrile infants ≤ 90 days old evaluated in an urban tertiary Pediatric Emergency Department from 2010-2018. Only infants with both blood and urine cultures were included. Test characteristics for detecting SBI and IBI were calculated for tests individually and in composite.

Results

Of 3461 included infants, 442 (12.7%) had SBIs and 56 (1.6%) had IBIs. Overall use of CRP (25%) and RVT (78%) increased over time, and 698 (22%) infants had complete testing with UA, WBC, CRP and RVT. When considering individual diagnostic tests (Table 1), risk of SBI with a normal CRP (1.4%), negative UA (0.18%) or positive RVT (2.6%) was lower than with a normal WBC (6.7%) alone. Risk of IBI was lowest among infants with a positive RVT (0.19%; vs 0.57%, 0.59%, 0.70% for CRP, UA, WBC respectively), and RVT performed best for detection of IBI (Sn 0.857; NPV 0.996). When risk-stratifying infants using tests in combination (Table 2), 43/3339 (1.3%) infants had a SBI despite meeting low-risk criteria with a normal WBC and UA (Sn 0.900; NPV 0.980), compared to 4/698 (0.57%) with a normal WBC, UA, CRP and positive RVT (Sn 0.951; NPV 0.981). IBI was present in 10/3339 (0.3%) infants stratified as low-risk by a normal WBC and UA (Sn 0.818; NPV 0.995), compared to 0/698 (0%) with a normal WBC, UA, CRP and positive RVT (Sn 1.00; NPV 1.00). Subanalysis restricted only to infants with complete testing yielded similar results.

Conclusion

This is the first study to compare use of CRP and RVT in addition to traditional biomarkers for febrile young infants. Use of these widely available tests in combination may improve risk-stratification to reduce unnecessary invasive testing and hospitalizations. Prospective efficacy and cost-effectiveness studies are warranted.
109 Effectiveness of Neuromuscular Electrical Stimulation for Children with Dysphagia: A Systematic Review
Authors: Propp Roni , Gill Peter , Marcus Sherna , Ren Lily Yuxi , Cohen Eyal , Friedman Jeremy , Mahant Sanjay
Published: October 2021

Primary Subject area

Complex Care

Background

Dysphagia is common in children with medical complexity and can result in undernutrition, respiratory complications and negatively impact child and caregiver quality of life; however, evidence on the effectiveness of treatments for dysphagia in children is limited. Neuromuscular electrical stimulation (NMES) is a novel proposed treatment for dysphagia where electrical current is applied to neck muscles using cutaneous electrodes during swallowing therapy. It is hypothesized that NMES improves dysphagia by strengthening swallowing muscles and/or enhancing sensory signals of the swallowing response.

Objectives

To systematically review the evidence on the effectiveness of NMES for treatment of oropharyngeal dysphagia in children.

Design/Methods

MEDLINE, EMBASE, PsycINFO, CINAHL, CENTRAL and Scopus databases were searched from inception to November 2020. Studies of children (18 years and younger) diagnosed with oropharyngeal dysphagia using NMES in the throat/neck region were included. Screening, data extraction, and risk of bias assessment followed PRISMA guidelines. Risk of bias was assessed using the Cochrane Collaboration’s tool for RCTs and the Newcastle-Ottawa tool for observational studies. [Registration: PROSPERO CRD42019147353]

Results

Of the 844 records screened, 26 were identified for full text review, and 8 studies were included (4 RCTs and 4 cohort studies). These studies represented 338 children, with a mean (or median) age below 7 years, including children with and without neurological impairments. In all studies, swallowing function as measured by imaging studies improved after NMES treatment; in the trials, the standardized mean difference ranged from 0.32 (95% CI -0.56, 1.20) to 1.18 (95% CI 0.40, 1.97) compared to control groups who received usual care without NMES. Seven of eight studies reported on the child’s feeding ability, and, with one exception, there was improvement in feeding ability (Figure 1). Few studies reported on health status (N=1), child’s quality of life (N=1), and adverse events and harms (N=1). No studies reported on the social impact on the child, impact on the caregiver, and the caregiver’s quality of life. In most studies, outcome follow-up was limited to less than 6 months. Overall, the studies demonstrated moderate to high risk of bias. A pooled intervention effect and meta-analysis was not conducted due to clinical heterogeneity.

Conclusion

NMES treatment may be beneficial in improving swallowing function for children with dysphagia, however, given the quality of the studies, inadequate outcome reporting, and short follow-up duration, additional well-designed RCTs are needed to establish its effectiveness.
110 Interim Federal Health Program (IFHP): Survey of Access & Utilization by Pediatric Health Care Providers
Authors: Leps Caroline , Monteiro Jessica , Barozzino Tony , Bowry Ashna , Rashid Meb , Sgro Michael , Suleman Shazeen
Published: October 2021

Primary Subject area

Public Health and Preventive Medicine

Background

Canada is currently facing an increasing number of refugees and refugee claimants, yet Canadian health professionals are underutilizing the system intended to provide these individuals with healthcare. The Interim Federal Health Program (IFHP) provides temporary healthcare coverage for those who are ineligible for provincial or territorial insurance, including resettled refugees and asylum seekers. Research suggests there are ongoing challenges around the program such as who is covered and what services are covered.

Objectives

The objective of this study was to assess Canadian pediatricians’ current understanding and utilization of the IFHP, and perceived barriers to its utilization.

Design/Methods

A one-time survey was administered via the Canadian Paediatric Surveillance Program. The ten question adaptive survey was available in English or French, in either paper or electronic format. Survey responses were collected for 6 weeks in early 2020 with two reminders sent prior to survey closing. In addition to descriptive statistics, multinomial logistic regressions were built to examine pediatrician use of the IFHP, work with IFHP-covered patients, and provider characteristics associated with registration and use.

Results

Of the 2,753 pediatricians and pediatric subspecialists surveyed, there were 1006 respondents (36.5% response rate). 52.2% of respondents had provided care to the IFHP-eligible patients in the previous 6 months. Of those participants, only 26.4% were registered IFHP providers, and just 10% could identify all services covered by the IFHP (Figure 1). Knowledge of 80% or more of supplemental benefits was associated with registration status (adjusted odds ratio [aOR] 1.92; 95% CI 1.09 - 3.37). Amongst those who knew they were not registered, 70.2% indicated they did not know they had to register. aOR demonstrated that those with fewer years of practice had higher odds of not knowing that they had to register (aOR 1.22; 95% CI 1.01 - 1.49)

Conclusion

We demonstrate that the IFHP is poorly utilized by pediatric providers, with low registration rates and poor understanding of the IFHP-covered supplemental services, even among those who have recently provided care to the IFHP-eligible patients. Efforts to improve registration and knowledge of the IFHP are essential to improving access to health care for refugee children and youth.

Funding: Study funded by the CPSP Resident Research Grant
126 BRUE and evaluation of higher-risk infants with overnight oximetry
Authors: Morin-Gagnon Raphaël , Gagnon Josée-Anne
Published: October 2021

Primary Subject area

Hospital Paediatrics

Background

BRUE (Brief resolved unexplained event) is a worrisome event for parents. Investigation guidelines for infants 2 months and older have been published, but an evaluation framework for higher-risk infants is still evolving.

Objectives

The goal of this study is to determine if an overnight oximetry for patients presenting with BRUE under the age of the 2 months would help to target patients at higher risk of recurrent BRUE. The secondary goals are to evaluate the characteristics of those infants, the rate of recurrence of BRUE and to evaluate the effectiveness of other investigations.

Design/Methods

This was an observational retrospective study of infants presenting with BRUE between the age of 7 days and 60 days between January 1 2010 and October 1 of 2018. Patients were selected if they matched the definition of BRUE defined by the American Academy of Pediatrics in 2016. Patient demographics and antecedents, characteristics of the events, investigations results, recurrence of BRUE, and hospitalizations until the age of 1 year were recorded.

Results

103 patients presented with BRUE under the age of 2 months. Of those, 63 (61.2%) were boys. Only four (3.9%) had a recurrence of BRUE. The mean corrected age at the presentation was 20.7 days. Thirty-three (32%) infants had an overnight oximetry; of those 19 (18.4%) had an abnormal result. An abnormal overnight oximetry result was associated with a lower risk of recurrent BRUE (0%) compared to infants without an oximetry (4.3%) or with a negative result (7.1%) (p=0.6195). 68.4% of patients with an abnormal overnight oximetry had received medical treatment (caffeine, oxygen or anti-acid), which was significantly higher than those with normal overnight oximetry (14.3%) or no oximetry (9.4%) (p < 0.0001). There was an association between male sex and abnormal overnight oximetry (p=0.0137). No other investigation was able to predict a higher risk of recurrent BRUE among those evaluated.

Conclusion

In our cohort, boys were more frequently affected and had a higher rate of abnormal overnight oximetry. One hypothesis is that BRUE under 2 months of age might be a presentation mode for immature respiratory control and boys might be at higher risk for such events. Even though an abnormal result was present in 18.4% of the overnight oximetry, this investigation was not able to identify infants at higher risk of recurrent BRUE. This could be partly explained by the fact that a recurrent BRUE is a rare event and that a majority of patients with abnormal overnight oximetry were treated medically, which might have prevented recurrence.
142 Costs Associated with Fetal Alcohol Spectrum Disorder: A comparison of Indigenous and Non-Indigenous Children
Authors: Stade Brenda , Gideon James , Bonifacio Joey (Herbert) , Campbell Douglas , Sgro Michael
Published: October 2021

Primary Subject area

Developmental Paediatrics

Background

The incidence of Fetal Alcohol Spectrum Disorder (FASD) is estimated to be 1 in 100 live births. Caused by prenatal exposure to alcohol, FASD is the leading cause of developmental and cognitive disabilities among Ontario’s children. No study has conducted a comparison of the costs associated with FASD among Indigenous children, and Non-Indigenous children.

Objectives

To calculate and compare an estimate of direct and indirect costs associated with FASD at the patient level among Indigenous children and Non-Indigenous children living in Ontario.

Design/Methods

A cross-sectional study design was used. Eight-hundred and thirty (830) participants completed the study tool. Participants included caregivers of children aged 3 months to 17.5 years, living in urban and rural communities throughout Ontario. Four-hundred and twelve (412) participants were Indigenous Ontarians, and 418 participants were Non-Indigenous Ontarians. Participants completed the Health Services Utilization Inventory (HSUI). Key cost components were elicited: direct costs (medical, education, social services, out-of-pocket costs); and indirect costs (productivity losses). Total average costs per child with FASD were calculated by summing the costs for each, in each cost component, and dividing by the sample size. Costs were extrapolated to one year. A t-test was used to compare costs associated with FASD in the two groups. A stepwise multiple regression analysis was used to identify significant determinants of costs.

Results

Total adjusted annual costs associated with FASD at the individual level was $51,543 (95% CI $46,825; $56,642) among Indigenous children compared to $36,435 (95% CI $31,935; $42,245), among Non-Indigenous children (p<0.01). Severity of the child’s condition and relationship of the child to the caregiver (biological, adoptive, foster) were significant determinants of costs in both groups (p < 0 .01). Age of diagnosis was a significant determinant of costs among the Indigenous group (p < 0.001) but was not a significant determinant in the Non-Indigenous group. On average, Indigenous children were diagnosed with FASD 3.9 years later than Non-Indigenous children.

Conclusion

Study results demonstrated the cost associated with FASD in Ontario was significantly greater among Indigenous children compared to Non-Indigenous children. Implications for practice, policy, and research are discussed.
A bifunctional MXene-modified scaffold for photothermal therapy and maxillofacial tissue regeneration
Authors: Li Fengji , Yan Yanling , Wang Yanan , Fan Yaru , Zou Huiru , Liu Han , Luo Rui , Li Ruixin , Liu Hao
Published: October 2021

Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumours in the oral and maxillofacial regions and is highly malignant and prone to recur despite the development of various effective treatments, including surgery and chemoradiotherapy. Actually, it is difficult to ensure the complete elimination of tumour cells, and maxillofacial bone defects caused by surgery are hard to heal by themselves. In addition, chemoradiotherapy can bring serious side effects. Therefore, it is imperative to develop a postoperative therapy to kill residual squamous cancer cells and repair bone defects without any side effects. Here, we prepared a three-dimensional (3D) scaffold by a 3D printing technique and freeze-drying method, which contained collagen, silk and hydroxyapatite (CSH) and was functionalized with MXene nanosheets (M-CSH). The considerable photothermal effect with long-term stability can significantly kill squamous CAL-27 cancer cells in vitro and inhibit tumour growth in vivo, increasing the probability of the M-CSH scaffold being applied in the photothermal therapy of OSCC. Moreover, the cell proliferation- and osteogenic-related protein expression of mouse embryonic osteogenic precursors (MC3T3-E1) indicated excellent biocompatibility and osteogenic activity of M-CSH scaffolds. The good compression modulus (52.83 ± 2.25 kPa) and in vivo bone formation performance made it possible to be used as reconstructive materials for bone defects. This scaffold is likely promising in future tissue engineering, especially for the multifunctional treatment of maxillofacial tumours.
Tick virome diversity in Hubei Province, China, and the influence of host ecology
Authors: Xu Lin , Guo Moujian , Hu Bing , Zhou Hong , Yang Wei , Hui Lixia , Huang Rui , Zhan Jianbo , Shi Weifeng , Wu Ying
Published: November 2021

Ticks are important vector hosts of pathogens which cause human and animal diseases worldwide. Diverse viruses have been discovered in ticks; however, little is known about the ecological factors that affect the tick virome composition and evolution. Herein, we employed RNA sequencing to study the virome diversity of the Haemaphysalis longicornis and Rhipicephalus microplus ticks sampled in Hubei Province in China. Twelve RNA viruses with complete genomes were identified, which belonged to six viral families: Flaviviridae, Matonaviridae, Peribunyaviridae, Nairoviridae, Phenuiviridae, and Rhabdoviridae. These viruses showed great diversity in their genome organization and evolution, four of which were proposed to be novel species. The virome diversity and abundance of R. microplus ticks fed on cattle were evidently high. Further ecological analyses suggested that host species and feeding status may be key factors affecting the tick virome structure. This study described a number of novel viral species and variants from ticks and, more importantly, provided insights into the ecological factors shaping the virome structures of ticks, although it clearly warrants further investigation.
Hypothesis awareness confounds asynchronous control conditions in indirect measures of the rubber hand illusion
Authors: Lush P. , Seth A. K. , Dienes Z.
Published: November 2021

Reports of changes in experiences of body location and ownership following synchronous tactile and visual stimulation of fake and real hands (rubber hand (RH) effects) are widely attributed to multisensory integration mechanisms. However, existing control methods for subjective report measures (asynchronous stroking and control statements) are confounded by participant hypothesis awareness; the report may reflect response to demand characteristics. Subjective report is often accompanied by indirect (also called ‘objective’ or ‘implicit’) measures. Here, we report tests of expectancies for synchronous ‘illusion’ and asynchronous ‘control’ conditions across two pre-registered studies (
n
= 140 and
n
= 45) for two indirect measures: proprioceptive drift (a change in perceived hand location) and skin conductance response (a measure of physiological arousal). Expectancies for synchronous condition measures were greater than for asynchronous conditions in both studies. Differences between synchronous and asynchronous control condition measures are therefore confounded by hypothesis awareness. This means indirect measures of RH effects may reflect compliance, bias and phenomenological control in response to demand characteristics, just as for subjective measures. Valid control measures are required to support claims of a role of multisensory integration for both direct and indirect measures of RH effects.
Cluster detection with random neighbourhood covering: application to invasive Group A Streptococcal disease
Authors: Cavallaro Massimo , Coelho Juliana , Ready Derren , Decraene Valerie , Lamagni Theresa , McCarthy Noel D. , Todkill Dan , Keeling Matt J.
Published: October 2021

The rapid detection of outbreaks is a key step in the effective control and containment of infectious diseases. In particular, the identification of cases which might be epidemiologically linked is crucial in directing outbreak-containment efforts shaping the intervention of public health authorities. Often this requires the detection of clusters of cases whose numbers exceed those expected by a background of sporadic cases. Quantifying exceedances rapidly is particularly challenging when only few cases are typically reported in a precise location and time. To address such important public health concerns, we present a general method which can detect spatio-temporal deviations from a Poisson point process and estimate the odd of an isolate being part of a cluster. This method can be applied to diseases where detailed geographical information is available. In addition, we propose an approach to explicitly take account of delays in microbial typing. As a case study, we considered invasive group A Streptococcus infection events as recorded and typed by Public Health England from 2015 to 2020.
Deep neural networks learn general and clinically relevant representations of the ageing brain
Authors: Leonardsen Esten H. , Peng Han , Kaufmann Tobias , Agartz Ingrid , Andreassen Ole A. , Celius Elisabeth Gulowsen , Espeseth Thomas , Harbo Hanne F. , Høgestøl Einar A. , de Lange Ann-Marie , Marquand Andre F. , Vidal-Piñeiro Didac , Roe James M. , Selbæk Geir , Sørensen Øystein , Smith Stephen M. , Westlye Lars T. , Wolfers Thomas , Wang Yunpeng
Published: October 2021

The discrepancy between chronological age and the apparent age of the brain based on neuroimaging data — the brain age delta — has emerged as a reliable marker of brain health. With an increasing wealth of data, approaches to tackle heterogeneity in data acquisition are vital. To this end, we compiled raw structural magnetic resonance images into one of the largest and most diverse datasets assembled (n=53542), and trained convolutional neural networks (CNNs) to predict age. We achieved state-of-the-art performance on unseen data from unknown scanners (n=2553), and showed that higher brain age delta is associated with diabetes, alcohol intake and smoking. Using transfer learning, the intermediate representations learned by our model complemented and partly outperformed brain age delta in predicting common brain disorders. Our work shows we can achieve generalizable and biologically plausible brain age predictions using CNNs trained on heterogeneous datasets, and transfer them to clinical use cases.
A Hidden Structural Variation in a Known IRD Gene: A Cautionary Tale of Two New Disease Candidate Genes
Authors: Scott Hilary A. , Larson Anna , Rong Shi Song , Mehrotra Sudeep , Butcher Rossano , Chao Katherine R. , Wiggs Janey L. , Place Emily M. , Pierce Eric A. , Bujakowska Kinga M.
Published: October 2021

Rod cone dystrophy (RCD), also known as retinitis pigmentosa, is an inherited condition leading to vision loss, affecting 1/3500 people. Over 270 genes are known to be implicated in the inherited retinal degenerations (IRDs), yet genetic diagnosis for ∼30% IRD of patients remains elusive despite advances in sequencing technologies. The goal of this study was to determine the genetic causality in a family with Rod-cone dystrophy (RCD). Family members were given a full ophthalmic exam at the Retinal Service at MEE and consented to genetic testing. Whole exome sequencing (WES) was performed and variants of interest were Sanger validated. Functional assays were conducted in zebrafish along with splicing assays in relevant cell lines to determine the impact on retinal function.

WES identified variants in two potential candidate genes that segregated with disease: GNL3 (G Protein Nucleolar 3) c.1187+3A>C and c.1568-8C>A; and PDE4DIP (Phosphodiester 4D Interacting Protein) c.3868G>A (p.Glu1290Lys) and c.4603G>A (p.Ala1535Thr). Both genes were promising candidates based on their retinal involvement (development and interactions with IRD-associated proteins), however the functional assays did not validate either gene. Subsequent WES reanalysis with an updated bioinformatics pipeline and widened search parameters led to the detection of a 94bp duplication in PRPF31 (pre-mRNA Processing Factor 31) c.73_266dup (p.Asp56GlyfsTer33) as the causal variant.

Our study demonstrates the importance of thorough functional characterization of new disease candidate genes, and the value of reanalyzing NGS sequence data, which in our case led to identification of a hidden pathogenic variant in a known IRD gene.
Onset and stepwise extensions of recombination suppression are common in mating-type chromosomes of Microbotryum anther-smut fungi
Authors: Duhamel Marine , Carpentier Fantin , Begerow Dominik , Hood Michael E. , de la Vega Ricardo C. Rodríguez , Giraud Tatiana
Published: October 2021

Sex chromosomes and mating-type chromosomes can display large genomic regions without recombination. Recombination suppression often extended stepwise with time away from the sex- or mating-type-determining genes, generating evolutionary strata of differentiation between alternative sex or mating-type chromosomes. In anther-smut fungi of the Microbotryum genus, recombination suppression evolved repeatedly, linking the two mating-type loci and extended multiple times in regions distal to the mating-type genes. Here, we obtained high-quality genome assemblies of alternative mating types for four Microbotryum fungi. We found an additional event of independent chromosomal rearrangements bringing the two mating-type loci on the same chromosome followed by recombination suppression linking them. We also found, in a new clade analysed here, that recombination suppression between the two mating-type loci occurred in several steps, with first an ancestral recombination suppression between one of the mating-type locus and its centromere; later, completion of recombination suppression up to the second mating-type locus occurred independently in three species. The estimated dates of recombination suppression between the mating-type loci ranged from 0.15 to 3.58 million years ago. In total, this makes at least nine independent events of linkage between the mating-type loci across the Microbotryum genus. Several mating-type locus linkage events occurred through the same types of chromosomal rearrangements, where similar chromosome fissions at centromeres represent convergence in the genomic changes leading to the phenotypic convergence. These findings further highlight Microbotryum fungi as excellent models to study the evolution of recombination suppression.
Promoter sequence and architecture determine expression variability and confer robustness to genetic variants
Authors: Einarsson Hjörleifur , Salvatore Marco , Vaagensø Christian , Alcaraz Nicolas , Bornholdt Jette , Rennie Sarah , Andersson Robin
Published: October 2021

Genetic and environmental exposures cause variability in gene expression. Although most genes are affected in a population, their effect sizes vary greatly, indicating the existence of regulatory mechanisms that could amplify or attenuate expression variability. Here, we investigate the relationship between the sequence and transcription start site architectures of promoters and their expression variability across human individuals. We find that expression variability can be largely explained by a promoter’s DNA sequence and its binding sites for specific transcription factors. We show that promoter expression variability reflects the biological process of a gene, demonstrating a selective trade-off between stability for metabolic genes and plasticity for responsive genes and those involved in signaling. Promoters with a rigid transcription start site architecture are more prone to have variable expression and to be associated with genetic variants with large effect sizes, while a flexible usage of transcription start sites within a promoter attenuates expression variability and limits genotypic effects. Our work provides insights into the variable nature of responsive genes and reveals a novel mechanism for supplying transcriptional and mutational robustness to essential genes through multiple transcription start site regions within a promoter.
PlasmodiumDDI1 is a potential therapeutic target and important chromatin-associated protein
Authors: Tanneru Nandita , Nivya M Angel , Adhikari Navin , Saxena Kanika , Rizvi Zeba , Sudhakar Renu , Nagwani Amit Kumar , Atul  , Abdul Al-Nihmi Faisal Mohammed , Kota Arun Kumar , Sijwali Puran Singh
Published: October 2021

DDI1 proteins are involved in a variety of cellular processes, including proteasomal degradation of specific proteins. All DDI1 proteins contain a ubiquitin-like (UBL) domain and a retroviral aspartyl protease (RVP) domain. Some DDI1 proteins also contain a ubiquitin-associated (UBA) domain. The three domains confer distinct activities to DDI1 proteins. The presence of RVP domain makes DDI1 a potential target of HIV protease inhibitors, which also block the development of malaria parasites. Hence, we investigated the DDI1 of malaria parasites to identify its roles during parasite development and potential as a therapeutic target. DDI1 proteins ofPlasmodiumand other Apicomplexan parasites share the UBL-RVP domain architecture, and some also contain the UBA domain.PlasmodiumDDI1 is expressed across all the major life cycle stages and is important for parasite survival, as conditional depletion of DDI1 protein in the mouse malaria parasitePlasmodium bergheiand the human malaria parasitePlasmodium falciparumcompromised parasite development. Infection of mice with DDI1 knock-downP. bergheiwas self-limiting and protected the recovered mice from subsequent infection with homologous as well as heterologous parasites, indicating potential of DDI1 knock-down parasites as a whole organism vaccine.P. falciparumDDI1 (PfDDI1) is associated with chromatin and DNA-protein crosslinks. PfDDI1-depleted parasites accumulated DNA-protein crosslinks and showed enhanced susceptibility to DNA damaging chemicals, indicating a role of PfDDI1 in removal of DNA-protein crosslinks. Knock-down of PfDDI1 increased susceptibility to the retroviral protease inhibitor lopinavir and antimalarial artemisinin, which suggests that simultaneous inhibition of DDI1 could potentiate antimalarial activity of these drugs. As DDI1 knock-down parasites confer protective immunity and it could be a target of HIV protease inhibitors,PlasmodiumDDI1 is a potential therapeutic target for malaria control.
Resistance-guided mining of bacterial genotoxins defines a family of DNA glycosylases
Authors: Bradley Noah P. , Wahl Katherine L. , Steenwyk Jacob L. , Rokas Antonis , Eichman Brandt F.
Published: October 2021

Unique DNA repair enzymes that provide self-resistance against genotoxic natural products have been discovered recently in bacterial biosynthetic gene clusters (BGCs). The DNA glycosylase AlkZ belongs to a superfamily of uncharacterized proteins found in antibiotic producers and pathogens, but despite its importance to azinomycin B resistance, the roles of AlkZ orthologs in production of other natural products are unknown. Here, we analyze the genomic distribution and use a resistance-based genome mining approach to identifyStreptomycesAlkZ homologs associated with known and uncharacterized BGCs. We show that the ortholog associated with synthesis of the alkylating agent hedamycin excises hedamycin-DNA adducts and provides resistance to the genotoxin in cells. Our results define AlkZ in self-resistance to specific antimicrobials and implicate a related but distinct homolog, which we name AlkX, in protection against an array of genotoxins. This work provides a framework for targeted discovery of new genotoxic compounds with therapeutic potential.
The behavioral variant of Alzheimer’s disease does not show a selective loss of Von Economo and phylogenetically related neurons in the anterior cingulate cortex
Authors: Singleton E.H. , Pijnenburg Y.A.L , Gami-Patel P. , Boon B.D.C. , Bouwman F. , Papma J. , Seelaar H. , Scheltens P. , Grinberg L.T. , Spina S. , Nana A.L. , Rabinovici G.D. , Seeley W.W. , Ossenkoppele R. , Dijkstra A.A.
Published: October 2021

Background

The neurobiological origins of the early and predominant behavioral changes seen in the behavioral variant of Alzheimer’s disease (bvAD) remain unclear. A selective loss of Von Economo Neurons (VENs) and phylogenetically related neurons have been observed in behavioral variant frontotemporal dementia (bvFTD) and several psychiatric diseases. Here, we assessed whether these specific neuronal populations show a selective loss in bvAD.

Methods

VENs and GABA receptor subunit theta (GABRQ)-immunoreactive pyramidal neurons of the anterior cingulate cortex (ACC) were quantified in post-mortem tissue of patients with bvAD (n=9) and compared to typical AD (tAD, n=6), bvFTD due to frontotemporal lobar degeneration based on TDP-43 pathology (FTLD, n=18) and controls (n=13) using ANCOVAs adjusted for age and Bonferroni correceted. In addition, ratios of VENs and GABRQ-immunoreactive (GABRQ-ir) pyramidal neurons over all Layer 5 neurons were compared between groups to correct for overall Layer 5 neuronal loss.

Results

The number of VENs or GABRQ-ir neurons did not differ significantly between bvAD (VENs: 26.0±15.3, GABRQ-ir pyramidal: 260.44±87.13) and tAD (VENs: 32.0±18.1,p=1.00, GABRQ-ir pyramidal: 349.83±109.64,p=0.38) and controls (VENs: 33.5±20.3,p=1.00, GABRQ-ir pyramidal: 339.38±95.88,p=0.37). Compared to bvFTD, patients with bvAD showed significantly more GABRQ-ir pyramidal neurons (bvFTD: 140.39±82.58,p=0.01) and no significant differences in number of VENs (bvFTD: 10.9±13.8,p=0.13). Results were similar when assessing the number of VENs and GABRQ-ir relative to all neurons of Layer 5.

Discussion

VENs and phylogenetically related neurons did not show a selective loss in the ACC in patients with bvAD. Our results suggest that, unlike in bvFTD, the clinical presentation in bvAD may not be related to the loss of VENs and related neurons in the ACC.
A neural substrate for Bayesian integration in human parietal cortex
Authors: Singletary Nicholas M. , Gottlieb Jacqueline , Horga Guillermo
Published: October 2021

Making adaptive decisions often requires inferring unobservable states based on unreliable information. Bayesian logic prescribes that individuals form probabilistic beliefs about a state by integrating the likelihood of new evidence with their prior beliefs, but human neuroimaging studies on probability representations have not typically examined this integration process. We developed an inference fMRI task in which participants estimated the posterior probability of a hidden state while we parametrically modulated the prior probability of the state, the likelihood of the supporting evidence, and a monetary penalty for estimation inaccuracy. Consistent with a neural substrate for Bayesian integration, activation in left posterior parietal cortex tracked the estimated posterior probability of the solicited state and its components of prior probability and likelihood, all independently of expected value. This activation further reflected deviations in individual reports from objective probabilities. Thus, this region may provide a neural substrate for humans’ ability to approximate Bayesian inference.
Chimeric chromosome landscapes of human somatic cell cultures show dependence on stress and regulation of genomic repeats by CGGBP1
Authors: Datta Subhamoy , Patel Manthan , Kashyap Sukesh , Patel Divyesh , Singh Umashankar
Published: October 2021

Genomes of somatic cells in culture are prone to spontaneous mutations due to errors in replication and DNA repair. Some of these errors, such as chromosomal fusions, are not rectifiable and subject to selection or elimination in growing cultures. Somatic cell cultures are thus expected to generate background levels of potentially stable chromosomal chimeras. A description of the landscape of such spontaneously generated chromosomal chimeras in cultured cells will help us understand the factors affecting somatic mosaicism. Here we show that short homology-associated non-homologous chromosomal chimeras occur in normal human fibroblasts and HEK293T cells at genomic repeats. The occurrence of chromosomal chimeras is enhanced by heat stress and depletion of a repeat regulatory protein CGGBP1. We also present evidence of homologous chromosomal chimeras between allelic copies in repeat-rich DNA obtained by methylcytosine immunoprecipitation. The formation of homologous chromosomal chimeras at Alu and L1 repeats increases upon depletion of CGGBP1. Our data are derived fromde novosequencing from three different cell lines under different experimental conditions and our chromosomal chimera detection pipeline is applicable to long read as well as short read sequencing platforms. These findings present significant information about the generation, sensitivity and regulation of somatic mosaicism in human cell cultures.
Netrins and receptors control Drosophila optic lobe organization and transmedullary neuron axon targeting
Authors: Zhang Yu , Lowe Scott , Li Xin
Published: October 2021

During development, integration of temporal patterning and spatial patterning of neural progenitors as well as Notch-dependent binary fate choice between sister neurons contribute to generation of neural diversity. How these upstream neural fate specification programs regulate downstream effector genes to control axon targeting and neuropil assembly remains less well-understood. Here we show that Notch-dependent binary fate choice in Drosophila medulla neurons regulates the expression of Netrin, and that Netrin pathway controls axon guidance of transmedullary (Tm) neurons and contributes to the organization of optic lobe neuropils. Netrins are enriched in the lobula where Tm axons target, and the attractive receptor Frazzled is expressed broadly in medulla neurons, while the repulsive receptor Unc-5 is excluded from Tm neurons and this is necessary for their correct targeting to the lobula. Frazzled is required collectively in a group of early-born Tm neurons to establish the inner optic chiasm (IOC) through which Tm axons target lobula. In addition, Frazzled acts in the layer-specific targeting step of Tm3 and Tm4 cell-autonomously, and is also required for the formation of the lobula branch of TmY3. Moreover, we show that the diffusibility of Netrins is necessary for Netrin enrichment in the lobula, the IOC formation and layer-specific targeting of Tm3 and Tm4. Netrin enrichment in the lobula is promoted by Frazzled expressed in Tm neurons, while Unc-5 appears to have an opposite role in Netrin distribution. Furthermore, we show that Netrin B is expressed in the Notch-on hemilineage of medulla neurons including most Tm and TmY neurons that target lobula, and loss of Su(H) abolished NetB expression in the medulla. Without medulla-originated NetB, Tm axons from late-born medulla columns cannot join the IOC. Therefore, the Notch-dependent binary fate choice regulates the assembly of the optic lobe neuropils by controlling the expression of Netrin.
Mllt11 regulates the migration and neurite outgrowth of cortical projection neurons during development
Authors: Stanton-Turcotte Danielle , Hsu Karolynn , Moore Samantha A. , Yamada Makiko , Fawcett James P. , Iulianella Angelo
Published: October 2021

The formation of connections within the mammalian neocortex is highly regulated by both extracellular guidance mechanisms and intrinsic gene expression programs. There are generally two types of cortical projection neurons: those that project locally and interhemispherically, and those that project to sub-cerebral structures such as the thalamus, hindbrain, and spinal cord. The regulation of cortical projection morphologies is not yet fully understood at the molecular level. Here we report a role for Mllt11 (Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene From Chromosome 1q) in the migration and neurite outgrowth of callosal projection neurons during brain formation. We show that Mllt11 expression is exclusive to developing neurons and is enriched in the developing cortical plate, particularly during the formation of the upper or superficial cortical layers. In cultured primary cortical neurons, Mllt11 is detected in varicosities and growth cones as well as the soma. Using conditional loss-of-function and gain-of-function analysis we show that Mllt11 is a required for neuritogenesis and proper migration of upper layer cortical projection neurons. Loss of Mllt11 in the superficial cortex leads to a severe reduction in fibres crossing the corpus callosum, a progressive loss in the maintenance of upper layer projection neuron gene expression, and dysplasia of dendritic arborisation patterns. Proteomic analysis revealed that Mllt11 associates with cytoskeletal components including stabilized microtubules consistent with a role in neuronal migration and neuritogenesis. Taken together, our findings support a role for Mllt11 in promoting the formation of mature projection neuron morphologies and connectivity in the cerebral cortex.
Regioisomers of singly bridged calix[6]crown-6 and their heavy alkali metal complexes: a molecular baseball glove for caesium(I)
Authors: Kim Seulgi , Jung Jong Hwa , Lee Shim Sung , Park In-Hyeok
Published: November 2021

We report the formation of heavy alkali metal complexes of bicyclic host molecules including the caesium(I) complex that catches the central metal ion with the deep pocket of the host similar to a baseball glove. For this, three regioisomers of singly bridged calix[6]crown-6 [1,2-bridged (H4
L
1,2), 1,3-bridged (H4
L
1,3) and 1,4-bridged (H4
L
1,4)] have been synthesized by alkylation of calix[6]arene with pentaethylene glycol ditosylate in the presence of M
2CO3 (M = Na, K, Rb and Cs). The larger the cation size of the metal carbonate, the higher the yield of the H4
L
1,4 isomer, indicating the size-based template effect. A combination of H4
L
1,2 and RbOH allowed isolation of the mononuclear rubidium(I) complex (1) in which the metal center is six-coordinated in a loose fashion, the remaining two oxygen donors in the crown loop and two phenols in the calix rim are uncoordinated. Notably, the complexation of H4
L
1,2 with CsOH yielded the mononuclear caesium(I) complex (2), in which all possible ten binding sites on the deep and good-fit pocket participate in coordination via high cooperativity between the crown loop and calix rim, similar to a baseball glove. In dipolar organic solution, the caesium(I) complex 2 remains intact. H4
L
1,4 afforded a dicesium(I) complex (3) and adjacent complexes are linked by intermolecular cation–π interactions, giving rise to a pseudo one-dimensional coordination polymer. These results provide insight into the metal carbonate-dependent synthesis of calix[6]crowns and the influence of regioisomers on caesium(I) complexation.
A policy prioritization framework using causal layered analysis and MCDM: case study of Iran’s environmental policies
Authors: Fouladgar Mohammad Majid , Borumand Kakhki Ahmad , Nasr Esfehani Alireza , Sedighi Mohammadsadegh
Published: October 2021

Purpose

This paper aims to propose a policy prioritization framework in view of a layered scenario building along with key stakeholder analysis and has been applied in a case study to determine the priority of Iran environmental policies at the horizon of 2030. A creative framework that covers future scenarios and allows for a more accurate and intelligent policy assessment and prioritization.

Design/methodology/approach

The general environmental policies of the Islamic Republic of Iran are evaluated, and observation policies in social area were identified. Causal layered analysis (CLA) is applied for policy prioritization based on layered probable scenarios and key stakeholder role consideration. The Multiple-criteria decision-making (MCDM) is also used for ranking General Environmental Policies by the technique for order of preference by similarity to ideal solution (TOPSIS).

Findings

Four uncertainties were obtained in different layers based on the CLA analysis, resulting in the creation of four main scenario and 16 discrete scenarios. Finally, Iran’s environmental policies were prioritized given the probable scenarios and the centralized policies on the social and political domains. The proposed model will be effective in policy-making in multilateral atmosphere to prioritize policies and alternative macro-strategies.

Originality/value

This paper shows that foresight and especially developed scenarios provide intelligent, efficient and effective planning and policy-making, and in addition to illustrating surrounding changes and probable future imagery, it generates common understanding and inter-subjective knowledge by increasing participation of various officials and stakeholders.