bluuebunny/crossref_metadata_2025 huggingface dataset:
Responding and navigating racialized microaggressions in STEM
Authors: Marshall Andrea , Pack Angela D , Owusu Sarah Afua , Hultman Rainbo , Drake David , Rutaganira Florentine U N , Namwanje Maria , Evans Chantell S , Garza-Lopez Edgar , Lewis Samantha C , Termini Christina M , AshShareef Salma , Hicsasmaz Innes , Taylor Brittany , McReynolds Melanie R , Shuler Haysetta , Hinton Antentor O
Published: May 2021

While it is commonly thought that microaggressions are isolated incidents, microaggressions are ingrained throughout the academic research institution (Young, Anderson and Stewart 2015; Lee et al. 2020). Persons Excluded from science because of Ethnicity and Race (PEERs) frequently experience microaggressions from various academicians, including graduate students, postdocs and faculty (Asai 2020; Lee et al. 2020). Here, we elaborate on a rationale for concrete actions to cope with and diminish acts of microaggressions that may otherwise hinder the inclusion of PEERs. We encourage Science, Technology, Engineering and Mathematics (STEM) departments and leadership to affirm PEER scholar identities and promote allyship by infusing sensitivity, responsiveness and anti-bias awareness.
Genome-wide screening of genes associated with momilactone B sensitivity in the fission yeast Schizosaccharomyces pombe
Authors: Tomita Keisuke , Yashiroda Yoko , Matsuo Yasuhiro , Piotrowski Jeff S , Li Sheena C , Okamoto Reika , Yoshimura Mami , Kimura Hiromi , Kawamura Yumi , Kawamukai Makoto , Boone Charles , Yoshida Minoru , Nojiri Hideaki , Okada Kazunori
Published: May 2021

Momilactone B is a natural product with dual biological activities, including antimicrobial and allelopathic properties, and plays a major role in plant chemical defense against competitive plants and pathogens. The pharmacological effects of momilactone B on mammalian cells have also been reported. However, little is known about the molecular and cellular mechanisms underlying its broad bioactivity. In this study, the genetic determinants of momilactone B sensitivity in yeast were explored to gain insight into its mode of action. We screened fission yeast mutants resistant to momilactone B from a pooled culture containing genome-wide gene-overexpressing strains in a drug-hypersensitive genetic background. Overexpression of pmd1, bfr1, pap1, arp9, or SPAC9E9.06c conferred resistance to momilactone B. In addition, a drug-hypersensitive, barcoded deletion library was newly constructed and the genes that imparted altered sensitivity to momilactone B upon deletion were identified. Gene Ontology and fission yeast phenotype ontology enrichment analyses predicted the biological pathways related to the mode of action of momilactone B. The validation of predictions revealed that momilactone B induced abnormal phenotypes such as multiseptated cells and disrupted organization of the microtubule structure. This is the first investigation of the mechanism underlying the antifungal activity of momilactone B against yeast. The results and datasets obtained in this study narrow the possible targets of momilactone B and facilitate further studies regarding its mode of action.
Maternal Factors Predicting Loss to Follow-Up from Newborn Hearing Screenings in New Jersey
Authors: Zeitlin Wendy , McInerney MaryRose , Aveni Kathryn , Scheperle Rachel , DeCristofano Angela
Published: May 2021

Because hearing loss in children can result in developmental deficits, early detection and intervention are critical. This article identifies a constellation of maternal factors that predict loss to follow-up (LTF) at the point of rescreening—the first follow-up for babies who did not pass the hearing screening performed at birth—through New Jersey’s early hearing detection and intervention program. Maternal factors are critical to consider, as mothers are often the primary decision makers around children’s health care. All data were obtained from the state’s department of health and included babies born between June 2015 and June 2017. Logistic regression was used to predict LTF. Findings indicate that non-Hispanic Black mothers, younger mothers, mothers with previous live births, and mothers with obesity were more likely to be LTF. Hispanic mothers and those enrolled in the state’s Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) program were less likely to be LTF. Mothers most at risk for LTF should be targeted for intervention to help children with hearing loss achieve the benefits from early intervention. Being a WIC recipient is a protective factor for LTF; therefore, elements of WIC could be used to reduce the state’s LTF rate.
Spatially varying phytoplankton seasonality on the Northwest Atlantic Shelf: a model-based assessment of patterns, drivers, and implications
Authors: Zang Zhengchen , Ji Rubao , Feng Zhixuan , Chen Changsheng , Li Siqi , Davis Cabell S
Published: May 2021

The signal of phytoplankton responses to climate-related forcing can be obscured by the heterogeneity of shelf seascapes, making them difficult to detect from fragmented observations. In this study, a physical–biological model was applied to the Northwest Atlantic Shelf to capture the seasonality of phytoplankton. The difference in phytoplankton seasonality between the Mid-Atlantic Bight (MAB) and the Gulf of Maine (GoM) is a result of the interplay between nutrients and temperature: In the MAB, relatively high temperature in the cold season and longer oligotrophic environment in the warm season contribute to an earlier winter bloom and a later fall bloom; in the GoM, low temperature and strong mixing limit phytoplankton growth from late fall to early spring, resulting in a later spring bloom and an earlier fall bloom. Although the temperature difference between the GoM and the MAB might decrease in the future, stratification and surface nutrient regimes in these two regions will remain different owing to distinct thermohaline structures and deep-water intrusion. The spatial heterogeneity of phytoplankton dynamics affects pelagic and benthic production through connections with zooplankton and benthic–pelagic coupling.
A worst-case approach for interest rate stresses and stock crashes
Authors: Beißer Marcel , Geisinger Leander , Korn Ralf
Published: May 2021

In the current low interest rate environment even sovereign bonds cannot be considered as risk-free investments. To care for this aspect we introduce a worst-case continuous-time portfolio problem with combined stresses, that is, both stocks and the money market account can experience shocks in the form of unpredictable downward jumps in their values. We characterize the worst-case optimal portfolio strategy as an indifference strategy that is the solution of a constrained optimization problem. Our results generalize existing results in a multi-asset setting. Numerical examples demonstrate new effects in the presence of interest rate shocks. These insights can be used for risk management in the presence of crash risks.
Vaccine Effectiveness Following Routine Immunization With Bivalent Human Papillomavirus (HPV) Vaccine: Protection Against Incident Genital HPV Infections From a Reduced-Dosing Schedule
Authors: Hoes Joske , King Audrey J , Klooster Tessa M Schurink van’t , Berkhof Johannes , Bogaards Johannes A , de Melker Hester E
Published: May 2021

Background

In the Netherlands, the bivalent human papillomavirus (HPV) vaccine has been offered to preadolescent girls via the National Immunization Program in a 2-dose schedule since 2014. The current study estimates vaccine effectiveness (VE) against HPV infections up to 4 years postvaccination among girls eligible for routine 2-dose immunization.

Methods

A cohort study (HAVANA2) was used in which participants annually filled out an online questionnaire and provided a vaginal self-sample for determination of HPV by the SPF10-LiPA25 assay, able to detect 25 HPV types. VE against incident type-specific infections and pooled outcomes was estimated by a Cox proportional hazards model with shared frailty between the HPV types.

Results

In total, 2027 girls were included in the study, 1098 (54.2%) of whom were vaccinated with 2 doses. Highest incidence rate was 5.0/1000 person-years (HPV-51) among vaccinated participants and 9.1/1000 person-years (HPV-74) among unvaccinated participants. Adjusted pooled VE was 84.0% (95% confidence interval [CI], 27.0%–96.5%) against incident HPV-16/18 infections and 86.5% (95% CI, 39.5%–97.08%) against cross-protective types HPV-31/33/45.

Conclusions

Four years postvaccination, 2 doses of bivalent HPV vaccine were effective in the prevention of incident HPV-16/18 infections and provided cross-protection to HPV-31/33/45. Our VE estimates rival those from 3-dose schedules, indicating comparable protection by 2-dose schedules.
Ocular transmission and manifestation for coronavirus disease: a systematic review
Authors: Almazroa Ahmed , Alamri Suhailah , Alabdulkader Balsam , Alkozi Hanan , Khan Altaf , Alghamdi Walead
Published: May 2021

Background

There is currently a lack of information regarding ocular tropism and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Globally, the cumulative number of coronavirus disease 2019 (COVID-19) cases is increasing daily. Thus the potential for ocular transmission and manifestations of SARS-CoV-2 requires more investigation.

Methods

A systematic search of electronic databases for ocular transmission and manifestations of SARS-CoV-2 was performed. Pooled cross-sectional studies were used for conducting a meta-analysis to estimate the prevalence of ocular transmission of SARS-CoV-2 to the respiratory system and ocular manifestations (associated symptoms) of SARS-CoV-2.

Results

The highest prevalence of SARS-CoV-2-positive tears using reverse transcription polymerase chain reaction was found to be 7.5%. However, the highest prevalence of ocular conjunctivitis associated with SARS-CoV-2 was 32%. Thus, SARS-CoV-2 can evidently infect the eye, as revealed in the conjunctival secretions of COVID-19 patients.

Conclusion

The available data reflect the influence of the ocular structure on SARS-CoV-2. The analysis showed that ocular manifestation is an indication for SARS-CoV-2, particularly conjunctivitis. Moreover, there is no evidence that the ocular structure can be an additional path of transmission for SARS-CoV-2, however, it warrants further investigation.
Green and Cost-Effective Extraction Techniques of Quercetin from Mixture of Nutraceuticals with Yield Analysis via Spectrophotometry and High-Performance Liquid Chromatography Methods
Authors: Gamal Mohammed , Abd-ElSalam Heba-Alla H , Naguib Ibrahim A , Al-Ghobashy Medhat A , Zaazaa Hala E , Abdelkawy M
Published: May 2021

Background

Extraction is the leading critical stage in the analysis of nutraceuticals. Ginkgo biloba (GB) has gained interest because of its therapeutic usages.

Objectives

The aim was to develop four cost-effective extraction techniques for the extraction of quercetin from GB in a sachet containing a mixture of nutraceuticals. These techniques are solid-phase extraction (SPE), liquid–liquid extraction, inverted dispersive liquid–liquid microextraction, and the QuEChERS (quick, easy, cheap, effective, rugged, and safe) method.

Method

Direct spectrophotometry was used to monitor the recovery of the standard quercetin throughout the optimization steps. The HPLC–UV method of analysis was optimized to quantify the yields from the extracts present in the complicated contents of the sachets. The present study was assessed by analytical Eco-Scale assessment (ESA) and the National Environmental Method Index (NEMI) for greenness in comparison with the literature.

Results

SPE showed the best cleanup outcomes. ESA and NEMI showed an adequate greenness of the proposed extraction protocol.

Conclusions

Quercetin (marker for GB) extraction from market nutraceutical sachets is considered an exemplar for analysis in the QC of nutraceuticals. Regarding the greenness results, the proposed method of extraction is better even with adequate greenness as the extraction was a one-step process, in comparison with multistep processes of previously published protocols. Accordingly, it is recommended for use in routine extraction and analysis of such nutraceuticals.

Highlights

Four extraction protocols have been developed. For GB ternary-mixture sachets, proper recovery was obtained using C18 SPE. The assessment of greenness of the proposed protocol guaranteed the superiority of the presented method. Safer sorbents and chemicals are favored for use in routine extraction of nutraceuticals.
The Development of an Organizational Safety Culture in the United States Forest Service
Authors: Flores David , Haire Emily
Published: May 2021

For over 100 years, the US Forest Service (USFS) has developed initiatives to improve safety outcomes. Herein we discuss the engineered solutions used from 1910 through 1994, when the agency relied on physical science to address the hazards of wildland fire suppression. We then interpret safety initiatives of the subsequent 25 years, as the USFS incorporated social science perspectives both into its understanding of emergency fire incidents and its mitigation of vulnerabilities across all fields of work. Tracing the safety programs using a historical sociology approach, we identify, within the agency’s narrative, three recent developments in its organizational safety culture: cultural awareness, cultural management, and cultural reorganization. This article describes how the development of top-down safety initiatives are questioned and shaped by employees who actively influence the trajectory of a safety culture in the USFS.
Cultural evolution leads to vocal iconicity in an experimental iterated learning task
Authors: Erben Johansson Niklas , Carr Jon W , Kirby Simon
Published: May 2021

Experimental and cross-linguistic studies have shown that vocal iconicity is prevalent in words that carry meanings related to size and shape. Although these studies demonstrate the importance of vocal iconicity and reveal the cognitive biases underpinning it, there is less work demonstrating how these biases lead to the evolution of a sound symbolic lexicon in the first place. In this study, we show how words can be shaped by cognitive biases through cultural evolution. Using a simple experimental setup resembling the game telephone, we examined how a single word form changed as it was passed from one participant to the next by a process of immediate iterated learning. About 1,500 naïve participants were recruited online and divided into five condition groups. The participants in the control-group received no information about the meaning of the word they were about to hear, while the participants in the remaining four groups were informed that the word meant either big or small (with the meaning being presented in text), or round or pointy (with the meaning being presented as a picture). The first participant in a transmission chain was presented with a phonetically diverse word and asked to repeat it. Thereafter, the recording of the repeated word was played for the next participant in the same chain. The sounds of the audio recordings were then transcribed and categorized according to six binary sound parameters. By modelling the proportion of vowels or consonants for each sound parameter, the small-condition showed increases of front unrounded vowels and the pointy-condition increases of acute consonants. The results show that linguistic transmission is sufficient for vocal iconicity to emerge, which demonstrates the role non-arbitrary associations play in the evolution of language.
Sequence-dependent recruitment of SRSF1 and SRSF7 to intronless lncRNA NKILA promotes nuclear export via the TREX/TAP pathway
Authors: Khan Misbah , Hou Shuai , Azam Sikandar , Lei Haixin
Published: May 2021

The TREX-TAP pathway is vital for mRNA export. For spliced mRNA, the TREX complex is recruited during splicing; however, for intronless mRNA, recruitment is sequence dependent. However, the export of cytoplasmic long noncoding RNA (lncRNA) is poorly characterized. We report the identification of a cytoplasmic accumulation region (CAR-N) in the intronless lncRNA, NKILA. CAR-N removal led to strong nuclear retention of NKILA, and CAR-N insertion promoted the export of cDNA transcripts. In vitro RNP purification via CAR-N, mass spectrometry, and siRNA screening revealed that SRSF1 and SRSF7 were vital to NKILA export, and identified a cluster of SRSF1/7 binding sites within a 55 nucleotide sequence in CAR-N. Significant nuclear enrichment of NKILA was observed for NKILA lacking CAR-N or the cluster of binding sites in knock-in models. Depletion of TREX-TAP pathway components resulted in strong nuclear retention of NKILA. RNA and protein immunoprecipitation verified that SRSF1/7 were bound to NKILA and interacted with UAP56 and ALYREF. Moreover, NKILA lacking CAR-N was unable to inhibit breast cancer cell migration. We concluded that the binding of SRSF1/7 to clustered motifs in CAR-N facilitated TREX recruitment, promoting the export of NKILA, and confirmed the importance of NKILA localization to its function.
The Miracle of Mercy
Authors: Campagna Giordana
Published: May 2021

Many states governed by the rule of law provide for mercy powers, most prominently the power to grant pardons. This raises a potential conflict: the rule of law requires that like cases be treated alike. Mercy, on the other hand, is usually understood as being unfettered by legal principles, including the principle of treating like cases alike. Focusing on state officials’ pardon powers as an example of mercy, this article argues that we should conceive of pardons as miracles. Like miracles which suspend individual laws of nature, pardons suspend legal rules on an individual and discretionary basis. Once suspended, the legal rules no longer apply to the given case, and consequently there is no conflict between pardons and the rule of law. As I will show, this discretionary suspension of legal rules is a prerequisite for pardons to fulfil their function as a corrective to undesirable legal results.
Distinct Responses of Vitis aestivalis ‘Norton’ and Vitis vinifera ‘Kishmish Vatkana’ to Seven Viruses Revealed by Small RNA Sequencing
Authors: Howard Susanne , Petersen Sylvia , Uhls Adam , Qiu Wenping
Published: May 2021

Grapevines are frequently infected by multiple viruses. Our previous study showed that Norton grapevine (Vitis aestivalis) is resistant to grapevine vein clearing virus (GVCV), a DNA virus in the family Caulimoviridae. To study the reaction of Norton to RNA viruses, we transferred seven RNA viruses to Norton from Kishmish Vatkana (KV) (V. vinifera) via graft transmission. We profiled viral small RNAs (vsRNAs) of the seven viruses and compared viral titers in Norton and KV. Total vsRNAs of grapevine leafroll-associated virus 1 (GLRaV-1), GLRaV-2, GLRaV-3, grapevine virus A (GVA), and grapevine Pinot gris virus (GPGV) were significantly less abundant in Norton than in KV, but total vsRNAs of grapevine fleck virus (GFkV) were more abundant in Norton than in KV. Total vsRNAs of grapevine rupestris stem pitting-associated virus (GRSPaV) were not different between Norton and KV. Grafting direction of Norton to KV or KV to Norton did not affect the quantity of vsRNAs. The genome coverage of GLRaV-1, GLRaV-2, GLRaV-3, and GVA vsRNAs was lower in Norton than KV. The 21- and 22-nucleotide classes of vsRNAs were predominant for all seven viruses. Virus quantification by quantitative PCR indicated that GLRaV-1 was undetectable in Norton; GLRaV-2, GLRaV-3, and GVA were less abundant in Norton; and GFkV was more abundant in Norton than in KV. These results demonstrated that Norton grapevine suppresses GLRaV-1, GLRaV-2, GLRaV-3, and GVA but supports GFkV in comparison with KV. This study revealed new facets of complex molecular interactions between grapevines and multiple viruses.
Development of a Novel Mentorship Platform to Foster Relational Mentoring, Empowered Vulnerability, and Professional Identity Formation in Undergraduate Medical Education
Authors: Chen Jie Jane , Kusner Jonathan J. , Saldaña Fidencio , Potter Jennifer
Published: May 2021

Problem

Mentorship is valuable to medical students undergoing professional identity formation. Many institutions lack infrastructure to facilitate the personalized mentoring that supports students’ integration of new professional identities with their personal identities and values.

Approach

The authors developed a novel mentorship platform called Weave via a multistep, iterative design process, incorporating in-person and survey-based student and faculty feedback. Features of Weave include clear communication of mentorship offerings and expectations, plus opportunities to engage mentors based on professional and personal (identity-based) attributes. Faculty at Harvard Medical School who created a mentor profile within the first 3 months of launch and students who visited the website within the same period were invited to complete usability surveys in February 2019; students were invited to complete impact surveys in August 2020.

Outcomes

Fifty-two of 132 invited faculty members (39.4%) and 80 of 185 students (43.2%) completed the usability surveys. Most of these faculty (86.5%) and students (73.8%) reported navigating the website was easy/very easy; 36 faculty (69.2%) created a mentor profile within 10 minutes. Key innovations highlighted by faculty and students were the listing of personal attributes and identities of diverse faculty; centralized, increased access to faculty mentors; ease of use; and provision of clear expectations. Nearly all students who completed the impact surveys agreed that Weave allowed them to connect with a faculty mentor whom they would not have found through other sources and to learn about the dimensions of diverse faculty.

Next Steps

Weave is a customizable online mentorship platform that fosters empowered vulnerability and increases dialogue between medical students and faculty based on professional and personal interests and identities. Weave may be expanded to other mentoring contexts and adapted for implementation at other institutions to help cultivate an institutional culture that values mentoring and to strengthen broader diversity and inclusion efforts.
Tryptanthrin Regulates Vascular Smooth Muscle Cell Phenotypic Switching in Atherosclerosis by AMP-Activated Protein Kinase/Acetyl-CoA Carboxylase Signaling Pathway
Authors: Shi Xiujin , Zhang Yi , Han Jialun , Peng Wenxing , Fang Zhenwei , Qin Ying , Xu Xiaoyu , Lin Jie , Xiao Fucheng , Zhao Limin , Lin Yang
Published: May 2021

Atherosclerosis (AS) is one of the most severe cardiovascular diseases involved in the phenotypic switching of vascular smooth muscle cells (VSMCs). Tryptanthrin is a natural product with broad biological activities. However, the effect of tryptanthrin on atherosclerotic progression is unclear. The aim of this study was to determine the role of tryptanthrin in AS and explore the potential mechanism. In vitro, primary VSMCs were stimulated with platelet-derived growth factor-BB (PDGF) to induce cell dedifferentiation. Treatment with tryptanthrin (5 μM or 10 μM) suppressed the proliferation and recovered the contractility of VSMCs in the presence of PDGF. The contractile proteins (α-smooth muscle actin, calponin, and SM22α) were increased, and the synthetic protein vimentin was decreased by tryptanthrin in PDGF-induced VSMCs. ApoE−/− mice fed with high-fat diet were used as an in vivo model of AS. Similarly, gavage administration of tryptanthrin (50 mg/kg or 100 mg/kg) attenuated VSMC phenotypic changes from a contractile to a synthetic state in aortic tissues of AS mice. The serum lipid level, atherosclerotic plaque formation, and arterial intimal hyperplasia were attenuated by tryptanthrin. Furthermore, tryptanthrin increased the expression levels of phosphorylated AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) both in vitro and in vivo. Administration of compound C, an AMPK inhibitor, reversed the inhibitory effect of tryptanthrin on VSMC dedifferentiation in vitro. Thus, we demonstrate that tryptanthrin protects against AS progression through the inhibition of VSMC switching from a contractile to a pathological synthetic phenotype by the activation of AMPK/ACC pathway. It provides novel insights into AS prevention and treatment.
Population Pharmacokinetic Analysis of Dexmedetomidine in Children using Real World Data from Electronic Health Records and Remnant Specimens
Authors: James Nathan T. , Breeyear Joseph H. , Caprioli Richard , Edwards Todd , Hachey Brian , Kannankeril Prince J. , Keaton Jacob M. , Marshall Matthew D. , Van Driest Sara L. , Choi Leena
Published: May 2021

Aim

Our objectives were to perform a population pharmacokinetic analysis of dexmedetomidine in children using remnant specimens and data from electronic health records (EHRs) and explore the impact of patient’s characteristics and pharmacogenetics on dexmedetomidine clearance.

Methods

Dexmedetomidine dosing and patient data were gathered from EHRs and combined with opportunistically sampled remnant specimens. Population pharmacokinetic models were developed using nonlinear mixed-effects modeling. The first stage developed a model without genotype variables; the second stage added pharmacogenetic effects.

Results

Our final study population included 354 post-cardiac surgery patients age 0 to 22 years (median 16 months). The final two-compartment model included allometric weight scaling and age maturation. Population parameter estimates and 95% confidence intervals were 27.3 L/hr (24.0 – 31.1 L/hr) for total clearance (CL), 161 L (139 – 187 L) for central compartment volume of distribution (V1), 26.0 L/hr (22.5 – 30.0 L/hr) for intercompartmental clearance (Q), and 7903 L (5617 – 11119 L) for peripheral compartment volume of distribution (V2). The estimate for postmenstrual age when 50% of adult clearance is achieved was 42.0 weeks (41.5 – 42.5 weeks) and the Hill coefficient estimate was 7.04 (6.99 – 7.08). Genotype was not statistically or clinically significant.

Conclusion

Our study demonstrates the use of real-world EHR data and remnant specimens to perform a population PK analysis and investigate covariate effects in a large pediatric population. Weight and age were important predictors of clearance. We did not find evidence for pharmacogenetic effects ofUGT1A4orUGT2B10genotype orCYP2A6risk score.

What is already known about this subject

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Previous dexmedetomidine pharmacokinetic (PK) studies in pediatric populations have limited sample size.

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Smaller studies present a challenge for identifying covariates that may impact individual PK profiles.

What this study adds

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We performed a dexmedetomidine population PK study with a large pediatric cohort using data obtained from electronic health records and remnant plasma specimens to enable increased sample size.

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xsDifferences in PK due toUGT1A4orUGT2B10variants orCYP2A6risk score are not clinically impactful for this population.
Characterization of the genetic architecture of BMI in infancy and early childhood reveals age-specific effects and implicates pathways involved in Mendelian obesity
Authors: Helgeland Øyvind , Vaudel Marc , Sole-Navais Pol , Flatley Christopher , Juodakis Julius , Bacelis Jonas , Koløen Ingvild L. , Knudsen Gun Peggy , Johansson Bente B. , Magnus Per , Kjennerud Ted Reichborn , Juliusson Petur B. , Stoltenberg Camilla , Holmen Oddgeir L. , Andreassen Ole A. , Jacobsson Bo , Njølstad Pål R. , Johansson Stefan
Published: May 2021

To elucidate the role of common genetic variation on infant and child weight development, we performed genome-wide association studies across 12 time points from birth to eight years in 28,681 children and their parents (27,088 mothers and 26,239 fathers) in the Norwegian Mother, Father and Child Cohort Study (MoBa). We identify 46 distinct loci associated with early childhood BMI at specific ages, matching different child growth phases, and representing four major trajectory patterns. Among these loci, 30 are independent of known birth weight and adult BMI loci, and 21 show peak effect between six months and three years, making these discoverable only at early age. Several of the 21 variants reside in/near genes previously implicated in severe forms of early-onset obesity, and monogenic obesity genes are enriched in the vicinity of the 46 loci. Four loci demonstrate evidence of several independent association signals as key drivers for BMI development near LEPR, GLP1R, PCSK1, and KLF14, all central to appetite and energy balance. At the KLF14 locus, we detect significant associations for maternally inherited alleles only, consistent with imprinting effects. Finally, we demonstrate how the BMI distribution stratified by different polygenic risk scores transitions from birth to adult profile throughout early childhood, and how age-specific polygenic risk scores improve the prediction of childhood obesity, outperforming scores based on adult BMI. In conclusion, our results offer a fine-grained characterization of the rapidly changing genetic association landscape sustaining early growth.
Genome-Wide Association Study of Non-Alcoholic Fatty Liver Disease Identifies Association with Apolipoprotein E
Authors: Fairfield Cameron J , Drake Thomas M , Pius Riinu , Bretherick Andrew D , Campbell Archie , Clark David W , Fallowfield Jonathan A , Hayward Caroline , Henderson Neil C , Joshi Peter K , Mills Nicholas L , Porteous David J , Ramachandran Prakash , Semple Robert K , Shaw Catherine A , Sudlow Cathie LM , Timmers Paul RHJ , Wilson James F , Wigmore Stephen J , Harrison Ewen M , Spiliopoulou Athina
Published: May 2021

Background & Aims

Genome-wide association studies (GWAS) have identified several risk loci for non-alcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines.

Approach & Results

We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for BMI and adjusting for alcohol intake. 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components and genotyping batch. We performed a GWA meta-analysis using available summary association statistics from two previously published case-control GWAS of NAFLD. Six risk loci were identified (P<5*10^(−8)) of which one is novel in GWAS (rs429358 in APOE) and five are known (PNPLA3, TM6SF2, GCKR, MARC1 and TRIB1). Rs429358 (P=2.17*10^(−11)) is a missense variant within the APOE gene determining ⍰4 vs ⍰2/⍰3 alleles. All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals) with others demonstrating consistent direction and magnitude of effect. All 6 loci were significant on meta-analysis including APOE P=3.42*10^(−13) with consistent direction and magnitude of effect in all 6 loci in all three studies. The ⍰4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95%CI 0.78-0.90] and homozygotes 0.64 [0.50-0.79]).

Conclusions

This GWAS demonstrates that the ∈4 allele of APOE is strongly associated with protection against NAFLD.
SARS-CoV-2 variants of concern, variants of interest and lineage A.27 are on the rise in Côte d’Ivoire
Authors: Augustin Anoh Etilé , Schubert Grit , Wayoro Oby , Pacôme Monemo , Belarbi Essia , Sachse Andreas , Calvignac-Spencer Sébastien , Leendertz Fabian , Diané Bamourou , Akoua-Koffi Chantal
Published: May 2021

SARS-CoV-2 variants of concern (VOC) and variants of interest (VOI) are heavily altering the COVID-19 pandemic’s course due to their increased transmissibility, virulence and immune escape abilities. Data on their spread in western sub-Saharan Africa is however still scarce. We therefore sequenced viral genomes from SARS-CoV-2 cases identified in central and northern Côte d’Ivoire between May 2020 and March 2021. We report the introduction of VOC B.1.1.7 as early as mid-January 2021, followed by detection of a single case of VOC B.1.351, as well as VOI B.1.525. Since early 2021 VOC/VOI are gradually dominating the SARS-CoV-2 virus pool in Côte d’Ivoire, as seen in other regions of the world. Intriguingly, we also find that another lineage, A.27, has also been on the rise over the same period. In sum, this study highlights again the extremely rapid local diffusion of VOC, VOI and possibly A.27, and the importance of further reinforcing capacities for genomic surveillance on the African continent.
Longitudinal Evaluation of mRNA Vaccinated Subjects using a Quidel Multianalyte Point-of-Care SARS-CoV-2 IgG Immunoassay
Authors: Chen Xi , Agarwal Sarika , Hoelscher Stewart , Egan Richard , Jaiswal Dipesh , Stassinopoulos Adonis , Reed Robert , McClure Jason , Kroll Werner
Published: May 2021

Infection from SARS-CoV-2 elicits an immune response to the nucleocapsid (N) and spike proteins (subunits S1 and S2). In this study, we set out to understand the utility of the multiplexed Quidel Sofia 2 SARS-CoV-2 IgG Antibody Fluorescent Immuno-Assay (FIA) that measures IgG antibodies against these three primary SARS-CoV-2 antigens from a single sample in 15 minutes. Using this assay with samples that were collected prior to the COVID-19 pandemic (n=816) and diseased state samples (n=99), the specificities for the three antigens were 98.4-99.9% and 98.0-100.0%, respectively. A longitudinal study was designed to collect weekly fingerstick, venous whole blood, serum and plasma samples from subjects vaccinated with the Moderna or Pfizer/BioNtech mRNA vaccines. The majority of these enrolled subjects had no known prior infection while a subset was known to have had prior COVID-19 infection. We found that the fingerstick whole blood samples performed as effectively as serum, plasma, and venous whole blood samples with a 95.8-99.5% agreement allowing physicians in a near-patient setting to rapidly provide results to their patients. Additionally, as this assay measures an IgG response against three viral proteins, S1, S2 and N, we were able to characterize immune response between i) naturally infected subjects, ii) vaccinated subjects with no prior infection, iii) vaccinated subjects with known prior infection, and iv) vaccinated subjects with prior asymptomatic exposure/infection. The Quidel Sofia 2 SARS-CoV-2 IgG FIA will aid in providing insights to the protective humoral responses as an increasing number of the world population is vaccinated against SARS-CoV-2.
A morphological transformation in respiratory syncytial virus leads to enhanced complement activation
Authors: Kuppan Jessica P. , Mitrovich Margaret D. , Vahey Michael D.
Published: May 2021

The complement system is a critical host defense against infection, playing a protective role that can also enhance disease if misregulated. Although many consequences of complement activation during viral infection are well-established, specific mechanisms that contribute to activation by different human viruses remain elusive. Here, we investigate complement activation by human respiratory syncytial virus (RSV), a respiratory pathogen that causes severe disease in infants, the immunocompromised, and the elderly. Using a strain of RSV harboring tags on the surface glycoproteins F and G, we were able to monitor opsonization of single RSV particles with monoclonal antibodies and complement components using fluorescence microscopy. These experiments revealed an antigenic hierarchy in complement activation, where antibodies that bind towards the apex of F in either the pre- or postfusion conformation are able to activate complement whereas other antibodies are not. Additionally, among antibodies that were able to activate complement, we observed preferential targeting of a subset of particles with globular morphology, in contrast to the more prevalent viral filaments. We found that enhanced complement activation on these particles arises from changes in surface curvature that occur when the viral matrix detaches from the surrounding membrane. This transformation occurs naturally over time under mild conditions, and correlates with the accumulation of postfusion F on the viral surface. Collectively, these results identify antigenic and biophysical characteristics of virus particles that contribute to the formation of immune complexes, and suggest models for how these factors may shape disease severity and adaptive immune responses to RSV.
Defective flow-migration coupling causes arteriovenous malformations in hereditary hemorrhagic telangiectasia
Authors: Park Hyojin , Furtado Jessica , Poulet Mathilde , Chung Minhwan , Yun Sanguk , Lee Sungwoon , Sessa William C , Franco Claudio , Schwartz Martin A , Eichmann Anne
Published: May 2021

Background

Activin receptor-like kinase 1 (ACVRL1, hereafterALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in theALK1gene cause type 2 hereditary hemorrhagic telangiectasia (HHT), a devastating disorder that leads to arteriovenous malformations (AVMs). Here we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles.

Methods

Using Cre lines that recombine in different subsets of arterial, capillary-venous or endothelial tip cells, we showed that capillary-venousAlk1deletion was sufficient to induce AVM formation in the postnatal retina.

Results

ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flowin vivoandin vitro. Mechanistically, ALK1 deficient cells exhibited increased integrin signaling interaction with VEGFR2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacological inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations inAlk1deficient mice.

Conclusions

Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of AVM formation in HHT disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in HHT patients.
Neuronal GPCR regulates the specificity of innate immunity against pathogen infection
Authors: Wibisono Phillip , Wibisono Shawndra , Watteyne Jan , Chen Chia-Hui , Sellegounder Durai , Beets Isabel , Liu Yiyong , Sun Jingru
Published: May 2021

A key question in current immunology is how the innate immune system generates high levels of specificity. Using theCaenorhabditis elegansmodel system, we demonstrate that functional loss of NMUR-1, a neuronal G protein-coupled receptor homologous to mammalian receptors for the neuropeptide neuromedin U, has diverse effects onC. elegansinnate immunity against various bacterial pathogens. Transcriptomic analyses and functional assays revealed that NMUR-1 modulatesC. eleganstranscription activity by regulating the expression of transcription factors involved in binding to RNA polymerase II regulatory regions, which, in turn, controls the expression of distinct immune genes in response to different pathogens. These results uncovered a molecular basis for the specificity ofC. elegansinnate immunity. Given the evolutionary conservation of NMUR-1 signaling in immune regulation across multicellular organisms, our study could provide mechanistic insights into understanding the specificity of innate immunity in other animals, including mammals.
Purifying selection on noncoding deletions of human regulatory loci detected using their cellular pleiotropy
Authors: Radke David W. , Sul Jae Hoon , Balick Daniel J. , Akle Sebastian ,   Alzheimer's Disease Neuroimaging Initiative, Green Robert C. , Sunyaev Shamil R.
Published: May 2021

Genomic deletions provide a powerful loss-of-function model in noncoding regions to assess the role of purifying selection on genetic variation. Regulatory element function is characterized by nonuniform tissue and cell type activity, necessarily linking the study of fitness consequences from regulatory variants to their corresponding cellular activity. We generated a callset of deletions from genomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and used deletions from The 1000 Genomes Project Consortium (1000GP) in order to examine whether purifying selection preserves noncoding sites of chromatin accessibility marked by DNase I hypersensitivity (DHS), histone modification (enhancer, transcribed, Polycomb-repressed, heterochromatin), and chromatin loop anchors. To examine this in a cellular activity-aware manner, we developed a statistical method, pleiotropy ratio score (PlyRS), which calculates a correlation-adjusted count of “cellular pleiotropy” for each noncoding base pair by analyzing shared regulatory annotations across tissues and cell types. By comparing real deletion PlyRS values to simulations in a length-matched framework and by using genomic covariates in analyses, we found that purifying selection acts to preserve both DHS and enhancer noncoding sites. However, we did not find evidence of purifying selection for noncoding transcribed, Polycomb-repressed, or heterochromatin sites beyond that of the noncoding background. Additionally, we found evidence that purifying selection is acting on chromatin loop integrity by preserving colocalized CTCF binding sites. At regions of DHS, enhancer, and CTCF within chromatin loop anchors, we found evidence that both sites of activity specific to a particular tissue or cell type and sites of cellularly pleiotropic activity are preserved by selection.
Improved grain mapping by laboratory X-ray diffraction contrast tomography
Authors: Fang H. , Juul Jensen D. , Zhang Y.
Published: May 2021

Laboratory diffraction contrast tomography (LabDCT) is a novel technique for non-destructive imaging of the grain structure within polycrystalline samples. To further broaden the use of this technique to a wider range of materials, both the spatial resolution and detection limit achieved in the commonly used Laue focusing geometry have to be improved. In this work, the possibility of improving both grain indexing and shape reconstruction was investigated by increasing the sample-to-detector distance to facilitate geometrical magnification of diffraction spots in the LabDCT projections. LabDCT grain reconstructions of a fully recrystallized iron sample, obtained in the conventional Laue focusing geometry and in a magnified geometry, are compared to one characterized by synchrotron X-ray diffraction contrast tomography, with the latter serving as the ground truth. It is shown that grain indexing can be significantly improved in the magnified geometry. It is also found that the magnified geometry improves the spatial resolution and the accuracy of the reconstructed grain shapes. The improvement is shown to be more evident for grains smaller than 40 µm than for larger grains. The underlying reasons are clarified by comparing spot features for different LabDCT datasets using a forward simulation tool.
Crystal structure of potassium triethylhydridoborate (`superhydride')
Authors: Fecker Ann Christin , Freytag Matthias , Walter Marc D. , Jones Peter G.
Published: May 2021

In the title compound, formally K+·C6H16B−, the contact sphere of potassium consists of eleven hydrogen atoms from three different anions, assuming an arbitrary cut-off of 3 Å. The shortest interaction, 2.53 (2) Å, involves the hydridic hydrogen H01, which fulfils a bridging function in the formation of chains of KHBEt3 units parallel to the a axis [K1—H01i 2.71 (2) Å, K1—H01—K1ii 126.7 (9)°, operators x∓1/2, −y + {3\over 2}, −z + 1].
(Cobaltoceniumylamido)pyridinium hexafluoridophosphate
Authors: Menia Daniel , Höfer Thomas , Wurst Klaus , Bildstein Benno
Published: May 2021

The title compound, [Co(C5H5)(C10H9N2)]PF6, was synthesized from deprotonated 1-aminopyridinium iodide, followed by microwave-assisted nucleophilic aromatic substitution of iodo-cobaltocenium iodide. After anion exchange with potassium hexafluoridophosphate, the title compound crystallizes as orange prisms in the space group Pc. This very stable pyridine nitrene adduct is the first example of a cobaltocenium derivative, formally containing a nitrene nitrogen species.
Coping with COVID-19: the role of accounting in shaping charities' financial resilience
Authors: Kober Ralph , Thambar Paul J.
Published: May 2021

Purpose

The purpose of this paper is to explore the role of accounting in shaping charities' financial resilience during the COVID-19 crisis.

Design/methodology/approach

A case study of a charity was conducted. The financial resilience framework (Barbera et al., 2017) was applied to explore how accounting contributes to charities' capacity to cope with crises.

Findings

The results show how the accounting practices of budgeting, forecasting and performance reporting (financial and nonfinancial), as well as “accounting talk,” form part of the anticipatory and coping capacities that provided the charity the financial resilience to navigate the COVID-19 crisis.

Practical implications

The paper evidences the important role accounting plays in establishing financial resilience to help charities cope with crises, particularly the importance of having accounting practices established prior to a crisis and accounting information forming part of managers' discussions. The study also demonstrates that financial reserves have an important buffering capacity role.

Originality/value

This is the first paper to examine the role of accounting within a charity during an economic crisis. The authors explore the role of accounting in shaping a charity's financial resilience and demonstrate the applicability of the financial resilience framework to a sudden, unexpected crisis such as COVID-19. They extend the accounting talk literature by highlighting its importance to a charity and during a crisis.
A validated business process modelling success factors model
Authors: Bandara Wasana , Gable Guy Grant , Tate Mary , Rosemann Michael
Published: May 2021

Purpose

Business process modelling (BPMo) projects are core to digital transformation projects as they provide the conceptual foundation to the orchestration of technologies along a process. Yet, success factors of BPMo projects have received little research attention to date. This study empirically validates a BPMo project success model, pointing to normative practice guidelines and important future research.

Design/methodology/approach

This research reports on the quantitative re-specification and validation of a business process modelling success model, employing survey responses from 261 process modellers worldwide.

Findings

The study distilled and validated a final set of success antecedents: Top Management Support, Project Management Capabilities, Stakeholder Input, Modeller Expertise and Modelling Tool Usage; and clearly evidences their relationships with each other and with two moderating variables – Importance and Complexity. The paper offers a nuanced explanation of the indirect role of top management support in building stakeholder involvement and explains how complex projects that are perceived as important being more likely to attract high levels of necessary stakeholder involvement. The authors conclude that top management needs to create an environment of co-ordinated excellence which spans both technical skills and resources, and a high level of committed engagement between stakeholders and technicians in order for BPMo projects to succeed.

Originality/value

This study is the first to operationalize and quantitatively test antecedents of BPMo project success and their interactions, presenting novel insights into how the success factors interact. Awareness of the more influential antecedents of successful process modelling projects offers valuable guidance for the planning, management and conduct of BPMo projects.