bluuebunny/crossref_metadata_2025 huggingface dataset:
Precision omics data integration and analysis with interoperable ontologies and their application for COVID-19 research
Authors: Wang Zhigang , He Yongqun
Published: June 2021

Omics technologies are widely used in biomedical research. Precision medicine focuses on individual-level disease treatment and prevention. Here, we propose the usage of the term ‘precision omics’ to represent the combinatorial strategy that applies omics to translate large-scale molecular omics data for precision disease understanding and accurate disease diagnosis, treatment and prevention. Given the complexity of both omics and precision medicine, precision omics requires standardized representation and integration of heterogeneous data types. Ontology has emerged as an important artificial intelligence component to become critical for standard data and metadata representation, standardization and integration. To support precision omics, we propose a precision omics ontology hypothesis, which hypothesizes that the effectiveness of precision omics is positively correlated with the interoperability of ontologies used for data and knowledge integration. Therefore, to make effective precision omics studies, interoperable ontologies are required to standardize and incorporate heterogeneous data and knowledge in a human- and computer-interpretable manner. Methods for efficient development and application of interoperable ontologies are proposed and illustrated. With the interoperable omics data and knowledge, omics tools such as OmicsViz can also be evolved to process, integrate, visualize and analyze various omics data, leading to the identification of new knowledge and hypotheses of molecular mechanisms underlying the outcomes of diseases such as COVID-19. Given extensive COVID-19 omics research, we propose the strategy of precision omics supported by interoperable ontologies, accompanied with ontology-based semantic reasoning and machine learning, leading to systematic disease mechanism understanding and rational design of precision treatment and prevention.

Short Abstract

Precision medicine focuses on individual-level disease treatment and prevention. Precision omics is a new strategy that applies omics for precision medicine research, which requires standardized representation and integration of individual genetics and phenotypes, experimental conditions, and data analysis settings. Ontology has emerged as an important artificial intelligence component to become critical for standard data and metadata representation, standardization and integration. To support precision omics, interoperable ontologies are required in order to standardize and incorporate heterogeneous data and knowledge in a human- and computer-interpretable manner. With the interoperable omics data and knowledge, omics tools such as OmicsViz can also be evolved to process, integrate, visualize and analyze various omics data, leading to the identification of new knowledge and hypotheses of molecular mechanisms underlying disease outcomes. The precision COVID-19 omics study is provided as the primary use case to illustrate the rationale and implementation of the precision omics strategy.
Transient Subplate Sublayer Forms Unique Corridor for Differential Ingrowth of Associative Pulvinar and Primary Visual Projection in the Prospective Visual Cortical Areas of the Human Fetal Occipital Lobe
Authors: Žunić Išasegi Iris , Kopić Janja , Smilović Dinko , Krsnik Željka , Kostović Ivica
Published: June 2021

Cytoarchitectonical parcellation of the visual cortex into the striate and extrastriate cortex requires complex histogenetic events within a precise spatio-temporal frame to attain the specification of areal domains and associated thalamocortical connections during the fetal brain development. We analyzed a deep subplate cellular monolayer (subplate “corridor” cells) present during a restricted period of 13–15 postconceptional weeks, showing the 3D caudo-ventro-medial position in the human fetal occipital lobe, corresponding to the segregation point of pulvinocortical and geniculocortical fibers at the prospective area 17/18 border. Immunofluorescence stainings revealed subplate “corridor” cells as the specific class of the deepest subplate neurons (NeuN+, Tbr1+, Cplx3+) expressing axon guidance molecules (Sema-3A+, EphA6+), presumably for the attraction of pulvinocortical axons and the repulsion of geniculocortical axons growing at that time (SNAP25+, Syn+, FN+). Furthermore, quantitative analysis of the subplate “corridor” region of interest, considering cell number, immunofluorescence signal intensity per cell and per region, revealed significant differences to other regions across the tangential circumference of the developing cerebral wall. Thus, our study sheds new light on the deepest subplate sublayer, strategically aligned along the growing axon systems in the prospective visual system, suggesting the establishment of the area 17/18 border by differential thalamocortical input during the fetal brain development.
Improved Survival Among Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) Treated With Remdesivir and Dexamethasone. A Nationwide Population-Based Cohort Study
Authors: Benfield Thomas , Bodilsen Jacob , Brieghel Christian , Harboe Zitta Barrella , Helleberg Marie , Holm Claire , Israelsen Simone Bastrup , Jensen Janne , Jensen Tomas Østergaard , Johansen Isik Somuncu , Johnsen Stine , Lindegaard Birgitte , Lundgren Jens , Meyer Christian Niels , Mohey Rajesh , Pedersen Lars , Nielsen Henrik , Nielsen Stig Lønberg , Obel Niels , Omland Lars Haukali , Podlekareva Daria , Poulsen Birgitte Klindt , Ravn Pernille , Sandholdt Haakon , Starling Jonathan , Storgaard Merete , Søborg Christian , Søgaard Ole Schmeltz , Tranborg Torben , Wiese Lothar , Christensen Hanne Rolighed
Published: June 2021

Background

There are limited data on outcomes of moderate to severe coronavirus disease 2019 (COVID-19) among patients treated with remdesivir and dexamethasone in a real-world setting. We sought to compare the effectiveness of standard of care (SOC) alone versus SOC plus remdesivir and dexamethasone.

Methods

Two population-based nationwide cohorts of individuals hospitalized with COVID-19 during February through December 2020 were studied. Death within 30 days and need of mechanical ventilation (MV) were compared by inverse probability of treatment weighted (ITPW) logistic regression analysis and shown as odds ratio (OR) with 95% confidence interval (CI).

Results

The 30-days mortality rate of 1694 individuals treated with remdesivir and dexamethasone in addition to SOC was 12.6% compared to 19.7% for 1053 individuals receiving SOC alone. This corresponded to a weighted OR of 30-day mortality of 0.47 (95% CI: .38–.57) for patients treated with remdesivir and dexamethasone compared to patients receiving SOC alone. Similarly, progression to MV was reduced (OR 0.36; 95% CI: .29–.46).

Conclusions

Treatment of moderate to severe COVID-19 during June through December that included remdesivir and dexamethasone was associated with reduced 30-day mortality and need of MV compared to treatment in February through May.
Universal Use of N95 Respirators in Healthcare Settings When Community Coronavirus Disease 2019 Rates Are High
Authors: Klompas Michael , Rhee Chanu , Baker Meghan A
Published: June 2021

The Centers for Disease Control and Prevention recommends N95 respirators for all providers who see patients with possible or confirmed coronavirus disease 2019 (COVID-19). We suggest that N95 respirators may be just as important for the care of patients without suspected COVID-19 when community incidence rates are high. This is because severe acute respiratory syndrome coronavirus 2 is most contagious before symptom onset. Ironically, by the time patients are sick enough to be admitted to the hospital with COVID-19, they tend to be less contagious. The greatest threat of transmission in healthcare facilities may therefore be patients and healthcare workers with early occult infection. N95 respirators’ superior fit and filtration provide superior exposure protection for healthcare providers seeing patients with early undiagnosed infection and superior source control to protect patients from healthcare workers with early undiagnosed infection. The probability of occult infection in patients and healthcare workers is greatest when community incidence rates are high. Universal use of N95 respirators may help decrease nosocomial transmission at such times.
Quality of life in breast cancer patients with cancer treatment-related cardiac dysfunction: a qualitative study
Authors: Koop Yvonne , van Zadelhof Nikita , Maas Angela H E M , Atsma Femke , El Messaoudi Saloua , Vermeulen Hester
Published: June 2021

Background

Although improved breast cancer (BC) treatment has decreased mortality, these anti-cancer regimens may have serious cardiovascular side effects that affect patients’ long-term prognosis and quality of life (QoL). BC patients with cancer treatment-related cardiac dysfunction (CTRCD) can suffer from a variety of symptoms, such as dyspnoea and fatigue. The impact of CTRCD after BC treatment on patients’ daily life has not been qualitatively explored yet.

Aims

This study aims to explore the influence of CTRCD on QoL of women with BC, as defined by the concept of positive health. Second, we aim to evaluate the personal experience with cardiac surveillance during the BC trajectory.

Methods and results

A qualitative study with semi-structured interviews was conducted and thematically analysed to explore the QoL and healthcare experiences of BC patients with CTRCD. Twelve patients participated in this study. Five themes are selected in response to the study objective: (i) patients: overwhelming fatigue, (ii) patients: mental burden of anxiety, (iii) social setting: lack of understanding and acceptance, (iv) medical specialists: lack of knowledge and acknowledgement, and (v) patients: need for personalized care.

Conclusion

This study identified core components of the impact CTRCD has on the QoL of BC patients. Patients experienced an increased health-related burden due to CTRCD, affecting their physical, social, and psychosocial well-being. Healthcare experiences were largely affected by a lack of acknowledgement and professional communication. Patients underlined the need for personalized care during follow-up.
Backlash advocacy and NGO polarization over women's rights in the United Nations
Authors: Cupać Jelena , Ebetürk Irem
Published: June 2021

The article observes that women's rights politics in the United Nations are caught in full-scale polarization between feminist and conservative non-governmental organizations (NGOs), particularly visible in their fights over institutional spaces and language. It then sets out to elucidate the process by which this polarization came about. It first ties it to specific reasons for which conservative NGOs entered the UN; namely, their intent to halt and reverse the progress of women's rights. Next, the article observes that this intent has given birth to a specific style of conservative NGOs' advocacy: backlash advocacy. This advocacy differs from regular advocacy in that it does not target only UN decision-makers, but also a rival NGO group and its normative record. Polarization results from feminist NGOs' defensively reciprocating this attack. The article contributes to the literature on international organization (IO)–NGO relations by specifying why conservative NGOs, considered unlikely IO utilizers, end up actively using the UN and by showing that this diversification in NGOs' utilization of the UN can have detrimental rather than positive institutional effects. The article also invites feminist NGOs to be more aware of the political dynamic that now entraps them, and to tailor their future strategies accordingly.
Internal State: Dynamic, Interconnected Communication Loops Distributed Across Body, Brain, and Time
Authors: Kanwal Jessleen K , Coddington Emma , Frazer Rachel , Limbania Daniela , Turner Grace , Davila Karla J , Givens Michael A , Williams Valarie , Datta Sandeep Robert , Wasserman Sara
Published: June 2021

Synopsis

Internal state profoundly alters perception and behavior. For example, a starved fly may approach and consume foods that it would otherwise find undesirable. A socially engaged newt may remain engaged in the presence of a predator, whereas a solitary newt would otherwise attempt to escape. Yet, the definition of internal state is fluid and ill-defined. As an interdisciplinary group of scholars spanning five career stages (from undergraduate to full professor) and six academic institutions, we came together in an attempt to provide an operational definition of internal state that could be useful in understanding the behavior and the function of nervous systems, at timescales relevant to the individual. In this perspective, we propose to define internal state through an integrative framework centered on dynamic and interconnected communication loops within and between the body and the brain. This framework is informed by a synthesis of historical and contemporary paradigms used by neurobiologists, ethologists, physiologists, and endocrinologists. We view internal state as composed of both spatially distributed networks (body–brain communication loops), and temporally distributed mechanisms that weave together neural circuits, physiology, and behavior. Given the wide spatial and temporal scales at which internal state operates—and therefore the broad range of scales at which it could be defined—we choose to anchor our definition in the body. Here we focus on studies that highlight body-to-brain signaling; body represented in endocrine signaling, and brain represented in sensory signaling. This integrative framework of internal state potentially unites the disparate paradigms often used by scientists grappling with body–brain interactions. We invite others to join us as we examine approaches and question assumptions to study the underlying mechanisms and temporal dynamics of internal state.
Bioeconomic benefits of managing fishing effort in a coexisting small- and large-scale fishery game
Authors: de Azevedo Eric Zettermann Dias , Pintassilgo Pedro , Dantas David Valença , Daura-Jorge Fábio Gonçalves
Published: June 2021

Fishing systems provide employment, income generation, poverty alleviation, and food security. The coexistence of small-scale fisheries (SSFs) and large-scale fisheries (LSFs) increases management complexity. Management actions have ecological and social implications that must be addressed carefully. We applied a bioeconomic game-theoretical model to the four-gear mullet fishery in southern Brazil—one industrial LSF (purse seine) and three artisanal SSFs (gillnet, beach seine, and drift net). All fishing gears target adult individuals during mullet's reproductive migration. First, we explored whether the current fishing efforts of all fishing gears could persist over time. Second, we investigated their interactions through a non-cooperative game. Finally, we studied the response of these interactions when fishing effort was restricted. We found that when the current fishing effort was maintained, the stock reduced to 26.4% of its capacity in 25 years. In addition, under non-cooperation, the traditional beach seine fleet exited the fishery. Interestingly, the constrained scenario had a coexistence output with increasing values for the final stock size and the per capita labour income, suggesting that limiting fishing effort can maintain all fishing gears in the fishery with social and ecological benefits.
Doubling Down: The Danger of Disclosing Secret Action
Authors: Otto Jacob , Spaniel William
Published: June 2021

When an actor catches a state taking an objectionable secret action, it faces a dilemma. Exposing the action could force unresolved states to terminate the behavior to save face. However, it could also provoke resolved states to double down on the activity now that others are aware of the infraction. We develop a model that captures this fundamental trade-off. Three main results emerge. First, the state and its opponent may engage in a form of collusion—opponents do not expose resolved states despite their distaste for the behavior. Second, when faced with uncertainty, the opponent may mistakenly expose a resolved type and induce escalation, leading the opponent to have ex post regret. Finally, as the strength of secret action increases, states may engage in it less often. This counterintuitive result is a consequence of the opponent's greater willingness to expose, which deters less resolved types.
Towards a knowledge base of medieval and renaissance geographical Latin works: The IMAGO ontology
Authors: Bartalesi Valentina , Metilli Daniele , Pratelli Nicolò , Pontari Paolo
Published: June 2021

In this article we present the first achievement of the Index Medii Aevi Geographiae Operum (IMAGO)—Italian National Research Project (2020–23), that is, the ontology we have created in order to formally represent the knowledge about the geographical works written in Middle Ages and Renaissance (6th–15th centuries). The IMAGO ontology is derived from a strict collaboration between the Institute of Information Science and Technologies (ISTI) of the Italian National Research Council (CNR) and the scholars who are involved in the project, who have supported ISTI-CNR in defining a conceptualization of the domain of knowledge. Following the re-use logic, we have selected as reference ontologies the International Committee on Documentation CRM vocabulary and its extension FRBRoo, including its in-progress reformulation, LRMoo. This research is included in a wider project context whose final aim is the creation of a knowledge base (KB) of Latin geographic literature of the Middle Ages and Renaissance Humanism in which the data are formally represented following the Linked Open Data paradigm and using the Semantic Web languages. At the end of the project, this KB will be accessed through a Web application that allows retrieving and consulting the collected data in a user-friendly way for scholars and general users, e.g. tables, maps, CSV files.
Comparative effects of combined use of alcohol with cannabis and tobacco on testicular function in rats
Authors: Nwonuma Charles Obiora , Osemwegie Osarenkhoe Omorefosa , Irokanulo Emenike Onyebum , Alejolowo Omokolade Oluwaseyi , Kayode Omowumi Titilola , Olaolu Tomilola Debby , Ada Adakole Sylvanus , Rotimi Damilare Emmanuel , Maimako Roltdelmwa Filibus , Adedayo Adeyinka Samuel , Ojo Oluwafemi Adeleke
Published: June 2021

Alcoholism has been linked to problems with male reproductive function. The combined effects of alcohol, cannabis, and tobacco were compared in this study. A total of 35 rats were assigned randomly into seven groups A–G: animals in A were administered distilled water. Animals in B–G were either administered alcohol orally (30 ml 40% alcohol) or exposed to smoke from ignited tobacco (exposure to smoke from 0.7 g tobacco for 5 min) or cannabis (exposure to smoke from 0.7 g tobacco and cannabis for 5 min): B (orally administered alcohol), C (exposed to the smoke from tobacco), D (exposed to smoke from cannabis), E (treated with alcohol and exposed to smoke from tobacco), F (treated with alcohol and exposed to smoke from cannabis), G (treated with alcohol and exposed to smokes from tobacco and cannabis). Assays were carried on the testicular homogenate after a 14-day treatment. There was a significant increase in activity of alkaline phosphatase (P ≤ 0.05), concentrations of cholesterol, glutathione reductase, and malondialdehyde in treated rats by the co-administration of alcohol with cannabis and tobacco compared with the control group. The combined treatment also caused degeneration and morphological distortions of testicular cells. The biochemical and histoarchitectural change was due to oxidative damage attributable to the synergistic effects. The high binding energy of tetrahydrocannabinol ligand to prostate acid phosphatase may be a prediction that the ligand can have an inhibitory effect on the function of enzymes in the prostate.
Phylodynamics reveals the role of human travel and contact tracing in controlling the first wave of COVID-19 in four island nations
Authors: Douglas Jordan , Mendes Fábio K , Bouckaert Remco , Xie Dong , Jiménez-Silva Cinthy L , Swanepoel Christiaan , de Ligt Joep , Ren Xiaoyun , Storey Matt , Hadfield James , Simpson Colin R , Geoghegan Jemma L , Drummond Alexei J , Welch David
Published: June 2021

New Zealand, Australia, Iceland, and Taiwan all saw success in controlling their first waves of Coronavirus Disease 2019 (COVID-19). As islands, they make excellent case studies for exploring the effects of international travel and human movement on the spread of COVID-19. We employed a range of robust phylodynamic methods and genome subsampling strategies to infer the epidemiological history of Severe acute respiratory syndrome coronavirus 2 in these four countries. We compared these results to transmission clusters identified by the New Zealand Ministry of Health by contact tracing strategies. We estimated the effective reproduction number of COVID-19 as 1–1.4 during early stages of the pandemic and show that it declined below 1 as human movement was restricted. We also showed that this disease was introduced many times into each country and that introductions slowed down markedly following the reduction of international travel in mid-March 2020. Finally, we confirmed that New Zealand transmission clusters identified via standard health surveillance strategies largely agree with those defined by genomic data. We have demonstrated how the use of genomic data and computational biology methods can assist health officials in characterising the epidemiology of viral epidemics and for contact tracing.
The Dynamic Nucleotide Selection Mechanism of DNA Polymerase I at Atomic Resolution
Authors: Wu Eugene Y. , Miller Bill R. , Parish Carol A.
Published: June 2021

Replicative DNA polymerases use complex induced fit mechanisms to distinguish substrates complementary to the template from mismatches with remarkable speed and accuracy. The transient conformations and their order in the mechanism underly the speed and accuracy of polymerases, yet are difficult to characterize due to the sub‐millisecond time scales of the transitions. We employed microsecond scale, all‐atom, explicit waters molecular dynamics to characterize and visualize the conformational changes that occur when DNA polymerase I, large fragment, from Bacillus stearothermophilus encounters a complementary dCTP or a mismatched dTTP opposite a template dG. The dCTP and the Mg2+ cofactor immediately formed a stable base pair with dG and induced fluctuations of the mobile fingers subdomain between the open conformation and a state intermediate between open and closed. The enzyme closed only upon the binding of a second cation to the active site, followed by a rotation of a conserved histidine towards the 3′‐OH of the growing primer strand. We speculate this is the deprotonation step that initiates catalysis. In the presence of the mismatched dTTP‐Mg2+, a weak base pair forms with dG, but quickly breaks, leading to near dissociation of the dTTP during the 3μs simulation. These simulations detail the complex polymerase mechanism and provide structural explanations for the behavior and high fidelity of dynamic DNA polymerases during nucleotide selection.

Support or Funding Information

The authors would like to acknowledge the Jeffress Trust Awards Program in Interdisciplinary Research for funding, as well as the University of Richmond for computing resources.

This work also used Extreme Science Engineering Discovery Environment (XSEDE) allocations TG‐MCB140003 and TG‐MCB140073, which are supported by National Science Foundation grant number OCI‐1053575. Additional computing resources were utilized as part of the MERCURY Consortium supported by NSF grant number CHE‐1229354
UNDERSTANDING A FUNDAMENTAL FORCE IN PROTEIN FOLDING: TUNING THE n ‐‐> > π* INTERACTION VIA DESIGNED PEPTIDES
Authors: Wenzell Nicole A , Ganguly Himal K , Pandey Anil K , Yap Glenn P.A , Zondlo Neal J
Published: June 2021

An n‐‐>π* interaction is a local interaction that orders two consecutive residues by delocalizing the lone pair of electrons from oxygen of the donor carbonyl to the antibonding orbital of the acceptor carbonyl carbon. This interaction is a recent discovery that gives insight into the inherent biases that proteins have to drive them to their folded state. By changing the electronics of the donor carbonyl on model proline‐based peptides, we can tune the strength of this n‐‐>π* interaction.

Proline can readily populate both the trans and cis conformations in a peptide bond. The n‐‐>v* interaction is shown to stabilize the trans conformation. Thus, in our model system the equilibrium constant of trans‐cis isomerization (Ktrans/cis) acts as a readout for the strength of the n‐‐>π* interaction. Greater electron donation on the donor carbonyl causes a stronger interaction, resulting in higher Ktrans/cis values. The electronics of the donor carbonyl in the model peptides were modulated by synthesizing a series of derivatives with varying electron‐donating capabilities on the donor carbonyl.

The series of derivatives synthesized were selected in order to compare their electron donating capabilities to their n‐‐>π* interaction strength. The derivatives synthesized for analysis were, Boc, pivaloyl, formyl, acetyl, monochloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl. These successfully synthesized derivatives provide a range of electronic character to be analyzed for the strength of the n‐‐>π* interaction in each compound.

The determination of the strength of the n‐‐>π* interaction was accomplished through combined analysis via 1H and 13C NMR and X‐ray crystallography. NMR analysis provides the Ktrans/cis values for each derivative and thus the strength of the nàπ* interaction. Electron donation involved in the n‐‐>π* interaction is seen via the chemical shifts of the 13C NMR. The chemical shift of the acceptor carbonyl moves downfield with stronger electron‐donating substituents, while carbonyls uninvolved in the interaction remain constant. X‐ray crystallography of the model peptides reveals insights into the n‐‐>π* interaction as it indicates the distance and angles of the interaction. Specifically, the more electron donating character of the acetyl compared to the formyl group results in a 0.3Å shorter distance (3.3‐3.0Å) and an angle (115°vs 90°) that more closely resembles an ideal nucleophilic attack (109.5°). The comparison of the Ktrans/cis values, the carbonyl chemical shifts, and the angles and distances of the donor‐acceptor carbonyl pair serve as direct readouts for the strength of the n‐‐>π* interaction, which varies depending on the electron donating character of the donor carbonyl.

Support or Funding Information

The David Plastino Scholars program at the University of Delaware as well as the National Science Foundation.
Bioengineering Proteoglycan‐based Matrices For Blood Contacting Applications
Authors: Lord Megan , Chuang Christine , Rnjak‐Kovacina Jelena , Cheng Bill , Lyons Guy , Whitelock John
Published: June 2021

Proteoglycans and their glycosaminoglycan chains are functional components of the extracellular matrix that modulate interactions with other extracellular matrix molecules, as well as with cells and growth factors. Perlecan is an abundant proteoglycan in the vascular basement membrane and contains a C‐terminal domain V (DV) with one glycosaminoglycan attachment site and an α2β1 integrin binding site. Perlecan can only be obtained in low abundance from natural sources, thus alternative sources are needed for therapeutic applications. The aim of this research was to bioengineer DV and to incorporate it into biomaterials for blood‐contacting applications.

Human DV was expressed in the human embryonic kidney cell line, HEK‐293 and purified by immunoaffinity chromatography and biochemically characterized with respect to protein core, glycosaminoglycan structure and yield. Human primary endothelial cell, smooth muscle cell and platelet adhesion were assessed.

DV was produced as two populations decorated with either chondroitin sulfate or heparan sulfate. The level of heparan sulfate substitution was increased by culturing the cells with higher glucose concentrations in the medium while there was no effect on the level of chondroitin sulfate. DV was produced with a yield of 2 mg/L, which is a 2.5 fold increase in the yield of endothelial‐derived perlecan.

The proteoglycan forms of DV were effective in promoting endothelial, but not smooth muscle cell or platelet adhesion. In the absence of glycosaminoglycans DV supported the adhesion of endothelial cells and platelets via integrin α2β1. However, while smooth muscle cells adhere to perlecan in the absence of glycosaminoglycan chains, these cells did not adhere to DV in the absence of glycosaminoglycans. This suggests that the proteoglycan forms of DV have potential roles in encouraging endothelialization of materials while inhibiting unwanted activities associated with platelet and smooth muscle cell adhesion. We have shown this to be the case for the full length perlecan when trialed in an ovine vascular graft model.

We are currently developing methods to combine DV with various biomaterials including a silk fibroin substrate through various chemical crosslinking methods. Early work in this area suggests that we can fine tune how both the protein and glycosaminoglycan components of DV are presented to maintain the vascular cell‐selective activities of DV.

Support or Funding Information

Funding provided by the Australian Research Council
Evaluation of Compounds that Inhibit Fatty Acid Uptake in Mice
Authors: Taylor Samuel , Saini Nipun , Montefusco David , Black Paul , DiRusso Concetta
Published: June 2021

Lipotoxicity is characterized by apoptosis due to the toxic spillover of fatty acids from adipocytes into non‐adipose tissue. Adipocytes function to store fat and then release free fatty acids during fasting and starvation. In obesity, however, storage capacity in adipocytes becomes limiting and circulating triglycerides and free fatty acids are elevated, which can lead to accumulation in non‐adipose tissue. This can result in dysfunction, especially in the liver, muscle and pancreas. The purpose of this research is to measure the degree of fatty acid uptake inhibition in mouse models by two long‐chain fatty acid transport protein inhibitors, designated lipofermata and grassofermata in previous work. 13C18‐labeled oleic acid provided in flaxseed oil was delivered to mice by gavage following administration of compound or vehicle in flaxseed oil and the animals were sacrificed and blood collected by cardiac puncture. Plasma, tissue, and fecal levels of 13C18‐oleate were assessed by gas chromatography/mass spectrometry (GC/MS) of fatty acid methyl ester preparations (FAMES) with selective ion monitoring (SIM). We found 13C18‐oleate uptake to be inhibited by approximately 40% (grassofermata) and 75% (lipofermata) in mice sacrificed six hours after labeled oleate gavage. This work demonstrates effective inhibition of these compounds in short‐term studies and calls for further characterization of these inhibitors in long‐term investigations, which may ultimately have implications as pharmaceutical therapies.

Support or Funding Information

Arnold and Mabel Beckman Foundation, USDA Hatch and NIFA
Oligomerization of wild‐type fumarase and a mutant associated with fumarate hydratase deficiency
Authors: Bulku Artemisa , Aleksanyan Naira , Berkmen Melanie
Published: June 2021

Fumarase, or fumarate hydratase, is an enzyme that participates in the citric acid cycle and catalyzes the reversible hydration of fumarate to malate. Homozygous germline mutations in FH, the human fumarate hydratase gene, are linked to fumarate hydratase deficiency (FHD). Clinical features of this inborn error of metabolism include encephalitis, seizures, brain abnormalities, and developmental delay. Fumarase protein sequences are evolutionarily conserved, with human FH and Escherichia coli FumC sharing a stunning 59% amino acid sequence identity. Crystallographic analyses of E. coli and yeast fumarase have revealed that fumarase is homotetrameric, with two substrate binding sites, called the A‐ and B‐sites. Previously, the Weaver lab used X‐ray crystallography and kinetic experiments to investigate wild‐type FumC and FumC (E315Q), a clinically relevant mutant associated with FHD (Estevez, Skarda, Spencer, Banaszak, and Weaver, Protein Science 11:1552–7, 2002). They found that the E315 residue is conserved, lies within the A‐site, and is critical for catalysis. In this study, we purified both proteins and used fumarase assays and blue native PAGE (BN‐PAGE) to analyze their enzymatic activity and oligomerization states, respectively. Consistent with the findings from Estevez et al., we found that the E315Q mutant has greatly reduced enzymatic activity but is able to form tetramers. In future studies, we plan on analyzing other fumarase variants that have not been previously characterized.

Support or Funding Information

NSF
Nutrient Intakes from Restaurants among U.S. Children Age 1–2 Years
Authors: Jarvis Ashley B. , Clemens John C. , Rhodes Donna G. , Moshfegh Alanna J.
Published: June 2021

Nationally representative one‐day dietary data of U.S. children age 1–2 years, excluding breast‐fed, (n=469) participating in What We Eat in America, NHANES 2011–2012 were analyzed to assess nutrient intakes from foods and beverages obtained from restaurants. The 5‐step USDA Automated Multiple‐Pass Method was used to collect the dietary data through a 24‐hour recall from a proxy knowledgeable about the child's intake. The source of each item (where obtained) was provided by the proxy. Restaurants include full service and quick service establishments as well as: cafeteria, not at school; sport/entertainment facility; vending truck. Restaurant consumers were defined as individuals who reported, on the intake day, at least one food or beverage item from a restaurant. On any given day, 28% of 1 year‐olds and 40% of 2 year‐olds were restaurant consumers. Among consumers, the contribution of restaurant items to total daily energy intake was 27±1.6%. Contribution of restaurant items to total daily intake of macronutrients was 28±1.6% for protein, 23±2.0% for carbohydrate, and 32±1.6% for total fat. Compared to energy and macronutrient intakes, the contribution was greater for sodium; on the day consumed, restaurant items contributed 34±1.6% to total daily sodium intake. For calcium, potassium, and lycopene restaurant items contributed 17±1.8, 21±1.6, and 44±6.2%, respectively to total daily nutrient intakes. Restaurant foods and beverages contributed over a fourth of calories and a third of sodium to the diets of 1–2 year‐olds, highlighting the importance of their consideration when making dietary recommendations or intervention strategies.

Support or Funding Information

This study was funded by the USDA Agricultural Research Service.
Blueberry Diet Derived 3‐(3‐hydroxyphenyl) Propionic Acid (PPA) Suppresses Osteoblastic Cell Senescence to Promote Bone Accretion in Mice
Authors: Chen Jin‐Ran , Lazarenko Oxana P. , Blackburn Michael L.
Published: June 2021

A blueberry (BB) supplemented diet has been previously shown to significantly stimulate bone formation in rapidly growing male and female rodents. Phenolic acids (PAs) are metabolites derived from polyphenols found in fruits and vegetables as a result of the actions of gut bacteria, and the levels of seven individual PAs were found to be at least 10 times higher in the serum of rats fed a BB‐containing diet compared to those fed a control diet. We have characterized the effects of one such BB‐associated serum PA, 3‐(3‐hydroxyphenyl) propionic acid (PPA), on stimulating osteoblastogenesis. To better understand the mechanistic actions of PPA on bone formation, we administered four doses of PPA (0.1, 0.5, 1 and 5 mg/kg/d) to one‐month‐old female C57BL6/J mice for thirty days. We found that stimulation of osteoblast differentiation and proliferation occurred in PPA treated osteoblastic cells. Using peripheral quantitative CT scan (pQCT) and micro‐CT analyses, we demonstrated differences in bone phenotypes between control and PPA‐treated animals, i.e., bone mass was significantly higher in 1 to 5 mg/kg/d PPA‐treated animals compared to controls (p<0.05). Micro‐CT showed bone volume and trabecular number in 1 mg/kg/d treated animals were 0.14±0.007 and 4.76±0.095 versus 0.12±0.02 and 4.33±0.33 in control animals (p<0.05). The bone formation marker alkaline phosphatase in both serum and bone marrow plasma was dose‐dependently increased in PPA‐treated animals. After aspiration of bone marrow, femur bone protein and RNA were isolated for Western blot and real‐time PCR analysis of signaling transduction. We found that PPA was able to suppress bone senescence signaling as evaluated by measuring senescence‐associated beta‐galactosidase activity, PPARγ, p53 and p21 expression (p<0.05 vs control). In conclusion, blueberry‐derived PPA is capable of altering the mesenchymal stem cell differentiation program and bone cell senescence. Thus, PPA or blueberry‐rich diets merit investigation as potential dietary alternatives to drugs for degenerative bone disorders or to promote bone growth during development. Supported in part by USDA‐ARS Project 6026‐51000‐010‐05S.

Support or Funding Information

Supported in part by USDA‐ARS Project 6026‐51000‐010‐05S
Characterization of Anthocyanins in Sweet Potato Shoots
Authors: Su Xiaoyu , Griffin Jason , Katz Benjamin , Tomich John , Wang Weiqun
Published: June 2021

We previously selected an anthocyanin‐enriched purple‐fleshed sweet potato P40 that prevented colorectal cancer in a murine model. The objectives of this study was to characterize anthocyanins in P40 shoots used as common edible greens. Eight anthocyanins have been identified and quantified in leaves of P40 by HPLC‐MS/MS, whereas fourteen anthocyanins have been found in the control white‐fleshed Bonita and orange‐fleshed Beauregard. The three most abundant anthocyanins were cyanidin 3‐caffeoyl‐p‐hydroxybenzoyl sophoroside‐5‐glucoside, peonidin 3‐caffeoyl sophoroside‐5‐glucoside, and cyanidin 3‐(6″‐caffeoyl‐6″‐feruloylsophoroside)‐5‐glucoside, which comprised up to 58% of total anthocyanins in leaves of P40. The content of anthocyanins in leaves of P40 (17 mg/kg dry matter) was much lower than that in the flesh (13,000 mg/kg dry matter). No anthocyanin was detectable in the stem. The content of anthocyanins in P40 greens was also much lower than that in the Bonita (563 mg/kg dry matter) and Beauregard (334 mg/kg dry matter). The total phenolic content in leaves of P40, as measured by Folin‐Ciocalteu, was 36.8±4.8 mg GAE/g dry weight, compared with Bonita at 46.7±2.1mg GAE/g dry weight and Beauregard at 41.2±5.0 mg GAE/g dry weight

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supported by USDA Cooperative KS511‐1001903
Food‐grade antimicrobial ɛ‐polylysine transiently perturbs the structure of the murine gut microbiome
Authors: You Xiaomeng , Einson Jonah , Lopez‐Peña Cynthia , Song Mingyue , Xiao Hang , McClements D. Julian , Sela David A.
Published: June 2021

A scientific consensus has emerged that dietary components could guide the establishment and maintenance of microbial communities that colonize the distal gastrointestinal tract. Although ubiquitous in various food systems, it is unknown to what extent that antimicrobial compounds interact with endogenous gut microbiota once consumed. In this study, we investigated the influence of food‐grade biopolymers (i.e. ɛ‐polylysine, pectin, and ɛ‐polylysine‐pectin complexes) on the murine microbiota. Accordingly, CD‐1 mice were fed biopolymers incorporated into a high‐fat diet over a 9‐week time course. Microbial phylogenetic diversity present in fecal extracts were ascertained by high‐throughput amplicon sequencing of the 16s rRNA gene. Moreover, community function was predicted from relative abundances of taxa using PICRUSt. Interestingly, dietary ɛ‐polylysine transiently altered the gut microbiome prior to restoration of the initial microbial population structure at the end of the feeding trial. This is indicative of a community adaptive response to ɛ‐polylysine that is now known to be active against microbes in vivo. Moreover when the cationic ɛ‐polylysine is associated with the anionic polymer pectin, this micro‐bioactive perturbation is mitigated. Finally, the absolute population structure of these murine gut microbial communities was observed to be sex‐dependent, but did not alter the response trajectory to exogenous biopolymers.

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USDA
Associations Between Plasma Fatty Acid Composition, Estimated Desaturase Indices, and Measures of Insulin Resistance in 4th‐ and 5th‐grade Children
Authors: Nguyen Lori M , Newman John W , Borkowska Alison G , Zidenberg‐Cherr Sheri , Dharmar Madan , Gray Ira J , Linnell Jessica D , Young Heather M , Scherr Rachel E
Published: June 2021

Lipidomics is often used to characterize the role of lipids in disease; however, few reports document lipid profiles of children. The aim of this study was to evaluate plasma fatty acid profiles in children and identify potential correlates with markers of metabolic health. The fatty acid profiles of children (n=85, ages 9–12) were determined. Anthropometric data, dietary intake data, and plasma were collected. Fasting plasma was analyzed for total fatty acids, glucose, insulin, and full lipid panels for this cross‐sectional study. Insulin resistance was estimated using calculated HOMA‐IR values. Pearson's correlation was used to exam the relationship between HOMA‐IR and blood biomarkers, analysis of covariance was used to determine differences between groups, and multivariate regression was used to determine the predictors of HOMA‐IR. An increased proportion of palmitic acid (16:0) often characterizes insulin resistant states. A negative correlation between HOMA‐IR values and 18:0/16:0 ratio (r=−0.37, P=0.005) was observed. When analyzed by HOMA‐IR quartiles, the highest quartile had a mean difference of −0.05 in the 18:0/16:0 ratio compared to the lowest quartile (P=0.030). A high stearoyl‐CoA‐desaturase (SCD) index, estimated by taking the ratio of 16:1n7/16:0, has been linked to obesity and metabolic syndrome and in this study HOMA‐IR correlated with SCD‐16 (r=0.35, P=0.001). Mean SCD index was greater among the third and fourth quartiles of HOMA‐IR compared to the first (P=0.020). A low Delta‐5‐Desaturase (Δ5D) is often associated with lower risk for metabolic diseases and mean Δ5D was highest in the fourth quartile of HOMA‐IR (P=0.02). In the linear regression model, BMI, 16:0 ratio, and Δ5D were the strongest predictors of HOMA‐IR (r2=0.38, P=0.01). Consistent with adult studies, insulin resistance in children appears to be associated with increased 16:0 proportions and SCD activity indices in plasma. Though these children appear healthy, the type and level of lipidomic markers may be indicative of the degree of insulin resistance. Evaluating plasma fatty acid profiles of children may help establish early disease risk.

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Funding provided by University of California Agriculture and Natural Resources Competitive Grant #11‐1018, USDA Training Grant 2011‐38420‐20082, USDA NIFA, Hatch project 221082, USDA Intramural Project 2032‐52530‐022‐00D, and NIH 1U24DK097154‐01. The USDA is an equal opportunity provider and employer.
Identification and Quantification of Carotenoids in Various Phenotypic Sorghum Accessions
Authors: Shen Yanting , Su Xiaoyu , Chen Xi , Rhodes Davina , Katz Benjamin , Tomich John , Wang Weiqun
Published: June 2021

Sorghum is a staple crop consumed in some regions of Africa and Asia, where vitamin A deficiency is prevalent. The objective of this study was to identify and quantify the carotenoids by LC‐MS in the diversity of phenotypic sorghum accessions. Totally, five carotenoids (α‐carotene, β‐carotene, lutein, zeaxanthin, and β‐crypoxanthin) were identified. Top three carotenoids (lutein, zeaxanthin and β‐carotene) accounted for more than half of the total carotenoids were quantitated. A high content of total carotenoids was detected in the sorghum accessions with yellow endosperm (PI533943, PI655996, PI656096, PI656010), but high β‐carotene content was found in the accessions with brown or yellow pericarp (PI656010, PI655996, PI656096). PI656010 possessed the highest content of both carotenoids and β‐carotene up to 43.7 and 18.6 ng/g dry weight, respectively. No carotenoids were detectable in the accessions with white/red pericarp or white endosperm (PI656112, PI297104). Developing an association of phenotypic diversity of sorghum varieties with carotenoid profile may contribute to a healthy benefit in vitamin A deficiency prevention.

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Supported by USDA Cooperative KS511‐1001903
Sex‐dependent expression of cytoprotective elements in the kidney in response to a hepatotoxic dose of acetaminophen
Authors: Cooper Daniel , Flores Katiria M , Renfro J Larry , Manautou Jose
Published: June 2021

Acetaminophen (APAP) overdose can cause liver and kidney necrosis. Male mice are known to be more susceptible to APAP hepatotoxicity than females, suggesting that gender‐related genotypic traits play a role in APAP toxicity. Gender‐related differences in susceptibility to APAP nephrotoxicity in mice are also well documented and attributed to differential renal expression of CYP2E1. Recent studies in our laboratory investigated the role of the transcription factor nuclear factor erythroid 2‐related factor 2 (Nrf2), the efflux transporter multidrug resistance‐associated protein 4 (Mrp4), and the drug metabolizing enzyme flavin‐containing mono‐oxygenase 3 (Fmo3) in sex‐dependent susceptibility to APAP‐induced hepatotoxicity in mice. However, the expression and potential role of Nrf2, Fmo3, and Mrp4 in the responsiveness of male and female mouse kidneys to toxic doses of APAP has not been investigated. In the current study, we examined gene expression and protein levels of Nrf2, Mrp4, and Fmo3 in the kidneys of APAP (400 mg/kg) and vehicle treated male and female mice. Plasma alanine aminotransferase (ALT) and blood urea nitrogen (BUN) levels were measured to assess liver and renal damage. Confirmation of tissue damage was made by histopathological analysis. Immunoblots and qRT‐PCR analysis revealed that basal renal Fmo3 gene and protein expression is significantly greater in male than female mice, while Mrp4 expression is higher in females. No differences in basal Nrf2 gene and protein expression were observed among genders. High plasma ALT values and histopathological analysis indicated the presence of hepatotoxicity in both males and females receiving APAP. Renal damage was not evident, as BUN values were within the normal range for both genders and the kidney histology was normal. In response to APAP treatment, no changes in renal expression of Mrp4 or Fmo3 were observed in either gender, consistent with the absence of renal pathology. However, renal Nrf2 gene and protein expression decreased significantly in female mice after APAP dosing. In conclusion, this study documents for the first time the difference in basal renal expression levels of Nrf2 and Fmo3 in male and female mice. Further studies will investigate the expression and regulation of these genes at doses of APAP resulting in renal oxidative stress and toxicity and their potential involvement in the sex‐dependent responses to APAP induced renal damage.

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Supported by NSF and NIH