bluuebunny/crossref_metadata_2025 huggingface dataset:
Proof-of-principle neural network models for classification, attribution, creation, style-mixing, and morphing of image data for genetic conditions
Authors: Duong Dat , Waikel Rebekah L. , Hu Ping , Tekendo-Ngongang Cedrik , Solomon Benjamin D.
Published: April 2021

Neural networks have shown strong potential to aid the practice of healthcare. Mainly due to the need for large datasets, these applications have focused on common medical conditions, where much more data is typically available. Leveraging publicly available data, we trained a neural network classifier on images of rare genetic conditions with skin findings. We used approximately100 images per condition to classify 6 different genetic conditions. Unlike other work related to these types of images, we analyzed both preprocessed images that were cropped to show only the skin lesions, as well as more complex images showing features such as the entire body segment, patient, and/or the background. The classifier construction process included attribution methods to visualize which pixels were most important for computer-based classification. Our classifier was significantly more accurate than pediatricians or medical geneticists for both types of images. Next, we trained two generative adversarial networks to generate new images. The first involved all of the genetic conditions and was used for style-mixing to demonstrate how the diversity of small datasets can be increased. The second focused on different disease stages for one condition and depicted how morphing can illustrate the disease progression of this condition. Overall, our findings show how computational techniques can be applied in multiple ways to small datasets to enhance the study of rare genetic diseases.
Variant Creutzfeldt-Jakob Disease: The Challenge of Preventing a Rare but Potentially Devastating Exposure
Authors: Pandey Ritambhara , Rai Devesh , Giles Julie , Laguio-Vila Maryrose , Lesho Emil
Published: April 2021

Although rare, patients with variant Creutzfeldt-Jakob Disease (vCJD) in their differential diagnosis of progressive dementia and movement disorder could continue to present to hospitals for care. However, U.S.-based infection control guidelines do not fully address the possibility of vCJD. After near-misses involving increasing numbers of patients with clinical findings and epidemiologic risks compatible with vCJD, or exposures to chronic wasting disease, we sought to improve recognition and prevention of iatrogenic spread of these prion-related diseases.
A CROSS-SECTIONAL SURVEY OF THE PREVALENCE AND THE RISK FACTORS OF TOBACCO USE AMONGST CONSTRUCTION ARTISANS IN EKITI STATE, NIGERIA
Authors: Olomofe Charles Oluwatemitope , Benyon Caryl M , Durowade Kabir Adekunle , Olomofe Oluwafunmike Ruth
Published: April 2021

Background

Construction artisans are those who perform skilled work relating to the erection or assembly of a large structure. These artisans are prone to tobacco use. This study aims to assess the prevalence and the associated risk factors of tobacco use amongst construction artisans in Ekiti State, Nigeria.

Materials and Methods

This cross-sectional study employed a multi-stage sampling technique to select participants (carpenters and bricklayers) artisans, journeymen, and their apprentices who were working in Ekiti State. Chi-square and logistic regression were used to test for association in bivariate and multivariate analyses respectively.

Results

The prevalence of ever-smoke amongst respondents was 19.3%. Multivariate analysis showed that artisans who were within the age range 31-40 years were four times more likely to use tobacco (OR=3.410; CI=1.476-7.878). Similarly, being in school and divorced/separated were associated with tobacco use.

Conclusion

Noting the increased prevalence of tobacco use among construction artisans when compared to the general population, and few self-reported cases of addiction amongst users demands action from communities and government at all levels.
Atypical N-glycosylation of SARS-CoV-2 impairs the efficient binding of Spike-RBM to the human-host receptor hACE2
Authors: Gámez Gustavo , Hermoso Juan A. , Carrasco-López César , Gómez-Mejia Alejandro , Muskus Carlos E. , Hammerschmidt Sven
Published: April 2021

SARS-CoV-2 internalization by human host cells relies on the molecular binding of its spike glycoprotein (SGP) to the angiotensin-converting-enzyme-2 (hACE2) receptor. It remains unknown whether atypical N-glycosylation of SGP modulates SARS-CoV-2 tropism for infections. Here, we address this question through an extensive bioinformatics analysis of publicly available structural and genetic data. We identified two atypical sequons (sequences of N-glycosylation: NGV 481-483 and NGV 501-503), strategically located on the receptor-binding motif (RBM) of SGP and facing the hACE2 receptor. Interestingly, the cryo-electron microscopy structure of trimeric SGP in complex with potent-neutralizing antibodies from convalescent patients revealed covalently-linked N-glycans in NGV 481-483 atypical sequons. Furthermore, NGV 501-503 atypical sequon involves the asparagine-501 residue, whose highly-transmissible mutation N501Y is present in circulating variants of major concerns and affects the SGP-hACE2 binding-interface through the well-knownhotspot-353. These findings suggest that atypical SGP post-translational modifications modulate the SGP-hACE2 binding-affinity affecting consequently SARS-CoV-2 transmission and pathogenesis.
Nonnegative matrix factorization integrates single-cell multi-omic datasets with partially overlapping features
Authors: Kriebel April R. , Welch Joshua D.
Published: April 2021

Single-cell genomic technologies provide an unprecedented opportunity to define molecular cell types in a data-driven fashion, but present unique data integration challenges. Integration analyses often involve datasets with partially overlapping features, including both shared features that occur in all datasets and features exclusive to a single experiment. Previous computational integration approaches require that the input matrices share the same number of either genes or cells, and thus can use only shared features. To address this limitation, we derive a novel nonnegative matrix factorization algorithm for integrating single-cell datasets containing both shared and unshared features. The key advance is incorporating an additional metagene matrix that allows unshared features to inform the factorization. We demonstrate that incorporating unshared features significantly improves integration of single-cell RNA-seq, spatial transcriptomic, SHARE-seq, and cross-species datasets. We have incorporated the UINMF algorithm into the open-source LIGER R package (https://github.com/welch-lab/liger).
Efficacy and breadth of adjuvanted SARS-CoV-2 receptor-binding domain nanoparticle vaccine in macaques
Authors: King Hannah A. D. , Gordon Joyce M. , Naouar Ines Elakhal , Ahmed Aslaa , Cincotta Camila Macedo , Subra Caroline , Peachman Kristina K. , Hack Holly H. , Chen Rita E. , Thomas Paul V. , Chen Wei-Hung , Sankhala Rajeshwer S. , Hajduczki Agnes , Martinez Elizabeth J. , Peterson Caroline E. , Chang William C. , Choe Misook , Smith Clayton , Headley Jarrett A. , Elyard Hanne A. , Cook Anthony , Anderson Alexander , Wuertz Kathryn McGuckin , Dong Ming , Swafford Isabella , Case James B. , Currier Jeffrey R. , Lal Kerri G. , Amare Mihret F. , Dussupt Vincent , Molnar Sebastian , Daye Sharon P. , Zeng Xiankun , Barkei Erica K. , Alfson Kendra , Staples Hilary M. , Carrion Ricardo , Krebs Shelly J. , Paquin-Proulx Dominic , Karasavvas Nicos , Polonis Victoria R. , Jagodzinski Linda L. , Vasan Sandhya , Scott Paul T. , Huang Yaoxing , Nair Manoj S. , Ho David D. , de Val Natalia , Diamond Michael S. , Lewis Mark G. , Rao Mangala , Matyas Gary R. , Gromowski Gregory D. , Peel Sheila A. , Michael Nelson L. , Modjarrad Kayvon , Bolton Diane L.
Published: April 2021

Emergence of novel variants of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean neutralizing antibody titers of 14,000-21,000. Rapid control of viral replication was achieved in the upper and lower airways of animals after high-dose SARS-CoV-2 respiratory challenge, with undetectable replication within four days in 7 of 8 animals receiving 50 µg RFN. Cross-neutralization activity against SARS-CoV-2 variant B.1.351 decreased only ∼2-fold relative to USA-WA1. In addition, neutralizing, effector antibody and cellular responses targeted the heterotypic SARS-CoV-1, highlighting the broad immunogenicity of RFN-ALFQ for SARS-like betacoronavirus vaccine development.

Significance Statement

The emergence of SARS-CoV-2 variants of concern (VOC) that reduce the efficacy of current COVID-19 vaccines is a major threat to pandemic control. We evaluate a SARS-CoV-2 Spike receptor-binding domain ferritin nanoparticle protein vaccine (RFN) in a nonhuman primate challenge model that addresses the need for a next-generation, efficacious vaccine with increased pan-SARS breadth of coverage. RFN, adjuvanted with a liposomal-QS21 formulation (ALFQ), elicits humoral and cellular immune responses exceeding those of current vaccines in terms of breadth and potency and protects against high-dose respiratory tract challenge. Neutralization activity against the B.1.351 VOC within two-fold of wild-type virus and against SARS-CoV-1 indicate exceptional breadth. Our results support consideration of RFN for SARS-like betacoronavirus vaccine development.
Cardiac Differentiation of Human Pluripotent Stem Cells Using Defined Extracellular Matrix Proteins Reveals Essential Role of Fibronectin
Authors: Zhang Jianhua , Tao Ran , Lalit Pratik A. , Carvalho Juliana L. , Markandeya Yogananda , Palecek Sean P. , Kamp Timothy J.
Published: April 2021

Research and therapeutic applications using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) require robust differentiation strategies. Efforts to improve hPSC-CM differentiation have largely overlooked the role of extracellular matrix (ECM). The present study investigates the ability of defined ECM proteins to promote hPSC cardiac differentiation. Fibronectin, laminin-111, and laminin-521 enabled hPSCs to attach and expand; however, fibronectin ECM either endogenously produced or exogenously added promoted, while laminins inhibited, cardiac differentiation in response to growth factors Activin A, BMP4, and bFGF. Inducible shRNA knockdown of fibronectin prevented Brachyury+mesoderm formation and subsequent hPSC-CM differentiation. Antibodies blocking fibronectin binding to integrin β1, but not α5, inhibited cardiac differentiation. Furthermore, inhibition of integrin-linked kinase blocked cardiac differentiation. These results identify fibronectin, laminin-111 and laminin-521 as defined substrates enabling cardiac differentiation of hPSCs and uncover the essential role of fibronectin and downstream signaling pathways in the early stage of hPSC-CM differentiation.
The Shu Complex Prevents Mutagenesis and Cytotoxicity of Single-Strand Specific Alkylation Lesions
Authors: Bonilla Braulio , Brown Alexander J. , Hengel Sarah R. , Rapchak Kyle S. , Mitchell Debra , Pressimone Catherine A. , Fagunloye Adeola A. , Luong Thong T. , Zaher Hani S. , Mosammaparast Nima , Malc Ewa P. , Mieczkowski Piotr A. , Roberts Steven A. , Bernstein Kara A.
Published: April 2021

Three-methyl cytosine (3meC) are toxic DNA lesions, blocking base pairing. Bacteria and humans, express members of the AlkB enzymes family, which directly remove 3meC. However, other organisms, including budding yeast, lack this class of enzymes. It remains an unanswered evolutionary question as to how yeast repairs 3meC, particularly in single-stranded DNA. The yeast Shu complex, a conserved homologous recombination factor, aids in preventing replication-associated mutagenesis from DNA base damaging agents such as methyl methanesulfonate (MMS). We found that MMS-treated Shu complex-deficient cells, exhibit a genome-wide increase in A:T and G:C substitutions mutations. The G:C substitutions displayed transcriptional and replicational asymmetries consistent with mutations resulting from 3meC. Ectopic expression of a human AlkB homolog in Shu-deficient yeast rescues MMS-induced growth defects and increased mutagenesis. Finally, the Shu complex exhibits increased affinity for 3meC-containing DNA. Thus, our work identifies a novel mechanism for coping with alkylation adducts.
Weak Task Synchronization of Default Mode Network in Task Based Paradigms
Authors: Tripathi Vaibhav , Garg Rahul
Published: April 2021

Default mode network (DMN) are the areas of the brain that get deactivated upon the presentation of externally focused, attention demanding tasks. Interestingly, these areas are consistently deactivated irrespective of the nature of the task. Recent evidence shows that the behavior of the DMN may be more nuanced than what was earlier believed. We wanted to investigate the dynamics of DMN further and utilized novel statistical approaches to study the same. We analysed four publicly available datasets (total 223 subjects) across seven tasks related to different cognitive modalities and found out that there is a large amount of variability in the presumed task-negative network across subjects, trials and regions. We designed a method called Inter Trial Temporal Synchronization Analysis (IT-TSA) and Inter Subject TSA (IS-TSA) to analyse variability across trials and subjects respectively. We found out that all task-negative regions and even weak task-positive regions have low synchronization across trials and subjects. We hypothesize that the DMN variability might be more due to neural differences rather than structural or HRF variations. We also investigated the use of non GLM technique like the Inter Subject Correlation (ISC) and found that it may only be suitable to study tightly synchronized task-positive regions. Our study challenges the understanding of DMN as a task-negative region and advances the findings that DMN acts as an active component associated with a unique set of self-referential, autobiographical processes which are deactivated differentially and non linearly across trials and subjects in the presence of extrinsic processes.

Highlights

Default Mode Network is weakly synchronized across trials and subjects in task paradigms.

Inter Subject Correlation is not suited to detect task-based activations in DMN.

Synchronization Analysis reveals temporal structure in fMRI data.
A unified model of the task-evoked pupil response
Authors: Burlingham Charlie S. , Mirbagheri Saghar , Heeger David J.
Published: April 2021

The pupil dilates and re-constricts following task events. It is popular to model this task-evoked pupil response as a linear transformation of event-locked impulses, the amplitudes of which are used as estimates of arousal. We show that this model is incorrect, and we propose an alternative model based on the physiological finding that a common neural input drives saccades and pupil size. The estimates of arousal from our model agreed with key predictions: arousal scaled with task difficulty and behavioral performance but was invariant to trial duration. Moreover, the model offers a unified explanation for a wide range of phenomena: entrainment of pupil size and saccade occurrence to task timing, modulation of pupil response amplitude and noise with task difficulty, reaction-time dependent modulation of pupil response timing and amplitude, a constrictory pupil response time-locked to saccades, and task-dependent distortion of this saccade-locked pupil response.
Uncovering the modified immunopeptidome reveals insights into principles of PTM-driven antigenicity
Authors: Kacen Assaf , Javitt Aaron , Kramer Matthias P. , Morgenstern David , Tsaban Tomer , Solomon Adam , Teo Guo Ci , da Veiga Leprevost Felipe , Barnea Eilon , Yu Fengchao , Admon Arie , Eisenbach Lea , Cafri Gal , Schueler-Furman Ora , Levin Yishai , Nesvizhskii Alexey I. , Merbl Yifat
Published: April 2021

Antigen processing and presentation are critical for modulating tumor-host interactions. While post-translational modifications (PTMs) can alter the binding and recognition of antigens, their identification remains challenging. Here we uncover the role PTMs may play in antigen presentation and recognition in human cancers by profiling 29 different PTM combinations in immunopeptidomics data from multiple clinical samples and cell lines. We established and validated an antigen discovery pipeline and showed that newly identified modified antigens from a murine cancer model are cancer-specific and can elicit T cell killing. Systematic analysis of PTMs across multiple cohorts defined new haplotype preferences and binding motifs in association with specific PTM types. By expanding the antigenic landscape with modifications, we uncover disease-specific targets, including thousands of novel cancer-specific antigens and reveal insight into PTM-driven antigenicity. Collectively, our findings highlight an immunomodulatory role for modified peptides presented on HLA I, which may have broad implications for T-cell mediated therapies in cancer and beyond.

Significance

Major efforts are underway to identify cancer-specific antigens for personalized immunotherapy. Here, we enrich the immunopeptidome landscape by uncovering thousands of novel putative antigens that are post-translationally modified. We define unique preferences for PTM-driven alterations affecting HLA binding and TCR recognition, which in turn alter tumor-immune interactions.

Conflict of interest statement

Authors declare no conflicts of interest.
Probing solution structure of the pentameric ligand-gated ion channel GLIC by small-angle neutron scattering
Authors: Lycksell Marie , Rovšnik Urška , Bergh Cathrine , Johansen Nicolai T , Martel Anne , Porcar Lionel , Arleth Lise , Howard Rebecca J , Lindahl Erik
Published: April 2021

Pentameric ligand-gated ion channels undergo subtle conformational cycling to control electrochemical signal transduction in many kingdoms of life. Several crystal structures have now been reported in this family, but the functional relevance of such models remains unclear. Here, we used small-angle neutron scattering (SANS) to probe ambient solution-phase properties of the pH-gated bacterial ion channel GLIC under resting and activating conditions. Data collection was optimized by inline paused-flow size-exclusion chromatography, and exchanging into deuterated detergent to hide the micelle contribution. Resting-state GLIC was the best-fit crystal structure to SANS curves, with no evidence for divergent mechanisms. Moreover, enhanced-sampling molecular dynamics simulations enabled differential modeling in resting versus activating conditions, with the latter corresponding to an intermediate ensemble of both the extracellular and transmembrane domains. This work demonstrates state-dependent changes in a pentameric ion channel by SANS, an increasingly accessible method for macromolecular characterization with the coming generation of neutron sources.
Investigating the Interplay Between Affective, Phonatory and Motoric Subsystems in Autism Spectrum Disorder Using a Multimodal Dialogue Agent
Authors: Kothare Hardik , Ramanarayanan Vikram , Roesler Oliver , Neumann Michael , Liscombe Jackson , Burke William , Cornish Andrew , Habberstad Doug , Sakallah Alaa , Markuson Sara , Kansara Seemran , Faerman Afik , Bensidi-Slimane Yasmine , Fry Laura , Portera Saige , Suendermann-Oeft David , Pautler David , Demopoulos Carly
Published: April 2021

We explore the utility of an on-demand multimodal conversational platform in extracting speech and facial metrics in children with Autism Spectrum Disorder (ASD). We investigate the extent to which these metrics correlate with objective clinical measures, particularly as they pertain to the interplay be-tween the affective, phonatory and motoric subsystems. 22 participants diagnosed with ASD engaged with a virtual agent in conversational affect production tasks designed to elicit facial and vocal affect. We found significant correlations between vocal pitch and loudness extracted by our platform during these tasks and accuracy in recognition of facial and vocal affect, as-sessed via the Diagnostic Analysis of Nonverbal Accuracy-2 (DANVA-2) neuropsychological task. We also found significant correlations between jaw kinematic metrics extracted using our platform and motor speed of the dominant hand assessed via a standardised neuropsychological finger tapping task. These findings offer preliminary evidence for the usefulness of these audiovisual analytic metrics and could help us better model the interplay between different physiological subsystems in individuals with ASD.
Lysosomal Exocytosis Releases Pathogenic α-Synuclein Species from Neurons
Authors: Xie Ying Xue , Naseri Nima N. , Fels Jasmine , Kharel Parinati , Na Yoonmi , Burré Jacqueline , Sharma Manu
Published: April 2021

Considerable evidence supports the release of pathogenic aggregates of the neuronal protein α-Synuclein (αSyn) into the extracellular space. While this release is proposed to instigate the neuron-to-neuron transmission and spread of αSyn pathology in synucleinopathies including Parkinson’s disease, the molecular-cellular mechanism(s) remain unclear. Here we show that pathogenic species of αSyn accumulate within neuronal lysosomes in mouse brains and primary neurons. We then find that neurons release these pathogenic αSyn species via SNARE-dependent lysosomal exocytosis; proposing a central mechanism for exocytosis of aggregated and degradation-resistant proteins from neurons.
Correlated evolution of parental care with dichromatism, colour, and patterns in anurans
Authors: Seshadri K S , Thaker Maria
Published: April 2021

Parental care is widespread among vertebrates, with clear fitness benefits. Caring parents however incur costs that include higher predation risk. Anurans have among the most diverse forms of parental care, and we test whether the occurrence of care is associated with morphology that minimizes predation risk. We first examine whether parental care co-occurs with sexual dichromatism, testing the hypothesis that when one sex is conspicuous, the other is cryptically patterned and cares for the young. From our phylogenetic comparative analyses of 988 anurans distributed globally, we find that parental care is less likely to co-occur with dichromatism, irrespective of the caring sex. We then examine whether colour gradients and patterns that enhance crypticity are associated with the occurrence of parental care. We found that species with male-only care were more likely to have Bars-Bands, but contrary to our expectation, other colours (Green-Brown, Red-Blue-Black, Yellow) and patterns (Plain, Spots, Mottled-Patches) were not associated with caregiving behaviours. The lack of strong correlations between dorsal morphology and parental care suggests that crypticity is not the dominant strategy to minimise predation risk for care-giving anurans, and that the evolution of body colour and parental care are driven by independent selection pressures.
Linearised loop kinematics to study pathways between conformations
Authors: Hoevenaars Antonius G.L. , André Ingemar
Published: April 2021

Abstract

Conformational changes are central to the function of many proteins. Characterization of these changes using molecular simulation requires methods to effectively sample pathways between protein conformational states. In this paper we present an iterative algorithm that samples conformational transitions in protein loops, referred to as the Jacobian-based Loop Transition (JaLT) algorithm. The method uses internal coordinates to minimise the sampling space, while Cartesian coordinates are used to maintain loop closure. Information from the two representations is combined to push sampling towards a desired target conformation. The innovation that enables the simultaneous use of Cartesian coordinates and internal coordinate is the linearisation of the inverse kinematics of a protein backbone. The algorithm uses the Rosetta all-atom energy function to steer sampling through low-energy regions and uses Rosetta’s side-chain energy minimiser to update side-chain conformations along the way. Because the JaLT algorithm combines a detailed energy function with a low-dimensional conformational space, it is positioned in between molecular dynamics (MD) and elastic network model (ENM) methods. As a proof of principle, we apply the JaLT algorithm to study the conformational transition between the open and occluded state in the MET20 loop of the Escherichia coli dihydrofolate reductase enzyme. Our results show that the algorithm generates semi-continuous pathways between the two states with realistic energy profiles. These pathways can be used to identify energy barriers along the transition. The effect of a single point mutation of the MET20 loop was also investigated and the predicted increase in energy barrier is consistent with the experimentally observed reduction in catalytic rate of the enzyme. Additionally, it is demonstrated how the JaLT algorithm can be used to identify dominant degrees of freedom during a transition. This can be valuable input for a more extensive characterization of the free energy pathway along a transition using molecular dynamics, which is often performed with a reduced set of degrees of freedom. This study has thereby provided the first examples of how linearisation of inverse kinematics can be applied to the analysis of proteins.
DruID: PersonalizedDrug Recommendations byIntegrating Multiple BiomedicalDatabases for Cancer
Authors: Liany Herty , Jeyasekharan Anand , Rajan Vaibhav
Published: April 2021

Advances in next-generation sequencing technologies have led to the development of personalized genomic profiles in diagnostic panels that inform oncologists of alterations in clinically relevant genes. While targeted therapies for some alterations may be found, an effective therapeutic strategy should consider multiple and dependent genetic interactions that affect cancer progression, a task which remains challenging. There are ongoing efforts to profile cancer cells in-vitro, both to catalog their genomic information and study their sensitivity to various drugs. There is a need for tools that can interpret the personalized genomic profile of a patient in light of information from these biological and pre-clinical studies and recommend potentially useful drugs. To address this need, we develop a new algorithmic framework called DruID, to effectively combine drug efficacy predictions from a deep neural network model with information, such as drug sensitivity, drug-drug interactions and genetic dependencies, from multiple publicly available databases. We empirically evaluate DruID on cancer cell line data on which efficacy of many drugs have been experimentally determined. We find that DruID outperforms competing approaches and promises to be a useful tool in clinical decision-making.
Virtual Parts Repository 2: Model-driven design of genetic regulatory circuits
Authors: Mısırlı Göksel , Yang Bill , James Katherine , Wipat Anil
Published: April 2021

Engineering genetic regulatory circuits is key to the creation of biological applications that are responsive to environmental changes. Computational models can assist in understanding especially large and complex circuits where manual analysis is infeasible, permitting a model-driven design process. However, there are still few tools that offer the ability to simulate the system under design. One of the reasons for this is the lack of accessible model repositories or libraries that cater for the modular composition of models of synthetic systems that do not yet exist in nature. Here, we present the Virtual Parts Repository 2, a resource to facilitate the model-driven design of genetic regulatory circuits, which provides reusable, modular and composable models. The repository is service-oriented and can be utilized by design tools in computational workflows. Designs provided in Synthetic Biology Open Language documents are used to derive system-scale and hierarchical Systems Biology Markup Language models. We also present a rule-based modeling abstraction based on reaction networks to facilitate scalable and modular modeling of complex and large designs. This modeling abstraction incorporates design patterns such as roadblocking, distributed deployment of genetic circuits using plasmids and cellular resource dependency. The computational resources and the modeling abstraction presented in this paper allow computational design tools to take advantage of computational simulations and ultimately help facilitate more predictable applications.

Graphical TOC Entry
Effect of market versus nonmarket environmental policy stringency on knowledge sourcing behavior for green technology: evidence from OECD countries
Authors: Choi Gunae , Cho Se Ho
Published: April 2021

Purpose

The purpose of this paper is to examine firms’ knowledge-sourcing behavior in green technology development with respect to the home country’s market- vs nonmarket environmental policy stringency.

Design/methodology/approach

This paper empirically analyzes the effects of market and nonmarket environmental policy stringency on firms’ knowledge sourcing activity with patent data from OECD countries during 1991–2010, across five categories of green technologies.

Findings

When a nation establishes more stringent market environmental policies, firms likely source more international knowledge rather than domestic knowledge about green technology, up to a point. After that level, this balance shifts (inverted U-shaped curve) due to the risks associated with greater investment costs and commerciality. Nonmarket environmental policies instead should exhibit a positive, linear relationship with international relative to domestic knowledge sourcing. This study also reveals the dynamic roles of a firm’s green technological capability with market-based environmental policy stringency and a substitutive role of the capability with nonmarket-based environmental policy stringency.

Research limitations/implications

This study shows the effect of market and nonmarket environmental policy stringency on firms’ knowledge sourcing. The findings provide meaningful implications for policymakers regarding the optimal levels of market and nonmarket environmental policy stringency that will enhance their countries’ green technology development.

Originality/value

This paper enriches the literature of environmental policy and knowledge sourcing and offers the direction of future research of how environmental policy stringency influences a firm’s knowledge sourcing for green technology development.
What doesn't kill you makes you stronger: Detoxification ability as a mechanism of honesty in a sexually selected signal
Authors: G‐Santoyo Isaac , González‐Tokman Daniel , Tapia‐Rodríguez Miguel , Córdoba‐Aguilar Alex
Published: April 2021

Sexual selection leads to the expression and maintenance of colourful signals. The metabolic pathways to produce such signals often involve toxic byproducts that can reduce survival. However, rather than discarding these otherwise harmful byproducts, animals may use them by integrating them into sexually selected traits.

We tested this using the damselfly Hetaerina americana, where males bear a red wing spot (RWS) that has evolved by intrasexual competition.

By using confocal microscopy and several biochemical techniques, we determined that the RWS are generated by ommochrome pigments derived from tryptophan metabolism.

Second, we injected a group of males with the toxic precursor of these ommochromes, 3‐hydroxy‐kynurenine (3‐Hk), confirming the toxicity of this compound in adult males.

Finally, we showed that adult males injected with a median lethal concentration of 3‐Hk had more ommochromes in their RWS than controls but similar survival, suggesting that the deposition of ommochrome pigment in the wing counteracts the 3‐HK toxicity.

Thus, we report that sexually selected pigmented signals may involve the co‐option of excreted compounds that could otherwise have lethal effects, a hypothesis we call ‘detoxifying ability signalling’. Our results provide new insights about the evolution of sexual signals, elucidating a mechanism for the evolution of honest indicators of quality that could have arisen due to natural selection.
Supplemental oxygen therapy in trauma patients: An exploratory registry‐based study
Authors: Christensen Mathias A. , Steinmetz Jacob , Velmahos George , Rasmussen Lars S.
Published: April 2021

Background

Supplemental oxygen (SO) is one of the most commonly administered drugs in trauma patients and is recommended by guidelines. However, evidence supporting uniform administration is sparse, and excess oxygen use has been shown to be harmful in other patient populations. We hypothesized that SO may be harmful in patients with oxygen saturation > 97%.

Methods

Patients with available information on SO‐therapy in the American Trauma Quality Improvement Program 2017 database were included. Patients were categorized into 3 groups according to Emergency Department (ED) oxygen saturation: (1) saturation < 94%; (2) saturation 94%‐97%; (3) saturation 98%‐100%. Primary outcome was in‐hospital mortality with comparisons made between patients who received SO or not. Secondary outcome was acute respiratory distress syndrome (ARDS). Patients were compared after propensity score matching.

Results

Overall, 864 340 patients were identified. Mean age was 47.4 ± 24.4 years, and median injury severity score was 9. SO was associated with an increased risk of in‐hospital mortality: (all patients: adjusted odds ratio [aOR] with 95% confidence interval [CI] 3.07 [2.92‐3.22], ED saturation <94%: 2.63 [2.38‐2.91], ED saturation 94%‐97%: 2.71 [2.47‐2.97], ED saturation >97%: 3.38 [3.16‐3.61]. Same pattern was seen for in‐hospital ARDS: (aOR 1.79, 95% CI [1.59‐2.02], ED saturation <94%: aOR 1.75, 95% CI [1.37‐2.24], ED saturation 94%‐97%: aOR 1.81, 95% CI [1.43‐2.29, ED saturation >97%: aOR 2.31, 95% CI [1.92‐2.79]).

Conclusion

Based on propensity matched, registry data for trauma patients, the administration of SO was associated with a higher incidence of in‐hospital mortality and ARDS. The highest risk was found in patients with an ED saturation >97%.
Identification of a large dataset of SNPs in hair‐fin anchovy (Setipinna tenuifilis) based on RAD‐seq
Authors: Peng Y. , Li J. S. , Zhang K. , Liu Y. F. , Li X. P. , Zhang H. , Gong L. , Liu L. Q. , Lü Z. M. , Liu B. J.
Published: April 2021

Hair‐fin anchovy (Setipinna tenuifilis) is an economically important fish distributed in the West Indian Ocean and the Northwest Pacific Ocean. In this study, 154 individuals in eight populations of S. tenuifilis were sequenced and 850 million raw reads were obtained using restriction site‐associated DNA sequencing (RAD‐seq). First, we identified 14 012 044 hypothetical SNP markers. A dataset of 199 903 high‐quality SNPs was collected after further screening. These SNPs have a strong ability to test the genetic diversity between the eight populations. The differentiation and genetic law between samples were explored based on SNPs in populations of S. tenuifilis. The results of this study will provide data for protecting the genetic resources of the species.
Peripheral markers of allergen‐specific immune activation predict clinical allergy in eosinophilic esophagitis
Authors: Dilollo Julianna , Rodríguez‐López Eric M. , Wilkey Leah , Martin Elizabeth K. , Spergel Jonathan M. , Hill David A.
Published: April 2021

Background

Eosinophilic esophagitis (EoE) is a T‐cell‐mediated disease that is caused by specific foods and results in esophageal dysfunction. Existing allergy testing modalities are not helpful when attempting to identify EoE‐causal foods necessitating empiric food elimination and recurrent endoscopy. The goal of this study was to identify and compare allergen‐specific immune features that can be assayed in a minimally invasive manner to predict clinical food allergy in EoE.

Methods

We obtained blood samples from control subjects (n = 17), subjects with clinical EoE milk allergy (n = 17), and subjects with immunoglobulin E‐mediated milk allergy (n = 9). We measured total and milk‐specific plasma immunoglobulin G (IgG)4 levels and peripheral memory CD4+ T helper (TH) cell proliferation and cytokine production after stimulation with endotoxin‐depleted milk proteins. Sensitivity and specificity for predicting clinical EoE milk allergy were calculated and compared between approaches.

Results

Total and milk‐specific IgG4 levels were not significantly different between control subjects and subjects with clinical EoE milk allergy. Stimulation with milk proteins caused TH lymphocytes from subjects with clinical EoE milk allergy to proliferate more (%P1 of 38.3 ± 4.6 vs. 12.7 ± 2.8, p < 0.0001), and produce more type 2 cytokines (%IL‐4+ of 33.7 ± 2.8 vs. 6.9 ± 1.6, p < 0.0001) than cells from control subjects. Milk‐dependent memory TH‐cell proliferation (sensitivity and specificity of 88% and 82%, respectively) and interleukin 4 (IL‐4) production (sensitivity and specificity of 100%) most strongly predicted clinical EoE milk allergy.

Conclusions

Peripheral markers of allergen‐specific immune activation may be useful in identifying EoE‐causal foods. Assaying milk‐dependent IL‐4 production by circulating memory TH lymphocytes most accurately predicts clinical EoE milk allergy.
Rigid reduced successor representation as a potential mechanism for addiction
Authors: Shimomura Kanji , Kato Ayaka , Morita Kenji
Published: April 2021

Difficulty in cessation of drinking, smoking, or gambling has been widely recognized. Conventional theories proposed relative dominance of habitual over goal‐directed control, but human studies have not convincingly supported them. Referring to the recently suggested “successor representation (SR)” of states that enables partially goal‐directed control, we propose a dopamine‐related mechanism that makes resistance to habitual reward‐obtaining particularly difficult. We considered that long‐standing behavior towards a certain reward without resisting temptation can (but not always) lead to a formation of rigid dimension‐reduced SR based on the goal state, which cannot be updated. Then, in our model assuming such rigid reduced SR, whereas no reward prediction error (RPE) is generated at the goal while no resistance is made, a sustained large positive RPE is generated upon goal reaching once the person starts resisting temptation. Such sustained RPE is somewhat similar to the hypothesized sustained fictitious RPE caused by drug‐induced dopamine. In contrast, if rigid reduced SR is not formed and states are represented individually as in simple reinforcement learning models, no sustained RPE is generated at the goal. Formation of rigid reduced SR also attenuates the resistance‐dependent decrease in the value of the cue for behavior, makes subsequent introduction of punishment after the goal ineffective, and potentially enhances the propensity of nonresistance through the influence of RPEs via the spiral striatum‐midbrain circuit. These results suggest that formation of rigid reduced SR makes cessation of habitual reward‐obtaining particularly difficult and can thus be a mechanism for addiction, common to substance and nonsubstance reward.
Pinealectomy and gonadectomy modulate amplitude, but not photoperiodic modulation of Clock gene expression in the Syrian hamster suprachiasmatic nuclei
Authors: Chakir Ibtissam , Tournier Benjamin B. , Touati Hanane , Poirel Vincent‐Joseph , Challet Etienne , Pevet Paul , Ouarour Ali , Vuillez Patrick
Published: April 2021

The duration of daytime light phase (photoperiod) controls reproduction in seasonal mammals. Syrian hamsters are sexually active when exposed to long photoperiod, while gonadal atrophy is observed after exposure to short photoperiod. The photorefractory period, or photorefractoriness, is a particular state of spontaneous recrudescence of sexual activity that occurs after a long‐term exposure to short photoperiod. Expression of core clock genes in the master circadian clock contained in the suprachiasmatic nuclei depends on photoperiodic conditions. Interestingly, the expression of the Clock gene is also modified in photorefractory Syrian hamsters. Since melatonin and testosterone levels in seasonal species are dependent on photoperiod, photoperiodic variations of Clock mRNA levels in the suprachiasmatic clock could be a consequence of these hormonal changes. To test this hypothesis, we analysed the effects of pinealectomy on Clock mRNA changes due to long to short photoperiod transition and of gonadectomy on Clock mRNA levels in photorefractory period. Our data show that the suprachiasmatic integration of the short photoperiod (assessed by a rhythmic expression profile of Clock) is independent of the presence of melatonin. Furthermore, constitutively low expression of Clock observed during the photorefractory period does not require the presence of either melatonin or testosterone. However, we show that both hormones provide positive feedback on average levels of Clock expression. Thus, our data support the hypothesis that daily variations of Clock levels in the suprachiasmatic nuclei are influenced by photoperiodic changes and the time spent in short photoperiod, independently of seasonal modifications of melatonin or testosterone levels.
Waterfalls mediate the longitudinal distribution of diadromous predatory fishes structuring communities in tropical, short, steep coastal streams
Authors: Ebner Brendan C. , Donaldson James A. , Murphy Helen , Thuesen Paul , Ford Andrew , Schaffer Jason , Keith Philippe
Published: April 2021

Tropical short, steep coastal streams are typically dominated by diadromous species, especially amphidromous fishes, crustaceans, and molluscs. We undertook a study to determine the distribution of fishes along the stream continuum and determine if substantial natural instream barriers influenced assemblage composition.

We surveyed fish assemblages in three short, steep coastal streams in the Australian Wet Tropics by snorkelling and performing single pass counts in each 100‐m section along the entire main channel from the high‐tide mark to the source (or near source: until fish were no longer recorded). A primary focus was mapping the distribution and relative abundance of sicydiine gobies, and we also estimated freshwater crustacean numbers (Caridea: Palaemonidae and Atyidae).

In total, 2,837 individual fish of 25 species were recorded upstream of the high‐tide mark across the three streams and the first records of an additional sicydiine goby (Smilosicyopus leprurus) were obtained from continental Australia. Consistent with findings from tropical Pacific island streams, we observed a shift in fish assemblage composition along the elevation gradient and in relation to major instream barriers (e.g. waterfalls >5 m, and high flow chutes across smooth bedrock surfaces). Species richness of diurnal predatory fishes was greatest in the lower course of streams and absent upstream of major instream barriers.

Diurnal predatory fishes were, in some instances, found upstream of barriers. Specifically, large adult (>200 mm total length) Kuhlia rupestris (diurnal predators) accessed reaches above challenging sequences of cascades combined with small waterfalls. In contrast, all sizes of that species, adult Kuhlia marginata (>150 mm total length) and a diversity of other diurnal predatory fishes occupied the lower course of streams including upstream of gentle cascade sequences or isolated small waterfalls.

Where abundances of diurnal predatory fishes were high, freshwater carideans were rarely observed. Peak densities of carideans were observed upstream of major barriers, with moderate densities in the upper mid‐course in the presence of few Kuhlia spp.

The current study demonstrates the value of complete single‐pass surveys of fish assemblages in tropical short, steep coastal streams by revealing the highly localised occupation of particular reaches by rare fishes. It also points towards the importance of stream‐specific characteristics, namely the position of waterfalls in dictating diadromous predator distribution with consequences for community structure, thereby aligning with the Riverine Discontinuum Concept.
Evolution of the unfolded protein response in plants
Authors: Howell Stephen H.
Published: April 2021

The unfolded protein response (UPR) in plants is elicited by endoplasmic reticulum stress, which can be brought about by adverse environmental conditions. The response is mediated by a conserved signalling network composed of two branches – one branch involving inositol requiring enzyme1‐ basic leucine zipper60 (IRE1‐bZIP60) signalling pathway and another branch involving the membrane transcription factors, bZIP17 and −28. The UPR has been reported in Chlamydomonas reinhardtii, a unicellular green alga, which lacks some canonical UPR signalling components found in vascular plants, raising the question whether C. reinhardtii uses other means such as oxidative signalling or Regulated IRE1‐Dependent Decay to activate the UPR. In vascular plants, IRE1 splices bZIP60 mRNA in response to endoplasmic reticulum stress by cutting at a site in the RNA that is highly conserved in structure and sequence. Monocots have a single IRE1 gene required for viability in rice, while dicots have two IRE1 genes, IRE1a and ‐b. Brassicas have a third IRE1 gene, IRE1c, which lacks a lumenal domain, but is required in combination with IRE1b for gametogenesis. Vascular and non‐vascular plants upregulate a similar set of genes in response to endoplasmic reticulum stress despite differences in the complexity of their UPR signalling networks.
Entrepreneurial Fraud: A Multidisciplinary Review and Synthesized Framework
Authors: Scheaf David J. , Wood Matthew S.
Published: April 2021

The practical relevance of entrepreneurial fraud has stimulated a wide array of research occurring in disciplinary silos. We take stock of the current state of the entrepreneurial fraud literature by conducting a multidisciplinary systematic literature review and synthesize the findings into a unified framework. Taking an inductive approach, our framework depicts the antecedents, inner workings, and ramifications of entrepreneurial fraud. Doing so, we reveal nuances in the inner workings of entrepreneurial fraud, such as variation in the focus and magnitude of deception used to obtain valuable resources from stakeholders and that fraud can service authentic entrepreneurial activities or nonentrepreneurial personal uses. Accounting for these distinctions reveals that fraud can result in a mixture of positive and negative consequences for perpetrators, victims, and societies.