bluuebunny/crossref_metadata_2025 huggingface dataset:
Nanobody Repertoires for Exposing Vulnerabilities of SARS-CoV-2
Authors: Mast Fred D. , Fridy Peter C. , Ketaren Natalia E. , Wang Junjie , Jacobs Erica Y. , Olivier Jean Paul , Sanyal Tanmoy , Molloy Kelly R. , Schmidt Fabian , Rutkowska Magda , Weisblum Yiska , Rich Lucille M. , Vanderwall Elizabeth R. , Dambrauskas Nicolas , Vigdorovich Vladimir , Keegan Sarah , Jiler Jacob B. , Stein Milana E. , Olinares Paul Dominic B. , Hatziioannou Theodora , Sather D. Noah , Debley Jason S. , Fenyö David , Sali Andrej , Bieniasz Paul D. , Aitchison John D. , Chait Brian T. , Rout Michael P.
Published: April 2021

Despite the great promise of vaccines, the COVID-19 pandemic is ongoing and future serious outbreaks are highly likely, so that multi-pronged containment strategies will be required for many years. Nanobodies are the smallest naturally occurring single domain antigen binding proteins identified to date, possessing numerous properties advantageous to their production and use. We present a large repertoire of high affinity nanobodies against SARS-CoV-2 Spike protein with excellent kinetic and viral neutralization properties, which can be strongly enhanced with oligomerization. This repertoire samples the epitope landscape of the Spike ectodomain inside and outside the receptor binding domain, recognizing a multitude of distinct epitopes and revealing multiple neutralization targets of pseudoviruses and authentic SARS-CoV-2, including in primary human airway epithelial cells. Combinatorial nanobody mixtures show highly synergistic activities, and are resistant to mutational escape and emerging viral variants of concern. These nanobodies establish an exceptional resource for superior COVID-19 prophylactics and therapeutics.
Gene co-expression analyses of health(span) across multiple species
Authors: Möller Steffen , Saul Nadine , Barrantes Israel , Gézsi András , Walter Michael , Antal Péter , Fuellen Georg
Published: April 2021

Health(span)-related gene clusters/modules were recently identified based on knowledge about the cross-species genetic basis of health, to interpret transcriptomic datasets describing health-related interventions. However, the cross-species comparison of health-related observations reveals a lot of heterogeneity, not least due to widely varying health(span) definitions and study designs, posing a challenge for the exploration of conserved healthspan modules and, specifically, their transfer across species.

To improve the identification and exploration of conserved/transferable healthspan modules, here we apply an established workflow based on gene co-expression network analyses employing GEO/ArrayExpress data for human and animal models, and perform a comprehensive meta-analysis of the resulting modules related to health(span), yielding a small set of health(span) candidate genes, backed by the literature.

For each experiment, WGCNA (weighted gene correlation network analysis) was thus used to infer modules of genes which correlate in their expression with a “health phenotype score” and to determine the most-connected (hub) genes for each such module, and their interactions. After mapping these hub genes to their human orthologs, 12 health(span) genes were identified in at least two species (ACTN3, ANK1, MRPL18, MYL1, PAXIP1, PPP1CA, SCN3B, SDCBP, SKIV2L, TUBG1, TYROBP, WIPF1), for which enrichment analysis by g:profiler finds an association with actin filament-based movement and associated organelles as well as muscular structures.

We conclude that a meta-study of hub genes from co-expression network analyses for the complex phenotype health(span), across multiple species, can yield molecular-mechanistic insights and can direct experimentalists to further investigate the contribution of individual genes and their interactions to health(span).
Local autocrine signaling of IGF1 synthesized and released by CA1 pyramidal neurons regulates plasticity of dendritic spines
Authors: Tu Xun , Jain Anant , Decker Helena , Yasuda Ryohei
Published: April 2021

Insulin-like growth factor 1 (IGF1) regulates hippocampal plasticity, learning, and memory. While circulating, liver-derived IGF1 is known to play an essential role in hippocampal function and plasticity, IGF1 is also synthesized in multiple brain regions, including the hippocampus. However, little is known about the role of hippocampus-derived IGF1 in synaptic plasticity, the type of cells that may provide relevant IGF1, and the spatiotemporal dynamics of IGF1 signaling. Here, using a new FRET sensor for IGF1 signaling, we show that IGF1 in the hippocampus is primarily synthesized in CA1 pyramidal neurons and released in an activity-dependent manner in mice. The local IGF1 release from dendritic spines triggers local autocrine IGF1 receptor activation on the same spine, regulating structural and electrophysiological plasticity of the activated spine. Thus, our study demonstrates a novel mechanism underlying synaptic plasticity by the synthesis and autocrine signaling of IGF1 specific to CA1 pyramidal neurons.
Misrouting of Glucagon and Stathmin-2 Towards Lysosomal System of α-Cells in Glucagon Hypersecretion of Diabetes
Authors: Asadi Farzad , Dhanvantari Savita
Published: April 2021

Glucagon hypersecretion from the pancreatic α-cell is a characteristic sign of diabetes, which exacerbates fasting hyperglycemia. Thus, targeting glucagon secretion from α-cells may be a promising approach for combating hyperglucagonemia. We have recently identified stathmin-2 as a protein that resides in α-cell secretory granules, and showed that it regulates glucagon secretion by directing glucagon towards the endolysosomal system in αTC1-6 cells. Here, we hypothesized that disruption of Stmn2-mediated trafficking of glucagon to the endolysosomes contributes to hyperglucagonemia. In isolated islets from male mice treated with streptozotocin (STZ) to induce diabetes, Arg-stimulated secretion of glucagon and Stmn2 was augmented. However, cell glucagon content was significantly increased (p<0.001), but Stmn2 levels were reduced (p<0.01) in STZ-treated mice, as measured by both ELISA and immunofluorescence intensity. Expression ofGcgmRNA increased ~4.5 times, whileStmn2mRNA levels did not change. Using confocal immunofluorescence microscopy, the colocalization of glucagon and Stmn2 in Lamp2A+lysosomes was dramatically reduced (p<0.001) in islets from diabetic mice, and the colocalization of Stmn2, but not glucagon, with the late endosome marker, Rab7, significantly (p<0.01) increased. Further studies were conducted in αTC1-6 cells cultured in media containing high glucose (16.7 mM) for two weeks to mimic glucagon hypersecretion of diabetes. Surprisingly, treatment of αTC1-6 cells with the lysosomal inhibitor bafilomycin A1 reduced K+-induced glucagon secretion, suggesting that high glucose may induce glucagon secretion from another lysosomal compartment. Both glucagon and Stmn2 co-localized with Lamp1, which marks secretory lysosomes, in cells cultured in high glucose. We propose that, in addition to enhanced trafficking and secretion through the regulated secretory pathway, the hyperglucagonemia of diabetes may also be due to re-routing of glucagon from the degradative Lamp2A+lysosome towards the secretory Lamp1+lysosome.
The homology analysis of ACE2 gene and its distinct expression in laboratory and wild animals
Authors: Wang Gang , Zhang A-Mei , Wang Binghui , Yin Jianhua , Feng Yue , Baloch zulqarnain , Xia Xueshan
Published: April 2021

Angiotensin-converting enzyme-2 (ACE2) has been recognized as an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cells while bats has been suspected as natural host of SARS-CoV-2. However, the detail of intermediate host or the route of transmission of SARS-CoV-2 is still unclear. In this study, we analyze the conservation of ACE2 gene in 11 laboratory and wild animals that live in close proximity either with Bats or human and further investigated its RNA and protein expression pattern in wild bats, mice and tree shrew. We verified that the wild-bats and mice were belonged to Hipposideros pomona and Rattus norvegicus, respectively. ACE2 gene is highly conserved among all 11 animals species at the DNA level. Phylogenetic analysis based on the ACE2 nucleotide sequences revealed that wild bat and Tree shrew were forming a cluster close to human. We further report that ACE2 RNA expression pattern is highly species-specific in different tissues of different animals. Most notably, we found that the expression pattern of ACE2 RNA and protein are very different in each animal species. In summary, our results suggested that ACE2 gene is highly conserved among all 11 animals species. However, different relative expression pattern of ACE2 RNA and protein in each animal species is interesting. Further research is needed to clarify the possible connection between different relative expression pattern of ACE2 RNA and protein in different laboratory and wild animal species and the susceptibility to SARS-CoV-2 infection.
The structure and flexibility analysis of the Arabidopsis Synaptotagmin 1 reveal the basis of its regulation at membrane contact sites
Authors: Benavente Juan Luis , Siliqi Dritan , Infantes Lourdes , Lagartera Laura , Mills Alberto , Gago Federico , Ruiz-López Noemí , Ángel Botella Miguel , Sánchez-Barrena María José , Albert Armando
Published: April 2021

Cell function requires the maintenance of membrane lipid homeostasis as changes in cellular environment unbalance this equilibrium. The non-vesicular lipid transfer at endoplasmic reticulum (ER) and plasma membrane (PM) contact sites (CS) is central to restore it. Extended synaptotagmins (E-Syts) are ER proteins that play a central role in this process as they act as molecular tethers with PM and as lipid transfer proteins between these organelles. E-Syts are constitutively anchored to the ER through an N-terminal hydrophobic segment and bind to the PM via C-terminal C2 domains. In plants, synaptotagmins (SYTs) are orthologous of E-Syts and regulate the ER-PM communication by the activity of their two C2 domains in response to abiotic stresses. We have combined macromolecular crystallography, small-angle X-ray scattering, structural bioinformatics and biochemical data to analyze the regulation of plant synaptotagmin 1 (SYT1). Our data show that the binding of SYT1 to the PM is regulated by the interaction of the first C2 domain through a Ca2+-dependent lipid binding site and by a site for phosphorylated forms of phosphatidylinositol in such a way that two different molecular signals are integrated in response to stress. In addition, our data show that SYT1 is highly flexible by virtue of up to three hinge points, including one that connects the two C2 domains. This feature provides conformational freedom to SYT1 to define a large and complementary interaction surface with the PM. This structural plasticity, in turn, may facilitate lipid extraction, protein loading and subsequent transfer between PM and ER.

Data Deposition

The atomic coordinates and structure factors have been deposited in the Protein Data Bank, https://www.pdb.org/ [PDB ID codes Ca2+ and Cd2+ complexes of SYT1C2A (7AS6 and 7ATP, respectively)]. The final SAXS models were deposited and are available at SASBDB https://www.sasbdb.org/ [ID codes SASDKG6 for the SMP2C2A construct SASDKJ9 for the C2AB construct and SASDKK9 in presence of Ca2+]
Rho and F-actin self-organize within an artificial cell cortex
Authors: Landino Jennifer , Leda Marcin , Michaud Ani , Swider Zachary T. , Prom Mariah , Field Christine M. , Bement William M. , Vecchiarelli Anthony G. , Goryachev Andrew B. , Miller Ann L.
Published: April 2021

The cell cortex, comprised of the plasma membrane and underlying cytoskeleton, undergoes dynamic reorganizations during a variety of essential biological processes including cell adhesion, cell migration, and cell division1,2. During cell division and cell locomotion, for example, waves of filamentous-actin (F-actin) assembly and disassembly develop in the cell cortex in a process termed “cortical excitability”3–7. In developing frog and starfish embryos, cortical excitability is generated through coupled positive and negative feedback, with rapid activation of Rho-mediated F-actin assembly followed in space and time by F-actin-dependent inhibition of Rho8,9. These feedback loops are proposed to serve as a mechanism for amplification of active Rho signaling at the cell equator to support furrowing during cytokinesis, while also maintaining flexibility for rapid error correction in response to movement of the mitotic spindle during chromosome segregation10. In this paper, we develop an artificial cortex based onXenopusegg extract and supported lipid bilayers (SLBs), to investigate cortical Rho and F-actin dynamics11. This reconstituted system spontaneously develops two distinct dynamic patterns: singular excitable Rho and F-actin waves and non-traveling oscillatory Rho and F-actin patches. Both types of dynamic patterns have properties and dependencies similar to the cortical excitability previously characterizedin vivo9. These findings directly support the longstanding speculation that the cell cortex is a self-organizing structure and present a novel approach for investigating mechanisms of Rho-GTPase-mediated cortical dynamics.

Highlights

An artificial cell cortex comprisingXenopusegg extract on a supported lipid bilayer self-organizes into complex, dynamic patterns of active Rho and F-actin

We identified two types of reconstituted cortical dynamics – excitable waves and coherent oscillations

Reconstituted waves and oscillations require Rho activity and F-actin polymerization
Macrophage and dendritic cell subset composition can distinguish endotypes in adjuvant-induced asthma mouse models
Authors: Özkan Müge , Eskiocak Yusuf Cem , Wingender Gerhard
Published: April 2021

Asthma is a heterogeneous disease with neutrophilic and eosinophilic asthma as the main endotypes that are distinguished according to the cells recruited to the airways and the related pathology. Eosinophilic asthma is the treatment-responsive endotype, which is mainly associated with allergic asthma. Neutrophilic asthma is a treatment-resistant endotype, affecting 5-10% of asthmatics. Although eosinophilic asthma is well-studied, a clear understanding of the endotypes is essential to devise effective diagnosis and treatment approaches for neutrophilic asthma. To this end, we directly compared adjuvant-induced mouse models of neutrophilic (CFA/OVA) and eosinophilic (Alum/OVA) asthma side-by-side. The immune response in the inflamed lung was analyzed by multi-parametric flow cytometry and immunofluorescence. We found that eosinophilic asthma was characterized by a preferential recruitment of interstitial macrophages and myeloid dendritic cells, whereas in neutrophilic asthma plasmacytoid dendritic cells, exudate macrophages, and GL7+activated B cells predominated. This differential distribution of macrophage and dendritic cell subsets reveals important aspects of the pathophysiology of asthma and holds the promise to be used as biomarkers to diagnose asthma endotypes.
Antibiotic Susceptibility Profile ofCampylobacter Sppfrom Poultry
Authors: Khalifa Khalda A. , Atif Elbrissi , Adel Rahim Igbal S. , Abdel Rahman Amgad M. , Ahmed Salwa A.
Published: April 2021

Campylobacteriosis is found among the four important worldwide food borne pathogens. In intensive poultry rearing systems in Sudan the use of oral antibiotics is essential to preserve health. Accordingly, there is a high threat for the thermophilicCampylobacter sppinhabitant in the intestinal tract of food animals to develop resistance to commonly used antibiotics. Contamination of broiler meat with pathogenic strains of resistantCampylobactercould, therefore, result in a form of campylobacteriosis in humans that is difficult to treat. To the best of our knowledge, there are no data available relating antibiotic resistant against these bacteria in poultry in Sudan, hence the aim of this study was to determine the antimicrobial susceptibility profile of thermophilicCampylobacterspp. isolated from broiler in Khartoum by disk diffusion. Sensitivity of fourteen isolates against seven antibiotics namely Neomycin, Nitrofurantoin, Nalidixic acid, Gentamycin, Streptomycin, Tetracycline and Erythromycin were studied. The result showed that Nitrofurantoin was found as highly sensitive (64.3%). It was also observed that Erythromycin, Gentamycin, Streptomycin and Neomycin verified the following resistant against isolates recovered 92.9%, 71.4%, 71.4%, 64.3% respectively. Multidrug resistant against five, four, three and two antibiotics was also reported. It was concluded that poultry meat in Khartoum could complicate the antimicrobial therapy in human as multidrug resistant of campylobacter was detected.
The effect of a canine semen activator supplementation or addiction on the long-term refrigeration quality of dog spermatozoa
Authors: Martínez-Barbitta Marcelo , Salinas Claudio Rivera
Published: April 2021

Within modern biotechnology, different tools have been developed to maximize canine semen conservation protocol to optimizing reproductive results and making their handling more flexible. In the last decades, the survival of refrigerated semen has been prolonged from 2-3d with the first basic diluents, to 10-14d using the most modern extenders. However, their main limitation is that sperm quality decreases during cold storage. Semen activators (SA) have been produced to provide the molecules necessary to maximize the sperm survival and quality with the aim to enhance fertility and prolificacy. In this study, the effect of SA was recorded by daily evaluation of chilled semen 14d. For this experiment, six adult healthy Neapolitan Mastiff dogs, were used as donors and the semen was manually collected. Spermatozoa-rich fractions of each suject was chilled using a new generation extender for long periods of time (d0) starting from the d1 to d14, different aliquot, with (experimental trial) and without SA (control trial), were evaluated daily for motility vigor, morphology and membrane integrity. The initial sperm concentration of extended semen was 417.3±170.4×106/mL (mean ± SEM) with 85.89±4.76% of MNS (morphologically normal sperm), 84.47±5.22 % vital sperm and a pH of 6.2±2.8. The initial vigor was 3.83±0.48, but after one min with SA, it rose to 4.45 ± 0.45 (P<0.001). The semen motility parameter increase significantly (P<0.05) in experimental trial, respect to control, starting to d2 at finish (except for d7). The vigor analysis significantly increase in experimental trial (P<0.05) during the most day of the study with the exclusion of d3 and d14. For evaluate the semen characteristics over time, the experiment was divided into T1 (d0-d5), T2 (d6-d10) and T3 (d11-d14) (P<0.001) in evaluation of morphology and membrane stability. The MNS reached 70% at d10 and finally 65% at d14, being considered normal and possibly fertile. With Host-s, 65% of MNS were also achieved at d14. The presence of glucose and fructose in the diluents used for refrigeration can exert very important effects given the fact that metabolic routes have been found in both sugars, providing both different and complementing effects. It can be concluded that the use of SA prior to artificial insemination improves the quality of chilled semen significantly, although it does not reverse the effects of deterioration due to cellular metabolism over time.
Intranasal gene therapy to prevent infection by SARS-CoV-2 variants
Authors: Sims Joshua J. , Greig Jenny A. , Michalson Kristofer T. , Lian Sharon , Martino R. Alexander , Meggersee Rosemary , Turner Kevin B. , Nambiar Kalyani , Dyer Cecilia , Hinderer Christian , Horiuchi Makoto , Yan Hanying , Huang Xin , Chen Shu-Jen , Wilson James M.
Published: April 2021

SARS-CoV-2 variants have emerged with enhanced pathogenicity and transmissibility, and escape from pre-existing immunity, suggesting first-generation vaccines and monoclonal antibodies may now be less effective. This manuscript demonstrates an approach for preventing clinical sequelae and the spread of SARS-CoV-2 variants. First, we affinity-matured an angiotensin-converting enzyme 2 (ACE2) decoy protein, achieving 1000-fold binding improvements that extend across a wide range of SARS-CoV-2 variants and distantly related, ACE2-dependent coronaviruses. Next, we demonstrated the expression of this decoy in proximal airway when delivered via intranasal administration of an AAV vector. This intervention significantly diminished clinical and pathologic consequences of SARS-CoV-2 challenge in a mouse model and achieved therapeutic levels of decoy expression at the surface of proximal airways when delivered intranasally to nonhuman primates. Importantly, this long-lasting, passive protection approach is applicable in vulnerable populations such as the elderly and immune-compromised that do not respond well to traditional vaccination. This approach could be useful in combating COVID-19 surges caused by SARS-CoV-2 variants and should be considered as a countermeasure to future pandemics caused by pre-emergent members, ACE2-dependent CoVs that are poised for zoonosis.

Author summary

SARS-CoV-2 variants have emerged with enhanced pathogenicity and transmissibility, and escape from pre-existing immunity, suggesting first-generation vaccines and monoclonal antibodies may now be less effective. This manuscript demonstrates an approach for preventing clinical sequelae and the spread of SARS-CoV-2 variants. First, we affinity-matured an angiotensin-converting enzyme 2 (ACE2) decoy protein, achieving 1000-fold binding improvements that extend across a wide range of SARS-CoV-2 variants and distantly related, ACE2-dependent coronaviruses. Next, we demonstrated the expression of this decoy in proximal airway when delivered via intranasal administration of an AAV vector. This intervention significantly diminished clinical and pathologic consequences of SARS-CoV-2 challenge in a mouse model and achieved therapeutic levels of decoy expression at the surface of proximal airways when delivered intranasally to nonhuman primates. Importantly, this long-lasting, passive protection approach is applicable in vulnerable populations such as the elderly and immune-compromised that do not respond well to traditional vaccination. This approach could be useful in combating COVID-19 surges caused by SARS-CoV-2 variants and should be considered as a countermeasure to future pandemics caused by pre-emergent members, ACE2-dependent CoVs that are poised for zoonosis.
Controlling gene expression timing through gene regulatory architecture
Authors: Ali Md Zulfikar , Brewster Robert C.
Published: April 2021

Gene networks typically involve the regulatory control of multiple genes with related function. This connectivity enables correlated control of the levels and timing of gene expression. Here we study how gene expression timing in the single-input module motif can be encoded in the regulatory DNA of a gene. Using stochastic simulations, we examine the role of binding affinity, TF regulatory function and network size in controlling the mean first-passage time to reach a fixed fraction of steady-state expression for both an auto-regulated TF gene and a target gene. We also examine how the variability in first-passage time depends on these factors. We find that both network size and binding affinity can dramatically speed up or slow down the response time of network genes, in some cases predicting more than a 100-fold change compared to that for a constitutive gene. Furthermore, these factors can also significantly impact the fidelity of this response. Importantly, these effects do not occur at “extremes” of network size or binding affinity, but rather in an intermediate window of either quantity.

Author summary

Regulated genes are able to respond to stimuli in order to ramp up or down production of specific proteins. Although there is considerable focus on the magnitude (or fold-change) of the response and how that depends on the architectural details of the regulatory DNA, the dynamics, which dictates the response time of the gene, is another key feature of a gene that is encoded within the DNA. Unraveling the rules that dictate both the response time of a gene and the precision of that response encoded in the DNA poses a fundamental problem. In this manuscript, we systematically investigate how the response time of genes in auto-regulatory networks is controlled by the molecular details of the network. In particular, we find that network size and TF-binding affinity are key parameters that can slow, in the case of auto-activation, or speed up, in the case of auto-repression, the response time of not only the auto-regulated gene but also the genes that are controlled by the auto-regulated TF. In addition, we find that the precision of the response depends crucially on these characteristics.
Theoretical causes of the Brazilian P.1 and P.2 lineages of the SARS-CoV-2 virus through molecular dynamics
Authors: Oliveira Micael D. L. , Oliveira Kelson M. T. , Silva Jonathas N. , Santos Clarice , Bessa João , de Freitas Rosiane
Published: April 2021

The newβ-coronavirus has been causing sad losses around the world and the emergence of new variants has caused great concern. This pandemic is of a proportion not seen since the Spanish Flu in 1918. Thus, throughout this research, the B.1.1.28 lineage of the P.1 clade (K417T, N501Y, E484K) that emerged in Brazil was studied, as well as the latest Delta variant. This is because the molecular mechanisms by which phenotypic changes in transmissibility or mortality remain unknown. Through molecular dynamics simulations with the NAMD 3 algorithm in the 50nsinterval, it was possible to understand the impact on structural stabilization on the interaction of the ACE2-RBD complex, as well as simulations in 30nsfor the neutralizing antibody P2B-2F6, with this antibody was derived from immune cells from patients infected with SARS-CoV-2. Although not all molecular dynamics analyzes support the hypothesis of greater stability in the face of mutations, there was a predominance of low fluctuations. Thus, 3 (three) analyzes corroborate the hypothesis of greater ACE2-RBD stability as a result of P.1, among them: Low mean RMSF values, greater formation of hydrogen bonds and low solvent exposure measured by the SASA value. An inverse behavior occurs in the interaction with neutralizing antibodies, since the mutations induce greater instability and thus hinder the recognition of antibodies in neutralizing the Spike protein, where we noticed a smaller number of hydrogen bonds as a result of P.1. Through MM-PBSA energy decomposition, we found that Van der Waals interactions predominated and were more favorable when the structure has P.1 strain mutations. Therefore, we believe that greater stabilization of the ACE2-RBD complex may be a plausible explanation for why some mutations are converging in different strains, such as E484K and N501Y. The P.1 concern variant still makes the Spike protein recognizable by antibodies, and therefore, even if the vaccines’ efficacy can be diminished, there are no results in the literature that nullify them.
Structure ofEscherichia colirespiratory complex I reconstituted into lipid nanodiscs reveals an uncoupled conformation
Authors: Kolata Piotr , Efremov Rouslan G.
Published: April 2021

Respiratory complex I is a multi-subunit membrane protein complex that reversibly couples NADH oxidation and ubiquinone reduction with proton translocation against trans-membrane potential. Complex I fromEscherichia coliis among the best functionally characterized complexes, but its structure remains unknown, hindering further mechanistic studies to understand the enzyme coupling mechanism. Here we describe the single particle cryo-electron microscopy (cryo-EM) structure of the entire catalytically activeE. colicomplex I reconstituted into lipid nanodiscs. The structure of this mesophilic bacterial complex I displays highly dynamic connection between the peripheral and membrane domains. The peripheral domain assembly is stabilized by unique terminal extensions and an insertion loop. The membrane domain structure reveals novel dynamic features. Unusual conformation of the conserved interface between the cytoplasmic and membrane domains suggests an uncoupled conformation of the complex. Based on these structural data we suggest a new simple and testable coupling mechanism for the molecular machine.
Functional genome and microbiome in blood of goats affected by the gastrointestinal pathogenHaemonchus contortus
Authors: Tilahun Yonathan
Published: April 2021

The Alpine goatCapra aegagrus hircusis parasitized by the barber pole worm (Haemonchus contortus). This relationship results in changes that affect the gene expression of the host, the pest, and the microbiome of both. Hematological parameters indicating genes that are expressed and/or the % Composition of abundant and diverse microbial flora are reflective of infestation. We explored the similarity/dissimilarity between and among blood samples of non-infected, infected, infected zoledronic acid-treated, and infected antibody (anti-γσ T cells) treated wethers under controlled conditions. We identified responses to barber pole worms using blood-based analysis of transcripts and the microbiome. Seven (7) days post-inoculation (dpi) we identified 7,627 genes associated with different treatment types. Across all treatments we identified fewer raw read counts and a reduced diversity in microbial flora on 7 dpi than in 21 dpi wethers. We also identified that there were differences in % Composition of microbial flora known to be associated with inflammation. This study identifies treatment specific genes, and an increase in microflora abundance and diversity as wethers age post infestation. Further,Firmicutes/Bacteriodetes(F/B) ratio reflect metabolic health, based on depression or elevation above thresholds defined by the baseline of non-infected hosts depending on the type of intrusion exhibited by the pest.
Early construction of the thalamocortical axon pathway requires JNK signaling within the ventral forebrain
Authors: Cunningham Jessica G. , Scripter James D. , Nti Stephany A. , Tucker Eric S.
Published: April 2021

Thalamocortical connectivity is essential for normal brain function. This important pathway is established during development, when thalamic axons extend a long distance through the forebrain before reaching the cerebral cortex. In this study, we identify a novel role for the c-Jun N-terminal Kinase (JNK) signaling pathway in guiding thalamocortical axons through intermediate target territories. Complete genetic removal of JNK signaling from theDistal-less 5/6(Dlx5/6) domain in mice prevents thalamocortical axons from crossing the diencephalon-telencephalon boundary (DTB) and the internal capsule fails to form. Ventral telencephalic cells critical for thalamocortical axon extension including corridor and guidepost neurons are also disrupted. In addition, corticothalamic, striatonigral, and nigrostriatal axons fail to cross the DTB. Analyses of different JNK mutants demonstrates that thalamocortical axon pathfinding has a non-autonomous requirement for JNK signaling. We conclude that JNK signaling within theDlx5/6territory enables the construction of major axonal pathways in the developing forebrain.

Impact statement

We find an obligate, non-autonomous requirement for JNK signaling in early thalamocortical axon pathfinding, providing new mechanistic insight into the establishment of axonal connections in the developing forebrain.
Thermodynamics and kinetics of aggregation of flexible peripheral membrane proteins
Authors: Sadeghi Mohsen , Noé Frank
Published: April 2021

Biomembrane remodeling is essential for cellular trafficking, with membrane-binding peripheral proteins playing a key role in it. Significant membrane remodeling as in endo- and exocytosis is often due to aggregates of many proteins with direct or membrane-mediated interactions. Understanding this process via computer simulations is extremely challenging: protein-membrane systems involve time- and lengthscales that make atomistic simulations impractical, while most coarse-grained models fall short in resolving dynamics and physical effects of protein and membrane flexibility. Here, we develop a coarse-grained model of the bilayer membrane bestrewed with rotationally-symmetric flexible proteins, parametrized to reflect local curvatures and lateral dynamics of proteins. We investigate the kinetics, equilibrium distributions, and the free energy landscape governing the formation and break-up of protein clusters on the surface of the membrane. We demonstrate how the flexibility of the proteins as well as their surface concentration play deciding roles in highly selective macroscopic aggregation behavior.
Mutagenesis of human cytomegalovirus glycoprotein L disproportionately disrupts gH/gL/gO over gH/gL/pUL128-131
Authors: Schultz Eric P. , Yu Qin , Stegmann Cora , Day Le Zhang , Lanchy Jean-Marc , Ryckman Brent J.
Published: April 2021

Cell-free and cell-to-cell spread of herpesviruses involves a core fusion apparatus comprised of the fusion protein glycoprotein B (gB) and the regulatory factor gH/gL. The human cytomegalovirus (HCMV) gH/gL/gO and gH/gL/pUL128-131 facilitate spread in different cell types. The gO and pUL128-131 components bind distinct receptors, but the how the gH/gL portion of the complexes functionally compare is not understood. We previously characterized a panel of gL mutants by transient expression and showed that many were impaired for gH/gL-gB dependent cell-cell fusion, but were still able to form gH/gL/pUL128-131 and induce receptor-interference. Here, the gL mutants were engineered into the HCMV BAC clones TB40/e-BAC4 (TB), TR and Merlin (ME), which differ in their utilization of the two complexes for entry and spread. Several of the gL mutations disproportionately impacted gH/gL/gO-dependent entry and spread over gH/gL/pUL128-131 processes. Effects of some mutants could be explained by impaired gH/gL/gO assembly, but other mutants impacted gH/gL/gO function. Soluble gH/gL/gO containing the L201 mutant failed to block HCMV infection despite unimpaired binding to PDGFRα, indicating the existence of other important gH/gL/gO receptors. Another mutant (L139) enhanced the gH/gL/gO-dependent cell-free spread of TR, suggesting a “hyperactive” gH/gL/gO. Recently published crystallography and cryo-EM studies suggest structural conservation of the gH/gL underlying gH/gL/gO and gH/gL/pUL128-131. However, our data suggest important differences in the gH/gL of the two complexes and support a model in which gH/gL/gO can provide an activation signal for gB.

IMPORTANCE

The endemicbeta-herpesvirus HCMV circulates in human populations as a complex mixture of genetically distinct variants, establishes lifelong persistent infections, and causes significant disease in neonates and immunocompromised adults. This study capitalizes on our recent characterizations of three genetically distinct HCMV BAC clones to discern the functions of the envelope glycoprotein complexes gH/gL/gO and gH/gL/pUL128-13, which are promising vaccine targets that share the herpesvirus core fusion apparatus component, gH/gL. Mutations in the shared gL subunit disproportionally affected gH/gL/gO, demonstrating mechanistic differences between the two complexes and may provide a basis for more refined evaluations of neutralizing antibodies.
HNF4A is required to specify glucocorticoid action in the liver
Authors: Hunter A. Louise , Poolman Toryn M. , Kim Donghwan , Gonzalez Frank J. , Bechtold David A. , Loudon Andrew S. I. , Iqbal Mudassar , Ray David W.
Published: April 2021

The glucocorticoid receptor (GR) is a nuclear hormone receptor critical to the regulation of energy metabolism and the inflammatory response. The actions of GR are highly dependent on cell type and environmental context. Here, we demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver-specificity of GR action. In normal mouse liver, the HNF4 motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites found within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodelled, with both loss and gain of GR recruitment evident. Lost sites are characterised by HNF4 motifs and weak GRE motifs. Gained sites are characterised by strong GRE motifs, and typically show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is further demonstrated by evidence of an altered transcriptional response to glucocorticoid treatment in theHnf4a-null liver.
Social and environmental accounting in developing countries: contextual challenges and insights
Authors: Qian Wei , Tilt Carol , Belal Ataur
Published: April 2021

Purpose

The purpose of this paper is to review most recent developments of social and environmental accounting (SEA) in the context of developing countries and to offer insights for the latest research in this field. It also provides an introduction to the AAAJ special issue.

Design/methodology/approach

The authors have undertaken a conceptual overview of the field developed in the past two decades (2001–2020) with a view to identify major themes, trends and future research directions.

Findings

The overview reveals that only 43 SEA papers addressing contextual challenges of developing countries have been published in leading accounting journals in the last 20 years. The coverage of these publications is concentrated in a small number of countries and regions. Interdisciplinary accounting journals, especially AAAJ, are the main publishing outlets in this field. The topic areas are dominated by social accounting challenges, with much less focus on environmental accounting, although developing countries are particularly exposed to the threats of climate change, water pollution and biodiversity loss. The literature reviewed uses elaborating, problematising and theorising contexts as three main contextualisation approaches to analyse contextual themes framed around regulatory, political, cultural and religious, and social-economic systems. Although various conceptual lenses have been adopted in the developing country SEA literature, the use of institutional theory and its various extensions to address political and cultural complexities seems to become more prominent, as shown in most of the contributions included in this special issue.

Research limitations/implications

This review is limited to leading accounting journals. SEA research increasingly published in other disciplines such as in management, social and environmental areas might provide a more comprehensive view in this research field.

Originality/value

In this paper,inter alia, the authors review and synthesise the previous literature in a conceptual framework, illustrating and highlighting the importance of contextual framing of SEA in developing countries. Based on this review, the authors propose some ideas for a future research agenda aiming to advance the field. The authors expect this paper and the special issue to act as a reference point for emerging SEA researchers from developing countries to raise more scholarly impactful enquiries in this area.
Multiobjective optimization of the flaxseed mucilage extraction process using normal-boundary intersection approach
Authors: Rocha Mariana Souza , Rocha Luiz Célio Souza , Feijó Marcia Barreto da Silva , Marotta Paula Luiza Limongi dos Santos , Mourão Samanta Cardozo
Published: April 2021

Purpose

The mucilage of theLinum usitatissimumL. seed (Linseed) is one of the natural mucilages that presents a great potential to provide a food hydrocolloid with potential applications in both food and pharmaceutical industries. To increase the yield and quality of linseed oil during its production process, it is necessary to previously extract its polysaccharides. Because of this, flax mucilage production can be made viable as a byproduct of oil extraction process, which is already a product of high commercial value consolidated in the market. Thus, the purpose of this work is to optimize the mucilage extraction process ofL. usitatissimumL. using the normal-boundary intersection (NBI) multiobjective optimization method.

Design/methodology/approach

Currently, the variables of the process of polysaccharide extraction from different sources are optimized using the response surface methodology. However, when the optimal points of the responses are conflicting it is necessary to study the best conditions to achieve a balance between these conflicting objectives (trade-offs) and to explore the available options it is necessary to formulate an optimization problem with multiple objectives. The multiobjective optimization method used in this work was the NBI developed to find uniformly distributed and continuous Pareto optimal solutions for a nonlinear multiobjective problem.

Findings

The optimum extraction point to obtain the maximum fiber concentration in the extracted material was pH 3.81, temperature of 46°C, time of 13.46 h. The maximum extraction yield of flaxseed was pH 6.45, temperature of 65°C, time of 14.41 h. This result confirms the trade-off relationship between the objectives. NBI approach was able to find uniformly distributed Pareto optimal solutions, which allows to analyze the behavior of the trade-off relationship. Thus, the decision-maker can set extraction conditions to achieve desired characteristics in mucilage.

Originality/value

The novelty of this paper is to confirm the existence of a trade-off relationship between the productivity parameter (yield) and the quality parameter (fiber concentration in the extracted material) during the flaxseed mucilage extraction process. The NBI approach was able to find uniformly distributed Pareto optimal solutions, which allows us to analyze the behavior of the trade-off relationship. This allows the decision-making to the extraction conditions according to the desired characteristics of the final product, thus being able to direct the extraction for the best applicability of the mucilage.
Spatial spillover effects of technological innovation on total factor energy efficiency: taking government environment regulations into account for three continents
Authors: Zafar Syed Zeeshan , Zhilin Qiao , Malik Haider , Abu-Rumman Ayman , Al Shraah Ata , Al-Madi Faisal , Alfalah Tasneem Faiez
Published: April 2021

Purpose

The discussion on energy efficiency has been increasing due to the increasing population, emissions of degradable and harmful pollutants, and clean energy substitutes are being developed in order to manage and control the energy requirements all over the world. Against this backdrop, the factors of technological innovation and environmental regulations have been determined as key indicators for the evaluation of sustainable developments and practices in the energy efficiency evaluation studies.

Design/methodology/approach

A two-stage analysis process has been configured for evaluation of the energy efficiency. The first stage includes the estimation of the Total factor energy efficiency scores using the data envelopment Multiplier input-oriented methodology, while the second stage includes the exploration of the impact of technological innovation and government environmental regulations on the Total factor energy efficiency scores obtained in the first step through the application of a spatial regression model.

Findings

This paper highlights the link between the need for and impact of energy efficiency innovations and shows that the energy efficiency goal can be fulfilled by incorporating laws on sustainability and incorporating strict regulations that allow for the use of clean energy, low carbon energy technologies.

Originality/value

The present study, furthermore, provides evidence from 15 countries, five from three different continents, i.e. Asia, Europe and Africa so that a cross-country performance of these factors can be evaluated. The main contribution of the present study is the evaluation of the technological innovation on energy efficiency. There have been studies evaluating various factors on the development of energy-efficient practices; however, the focus on the role of technological innovation and governmental regulations has been scarce.
The nexus between dynamic capabilities and competitive firm performance: the mediating role of open innovation
Authors: Pundziene Asta , Nikou Shahrokh , Bouwman Harry
Published: April 2021

Purpose

Prior research has reported the indirect implications of firm's dynamic capabilities on their competitive firm performance. Our attention now turns to open innovation since it has been confirmed to be an influential factor contributing to the superior performance of technological firms. So far there has been little research on assessing the relationship between a firm's dynamic capabilities as an antecedent of the competitive performance of the firm or investigations into the mediating role of open innovation in this relationship.

Design/methodology/approach

Drawing on the theory of dynamic capabilities, we developed a framework as a way to better understand the role of open innovation, which could then help to better explain the relationship between firms' dynamics capabilities and their competitive firm performance. Based on the empirical data of 465 firms operating in innovative and non-innovative industries, we employed structural equation modelling (SEM) to examine the research hypotheses and the path relationships in the proposed model.

Findings

The SEM analysis revealed that a firm's dynamic capabilities significantly impact its open innovation performance and that open innovation, consequently, impacts the competitive performance of the firm. Moreover, the results show that the path between dynamic capabilities and competitive firm performance is partially mediated through open innovation.

Practical implications

The findings provide practical implications and draw managerial attention to the importance of: (1) investing in innovation, (2) engaging customers in the innovation process and (3) maintaining innovation management excellence as significant antecedent factors in increasing competitive firm performance.

Originality/value

Considering the lack of empirical research in the literature on the links between dynamic capabilities and open innovation, this paper contributes to the dynamic capabilities and open innovation literature by confirming that open innovation not only mediates the relationship between these two aspects but also strengthens the effect the dynamic capabilities have on competitive firm performance. Besides, due to the significant impact of dynamic capabilities on open innovation, dynamic capabilities might be regarded as an antecedent of open innovation.