bluuebunny/crossref_metadata_2025 huggingface dataset:
Embedding of exogenous B cell epitopes on the surface of UreB structure generates a broadly reactive antibody response againstHelicobacter pylori
Authors: Ma Junfei , Wang Shuying , Ji Qianyu , Qiu Jingxuan , Liu Qing
Published: February 2021

SinceHelicobacter pylori(H. pylori) resistance to antibiotic regimens is increased, vaccination is becoming an increasingly important alternative therapy to controlH. pyloriinfection. UreB, FlaA, AlpB, SabA, and HpaA proteins ofH. pyloriwere previously proved to be used as candidate vaccine antigens. Here, we developed an engineered antigen based on a recombinant chimeric protein containing a structural scaffold from UreB and B cell epitopes from FlaA, AlpB, SabA, and HpaA. The multi-epitope chimeric antigen, named MECU, could generate a broadly reactive antibody response including antigen-specific antibodies and neutralizing antibodies againstH. pyloriurease and adhesins. Moreover, therapeutic immunization with MECU could reduceH. pyloricolonization in the stomach and protect the stomach in BALB/c mice. This study not only provides a promising immunotherapy to controlH. pyloriinfection, but also offers a reference for antigen engineering against other pathogens.
Characterization of a Novel Type Homoserine Dehydrogenase Only with High Oxidation Activity fromArthrobacter nicotinovorans
Authors: Liang Xinxin , Deng Huaxiang , Bai Yajun , Fan Tai-Ping , Zheng Xiaohui , Cai Yujie
Published: February 2021

Homoserine dehydrogenase (HSD) is a key enzyme in the synthesis pathway of the aspartate family of amino acids. HSD can catalyze the reversible reaction of L-aspartate-β-semialdehyde (L-ASA) to L-homoserine (L-Hse). In direct contrast, growth characteristic studies of some bacterial such asArthrobacter nicotinovoransshowed that the bacterium could grow well in medium with L-homoserine as sole carbon, nitrogen and energy source, but the genes responsible for the degradation of L-Hse remain unknown. Based on the function and sequence analysis of HSD, one putative homoserine dehydrogenase fromA.nicotinovoranswas named AnHSD, which was different from those HSDs that from the aspartic acid metabolic pathway, might be responsible for the degradation of L-Hse. Surprisingly, the analysis showed that the purified AnHSD exhibited specific L-Hse oxidation activity without reducing activity. At pH 10.0 and 40 °C, TheKmandKcatof AnHSD was 6.30 ± 1.03 mM and 462.71 s-1, respectively. AnHSD was partiality for NAD+cofactor, as well as insensitive to feedback inhibition of downstream amino acids of aspartic acid family. The physiological role of AnHSD inA.nicotinovoransis discussed. These findings provide a novel insight for a better understanding of an alternative genetic pathway for L-Hse catabolism which was dominated by the novel HSD.

Importance

L-homoserine is an important building block for the synthesis of L-threonine, L-methionine, L-lysine which from aspartic acid family amino acids. However, some bacteria can make use of L-homoserine as a sole carbon and nitrogen source. Although the microbial degradation of L-homoserine has been studied several times, the genes involved and the molecular mechanisms remain unclear. In this study, we show that AnHSD responsible for the catabolism of L-homoserine in strainArthrobacter nicotinovorans, as a special homoserine dehydrogenase with high diversity exists inArthrobacter,Microbacterium,Rhizobium. We report for the first time that this novel homoserine dehydrogenase is now proposed to play a crucial role in that L-homoserine can use as a sole carbon and nitrogen source. This study is aimed at elucidating the enzymatic properties and function features of homoserine dehydrogenase fromArthrobacter nicotinovorans. These findings provide new insight into the catabolism of L-homoserine in bacteria.
Promises and pitfalls of Topological Data Analysis for brain connectivity analysis
Authors: Caputi Luigi , Pidnebesna Anna , Hlinka Jaroslav
Published: February 2021

Developing sensitive and reliable methods to distinguish normal and abnormal brain states is a key neuroscientific challenge. Topological Data Analysis, despite its relative novelty, already generated many promising applications, including in neuroscience. We conjecture its prominent tool of persistent homology may benefit from going beyond analysing structural and functional connectivity to effective connectivity graphs capturing the direct causal interactions or information flows. Therefore, we assess the potential of persistent homology to directed brain network analysis by testing its discriminatory power in two distinctive examples of disease-related brain connectivity alterations: epilepsy and schizophrenia. We estimate connectivity from functional magnetic resonance imaging and electrophysiology data, employ Persistent Homology and quantify its ability to distinguish healthy from diseased brain states by applying a support vector machine to features quantifying persistent homology structure.

We show how this novel approach compares to classification using standard undirected approaches and original connectivity matrices. In the schizophrenia classification, topological data analysis generally performs close to random, while classifications from raw connectivity perform substantially better; potentially due to topographical, rather than topological, specificity of the differences. In the easier task of seizure discrimination from scalp electroencephalography data, classification based on persistent homology features generally reached comparable performance to using raw connectivity, albeit with typically smaller accuracies obtained for the directed (effective) connectivity compared to the undirected (functional) connectivity. Specific applications for topological data analysis may open when direct comparison of connectivity matrices is unsuitable - such as for intracranial electrophysiology with individual number and location of measurements. While standard homology performed overall better than directed homology, this could be due to notorious technical problems of accurate effective connectivity estimation.
Up-regulation of bundle sheath electron transport capacity under limiting light in C4Setaria viridis
Authors: Ermakova Maria , Bellasio Chandra , Fitzpatrick Duncan , Furbank Robert T. , Mamedov Fikret , von Caemmerer Susanne
Published: February 2021

C4photosynthesis is a biochemical pathway that operates across mesophyll and bundle sheath (BS) cells to increase CO2concentration at the site of CO2fixation. C4plants benefit from high irradiance but their efficiency decreases under shade causing a loss of productivity in crop canopies. We investigated shade acclimation responses of a model NADP-ME monocotSetaria viridisfocussing on cell-specific electron transport capacity. Plants grown under low light (LL) maintained CO2assimilation rates similar to high light plants but had an increased chlorophyll and light-harvesting-protein content, predominantly in BS cells. Photosystem II (PSII) protein abundance, oxygen-evolving activity and the PSII/PSI ratio all increased in LL BS cells indicating a higher capacity for linear electron flow. PSI, ATP synthase, Cytochromeb6fand the chloroplastic NAD(P) dehydrogenase complex, which constitute the BS cyclic electron flow machinery, were all upregulated in LL plants. A decline in PEP carboxylase activity in mesophyll cells and a consequent shortage of reducing power in BS chloroplasts was associated with the more oxidised redox state of the plastoquinone pool in LL plants and the formation of PSII - light-harvesting complex II supercomplexes with an increased oxygen evolution rate. Our results provide evidence of a redox regulation of the supramolecular composition of Photosystem II in BS cells in response to shading. This newly identified link contributes to understanding the regulation of PSII activity in C4plants and will support strategies for crop improvement including the engineering of C4photosynthesis into C3plants.

Significance statement

The efficiency of C4photosynthesis decreases under low irradiance causing a loss of productivity in crop canopies. We investigate shade acclimation of a model NADP-ME monocot, analysing cell-specific protein expression and electron transport capacity. We propose a regulatory pathway controlling abundance and activity of Photosystem II in bundle sheath cells in response to irradiance.
Calcium Sensitive Allostery Regulates the PI(4,5)P2 Binding Site of the Dysferlin C2A Domain
Authors: Otto Shauna C. , Reardon Patrick N. , Kumar Tanushri M. , Kuykendall Chapman J. , Johnson Colin P.
Published: February 2021

C2 domains are the second-most abundant calcium binding module in the proteome. Activity of the muscular dystrophy associated protein dysferlin is dependent on the C2A domain at the N-terminus of the protein, which couples calcium and PI(4,5)P2 binding through an unknown mechanism. Using solution state nuclear magnetic resonance spectroscopy we confirm the phosphoinositide binding site for the domain and find that calcium binding attenuates millisecond to microsecond motions at both in the calcium binding loops and the concave face of the C2A, including a portion of the phosphoinositide binding site. Our results support a model whereby increasing calcium concentrations shift the phosphoinositide binding pocket of C2A into a binding-competent state, allowing for calcium dependent membrane targeting. This model contrasts with the canonical mechanism for C2 domain-phosphoinositide interaction and provides a basis for how pathogenic mutations in the C2A domain result in loss of function and disease.
Effects of Intravenous Magnesium Sulfate on Calcium-Regulating Hormones, Plasma and Urinary Electrolytes in Healthy Horses
Authors: Schumacher Stephen A. , Kamr Ahmed M. , Lakritz Jeffrey , Burns Teresa A. , Bertone Alicia L. , Toribio Ramiro E.
Published: February 2021

Intravenous magnesium sulfate (MgSO4) is used in equine practice to treat hypomagnesemia, dysrhythmias, neurological disorders, and calcium dysregulation. MgSO4is also used as a calming agent in equestrian events. Hypercalcemia affects calcium-regulating hormones, as well as plasma and urinary electrolytes; however, the effect of hypermagnesemia on these variables is unknown. The goal of this study was to investigate the effect of hypermagnesemia on blood parathyroid hormone (PTH), calcitonin (CT), ionized calcium (Ca2+), ionized magnesium (Mg2+), sodium (Na+), potassium (K+), chloride (Cl-) and their urinary fractional excretion (F) after intravenous administration of MgSO4in healthy horses. Twelve healthy female horses of 4-18 years of age and 432-600 kg of body weight received a single intravenous dose of MgSO4(60 mg/kg) over 5 minutes, and blood and urine samples were collected at different time points over 360 minutes. Plasma Mg2+concentrations increased 3.7-fold over baseline values at 5 minutes and remained elevated for 120 minutes (P < 0.05), Ca2+concentrations decreased from 30-60 minutes (P < 0.05), but Na+, K+and Cl-concentrations did not change. Serum PTH concentrations dropped initially to rebound and remain elevated from 30 to 60 minutes, while CT concentrations increased at 5 minutes to return to baseline by 10 minutes (P < 0.05). The FMg, FCa, FNa, FK, and FCl increased, while urine osmolality decreased from 30-60 minutes compared baseline (P < 0.05). Experimental hypermagnesemia alters calcium-regulating hormones (PTH, CT), reduces plasma Ca2+concentrations, and increases the urinary excretion of Mg2+, Ca2+, K+, Na+and Cl-in healthy horses. This information has clinical implications on the short-term effects of hypermagnesemia on calcium-regulating hormones as well as plasma and urine electrolytes.
NeuronMotif: Deciphering transcriptional cis-regulatory codes from deep neural networks
Authors: Wei Zheng , Hua Kui , Wei Lei , Ma Shining , Jiang Rui , Li Yanda , Wong Wing Hung , Wang Xiaowo
Published: February 2021

Discovering DNA regulatory sequence motifs and their relative positions are vital to understand the mechanisms of gene expression regulation. Such complicated motif grammars are difficult to be summarized from shallow models. Although Deep Convolutional Neural Network (DCNN) achieved great success in annotating cis-regulatory elements, few combinatorial motif grammars have been accurately interpreted due to the mixed signal in DCNN. To address this problem, we proposed NeuronMotif, a general backward decoupling algorithm, to reveal the homo-/hetero-typic motif combinations and arrangements embedded in convolutional neurons. We applied NeuronMotif on several widely-used DCNN models. Many uncovered motif grammars of deep convolutional neurons are supported by literature or ATAC-seq footprinting. We further diagnosed the sick neurons that are sensitive to adversarial noises, which can guide DCNN architecture optimization for better prediction performance and motif feature extraction. Overall, NeuronMotif enables decoding cis-regulatory codes from deep convolutional neurons and understanding DCNN from a novel perspective.
Vocal plasticity in harbour seal pups
Authors: Borda Laura Torres , Jadoul Yannick , Rasilo Heikki , Casals Anna Salazar , Ravignani Andrea
Published: February 2021

Vocal plasticity can occur in response to environmental and biological factors, including conspecifics’ vocalisations and noise. Pinnipeds are one of the few mammalian groups capable of vocal learning, and are therefore relevant to understanding the evolution of vocal plasticity in humans and other animals. Here, we investigate the vocal plasticity of harbour seals (Phoca vitulina), a species with vocal learning abilities attested in adulthood but not puppyhood. To zoom into early mammalian vocal development, we tested 1-3 weeks old seal pups. We tailored noise playbacks to this species and age to induce seal pups to shift their fundamental frequency (F0), rather than adapt call amplitude or temporal characteristics. We exposed individual pups to bandpass-filtered noise, which purposely spanned – and masked – their typical range of F0s, and simultaneously recorded pups’ spontaneous calls. Seals were able to modify their vocalisations quite unlike most mammals: They lowered their F0 in response to increased noise. This modulation was punctual and adapted to the particular noise condition. In addition, higher noise induced less dispersion around the mean F0, suggesting that pups may have been actively focusing their phonatory efforts to target lower frequencies. Noise masking did not seem to affect call amplitude. However, one seal showed two characteristics of the Lombard effect known for human speech in noise: significant increase in call amplitude and flattening of spectral tilt. Our relatively low noise levels may have favoured F0 shifts while inhibiting amplitude adjustments. This lowering of F0 is quite unusual, as other animals commonly display no F0 shift independently of noise amplitude. Our data represents a relatively rare case in mammalian neonates, and may have implications for the evolution of vocal plasticity across species, including humans.
Co-culturingHyphomicrobium nitrativoransstrain NL23 andMethylophaga nitratireducenticrescensstrain JAM1 allows sustainable denitrifying activities under marine conditions
Authors: Alexandra Cucaita , Marianne Piochon , Richard Villemur
Published: February 2021

Hyphomicrobium nitrativoransstrain NL23 andMethylophaga nitratireducenticrescensstrain JAM1 were the principal bacteria involved in the denitrifying activities of a methanol-fed, fluidized marine denitrification reactor. We believe that a tight relationship has developed between these two strains to achieve denitrification in the reactor under marine conditions. To characterize the potential synergy between strain JAM1 and strain NL23, we compared some of their physiological traits, and performed co-cultures. Pure cultures of strain JAM1 had a readiness to reduce nitrate (NO3−) with no lag phase for growth contrary to pure cultures of strain NL23, which has a 2-3 days lag phase before NO3− starts to be consumed and growth to occur. Compared to strain NL23, strain JAM1 has a higher μmax for growth and higher specific NO3− reduction rates. Antagonist assays showed no sign of exclusion by both strains. Planktonic co-cultures could only be performed on low NaCl concentrations for strain NL23 to survive. Denitrification rates were twice higher in the planktonic co-cultures than those measured in strain NL23 pure cultures. Biofilm co-cultures were performed for several months in a 500-mL bioreactor filled with Bioflow supports, and operated under fed-batch mode with increasing concentrations of NaCl for strain NL23 to acclimate to marine conditions. Under these conditions, the biofilm co-cultures showed sustained denitrifying activities and surface colonization by both strains. Increase in ectoine concentrations produced by strain JAM1 was observed in the biofilm with increasing NaCl concentrations. These results illustrate the capacity of both strains to act together in performing denitrification under marine environments. Although strain JAM1 did not contribute in better specific denitrifying activities in the biofilm co-cultures, its presence was essential for strain NL23 to survive in a medium with NaCl concentrations > 1.0%. We believe that ectoine is an important factor for the survival of strain NL23 in these environments.
“Single-subject studies”-derived analyses unveil altered biomechanisms between very small cohorts: implications for rare diseases
Authors: Aberasturi Dillon , Pouladi Nima , Zaim Samir Rachid , Kenost Colleen , Berghout Joanne , Piegorsch Walter W. , Lussier Yves A.
Published: February 2021

Motivation

Identifying altered transcripts between very small human cohorts is particularly challenging and is compounded by the low accrual rate of human subjects in rare diseases or sub-stratified common disorders. Yet,single-subjectstudies (S3) can compare paired transcriptome samples drawn from the same patient under two conditions (e.g., treated vs pre-treatment) and suggest patient-specific responsive biomechanisms based on the overrepresentation of functionally defined gene sets. These improve statistical power by: (i) reducing the total features tested and (ii) relaxing the requirement of within-cohort uniformity at the transcript level. We proposeInter-N-of-1, a novel method, to identify meaningful biomechanism differences between very small cohorts by using the effect size of “single-subject-study”-derived responsive biomechanisms.

Results

In each subject,Inter-N-of-1requires applying previously published S3-typeN-of-1-pathways MixEnrichto two paired samples (e.g., diseased vs unaffected tissues) for determining patient-specificenrichedgenessets: Odds Ratios (S3-OR) and S3-variance using Gene Ontology Biological Processes. To evaluate small cohorts, we calculated the precision and recall ofInter-N-of-1and that of a control method (GLM+EGS) when comparing two cohorts of decreasing sizes (from 20 vs 20 to 2 vs 2) in a comprehensive six-parameter simulation and in a proof-of-concept clinical dataset. In simulations, theInter-N-of-1median precision and recall are > 90% and >75% in cohorts of 3 vs 3 distinct subjects (regardless of the parameter values), whereas conventional methods outperformInter-N-of-1at sample sizes 9 vs 9 and larger. Similar results were obtained in the clinical proof-of-concept dataset.

Availability

R software is available at Lussierlab.net/BSSD.

Contact

Lussier.y@gmail.com,Piegorsch@math.arizona.edu
Mitochondrial Fission Regulates Transcription of Ribosomal Protein Genes in Embryonic Hearts
Authors: Zhao Qiancong , Yan Shun , Lu Jin , Parker Danitra J. , Wu Huiying , Sun Qianchuang , Crossman David K. , Liu Shanrun , Wang Qin , Sesaki Hiromi , Mitra Kasturi , Liu Kexiang , Jiao Kai
Published: February 2021

Mitochondrial dysfunction causes severe congenital heart diseases and prenatal/neonatal lethality. The lack of sufficient knowledge regarding how mitochondrial abnormalities affect cardiogenesis poses a major barrier for the development of clinical applications that target inborn heart defects due to mitochondrial deficiency. Mitochondrial morphology, which is regulated by fission and fusion, plays key roles in determining mitochondrial activity.Drp1encodes a dynamin-related GTPase required for mitochondrial fission. To investigate the role of mitochondrial fission on cardiogenesis during the embryonic metabolic shift period, we specifically inactivatedDrp1in second heart field derived structures. Deletion ofDrp1in embryonic cardiomyocytes led to severe defects in mitochondrial morphology, ultrastructure, and activity. These defects caused increased cell death, decreased cell survival, disorganized cardiomyocytes, and embryonic lethality. Through characterizing this model, we reveal a novel AMPK-SIRT7-GABPB axis that relays the mitochondrial fission anomaly to reduced transcription of ribosomal protein genes in mutant cardiomyocytes. We therefore provide the first mouse genetic evidence to show that mitochondrial fission is essential for embryonic heart development. Furthermore, we uncovered a novel signaling cascade that mediates the crosstalk between mitochondrial dysfunction and protein synthesis. Our research provides further mechanistic insight regarding how mitochondrial dysfunction causes pathological molecular and cellular alterations during cardiogenesis.
Succinate metabolism uncouples retinal pigment epithelium mitochondria
Authors: Hass Daniel T. , Bisbach Celia M. , Robbings Brian M. , Kamat Varun S , Sadilek Martin , Sweet Ian R. , Hurley James B.
Published: February 2021

Succinate is central in energy metabolism. It is thought to be made and consumed within mitochondria, and not to cross the plasma membrane. Contrary to the canonical role of succinate, it is produced in the retina and released into the extracellular milleau. It is unknown how this affects adjacent retinal pigment epithelium, within eyecup tissue. By measuring consumption of13C4-succinate and O2we probe metabolism of the eyecup, we find robust succinate consumption by eyecup but not retina tissue. Succinate-dependant stimulation of eyecup respiration is oligomycin resistant; indicating that in eyecup tissue succinate uncouples mitochondrial ATP synthesis from respiration.
Protomer alignment modulates specificity of RNA substrate recognition by Ire1
Authors: Li Weihan , Crotty Kelly , Ruiz Diego Garrido , Voorhies Mark , Rivera Carlos , Sil Anita , Mullins R. Dyche , Jacobson Matthew P. , Peschek Jirka , Walter Peter
Published: February 2021

The unfolded protein response (UPR) maintains protein folding homeostasis in the endoplasmic reticulum (ER). In metazoan cells, the Ire1 branch of the UPR initiates two functional outputs— non-conventional mRNA splicing and selective mRNA decay (RIDD). By contrast, Ire1 orthologs fromSaccharomyces cerevisiaeandSchizosaccharomyces pombeare specialized for only splicing or RIDD, respectively. The functional specialization lies in Ire1’s RNase activity, which is either stringently splice-site specific (as inS. cerevisiae) or promiscuous (as inS. pombe). Here, we developed an assay that reports on Ire1’s RNase promiscuity. We found that conversion of two amino acids within the RNase domain ofS. cerevisiaeIre1 to theirS. pombecounterparts rendered it promiscuous. Using biochemical assays and computational modeling, we show that the mutations rewired a pair of salt bridges at Ire1 RNase domain’s dimer interface, changing its protomer alignment. Thus, Ire1 protomer alignment affects its substrates specificity.
A like-for-like comparison of lightweight-mapping pipelines for single-cell RNA-seq data pre-processing
Authors: Zakeri Mohsen , Srivastava Avi , Sarkar Hirak , Patro Rob
Published: February 2021

Recently, Booeshaghi and Pachter (1) published a benchmark comparing the kallisto-bustools pipeline (2) for single-cell data pre-processing to the alevin-fry pipeline (3). Their benchmarking adopted drastically dissimilar configurations for these two tools, and overlooked the time- and space-frugal configurations of alevin-fry previously benchmarked by Sarkar et al. (3). In this manuscript, we provide a small set of modifications to the benchmarking scripts of Booeshaghi and Pachter that are necessary to perform a like-for-like comparison between kallisto-bustools and alevin-fry. We also address some misuses of the alevin-fry commands and include important data on the exact reference transcriptomes used for processing1. Using the same benchmarking scripts of Booeshaghi and Pachter (1), we demonstrate that, when configured to match the computational com-plexity of kallisto-bustools as closely as possible, alevin-fry processes data faster (~2.08 times as fast on average) and uses less peak memory (~ 0.34 times as much on average) compared to kallisto-bustools, while producing results that are similar when assessed in the manner done by Booeshaghi and Pachter (1). This is a notable inversion of the performance characteristics presented in the previous benchmark.
An endogenous opioid circuit determines state-dependent appetitive behavior
Authors: Castro Daniel C. , Oswell Corinna S. , Zhang Eric T. , Pedersen Christian E. , Piantadosi Sean C. , Rossi Mark A. , Hunker Avery , Guglin Anthony , Morón Jose A. , Zweifel Larry S. , Stuber Garret D. , Bruchas Michael R.
Published: February 2021

Mu-opioid peptide receptor (MOPR) stimulation alters respiration, analgesia, and reward behavior, and can induce addiction and drug overdose. Despite its evident importance, the endogenous mechanisms for MOPR regulation of appetitive behavior have remained unknown. Here we report that endogenous MOPR regulation of appetitive behavior in mice acts through a specific dorsal raphe to nucleus accumbens projection. MOPR-mediated inhibition of raphe terminals is necessary and sufficient to determine appetitive behavioral state while select enkephalin-containing NAc ensembles are engaged prior to reward consumption, suggesting that local enkephalin release is the source of endogenous MOPR ligand. Selective modulation of NAc enkephalin neurons and CRISPR-Cas9-mediated disruption of enkephalin substantiate this finding. These results isolate a fundamental endogenous opioid circuit for state-dependent appetitive behavior and suggest alternative mechanisms for opiate modulation of reward.
Full assembly of HIV-1 particles requires assistance of the membrane curvature factor IRSp53
Authors: Inamdar Kaushik , Tsai Feng-Ching , de Poret Aurore , Dibsy Rayane , Manzi John , Merida Peggy , Muller Remi , Lappalainen Pekka , Roingeard Philippe , Mak Johnson , Bassereau Patricia , Favard Cyril , Muriaux Delphine
Published: February 2021

During HIV-1 particle formation, the requisite plasma membrane curvature is thought to be solely driven by the retroviral Gag protein. Here, we reveal that the cellular I-BAR protein IRSp53 is required for the progression of HIV-1 membrane curvature to complete particle assembly. Partial gene editing of IRSp53 induces a decrease in viral particle production and a viral bud arrest at half completion. Single molecule localization microscopy at the cell plasma membrane shows a preferential localization of IRSp53 around HIV-1 Gag assembly sites. In addition, we observe the presence of IRSp53 in purified HIV-1 particles. Finally, HIV-1 Gag protein localizes preferentially to IRSp53 I-BAR domain induced curved membranes on giant unilamellar vesicles. Overall, our data reveal a strong interplay between IRSp53 I-BAR and Gag at membranes during virus assembly. This highlights IRSp53 as a crucial host factor in HIV-1 membrane curvature and its requirement for full HIV-1 particle assembly.
Modelling spinal locomotor circuits for movements in developing zebrafish
Authors: Roussel Yann , Gaudreau Stephanie F. , Kacer Emily R. , Sengupta Mohini , Bui Tuan V.
Published: February 2021

Many spinal circuits dedicated to locomotor control have been identified in the developing zebrafish. How these circuits operate together to generate the various swimming movements during development remains to be clarified. In this study, we iteratively built models of developing zebrafish spinal circuits coupled to simplified musculoskeletal models that reproduce coiling and swimming movements. The neurons of the models were based upon morphologically or genetically identified populations in the developing zebrafish spinal cord. We simulated intact spinal circuits as well as circuits with silenced neurons or altered synaptic transmission to better understand the role of specific spinal neurons. Analysis of firing patterns and phase relationships helped identify possible mechanisms underlying the locomotor movements of developing zebrafish. Notably, our simulations demonstrated how the site and the operation of rhythm generation could transition between coiling and swimming. The simulations also underlined the importance of contralateral excitation to multiple tail beats. They allowed us to estimate the sensitivity of spinal locomotor networks to motor command amplitude, synaptic weights, length of ascending and descending axons, and firing behaviour. These models will serve as valuable tools to test and further understand the operation of spinal circuits for locomotion.
Suppressing evolution through environmental switching
Authors: Morsky Bryce , Vural Dervis Can
Published: February 2021

Ecology and evolution under changing environments are important in many subfields of biology with implications for medicine. Here, we explore an example: the consequences of fluctuating environments on the emergence of antibiotic resistance, which is an immense and growing problem. Typically, high doses of antibiotics are employed to eliminate the infection quickly and minimize the time under which resistance may emerge. However, this strategy may not be optimal. Since competition can reduce fitness and resistance typically has a reproductive cost, resistant mutants’ fitness can depend on their environment. Here we show conditions under which environmental varying fitness can be exploited to prevent the emergence of resistance. We develop a stochastic Lotka-Volterra model of a microbial system with competing phenotypes: a wild strain susceptible to the antibiotic, and a mutant strain that is resistant. We investigate the impact of various pulsed applications of antibiotics on population suppression. Leveraging competition, we show how a strategy of environmental switching can suppress the infection while avoiding resistant mutants. We discuss limitations of the procedure depending on the microbe and pharmacodynamics and methods to ameliorate them.
ZC3H4 restricts non-coding transcription in human cells
Authors: Estell Chris , Davidson Lee , Steketee Pieter C. , Monier Adam , West Steven
Published: February 2021

The human genome encodes thousands of non-coding RNAs. Many of these terminate early and are then rapidly degraded, but how their transcription is restricted is poorly understood. In a screen for protein-coding gene termination factors, we identified ZC3H4. However, its depletion causes upregulation and extension of hundreds of unstable transcripts, particularly antisense RNAs and those transcribed from so-called super-enhancers. These loci are occupied by ZC3H4, suggesting that it directly functions in their transcription. Consistently, engineered tethering of ZC3H4 to reporter RNA promotes its degradation by the exosome. ZC3H4 is metazoan-specific - interesting when considering its impact on enhancer RNAs that are less prominent in single-celled organisms. Finally, ZC3H4 loss causes a substantial reduction in cell proliferation, highlighting its overall importance. In summary, we identify ZC3H4 as a factor that plays an important role in restricting non-coding transcription in multi-cellular organisms.
HotspotESR1mutations are multimodal and contextual drivers of breast cancer metastasis
Authors: Li Zheqi , Wu Yang , Yates Megan E. , Tasdemir Nilgun , Bahreini Amir , Chen Jian , Levine Kevin M. , Priedigkeit Nolan M. , Ali Simak , Buluwela Laki , Arnesen Spencer , Gertz Jason , Richer Jennifer K. , Troness Benjamin , El-Ashry Dorraya , Zhang Qiang , Gerratana Lorenzo , Zhang Youbin , Cristofanilli Massimo , Montanez Maritza A. , Sundd Prithu , Wallace Callen T. , Watkins Simon C. , Zhu Li , Tseng George C. , Wagle Nikhil , Carroll Jason S. , Jank Paul , Denkert Carsten , Karsten Maria M , Blohmer Jens-Uwe , Park Ben H. , Lucas Peter C. , Atkinson Jennifer M. , Lee Adrian V. , Oesterreich Steffi
Published: February 2021

Constitutively active estrogen receptor-α (ER/ESR1) mutations have been identified in approximately one third of ER+ metastatic breast cancer. Although these mutations are known mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence ofESR1mutations exclusively in distant, but not local recurrences. In concordance with transcriptomic profiling ofESR1mutant tumors, genome-edited Y537S and D538G cell models have a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and theTIMP3/MMPaxis, which functionally confers enhanced cell-cell contacts while decreased cell-ECM adhesion. Context-dependent migratory phenotypes revealed co-targeting of Wnt and ER as vulnerability. Mutant ESR1 exhibits non-canonical regulation of several metastatic pathways including secondary transactivation andde novoFOXA1-driven chromatin remodeling. Collectively, our data supports evidence forESR1mutation-driven metastases and provides insight for future preclinical therapeutic strategies.

Significance

Context and allele-dependent transcriptome and cistrome reprogramming in genome-editedESR1mutation cell models elicit diverse metastatic phenotypes, including but not limited to alterations in cell adhesion and migration. The gain-of-function mutations can be pharmacologically targeted, and thus may be key components of novel therapeutic treatment strategies for ER-mutant metastatic breast cancer.
An invariantTrypanosoma vivaxvaccine antigen inducing protective immunity
Authors: Autheman Delphine , Crosnier Cécile , Clare Simon , Goulding David A. , Brandt Cordelia , Harcourt Katherine , Tolley Charlotte , Galaway Francis , Khushu Malhar , Ong Han , Ramirez Alessandra Romero , Duffy Craig W. , Jackson Andrew P. , Wright Gavin J.
Published: February 2021

Trypanosomes are protozoan parasites that cause infectious diseases including human African trypanosomiasis (sleeping sickness), and nagana in economically-important livestock animals1,2. An effective vaccine against trypanosomes would be an important control tool, but the parasite has evolved sophisticated immunoprotective mechanisms including antigenic variation3that present an apparently insurmountable barrier to vaccination. Here we show using a systematic genome-led vaccinology approach4and a murine model ofTrypanosoma vivaxinfection5that protective invariant subunit vaccine antigens can be identified. Vaccination with a single recombinant protein comprising the extracellular region of a conserved cell surface protein localised to the flagellum membrane termed “invariant flagellum antigen fromT. vivax” (IFX) induced long-lasting protection. Immunity was passively transferred with immune serum, and recombinant monoclonal antibodies to IFX could induce sterile protection and revealed multiple mechanisms of antibody-mediated immunity, including a major role for complement. Our discovery identifies a vaccine candidate for an important parasitic disease that has constrained the socioeconomic development of sub-Saharan African countries6and challenges long-held views that vaccinating against trypanosome infections cannot be achieved.
Rabies anterograde monosynaptic tracing reveals organization of spinal sensory circuits
Authors: Pimpinella Sofia , Zampieri Niccolò
Published: February 2021

Somatosensory neurons detect vital information about the environment and internal status of the body, such as temperature, touch, itch and proprioception. The circuit mechanisms controlling the coding of somatosensory information and the generation of appropriate behavioral responses are not clear yet. In order to address this issue, it is important to define the precise connectivity patterns between primary sensory afferents dedicated to the detection of different stimuli and recipient neurons in the central nervous system. In this study we used a rabies tracing approach for mapping spinal circuits receiving sensory input from distinct, genetically defined, modalities. We analyzed the anatomical organization of spinal circuits involved in coding of thermal and mechanical stimuli and showed that somatosensory information from distinct modalities is relayed to partially overlapping ensembles of interneurons displaying stereotyped laminar organization, thus highlighting the importance of positional features and population coding for the processing and integration of somatosensory information.
External technology acquisition, exploitation and process innovation performance in emerging market small and medium sized enterprises: the moderating role of organizational slack
Authors: Charmjuree Thammanoon , Badir Yuosre F. , Safdar Umar
Published: February 2021

Purpose

This study is among the very few to examine the firm's simultaneous use of both dimensions of open innovation and its influences on the firm's process innovation performance (PIP). Specifically, the authors consider the relationship between firm's external technology acquisition (ETA) and external technology exploitation (ETE) and examine their direct, indirect and mediating effect on the firm's PIP. The authors also examine the moderating effect of the organizations' unabsorbed slack (UASL) on the relationship between ETA and ETE.

Design/methodology/approach

Analyzing data collected from 311 small- and medium-sized software development firms in emerging market; Thailand, we show that both ETA and ETE have a positive effect on PIP and that ETE fully mediates the relationship between ETA and PIP.

Findings

The authors show that both ETA and ETE have a positive effect on PIP and that ETE fully mediates the relationship between ETA and PIP. Moreover, the relationship between ETA and ETE is positively moderated by the firms' unabsorbed slack (UASL) and that the influence of ETA on PIP through ETE is stronger under higher unabsorbed slack.

Originality/value

The authors extend the “traditional” performance outcome of outbound dimension of open innovation concept, which focuses exclusively on commercialization and market (Chesbrough, 2003b), by showing that ETE positively influences the firm's PIP. Moreover, the study explains the mechanism through which ETA influence the firm's PIP by proposing that ETE fully mediates the relationship between ETA and PIP.
University students' knowledge about and attitudes toward e-cigarette use and factors influencing students' e-cigarette use
Authors: Chudech Surapong , Janmaimool Piyapong
Published: February 2021

Purpose

This study aims to investigate university students' knowledge about and attitudes toward e-cigarette (EC) use. It will also examine whether students' EC use is associated with knowledge about and attitudes toward EC use. The study also aims to analyze the determinants of students' use of ECs. The effects of gender, smoking behavior and friends' and family members' smoking behaviors on students' use of ECs were analyzed.

Design/methodology/approach

Completed questionnaire surveys were received from 1,362 students at King Mongkut's University of Technology Thonburi in Bangkok City, Thailand, in November and December 2019. Chi-square tests and an independent samples t-test were conducted to determine whether students' knowledge about ECs and attitudes toward EC use influenced their use of ECs. A logistic regression analysis was performed to identify significant factors affecting students' use of ECs.

Findings

The results revealed that students' EC use was associated with knowledge about ECs: Students with less knowledge about the harmful effects of ECs were more likely to use them. In addition, students who were EC users had more positive attitudes toward EC use than those who were not EC users. The results also revealed that male students, students who had also smoked tobacco cigarettes and students with friends who smoked tobacco cigarettes were more likely to use ECs. These results could suggest strategies to reduce the use of ECs among university students.

Originality/value

This study provides deep understanding about university students' knowledge about and attitudes toward EC use and their participation in EC use. The result clearly shows university students who are participating in EC use still have less knowledge about EC, thus, they have positive attitudes toward ECs. Gaining social acceptance from friends who use EC also influences students' decision to use EC. Therefore, EC use among students could significantly increase overall EC use.
Using the social exchange theory to explore the employee-organization relationship in the hospitality industry
Authors: Meira Jessica Vieira de Souza , Hancer Murat
Published: February 2021

Purpose

This research developed a conceptual model for the hospitality industry based on the employee-organization relationship using the social exchange theory as the theoretical framework. This study aims to consider perceived organizational support as the psychological empowerment antecedent, while work engagement and service-oriented organizational citizenship behavior were considered as its outcome. This study also tested psychological empowerment as a mediator of these relationships.

Design/methodology/approach

Data were gathered from a sample of frontline hotel employees and analyzed through partial least squares structural equation modeling. A total of 242 completed and validated questionnaires were used for the analysis.

Findings

Perceived organizational support had a significant relationship with psychological empowerment (through meaning, competence, self-determination and impact), which also had a significant relationship with work engagement (through meaning and impact) and service-oriented organizational citizenship behavior (through meaning, self-determination and impact). Psychological empowerment partially mediated the relationship between perceived organizational support with work engagement and service-oriented organizational citizenship behavior.

Originality/value

Although psychological empowerment is receiving further empirical attention in the hospitality field, little is known about its antecedents and outcomes. Hence, this research extends previous studies using the social exchange theory to fill these literature gaps and create a conceptual model for the hospitality industry based on the employee-organization relationship.
Designing a talent-based model for recruiting faculty members at Iranian regional comprehensive universities
Authors: Romiani Unes , Abili Khodayar , Pourkaremi Javad , Farahbakhsh Saeid
Published: February 2021

Purpose

The purpose of this paper is to design a talent-based model for recruiting faculty members at regional comprehensive universities in Iran.

Design/methodology/approach

To achieve the purpose, grounded theory approach was used. The research population consisted of all experts in the field of higher education in Iran. Nineteen experts were selected through purposeful sampling by Snowball method and based on theoretical saturation. To collect the data, a semi-structured interview was used and for the data analysis, a thematic analysis technique was applied.

Findings

The findings showed that the model for recruiting the faculty members in Iranian regional universities included four components: Personal Characteristics, Professional Capabilities, Behavioral Capabilities and Cognitive Capabilities.

Practical implications

This research identified the recruiting components and its results can be used to recruit capable faculty members purposefully and in accordance with the Iranian academic strategic plan. The method of this study can be applied in other applied fields as well.

Originality/value

This study adds to the authors' knowledge about recruiting of the faculty members and also the factors that can be helpful in a talent-based selection. Therefore, in order to have capable faculty members, universities should make an effort to identify relevant components and design a comprehensive model to recruit more capable faculty members.
Plant blindness and sustainability
Authors: Thomas Howard , Ougham Helen , Sanders Dawn
Published: February 2021

Purpose

The present paper aims to examine the concept of “plant blindness” in the context of current sustainability debates. “Plant blindness” was the term introduced in 1999 by the botanists and educators James H Wandersee and Elisabeth E Schussler to describe what they saw as a pervasive insensitivity to the green environment and a general neglect of plants on the part of biology education.

Design/methodology/approach

The fundamental importance of plants for life on Earth and the socio-educational challenges of redacted awareness of this importance are considered. Also, the diverse physiological, psychological, philosophical, cultural and geopolitical origins and consequences of indifference to plants in relation to aspects of sustainability agendas are examined with special reference to education.

Findings

An examination of the outcomes of a range of research and practical initiatives reveals how multidisciplinary approaches to education and public engagement have the potential to address the challenge of “plant blindness”. The need for these opportunities to be reflected in curriculums is not widely appreciated, and the socio-economic forces of resistance to confronting plant neglect continue to be formidable.

Originality/value

Plant blindness is a relatively new field of research, and the full breadth of its implications are only gradually becoming apparent. If the present paper contributes to positioning plants as an essential element in sustainability education and practice, it will have met its objective.
Resource indivisibility, lumpy costs and the multinationality–performance relationship
Authors: Ref Ohad , Gnizy Itzhak
Published: February 2021

Purpose

The relationship between multinationality and firm performance is a central issue in the international marketing and business literatures. Predominantly, this body of research has tried to identify a single, generalized pattern for this relationship. However, despite the vast number of studies, results have been characterized as mixed or inconsistent. In this study, we take a fresh look at this relationship.

Design/methodology/approach

We focus on a key inducement to expand firm multinationality – the search for a more efficient way to exploit firm resources, and also on a specific operationalization of multinationality – firm geographic scope. We use a formal analytical model analyzing the trade-off between benefits and costs arising from expanding firm geographic scope and emphasizing the role of lumpy costs emanating from resource indivisibility.

Findings

The relationship between geographic scope and performance cannot be confined to a single pattern, but instead, may have any one of a set of patterns: negatively monotonic shape, inverted U-shape, S-shape, M-shape or, multiple-wave inverted U-shape.

Practical implications

The current study offers managers some guidelines to identify which of the above patterns fits their firm's specific case, and to identify the optimal level of geographic scope for their firm.

Originality/value

We conclude that the search for a single, generalized pattern for multinationality-performance is largely futile, whereas the focus on specific inducements and operationalizations for multinationality allows us to explain when and why specific patterns are more likely to occur.