bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluoxetine rescues rotarod motor deficits inMecp2heterozygous mouse model of Rett syndrome via brain serotonin
Authors: Villani Claudia , Sacchetti Giuseppina , Carli Mirjana , Invernizzi Roberto W.
Published: June 2020

Motor skill is a specific area of disability of Rett syndrome (RTT), a rare disorder occurring almost exclusively in girls, caused by loss-of-function mutations of the X-linkedmethyl-CpG-binding protein2(MECP2) gene, encoding the MECP2 protein, a member of the methyl-CpG-binding domain nuclear proteins family. Brain 5-HT, which is defective in RTT patients andMecp2mutant mice, regulates motor circuits and SSRIs enhance motor skill learning and plasticity.

In the present study, we used heterozygous (Het)Mecp2female andMecp2-null male mice to investigate whether fluoxetine, a SSRI with pleiotropic effects on neuronal circuits, rescues motor coordination deficits. Repeated administration of 10 mg/kg fluoxetine fully rescued rotarod deficit inMecp2Het mice regardless of age, route of administration or pre-training to rotarod. The motor improvement was confirmed in the beam walking test while no effect was observed in the hanging-wire test, suggesting a preferential action of fluoxetine on motor coordination. Citalopram mimicked the effects of fluoxetine, while the inhibition of 5-HT synthesis abolished the fluoxetine-induced improvement of motor coordination.Mecp2null mice, which responded poorly to fluoxetine in the rotarod, showed reduced 5-HT synthesis in the prefrontal cortex, hippocampus and striatum, and reduced efficacy of fluoxetine in raising extracellular 5-HT as compared to female mutants. No sex differences were observed in the ability of fluoxetine to desensitize 5-HT1Aautoreceptors upon repeated administration. These findings indicate that fluoxetine rescues motor coordination inMecp2Het mice through its ability to enhance brain 5-HT and suggest that drugs enhancing 5-HT neurotransmission may have beneficial effects on motor symptoms of RTT.
Understanding the host-microbe interactions using metabolic modeling
Authors: Jansma Jack , El Aidy Sahar
Published: June 2020

The human gut harbors an enormous number of symbiotic microbes, which is vital for human health. However, interactions within the complex microbiota community and between the microbiota and its host are challenging to elucidate, limiting development in the treatment for a variety of diseases associated with microbiota dysbiosis. UsingIn silicosimulation methods based on flux balance analysis, those interactions can be better investigated. Flux balance analysis uses an annotated genome-scale reconstruction of a metabolic network to determine the distribution of metabolic fluxes that represent the complete metabolism of a bacterium in a certain metabolic environment such as the gut. Simulation of a set of bacterial species in a shared metabolic environment can enable the study of the effect of numerous perturbations, such as dietary changes or addition of a probiotic species in a personalized manner. This review aims to introduce these applications of flux balance analysis to experimental biologists and discusses its potential use to improve human health.
Evidence of shifts towards neural states of stability during the retrieval of real-life episodic memories
Authors: Fuentemilla L , Nicolás B , Kastrinogiannis A , Silva M
Published: June 2020

How does one retrieve real-life episodic memories? Here, we tested the hypothesis, derived from computational models, that successful retrieval relies on neural dynamics patterns that rapidly shift towards stable states. We implemented cross-temporal correlation analysis of electroencephalographic (EEG) recordings while participants retrieved episodic memories cued by pictures collected with a wearable camera depicting real-life episodes taking place at “home” and at “the office”. We found that the retrieval of real-life episodic memories is supported by rapid shift towards brain states of stable activity, that the degree of neural stability is associated with the participants’ ability to recollect the episodic content cued by the picture, and that each individual elicits stable EEG patterns that were not shared with other participants. These results indicate that the retrieval of autobiographical memory episodes is supported by rapid shifts of neural activity towards stable states.
Pan-cancer detection of driver genes at the single-patient resolution
Authors: Nulsen Joel , Misetic Hrvoje , Yau Christopher , Ciccarelli Francesca D.
Published: June 2020

Background

Identifying the complete repertoire of genes that drive cancer in individual patients is crucial for precision oncology. Most established methods identify driver genes that are recurrently altered across patient cohorts. However, mapping these genes back to patients leaves a sizeable fraction with few or no drivers, hindering our understanding of cancer mechanisms and limiting the choice of therapeutic interventions.

Results

We present sysSVM2, a machine learning software that integrates cancer genetic alterations with gene systems-level properties to predict drivers in individual patients. Using simulated pan-cancer data, we optimise sysSVM2 for application to any cancer type. We benchmark its performance on real cancer data and validate its applicability to a rare cancer type with few known driver genes. We show that drivers predicted by sysSVM2 have a low false-positive rate, are stable and disrupt well-known cancer-related pathways.

Conclusions

sysSVM2 can be used to identify driver alterations in patients lacking sufficient canonical drivers or belonging to rare cancer types for which assembling a large enough cohort is challenging, furthering the goals of precision oncology. As resources for the community, we provide the code to implement sysSVM2 and the pre-trained models in all TCGA cancer types (https://github.com/ciccalab/sysSVM2).
High Content Screening and Proteomic Analysis Identify a Kinase Inhibitor that rescues pathological phenotypes in a Patient-Derived Model of Parkinson’s Disease
Authors: Antoniou Nasia , Prodromidou Kanella , Kouroupi Georgia , Samiotaki Martina , Panayotou George , Xilouri Maria , Stefanis Leonidas , Grailhe Regis , Taoufik Era , Matsas Rebecca
Published: June 2020

Combining high throughput screening approaches with induced pluripotent stem cell (iPSC)-based disease modeling represents a promising unbiased strategy to identify therapies for neurodegenerative disorders. Here we applied high content imaging on iPSC-derived neurons from patients with familial Parkinson’s disease bearing the G209A (p.A53T) α-synuclein (αSyn) mutation and launched a screening campaign on a small kinase inhibitor library. We thus identified the multi-kinase inhibitor BX795 that at a single dose effectively restores disease-associated neurodegenerative phenotypes. Proteomics profiling mapped the molecular pathways underlying the protective effects of BX795, comprising a cohort of 118 protein-mediators of the core biological processes of RNA metabolism, protein synthesis, modification and clearance, and stress response, all linked to the mTORC1 signaling hub. In agreement, expression of human p.A53T-αSyn in neuronal cells affected key components of the mTORC1 pathway resulting in aberrant protein synthesis that was restored in the presence of BX795 with concurrent facilitation of autophagy. Taken together, we have identified a promising small molecule with neuroprotective actions as candidate therapeutic for PD and other protein conformational disorders.
ABA analogue produced byBacillus marisflavimodulates the physiological response of host-plant under drought stress
Authors: Gowtham H.G. , Duraivadivel P. , Ayusman S. , Sayani D. , Gholap S.L. , Niranjana S.R. , Hariprasad P.
Published: June 2020

Present study aims to understand the molecular mechanism involved in beneficial rhizobacteria mediated alleviation of drought stress in host plant.Bacillus marisflaviCRDT-EB-1 isolated from the rhizosphere soil was found effective in inducing resistance against drought stress in mustard seedlings. Among the different bacterial derivatives tested, the culture filtrate was found to contain bioactive molecules. Solvent extract of bacterial culture filtrate yielded seven distinct bands/ fractions on thin layer chromatography (TLC). The fraction four (F4) with Rfvalue 0.35-0.40 was significant in reducing adverse effect of drought stress in host plants. Application of F4 resulted in delayed drooping point and higher drought tolerance index (3.34), induced stomatal closure (9.648 μ), seed germination inhibition (12%), and reduced the GA3induced α-amylase activity in germinating barley seeds. On TLC, F4 turned colorless to orange color upon the spray of 2,4-dinitrophenylhydrazine reagent indicated the presence of aldehyde group. Supporting to this, the peaks between 9.8 to 10.0 ppm in1H-NMR chromatogram confirmed the presence of aldehyde group. Upon LC-MS/MS analysis of crude extract of culture filtrate and F4 revealed the presence of compounds with the molecular mass 250.33 and 266.33. By analyzing these data, the identity of the bioactive compounds were predicted as xanthoxin and xanthoxic acid, which are well-known precursor of Abscisic acid (ABA) in plants. The present study concludes the capability of ABA analogue (xanthoxin like compounds) production byB. marisflaviCRDT-EB-1 and its involvement in inducing drought stress tolerance in the host plant.
Functional Sensitivity and Mutational Robustness of Proteins
Authors: Tang Qian-Yuan , Hatakeyama Testsuhiro S. , Kaneko Kunihiko
Published: June 2020

Sensitivity and robustness appear to be contrasting concepts. However, natural proteins are robust enough to tolerate random mutations, meanwhile be susceptible enough to sense environmental signals, exhibiting both high functional sensitivity (i.e., plasticity) and mutational robustness. Uncovering how these two aspects are compatible is a fundamental question in the protein dynamics and genotype-phenotype relation. In this work, a general framework is established to analyze the dynamics of protein systems under both external and internal perturbations. We introduce fluctuation entropy for the functional sensitivity and the spectrum entropy for the mutational robustness. The compatibility of sensitivity and robustness is analyzed by the optimization of two entropies, which leads to the power-law vibration spectrum of proteins. These power-law behaviors are confirmed extensively by protein data, as a hallmark of criticality. Moreover, the dependence of functional sensitivity and mutational robustness on the protein size suggests a general evolutionary constraint for proteins with different chain lengths. This framework can also establish a general link of the criticality with robustness-plasticity compatibility, both of which are ubiquitous features in biological systems.
Functional Suppression of Premotor Activity in a Transient Model of Motor Cortex Injury
Authors: Elliott Kevin C. , Borrell Jordan A. , Barbay Scott , Nudo Randolph J.
Published: June 2020

Cortical injuries (e.g. – strokes or traumatic brain injuries) can create a host of secondary events that further impair the brain’s sensory, motor, or cognitive capabilities. Here, we attempted to isolate the acute effects of the primary injury – the loss of cortical activity – on rodent motor cortex (caudal forelimb area, CFA) without the secondary effects that arise from damage to cortical tissue. We then observed the effects of this loss of activity on the rodent premotor cortex (rostral forelimb area, RFA). In anesthetized rats, CFA was temporarily inactivated with the GABA-A agonist muscimol, disrupting motor network function while leaving neural connectivity intact. Using intracortical microstimulation (ICMS) techniques, we found that CFA inactivation completely abolished ICMS-evoked forelimb movement from RFA yet spared some CFA evoked-movement. Neural recordings confirmed that neural suppression by muscimol was isolated to CFA and did not spread into RFA. We next observed how CFA inactivation suppressed RFA influence on forelimb muscles by obtaining intramuscular electromyographical (EMG) recordings from forelimb muscles during ICMS. EMG recordings showed that despite the presence of evoked movement in CFA, but not RFA, muscle activation in both areas were similarly reduced. These results suggest that the primary reason for the loss of ICMS-evoked movement in RFA is not reduced forelimb muscle activity, but rather a loss of the specific activity between RFA and CFA. Therefore, within the intact motor network of the rat, RFA’s influence on forelimb movement is mediated by CFA, similar to the premotor and motor organization observed in non-human primates.
Integrity of anterior corpus callosum is well related to language impairment after traumatic brain injury
Authors: Lee Hae In , Cho Minjae , Na Yoonhye , Hwang Yu Mi , Pyun Sung-Bom
Published: June 2020

Background

The corpus callosum (CC) serves as the bridge that relays information between the two cerebral hemispheres, and is one of the most commonly injured areas after traumatic brain injury (TBI). This study was designed to investigate the association between the CC integrity and language function after TBI.

Methods

We retrospectively enrolled 30 patients with TBI who underwent diffusion tensor imaging and language function evaluation using the Western Aphasia Battery. The CC was divided into five segments (C1-C5) according to its projecting fibers using Hofer’s method, and fractional anisotropy (FA) values were measured using DSI studio software. The FA values of the left arcuate fasciculus and cingulum for language function and executive function, respectively, were also evaluated. Twelve healthy controls were also enrolled to compare the FA values of these tracts.

Results

The FA values of the cingulum and left arcuate fasciculus were significantly correlated with all language scores. The FA values of the entire CC were significantly correlated with the fluency, repetition, and aphasia quotient scores. The FA values of the anterior CC segment (C1 and C2) significantly correlated with the aphasia quotient score; C1 with the fluency score; and C2 with the fluency, comprehension, and repetition scores. However, the FA values of the posterior CC (C3-C5) were not significantly correlated with any of the language subset scores.

Conclusion

The language function in patients with TBI is correlated with the integrity of the white matter tracts important for language and attention processes. Moreover, disruption of the CC is common after TBI, and the anterior CC segment plays an important role in language impairment after TBI. Therefore, analyzing CC integrity using diffusion tensor imaging can help predict language impairment in patients with TBI.
EnteropathogenicEscherichia coli(EPEC) Infection Induces Diarrhea, Intestinal Damage, Metabolic Alterations and Increased Intestinal Permeability in a Murine Model
Authors: Ledwaba Solanka E. , Costa Deiziane V.S. , Bolick David T. , Giallourou Natasa , Medeiros Pedro H.Q.S. , Swann J Jonathan R. , Traore-Hoffman Afsatou N. , Potgieter Natasha , Nataro James P. , Guerrant Richard L.
Published: June 2020

EnteropathogenicE. coli(EPEC) are recognized as one of the leading bacterial causes of infantile diarrhea worldwide. Weaned C57BL/6 mice pretreated with antibiotics were challenged orally with wild-type EPEC orescNmutant (lacking type 3 secretion system) to determine colonization, inflammatory responses and clinical outcomes during infection. Antibiotic disruption of intestinal microbiota enabled efficient colonization by wild-type EPEC resulting in growth impairment and diarrhea. Increase in inflammatory biomarkers, chemokines, cellular recruitment and pro-inflammatory cytokines were observed in intestinal tissues. Metabolomic changes were also observed in EPEC infected mice with changes in TCA cycle intermediates, increased creatine excretion and shifts in gut microbial metabolite levels. In addition, by 7 days after infection, although weights were recovering, EPEC-infected mice had increased intestinal permeability and decreased colonic claudin-1 levels. TheescNmutant colonized the mice, but had no weight changes or increased inflammatory biomarkers, showing the importance of the T3SS in EPEC virulence in this model. In conclusion, a murine infection model treated with antibiotics has been developed to mimic many clinical outcomes seen in children with EPEC infection and to examine potential roles of selected virulence traits. This model can help in further understanding mechanisms involved in the pathogenesis of EPEC infections and potential outcomes and thus assist in the development of potential preventive or therapeutic interventions.
Convergence of cortical types and functional motifs in the mesiotemporal lobe
Authors: Paquola Casey , Benkarim Oualid , DeKraker Jordan , Lariviere Sara , Frässle Stefan , Royer Jessica , Tavakol Shahin , Valk Sofie , Bernasconi Andrea , Bernasconi Neda , Khan Ali , Evans Alan , Razi Adeel , Smallwood Jonathan , Bernhardt Boris
Published: June 2020

Abstract

The parahippocampus-hippocampus complex in the mesiotemporal lobe (MTL) is implicated in many different cognitive processes, is compromised in numerous disorders, and exhibits a unique cytoarchitectural transition from six-layered isocortex to three-layered allocortex. Our study leveraged an ultra-high-resolution histological reconstruction of a human brain to (i) develop a continuous surface model of the MTL iso-to-allocortex transition and (ii) quantitatively characterise the region’s cytoarchitecture. We projected the model into the native space ofin vivofunctional magnetic resonance imaging of healthy adults to (iii) construct a generative model of its intrinsic circuitry and (iv) determine its relationship with distributed functional dynamics of macroscale isocortical fluctuations. We provide evidence that the most prominent axis of cytoarchitectural differentiation of the MTL follows infolding from iso-to-allocortex and is defined by depth-specific variations in neuron density. Intrinsic effective connectivity exhibited a more complex relationship to MTL geometry, varying across both iso-to-allocortical and anterior-posterior axes. Variation along the long axis of the MTL was associated with differentiation between transmodal and unimodal systems, with anterior regions linked to transmodal cortex. In contrast, the iso-to-allocortical gradient was associated with the multiple demand system, with isocortex linked to regions activated when task demands prohibit the use of prior knowledge. Our findings establish a novel model of the MTL, in which its broad influence on neural function emerges through the combination micro- and macro-scale structural features.
A predictive coarse-grained model for position-specific effects of post-translational modifications on disordered protein phase separation
Authors: Perdikari T. M. , Jovic N. , Dignon G. L. , Kim Y. C. , Fawzi N. L. , Mittal J.
Published: June 2020

Biomolecules undergo liquid-liquid phase separation (LLPS) resulting in the formation of multicomponent protein-RNA membraneless organelles in cells. However, the physiological and pathological role of post translational modifications (PTMs) on the biophysics of phase behavior is only beginning to be probed. To study the effect of PTMs on LLPSin silico, we extend our transferable coarse-grained model of intrinsically disordered proteins to include phosphorylated and acetylated amino acids. Using the parameters for modified amino acids available for fixed charge atomistic forcefields, we parameterize the size and atomistic hydropathy of the coarse-grained modified amino acid beads, and hence the interactions between the modified and natural amino acids. We then elucidate how the number and position of phosphorylated and acetylated residues alter the protein’s single chain compactness and its propensity to phase separate. We show that both the number and the position of phosphorylated threonines/serines or acetylated lysines can serve as a molecular on/off switch for phase separation in the well-studied disordered regions of FUS and DDX3X, respectively. We also compare modified residues to their commonly used PTM mimics for their impact on chain properties. Importantly, we show that the model can predict and capture experimentally measured differences in the phase behavior for position-specific modifications, showing that the position of modifications can dictate phase separation. In sum, this model will be useful for studying LLPS of post-translationally modified intrinsically disordered proteins and predicting how modifications control phase behavior with position-specific resolution.

Statement of Significance

Post-translational modifications are important regulators of liquid-liquid phase separation (LLPS) which drives the formation of biomolecular condensates. Theoretical methods can be used to characterize the biophysical properties of intrinsically disordered proteins (IDPs). Our recent framework for molecular simulations using a Cα-centered coarse-grained model can predict the effect of various perturbations such as mutations (Dignon et al.PloS Comput. Biol, 2018) and temperature (Dignon et al,ACS Cent. Sci., 2019) on LLPS. Here, we expand this framework to incorporate modified residues like phosphothreonine, phosphoserine and acetylysine. This model will prove useful for simulating the phase separation of post-translationally modified IDPs and predicting how position-specific modifications can control phase behavior across the large family of proteins known to be phosphorylated and acetylated.
Structural basis for potent neutralization of SARS-CoV-2 and role of antibody affinity maturation
Authors: Hurlburt Nicholas K. , Wan Yu-Hsin , Stuart Andrew B. , Feng Junli , McGuire Andrew T. , Stamatatos Leonidas , Pancera Marie
Published: June 2020

SARS-CoV-2 is a betacoronavirus virus responsible for the COVID-19 pandemic. Here, we determined the X-ray crystal structure of a potent neutralizing monoclonal antibody, CV30, isolated from a patient infected with SARS-CoV-2, in complex with the receptor binding domain (RBD). The structure reveals CV30’s epitope overlaps with the human ACE2 receptor binding site thus providing the structural basis for its neutralization by preventing ACE2 binding.
Ordered dephosphorylation initiated by the selective proteolysis of cyclin B drives mitotic exit
Authors: Holder James , Mohammed Shabaz , Barr Francis A.
Published: June 2020

APC/C-mediated proteolysis of cyclin B and securin promotes entry into anaphase, inactivating CDK1 and permitting chromosome segregation, respectively. Reduction of CDK1 activity relieves inhibition of the CDK1-opposing phosphatases PP1 and PP2A-B55 leading to dephosphorylation of substrates crucial for mitotic exit. Meanwhile, continued APC/C activity is required to target various proteins, including Aurora and Polo kinases, for degradation. Together, these activities orchestrate a complex series of events during mitotic exit. However, the relative importance of regulated proteolysis and dephosphorylation in dictating the order and timing of these events remains unclear. Using high temporal-resolution mass spectrometry, we compare the relative extent of proteolysis and protein dephosphorylation. This reveals highly-selective rapid (∼5min half-life) proteolysis of cyclin B, securin and geminin at the metaphase to anaphase transition, followed by slow proteolysis (>60 min half-life) of other mitotic regulators. Protein dephosphorylation requires APC/C-dependent destruction of cyclin B and was resolved into PP1-dependent fast, intermediate and slow categories with unique sequence motifs. We conclude that dephosphorylation initiated by the selective proteolysis of cyclin B drives the bulk of changes observed during mitotic exit.
Pandora: 4-D white matter bundle population-based atlases derived from diffusion MRI fiber tractography
Authors: Hansen Colin B , Yang Qi , Lyu Ilwoo , Rheault Francois , Kerley Cailey , Chandio Bramsh Qamar , Fadnavis Shreyas , Williams Owen , Shafer Andrea T. , Resnick Susan M. , Zald David H. , Cutting Laurie , Taylor Warren D , Boyd Brian , Garyfallidis Eleftherios , Anderson Adam W , Descoteaux Maxime , Landman Bennett A , Schilling Kurt G
Published: June 2020

Brain atlases have proven to be valuable neuroscience tools for localizing regions of interest and performing statistical inferences on populations. Although many human brain atlases exist, most do not contain information about white matter structures, often neglecting them completely or labelling all white matter as a single homogenous substrate. While few white matter atlases do exist based on diffusion MRI fiber tractography, they are often limited to descriptions of white matter as spatially separate “regions” rather than as white matter “bundles” or fascicles, which are well-known to overlap throughout the brain. Additional limitations include small sample sizes, few white matter pathways, and the use of outdated diffusion models and techniques. Here, we present a new population-based collection of white matter atlases represented in both volumetric and surface coordinates in a standard space. These atlases are based on 2443 subjects, and include 216 white matter bundles derived from 6 different state-of-the-art tractography techniques. This atlas is freely available and will be a useful resource for parcellation and segmentation.
Methionine synthase is essential for cancer cell proliferation in physiological folate environments
Authors: Sullivan Mark R. , Darnell Alicia M. , Reilly Montana F. , Lewis Caroline A. , Vander Heiden Matthew G.
Published: June 2020

Targeting folate metabolism can be an effective way to treat cancer. The enzyme methionine synthase catalyzes a key reaction in both folate and methionine metabolism. Early work suggested that inhibiting methionine synthase might restrain tumor growth, though the mechanism remains unclear. We find that due to its specific role in processing folates, methionine synthase is required for cancer proliferation. However, widely used cell culture conditions obscure the proliferative and metabolic consequences of methionine synthase inhibition. Complete dependence on methionine synthase only arises when 5-methyl tetrahydrofolate, the major folate found in circulation, is the predominant folate source provided to cells. In these physiological folate conditions, methionine synthase activity is necessary to maintain intracellular levels of nucleotides, but not methionine. These data reveal that the extracellular environment can alter the essentiality of methionine synthase and suggest that this enzyme plays a crucial cell-autonomous role in supporting nucleotide synthesis and cell proliferation in physiological contexts.
MonitoringS. pombegenome stress by visualizing end-binding protein Ku
Authors: Jones Chance , Forsburg Susan L
Published: June 2020

Studies of genome stability have exploited visualization of fluorescently tagged proteins in live cells to characterize DNA damage, checkpoint, and repair responses. In this report, we describe a new tool for fission yeast, a tagged version of the end-binding protein Pku70 which is part of the KU protein complex. We compare Pku70 localization to other markers upon treatment to various genotoxins, and identify a unique pattern of distribution. Pku70 provides a new tool to define and characterize DNA lesions and the repair response.
Self-fertilization, but not mating strategy, predicts the evolution of sex allocation plasticity in a hermaphroditic flatworm genus
Authors: Singh Pragya , Schärer Lukas
Published: June 2020

Sex allocation (SA) theory in simultaneous hermaphrodites predicts that optimal SA is influenced by local sperm competition (LSC), which occurs when related sperm compete to fertilize a given set of eggs. Different factors, including the mating strategy and the ability to self-fertilize, are predicted to affect LSC and hence the optimal SA. Moreover, since the LSC experienced by an individual can vary temporally and spatially, this can favour the evolution of SA plasticity. Here, using seven species of the free-living flatworm genus Macrostomum, we document sizable interspecific variation in SA, but neither their mating strategy nor their ability to self-fertilize significantly predicted SA among these species. Since we also found considerable interspecific variation in SA plasticity, we further estimated standardized effect sizes for plasticity in response to i) the presence of mating partners (i.e. in isolation vs. with partners) and ii) the strength of LSC (i.e. in small vs. large groups). We found that self-fertilization predicted SA plasticity with respect to the presence of mating partners, with plasticity being lower for self-fertilizing species. Finally, we showed that interspecific variation in SA is higher than intraspecific variation due to SA plasticity. Our study suggests that both SA and SA plasticity are evolutionarily labile, with self-fertilization predicting the latter in Macrostomum.
ZZ Top: faster and more adaptive Z chromosome evolution in two Lepidoptera
Authors: Mongue Andrew J. , Hansen Megan E. , Walters James R.
Published: June 2020

The rate of divergence for Z or X chromosomes is theoretically predicted to be greater than autosomes, but the possible explanations for this pattern vary, as do empirical results from diverse taxa. Even among moths and butterflies (Lepidoptera), which generally share a single-origin Z chromosome, the handful of available studies give mixed support for faster or more adaptive evolution of the Z chromosome, depending on the species assayed. Here, we examine the molecular evolution of Z chromosomes in two additional lepidopteran species: the Carolina sphinx moth and the monarch butterfly, the latter of which possesses a recent chromosomal fusion yielding a segment of newly Z-linked DNA. We find evidence for both faster and more adaptive Z chromosome evolution in both species, though this effect is strongest in the neo-Z portion of the monarch sex chromosome. The neo-Z is less male-biased than expected of a Z chromosome, and unbiased and female-biased genes drive the signal for adaptive evolution here. Together these results suggest that male-biased gene accumulation and haploid selection have opposing effects on long-term rates of adaptation and may help explain the discrepancies in previous findings as well as the repeated evolution of neo-sex chromosomes in Lepidoptera.
Deep multitask learning of gene risk for comorbid neurodevelopmental disorders
Authors: Beyreli Ilayda , Karakahya Oguzhan , Cicek A. Ercument
Published: June 2020

Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) are comorbid neurodevelopmental disorders with complex genetic architectures. Despite large-scale sequencing studies only a fraction of the risk genes were identified for both. Here, we present a novel network-based gene risk prioritization algorithm named DeepND that performs cross-disorder analysis to improve prediction power by exploiting the comorbidity of ASD and ID via multitask learning. Our model leverages information from gene coexpression networks that model human brain development using graph convolutional neural networks and learns which spatio-temporal neurovelopmental windows are important for disorder etiologies. We show that our approach substantially improves the state-of-the-art prediction power in both single-disorder and cross-disorder settings. DeepND identifies prefrontal and primary motor-somatosensory cortex brain region, and periods from early fetal to mid fetal periods and from early childhood to young adulthood as the highest neurodevelopmental risk windows for both ASD and ID. Finally, we investigate frequent ASD and ID associated copy number variation regions and report our findings for several susceptibility gene candidates. DeepND can be generalized to analyze any combinations of comorbid disorders and is released athttp://github.com/ciceklab/deepnd.
SARS-CoV-2 Neutralizing Antibody Responses Are More Robust in Patients with Severe Disease
Authors: Wang Pengfei , Liu Lihong , Nair Manoj S. , Yin Michael T. , Luo Yang , Wang Qian , Yuan Ting , Mori Kanako , Solis Axel Guzman , Yamashita Masahiro , Purpura Lawrence J. , Laracy Justin C. , Yu Jian , Sodroski Joseph , Huang Yaoxing , Ho David D.
Published: June 2020

We studied plasma antibody responses of 35 patients about 1 month after SARS-CoV-2 infection. Titers of antibodies binding to the viral nucleocapsid and spike proteins were significantly higher in patients with severe disease. Likewise, mean antibody neutralization titers against SARS-CoV-2 pseudovirus and live virus were higher in the sicker patients, by ~5-fold and ~7-fold, respectively. These findings have important implications for those pursuing plasma therapy, isolation of neutralizing monoclonal antibodies, and determinants of immunity.
A temporal map of maternal immune activation-induced changes reveals a shift in neurodevelopmental timing and perturbed cortical development in mice
Authors: Canales Cesar P. , Estes Myka L. , Cichewicz Karol , Angara Kartik , Aboubechara John Paul , Cameron Scott , Prendergast Kathryn , Su-Feher Linda , Zdilar Iva , Kreun Ellie J. , Connolly Emma C. , Seo Jin M. , Goon Jack B. , Farrelly Kathleen , Stradleigh Tyler , van der List Deborah , Haapanen Lori , Van de Water Judy , Vogt Daniel , McAllister A. Kimberley , Nord Alex S.
Published: June 2020

Background

Environmental insults that activate the maternal immune system are potent primers of developmental neuropathology and maternal immune activation (MIA) has emerged as a risk factor for neurodevelopmental and psychiatric disorders. Animal models of MIA provide an opportunity to identify molecular pathways that initiate disease processes and lead to neuropathology and behavioral deficits in offspring. MIA-induced behaviors are accompanied by anatomical and neurochemical alterations in adult offspring that parallel those seen in affected human populations.

Methods

We performed transcriptional profiling and neuroanatomical characterization in a time course across mouse embryonic cortical development, following MIA via single injection of the viral mimic polyinosinic:polycytidylic acid (polyI:C) at E12.5. Transcriptional changes identified in the cortex of MIA offspring at E17.5 were validated and mapped to cortical neuroanatomy and cell types via protein analysis and immunohistochemistry.

Results

MIA induced strong transcriptomic signatures, including induction of genes associated with hypoxia, immune signaling, and angiogenesis. The acute response identified 6h after the MIA insult was followed by changes in proliferation, neuronal and glial differentiation, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cell types in germinal zones and alterations in neuronal and glial cell types across cortical lamina were identified in the MIA-exposed cortex.

Conclusions

MIA-induced transcriptomic signatures in fetal offspring overlap significantly with perturbations identified in neurodevelopmental disorders (NDDs), and provide novel insights into alterations in molecular and developmental timing processes linking MIA and neuropathology, potentially revealing new targets for development of novel approaches for earlier diagnosis and treatment of these disorders.
Calreticulin co-expression supports high level production of a recombinant SARS-CoV-2 spike mimetic inNicotiana benthamiana
Authors: Margolin Emmanuel , Verbeek Matthew , Meyers Ann , Chapman Ros , Williamson Anna-Lise , Rybicki Edward P
Published: June 2020

An effective prophylactic vaccine is urgently needed to protect against SARS-CoV-2 infection. The viral spike, which mediates entry into cells by interacting with the host angiotensin-converting enzyme 2, is the primary target of most vaccines in development. These vaccines aim to elicit protective immunity against the glycoprotein by use of inactivated virus, vector-mediated delivery of the antigenin vivo, or by direct immunization with the purified antigen following expression in a heterologous system. These approaches are mostly dependent on the growth of mammalian or insect cells, which requires a sophisticated infrastructure that is not generally available in developing countries due to the incumbent costs which are prohibitive. Plant-based subunit vaccine production has long been considered as a cheaper alternative, although low expression yields and differences along the secretory pathway to mammalian cells have posed a challenge to producing certain viral glycoproteins. Recent advances that have enabled many of these constraints to be addressed include expressing the requisite human proteins in plants to support the maturation of the protein of interest. In this study we investigated these approaches to support the production of a soluble and putatively trimeric SARS-CoV-2 spike mimetic inNicotiana benthamianavia transientAgrobacterium-mediatedexpression. The co-expression of human calreticulin dramatically improved the accumulation of the viral spike, which was barely detectable in the absence of the co-expressed accessory protein. The viral antigen was efficiently processed even in the absence of co-expressed furin, suggesting that processing may have occurred at the secondary cleavage site and was mediated by an endogenous plant protease. In contrast, the spike was not efficiently processed when expressed in mammalian cells as a control, although the co-expression of furin improved processing considerably. This study demonstrates the feasibility of molecular engineering to improve the production of viral glycoproteins in plants, and supports plant-based production of SARS-CoV-2 spike-based vaccines and reagents for serological assays.
The Human Telomeric Proteome During Telomere Replication
Authors: Lin Chih-Yi Gabriela , Näger Anna Christina , Lunardi Thomas , Vančevska Aleksandra , Lossaint Gérald , Lingner Joachim
Published: June 2020

Telomere shortening can cause detrimental diseases and contribute to aging. It occurs due to the end replication problem in cells lacking telomerase. Furthermore, recent studies revealed that telomere shortening can be attributed to difficulties of the semi-conservative DNA replication machinery to replicate through the bulk of telomeric DNA repeats. To investigate telomere replication in a comprehensive manner, we develop QTIP-iPOND, which enables purification of proteins that associate with telomeres specifically during replication. We identify in addition to the core replisome a large number of proteins that associate with telomere replication forks and validate their importance. We find that POT1 is depleted, whereas histone H1 is specifically enriched, at telomere replication forks. Our work reveals the dynamic changes of the telomeric proteome during replication, providing a valuable resource of telomere replication proteins. To our knowledge, this is the first study that examines the replisome at a specific region of the genome.
Indirect and Direct Cannabinoid Agonists Differentially Affect Mesolimbic Dopamine Release and Related Behaviors
Authors: Honeywell Kevin M. , Freels Timothy G. , McWain Megan A. , Chaffin Abigail S. , Nolen Hunter G. , Sable Helen J. , Lester Deranda B.
Published: June 2020

The cannabinoid system is being researched as a potential pharmaceutical target for a multitude of disorders. The present study examined the effect of indirect and direct cannabinoid agonists on mesolimbic dopamine release and related behaviors in C57BL/6J (B6) mice. The indirect cannabinoid agonistN-arachidonoyl serotonin (AA-5-HT) indirectly agonizes the cannabinoid system by preventing the metabolism of endocannabinoids through fatty acid amide hydrolase (FAAH) inhibition while also inhibiting transient receptor potential vanilloid type 1 (TRPV1) channels. Effects of AA-5-HT were compared with the direct cannabinoid receptor type 1 (CB1R) agonist arachidonoyl-2’-chloroethylamide (ACEA). In Experiment 1, mice were pretreated with 7 daily injections of AA-5-HT, ACEA, or vehicle prior to assessments of locomotor activity using open field (OF) testing and phasic dopamine release usingin vivofixed potential amperometry. Chronic exposure to AA-5-HT did not alter locomotor activity or mesolimbic dopamine functioning. Chronic exposure to ACEA did not alter locomotor activity but did decrease phasic dopamine release while increasing the dopaminergic response to cocaine. In Experiment 2, mice underwent AA-5-HT, ACEA, or vehicle conditioned place preference (CPP) then saccharin preference testing, a measure commonly associated with anhedonia. Mice did not develop a CPP or aversion for AA-5-HT or ACEA, and repeated exposure to AA-5-HT or ACEA did not alter saccharin preference. Altogether, the findings suggest that neither of these drugs induce behaviors that are classically associated with abuse liability in mice; however, direct CB1R agonism may play more of a role in mediating mesolimbic dopamine functioning than indirect cannabinoid agonism.
Analytical solution for active pressure of narrow backfills considering arching effect
Authors: Ghobadi Sahar , Shahir Hadi
Published: June 2020

Purpose

The purpose of this paper is to study the distribution of active earth pressure in retaining walls with narrow cohesion less backfill considering arching effects.

Design/methodology/approach

To this end, the approach of principal stresses rotation was used to consider the arching effects.

Findings

According to the presented formulation, the active soil pressure distribution is nonlinear with zero value at the wall base. The proposed formulation implies that by increasing the frictional forces at both sides of the backfill, the arching effect is increased and so, the lateral earth pressure on the retaining wall is decreased. Also, by narrowing the backfill space, the lateral earth pressure is extremely decreased.

Originality/value

A comprehensive analytical solution for the active earth pressure of narrow backfills is presented, such that the effects of the surcharge and the characteristics of the stable back surface are considered. The magnitude and height of the application of lateral active force are also derived.
A model for examining the effects of communication on innovation performance: emphasis on the intermediary role of strategic decision-making speed
Authors: Rahimnia Fariborz , Molavi Homa
Published: June 2020

Purpose

In recent years, rapid changes in the economic situation and high levels of competition have increased the need for innovation in order to gain success. In such circumstances, organizational strategists are considered as critical in determining the success or failure of organizations. Using innovation in various aspects of organizational operations is the most important factor to achieve sustainable competitive advantages in industry. As a result, analyzing the effective factors involved in promoting the efficiency of innovative activities in the organization and ways of achieving it are of utmost importance. Thus, this paper examines the relationship between communication and innovation performance with respect to the intermediary role of strategic decision-making process speed.

Design/methodology/approach

The present study has used quantitative methodology and questionnaire to collect data from 450 managers and members who are involved in the decision-making process in 150 companies operating in the food-industry sector. Data analysis was done by using structural equation modeling and AMOS software.

Findings

The results of the data analysis suggest that communication and strategic decision-making speed possess a significant positive impact on innovation performance. Also, strategic decision-making speed has sufficiently played the intermediary role between communication and innovation performance.

Originality/value

This survey specifies the effects of communication on the success of making fast strategic decision and innovation performance which aid Iranian food companies to tackle one of the managerial challenges: postponing strategic decisions due to lack of efficient communication to get information. In addition, to the best of the authors' knowledge, this essay is a first in Iran.
Does climate for creativity mediate the impact of servant leadership on management innovation and innovative behavior in the hotel industry?
Authors: Karatepe Osman M. , Aboramadan Mohammed , Dahleez Khalid Abed
Published: June 2020

Purpose

Drawing from theory of organizational creativity, servant leadership (SEL), social exchange and social learning theories, this paper aims to propose a research model where climate for creativity mediates the influence of SEL on management innovation and innovative behavior. The model also investigates the linkage between innovative behavior and management innovation.

Design/methodology/approach

Data collected from Arab hotel employees in Palestine were used to gauge the aforesaid linkages through structural equation modeling. Common method variance was checked through an unmeasured latent method factor.

Findings

The results reveal that climate for creativity mediates the impact of SEL on management innovation and innovative behavior. Successful SEL practices enable the organization to have climate for creativity, which, in turn, leads to management innovation and innovative behavior. Furthermore, hotel employees’ innovative behavior fosters management innovation.

Practical implications

Top management should have a high level of commitment to the SEL philosophy, which boosts climate for creativity and innovative behavior. It should also capitalize on climate for creativity to activate management innovation. In such an environment, management has to ensure that the supervisors are servant leaders and non-managerial employees are the potential servant leaders. Once employees are trained, empowered and rewarded in an environment which highlights effective SEL practices, they will be more eager to contribute to the company by exhibiting innovative behavior at elevated levels.

Originality/value

Despite a number of studies in the current literature, evidence concerning the effect of SEL on management innovation and innovative behavior simultaneously is scarce. There is still a dearth of evidence pertaining to the underlying mechanism through which SEL fosters management innovation and innovative behavior. In addition, evidence appertaining to the impact of innovative behavior on management innovation is scarce. The study fills in these voids.
Teacher's withdrawal behavior: examining the impact of principals' innovative behavior and climate of organizational learning
Authors: Da'as Rima'a , Watted Abeer , Barak Miri
Published: June 2020

Purpose

The study aims to test an innovative model that explores the direct and indirect relationships between principals' innovative behavior, climate of organizational learning and a teacher's intent to leave his or her school and take a voluntary absence.

Design/methodology/approach

Data were collected from a survey of 1,529 teachers from 107 Arab elementary schools randomly selected from the database of the Israeli educational system. To test the proposed multilevel model, we conducted multilevel structural equation modeling (ML-SEM).

Findings

The analysis confirmed that organizational learning climate is a prominent mediator between principals' innovative behavior and a teacher's intent to leave and his/her voluntary absence.

Originality/value

This research advances our understanding of leaders' innovative construct in an educational context and adds to the body of research directed at identifying administrative support and work-related factors that may negatively relate to a teacher's absenteeism or intent to leave and are amenable to leadership intervention.