bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of spontaneous firing of fusiform neurons from the dorsal cochlear nucleus of mice occurs after hearing onset
Authors: Benites Nikollas M. , Rodrigues Beatriz , Silveira Carlos H. , Leão Ricardo M. 
Published: September 2021

AbstractThe dorsal cochlear nucleus (DCN) in the auditory brainstem integrates auditory and somatosensory information. Mature fusiform neurons express two qualitative intrinsic states in equal proportions: quiet, with no spontaneous regular action potential firing, or active, with regular spontaneous action potential firing. However, how these firing states and other electrophysiological properties of fusiform neurons develop during early postnatal days to adulthood is not known. Thus, we recorded fusiform neurons from mice from P4 to P21 and analyzed their electrophysiological properties. In the pre-hearing phase (P4-P13), we found that fusiform neurons are mostly quiet, with the active state emerging after hearing onset at P14. Subthreshold properties present more variations before hearing onset, while action potential properties vary more after P14, developing bigger, shorter, and faster action potentials. Interestingly, the activity threshold is more depolarized in pre-hearing cells suggesting that persistent sodium current (INaP) increases its expression after hearing. In fact, INaP increases its expression after hearing, accordingly with the development of active neurons. Thus, we suggest that the post-hearing expression of INaP creates the active state of the fusiform neuron. At the same time, other changes refine the passive membrane properties and increase the speed of action potential firing of fusiform neurons.
Prevalent uses and evolution of exonic regulatory sequences in the human genome
Authors: Chen Jing , Ni Pengyu , Niu Meng , Guo Jun-tao , Su Zhengsheng 
Published: September 2021

AbstractBackgroundIt has long been known that exons can be used as cis-regulatory sequences such as enhancers. However, the prevalence of such dual-use of exons and how they evolve remain elusive. Our recently predicted highly accurate, large sets of cis-regulatory module candidates (CRMCs) and non-CRMCs in the human genome positioned us to address these questions.ResultsWe found that exonic transcription factor binding sites (TFBSs) occupied at least a third of the total exon lengths, and 96.7% of genes had exonic TFBSs. Both A/T and C/G in exonic TFBSs are more likely under evolutionary constraints than those in non-CRMC exons. Interestingly, exonic TFBSs in codons tend to encode loops rather than more critical helices and strands in protein structures, while exonic TFBSs in untranslated regions (UTRs) tend to avoid positions where known UTR-related functions are located. Moreover, active exonic TFBSs tend to be in close physical proximity to distal promoters whose immediately downstream genes have elevated transcription levels, suggesting that they might be involved in transcriptional regulation of target genes. It is highly possible that less critical positions in an exon that is physically close to a promoter can evolve into a TFBS when no non-exonic sequences are physically available to the promoter.ConclusionsExonic TFBSs might be more prevalent than originally thought and are likely in dual-use. Possible detrimental effects caused by such dual-use can be reduced by using less critical exonic positions. We proposed a parsimonious model to explain how a stretch of codons evolve into a TFBS.
Dominant carnivore loss benefits native avian and invasive mammalian scavengers
Authors: Fielding Matthew W. , Cunningham Calum X. , Buettel Jessie C. , Stojanovic Dejan , Jones Menna E. , Brook Barry W. 
Published: September 2021

AbstractScavenging by large carnivores is integral for ecosystem functioning by limiting the build-up of carrion and facilitating widespread energy flows. However, top carnivores have declined across the world, triggering trophic shifts within ecosystems. In this study, we use a natural ‘removal experiment’ of disease-driven decline and island extirpation of native mammalian (marsupial) carnivores to investigate top-down control on utilisation of experimentally placed carcasses by two mesoscavengers – the invasive feral cat and native forest raven. Ravens were the main beneficiary of carnivore loss, scavenging for five times longer in the absence of native mammalian carnivores. Cats scavenged on almost half of all carcasses in the region without dominant native carnivores. This was eight times more than in areas where other carnivores were at high densities. In the absence of native mammalian carnivores, all carcasses persisted in the environment for 3 weeks. Our results reveal the efficiency of carrion consumption by mammalian scavengers. These services are not readily replaced by less-efficient facultative scavengers. This demonstrates the significance of global carnivore conservation and supports novel management approaches, such as rewilding in areas where the natural suite of carnivores is missing.
SARS-CoV-2 originated from SARS-CoV-1-related Bat-CoVs through Pan-CoVs rather than from SARS-CoV-2-related Bat-CoVs
Authors: Desingu Perumal Arumugam , Nagarajan K. 
Published: September 2021

AbstractThe emergence of the novel SARS-CoV-2 in 2019 sparked a dispute concerning its origin. Here, we report that the SARS-CoV-2 originated through pangolin-coronavirus (Pan-CoVs) from the SARS-CoV-related-bat-coronaviruses (SARS-CoV-1-rB-CoVs) rather than from SARS-CoV-2-related-bat-coronaviruses (SARS-CoV-2-rB-CoVs), in contrast to the previous thought. Further, our analyses strongly suggest that the Pan-CoVs evolved from the SARS-CoV-1-rB-CoVs without recombination. Further, our results suggest that the SARS-CoV-1-rB-CoVs’ perhaps jumped into the pangolin, which forced the viruses to mutate and adapt to the new host, and resulted in the origin of Pan-CoVs. Surprisingly, the Pan-CoVs formed an evolutionary intermediate between SARS-CoV-2 and SARS-CoV-2-rB-CoVs at the spike gene. Our findings also suggest that the Pan-CoV/GX and Pan-CoV/Guangdong lineages recombined to form the SARS-CoV-2 spike gene. We also found evidence that the SARS-CoV-2-rB-CoVs spike gene evolved via recombination between Pan-CoV/Guangdong and SARS-CoV-1-rB-CoVs. Overall, our findings suggest that the SARS-CoV-2 emerged from SARS-CoV-1-rB-CoVs through host jumping.
Assembly formation is stabilized by Parvalbumin neurons and accelerated by Somatostatin neurons
Authors: Lagzi Fereshteh , Bustos Martha Canto , Oswald Anne-Marie , Doiron Brent 
Published: September 2021

AbstractLearning entails preserving the features of the external world in the neuronal representations of the brain, and manifests itself in the form of strengthened interactions between neurons within assemblies. Hebbian synaptic plasticity is thought to be one mechanism by which correlations in spiking promote assembly formation during learning. While spike timing dependent plasticity (STDP) rules for excitatory synapses have been well characterized, inhibitory STDP rules remain incomplete, particularly with respect to sub-classes of inhibitory interneurons. Here, we report that in layer 2/3 of the orbitofrontal cortex of mice, inhibition from parvalbumin (PV) interneurons onto excitatory (E) neurons follows a symmetric STDP function and mediates homeostasis in E-neuron firing rates. However, inhibition from somatostatin (SOM) interneurons follows an asymmetric, Hebbian STDP rule. We incorporate these findings in both large scale simulations and mean-field models to investigate how these differences in plasticity impact network dynamics and assembly formation. We find that plasticity of SOM inhibition builds lateral inhibitory connections and increases competition between assemblies. This is reflected in amplified correlations between neurons within assembly and anti-correlations between assemblies. An additional finding is that the emergence of tuned PV inhibition depends on the interaction between SOM and PV STDP rules. Altogether, we show that incorporation of differential inhibitory STDP rules promotes assembly formation through competition, while enhanced inhibition both within and between assemblies protects new representations from degradation after the training input is removed.
Myelin speeds cortical oscillations by consolidating phasic parvalbumin-mediated inhibition
Authors: Dubey Mohit , Pascual-Garcia Maria , Helmes Koke , Wever Dennis D. , Hamada Mustafa S. , Kushner Steven A. , Kole Maarten H. P. 
Published: September 2021

SummaryParvalbumin-positive (PV+) γ-aminobutyric acid (GABA) interneurons are critically involved in producing rapid network oscillations and cortical microcircuit computations but the significance of PV+ axon myelination to the temporal features of inhibition remains elusive. Here using toxic and genetic models of demyelination and dysmyelination, respectively, we find that loss of compact myelin reduces PV+ interneuron presynaptic terminals, increases failures and the weak phasic inhibition of pyramidal neurons abolishes optogenetically driven gamma oscillations in vivo. Strikingly, during periods of quiet wakefulness selectively theta rhythms are amplified and accompanied by highly synchronized interictal epileptic discharges. In support of a causal role of impaired PV-mediated inhibition, optogenetic activation of myelin-deficient PV+ interneurons attenuated the power of slow theta rhythms and limited interictal spike occurrence. Thus, myelination of PV axons is required to consolidate fast inhibition of pyramidal neurons and enable behavioral state-dependent modulation of local circuit synchronization.
CRISPR screens identify gene targets and drug repositioning opportunities at breast cancer risk loci
Authors: Tuano Natasha K , Beesley Jonathan , Manning Murray , Shi Wei , Malaver-Ortega Luis F , Paynter Jacob , Black Debra , Civitarese Andrew , McCue Karen , Hatzipantelis Aaron , Hillman Kristine , Kaufmann Susanne , Sivakumaran Haran , Polo Jose M , Reddel Roger , Band Vimla , French Juliet D , Edwards Stacey L , Powell David , Chenevix-Trench Georgia , Rosenbluh Joseph 
Published: September 2021

SummaryGenome-wide association studies (GWAS) have identified >200 loci associated with breast cancer (BC) risk. The majority of candidate causal variants (CCVs) are in non-coding regions and are likely to modulate cancer risk by regulating gene expression. We recently developed a scoring system, INQUISIT, to predict candidate risk genes at BC-risk loci. Here, we used pooled CRISPR activation and suppression screens to validate INQUISIT predictions, and to define the cancer phenotypes they mediate. We measured proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on the DNA damage response. We performed 60 CRISPR screens and identified 21 high-confidence INQUISIT predictions that mediate a cancer phenotype. We validated the direct regulation of a subset of genes by BC-risk variants using HiCHIP and CRISPRqtl. Furthermore, we show the utility of expression profiling for drug repurposing against these targets. We provide a platform for identifying gene targets of risk variants, and lay a blueprint of interventions for BC risk reduction and treatment.
MTCL2 promotes asymmetric microtubule organization by crosslinking microtubules on the Golgi membrane
Authors: Matsuoka Risa , Miki Masateru , Mizuno Sonoko , Ito Yurina , Yamada Chihiro , Suzuki Atsushi 
Published: September 2021

AbstractThe Golgi complex plays an active role in organizing asymmetric microtubule arrays essential for polarized vesicle transport. The coiled-coil protein MTCL1 stabilizes microtubules nucleated from the Golgi membrane. Here, we report an MTCL1 paralog, MTCL2, which preferentially acts on the perinuclear microtubules accumulated around the Golgi. MTCL2 associates with the Golgi membrane through the N-terminal coiled-coil region and directly binds microtubules through the conserved C-terminal domain without promoting microtubule stabilization. Knockdown of MTCL2 significantly impaired microtubule accumulation around the Golgi as well as the compactness of the Golgi ribbon assembly structure. Given that MTCL2 forms parallel oligomers through homo-interaction of the central coiled-coil motifs, our results indicate that MTCL2 promotes asymmetric microtubule organization by crosslinking microtubules on the Golgi membrane. Results of in vitro wound healing assays further suggest that this function of MTCL2 enables integration of the centrosomal and Golgi-associated microtubules on the Golgi membrane, supporting directional migration. Additionally, the results demonstrated the involvement of CLASPs and giantin in mediating the Golgi association of MTCL2.
BMSC-Derived Exosomal MiRNAs Can Modulate Bone Restoration in Diabetic Rats with Femoral Defects
Authors: Wang Ning , Liu Xuanchen , Tang Zhen , Wei Xinghui , Dong Hui , Liu Yichao , Wu Hao , Wu Zhigang , Li Xiaokang , Ma Xue , Guo Zheng 
Published: September 2021

AbstractThe exosomal miRNAs of BMSCs participate in hyperglycemia induced poor healing of bone defects. Here, we demonstrate that exosomes derived from BMSCs harvested from diabetes mellitus(DM) rats suppressed bone formation when administered to normal rats with bone defects. Using high-throughput sequencing analysis of microRNA molecules, high miR-140-3p levels were expressed in exosomes released by N-BMSCs. Using TargetScan software and luciferase activity assays,plxnb1was identified as the downstream molecular target of exosomal miR-140-3p that regulated osteogenesis. Transplantation of exosomes that overexpressed miR-140-3p into DM rats promoted the restoration of bone defects. Furthermore, miR-140-3p significantly promoted the differentiation of DM-BMSCs into osteoblasts and inhibited the expression p-RohA and p-ROCK in the plexin B1 signaling pathway. Taken together, these observations suggest that DM decreases the levels of exosomal miR-140-3p, which impedes bone formation and the differentiation of BMSCs. MiR-140-3p may represent a potential therapeutic target for DM related to abnormal bone metabolism.
Can two wrongs make a right? F508del-CFTR ion channel rescue by second-site mutations in its transmembrane domains
Authors: Prins Stella , Corradi Valentina , Sheppard David N. , Tieleman D. Peter , Vergani Paola 
Published: September 2021

AbstractDeletion of phenylalanine 508 (F508del), in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel, is the most common cause of cystic fibrosis (CF). F508 is located on nucleotide-binding domain 1 (NBD1) in contact with cytosolic extensions of transmembrane helices, in particular intracellular loop 4 (ICL4). We carried out a mutagenesis scan of ICL4 by introducing five or six second-site mutations at eleven positions in cis with F508del, and quantifying changes in membrane proximity and ion-channel function of CFTR. The scan strongly validated the effectiveness of R1070W at rescuing F508del defects. Molecular dynamics simulations highlighted two features characterizing the ICL4/NBD1 interface of F508del/R1070W-CFTR: flexibility, with frequent transient formation of interdomain hydrogen bonds, and loosely stacked aromatic sidechains, (F1068, R1070W, and F1074, mimicking F1068, F508 and F1074 in wild-type CFTR). F508del-CFTR had a distorted aromatic stack, with F1068 displaced towards space vacated by F508. In F508del/R1070F-CFTR, which largely retained F508del defects, R1070F could not form hydrogen bonds, and the interface was less flexible. Other ICL4 second-site mutations which partially rescued F508del-CFTR are F1068M and F1074M. Methionine side chains allow hydrophobic interactions without the steric rigidity of aromatic rings, possibly conferring flexibility to accommodate the absence of F508 and retain a dynamic interface. Finally, two mutations identified in a yeast scan (A141S and R1097T, on adjacent transmembrane helices linked to ICL1 and ICL4) also partially rescued F508del-CFTR function. These studies highlight the importance of hydrophobic interactions and conformational flexibility at the ICL4/NBD1 interface, advancing understanding of the structural underpinning of F508del dysfunction.
The birth-and-death evolution of cytochrome P450 genes in bees
Authors: Darragh Kathy , Nelson David R. , Ramírez Santiago R. 
Published: September 2021

AbstractThe birth-and-death model of multigene family evolution describes how families can expand by duplication and contract by gene deletion and formation of pseudogenes. The phylogenetic stability of a gene is thought to be related to the degree of functional importance. However, it is unclear how much evolution of a gene in a gene family is driven by adaptive versus neutral processes. The cytochrome P450s are one of the most diverse and well-studied multigene families, involved in both physiological and xenobiotic functions. Bees have a high toxin exposure due to their diet of nectar and pollen, as well as the resin-collecting behavior exhibited by some bees. Here, we describe the P450s of the orchid bee Euglossa dilemma. Orchid bees are a neotropical clade in which males form perfume bouquets used in courtship displays by collecting a diverse set of volatile compounds, resulting in high chemical compound exposure. We conducted phylogenetic and selection analyses across ten bee species encompassing three bee families. We do not find a relationship between the ecology of a bee species and its P450 repertoire. Our analyses reveal that P450 clades can be classified into stable and unstable clades, and that genes involved in xenobiotic metabolism are more likely to belong to unstable clades. Furthermore, we find that unstable clades are under more dynamic evolutionary pressures, with signals of adaptive evolution detected, suggesting that both gene duplication and positive selection driving sequence divergence have played a role in the diversification of bee P450s. Our works highlights the complexity of multigene family evolution which does not always follow generalized predictions.Significance statementGene family evolution is characterized by deletion and duplication, but it is unclear if this is driven by adaptive or neutral evolutionary processes. To investigate the dynamics of gene family evolution we analyze the P450s of ten bee species, a well-studied gene family involved in both physiological and detoxification roles. We find that genes involved in detoxification are more likely to belong to unstable clades, exhibit dynamic evolutionary pressures, and show signals of adaptive evolution. However, we do not find evidence for a relationship between resin collection or sociality, and the P450 repertoire of a bee species. Our findings highlight the complexity of multigene family evolution which does not always follow generalized predictions.
Effective expression analysis using gene interaction matrices and convolutional neural networks
Authors: Pillai Arvind , Grabowski Piotr , John Bino 
Published: September 2021

AbstractArtificial intelligence recently experienced a renaissance with the advancement of convolutional neural networks (CNNs). CNNs require spatially meaningful matrices (e.g., image data) with recurring patterns, limiting its applicability to high-throughput omics data. We present GIM, a simple, CNN-ready framework for omics data to detect both individual and network-level entities of biological importance. Using gene expression data, we show that GIM-CNNs can outperform comparable neural networks in performance and their design facilitates network-level interpretability. GIM-CNNs provide a means to discover novel disease-relevant factors beyond individual genes and their expression, factors that are likely missed by standard differential gene expression approaches.
A G-lectin Receptor Kinase is a Negative Regulator of Arabidopsis Immunity Against Root-Knot Nematode Meloidogyne incognita
Authors: Zhou Dongmei , Godinez-Vidal Damaris , He Jiangman , Teixeira Marcella , Guo Jingzhe , Wei Lihui , Van Norman Jaimie M. , Kaloshian Isgouhi 
Published: September 2021

AbstractRoot-knot nematodes (Meloidogyne spp., RKN) are responsible for extensive crop losses worldwide. For infection, they penetrate plant roots, migrate between plant cells, and establish feeding sites, known as giant cells, in the root pericycle. Previously, we found that nematode perception and early plant responses were similar to those for microbial pathogens and require the BAK1 co-receptor in Arabidopsis thaliana and tomato. To identify additional receptors involved in this process, we implemented a reverse genetic screen for resistance or sensitivity to RKN using Arabidopsis T-DNA alleles of genes encoding transmembrane receptor-like kinases. This screen identified a pair of allelic mutations with enhanced resistance to RKN in a gene we named ENHANCED RESISTANCE TO NEMATODES 1 (ERN1). ERN1 encodes a G-type lectin receptor kinase (G-LecRK) with a single pass transmembrane domain. Further characterization showed that ern1 mutants displayed stronger activation of MAP kinases, elevated levels of the defense marker MYB51, and enhanced H202 accumulation in roots upon RKN elicitor treatments. Elevated MYB51 expression and ROS burst were also observed in leaves of ern1 mutants upon flg22 treatment. Complementation of ern1.1 with 35S- or native promotor-driven ERN1 rescued the RKN infection and enhanced defense phenotypes. Taken together, our results indicate that ERN1 is an important negative regulator of immunity.One sentence summaryA plasma membrane localized G-lectin receptor kinase acts as a negative immune regulator by interfering with defense responses activated by nematode and microbial elicitors.
Are andragogy and heutagogy the secret recipe for transdisciplinary entrepreneurship education?
Authors: Martínez Lizbeth , Muñoz Jaime 
Published: September 2021

Purpose
This study aims to construct an entrepreneurship educational pattern applicable to all disciplines at the undergraduate level. The proposal focusses on two-course models of transdisciplinary entrepreneurship education (TEE), which involve andragogy and heutagogy as the basis of entrepreneurial competency development.

Design/methodology/approach
The competencies acquired during the proposed course models for TEE are analysed through Bayesian methods. The study is conducted using 400 opinions of students from Tecnologico de Monterrey in Mexico City.

Findings
The proposed TEE models are auspicious for establishing an educational pattern to develop entrepreneurship competencies in undergraduate students with the independence of their school of origin.

Originality/value
Nowadays, universities recognise the importance of providing entrepreneurship education as part of their mission. However, well-defined canons to guide such teaching are still non-existent. This paper fills a gap on what and how to teach TEE. By providing a new competency classification based on soft and technical skills, the authors contribute to the pattern of what to teach in entrepreneurship. The authors provide guidance on the teaching methods for TEE through two-course models based on andragogy and heutagogy. Moreover, their efficacy is measured using the students’ perception of the acquired competencies and their usefulness.