bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular and morphological analyses support recognition ofProstanthera volucris(Lamiaceae), a new species from the Central Tablelands of New South Wales
Authors: O’Donnell Ryan P. , Bruhl Jeremy J. , Telford Ian R.H. , Wilson Trevor C. , Zimmer Heidi C. , Taseski Guy M. , Andrew Rose L. 
Published: December 2021

AbstractResearch into the systematics ofProstantherahas recently revealed a close evolutionary relationship amongP. phylicifolia s. str., the critically endangeredP. gilesii, and a population of uncertain identity from the Central Tablelands of New South Wales, Australia. Previous analyses were unable to establish whether genetic boundaries separated these taxa. This study aimed to assess the species boundaries among these three taxa using a combination of single-nucleotide polymorphisms (SNP) sampled at the population-scale and multivariate analysis of morphological characters. Non-parametric and parametric statistics, neighbour-network analysis, phylogenetic analysis, and ancestry coefficient estimates all provided support for discrete genetic differences between the three taxa. Morphological phenetic analysis identified a suite of characters that distinguished each of these taxa. This corroboration of evidence supports the presence of three independently evolving lineages.Prostanthera gilesiiandP. phylicifolia s. str.are distinct species independent from the third taxon which is described here asP. volucrisR.P.O’Donnell. A detailed description, diagnostic line drawings and photographs are provided. We evaluateP. volucrisas satisfying criteria to be considered Critically Endangered.
Single spikes drive sequential propagation and routing of activity in a cortical network
Authors: Riquelme Juan Luis , Hemberger Mike , Laurent Gilles , Gjorgjieva Julijana 
Published: December 2021

AbstractSingle spikes can trigger repeatable firing sequences in cortical networks. The mechanisms that support reliable propagation of activity from such small events and their functional consequences remain unclear. By constraining a recurrent network model with experimental statistics from turtle cortex, we generate reliable and temporally precise sequences from single spike triggers. We find that rare strong connections support sequence propagation, while dense weak connections modulate propagation reliability. We identify sections of sequences corresponding to divergent branches of strongly connected neurons which can be selectively gated. Applying eternal inputs to specific neurons in the sparse backbone of strong connections can effectively control propagation and route activity within the network. Finally, we demonstrate that concurrent sequences interact reliably, generating a highly combinatorial space of sequence activations. Our results reveal the impact of individual spikes in cortical circuits, detailing how repeatable sequences of activity can be triggered, sustained, and controlled during cortical computations.
Alcohol availability during withdrawal gates the impact of alcohol vapor exposure on responses to alcohol cues
Authors: Carpio M.J. , Gao Runbo , Wooner Erica , Cayton Christelle A. , Richard Jocelyn M. 
Published: December 2021

AbstractBackgroundChronic intermittent ethanol (CIE) vapor inhalation is a widely used model of alcohol dependence, but the impact of CIE on cue-elicited alcohol seeking is not well understood. Here, we assessed the effects of CIE on alcohol-seeking elicited by previously learned cues, and on acquisition of new cue-alcohol associations.MethodsIn Experiment 1, male and female Long Evans rats were first trained in a discriminative stimulus (DS) task, in which one auditory cue (the DS) predicts the availability of 15% ethanol and a control cue (the NS) predicts nothing. Rats then underwent CIE or served as controls. Subsets of each group received access to oral ethanol twice a week during acute withdrawal. After CIE, rats were presented with the DS and NS cues under extinction and retraining conditions to determine whether they would alter their responses to these cues. In Experiment 2, rats underwent CIE prior to training in the DS task. We also assessed alcohol consumption, aversion-resistant drinking, somatic withdrawal symptoms, and behavior in an open field.ResultsWe found that CIE enhanced behavioral responses to previously learned alcohol cues, but only in rats that received access to alcohol during acute withdrawal. CIE disrupted cue responses in rats that did not. When CIE occurred before cue learning, male rats were slower to develop cue responses and less likely to enter the alcohol port, even though they had received alcohol during acute withdrawal. We also found that CIE increased alcohol consumption and aversion-resistant drinking in male but not female rats.ConclusionsThese results suggest that CIE alone does not potentiate the motivational value of alcohol cues, but that an increase in cue responses requires the potentiation of the value of alcohol during acute withdrawal. Further, under some conditions CIE may disrupt responses to previously learned and subsequently acquired alcohol cues.
SerpinB3 drives cancer stem cell survival in glioblastoma
Authors: Lauko Adam , Volovetz Josephine , Turaga Soumya M. , Bayik Defne , Silver Daniel J. , Mitchell Kelly , Mulkearns-Hubert Erin E. , Watson Dionysios C. , Desai Kiran , Midha Manav , Hao Jing , McCortney Kathleen , Steffens Alicia , Naik Ulhas , Ahluwalia Manmeet S. , Bao Shideng , Horbinski Craig , Yu Jennifer , Lathia Justin D. 
Published: December 2021

AbstractDespite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC therapeutic resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. The knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. Mechanistically, SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced with radiation. Finally, we found that SerpinB3 knockdown dramatically increased the efficacy of radiation in pre-clinical models. Taken together, our findings identify a novel GBM CSC-specific survival mechanism involving a previously uninvestigated cysteine protease inhibitor, SerpinB3, and provide a potential target to improve the efficacy of standard-of-care GBM therapies against therapeutically resistant CSCs.SummaryLauko et al. demonstrate a functional role for SerpinB3, which is elevated in glioblastoma cancer stem cells and protects against lysosomal-mediated cell death. SerpinB3 can be targeted to increase the efficacy of radiation in glioblastoma pre-clinical models.
The role of the angular gyrus in semantic cognition – A synthesis of five functional neuroimaging studies
Authors: Kuhnke Philipp , Chapman Curtiss A. , Cheung Vincent K.M. , Turker Sabrina , Graessner Astrid , Martin Sandra , Williams Kathleen A. , Hartwigsen Gesa 
Published: December 2021

AbstractSemantic knowledge is central to human cognition. The angular gyrus (AG) is widely considered a key brain region for semantic cognition. However, the role of the AG in semantic processing is controversial. Key controversies concern response polarity (activation vs. deactivation) and its relation to task difficulty, lateralization (left vs. right AG), and functional-anatomical subdivision (PGa vs. PGp subregions). Here, we combined the fMRI data of five studies on semantic processing (n = 172) and analyzed the response profiles from the same anatomical regions-of-interest for left and right PGa and PGp. We found that the AG was consistently deactivated during non-semantic conditions, whereas response polarity during semantic conditions was inconsistent. However, the AG consistently showed relative response differences between semantic and non-semantic conditions, and between different semantic conditions. A combined analysis across all studies revealed that AG responses could be best explained by separable effects of task difficulty and semantic processing demand. Task difficulty effects were stronger in PGa than PGp, regardless of hemisphere. Semantic effects were stronger in left than right AG, regardless of subregion. These results suggest that the AG is engaged in both domain-general task-difficulty-related processes and domain-specific semantic processes. In semantic processing, we propose that left AG acts as a “multimodal convergence zone” that binds different semantic features associated with the same concept, enabling efficient access to task-relevant features.
Alignment of genetic differentiation across trophic levels in a fig community
Authors: Woodruff Gavin C. , Willis John H. , Phillips Patrick C. 
Published: December 2021

SummaryEcological interactions can generate close associations among species, which can in turn generate a high degree of overlap in their spatial distributions. Co-occurrence is likely to be particularly intense when species exhibit obligate comigration, in which they not only overlap in spatial distributions but also travel together from patch to patch. In theory, this pattern of ecological co-occurrence should leave a distinct signature in the pattern of genetic differentiation within and among species. Perhaps the most famous mutual co-isolation partners are fig trees and their co-evolved wasp pollinators. Here, we add another tropic level to this system by examining patterns of genomic diversity in the nematodeCaenorhabditis inopinata, a close relative of theC. elegansmodel system that thrives in figs and obligately disperses on fig wasps. We performed RADseq on individual worms isolated from the field across three Okinawan island populations. The male/femaleC. inopinatais about five times more diverse than the hermaphroditicC. elegans, and polymorphism is enriched on chromosome arms relative to chromosome centers.FSTis low among island population pairs, and clear population structure could not be easily detected among figs, trees, and islands, suggesting frequent migration of wasps between islands. Moreover, inbreeding coefficients are elevated inC. inopinata, consistent with field observations suggesting smallC. inopinatafounding populations in individual figs. These genetic patterns inC. inopinataoverlap with those previously reported in its specific fig wasp vector and are consistent withC. inopinatapopulation dynamics being driven by wasp dispersal. Thus, interspecific interactions can align patterns of genetic diversity across species separated by hundreds of millions of years of evolutionary divergence.HighlightsThe fig-dwelling female/male nematodeCaenorhabditis inopinatais five times more diverse than its closest relative, the self-fertilizing nematodeC. elegans.C. inopinatamigrates frequently among three Okinawan islands despite high levels of inbreeding within individual figs.C. inopinatahas patterns of genetic diversity that mirror its fig wasp vector.Ecological specialization aligns patterns of genetic differentiation in closely interacting species.
Comprehensive Fitness Landscape of a Multi-Geometry Protein Capsid Informs Machine Learning Models of Assembly
Authors: Brauer Daniel D. , Santiago Celine B. , Merz Zoe N. , McCarthy Esther , Tullman-Ercek Danielle , Francis Matthew B. 
Published: December 2021

AbstractVirus-like particles (VLPs) are non-infections viral-derived nanomaterials poised for biotechnological applications due to their well-defined, modular self-assembling architecture. Although progress has been made in understanding the complex effects that mutations may have on VLPs, nuanced understanding of the influence particle mutability has on quaternary structure has yet to be achieved. Here, we generate and compare the apparent fitness landscapes of two capsid geometries (T=3 and T=1 icosahedral) of the bacteriophage MS2 VLP. We find significant shifts in mutability at the symmetry interfaces of the T=1 capsid when compared to the wildtype T=3 assembly. Furthermore, we use the generated landscapes to benchmark the performance of in silico mutational scanning tools in capturing the effect of missense mutation on complex particle assembly. Finding that predicted stability effects correlated relatively poorly with assembly phenotype, we used a combination of de novo features in tandem with in silico results to train machine learning algorithms for the classification of variant effects on assembly. Our findings not only reveal ways that assembly geometry affects the mutable landscape of a self-assembled particle, but also establish a template for the generation of predictive mutational models of self-assembled capsids using minimal empirical training data.
Evolution of Gram+ Streptococcus pyogenes has maximized efficiency of the Sortase A cleavage site
Authors: Readnour Bradley M. , Ayinuola Yetunde A. , Russo Brady T. , Liang Zhong , Fischetti Vincent A. , Ploplis Victoria A. , Lee Shaun W. , Castellino Francis J. 
Published: December 2021

ABSTRACTHuman plasminogen (hPg)-binding M-protein (PAM), a major virulence factor of Pattern D Streptococcus pyogenes (GAS), is the primary receptor responsible for binding and activating hPg. PAM is covalently bound to the cell wall (CW) through cell membrane (CM)-resident sortase A (SrtA)-catalyzed cleavage of the PAM-proximal C-terminal LPST↓-GEAA motif present immediately upstream of its transmembrane domain (TMD), and subsequent transpeptidation to the CW. These steps expose the N-terminus of PAM to the extracellular milieu (EM) to interact with PAM ligands, e.g., hPg. Previously, we found that inactivation of SrtA showed little reduction in functional binding of PAM to hPg, indicating that PAM retained in the cell membrane (CM) by the TMD nonetheless exposed its N-terminus to the EM. In the current study, we assessed the effects of mutating the Thr4 (P1) residue of the SrtA-cleavage site in PAM (Thr355 in PAM) to delay PAM in the CM in the presence of SrtA. Using rSrtA in vitro, LPSYGEAA and LPSWGEAA peptides were shown to have low activities, while LPSTGEAA had the highest activity. Isolated CM fractions of AP53/ΔSrtA cells showed that LPSYGEAA and LPSWGEAA peptides were cleaved at substantially faster rates than LPSTGEAA, even in CMs with an AP53/ΔSrtA/PAM[T355Y] double mutation, but the transpeptidation step did not occur. These results implicate another CM-resident enzyme that cleaves LPSYGEAA and LPSWGEAA motifs, most likely LPXTGase, but cannot catalyze the transpeptidation step. We conclude that the natural P1 (Thr) of the SrtA cleavage site has evolved to dampen PAM from nonfunctional cleavage by LPXTGase.IMPORTANCEWe show in this study that functional cleavage of the sortase A (SrtA) cleavage signal for M-protein, LPST*GEAA, in the Gram+ cell membrane, which allows transpeptidation of M-protein to the cell wall, as opposed to non-functional cleavage by the highly active cell membrane nonribosomal enzyme, LPXTGase, at the downstream G-residue, is highly dependent on the presence of T at position 4. From our studies, we conclude that Streptococcus pyogenes has evolved in a manner that maximized T at this position so that SrtA preferentially cleaved the sorting signal in order that the virulence factor, M-protein, was stabilized on the cell surface through covalent attachment to the cell wall.
The first sheep graph-based pan-genome reveals the spectrum of structural variations and their effects on tail phenotypes
Authors: Li Ran , Gong Mian , Zhang Xinmiao , Wang Fei , Liu Zhenyu , Zhang Lei , Xu Mengsi , Zhang Yunfeng , Dai Xuelei , Zhang Zhuangbiao , Fang Wenwen , Yang Yuta , Zhang Huanhuan , Fu Weiwei , Cao Chunna , Yang Peng , Ghanatsaman Zeinab Amiri , Negari Niloufar Jafarpour , Nanaei Hojjat Asadollahpour , Yue Xiangpeng , Song Yuxuan , Lan Xianyong , Deng Weidong , Wang Xihong , Xiang Ruidong , Ibeagha-Awemu Eveline M. , Heslop-Harrison Pat (J.S.) , Lenstra Johannes A. , Gan Shangquan , Jiang Yu 
Published: December 2021

AbstractStructural variations (SVs) are a major contributor to genetic diversity and phenotypic variations, but their prevalence and functions in domestic animals are largely unexplored. Here, we assembled 26 haplotype-resolved genome assemblies from 13 genetically diverse sheep using PacBio HiFi sequencing. We constructed a graph-based ovine pan-genome and discovered 142,422 biallelic insertions and deletions, 7,028 divergent alleles and 13,419 multiallelic variations. We then used a graph-based approach to genotype the biallelic SVs in 684 individuals from 45 domestic breeds and two wild species. Integration with RNA-seq data allows to identify candidate expression-associated SVs. We demonstrate a direct link of SVs and phenotypes by localizing the putative causative insertion in HOXB13 gene responsible for the long-tail trait and identifying multiple large SVs associated with the fat-tail. Beyond generating a benchmark resource for ovine structural variants, our study highlights that animal genetic research will greatly benefit from using a pan-genome graph rather than a single reference genome.
Optineurin deficiency induces patchy hair loss but it is not sufficient to cause amyotrophic lateral sclerosis in mice
Authors: Moharir Shivranjani C , Swarup Ghanshyam 
Published: December 2021

AbstractGenetic alterations and environmental factors contribute towards pathogenesis of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. Various types of mutations in the autophagy receptor protein optineurin (coded by OPTN gene) including deletions are causatively associated with ALS. To explore the role of OPTN in ALS pathogenesis, we used Optn knockout mice to study the features of ALS. The Optn-deficient mice did not show kyphosis, loss of body weight, weakening of front paw-grip strength or limb muscle strength. However, several Optn-deficient mice showed patchy loss of hair, which increased with age. Our results suggest that optineurin deficiency alone is not sufficient to induce ALS-like symptoms in mice. We suggest that optineurin deficiency may require cooperation with other genetic or environmental factors to cause ALS. Since endoplasmic reticulum (ER) stress plays an important role in ALS pathogenesis, and Optn modulates ER stress response signaling, Optn deficiency may contribute to ALS pathogenesis partly by potentiating ER stress response signaling.
Overcoming a “forbidden phenotype”: The parrot’s head supports, propels, and powers tripedal locomotion
Authors: Young Melody W. , Dickinson Edwin , Flaim Nicholas D. , Granatosky Michael C. 
Published: December 2021

AbstractNo vertebrate, living or extinct, is known to have possessed an odd number of limbs. Despite this “forbidden phenotype", gaits that utilize odd numbers of limbs (e.g., tripedalism or pentapedalism) have evolved in both avian and mammalian lineages. Tripedal locomotion is commonly employed by parrots during climbing, who utilize their beaks as an additional support. However, it is unclear whether the beak functions simply as a stabilizing hook, or as a propulsive limb. Here, we present data on kinetics of tripedal climbing in six rosy-faced lovebirds (Agapornis rosiecollis). Our findings demonstrate that parrots utilize cyclical tripedal gaits when climbing and the beak and hindlimbs generate comparable propulsive and tangential substrate reaction forces and power. Propulsive and tangential forces generated by the beak are of equal or greater magnitudes to those forces generated by the forelimbs of humans and non-human primates during vertical climbing. We conclude that the feeding apparatus and neck musculature of parrots has been co-opted to function biomechanically as a third limb during vertical climbing. We hypothesize that this exaptation required substantive alterations to the neuromuscular system including enhanced force-generating capabilities of the neck musculature and modifications to limb central pattern generators.
Activation of retinoic acid receptor reduces metastatic prostate cancer bone lesions through blocking endothelial-to-osteoblast transition
Authors: Yu Guoyu , Corn Paul G. , Shen Pengfei , Song Jian H. , Lee Yu-Chen , Lin Song-Chang , Pan Jing , Agarwal Sandeep K. , Panaretakis Theocharis , Pacifici Maurizio , Logothetis Christopher J. , Yu-Lee Li-Yuan , Lin Sue-Hwa 
Published: December 2021

AbstractMetastatic prostate cancer (PCa) in bone induces bone-forming lesions that contribute to progression and therapy resistance. Currently strategies targeting PCa-induced bone formation are lacking. We previously showed that PCa-induced bone originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition in response to tumor-secreted BMP4. Here, we show that activation of retinoic acid receptor (RAR) inhibits EC-to-OSB transition and reduces PCa-induced bone formation. We found that palovarotene, a RARγ agonist being tested for heterotopic ossification in fibrodysplasia ossificans progressiva, inhibited EC-to-OSB transition and osteoblast mineralizationin vitro, and decreased tumor-induced bone formation and tumor growth in several osteogenic PCa models. RARα/β/γ isoform knockdown in 2H11 ECs blocked EC-to-OSB transition and osteoblast mineralization. Pan-RAR agonist ATRA inhibited MycCaP-BMP4-induced bone formation and tumor growth under castration. Furthermore, palovarotene or ATRA reduced plasma Tenascin C, a factor secreted by EC-OSB cells, which may be used to monitor treatment response. Mechanistically, BMP4-activated pSmad1 forms a complex with RAR in the nucleus of 2H11 cells. RAR activation by palovarotene or ATRA causes pSmad1 degradation by recruiting E3-ubiquitin ligase Smurf1 into the nuclear pSmad1/RARγ complex. Our findings suggest that palovarotene can be repurposed to target PCa-induced bone formation to improve clinical outcomes for bone metastasis.
Neuro-anatomical and neuro-molecular markers in salience network and their integration in machine learning-based prediction of cognitive dysfunction in mild cognitive impairment
Authors: Chand Ganesh B. , Thakuri Deepa S. , Soni Bhavin 
Published: December 2021

AbstractRecent studies indicate disrupted functional mechanisms of salience network regions, especially right anterior insula (RAI), left AI (LAI), and anterior cingulate cortex (ACC), in mild cognitive impairment (MCI). However, the underlying neuro-anatomical and neuro-molecular mechanisms in these regions are not clearly understood yet. It is also unknown whether integration of multi-modal neuro-anatomical and neuro-molecular markers could predict cognitive impairment better in MCI. Herein we quantified neuro-anatomical volumetric markers via structural magnetic resonance imaging (sMRI) and neuro-molecular amyloid markers via positron emission tomography with Pittsburgh compound B (PET PiB) in SN regions of MCI (n = 33) and healthy controls (n = 27). We found that neuro-anatomical markers are significantly reduced while neuro-molecular markers are significantly elevated in SN nodes of MCI compared to healthy controls (p < 0.05). These altered markers in MCI patients were associated with their worse cognitive performance (p < 0.05). Our machine learning-based modeling further suggested that the integration of multi-modal markers predicts cognitive impairment in MCI superiorly compared to using single modality-specific markers. Overall, these findings shed light on the underlying neuro-anatomical volumetric and neuro-molecular amyloid alterations in SN regions and show the significance of multi-modal markers integration approach in better predicting cognitive impairment in MCI.