bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fast adaptation of cooperative channels engenders Hopf bifurcations in auditory hair cells
Authors: Gianoli Francesco , Hogan Brenna , Dilly Émilien , Risler Thomas , Kozlov Andrei S. 
Published: October 2021

ABSTRACTSince the pioneering work of Thomas Gold published in 1948, it has been known that we owe our sensitive sense of hearing to a process in the inner ear that can amplify incident sounds on a cycle-by-cycle basis. Termed the active process, it uses energy to counteract the viscous dissipation associated with sound-evoked vibrations of the ear’s mechanotransduction apparatus. Despite its importance, the mechanism of the active process and the proximate source of energy that powers it have remained elusive—especially at the high frequencies characteristic of mammalian hearing. This is partly due to our insufficient understanding of the mechanotransduction process in hair cells, the sensory receptors and amplifiers of the inner ear. It has previously been proposed that a cyclical binding of Ca2+ ions to individual mechanotransduction channels could power the active process. That model, however, relied on tailored reaction rates that structurally forced the direction of the cycle. Here, we ground our study on our previous model of hair-cell mechanotransduction, which relied on the cooperative gating of pairs of channels, and incorporate into it the cyclical binding of Ca2+ ions. With a single binding site per channel and reaction rates drawn from thermodynamic principles, our model shows that hair cells behave as nonlinear oscillators that exhibit Hopf bifurcations, dynamical instabilities long understood to be signatures of the active process. Using realistic parameter values, we find bifurcations at frequencies in the kilohertz range with physiological Ca2+ concentrations. In contrast to the myosin-based mechanism, responsible for low-frequency relaxation oscillations in the vestibular hair cells of amphibians, the current model relies on the electrochemical gradient of Ca2+ as the only energy source for the active process and on the relative motion of cooperative channels within the stereociliary membrane as the single mechanical driver. Equipped with these two mechanisms, a hair bundle proves capable of operating at frequencies in the kilohertz range, characteristic of mammalian hearing.SIGNIFICANCEHow the inner ear amplifies incident sounds at audible frequencies of several kilohertz is a key question that has remained unanswered despite decades of research into several candidate mechanisms. Here, we model the behavior of hair cells, the sensory receptors of the inner ear, and show that they can undergo oscillatory instabilities called Hopf bifurcations due to the effect of Ca2+ on the cooperative opening and closing of mechanotransduction ion channels. Close to the bifurcation point, a hair cell behaves as a nonlinear oscillator that can amplify its input on a cycle-by-cycle basis. We find that our proposed mechanism can operate in the kilohertz range.
The R346K Mutation in the Mu Variant of SARS-CoV-2 Alter the Interactions with Monoclonal Antibodies from Class 2: A Free Energy of Perturbation Study
Authors: Fratev Filip 
Published: October 2021

AbstractThe Mu variant of SARS-CoV-2 has been recently classified as a variant of interest (VOI) by the world health organization (WHO) but limited data are available at the moment. In particular, a special attention was given to the R346K mutation located in the receptor binding domain (RBD). In the current study we performed Free energy of perturbation (FEP) calculations to elucidate it possible impact on a set of neutralizing monoclonal antibodies (mAbs) which have been shown to be strong inhibitors of the most other known COVID-19 variants. Our results show that R346K affects the class 2 antibodies but its effect is not so significant (0.66 kcal/mol); i.e. reduces the binding with RBD about 3 times. An identical value was calculated also in the presence of both class 1 and class 2 antibodies (BD-812/836). Further, a similar reduction in the binding (0.4 kcal/mol) was obtained for BD-821/771 pair of mAbs. For comparison, the addition of K417N mutation, present in the newly registered Mu variant in July 2021 in UK, affected the class 1 mAbs by 1.29 kcal/mol reducing stronger the binding by about 10 times. Thus, the resistance effect of R346K mutation in the Mu variant is possible but not so significant and is due to the additional decrease of antibody neutralization based on the reduced binding of class 2 antibodies.
Prion-like α-synuclein pathology in the brains of infants: Krabbe disease as a novel seed-competent α-synucleinopathy
Authors: Hatton Christopher , Ghanem Simona S. , Koss David J. , Abdi Ilham Y. , Gibbons Elizabeth , Guerreiro Rita , Bras Jose ,   International DLB Genetics Consortium, Walker Lauren , Gelpi Ellen , Heywood Wendy , Outeiro Tiago F. , Attems Johannes , McFarland Bobby , Forsyth Rob , El-Agnaf Omar M. , Erskine Daniel 
Published: October 2021

AbstractKrabbe disease (KD) is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are associated with increased risk of Lewy body diseases (LBD), an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in KD has pathological similarities to that in LBD, we compared post-mortem KD tissue to that of infant control cases and identified alterations to α-synuclein localisation and expression of modifications associated with LBD. To determine whether α-synuclein in KD displayed pathogenic properties associated with LBD we evaluated its seeding capacity using the real-time quaking-induced conversion assay. Strikingly, seeded aggregation of α-synuclein resulted in the formation of fibrillar aggregates similar to those observed in LBD, confirming the prion-like capacity of KD-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it can result from alterations to biological processes such as sphingolipid homeostasis. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in LBD.
The Nup2 meiotic-autonomous region relieves autoinhibition of Nup60 to promote progression of meiosis and sporulation in Saccharomyces cerevisiae
Authors: Komachi Kelly , Burgess Sean M. 
Published: October 2021

AbstractDuring meiosis, chromosomes undergo dramatic changes in structural organization, nuclear positioning, and motion. Although the nuclear pore complex has been shown to affect genome organization and function in vegetative cells, its role in meiotic chromosome dynamics has remained largely unexplored. Recent work in the budding yeast Saccharomyces cerevisiae demonstrated that the mobile nucleoporin Nup2 is required for normal progression through meiosis I prophase and sporulation in strains where telomere-led chromosome movement has been compromised. The meiotic autonomous region (MAR), a short fragment of Nup2 responsible for its role in meiosis, was shown to localize to the nuclear envelope via Nup60 and to bind to meiotic chromosomes. To understand the relative contribution these two activities have on MAR function, we first carried out a screen for MAR mutants defective in sporulation and found that all the mutations disrupt interaction with both Nup60 and meiotic chromosomes. Moreover, nup60 mutants phenocopy nup2 mutants, exhibiting similar nuclear division kinetics, sporulation efficiencies, and genetic interactions with mutations that affect the telomere bouquet. Although full-length Nup60 requires Nup2 for function, removal of Nup60’s C-terminus allows Nup60 to bind meiotic chromosomes and promote sporulation without Nup2. In contrast, binding of the MAR to meiotic chromosomes is completely dependent on Nup60. Our findings uncover an inhibitory function for the Nup60 C-terminus and suggest that Nup60 mediates recruitment of meiotic chromosomes to the nuclear envelope, while Nup2 plays a secondary role counteracting Nup60’s autoinhibition.
AMPK mediates early activation of the unfolded protein response through a positive feedback loop in palmitate-treated muscle cells
Authors: Gong Jing , Wang Lu , Tao Wuchen , Liu Zonghan , Pang Xiangsheng , Li Wenjiong , Liu Yaxuan , Chen Xiaoping , Zhang Peng 
Published: October 2021

AbstractActivation of the unfolded protein response (UPR) is closely associated with the pathogenesis of many metabolic diseases including obesity and type 2 diabetes. There is increasing evidence for the interdependence of the UPR and metabolic signaling pathways. The AMP-activated protein kinase (AMPK) signaling pathway controls energy balance in eukaryotes. The aim of this study was to investigate the possible interaction between AMPK signaling and the UPR in muscle cells exposed to a saturated fatty acid, as well as the underlying mechanism. The UPR was induced in C2C12 myotubes by treatment with palmitate along with activation of AMPK signaling. Inhibiting the AMPK pathway with compound C attenuated palmitate-induced UPR activation, while inhibiting the UPR with taurourdodeoxycholic acid alleviated palmitate-induced AMPK activation, suggesting a positive feedback loop between the UPR and AMPK. Additionally, 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide, an AMPK agonist, caused a dose- and time-dependent upregulation of genes related to the UPR, including activating transcription factor (ATF)4, binding immunoglobulin protein (BIP), and growth arrest and DNA damage-inducible protein (GADD)34. These results provide the first evidence for the involvement of AMPK signaling in the early activation of the UPR induced by saturated fatty acid in skeletal muscle, and suggest that physiologic or pharmacologic activation of the AMPK pathway (ie, by exercise or metformin, respectively) can promote skeletal muscle health and function and thus improve quality of life for individuals with metabolic disorder due to a high-fat diet or obesity.
Membrane permeability differentiation at the lipid divide
Authors: Łapińska Urszula , Glover Georgina , Kahveci Zehra , Irwin Nicholas A. T. , Milner David S. , Tourte Maxime , Albers Sonja-Verena , Santoro Alyson E. , Richards Thomas A. , Pagliara Stefano 
Published: October 2021

ABSTRACTOne of the deepest branches in the tree of life separates the Archaea from the Bacteria. These prokaryotic groups have distinct cellular systems including fundamentally different phospholipid membrane bilayers. This dichotomy has been termed the lipid divide and possibly bestows different biophysical and biochemical characteristics on each cell type. Classic experiments suggest that bacterial membranes (formed from lipids extracted fromEscherichia colifor example) show permeability to key metabolites comparable to archaeal membranes (formed from lipids extracted fromHalobacterium salinarum), yet systematic analyses based on direct measurements of membrane permeability are absent. Here we develop a new approach for assessing the membrane permeability of ~10 μm unilamellar vesicles, consisting of an aqueous medium enclosed by a single lipid bilayer. Comparing the permeability of eighteen metabolites demonstrates that diether glycerol-1-phosphate lipids with methyl branches, often the most abundant membrane lipids of known archaea, are permeable to a wide range of compounds useful for core metabolic networks, including amino acids, sugars, and nucleobases. Permeability is significantly lower in diester glycerol-3-phosphate lipids without methyl branches, the common building block of bacterial membranes. To identify the membrane characteristics that determine permeability we use this experimental platform to test a variety of lipid forms bearing a diversity of intermediate characteristics. We found that increased membrane permeability is dependent on both the methyl branches present on the archaeal phospholipid tails and the ether bond between the tails and the head group. These permeability differences must have had profound effects on the cell physiology and proteome evolution of early prokaryotic forms. To explore this further, we compare the abundance and distribution of transmembrane transporter-encoding protein families present on genomes sampled from across the prokaryotic tree of life. Archaea have a reduced repertoire of transporter gene families, consistent with increased membrane permeation. These results demonstrate that the lipid divide demarcates a clear difference in permeability function with implications for understanding some of the earliest transitions in cell evolution.
Early evolution of beetles regulated by the end-Permian deforestation
Authors: Zhao Xianye , Yu Yilun , Clapham Matthew E. , Yan Evgeny , Chen Jun , Jarzembowski Edmund A. , Zhao Xiangdong , Wang Bo 
Published: October 2021

AbstractThe end-Permian mass extinction (EPME) led to a severe terrestrial ecosystem collapse. However, the ecological response of insects—the most diverse group of organisms on Earth—to the EPME remains poorly understood. Here, we analyse beetle evolutionary history based on taxonomic diversity, morphological disparity, phylogeny, and ecological shifts from the Early Permian to Middle Triassic, using a comprehensive new data set. Permian beetles were dominated by xylophagous stem groups with a high diversity and disparity, which probably played an underappreciated role in the Permian carbon cycle. Our suite of analyses shows that Permian xylophagous beetles suffered a severe extinction during the EPME largely due to the collapse of forest ecosystems, resulting in an Early Triassic gap of xylophagous beetles. New xylophagous beetles appeared widely in the early Middle Triassic, which is consistent with the restoration of forest ecosystems. Our results highlight the ecological significance of insects in deep-time terrestrial ecosystems.
Predicting Individual Traits from Unperformed Tasks
Authors: Gal Shachar , Tik Niv , Bernstein-Eliav Michal , Tavor Ido 
Published: October 2021

AbstractRelating individual differences in cognitive traits to brain functional organization is a long-lasting challenge for the neuroscience community. Individual intelligence scores were previously predicted from whole-brain connectivity patterns, extracted from functional magnetic resonance imaging (fMRI) data acquired at rest. Recently, it was shown that task-induced brain activation maps outperform these resting-state connectivity patterns in predicting individual intelligence, suggesting that a cognitively demanding environment improves prediction of cognitive abilities. Here, we use data from the Human Connectome Project to predict task-induced brain activation maps from resting-state fMRI, and proceed to use these predicted activity maps to further predict individual differences in a variety of traits. While models based on original task activation maps remain the most accurate, models based on predicted maps significantly outperformed those based on the resting-state connectome. Thus, we provide a promising approach for the evaluation of measures of human behavior from brain activation maps, that could be used without having participants actually perform the tasks.
A multi-omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells
Authors: Hinzman Charles P. , Bansal Shivani , Li Yaoxiang , Iliuk Anton , Girgis Michael , Singh Baldev , Herremans Kelly M. , Trevino Jose G. , Singh Vijay K. , Banerjee Partha P. , Cheema Amrita K. 
Published: October 2021

AbstractAlthough cancer-derived extracellular vesicles (cEVs) are thought to play a pivotal role in promoting cancer progression events, their precise effect on neighboring normal cells is unknown. In this study, we investigated the impact of pancreatic cancer ductal adenocarcinoma (PDAC) derived EVs on recipient non-tumorigenic pancreatic normal epithelial cells upon internalization. We show that PDAC cEVs increase the proliferation and invasive capability of treated normal cells. We further demonstrate that cEVs induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in treated normal pancreatic epithelial cells within 24 hours. Subsequently, these cells release several inflammatory cytokines. Leveraging a layered multi-omics approach, we analyzed EV cargo from a panel of 6 PDAC and 2 normal pancreas cell lines, using multiple EV isolation methods. We found that cEVs were enriched for an array of biomolecules which can induce or regulate ER stress and the UPR, including palmitic acid, sphingomyelins, metabolic regulators of tRNA charging and proteins which regulate trafficking and degradation. We further show that palmitic acid, at doses relevant to those found in cEVs, is sufficient to induce ER stress in normal pancreas cells. These results suggest that cEV cargo packaging may be designed to disseminate proliferative and invasive characteristics upon internalization by distant recipient normal cells, hitherto unreported. This study is among the first to highlight a major role for PDAC cEVs to induce stress in treated normal pancreas cells that may modulate a systemic response leading to altered phenotypes. For the first time, our study implicates cEV transported palmitic acid as a potential driver in this process. These findings highlight the importance of EVs in mediating disease etiology and open potential areas of investigation toward understanding the role of cEV lipids in promoting cell transformation in the surrounding microenvironment.
Creatine transporter deficient rat model show motor dysfunction, cerebellar alterations and muscle creatine deficiency without muscle atrophy
Authors: Duran-Trio Lara , Fernandes-Pires Gabriella , Grosse Jocelyn , Soro-Arnaiz Ines , Roux-Petronelli Clothilde , Binz Pierre-Alain , De Bock Katrien , Cudalbu Cristina , Sandi Carmen , Braissant Olivier 
Published: October 2021

ABSTRACTCreatine (Cr) is a nitrogenous organic acid and plays roles as fast phosphate energy buffer to replenish ATP, osmolyte, antioxidant, neuromodulator, and as a compound with anabolic and ergogenic properties in muscle. Cr is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Loss-of-function mutations in the genes encoding for the enzymes or the transporter cause Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain Cr deficiency, intellectual disability with severe speech delay, behavioral troubles, epilepsy and motor dysfunction. Among CCDS, the X-linked Cr transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different animal models of CTD show reduced brain Cr levels, cognitive deficiencies and together they cover other traits similar to those of patients. However, motor function was poorly explored in CTD models and some controversies in the phenotype exist in comparison with CTD patients. Our recently described Slc6a8Y389C knock-in (KI) rat model of CTD showed mild impaired motor function, morphological alterations in cerebellum, reduced muscular mass, Cr deficiency and increased guanidinoacetate content in muscle, although no consistent signs of muscle atrophy. Our results indicate that such motor dysfunction co-occurred with both nervous and muscle dysfunction, suggesting that muscle strength and performance as well as neuronal connectivity might be affected by this Cr deficiency in muscle and brain.
Phylogenomic analyses in the apple genus Malus s.l. reveal widespread hybridization and allopolyploidy driving the diversifications, with insights into the complex biogeographic history in the Northern Hemisphere
Authors: Liu Bin-Bin , Ren Chen , Kwak Myounghai , Hodel Richard G.J. , Xu Chao , He Jian , Zhou Wen-Bin , Huang Chien-Hsun , Ma Hong , Qian Guan-Ze , Hong De-Yuan , Wen Jun 
Published: October 2021

AbstractPhylogenomic evidence from an increasing number of studies has demonstrated that different data sets and analytical approaches often reconstruct strongly supported but conflicting relationships. In this study, hundreds of single-copy nuclear (SCN) genes (785) and complete plastomes (75) were used to infer the phylogenetic relationships and estimate the historical biogeography of the apple genus Malus sensu lato, an economically important lineage disjunctly distributed in the Northern Hemisphere involved in known and suspected hybridization and allopolyploidy events. The nuclear phylogeny recovered the monophyly of Malus s.l. (including Docynia); however, it was supported to be biphyletic in the plastid phylogeny. An ancient chloroplast capture event best explains the cytonuclear discordance that occurred in the Eocene in western North America. Our conflict analysis demonstrated that ILS, hybridization, and allopolyploidy could explain the widespread nuclear gene tree discordance. We detected one deep hybridization event (Malus doumeri) involving the ancestor of pome-bearing species and Docynia delavayi, and one recent hybridization event (Malus coronaria) between M. sieversii and a combined clade of M. ioensis and M. angustifolia. Furthermore, our historical biogeographic analysis combining living and fossil species supported a widespread East Asian-western North American origin of Malus s.l., followed by a series of extinction events in the Eocene in northern East Aisa and western North America. This study provides a valuable evolutionary framework for the breeding and crop improvement of apples and their close relatives.
gcFront: a tool for determining a Pareto front of growth-coupled cell factory designs
Authors: Legon Laurence , Corre Christophe , Bates Declan G. , Mannan Ahmad A. 
Published: October 2021

ABSTRACTMotivationA widely applicable strategy to create cell factories is to knock out (KO) genes or reactions to redirect cell metabolism so that chemical synthesis is made obligatory when the cell grows at its maximum rate. Synthesis is thus growth-coupled, and the stronger the coupling the more deleterious any impediments in synthesis are to cell growth, making high producer phenotypes evolutionarily robust. Additionally, we desire that these strains grow and synthesise at high rates. Genome-scale metabolic models can be used to explore and identify KOs that growth-couple synthesis, but these are rare in an immense design space, making the search difficult and slow.ResultsTo address this multi-objective optimization problem, we developed a software tool named gcFront - using a genetic algorithm it explores KOs that maximise cell growth, product synthesis, and coupling strength. Moreover, our measure of coupling strength facilitates the search so that gcFront not only finds a growth coupled design in minutes but also outputs many alternative Pareto optimal designs from a single run - granting users flexibility in selecting designs to take to the lab.Availability and ImplementationgcFront, with documentation and a workable tutorial, is freely available at GitHub: https://github.com/lLegon/gcFront, the repository of which is archived at Zenodo, DOI: 10.5281/zenodo.6338595 (Legon et al., 2022).Supplementary InformationSupplementary notes and data files are available at Bioinformatics online.