bluuebunny/crossref_metadata_2025_split huggingface dataset:
CLAVATA3 mediated simultaneous control of transcriptional and post-translational processes provides robustness to the WUSCHEL gradient
Authors: Plong Alexander , Rodriguez Kevin , Alber Mark , Chen Weitao , Reddy G. Venugopala 
Published: November 2021

AbstractRegulation of the homeodomain transcription factor WUSCHEL concentration is critical for stem cell homeostasis in Arabidopsis shoot apical meristems. WUSCHEL regulates the transcription of CLAVATA3 through a concentration-dependent activation-repression switch. CLAVATA3, a secreted peptide, activates receptor kinase signaling to repress WUSCHEL transcription. Considering the revised regulation, CLAVATA3 mediated repression of WUSCHEL transcription alone will lead to an unstable system. Here we show that CLAVATA3 signaling regulates nuclear-cytoplasmic partitioning of WUSCHEL to control nuclear levels and its diffusion into adjacent cells. Our work also reveals that WUSCHEL directly interacts with EXPORTINS via EAR-like domain which is also required for destabilizing WUSCHEL in the cytoplasm. We develop a combined experimental and computational modeling approach that integrates CLAVATA3-mediated transcriptional repression of WUSCHEL and post-translational control of nuclear levels with the WUSCHEL concentration-dependent regulation of CLAVATA3. We show that the dual control by the same signal forms a seamless connection between de novo WUSCHEL synthesis and sub-cellular partitioning in providing robustness to the WUSCHEL gradient.
Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient as a source of immune escape variants
Authors: Weigang Sebastian , Fuchs Jonas , Zimmer Gert , Schnepf Daniel , Kern Lisa , Beer Julius , Luxenburger Hendrik , Ankerhold Jakob , Falcone Valeria , Kemming Janine , Hofmann Maike , Thimme Robert , Neumann-Haefelin Christoph , Ulferts Svenja , Grosse Robert , Hornuss Daniel , Tanriver Yakup , Rieg Siegbert , Wagner Dirk , Huzly Daniela , Schwemmle Martin , Panning Marcus , Kochs Georg 
Published: November 2021

AbstractThe origin of SARS-CoV-2 variants of concern remains unclear. Here, we test whether intra-host virus evolution during persistent infections could be a contributing factor by characterizing the long-term SARS-CoV-2 infection dynamics in an immunosuppressed kidney transplant recipient. Applying RT-qPCR and next-generation sequencing (NGS) of sequential respiratory specimens, we identify several mutations in the viral genome late in infection. We demonstrate that a late viral isolate exhibiting genome mutations similar to those found in variants of concern first identified in UK, South Africa, and Brazil, can escape neutralization by COVID-19 antisera. Moreover, infection of susceptible mice with this patient’s escape variant elicits protective immunity against re-infection with either the parental virus and the escape variant, as well as high neutralization titers against the alpha and beta SARS-CoV-2 variants, B.1.1.7 and B.1.351, demonstrating a considerable immune control against such variants of concern. Upon lowering immunosuppressive treatment, the patient generated spike-specific neutralizing antibodies and resolved the infection. Our results suggest that immunocompromised patients could be a source for the emergence of potentially harmful SARS-CoV-2 variants.
Real-time observation of Cooper pair splitting showing strong non-local correlations
Authors: Ranni Antti , Brange Fredrik , Mannila Elsa T. , Flindt Christian , Maisi Ville F. 
Published: November 2021

AbstractControlled generation and detection of quantum entanglement between spatially separated particles constitute an essential prerequisite both for testing the foundations of quantum mechanics and for realizing future quantum technologies. Splitting of Cooper pairs from a superconductor provides entangled electrons at separate locations. However, experimentally accessing the individual split Cooper pairs constitutes a major unresolved issue as they mix together with electrons from competing processes. Here, we overcome this challenge with the first real-time observation of the splitting of individual Cooper pairs, enabling direct access to the time-resolved statistics of Cooper pair splitting. We determine the correlation statistics arising from two-electron processes and find a pronounced peak that is two orders of magnitude larger than the background. Our experiment thereby allows to unambiguously pinpoint and select split Cooper pairs with 99% fidelity. These results open up an avenue for performing experiments that tap into the spin-entanglement of split Cooper pairs.
Evolving contact mechanics and microstructure formation dynamics of the lithium metal-Li7La3Zr2O12 interface
Authors: Chang Wesley , May Richard , Wang Michael , Thorsteinsson Gunnar , Sakamoto Jeff , Marbella Lauren , Steingart Daniel 
Published: November 2021

AbstractThe dynamic behavior of the interface between the lithium metal electrode and a solid-state electrolyte plays a critical role in all-solid-state battery performance. The evolution of this interface throughout cycling involves multiscale mechanical and chemical heterogeneity at the micro- and nano-scale. These features are dependent on operating conditions such as current density and stack pressure. Here we report the coupling of operando acoustic transmission measurements with nuclear magnetic resonance spectroscopy and magnetic resonance imaging to correlate changes in interfacial mechanics (such as contact loss and crack formation) with the growth of lithium microstructures during cell cycling. Together, the techniques reveal the chemo-mechanical behavior that governs lithium metal and Li7La3Zr2O12 interfacial dynamics at various stack pressure regimes and with voltage polarization.
An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions
Authors: Routhier Julie , Pons Stéphanie , Freidja Mohamed Lamine , Dalstein Véronique , Cutrona Jérôme , Jonquet Antoine , Lalun Nathalie , Mérol Jean-Claude , Lathrop Mark , Stitzel Jerry A. , Kervoaze Gwenola , Pichavant Muriel , Gosset Philippe , Tournier Jean-Marie , Birembaut Philippe , Dormoy Valérian , Maskos Uwe 
Published: November 2021

AbstractChronic Obstructive Pulmonary Disease is a generally smoking-linked major cause of morbidity and mortality. Genome-wide Association Studies identified a locus including a non-synonymous single nucleotide polymorphism in CHRNA5, rs16969968, encoding the nicotinic acetylcholine receptor α5 subunit, predisposing to both smoking and Chronic Obstructive Pulmonary Disease. Here we report that nasal polyps from rs16969968 non-smoking carriers exhibit airway epithelium remodeling and inflammation. These hallmarks of Chronic Obstructive Pulmonary Disease occur spontaneously in mice expressing human rs16969968. They are significantly amplified after exposure to porcine pancreatic elastase, an emphysema model, and to oxidative stress with a polymorphism-dependent alteration of lung function. Targeted rs16969968 expression in epithelial cells leads to airway remodeling in vivo, increased proliferation and production of pro-inflammatory cytokines through decreased calcium entry and increased adenylyl-cyclase activity. We show that rs16969968 directly contributes to Chronic Obstructive Pulmonary Disease-like lesions, sensitizing the lung to the action of oxidative stress and injury, and represents a therapeutic target.
Single-cell normalization and association testing unifying CRISPR screen and gene co-expression analyses with Normalisr
Authors: Wang Lingfei 
Published: November 2021

AbstractSingle-cell RNA sequencing (scRNA-seq) provides unprecedented technical and statistical potential to study gene regulation but is subject to technical variations and sparsity. Furthermore, statistical association testing remains difficult for scRNA-seq. Here we present Normalisr, a normalization and statistical association testing framework that unifies single-cell differential expression, co-expression, and CRISPR screen analyses with linear models. By systematically detecting and removing nonlinear confounders arising from library size at mean and variance levels, Normalisr achieves high sensitivity, specificity, speed, and generalizability across multiple scRNA-seq protocols and experimental conditions with unbiased p-value estimation. The superior scalability allows us to reconstruct robust gene regulatory networks from trans-effects of guide RNAs in large-scale single cell CRISPRi screens. On conventional scRNA-seq, Normalisr recovers gene-level co-expression networks that recapitulated known gene functions.
Metamachines of pluripotent colloids
Authors: Aubret Antoine , Martinet Quentin , Palacci Jeremie 
Published: November 2021

AbstractMachines enabled the Industrial Revolution and are central to modern technological progress: A machine’s parts transmit forces, motion, and energy to one another in a predetermined manner. Today’s engineering frontier, building artificial micromachines that emulate the biological machinery of living organisms, requires faithful assembly and energy consumption at the microscale. Here, we demonstrate the programmable assembly of active particles into autonomous metamachines using optical templates. Metamachines, or machines made of machines, are stable, mobile and autonomous architectures, whose dynamics stems from the geometry. We use the interplay between anisotropic force generation of the active colloids with the control of their orientation by local geometry. This allows autonomous reprogramming of active particles of the metamachines to achieve multiple functions. It permits the modular assembly of metamachines by fusion, reconfiguration of metamachines and, we anticipate, a shift in focus of self-assembly towards active matter and reprogrammable materials.
Sensory-motor cortices shape functional connectivity dynamics in the human brain
Authors: Kong Xiaolu , Kong Ru , Orban Csaba , Wang Peng , Zhang Shaoshi , Anderson Kevin , Holmes Avram , Murray John D. , Deco Gustavo , van den Heuvel Martijn , Yeo B. T. Thomas 
Published: November 2021

AbstractLarge-scale biophysical circuit models provide mechanistic insights into the micro-scale and macro-scale properties of brain organization that shape complex patterns of spontaneous brain activity. We developed a spatially heterogeneous large-scale dynamical circuit model that allowed for variation in local synaptic properties across the human cortex. Here we show that parameterizing local circuit properties with both anatomical and functional gradients generates more realistic static and dynamic resting-state functional connectivity (FC). Furthermore, empirical and simulated FC dynamics demonstrates remarkably similar sharp transitions in FC patterns, suggesting the existence of multiple attractors. Time-varying regional fMRI amplitude may track multi-stability in FC dynamics. Causal manipulation of the large-scale circuit model suggests that sensory-motor regions are a driver of FC dynamics. Finally, the spatial distribution of sensory-motor drivers matches the principal gradient of gene expression that encompasses certain interneuron classes, suggesting that heterogeneity in excitation-inhibition balance might shape multi-stability in FC dynamics.
Coordination environment dependent selectivity of single-site-Cu enriched crystalline porous catalysts in CO2 reduction to CH4
Authors: Zhang Yu , Dong Long-Zhang , Li Shan , Huang Xin , Chang Jia-Nan , Wang Jian-Hui , Zhou Jie , Li Shun-Li , Lan Ya-Qian 
Published: November 2021

AbstractThe electrochemical CO2reduction to high-value-added chemicals is one of the most promising and challenging research in the energy conversion field. An efficient ECR catalyst based on a Cu-based conductive metal-organic framework (Cu-DBC) is dedicated to producing CH4with superior activity and selectivity, showing a Faradaic efficiency of CH4as high as ~80% and a large current density of −203 mA cm−2at −0.9 V vs. RHE. The further investigation based on theoretical calculations and experimental results indicates the Cu-DBC with oxygen-coordinated Cu sites exhibits higher selectivity and activity over the other two crystalline ECR catalysts with nitrogen-coordinated Cu sites due to the lower energy barriers of Cu-O4sites during ECR process. This work unravels the strong dependence of ECR selectivity on the Cu site coordination environment in crystalline porous catalysts, and provides a platform for constructing highly selective ECR catalysts.
Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren
Authors: Liu Heng , Sun Dapeng , Myasnikov Alexander , Damian Marjorie , Baneres Jean-Louis , Sun Ji , Zhang Cheng 
Published: November 2021

AbstractThe hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling. Acylation of ghrelin at Ser3 is required for its agonistic action on GHSR. Synthetic agonists of GHSR are under clinical evaluation for disorders related to appetite and growth hormone dysregulation. Here, we report high-resolution cryo-EM structures of the GHSR-Gi signaling complex with ghrelin and the non-peptide agonist ibutamoren as an investigational new drug. Our structures together with mutagenesis data reveal the molecular basis for the binding of ghrelin and ibutamoren. Structural comparison suggests a salt bridge and an aromatic cluster near the agonist-binding pocket as important structural motifs in receptor activation. Notable structural variations of the Gi and GHSR coupling are observed in our cryo-EM analysis. Our results provide a framework for understanding GHSR signaling and developing new GHSR agonist drugs.
Molecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3′,2′-cGAMP as the second messenger
Authors: Fatma Shirin , Chakravarti Arpita , Zeng Xuankun , Huang Raven H. 
Published: November 2021

AbstractCyclic-oligonucleotide-based antiphage signaling systems (CBASS) are diverse and abundant in bacteria. Here, we present the biochemical and structural characterization of two CBASS systems, composed of CdnG and Cap5, from Asticcacaulis sp. and Lactococcus lactis. We show that CdnG from Asticcacaulis sp. synthesizes 3′,2′-cGAMP in vitro, and 3′,2′-cGAMP is the biological signaling molecule that activates Cap5 for DNA degradation. Crystal structures of Cap5, together with the SAVED domain in complex with 3′,2′-cGAMP, provide insight into the architecture of Cap5 as well as molecular recognition of 3′,2′-cGAMP by the SAVED domain of Cap5. Amino acid conservation of the SAVED domain of Cap5, together with mutational studies, led us to propose a mechanism of Back-to-Front stacking of two SAVED domains, mediated by 3′,2′-cGAMP, to activate HNH nuclease domain for DNA degradation. This study of the most abundant CBASS system provides insights into the mechanisms employed by bacteria in their conflicts against phage.
Hepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primates
Authors: Costa-Verdera Helena , Collaud Fanny , Riling Christopher R. , Sellier Pauline , Nordin Jayme M. L. , Preston G. Michael , Cagin Umut , Fabregue Julien , Barral Simon , Moya-Nilges Maryse , Krijnse-Locker Jacomina , van Wittenberghe Laetitia , Daniele Natalie , Gjata Bernard , Cosette Jeremie , Abad Catalina , Simon-Sola Marcelo , Charles Severine , Li Mathew , Crosariol Marco , Antrilli Tom , Quinn William J. , Gross David A. , Boyer Olivier , Anguela Xavier M. , Armour Sean M. , Colella Pasqualina , Ronzitti Giuseppe , Mingozzi Federico 
Published: November 2021

AbstractPompe disease (PD) is a severe neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). PD is currently treated with enzyme replacement therapy (ERT) with intravenous infusions of recombinant human GAA (rhGAA). Although the introduction of ERT represents a breakthrough in the management of PD, the approach suffers from several shortcomings. Here, we developed a mouse model of PD to compare the efficacy of hepatic gene transfer with adeno-associated virus (AAV) vectors expressing secretable GAA with long-term ERT. Liver expression of GAA results in enhanced pharmacokinetics and uptake of the enzyme in peripheral tissues compared to ERT. Combination of gene transfer with pharmacological chaperones boosts GAA bioavailability, resulting in improved rescue of the PD phenotype. Scale-up of hepatic gene transfer to non-human primates also successfully results in enzyme secretion in blood and uptake in key target tissues, supporting the ongoing clinical translation of the approach.
Multidrug-resistant Neisseria gonorrhoeae infection in heterosexual men with reduced susceptibility to ceftriaxone, first report in Thailand
Authors: Kueakulpattana Naris , Wannigama Dhammika Leshan , Luk-in Sirirat , Hongsing Parichart , Hurst Cameron , Badavath Vishnu Nayak , Jenjaroenpun Piroon , Wongsurawat Thidathip , Teeratakulpisan Nipat , Kerr Stephen J. , Abe Shuichi , Phattharapornjaroen Phatthranit , Shein Aye Mya Sithu , Saethang Thammakorn , Chantaravisoot Naphat , Amarasiri Mohan , Higgins Paul G. , Chatsuwan Tanittha 
Published: November 2021

AbstractThe global rapid emergence of azithromycin/ceftriaxone resistant Neisseria gonorrhoeae threatens current recommend azithromycin/ceftriaxone dual therapy for gonorrhea to ensure effective treatment. Here, we identified the first two N. gonorrhoeae isolates with decreased ceftriaxone susceptibility in Thailand. Among 134 N. gonorrhoeae isolates collected from Thai Red Cross Anonymous Clinic, Bangkok, two isolates (NG-083 and NG-091) from urethral swab in male heterosexual patients had reduced susceptibility to ceftriaxone (MICs of 0.125 mg/L). Both were multidrug resistant and strong biofilm producers with ceftriaxone tolerance (MBEC > 128 mg/L). NG-083 and NG-091 remained susceptible to azithromycin (MIC of 1 mg/L and 0.5 mg/L, respectively). Reduced susceptibility to ceftriaxone was associated with alterations in PBP2, PBP1, PorB, MtrR, and mtrR promoter region. NG-083 belonged to sequence type (ST) 7235 and NG-091 has new allele number of tbpB with new ST. Molecular docking revealed ceftriaxone weakly occupied the active site of mosaic XXXIV penicillin-binding protein 2 variant in both isolates. Molecular epidemiology results revealed that both isolates display similarities with isolates from UK, USA, and The Netherlands. These first two genetically related gonococcal isolates with decreased ceftriaxone susceptibility heralds the threat of treatment failure in Thailand, and importance of careful surveillance.
Link between serum lipid signature and prognostic factors in COVID-19 patients
Authors: Dei Cas Michele , Ottolenghi Sara , Morano Camillo , Rinaldo Rocco , Roda Gabriella , Chiumello Davide , Centanni Stefano , Samaja Michele , Paroni Rita 
Published: November 2021

AbstractAlthough the serum lipidome is markedly affected by COVID-19, two unresolved issues remain: how the severity of the disease affects the level and the composition of serum lipids and whether serum lipidome analysis may identify specific lipids impairment linked to the patients' outcome. Sera from 49 COVID-19 patients were analyzed by untargeted lipidomics. Patients were clustered according to: inflammation (C-reactive protein), hypoxia (Horowitz Index), coagulation state (D-dimer), kidney function (creatinine) and age. COVID-19 patients exhibited remarkable and distinctive dyslipidemia for each prognostic factor associated with reduced defense against oxidative stress. When patients were clustered by outcome (7 days), a peculiar lipidome signature was detected with an overall increase of 29 lipid species, including—among others—four ceramide and three sulfatide species, univocally related to this analysis. Considering the lipids that were affected by all the prognostic factors, we found one sphingomyelin related to inflammation and viral infection of the respiratory tract and two sphingomyelins, that are independently related to patients' age, and they appear as candidate biomarkers to monitor disease progression and severity. Although preliminary and needing validation, this report pioneers the translation of lipidome signatures to link the effects of five critical clinical prognostic factors with the patients' outcomes.
Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition
Authors: Vo Thanh-Trang , Herzog Lee-or , Buono Roberta , Lee Jong-Hoon Scott , Mallya Sharmila , Duong Madeleine R. , Thao Joshua , Gotesman Moran , Fruman David A. 
Published: November 2021

AbstractThe mechanistic target of rapamycin (mTOR) is a kinase whose activation is associated with poor prognosis in pre-B cell acute lymphoblastic leukemia (B-ALL). These and other findings have prompted diverse strategies for targeting mTOR signaling in B-ALL and other B-cell malignancies. In cellular models of Philadelphia Chromosome-positive (Ph+) B-ALL, mTOR kinase inhibitors (TOR-KIs) that inhibit both mTOR-complex-1 (mTORC1) and mTOR-complex-2 (mTORC2) enhance the cytotoxicity of tyrosine kinase inhibitors (TKIs) such as dasatinib. However, TOR-KIs have not shown substantial efficacy at tolerated doses in blood cancer clinical trials. Selective inhibition of mTORC1 or downstream effectors provides alternative strategies that may improve selectivity towards leukemia cells. Of particular interest is the eukaryotic initiation factor 4F (eIF4F) complex that mediates cap-dependent translation. Here we use novel chemical and genetic approaches to show that selective targeting of either mTORC1 kinase activity or components of the eIF4F complex sensitizes murine BCR-ABL-dependent pre-B leukemia cells to dasatinib. SBI-756, a small molecule inhibitor of eIF4F assembly, sensitizes human Ph+ and Ph-like B-ALL cells to dasatinib cytotoxicity without affecting survival of T lymphocytes or natural killer cells. These findings support the further evaluation of eIF4F-targeted molecules in combination therapies with TKIs in B-ALL and other blood cancers.
Claudin-9 constitutes tight junctions of folliculo-stellate cells in the anterior pituitary gland
Authors: Higashi Atsuko Y. , Higashi Tomohito , Furuse Kyoko , Ozeki Kana , Furuse Mikio , Chiba Hideki 
Published: November 2021

AbstractThe anterior pituitary gland regulates growth, metabolism, and reproduction by secreting hormones. Folliculo-stellate (FS) cells are non-endocrine cells located among hormone-producing cells in the anterior pituitary glands. They form follicular lumens, which are sealed by tight junctions (TJs). Although FS cells are hypothesized to contribute to fine-tuning of endocrine cells, little is known about the exact roles of FS cells. Here, we investigated the molecular composition of TJs in FS cells. We demonstrated that occludin is a good marker for TJs in the pituitary gland and examined the structure of the lumens surrounded by FS cells. We also found that claudin-9 is a major component of TJs in the FS cells. In immunoelectron microscopy, claudin-9 was specifically localized at TJs of the FS cells. The expression of claudin-9 was gradually increased in the pituitary gland after birth, suggesting that claudin-9 is developmentally regulated and performs some specific functions on the paracellular barrier of follicles in the pituitary gland. Furthermore, we found that angulin-1, angulin-2, and tricellulin are localized at the tricellular contacts of the FS cells. Our findings provide a first comprehensive molecular profile of TJs in the FS cells, and may lead us towards unveiling the FS cell functions.