bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developmental disruption and restoration of brain synaptome architecture in the murine Pax6 neurodevelopmental disease model
Authors: Tomas-Roca Laura , Qiu Zhen , Fransén Erik , Gokhale Ragini , Bulovaite Edita , Price David J. , Komiyama Noboru H. , Grant Seth G. N. 
Published: November 2022

AbstractNeurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Nevertheless, spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence can occur in many disorders, suggesting that brain circuits possess an intrinsic capacity to overcome the deficits arising from some germline mutations. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6, a neurodevelopmental disorder model. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the molecular composition of excitatory synapses, the postnatal expansion of synapse diversity and the acquisition of normal synaptome architecture were delayed in all brain regions, interfering with networks and electrophysiological simulations of cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synapse diversity and synaptome architecture to the normal developmental trajectory. Synapse subtypes with rapid protein turnover mediated the synaptome remodeling. This brain-wide capacity for remodeling of synapse molecular composition to recover and maintain the developmental trajectory of synaptome architecture may help confer resilience to neurodevelopmental genetic disorders.
Glycolytic flux control by drugging phosphoglycolate phosphatase
Authors: Jeanclos Elisabeth , Schlötzer Jan , Hadamek Kerstin , Yuan-Chen Natalia , Alwahsh Mohammad , Hollmann Robert , Fratz Stefanie , Yesilyurt-Gerhards Dilan , Frankenbach Tina , Engelmann Daria , Keller Angelika , Kaestner Alexandra , Schmitz Werner , Neuenschwander Martin , Hergenröder Roland , Sotriffer Christoph , von Kries Jens Peter , Schindelin Hermann , Gohla Antje 
Published: November 2022

AbstractTargeting the intrinsic metabolism of immune or tumor cells is a therapeutic strategy in autoimmunity, chronic inflammation or cancer. Metabolite repair enzymes may represent an alternative target class for selective metabolic inhibition, but pharmacological tools to test this concept are needed. Here, we demonstrate that phosphoglycolate phosphatase (PGP), a prototypical metabolite repair enzyme in glycolysis, is a pharmacologically actionable target. Using a combination of small molecule screening, protein crystallography, molecular dynamics simulations and NMR metabolomics, we discover and analyze a compound (CP1) that inhibits PGP with high selectivity and submicromolar potency. CP1 locks the phosphatase in a catalytically inactive conformation, dampens glycolytic flux, and phenocopies effects of cellular PGP-deficiency. This study provides key insights into effective and precise PGP targeting, at the same time validating an allosteric approach to control glycolysis that could advance discoveries of innovative therapeutic candidates.
Variant-specific symptoms of COVID-19 in a study of 1,542,510 adults in England
Authors: Whitaker Matthew , Elliott Joshua , Bodinier Barbara , Barclay Wendy , Ward Helen , Cooke Graham , Donnelly Christl A. , Chadeau-Hyam Marc , Elliott Paul 
Published: November 2022

AbstractInfection with SARS-CoV-2 virus is associated with a wide range of symptoms. The REal-time Assessment of Community Transmission −1 (REACT-1) study monitored the spread and clinical manifestation of SARS-CoV-2 among random samples of the population in England from 1 May 2020 to 31 March 2022. We show changing symptom profiles associated with the different variants over that period, with lower reporting of loss of sense of smell or taste for Omicron compared to previous variants, and higher reporting of cold-like and influenza-like symptoms, controlling for vaccination status. Contrary to the perception that recent variants have become successively milder, Omicron BA.2 was associated with reporting more symptoms, with greater disruption to daily activities, than BA.1. With restrictions lifted and routine testing limited in many countries, monitoring the changing symptom profiles associated with SARS-CoV-2 infection and effects on daily activities will become increasingly important.
Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish
Authors: Fasano Giulia , Muto Valentina , Radio Francesca Clementina , Venditti Martina , Mosaddeghzadeh Niloufar , Coppola Simona , Paradisi Graziamaria , Zara Erika , Bazgir Farhad , Ziegler Alban , Chillemi Giovanni , Bertuccini Lucia , Tinari Antonella , Vetro Annalisa , Pantaleoni Francesca , Pizzi Simone , Conti Libenzio Adrian , Petrini Stefania , Bruselles Alessandro , Prandi Ingrid Guarnetti , Mancini Cecilia , Chandramouli Balasubramanian , Barth Magalie , Bris Céline , Milani Donatella , Selicorni Angelo , Macchiaiolo Marina , Gonfiantini Michaela V. , Bartuli Andrea , Mariani Riccardo , Curry Cynthia J. , Guerrini Renzo , Slavotinek Anne , Iascone Maria , Dallapiccola Bruno , Ahmadian Mohammad Reza , Lauri Antonella , Tartaglia Marco 
Published: November 2022

AbstractVesicle biogenesis, trafficking and signaling via Endoplasmic reticulum-Golgi network support essential developmental processes and their disruption lead to neurodevelopmental disorders and neurodegeneration. We report that de novo missense variants in ARF3, encoding a small GTPase regulating Golgi dynamics, cause a developmental disease in humans impairing nervous system and skeletal formation. Microcephaly-associated ARF3 variants affect residues within the guanine nucleotide binding pocket and variably perturb protein stability and GTP/GDP binding. Functional analysis demonstrates variably disruptive consequences of ARF3 variants on Golgi morphology, vesicles assembly and trafficking. Disease modeling in zebrafish validates further the dominant behavior of the mutants and their differential impact on brain and body plan formation, recapitulating the variable disease expression. In-depth in vivo analyses traces back impaired neural precursors’ proliferation and planar cell polarity-dependent cell movements as the earliest detectable effects. Our findings document a key role of ARF3 in Golgi function and demonstrate its pleiotropic impact on development.
Remote near-field spectroscopy of vibrational strong coupling between organic molecules and phononic nanoresonators
Authors: Dolado Irene , Maciel-Escudero Carlos , Nikulina Elizaveta , Modin Evgenii , Calavalle Francesco , Chen Shu , Bylinkin Andrei , Alfaro-Mozaz Francisco Javier , Li Jiahan , Edgar James H. , Casanova Fèlix , Vélez Saül , Hueso Luis E. , Esteban Ruben , Aizpurua Javier , Hillenbrand Rainer 
Published: November 2022

AbstractPhonon polariton (PhP) nanoresonators can dramatically enhance the coupling of molecular vibrations and infrared light, enabling ultrasensitive spectroscopies and strong coupling with minute amounts of matter. So far, this coupling and the resulting localized hybrid polariton modes have been studied only by far-field spectroscopy, preventing access to modal near-field patterns and dark modes, which could further our fundamental understanding of nanoscale vibrational strong coupling (VSC). Here we use infrared near-field spectroscopy to study the coupling between the localized modes of PhP nanoresonators made of h-BN and molecular vibrations. For a most direct probing of the resonator-molecule coupling, we avoid the direct near-field interaction between tip and molecules by probing the molecule-free part of partially molecule-covered nanoresonators, which we refer to as remote near-field probing. We obtain spatially and spectrally resolved maps of the hybrid polariton modes, as well as the corresponding coupling strengths, demonstrating VSC on a single PhP nanoresonator level. Our work paves the way for near-field spectroscopy of VSC phenomena not accessible by conventional techniques.
Creep fronts and complexity in laboratory earthquake sequences illuminate delayed earthquake triggering
Authors: Cebry Sara Beth L. , Ke Chun-Yu , Shreedharan Srisharan , Marone Chris , Kammer David S. , McLaskey Gregory C. 
Published: November 2022

AbstractEarthquakes occur in clusters or sequences that arise from complex triggering mechanisms, but direct measurement of the slow subsurface slip responsible for delayed triggering is rarely possible. We investigate the origins of complexity and its relationship to heterogeneity using an experimental fault with two dominant seismic asperities. The fault is composed of quartz powder, a material common to natural faults, sandwiched between 760 mm long polymer blocks that deform the way 10 meters of rock would behave. We observe periodic repeating earthquakes that transition into aperiodic and complex sequences of fast and slow events. Neighboring earthquakes communicate via migrating slow slip, which resembles creep fronts observed in numerical simulations and on tectonic faults. Utilizing both local stress measurements and numerical simulations, we observe that the speed and strength of creep fronts are highly sensitive to fault stress levels left behind by previous earthquakes, and may serve as on-fault stress meters.
Peak refreezing in the Greenland firn layer under future warming scenarios
Authors: Noël Brice , Lenaerts Jan T. M. , Lipscomb William H. , Thayer-Calder Katherine , van den Broeke Michiel R. 
Published: November 2022

AbstractFirn (compressed snow) covers approximately 90$$\%$$%of the Greenland ice sheet (GrIS) and currently retains about half of rain and meltwater through refreezing, reducing runoff and subsequent mass loss. The loss of firn could mark a tipping point for sustained GrIS mass loss, since decades to centuries of cold summers would be required to rebuild the firn buffer. Here we estimate the warming required for GrIS firn to reach peak refreezing, using 51 climate simulations statistically downscaled to 1 km resolution, that project the long-term firn layer evolution under multiple emission scenarios (1850–2300). We predict that refreezing stabilises under low warming scenarios, whereas under extreme warming, refreezing could peak and permanently decline starting in southwest Greenland by 2100, and further expanding GrIS-wide in the early 22$${}^{{nd}}$$ndcentury. After passing this peak, the GrIS contribution to global sea level rise would increase over twenty-fold compared to the last three decades.
SuperFi-Cas9 exhibits remarkable fidelity but severely reduced activity yet works effectively with ABE8e
Authors: Kulcsár Péter István , Tálas András , Ligeti Zoltán , Krausz Sarah Laura , Welker Ervin 
Published: November 2022

AbstractSeveral advancements have been made to SpCas9, the most widely used CRISPR/Cas genome editing tool, to reduce its unwanted off-target effects. The most promising approach is the development of increased-fidelity nuclease (IFN) variants of SpCas9, however, their fidelity has increased at the cost of reduced activity. SuperFi-Cas9 has been developed recently, and it has been described as a next-generation high-fidelity SpCas9 variant, free from the drawbacks of first-generation IFNs. In this study, we characterize the on-target activity and the off-target propensity of SuperFi-Cas9 in mammalian cells, comparing it to first-generation IFNs. SuperFi-Cas9 demonstrates strongly reduced activity but high fidelity features that are in many aspects similar to those of some first-generation variants, such as evo- and HeFSpCas9. SuperFi-cytosine (CBE3) and -adenine (ABE7.10) base editors, as well as SuperFi-prime editor show no meaningful activity. When combined with ABE8e, SuperFi-Cas9, similarly to HeFSpCas9, executes DNA editing with high activity as well as high specificity reducing both bystander and SpCas9-dependent off-target base editing.
pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation
Authors: Boix Olga , Martinez Marion , Vidal Santiago , Giménez-Alejandre Marta , Palenzuela Lluís , Lorenzo-Sanz Laura , Quevedo Laura , Moscoso Olivier , Ruiz-Orera Jorge , Ximénez-Embún Pilar , Ciriaco Nikaoly , Nuciforo Paolo , Stephan-Otto Attolini Camille , Albà M. Mar , Muñoz Javier , Tian Tian V. , Varela Ignacio , Vivancos Ana , Ramón y Cajal Santiago , Muñoz Purificación , Rivas Carmen , Abad María 
Published: November 2022

AbstractThe human transcriptome contains thousands of small open reading frames (sORFs) that encode microproteins whose functions remain largely unexplored. Here, we show that TINCR lncRNA encodes pTINCR, an evolutionary conserved ubiquitin-like protein (UBL) expressed in many epithelia and upregulated upon differentiation and under cellular stress. By gain- and loss-of-function studies, we demonstrate that pTINCR is a key inducer of epithelial differentiation in vitro and in vivo. Interestingly, low expression of TINCR associates with worse prognosis in several epithelial cancers, and pTINCR overexpression reduces malignancy in patient-derived xenografts. At the molecular level, pTINCR binds to SUMO through its SUMO interacting motif (SIM) and to CDC42, a Rho-GTPase critical for actin cytoskeleton remodeling and epithelial differentiation. Moreover, pTINCR increases CDC42 SUMOylation and promotes its activation, triggering a pro-differentiation cascade. Our findings suggest that the microproteome is a source of new regulators of cell identity relevant for cancer.
Single atom catalysts in Van der Waals gaps
Authors: Jiang Huaning , Yang Weiwei , Xu Mingquan , Wang Erqing , Wei Yi , Liu Wei , Gu Xiaokang , Liu Lixuan , Chen Qian , Zhai Pengbo , Zou Xiaolong , Ajayan Pulickel M. , Zhou Wu , Gong Yongji 
Published: November 2022

AbstractSingle-atom catalysts provide efficiently utilized active sites to improve catalytic activities while improving the stability and enhancing the activities to the level of their bulk metallic counterparts are grand challenges. Herein, we demonstrate a family of single-atom catalysts with different interaction types by confining metal single atoms into the van der Waals gap of two-dimensional SnS2. The relatively weak bonding between the noble metal single atoms and the host endows the single atoms with more intrinsic catalytic activity compared to the ones with strong chemical bonding, while the protection offered by the layered material leads to ultrahigh stability compared to the physically adsorbed single-atom catalysts on the surface. Specifically, the trace Pt-intercalated SnS2 catalyst has superior long-term durability and comparable performance to that of commercial 10 wt% Pt/C catalyst in hydrogen evolution reaction. This work opens an avenue to explore high-performance intercalated single-atom electrocatalysts within various two-dimensional materials.
Influenza A virus reassortment in mammals gives rise to genetically distinct within-host subpopulations
Authors: Ganti Ketaki , Bagga Anish , Carnaccini Silvia , Ferreri Lucas M. , Geiger Ginger , Joaquin Caceres C. , Seibert Brittany , Li Yonghai , Wang Liping , Kwon Taeyong , Li Yuhao , Morozov Igor , Ma Wenjun , Richt Juergen A. , Perez Daniel R. , Koelle Katia , Lowen Anice C. 
Published: November 2022

AbstractInfluenza A virus (IAV) genetic exchange through reassortment has the potential to accelerate viral evolution and has played a critical role in the generation of multiple pandemic strains. For reassortment to occur, distinct viruses must co-infect the same cell. The spatio-temporal dynamics of viral dissemination within an infected host therefore define opportunity for reassortment. Here, we used wild type and synonymously barcoded variant viruses of a pandemic H1N1 strain to examine the within-host viral dynamics that govern reassortment in guinea pigs, ferrets and swine. The first two species are well-established models of human influenza, while swine are a natural host and a frequent conduit for cross-species transmission and reassortment. Our results show reassortment to be pervasive in all three hosts but less frequent in swine than in ferrets and guinea pigs. In ferrets, tissue-specific differences in the opportunity for reassortment are also evident, with more reassortants detected in the nasal tract than the lower respiratory tract. While temporal trends in viral diversity are limited, spatial patterns are clear, with heterogeneity in the viral genotypes detected at distinct anatomical sites revealing extensive compartmentalization of reassortment and replication. Our data indicate that the dynamics of viral replication in mammals allow diversification through reassortment but that the spatial compartmentalization of variants likely shapes their evolution and onward transmission.
Optical cavity-mediated exciton dynamics in photosynthetic light harvesting 2 complexes
Authors: Wu Fan , Finkelstein-Shapiro Daniel , Wang Mao , Rosenkampff Ilmari , Yartsev Arkady , Pascher Torbjörn , Nguyen- Phan Tu C. , Cogdell Richard , Börjesson Karl , Pullerits Tönu 
Published: November 2022

AbstractStrong light-matter interaction leads to the formation of hybrid polariton states and alters the photophysical dynamics of organic materials and biological systems without modifying their chemical structure. Here, we experimentally investigated a well-known photosynthetic protein, light harvesting 2 complexes (LH2) from purple bacteria under strong coupling with the light mode of a Fabry-Perot optical microcavity. Using femtosecond pump probe spectroscopy, we analyzed the polariton dynamics of the strongly coupled system and observed a significant prolongation of the excited state lifetime compared with the bare exciton, which can be explained in terms of the exciton reservoir model. Our findings indicate the potential of tuning the dynamic of the whole photosynthetic unit, which contains several light harvesting complexes and reaction centers, with the help of strong exciton-photon coupling, and opening the discussion about possible design strategies of artificial photosynthetic devices.
A fourth dose of the inactivated SARS-CoV-2 vaccine redistributes humoral immunity to the N-terminal domain
Authors: Wang Ji , Deng Caiguangxi , Liu Ming , Liu Yihao , Li Liubing , Huang Zhangping , Shang Liru , Jiang Juan , Li Yongyong , Mo Ruohui , Zhang Hui , Liu Min , Peng Sui , Xiao Haipeng 
Published: November 2022

AbstractThe effectiveness of a 3rddose of SARS-CoV-2 vaccines waned quickly in the Omicron-predominant period. In response to fast-waning immunity and the threat of Omicron variant of concern (VOC) to healthcare workers (HCWs), we conduct a non-randomized trial (ChiCTR2200055564) in which 38 HCWs volunteer to receive a homologous booster of inactivated vaccines (BBIBP-CorV) 6 months after the 3rddose. The primary and secondary outcomes are neutralizing antibodies (NAbs) and the receptor-binding domain (RBD)-directed antibodies, respectively. The 4thdose recalls waned immunity while having distinct effects on humoral responses to different antigens. The peak antibody response to the RBD induced by the 4thdose is inferior to that after the 3rddose, whereas responses to the N-terminal domain (NTD) of spike protein are further strengthened significantly. Accordingly, the 4thdose further elevates the peak level of NAbs against ancestral SARS-CoV-2 and Omicron BA.2, but not BA.1 which has more NTD mutations. No severe adverse events related to vaccination are recorded during the trial. Here, we show that redistribution of immune focus after repeated vaccinations may modulate cross-protective immune responses against different VOCs.
Stromal FOXF2 suppresses prostate cancer progression and metastasis by enhancing antitumor immunity
Authors: Jia Deyong , Zhou Zhicheng , Kwon Oh-Joon , Zhang Li , Wei Xing , Zhang Yiqun , Yi Mingyang , Roudier Martine P. , Regier Mary C. , Dumpit Ruth , Nelson Peter S. , Headley Mark , True Lawrence , Lin Daniel W. , Morrissey Colm , Creighton Chad J. , Xin Li 
Published: November 2022

AbstractCancer-associated fibroblasts (CAFs) mediate an immunosuppressive effect, but the underlying mechanism remains incompletely defined. Here we show that increasing prostatic stromal Foxf2 suppresses the growth and progression of both syngeneic and autochthonous mouse prostate cancer models in an immunocompetent context. Mechanistically, Foxf2 moderately attenuates the CAF phenotype and transcriptionally downregulates Cxcl5, which diminish the immunosuppressive myeloid cells and enhance T cell cytotoxicity. Increasing prostatic stromal Foxf2 sensitizes prostate cancer to the immune checkpoint blockade therapies. Augmenting lung stromal Foxf2 also mediates an immunosuppressive milieu and inhibits lung colonization of prostate cancer. FOXF2 is expressed higher in the stroma of human transition zone (TZ) than peripheral zone (PZ) prostate. The stromal FOXF2 expression level in primary prostate cancers inversely correlates with the Gleason grade. Our study establishes Foxf2 as a stromal transcription factor modulating the tumor immune microenvironment and potentially explains why cancers are relatively rare and indolent in the TZ prostate.
Disulfiram ameliorates nonalcoholic steatohepatitis by modulating the gut microbiota and bile acid metabolism
Authors: Lei Yuanyuan , Tang Li , Chen Qiao , Wu Lingyi , He Wei , Tu Dianji , Wang Sumin , Chen Yuyang , Liu Shuang , Xie Zhuo , Wei Hong , Yang Shiming , Tang Bo 
Published: November 2022

AbstractNonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, we investigate the potential for repurposing disulfiram (DSF), a drug commonly used to treat chronic alcoholism, for NASH. Using a mouse model, we show that DSF ameliorates NASH in a gut microbiota-dependent manner. DSF modulates the gut microbiota and directly inhibits the growth of Clostridium. Administration of Clostridium abolishes the ameliorating effects of DSF on NASH. Mechanistically, DSF reduces Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis, which in turn activates hepatic farnesoid X receptor signaling to ameliorate NASH. To assess the effect of DSF on human gut microbiota, we performed a self-controlled clinical trial (ChiCTR2100048035), including 23 healthy volunteers who received 250 mg-qd DSF for 7 days. The primary objective outcomes were to assess the effects of the intervention on the diversity, composition and functional profile of gut microbiota. The pilot study shows that DSF also reduces Clostridium-mediated 7α-dehydroxylation activity. All volunteers tolerated DSF well and there were no serious adverse events in the 7-day follow-up period. Transferring fecal microbiota obtained from DSF-treated humans into germ-free mice ameliorates NASH. Collectively, the observations of similar ameliorating effects of DSF on mice and humans suggest that DSF ameliorates NASH by modulating the gut microbiota and bile acid metabolism.