bluuebunny/crossref_metadata_2025_split huggingface dataset:
Network medicine for disease module identification and drug repurposing with the NeDRex platform
Authors: Sadegh Sepideh , Skelton James , Anastasi Elisa , Bernett Judith , Blumenthal David B. , Galindez Gihanna , Salgado-Albarrán Marisol , Lazareva Olga , Flanagan Keith , Cockell Simon , Nogales Cristian , Casas Ana I. , Schmidt Harald H. H. W. , Baumbach Jan , Wipat Anil , Kacprowski Tim 
Published: November 2021

AbstractTraditional drug discovery faces a severe efficacy crisis. Repurposing of registered drugs provides an alternative with lower costs and faster drug development timelines. However, the data necessary for the identification of disease modules, i.e. pathways and sub-networks describing the mechanisms of complex diseases which contain potential drug targets, are scattered across independent databases. Moreover, existing studies are limited to predictions for specific diseases or non-translational algorithmic approaches. There is an unmet need for adaptable tools allowing biomedical researchers to employ network-based drug repurposing approaches for their individual use cases. We close this gap with NeDRex, an integrative and interactive platform for network-based drug repurposing and disease module discovery. NeDRex integrates ten different data sources covering genes, drugs, drug targets, disease annotations, and their relationships. NeDRex allows for constructing heterogeneous biological networks, mining them for disease modules, prioritizing drugs targeting disease mechanisms, and statistical validation. We demonstrate the utility of NeDRex in five specific use-cases.
Gene editing enables rapid engineering of complex antibiotic assembly lines
Authors: Thong Wei Li , Zhang Yingxin , Zhuo Ying , Robins Katherine J. , Fyans Joanna K. , Herbert Abigail J. , Law Brian J. C. , Micklefield Jason 
Published: November 2021

AbstractRe-engineering biosynthetic assembly lines, including nonribosomal peptide synthetases (NRPS) and related megasynthase enzymes, is a powerful route to new antibiotics and other bioactive natural products that are too complex for chemical synthesis. However, engineering megasynthases is very challenging using current methods. Here, we describe how CRISPR-Cas9 gene editing can be exploited to rapidly engineer one of the most complex megasynthase assembly lines in nature, the 2.0 MDa NRPS enzymes that deliver the lipopeptide antibiotic enduracidin. Gene editing was used to exchange subdomains within the NRPS, altering substrate selectivity, leading to ten new lipopeptide variants in good yields. In contrast, attempts to engineer the same NRPS using a conventional homologous recombination-mediated gene knockout and complementation approach resulted in only traces of new enduracidin variants. In addition to exchanging subdomains within the enduracidin NRPS, subdomains from a range of NRPS enzymes of diverse bacterial origins were also successfully utilized.
Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms
Authors: Ornik-Cha Alina , Wilhelm Julia , Kobylka Jessica , Sjuts Hanno , Vargiu Attilio V. , Malloci Giuliano , Reitz Julian , Seybert Anja , Frangakis Achilleas S. , Pos Klaas M. 
Published: November 2021

AbstractUpon antibiotic stress Gram-negative pathogens deploy resistance-nodulation-cell division-type tripartite efflux pumps. These include a H+/drug antiporter module that recognizes structurally diverse substances, including antibiotics. Here, we show the 3.5 Å structure of subunit AdeB from theAcinetobacter baumanniiAdeABC efflux pump solved by single-particle cryo-electron microscopy. The AdeB trimer adopts mainly a resting state with all protomers in a conformation devoid of transport channels or antibiotic binding sites. However, 10% of the protomers adopt a state where three transport channels lead to the closed substrate (deep) binding pocket. A comparison between drug binding of AdeB andEscherichia coliAcrB is made via activity analysis of 20 AdeB variants, selected on basis of side chain interactions with antibiotics observed in the AcrB periplasmic domain X-ray co-structures with fusidic acid (2.3 Å), doxycycline (2.1 Å) and levofloxacin (2.7 Å). AdeABC, compared to AcrAB-TolC, confers higher resistance toE. colitowards polyaromatic compounds and lower resistance towards antibiotic compounds.
scCODA is a Bayesian model for compositional single-cell data analysis
Authors: Büttner M. , Ostner J. , Müller C. L. , Theis F. J. , Schubert B. 
Published: November 2021

AbstractCompositional changes of cell types are main drivers of biological processes. Their detection through single-cell experiments is difficult due to the compositionality of the data and low sample sizes. We introduce scCODA (https://github.com/theislab/scCODA), a Bayesian model addressing these issues enabling the study of complex cell type effects in disease, and other stimuli. scCODA demonstrated excellent detection performance, while reliably controlling for false discoveries, and identified experimentally verified cell type changes that were missed in original analyses.
Initiation of cytosolic plant purine nucleotide catabolism involves a monospecific xanthosine monophosphate phosphatase
Authors: Heinemann Katharina J. , Yang Sun-Young , Straube Henryk , Medina-Escobar Nieves , Varbanova-Herde Marina , Herde Marco , Rhee Sangkee , Witte Claus-Peter 
Published: November 2021

AbstractIn plants, guanosine monophosphate (GMP) is synthesized from adenosine monophosphate via inosine monophosphate and xanthosine monophosphate (XMP) in the cytosol. It has been shown recently that the catabolic route for adenylate-derived nucleotides bifurcates at XMP from this biosynthetic route. Dephosphorylation of XMP and GMP by as yet unknown phosphatases can initiate cytosolic purine nucleotide catabolism. Here we show that Arabidopsis thaliana possesses a highly XMP-specific phosphatase (XMPP) which is conserved in vascular plants. We demonstrate that XMPP catalyzes the irreversible entry reaction of adenylate-derived nucleotides into purine nucleotide catabolism in vivo, whereas the guanylates enter catabolism via an unidentified GMP phosphatase and guanosine deaminase which are important to maintain purine nucleotide homeostasis. We also present a crystal structure and mutational analysis of XMPP providing a rationale for its exceptionally high substrate specificity, which is likely required for the efficient catalysis of the very small XMP pool in vivo.
Plant LHC-like proteins show robust folding and static non-photochemical quenching
Authors: Skotnicová Petra , Staleva-Musto Hristina , Kuznetsova Valentyna , Bína David , Konert Minna M. , Lu Shan , Polívka Tomáš , Sobotka Roman 
Published: November 2021

AbstractLife on Earth depends on photosynthesis, the conversion of light energy into chemical energy. Plants collect photons by light harvesting complexes (LHC)—abundant membrane proteins containing chlorophyll and xanthophyll molecules. LHC-like proteins are similar in their amino acid sequence to true LHC antennae, however, they rather serve a photoprotective function. How pigments associated with LHC-like proteins are organised and how they contribute to protein function has not yet been determined. Here, we characterize plant LHC-like proteins (LIL3 and ELIP2) produced in the cyanobacterium Synechocystis sp. PCC 6803 (hereafter Synechocystis). Both proteins were associated with chlorophyll a (Chl) and zeaxanthin and LIL3 was shown to be capable of quenching Chl fluorescence via direct energy transfer from the Chl Qy state to zeaxanthin S1 state. Interestingly, the ability of the ELIP2 protein to quench can be acquired by modifying its N-terminal sequence. By employing Synechocystis carotenoid mutants and site-directed mutagenesis we demonstrate that, although LIL3 does not need pigments for folding, pigments stabilize the LIL3 dimer.
SARS-CoV-2 transmission across age groups in France and implications for control
Authors: Tran Kiem Cécile , Bosetti Paolo , Paireau Juliette , Crépey Pascal , Salje Henrik , Lefrancq Noémie , Fontanet Arnaud , Benamouzig Daniel , Boëlle Pierre-Yves , Desenclos Jean-Claude , Opatowski Lulla , Cauchemez Simon 
Published: November 2021

AbstractThe shielding of older individuals has been proposed to limit COVID-19 hospitalizations while relaxing general social distancing in the absence of vaccines. Evaluating such approaches requires a deep understanding of transmission dynamics across ages. Here, we use detailed age-specific case and hospitalization data to model the rebound in the French epidemic in summer 2020, characterize age-specific transmission dynamics and critically evaluate different age-targeted intervention measures in the absence of vaccines. We find that while the rebound started in young adults, it reached individuals aged ≥80 y.o. after 4 weeks, despite substantial contact reductions, indicating substantial transmission flows across ages. We derive the contribution of each age group to transmission. While shielding older individuals reduces mortality, it is insufficient to allow major relaxations of social distancing. When the epidemic remains manageable (R close to 1), targeting those most contributing to transmission is better than shielding at-risk individuals. Pandemic control requires an effort from all age groups.
Volcanic activity and hazard in the East African Rift Zone
Authors: Biggs Juliet , Ayele Atalay , Fischer Tobias P. , Fontijn Karen , Hutchison William , Kazimoto Emmanuel , Whaler Kathy , Wright Tim J. 
Published: November 2021

AbstractOver the past two decades, multidisciplinary studies have unearthed a rich history of volcanic activity and unrest in the densely-populated East African Rift System, providing new insights into the influence of rift dynamics on magmatism, the characteristics of the volcanic plumbing systems and the foundation for hazard assessments. The raised awareness of volcanic hazards is driving a shift from crisis response to reducing disaster risks, but a lack of institutional and human capacity in sub-Saharan Africa means baseline data are sparse and mitigating geohazards remains challenging.
Cell-fate transition and determination analysis of mouse male germ cells throughout development
Authors: Zhao Jiexiang , Lu Ping , Wan Cong , Huang Yaping , Cui Manman , Yang Xinyan , Hu Yuqiong , Zheng Yi , Dong Ji , Wang Mei , Zhang Shu , Liu Zhaoting , Bian Shuhui , Wang Xiaoman , Wang Rui , Ren Shaofang , Wang Dazhuang , Yao Zhaokai , Chang Gang , Tang Fuchou , Zhao Xiao-Yang 
Published: November 2021

AbstractMammalian male germ cell development is a stepwise cell-fate transition process; however, the full-term developmental profile of male germ cells remains undefined. Here, by interrogating the high-precision transcriptome atlas of 11,598 cells covering 28 critical time-points, we demonstrate that cell-fate transition from mitotic to post-mitotic primordial germ cells is accompanied by transcriptome-scale reconfiguration and a transitional cell state. Notch signaling pathway is essential for initiating mitotic arrest and the maintenance of male germ cells’ identities. Ablation of HELQ induces developmental arrest and abnormal transcriptome reprogramming of male germ cells, indicating the importance of cell cycle regulation for proper cell-fate transition. Finally, systematic human-mouse comparison reveals potential regulators whose deficiency contributed to human male infertility via mitotic arrest regulation. Collectively, our study provides an accurate and comprehensive transcriptome atlas of the male germline cycle and allows for an in-depth understanding of the cell-fate transition and determination underlying male germ cell development.
A supergene underlies linked variation in color and morphology in a Holarctic songbird
Authors: Funk Erik R. , Mason Nicholas A. , Pálsson Snæbjörn , Albrecht Tomáš , Johnson Jeff A. , Taylor Scott A. 
Published: November 2021

AbstractThe genetic architecture of a phenotype can have considerable effects on the evolution of a trait or species. Characterizing genetic architecture provides insight into the complexity of a given phenotype and, potentially, the role of the phenotype in evolutionary processes like speciation. We use genome sequences to investigate the genetic basis of phenotypic variation in redpoll finches (Acanthis spp.). We demonstrate that variation in redpoll phenotype is broadly controlled by a ~55-Mb chromosomal inversion. Within this inversion, we find multiple candidate genes related to melanogenesis, carotenoid coloration, and bill shape, suggesting the inversion acts as a supergene controlling multiple linked traits. A latitudinal gradient in ecotype distribution suggests supergene driven variation in color and bill morphology are likely under environmental selection, maintaining supergene haplotypes as a balanced polymorphism. Our results provide a mechanism for the maintenance of ecotype variation in redpolls despite a genome largely homogenized by gene flow.
Architecture of the outer-membrane core complex from a conjugative type IV secretion system
Authors: Amin Himani , Ilangovan Aravindan , Costa Tiago R. D. 
Published: November 2021

AbstractConjugation is one of the most important processes that bacteria utilize to spread antibiotic resistance genes among bacterial populations. Interbacterial DNA transfer requires a large double membrane-spanning nanomachine called the type 4 secretion system (T4SS) made up of the inner-membrane complex (IMC), the outer-membrane core complex (OMCC) and the conjugative pilus. The iconic F plasmid-encoded T4SS has been central in understanding conjugation for several decades, however atomic details of its structure are not known. Here, we report the structure of a complete conjugative OMCC encoded by the pED208 plasmid from E. coli, solved by cryo-electron microscopy at 3.3 Å resolution. This 2.1 MDa complex has a unique arrangement with two radial concentric rings, each having a different symmetry eventually contributing to remarkable differences in protein stoichiometry and flexibility in comparison to other OMCCs. Our structure suggests that F-OMCC is a highly dynamic complex, with implications for pilus extension and retraction during conjugation.
Defect engineering on V2O3 cathode for long-cycling aqueous zinc metal batteries
Authors: Zhu Kefu , Wei Shiqiang , Shou Hongwei , Shen Feiran , Chen Shuangming , Zhang Pengjun , Wang Changda , Cao Yuyang , Guo Xin , Luo Mi , Zhang Hongjun , Ye Bangjiao , Wu Xiaojun , He Lunhua , Song Li 
Published: November 2021

AbstractDefect engineering is a strategy that is attracting widespread attention for the possibility of modifying battery active materials in order to improve the cycling stability of the electrodes. However, accurate investigation and quantification of the effect of the defects on the electrochemical energy storage performance of the cell are not trivial tasks. Herein, we report the quantification of vanadium-defective clusters (i.e., up to 5.7%) in the V2O3 lattice via neutron and X-ray powder diffraction measurements, positron annihilation lifetime spectroscopy, and synchrotron-based X-ray analysis. When the vanadium-defective V2O3 is employed as cathode active material in an aqueous Zn coin cell configuration, capacity retention of about 81% after 30,000 cycles at 5 A g−1 is achieved. Density functional theory calculations indicate that the vanadium-defective clusters can provide favorable sites for reversible Zn-ion storage. Moreover, the vanadium-defective clusters allow the storage of Zn ions in V2O3, which reduces the electrostatic interaction between the host material and the multivalent ions.
Hematopoiesis under telomere attrition at the single-cell resolution
Authors: Thongon Natthakan , Ma Feiyang , Santoni Andrea , Marchesini Matteo , Fiorini Elena , Rose Ashley , Adema Vera , Ganan-Gomez Irene , Groarke Emma M. , Gutierrez-Rodrigues Fernanda , Chen Shuaitong , Lockyer Pamela , Schneider Sarah , Bueso-Ramos Carlos , Montalban-Bravo Guillermo , Class Caleb A. , Soltysiak Kelly A. , Pellegrini Matteo , Sahin Ergun , Bertuch Alison A. , DiNardo Courtney D. , Garcia-Manero Guillermo , Young Neal S. , Dwyer Karen , Colla Simona 
Published: November 2021

AbstractThe molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells’ self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells’ skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance.
Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,
Authors: Lv Dongwen , Pal Pratik , Liu Xingui , Jia Yannan , Thummuri Dinesh , Zhang Peiyi , Hu Wanyi , Pei Jing , Zhang Qi , Zhou Shuo , Khan Sajid , Zhang Xuan , Hua Nan , Yang Qingping , Arango Sebastian , Zhang Weizhou , Nayak Digant , Olsen Shaun K. , Weintraub Susan T. , Hromas Robert , Konopleva Marina , Yuan Yaxia , Zheng Guangrong , Zhou Daohong 
Published: November 2021

AbstractPROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.
Species richness and identity both determine the biomass of global reef fish communities
Authors: Lefcheck Jonathan S. , Edgar Graham J. , Stuart-Smith Rick D. , Bates Amanda E. , Waldock Conor , Brandl Simon J. , Kininmonth Stuart , Ling Scott D. , Duffy J. Emmett , Rasher Douglas B. , Agrawal Aneil F. 
Published: November 2021

AbstractChanging biodiversity alters ecosystem functioning in nature, but the degree to which this relationship depends on the taxonomic identities rather than the number of species remains untested at broad scales. Here, we partition the effects of declining species richness and changing community composition on fish community biomass across >3000 coral and rocky reef sites globally. We find that high biodiversity is 5.7x more important in maximizing biomass than the remaining influence of other ecological and environmental factors. Differences in fish community biomass across space are equally driven by both reductions in the total number of species and the disproportionate loss of larger-than-average species, which is exacerbated at sites impacted by humans. Our results confirm that sustaining biomass and associated ecosystem functions requires protecting diversity, most importantly of multiple large-bodied species in areas subject to strong human influences.
6 nm super-resolution optical transmission and scattering spectroscopic imaging of carbon nanotubes using a nanometer-scale white light source
Authors: Ma Xuezhi , Liu Qiushi , Yu Ning , Xu Da , Kim Sanggon , Liu Zebin , Jiang Kaili , Wong Bryan M. , Yan Ruoxue , Liu Ming 
Published: November 2021

AbstractOptical transmission and scattering spectroscopic microscopy at the visible and adjacent wavelengths denote one of the most informative and inclusive characterization methods in material research. Unfortunately, restricted by the diffraction limit of light, it cannot resolve the nanoscale variation in light absorption and scattering, diagnostics of the local inhomogeneity in material structure and properties. Moreover, a large quantity of nanomaterials has anisotropic optical properties that are appealing yet hard to characterize through conventional optical methods. There is an increasing demand to extend the optical hyperspectral imaging into the nanometer length scale. In this work, we report a super-resolution hyperspectral imaging technique that uses a nanoscale white light source generated by superfocusing the light from a tungsten-halogen lamp to simultaneously obtain optical transmission and scattering spectroscopic images. A 6-nm spatial resolution in the visible to near-infrared wavelength regime (415–980 nm) is demonstrated on an individual single-walled carbon nanotube (SW-CNT). Both the longitudinal and transverse optical electronic transitions are measured, and the SW-CNT chiral indices can be identified. The band structure modulation in a SW-CNT through strain engineering is mapped.
Self-activating anti-infection implant
Authors: Fu Jieni , Zhu Weidong , Liu Xiangmei , Liang Chunyong , Zheng Yufeng , Li Zhaoyang , Liang Yanqin , Zheng Dong , Zhu Shengli , Cui Zhenduo , Wu Shuilin 
Published: November 2021

AbstractClinically, it is difficult to endow implants with excellent osteogenic ability and antibacterial activity simultaneously. Herein, the self-activating implants modified with hydroxyapatite (HA)/MoS2 coating are designed to prevent Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) infections and accelerate bone regeneration simultaneously. The electron transfer between bacteria and HA/MoS2 is triggered when bacteria contacted with the material. RNA sequencing data reveals that the expression level of anaerobic respiration–related genes is up-regulated and the expression level of aerobic respiration–related genes is down-regulated when bacteria adhere to the implants. HA/MoS2 presents a highly effective antibacterial efficacy against both S. aureus and E. coli because of bacterial respiration–activated metabolic pathway changes. Meanwhile, this coating promotes the osteoblastic differentiation of mesenchymal stem cells by altering the potentials of cell membrane and mitochondrial membrane. The proposed strategy exhibits great potential to endow implants with self-activating anti-infection performance and osteogenic ability simultaneously.