bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO
Authors: de la Fuente-Alonso Andrea , Toral Marta , Alfayate Alvaro , Ruiz-Rodríguez María Jesús , Bonzón-Kulichenko Elena , Teixido-Tura Gisela , Martínez-Martínez Sara , Méndez-Olivares María José , López-Maderuelo Dolores , González-Valdés Ileana , Garcia-Izquierdo Eusebio , Mingo Susana , Martín Carlos E. , Muiño-Mosquera Laura , De Backer Julie , Nistal J. Francisco , Forteza Alberto , Evangelista Arturo , Vázquez Jesús , Campanero Miguel R. , Redondo Juan Miguel 
Published: May 2021

AbstractThoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.
Observation of ordered organic capping ligands on semiconducting quantum dots via powder X-ray diffraction
Authors: Calvin Jason J. , Kaufman Tierni M. , Sedlak Adam B. , Crook Michelle F. , Alivisatos A. Paul 
Published: May 2021

AbstractPowder X-ray diffraction is one of the key techniques used to characterize the inorganic structure of colloidal nanocrystals. The comparatively low scattering factor of nuclei of the organic capping ligands and their propensity to be disordered has led investigators to typically consider them effectively invisible to this technique. In this report, we demonstrate that a commonly observed powder X-ray diffraction peak around $$q=1.4{\AA}^{-1}$$
q
=
1.4

Å

−
1

observed in many small, colloidal quantum dots can be assigned to well-ordered aliphatic ligands bound to and capping the nanocrystals. This conclusion differs from a variety of explanations ascribed by previous sources, the majority of which propose an excess of organic material. Additionally, we demonstrate that the observed ligand peak is a sensitive probe of ligand shell ordering. Changes as a function of ligand length, geometry, and temperature can all be readily observed by X-ray diffraction and manipulated to achieve desired outcomes for the final colloidal system.
Asymmetric cell division shapes naive and virtual memory T-cell immunity during ageing
Authors: Borsa Mariana , Barandun Niculò , Gräbnitz Fabienne , Barnstorf Isabel , Baumann Nicolas S. , Pallmer Katharina , Baumann Samira , Stark Dominique , Balaz Miroslav , Oetiker Nathalie , Wagen Franziska , Wolfrum Christian , Simon Anna Katharina , Joller Nicole , Barral Yves , Spörri Roman , Oxenius Annette 
Published: May 2021

AbstractEfficient immune responses rely on heterogeneity, which in CD8+ T cells, amongst other mechanisms, is achieved by asymmetric cell division (ACD). Here we find that ageing, known to negatively impact immune responses, impairs ACD in murine CD8+ T cells, and that this phenotype can be rescued by transient mTOR inhibition. Increased ACD rates in mitotic cells from aged mice restore the expansion and memory potential of their cellular progenies. Further characterization of the composition of CD8+ T cells reveals that virtual memory cells (TVM cells), which accumulate during ageing, have a unique proliferation and metabolic profile, and retain their ability to divide asymmetrically, which correlates with increased memory potential. The opposite is observed for naive CD8+ T cells from aged mice. Our data provide evidence on how ACD modulation contributes to long-term survival and function of T cells during ageing, offering new insights into how the immune system adapts to ageing.
Taxonomic signatures of cause-specific mortality risk in human gut microbiome
Authors: Salosensaari Aaro , Laitinen Ville , Havulinna Aki S. , Meric Guillaume , Cheng Susan , Perola Markus , Valsta Liisa , Alfthan Georg , Inouye Michael , Watrous Jeramie D. , Long Tao , Salido Rodolfo A. , Sanders Karenina , Brennan Caitriona , Humphrey Gregory C. , Sanders Jon G. , Jain Mohit , Jousilahti Pekka , Salomaa Veikko , Knight Rob , Lahti Leo , Niiranen Teemu 
Published: May 2021

AbstractThe collection of fecal material and developments in sequencing technologies have enabled standardised and non-invasive gut microbiome profiling. Microbiome composition from several large cohorts have been cross-sectionally linked to various lifestyle factors and diseases. In spite of these advances, prospective associations between microbiome composition and health have remained uncharacterised due to the lack of sufficiently large and representative population cohorts with comprehensive follow-up data. Here, we analyse the long-term association between gut microbiome variation and mortality in a well-phenotyped and representative population cohort from Finland (n = 7211). We report robust taxonomic and functional microbiome signatures related to the Enterobacteriaceae family that are associated with mortality risk during a 15-year follow-up. Our results extend previous cross-sectional studies, and help to establish the basis for examining long-term associations between human gut microbiome composition, incident outcomes, and general health status.
Macrocyclic peptides exhibit antiviral effects against influenza virus HA and prevent pneumonia in animal models
Authors: Saito Makoto , Itoh Yasushi , Yasui Fumihiko , Munakata Tsubasa , Yamane Daisuke , Ozawa Makoto , Ito Risa , Katoh Takayuki , Ishigaki Hirohito , Nakayama Misako , Shichinohe Shintaro , Yamaji Kenzaburo , Yamamoto Naoki , Ikejiri Ai , Honda Tomoko , Sanada Takahiro , Sakoda Yoshihiro , Kida Hiroshi , Le Thi Quynh Mai , Kawaoka Yoshihiro , Ogasawara Kazumasa , Tsukiyama-Kohara Kyoko , Suga Hiroaki , Kohara Michinori 
Published: May 2021

AbstractMost anti-influenza drugs currently used, such as oseltamivir and zanamivir, inhibit the enzymatic activity of neuraminidase. However, neuraminidase inhibitor-resistant viruses have already been identified from various influenza virus isolates. Here, we report the development of a class of macrocyclic peptides that bind the influenza viral envelope protein hemagglutinin, named iHA. Of 28 iHAs examined, iHA-24 and iHA-100 have inhibitory effects on the in vitro replication of a wide range of Group 1 influenza viruses. In particular, iHA-100 bifunctionally inhibits hemagglutinin-mediated adsorption and membrane fusion through binding to the stalk domain of hemagglutinin. Moreover, iHA-100 shows powerful efficacy in inhibiting the growth of highly pathogenic influenza viruses and preventing severe pneumonia at later stages of infection in mouse and non-human primate cynomolgus macaque models. This study shows the potential for developing cyclic peptides that can be produced more efficiently than antibodies and have multiple functions as next-generation, mid-sized biomolecules.
Selective and noncovalent targeting of RAS mutants for inhibition and degradation
Authors: Teng Kai Wen , Tsai Steven T. , Hattori Takamitsu , Fedele Carmine , Koide Akiko , Yang Chao , Hou Xuben , Zhang Yingkai , Neel Benjamin G. , O’Bryan John P. , Koide Shohei 
Published: May 2021

AbstractActivating mutants of RAS are commonly found in human cancers, but to date selective targeting of RAS in the clinic has been limited to KRAS(G12C) through covalent inhibitors. Here, we report a monobody, termed 12VC1, that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS. The crystal structures reveal that 12VC1 recognizes the mutations through a shallow pocket, and 12VC1 competes against RAS-effector interaction. When expressed intracellularly, 12VC1 potently inhibits ERK activation and the proliferation of RAS-driven cancer cell lines in vitro and in mouse xenograft models. 12VC1 fused to VHL selectively degrades the KRAS mutants and provides more extended suppression of mutant RAS activity than inhibition by 12VC1 alone. These results demonstrate the feasibility of selective targeting and degradation of KRAS mutants in the active state with noncovalent reagents and provide a starting point for designing noncovalent therapeutics against oncogenic RAS mutants.
Conserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation
Authors: Mijnheer Gerdien , Lutter Lisanne , Mokry Michal , van der Wal Marlot , Scholman Rianne , Fleskens Veerle , Pandit Aridaman , Tao Weiyang , Wekking Mark , Vervoort Stephin , Roberts Ceri , Petrelli Alessandra , Peeters Janneke G. C. , Knijff Marthe , de Roock Sytze , Vastert Sebastiaan , Taams Leonie S. , van Loosdregt Jorg , van Wijk Femke 
Published: May 2021

AbstractTreg cells are critical regulators of immune homeostasis, and environment-driven Treg cell differentiation into effector (e)Treg cells is crucial for optimal functioning. However, human Treg cell programming in inflammation is unclear. Here, we combine transcriptional and epigenetic profiling to identify a human eTreg cell signature. Inflammation-derived functional Treg cells have a transcriptional profile characterized by upregulation of both a core Treg cell (FOXP3, CTLA4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identify a specific human eTreg cell signature that includes the vitamin D receptor (VDR) as a predicted regulator in eTreg cell differentiation. H3K27ac/H3K4me1 occupancy indicates an altered (super-)enhancer landscape, including enrichment of the VDR and BATF binding motifs. The Treg cell profile has striking overlap with tumor-infiltrating Treg cells. Our data demonstrate that human inflammation-derived Treg cells acquire a conserved and specific eTreg cell profile guided by epigenetic changes, and fine-tuned by environment-specific adaptations.
Scalable recombinase-based gene expression cascades
Authors: Kim Tackhoon , Weinberg Benjamin , Wong Wilson , Lu Timothy K. 
Published: May 2021

AbstractTemporal modulation of the expression of multiple genes underlies complex complex biological phenomena. However, there are few scalable and generalizable gene circuit architectures for the programming of sequential genetic perturbations. Here, we describe a modular recombinase-based gene circuit architecture, comprising tandem gene perturbation cassettes (GPCs), that enables the sequential expression of multiple genes in a defined temporal order by alternating treatment with just two orthogonal ligands. We use tandem GPCs to sequentially express single-guide RNAs to encode transcriptional cascades that trigger the sequential accumulation of mutations. We build an all-in-one gene circuit that sequentially edits genomic loci, synchronizes cells at a specific stage within a gene expression cascade, and deletes itself for safety. Tandem GPCs offer a multi-tiered cellular programming tool for modeling multi-stage genetic changes, such as tumorigenesis and cellular differentiation.
Sugar transporters enable a leaf beetle to accumulate plant defense compounds
Authors: Yang Zhi-Ling , Nour-Eldin Hussam Hassan , Hänniger Sabine , Reichelt Michael , Crocoll Christoph , Seitz Fabian , Vogel Heiko , Beran Franziska 
Published: May 2021

AbstractMany herbivorous insects selectively accumulate plant toxins for defense against predators; however, little is known about the transport processes that enable insects to absorb and store defense compounds in the body. Here, we investigate how a specialist herbivore, the horseradish flea beetle, accumulates glucosinolate defense compounds from Brassicaceae in the hemolymph. Using phylogenetic analyses of coleopteran major facilitator superfamily transporters, we identify a clade of glucosinolate-specific transporters (PaGTRs) belonging to the sugar porter family.PaGTRsare predominantly expressed in the excretory system, the Malpighian tubules. Silencing ofPaGTRs leads to elevated glucosinolate excretion, significantly reducing the levels of sequestered glucosinolates in beetles. This suggests thatPaGTRs reabsorb glucosinolates from the Malpighian tubule lumen to prevent their loss by excretion. Ramsay assays corroborated the selective retention of glucosinolates by Malpighian tubules ofP. armoraciaein situ. Thus, the selective accumulation of plant defense compounds in herbivorous insects can depend on the ability to prevent excretion.
Hierarchical communication of chirality for aromatic oligoamide sequences
Authors: Zhang Jiajia , Luo Dan , Ma Chunmiao , Huang Lu , Gan Quan 
Published: May 2021

AbstractThe communication of chirality at a molecular and supramolecular level is the fundamental feature capable of transmitting and amplifying chirality information. Yet, the limitation of one-step communication mode in many artificial systems has precluded the ability of further processing the chirality information. Here, we report the chirality communication of aromatic oligoamide sequences within the interpenetrated helicate architecture in a hierarchical manner, specifically, the communication is manipulated by three sequential steps: (i) coordination, (ii) concentration, and (iii) ion stimulus. Such approach enables the information to be implemented progressively and reversibly to different levels. Furthermore, the chiral information on the side chains can be accumulated and transferred to the helical backbones of the sequences, resulting in that one of ten possible diastereoisomers of the interpenetrated helicate is finally selected. The circular dichroism experiments with a mixture of chiral and achiral ligands demonstrate a cooperative behavior of these communications, leading to amplification of chiral information.
Integration of machine learning and genome-scale metabolic modeling identifies multi-omics biomarkers for radiation resistance
Authors: Lewis Joshua E. , Kemp Melissa L. 
Published: May 2021

AbstractResistance to ionizing radiation, a first-line therapy for many cancers, is a major clinical challenge. Personalized prediction of tumor radiosensitivity is not currently implemented clinically due to insufficient accuracy of existing machine learning classifiers. Despite the acknowledged role of tumor metabolism in radiation response, metabolomics data is rarely collected in large multi-omics initiatives such as The Cancer Genome Atlas (TCGA) and consequently omitted from algorithm development. In this study, we circumvent the paucity of personalized metabolomics information by characterizing 915 TCGA patient tumors with genome-scale metabolic Flux Balance Analysis models generated from transcriptomic and genomic datasets. Metabolic biomarkers differentiating radiation-sensitive and -resistant tumors are predicted and experimentally validated, enabling integration of metabolic features with other multi-omics datasets into ensemble-based machine learning classifiers for radiation response. These multi-omics classifiers show improved classification accuracy, identify clinical patient subgroups, and demonstrate the utility of personalized blood-based metabolic biomarkers for radiation sensitivity. The integration of machine learning with genome-scale metabolic modeling represents a significant methodological advancement for identifying prognostic metabolite biomarkers and predicting radiosensitivity for individual patients.
Structural visualization of transcription activated by a multidrug-sensing MerR family regulator
Authors: Yang Yang , Liu Chang , Zhou Wei , Shi Wei , Chen Ming , Zhang Baoyue , Schatz David G. , Hu Yangbo , Liu Bin 
Published: May 2021

AbstractBacterial RNA polymerase (RNAP) holoenzyme initiates transcription by recognizing the conserved –35 and –10 promoter elements that are optimally separated by a 17-bp spacer. The MerR family of transcriptional regulators activate suboptimal 19–20 bp spacer promoters in response to myriad cellular signals, ranging from heavy metals to drug-like compounds. The regulation of transcription by MerR family regulators is not fully understood. Here we report one crystal structure of a multidrug-sensing MerR family regulator EcmrR and nine cryo-electron microscopy structures that capture the EcmrR-dependent transcription process from promoter opening to initial transcription to RNA elongation. These structures reveal that EcmrR is a dual ligand-binding factor that reshapes the suboptimal 19-bp spacer DNA to enable optimal promoter recognition, sustains promoter remodeling to stabilize initial transcribing complexes, and finally dissociates from the promoter to reverse DNA remodeling and facilitate the transition to elongation. Our findings yield a comprehensive model for transcription regulation by MerR family factors and provide insights into the transition from transcription initiation to elongation.
Ternary nickel–tungsten–copper alloy rivals platinum for catalyzing alkaline hydrogen oxidation
Authors: Qin Shuai , Duan Yu , Zhang Xiao-Long , Zheng Li-Rong , Gao Fei-Yue , Yang Peng-Peng , Niu Zhuang-Zhuang , Liu Ren , Yang Yu , Zheng Xu-Sheng , Zhu Jun-Fa , Gao Min-Rui 
Published: May 2021

AbstractOperating fuel cells in alkaline environments permits the use of platinum-group-metal-free (PGM-free) catalysts and inexpensive bipolar plates, leading to significant cost reduction. Of the PGM-free catalysts explored, however, only a few nickel-based materials are active for catalyzing the hydrogen oxidation reaction (HOR) in alkali; moreover, these catalysts deactivate rapidly at high anode potentials owing to nickel hydroxide formation. Here we describe that a nickel–tungsten–copper (Ni5.2WCu2.2) ternary alloy showing HOR activity rivals Pt/C benchmark in alkaline electrolyte. Importantly, we achieved a high anode potential up to 0.3 V versus reversible hydrogen electrode on this catalyst with good operational stability over 20 h. The catalyst also displays excellent CO-tolerant ability that Pt/C catalyst lacks. Experimental and theoretical studies uncover that nickel, tungsten, and copper play in synergy to create a favorable alloying surface for optimized hydrogen and hydroxyl bindings, as well as for the improved oxidation resistance, which result in the HOR enhancement.
Identification of poly(ADP-ribose) polymerase 9 (PARP9) as a noncanonical sensor for RNA virus in dendritic cells
Authors: Xing Junji , Zhang Ao , Du Yong , Fang Mingli , Minze Laurie J. , Liu Yong-Jun , Li Xian Chang , Zhang Zhiqiang 
Published: May 2021

AbstractInnate immune cells are critical in protective immunity against viral infections, involved in sensing foreign viral nucleic acids. Here we report that the poly(ADP-ribose) polymerase 9 (PARP9), a member of PARP family, serves as a non-canonical sensor for RNA virus to initiate and amplify type I interferon (IFN) production. We find knockdown or deletion of PARP9 in human or mouse dendritic cells and macrophages inhibits type I IFN production in response to double strand RNA stimulation or RNA virus infection. Furthermore, mice deficient for PARP9 show enhanced susceptibility to infections with RNA viruses because of the impaired type I IFN production. Mechanistically, we show that PARP9 recognizes and binds viral RNA, with resultant recruitment and activation of the phosphoinositide 3-kinase (PI3K) and AKT3 pathway, independent of mitochondrial antiviral-signaling (MAVS). PI3K/AKT3 then activates the IRF3 and IRF7 by phosphorylating IRF3 at Ser385 and IRF7 at Ser437/438 mediating type I IFN production. Together, we reveal a critical role for PARP9 as a non-canonical RNA sensor that depends on the PI3K/AKT3 pathway to produce type I IFN. These findings may have important clinical implications in controlling viral infections and viral-induced diseases by targeting PARP9.
N-aryl pyrido cyanine derivatives are nuclear and organelle DNA markers for two-photon and super-resolution imaging
Authors: Uno Kakishi , Sugimoto Nagisa , Sato Yoshikatsu 
Published: May 2021

AbstractLive cell imaging using fluorescent DNA markers are an indispensable molecular tool in various biological and biomedical fields. It is a challenge to develop DNA probes that avoid UV light photo-excitation, have high specificity for DNA, are cell-permeable and are compatible with cutting-edge imaging techniques such as super-resolution microscopy. Herein, we present N-aryl pyrido cyanine (N-aryl-PC) derivatives as a class of long absorption DNA markers with absorption in the wide range of visible light. The high DNA specificity and membrane permeability allow the staining of both organelle DNA as well as nuclear DNA, in various cell types, including plant tissues, without the need for washing post-staining. N-aryl-PC dyes are also highly compatible with a separation of photon by lifetime tuning method in stimulated emission depletion microscopy (SPLIT-STED) for super-resolution imaging as well as two-photon microscopy for deep tissue imaging, making it a powerful tool in the life sciences.
A SARS-CoV-2 antibody curbs viral nucleocapsid protein-induced complement hyperactivation
Authors: Kang Sisi , Yang Mei , He Suhua , Wang Yueming , Chen Xiaoxue , Chen Yao-Qing , Hong Zhongsi , Liu Jing , Jiang Guanmin , Chen Qiuyue , Zhou Ziliang , Zhou Zhechong , Huang Zhaoxia , Huang Xi , He Huanhuan , Zheng Weihong , Liao Hua-Xin , Xiao Fei , Shan Hong , Chen Shoudeng 
Published: May 2021

AbstractAlthough human antibodies elicited by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein are profoundly boosted upon infection, little is known about the function of N-reactive antibodies. Herein, we isolate and profile a panel of 32 N protein-specific monoclonal antibodies (mAbs) from a quick recovery coronavirus disease-19 (COVID-19) convalescent patient who has dominant antibody responses to the SARS-CoV-2 N protein rather than to the SARS-CoV-2 spike (S) protein. The complex structure of the N protein RNA binding domain with the highest binding affinity mAb (nCoV396) reveals changes in the epitopes and antigen’s allosteric regulation. Functionally, a virus-free complement hyperactivation analysis demonstrates that nCoV396 specifically compromises the N protein-induced complement hyperactivation, which is a risk factor for the morbidity and mortality of COVID-19 patients, thus laying the foundation for the identification of functional anti-N protein mAbs.
Marine ice-cliff instability modeling shows mixed-mode ice-cliff failure and yields calving rate parameterization
Authors: Crawford Anna J. , Benn Douglas I. , Todd Joe , Åström Jan A. , Bassis Jeremy N. , Zwinger Thomas 
Published: May 2021

AbstractMarine ice-cliff instability could accelerate ice loss from Antarctica, and according to some model predictions could potentially contribute >1 m of global mean sea level rise by 2100 at current emission rates. Regions with over-deepening basins >1 km in depth (e.g., the West Antarctic Ice Sheet) are particularly susceptible to this instability, as retreat could expose increasingly tall cliffs that could exceed ice stability thresholds. Here, we use a suite of high-fidelity glacier models to improve understanding of the modes through which ice cliffs can structurally fail and derive a conservative ice-cliff failure retreat rate parameterization for ice-sheet models. Our results highlight the respective roles of viscous deformation, shear-band formation, and brittle-tensile failure within marine ice-cliff instability. Calving rates increase non-linearly with cliff height, but runaway ice-cliff retreat can be inhibited by viscous flow and back force from iceberg mélange.