bluuebunny/crossref_metadata_2025_split huggingface dataset:
Urinary metabolic biomarkers of diet quality in European children are associated with metabolic health
Authors: Stratakis Nikolaos , Siskos Alexandros P. , Papadopoulou Eleni , Nguyen Anh N. , Zhao Yinqi , Margetaki Katerina , Lau Chung-Ho E. , Coen Muireann , Maitre Lea , Fernández-Barrés Silvia , Agier Lydiane , Andrusaityte Sandra , Basagaña Xavier , Brantsaeter Anne Lise , Casas Maribel , Fossati Serena , Grazuleviciene Regina , Heude Barbara , McEachan Rosemary R C , Meltzer Helle Margrete , Millett Christopher , Rauber Fernanda , Robinson Oliver , Roumeliotaki Theano , Borràs Eva , Sabidó Eduard , Urquiza Jose , Vafeiadi Marina , Vineis Paolo , Voortman Trudy , Wright John , Conti David V. , Vrijheid Martine , Keun Hector C. , Chatzi Leda 
Published: September 2021

AbstractUrinary metabolic profiling is a promising powerful tool to reflect dietary intake and can help understand metabolic alterations in response to diet quality. Here, we used1H-NMR spectroscopy in a multi-country study in European children (1147 children from 6 different cohorts) and identified a common panel of 4 urinary metabolites (hippurate,N-methylnicotinic acid, urea and sucrose) that was predictive of Mediterranean diet adherence (KIDMED) and ultra-processed food (UPF) consumption and also had higher capacity in discriminating children’s diet quality than that of established sociodemographic determinants. Further, we showed that the identified metabolite panel also reflected the associations of these diet quality indicators with C-peptide, a stable and accurate marker of insulin resistance and future risk of metabolic disease. This methodology enables objective assessment of dietary patterns in European child populations, complementary to traditional questionary methods, and can be used in future studies to evaluate diet quality. Moreover, this knowledge can provide mechanistic evidence of common biological pathways that characterize healthy and unhealthy dietary patterns, and diet-related molecular alterations that could associate to metabolic disease.
A strategy to assess spillover risk of bat SARS-related coronaviruses in Southeast Asia
Authors: Sánchez Cecilia A. , Li Hongying , Phelps Kendra L. , Zambrana-Torrelio Carlos , Wang Lin-Fa , Olival Kevin J. , Daszak Peter 
Published: September 2021

AbstractEmerging diseases caused by coronaviruses of likely bat origin (e.g. SARS, MERS, SADS and COVID-19) have disrupted global health and economies for two decades.Evidence suggests that some bat SARS-related coronaviruses (SARSr-CoVs) could infect people directly, and that their spillover is more frequent than previously recognized. Each zoonotic spillover of a novel virus represents an opportunity for evolutionary adaptation and further spread; therefore, quantifying the extent of this “hidden” spillover may help target prevention programs. We derive biologically realistic range distributions for known bat SARSr-CoV hosts and quantify their overlap with human populations. We then use probabilistic risk assessment and data on human-bat contact, human SARSr-CoV seroprevalence, and antibody duration to estimate that ∼400,000 people (median: ∼50,000) are infected with SARSr-CoVs annually in South and Southeast Asia. These data on the geography and scale of spillover can be used to target surveillance and prevention programs for potential future bat-CoV emergence.
Antibody responses to BNT162b2 mRNA vaccine: infection-naïve individuals with abdominal obesity warrant attention
Authors: Malavazos Alexis Elias , Basilico Sara , Iacobellis Gianluca , Milani Valentina , Cardani Rosanna , Boniardi Federico , Dubini Carola , Prandoni Ilaria , Capitanio Gloria , Renna Laura Valentina , Boveri Sara , Carrara Matteo , Spuria Giovanni , Cuppone Teresa , D’acquisto Aurelia , Carpinelli Luca , Sacchi Marta , Morricone Lelio , Secchi Francesco , Costa Elena , Menicanti Lorenzo , Nisoli Enzo , Carruba Michele , Ambrogi Federico , Corsi Romanelli Massimiliano Marco 
Published: September 2021

ABSTRACTObjectiveThe excess of visceral adipose tissue might hinder and delay the immune response. How people with abdominal obesity will respond to mRNA vaccines against SARS-CoV-2 is yet to be established. We evaluated SARS-CoV-2-specific antibody responses after the first and second dose of the BNT162b2 mRNA vaccine comparing the response of individuals affected by abdominal obesity (AO) to those without, discerning between individuals with or without prior infection.MethodsIgG neutralizing antibodies against the Trimeric complex (IgG-TrimericS) were measured at four time points: at baseline, at day 21 after vaccine dose-1, at one month and three months after dose-2. Nucleocapsid antibodies were assessed to detect prior SARS-CoV-2 infection. Waist circumference was measured to determine abdominal obesity.ResultsBetween the first and third month after vaccine dose-2, the drop in IgG-TrimericS levels was more remarkable in individuals with AO compared to those without AO (2.44 fold [95%CI: 2.22-2.63] vs 1.82 fold [95%CI: 1.69-1.92], respectively, p<0.001). Multiple linear regression confirmed this result even when adjusting for possible confounders (p<0.001).ConclusionsOur findings highlight the need to extend the duration of serological monitoring of antibody levels in infection-naive individuals with abdominal obesity, a higher-risk population category in terms of possible weaker antibody response.
Variants inALDH1A2reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis
Authors: Zhu Linyi , Kamalathevan Pragash , Koneva Lada , Zarebska Jadwiga Miotla , Chanalaris Anastasios , Ismail Heba , Wiberg Akira , Ng Michael , Muhammed Hayat , Watt Fiona E. ,   The Oxford Hand Surgical Team, Sansom Stephen , Furniss Dominic , Gardiner Matthew D. , Vincent Tonia L. 
Published: September 2021

AbstractOver 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease modifying treatments for this disabling condition. Common polymorphic variants inALDH1A2, that encodes the key enzyme in the synthesis of all-trans retinoic acid (atRA), have been associated with severe hand OA. In this study, we sought to elucidate the biological significance of this association. We first confirmed thatALDH1A2risk variants were associated with hand OA in UK Biobank. Articular cartilage was acquired from 33 consenting individuals with hand OA at the time of routine hand OA surgery. They were stratified by genotype and RNA sequencing performed. A reciprocal relationship betweenALDH1A2mRNA and inflammatory genes was observed. Articular cartilage injury up-regulates similar inflammatory genes by a process that we have previously termed mechanoflammation, and which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-dependent genes, indicative of cellular atRA levels, and both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator activated receptor (PPAR)-γ dependent mechanism. Talarozole, delivered by minipump, was able to suppress mechano-inflammatory genes in articular cartilagein vivo6h after mouse knee joint destabilization, and reduced cartilage degradation and osteophyte formation after 4 weeks. These data show that boosting atRA suppresses mechanoflammation in the articular cartilagein vitroandin vivo, and identifies RAMBAs as potential disease modifying drugs in OA.One Sentence SummaryAnalysis of hand OA cartilage stratified byALDH1A2polymorphic variants reveals a targetable, anti-inflammatory role for retinoic acid in OA.
Structure-activity relationships of B.1.617 and other SARS-CoV-2 spike variants
Authors: Yang Tzu-Jing , Yu Pei-Yu , Chang Yuan-Chih , Chang Ning-En , Tsai Yu-Xi , Liang Kang-Hao , Draczkowski Piotr , Lin Bertina , Wang Yong-Sheng , Chien Yu-Chun , Khoo Kay-Hooi , Wu Han-Chung , Hsu Shang-Te Danny 
Published: September 2021

AbstractThe surge of COVID-19 infection cases is spurred by emerging SARS-CoV-2 variants such as B.1.617. Here we report 38 cryo-EM structures, corresponding to the spike protein of the Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Kappa (B.1.617.1) variants in different functional states with and without its receptor, ACE2. Mutations on the N-terminal domain not only alter the conformation of the highly antigenic supersite of the Delta variant, but also remodel the glycan shield by deleting or adding N-glycans of the Delta and Gamma variants, respectively. Substantially enhanced ACE2 binding was observed for all variants, whose mutations on the receptor binding domain modulate the electrostatics of the binding interfaces. Despite their abilities to escape host immunity, all variants can be potently neutralized by three unique antibodies.
A screen for mutants deficient in coronatine-mediated suppression of root immunity identifies Arabidopsis SDA1 as a novel integrator of immunity and phytohormone signaling
Authors: Song Yi , Zhang Xue-Cheng , Qiu Yichun , Briggs Annika , Millet Yves , Bartenstein Diana , Mankiw Catherine , Cerulli Mary L. , Bush Jenifer , Adams Keith L. , Diener Andrew C. , Ausubel Frederick M. , Haney Cara H. 
Published: September 2021

AbstractDespite the importance of the root immune system in the interaction with rhizosphere microbes, the majority of genetic screens for immunity regulators have been performed in leaves. A previous screen identified 27 hsm (hormone-mediated suppression of MAMP-triggered immunity) mutants that are impaired in jasmonic acid (JA)-mediated suppression of pattern-triggered immunity (PTI) in roots. Here we characterized 16 of the hsm mutants that retain JA sensitivity and are potential negative regulators of root immunity. We found that the majority of hsm mutants show enhanced resistance to Fusarium, a root fungal pathogen; however, only a subset are more resistant to a foliar pathogen. Surprisingly, 12 of 16 hsm mutants are also impaired in abscisic acid (ABA)-mediated suppression of PTI, suggesting a largely shared pathway between JA- and ABA-mediated immune suppression in roots. Although all hsm mutants are insensitive to JA-mediated suppression of root immunity, hsm4 shows hypersensitivity to JA-mediated root growth inhibition and JA-induced gene expression. Consistently, hsm4 is more resistant to leaf pathogens, suggesting that HSM4 is a negative regulator of both root and leaf immunity. Hsm4 was mapped to a mutation in a conserved ARM-repeat protein homologous to yeast SDA1, which has been reported to regulate 60S ribosome biogenesis. As translational reprogramming is a critical layer of immune regulation, this work suggests that AtSDA1 is a novel negative translational regulator of immunity. Additionally, a comprehensive characterization of all 16 hsm mutants provides a genetic toolkit to identify novel mechanisms that regulate root immunity.
Distinct roles of glutamine metabolism in benign and malignant cartilage tumors with IDH mutations
Authors: Zhang Hongyuan , Puviindran Vijitha , Nadesan Puviindran , Ding Xiruo , Shen Leyao , Tang Yuning J. , Tsushima Hidetoshi , Yahara Yasuhito , Ban Ga I , Zhang Guo-Fang , Karner Courtney M. , Alman Benjamin 
Published: September 2021

AbstractEnchondromas and chondrosarcomas are common cartilage neoplasms that are either benign or malignant respectively. The majority of these tumors harbor mutations in either IDH1 or IDH2. Glutamine metabolism has been implicated as a critical regulator of tumors with IDH mutations. Chondrocytes and chondrosarcomas with mutations in the IDH1 or IDH2 genes showed enhanced glutamine utilization in downstream metabolism. Using genetic and pharmacological approaches, we demonstrated that glutaminase-mediated glutamine metabolism played distinct roles in enchondromas and chondrosarcomas with IDH1 or IDH2 mutations. Deletion of glutaminase in chondrocytes with Idh1 mutation increased the number and size of enchondroma-like lesions. Pharmacological inhibition of glutaminase in chondrosarcoma xenografts reduced overall tumor burden. Glutamine affected cell differentiation and viability in these tumors differently through different downstream metabolites. During murine enchondroma-like lesion development, glutamine-derived α-ketoglutarate promoted hypertrophic chondrocyte differentiation and regulated chondrocyte proliferation. In human chondrosarcoma, glutamine-derived non-essential amino acids played an important role in preventing cell apoptosis. This study reveals that glutamine metabolism can play distinct roles in benign and malignant cartilage tumors sharing the same genetic mutations. Inhibiting GLS may provide a therapeutic approach to suppress chondrosarcoma tumor growth.
Thermoregulatory morphodynamics of honeybee clusters
Authors: Peters Jacob M. , Peleg Orit , Mahadevan L. 
Published: September 2021

AbstractDuring reproductive swarming, honeybees form clusters of more than 10,000 bees that hang from structures in the environment (e.g., tree branches) and are exposed to diurnal variations in ambient temperature for up to one week during the search for a new nesting site. Swarm clusters collectively modulate their morphology in response to these variations (i.e., expanding/contracting in response to heating/cooling) to maintain their internal temperature within a tolerable range and to avoid exhausting their honey stores prematurely. To understand the spatiotemporal aspects of thermoregulatory morphing, we measured the change in size and shape of swarm clusters over time and the internal temperature profiles in response to dynamic temperature ramp perturbations. We found that swarm clusters can achieve a twofold increase/decrease their volume/density when heated from 15°C to 30°C, but they do not reach an equilibrium size or shape when held at 30°C for 5 hours, long after the core temperature of the cluster has stabilized. Furthermore, the changes in cluster shape and size are hysteretic, contracting in response to cooling faster than expanding in response to heating. Although the contact diameter of the cluster increased continuously when the swarm is heated, the change in length of the swarm (base to tip) over time is non-monotonic. Consequently, the aspect ratio of the swarm fluctuated continuously even when held at a constant temperature. Taken together, our results quantify the hysteretic and anisotropic morphological responses of swarm clusters to ambient temperature variations while suggesting that both mechanical constraints and heat transfer govern the thermoregulatory morphing dynamics of swarm clusters.
Glucose controls co-translation of structurally related mRNAs via the mTOR and eIF2 pathways in human pancreatic beta cells
Authors: Bulfoni Manuel , Bouyioukos Costas , Zakaria Albatoul , Nigon Fabienne , Rapone Roberta , Maestro Laurence Del , Ait-Si-Ali Slimane , Scharfmann Raphaël , Cosson Bertrand 
Published: September 2021

ABSTRACTPancreatic beta cell response to glucose is critical for the maintenance of normoglycemia. A strong transcriptional response was classically described in rodent models but, interestingly, not in human cells. In this study, we exposed human pancreatic beta cells to an increased concentration of glucose and analysed at a global level the mRNAs steady state levels and their translationalability. Polysome profiling analysis showed an early acute increase in protein synthesis and a specific translation regulation of more than 400 mRNAs, independently of their transcriptional regulation. We clustered the co-regulated mRNAs according to their behaviour in translation in response to glucose and discovered common structural and sequence mRNA features. Among them mTOR- and eIF2-sensitive elements have a predominant role to increase mostly the translation of mRNAs encoding for proteins of the translational machinery. Furthermore, we show that mTOR and eIF2α pathways are independently regulated in response to glucose, participating to a translational reshaping to adapt beta cell metabolism. The early acute increase in the translation machinery components prepare the beta cell for further protein demand due to glucose-mediated metabolism changes.AUTHOR SUMMARYAdaptation and response to glucose of pancreatic beta cells is critical for the maintenance of normoglycemia. Its deregulation is associated to Diabetic Mellitus (DM), a significant public health concern worldwide with an increased incidence of morbidity and mortality. Despite extensive research in rodent models, gene expression regulation in response to glucose remains largely unexplored in human cells. In our work, we have tackled this question by exposing human EndoC-BH1 cells to high glucose concentration. Using polysome profiling, the gold standard technique to analyse cellular translation activity, we observed a global protein synthesis increase, independent from transcription activity. Among the specific differentially translated mRNAs, we found transcripts coding for ribosomal proteins, allowing the cell machinery to be engaged in a metabolic response to glucose. Therefore, the regulation in response to glucose occurs mainly at the translational level in human cells, and not at the transcriptional level as described in the classically used rodent models.Furthermore, by comparing the features of the differentially translated mRNAs, and classifying them according to their translational response, we show that the early response to glucose occurs through the coupling of mRNA structure and sequence features impacting translation and regulation of specific signalling pathways. Collectively, our results support a new paradigm of gene expression regulation on the translation level in human beta cells.
USP5 enhances SGTA mediated protein quality control
Authors: Hill Jake , Nyathi Yvonne 
Published: September 2021

AbstractMislocalised membrane proteins (MLPs) present a risk to the cell due to exposed hydrophobic amino acids which cause MLPs to aggregate. Previous studies identified SGTA as a key component of the machinery that regulates the quality control of MLPs. Overexpression of SGTA promotes deubiqutination of MLPs resulting in their accumulation in cytosolic inclusions, suggesting SGTA acts in collaboration with deubiquitinating enzymes (DUBs) to exert these effects. However, the DUBs that play a role in this process have not been identified. In this study we have identified the ubiquitin specific peptidase 5 (USP5) as a DUB important in regulating the quality control of MLPs. We show that USP5 is in complex with SGTA, and this association is increased in the presence of an MLP. Overexpression of SGTA results in an increase in steady-state levels of MLPs suggesting a delay in proteasomal degradation of substrates. However, our results show that this effect is strongly dependent on the presence of USP5. We find that in the absence of USP5, the ability of SGTA to increase the steady state levels of MLPs is compromised. Moreover, knockdown of USP5 results in a reduction in the steady state levels of MLPs, while overexpression of USP5 increases the steady state levels. Our findings suggest that the interaction of SGTA with USP5 enables specific MLPs to escape proteasomal degradation allowing selective modulation of MLP quality control. These findings progress our understanding of aggregate formation, a hallmark in a range of neurodegenerative diseases and type II diabetes, as well as physiological processes of aggregate clearance.
Specificity and sensitivity of an RNA targeting type III CRISPR complex coupled with a NucC endonuclease effector
Authors: Grüschow Sabine , Adamson Catherine S. , White Malcolm F. 
Published: September 2021

ABSTRACTType III CRISPR systems detect invading RNA, resulting in the activation of the enzymatic Cas10 subunit. The Cas10 cyclase domain generates cyclic oligoadenylate (cOA) second messenger molecules, activating a variety of effector nucleases that degrade nucleic acids to provide immunity. The prophage-encoded Vibrio metoecus type III-B (VmeCmr) locus is uncharacterised, lacks the HD nuclease domain in Cas10 and encodes a NucC DNA nuclease effector that is also found associated with Cyclic-oligonucleotide-based anti-phage signalling systems (CBASS). Here we demonstrate that VmeCmr is activated by target RNA binding, generating cyclic-triadenylate (cA3) to stimulate a robust NucC-mediated DNase activity. The specificity of VmeCmr is probed, revealing the importance of specific nucleotide positions in segment 1 of the RNA duplex and the protospacer flanking sequence (PFS). We harness this programmable system to demonstrate the potential for a highly specific and sensitive assay for detection of the SARS-CoV-2 virus RNA with a limit of detection (LoD) of 2 fM using a commercial plate reader without any extrinsic amplification step. The sensitivity is highly dependent on the guide RNA used, suggesting that target RNA secondary structure plays an important role that may also be relevant in vivo.
A non-bactericidal cathelicidin provides prophylactic efficacy against bacterial infection by driving phagocyte influx
Authors: Yang Yang , Wu Jing , Li Qiao , Mu Lixian , Hui Li , Li Min , Xu Wei , Yang Hailong , Wei Lin 
Published: September 2021

AbstractThe roles of bactericidal cathelicidins against bacterial infection have been extensively studied. However, the anti-bacterial property and mechanism of action of non-bactericidal cathelicidins are rarely known. Herein, a novel naturally occurring cathelicidin (PopuCATH) from tree frog (Polypedates puerensis) didn’t show any direct anti-bacterial activity in vitro. Intriguingly, intraperitoneal injection of PopuCATH before bacterial inoculation significantly reduced the bacterial load in tree frogs and mice, and reduced the inflammatory response induced by bacterial inoculation in mice. PopuCATH pretreatment also increased the survival rates of septic mice induced by a lethal dose of bacterial inoculation or cecal ligation and puncture (CLP). Intraperitoneal injection of PopuCATH significantly drove the leukocyte influx in both frogs and mice. In mice, PopuCATH rapidly drove neutrophil, monocyte/macrophage influx in mouse abdominal cavity and peripheral blood with a negligible impact on T and B lymphocytes, and neutrophils, monocytes/macrophages, but not T and B lymphocytes, were required for the preventive efficacy of PopuCATH. PopuCATH did not directly act as chemoattractant for phagocytes, but PopuCATH obviously drove phagocyte migration when it was cultured with macrophages. PopuCATH significantly elicited chemokine/cytokine production in macrophages through activating p38/ERK mitogen-activated protein kinases (MAPKs) and NF-κB p65. PopuCATH markedly enhanced neutrophil phagocytosis via promoting the release of neutrophil extracellular traps (NETs). Additionally, PopuCATH showed low side effects both in vitro and in vivo. Collectively, PopuCATH acts as a host-based immune defense regulator that provides prophylactic efficacy against bacterial infection without direct antimicrobial effects. Our findings reveal a non-bactericidal cathelicidin which possesses unique anti-bacterial action, and highlight the potential of PopuCATH to prevent bacterial infection.