bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integration of Protein Interactome Networks with Congenital Heart Disease Variants Reveals Candidate Disease Genes
Authors: Gonzalez-Teran Barbara , Pittman Maureen , Felix Franco , Richmond-Buccola Desmond , Thomas Reuben , Choudhary Krishna , Moroni Elisabetta , Colombo Giorgio , Alexanian Michael , Cole Bonnie , Samse-Knapp Kaitlen , McGregor Michael , Gifford Casey A. , Huttenhain Ruth , Gelb Bruce D. , Conklin Bruce R. , Black Brian L. , Bruneau Benoit G. , Krogan Nevan J. , Pollard Katherine S. , Srivastava Deepak 
Published: January 2021

SUMMARYCongenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains a challenge despite large-scale genomic sequencing efforts. We hypothesized that genetic determinants for CHDs may lie in protein interactomes of GATA4 and TBX5, two transcription factors that cause CHDs. Defining their interactomes in human cardiac progenitors via affinity purification-mass spectrometry and integrating results with genetic data from thePediatric Cardiac Genomic Consortiumrevealed an enrichment ofde novovariants among proteins that interact with GATA4 or TBX5. A consolidative score that prioritized interactome members based on variant, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied cardiac developmental genes, resulting in co-activation, and the GLYR1 missense variant associated with CHD disrupted interaction with GATA4. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating the contribution of genetic variants in disease.
Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state
Authors: Cao Anne-Marinette , Quast Robert B. , Fatemi Fataneh , Rondard Philippe , Pin Jean-Philippe , Margeat Emmanuel 
Published: January 2021

AbstractMuch hope in drug development comes from the discovery of positive allosteric modulators (PAM) that display target subtype selectivity, and act by increasing agonist potency and efficacy. How such compounds can allosterically influence agonist action remains unclear. Metabotropic glutamate receptors (mGlu) are G protein-coupled receptors that represent promising targets for brain diseases, and for which PAMs acting in the transmembrane domain have been developed. Here, we explore the effect of a PAM on the structural dynamics of mGlu2 in optimized detergent micelles using single molecule FRET at submillisecond timescales. We show that glutamate only partially stabilizes the extracellular domains in the active state. Full activation is only observed in the presence of a PAM or the Gi protein. Our results provide important insights on the role of allosteric modulators in mGlu activation, by stabilizing the active state of a receptor that is otherwise rapidly oscillating between active and inactive states.
Interferon alpha-based combinations suppress SARS-CoV-2 infection in vitro and in vivo
Authors: Ianevski Aleksandr , Yao Rouan , Zusinaite Eva , Lello Laura Sandra , Wang Sainan , Jo Eunji , Yang Jaewon , Ravlo Erlend , Wang Wei , Lysvand Hilde , Løseth Kirsti , Oksenych Valentyn , Tenson Tanel , Windisch Marc P. , Poranen Minna , Nieminen Anni I. , Nordbø Svein Arne , Fenstad Mona Høysæter , Grødeland Gunnveig , Aukrust Pål , Trøseid Marius , Kantele Anu , Vitkauskiene Astra , Legrand Nicolas , Merits Andres , Bjørås Magnar , Kainov Denis E. 
Published: January 2021

AbstractThere is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. In the present study, we found that recombinant human interferon-alpha (IFNa) triggers intrinsic and extrinsic cellular antiviral responses, as well as reduces replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. Although IFNa alone was insufficient to completely abolish SARS-CoV-2 replication, combinations of IFNa with remdesivir or other antiviral agents (EIDD-2801, camostat, cycloheximide, or convalescent serum) showed strong synergy and effectively inhibited SARS-CoV-2 infection in human lung epithelial Calu-3 cells. Furthermore, we showed that the IFNa-remdesivir combination suppressed virus replication in human lung organoids, and that its single prophylactic dose attenuated SARS-CoV-2 infection in lungs of Syrian hamsters. Transcriptome and metabolomic analyses showed that the combination of IFNa-remdesivir suppressed virus-mediated changes in infected cells, although it affected the homeostasis of uninfected cells. We also demonstrated synergistic antiviral activity of IFNa2a-based combinations against other virus infections in vitro. Altogether, our results indicate that IFNa2a-based combination therapies can achieve higher efficacy while requiring lower dosage compared to monotherapies, making them attractive targets for further pre-clinical and clinical development.
Divergent metabolism betweenTrypanosoma congolenseandTrypanosoma bruceiresults in differential drug sensitivity
Authors: Steketee P. C. , Dickie E. A. , Iremonger J. , Crouch K. , Paxton E. , Jayaraman S. , Alfituri O. A. , Awuah-Mensah G. , Ritchie R. , Schnaufer A. , de Koning H. P. , Gadelha C. , Wickstead B. , Barrett M. P. , Morrison L. J. 
Published: January 2021

AbstractAnimal African Trypanosomiasis (AAT) is a debilitating livestock disease prevalent across sub-Saharan Africa, a main cause of which is the protozoan parasiteTrypanosoma congolense. In comparison to the well-studiedT. brucei, there is a major paucity of knowledge regarding the biology ofT. congolense. Here, we use a combination of omics technologies and novel genetic tools to characterise core metabolism inT. congolensemammalian-infective bloodstream-form parasites, and test whether metabolic differences compared toT. bruceiimpact upon drug sensitivity. LikeT. brucei, glycolysis plays a major part inT. congolenseenergy metabolism. However, the rate of glucose uptake is significantly reduced inT. congolense, with cells remaining viable when cultured in concentrations as low as 2 mM. Instead of pyruvate, the primary glycolytic endpoints are succinate, malate and acetate. Comparative transcriptomics analysis showed higher levels of activity associated with the mitochondrial pyruvate dehydrogenase complex, acetate generation and the succinate shunt inT. congolense. However, based on omics analysis and chemical inhibition, there does not appear to be significant levels of oxidative phosphorylation. Stable-isotope labelling of glucose enabled the comparison of carbon usage betweenT. bruceiandT. congolense, highlighting differences in nucleotide and fatty acid metabolism. To validate the metabolic similarities and differences, both species were treated with pharmacological inhibitors, confirming a lack of essential electron transport chain activity inT. congolense,but increased sensitivity to inhibition of mitochondrial pyruvate import. Strikingly,T. congolenseexhibited significant resistance to inhibitors of fatty acid synthesis, including a 780-fold greater EC50against the lipase and fatty acid synthase inhibitor Orlistat, compared toT. brucei. These data highlight that bloodstream formT. congolensediverges fromT. bruceiin key areas of metabolism, with several features that are intermediate between bloodstream- and insect-stageT. brucei. These results have implications for drug development, mechanisms of drug resistance and host-pathogen interactions.
Relocation of rDNA repeats for repair is dependent on SUMO-mediated nucleolar release by the Cdc48/p97 segregase
Authors: Capella Matías , Mandemaker Imke K. , den Brave Fabian , Caballero Lucía Martín , Pfander Boris , Ladurner Andreas G. , Jentsch Stefan , Braun Sigurd 
Published: January 2021

AbstractRibosomal RNA genes (rDNA) are highly unstable and susceptible to rearrangement due to active transcription and their repetitive nature. Compartmentalization of rDNA in the nucleolus suppresses uncontrolled recombination. However, broken repeats must be released to the nucleoplasm to allow repair by homologous recombination. The process of rDNA relocation is conserved from yeast to humans, but the underlying molecular mechanisms are currently unknown. Here we show that DNA damage induces phosphorylation of the CLIP-cohibin complex, releasing membrane-tethered rDNA from the nucleolus inSaccharomyces cerevisiae. Downstream of phosphorylation, SUMOylation targets CLIP-cohibin for disassembly mediated by the Cdc48/p97 chaperone, which recognizes SUMOylated CLIP-cohibin through its cofactor, Ufd1. Consistent with a conserved mechanism, UFD1L depletion impairs rDNA release in human cells. The dynamic and regulated assembly and disassembly of the rDNA-tethering complex is therefore a key determinant of nucleolar rDNA release and genome integrity.
Extracellular matrix changes in colorectal carcinoma and correlation with lymph node metastasis
Authors: Theodoro Thérèse Rachell , Serrano Rodrigo Lorenzetti , Turke Karine Corcione , Saad Sarhan Sydney , Ribeiro Junior Marcelo Augusto Fontenelle , Waisberg Jaques , Pinhal Maria Aparecida Silva 
Published: January 2021

AbstractThe process of proliferation and invasion of tumor cells depends on changes in the extracellular matrix (ECM) through the activation of enzymes and alterations in the profile of ECM components. We aimed to investigate the mRNA and protein expression of ECM components such as heparanase (HPSE), heparanase-2 (HPSE2), matrix metalloproteinase-9 (MMP-9), and syndecan-1 (SYND1) in neoplastic and non-neoplastic tissues of patients with colorectal carcinoma (CRC). It is a cross-sectional study in which twenty-four adult patients that had CRC were submitted to resection surgery. We analyzed the expression of HPSE, HPSE2, MMP-9, and SYND1 by quantitative RT-PCR and immunohistochemistry. Differing from most of the studies that compare the mRNA expression between tumor samples and non-neoplastic tissues, we decided to investigate whether variations exist in the expression of the ECM components between the affected tissue and nontumoral tissue collected from the same patient with CRC. We removed both tissue samples immediately after the surgical resection of CRC. The data showed higher mRNA and protein expression of HPSE2 (P = 0.0058), MMP-9 (P = 0.0268), and SYND1 (P = 0.0002) in tumor samples compared to the non-neoplastic tissues, while there was only an increase in the level of HPSE protein in tumor tissues. A greater expression of HPSE2 was observed in patients with lymph node metastasis (P = 0.048), suggesting that such protein can be a marker of lymph node metastasis in CRC.
Seroprevalence and associated risk factors ofToxoplasma gondiiinfections among pregnant women in Makassar, Indonesia
Authors: Polanunu Nurul Fadilah Ali , Wahyuni Sitti , Hamid Firdaus 
Published: January 2021

AbstractThe protozoan parasite,Toxoplasma gondiiis estimated to infect one-third of the world’s population. Infection in pregnant women can cause severe conditions for their babies. Until now, there is no data regardingToxoplasmainfection from Makassar pregnant mothers. This study aims to obtain information onToxoplasmaspecific antibodies and to measure the risk factor associate with parasite infection. This cross-sectional study conducted in 9 of 47 primary health centres (Puskesmas) in Makassar. Blood samples and questionnaires were collected from 184 pregnant women aged 15-42 years old from September to October 2020. ELISA technique was used to examine the IgG and IgM antibodies. Univariable and multivariable analyses were carried out to measure factors that independently associate withToxoplasmaantibody positivity. Our result showed the range ofToxoplasmaIgM and IgG are 0.06-1.01 and 0.09-3.01, respectively. While no one of our participants has an acuteToxoplasma gondiiinfection (IgM positive), we found 32,6% pregnant mothers are exposed to parasite (positive IgG). Contact with cats [OR(95CI): 8.04 (3.09-20.87)], consume chicken satay [OR(95CI): 7.46(3.06-18.21)] and consume un-boiled water [OR(95CI): 5.23(1.57-17.38)] are independently associate with positiveToxoplasmaIgG antibody. Based on the result, we conclude that pregnant women in Makassar are exposed toT. gondiiand the cyst of parasite contaminates food and water in Makassar.
Crystallographic molecular replacement using anin silico-generated search model of SARS-CoV-2 ORF8
Authors: Flower Thomas G. , Hurley James H. 
Published: January 2021

AbstractThe majority of crystal structures are determined by the method of molecular replacement (MR). The range of application of MR is limited mainly by the need for an accurate search model. In most cases, pre-existing experimentally determined structures are used as search models. In favorable cases,ab initiopredicted structures have yielded search models adequate for molecular replacement. The ORF8 protein of SARS-CoV-2 represents a challenging case for MR using anab initioprediction because ORF8 has an all β-sheet fold and few orthologs. We previously determined experimentally the structure of ORF8 using the single anomalous dispersion (SAD) phasing method, having been unable to find an MR solution to the crystallographic phase problem. Following a report of an accurate prediction of the ORF8 structure, we assessed whether the predicted model would have succeeded as an MR search model. A phase problem solution was found, and the resulting structure was refined, yielding structural parameters equivalent to the original experimental solution.
Proteomic interrogation of the pathogen-host interface in cholera
Authors: Zoued Abdelrahim , Zhang Hailong , Zhang Ting , Giorgio Rachel T. , Kuehl Carole J. , Fakoya Bolutife , Sit Brandon , Waldor Matthew K. 
Published: January 2021

SummaryThe microbial cell surface is a critical site of microbe-host interactions that often control infection outcomes. Here, using the infant rabbit model of cholera, which provides an abundant source ofin vivo Vibrio choleraecells and diarrheal fluid, we investigated the proteomic composition of this interface. Bulk diarrheal fluid proteomes revealed that cholera toxin accounts for the vast majority of the host proteins present during infection. We developed a surface biotinylation protocol to purify and quantify both bacterial and host proteins present on the surface of diarrheal fluid-derivedV. cholerae. We found that SP-D, a toxin-dependent host protein that directly binds theV. choleraesurface, is a novel intestinal defense factor. OtherV. cholerae-bound host proteins also bound distinct taxa of the murine intestinal microbiota. Proteomic investigation of the microbial surface-host interface should be a valuable tool for probing microbe-host interactions and their influence on homeostasis and infection.
Long term impact on lung function of patients with moderate and severe COVID-19. A prospective cohort study
Authors: Qureshi Sonia , Nasir Nosheen , Rashid Naveed Haroon , Ahmed Naveed , Haq Zoya , Qamar Farah Naz 
Published: January 2021

AbstractIntroductionA significant number of patients continue to recover from COVID-19; however, little is known about the lung function capacity among survivors. We aim to determine the long-term impact on lung function capacity in patients who have survived moderate or severe COVID-19 disease in a resource-poor setting.Methods and analysisThis prospective cohort study will include patients aged 15 years and above and have reverse transcriptase-polymerase chain reaction (RT-PCR) positive for COVID 19 (nasopharyngeal or oropharyngeal). Patients with a pre-existing diagnosis of obstructive or interstitial lung disease, lung fibrosis and cancers, connective tissue disorders, autoimmune conditions affecting the lungs, underlying heart disease, history of syncope and refuse to participate will be excluded. Pulmonary function will be assessed using spirometry and diffusion lung capacity for carbon monoxide (DLCO) at three- and six-months interval. A chest X-ray at three and six-month follow-up and CT-chest will be performed if clinically indicated after consultation with the study pulmonologist or Infectious Disease (ID) physician. Echocardiogram (ECHO) to look for pulmonary hypertension at the three months visit and repeated at six months if any abnormality is identified initially. Data analysis will be performed using standard statistical software.Ethics and disseminationThe proposal was reviewed and approved by ethics review committee (ERC) of the institution (ERC reference number 2020-4735-11311). Informed consent will be obtained from each study participant. The results will be disseminated among study participants, institutional, provincial and national level through seminars and presentations. Moreover, the scientific findings will be published in high-impact peer-reviewed medical journals.Strengths and Limitations of this study-The study has the potential to develop context-specific evidence on the long-term impact on lung function among COVID-19 survivors-Findings will play key role in understanding the impact of the disease on vital functions and help devise rehabilitative strategies to best overcome the effects of disease-This is a single-center, study recruiting only a limited number of COVID-19 survivors-The study participants may loss-to-follow up due to uncertain conditions and disease reemergence
Fertilization alters protistan consumers and parasites in crop‐associated microbiomes
Authors: Sun Anqi , Jiao Xiao‐Yan , Chen Qinglin , Trivedi Pankaj , Li Zixin , Li Fangfang , Zheng Yong , Lin Yongxin , Hu Hang‐Wei , He Ji‐Zheng 
Published: January 2021

SummaryCrop plants carry an enormous diversity of microbiota that provide massive benefits to hosts. Protists, as the main microbial consumers and a pivotal driver of biogeochemical cycling processes, remain largely understudied in the plant microbiome. Here, we characterized the diversity and composition of protists in sorghum leaf phyllosphere, and rhizosphere and bulk soils, collected from an 8‐year field experiment with multiple fertilization regimes. Phyllosphere was an important habitat for protists, dominated by Rhizaria, Alveolata and Amoebozoa. Rhizosphere and bulk soils had a significantly higher diversity of protists than the phyllosphere, and the protistan community structure significantly differed among the three plant–soil compartments. Fertilization significantly altered specific functional groups of protistan consumers and parasites. Variation partitioning models revealed that soil properties, bacteria and fungi predicted a significant proportion of the variation in the protistan communities. Changes in protists may in turn significantly alter the compositions of bacterial and fungal communities from the top‐down control in food webs. Altogether, we provide novel evidence that fertilization significantly affects the functional groups of protistan consumers and parasites in crop‐associated microbiomes, which have implications for the potential changes in their ecological functions under intensive agricultural managements.
A high‐throughput ultrasonic spraying inoculation method promotes colony cultivation of rare microbial species
Authors: Huang Xizhi , Li Pengjie , Zhou Mengfan , Li Yiwei , Ou Xiaowen , Chen Peng , Guggenberger Georg , Liu Bi‐Feng 
Published: January 2021

SummaryCurrent method for obtaining microbial colonies still relies on traditional dilution and spreading plate (DSP) procedures, which is labor‐intensive, skill‐dependent, low‐throughput and inevitably causing dilution‐to‐extinction of rare microorganisms. Herein, we proposed a novel ultrasonic spraying inoculation (USI) method that disperses microbial suspensions into millions of aerosols containing single cells, which lately be deposited freely on a gel plate to achieve high‐throughput culturing of colonies. Compared with DSP, USI significantly increased both distributing uniformity and throughput of the colonies on agar plates, improving the minimal colony‐forming abundance of rare Escherichia coli mixed in a lake sample from 1% to 0.01%. Applying this novel USI to a lake sample, 16 cellulose‐degrading colonies were screened out among 4766 colonies on an enlarged 150‐mm‐diameter LB plate. Meanwhile, they could only be occasionally observed when using commonly used DSP procedures. 16S rRNA sequencing further showed that USI increased colony‐forming species from 11 (by DSP) to 23, including seven completely undetectable microorganisms in DSP‐reared communities. In addition to avoidance of dilution‐to‐extinction, operation‐friendly USI efficiently inoculated microbial samples on the agar plate in a high‐throughput and single‐cell form, which eliminated masking or out‐competition from other species in associated groups, thereby improving rare species cultivability.
Cross‐linguistic contributions of acoustic cues and prosodic awareness to first and second language vocabulary knowledge
Authors: Chung Wei‐Lun , Jarmulowicz Linda , Bidelman Gavin M. 
Published: January 2021

BackgroundSeveral studies have revealed that prosody contributes to reading acquisition. However, the relation between awareness of prosodic patterns and different facets of language ability (e.g., vocabulary knowledge) in school‐age children remains unclear. This study measured awareness of prosodic patterns using non‐speech and speech stimuli.MethodsHierarchical regression equations were computed to examine links among auditory cues (e.g., amplitude rise time, pitch contour and interval), language‐specific prosodic awareness and children's vocabulary knowledge in Mandarin as a first language (L1) and English as a second language (L2) after controlling for age and nonverbal IQ.ResultsResults revealed that (1) amplitude envelope rise time discrimination predicted Mandarin L1 and English L2 vocabulary knowledge, (2) Mandarin tone perception and rhyme awareness did not predict Mandarin L1 vocabulary and (3) English rhyme awareness better predicted English L2 vocabulary than did stress production.ConclusionOur findings suggest that (1) amplitude rise time, which signals syllable boundaries, is a cross‐linguistic predictor of vocabulary knowledge and (2) the development of English L2 vocabulary may depend on phonological more than prosodic awareness.
Father Absence in Pregnancy or During Childhood and Pubertal Development in Girls and Boys: A Population‐Based Cohort Study
Authors: Gaml‐Sørensen Anne , Brix Nis , Ernst Andreas , Lunddorf Lea Lykke Harrits , Ramlau‐Hansen Cecilia Høst 
Published: January 2021

This cohort study, including 15,810 children born 2000–2003 in Denmark, aimed to investigate the association between father absence in pregnancy or during childhood and pubertal development in girls and boys. The children were followed from 11 years of age and throughout pubertal development. Mean age differences according to exposure groups were estimated for each pubertal marker separately and for a combined pubertal marker. The results suggested that father absence in pregnancy and during childhood was associated with earlier pubertal development in girls, and father absence from late childhood was associated with earlier pubertal development in boys. The paternal investment theory, the psychosocial acceleration theory and the energetics theory were explored, and did not seem to explain the observed associations.