bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diverse logics and grammar encode notochord enhancers
Authors: Song Benjamin P , Ragsac Michelle F , Tellez Krissie , Jindal Granton A , Grudzien Jessica L , Le Sophia H , Farley Emma K 
Published: July 2022

ABSTRACTThe notochord is a key structure during chordate development. We have previously identified several enhancers regulated by Zic and ETS that encode notochord activity within the marine chordate Ciona robusta (Ciona). To better understand the role of Zic and ETS within notochord enhancers, we tested 90 genomic elements containing Zic and ETS sites for expression in developing Ciona embryos using a whole-embryo, massively parallel reporter assay. We discovered that 39/90 of the elements were active in developing embryos; however only 10% were active within the notochord, indicating that more than just Zic and ETS sites are required for notochord expression. Further analysis revealed notochord enhancers were regulated by three groups of factors: (1) Zic and ETS, (2) Zic, ETS and Brachyury (Bra), and (3) Zic, ETS, Bra and FoxA. One of these notochord enhancers, regulated by Zic and ETS, is located upstream of laminin alpha, a gene critical for notochord development in both Ciona and vertebrates. Reversing the ETS sites in this enhancer greatly diminish expression, indicating that enhancer grammar is critical for enhancer activity. Strikingly, we find clusters of Zic and ETS binding sites within the introns of mouse and human laminin alpha 1 with conserved enhancer grammar. Our analysis also identified two notochord enhancers regulated by Zic, ETS, FoxA and Bra binding sites: the Bra Shadow (BraS) enhancer located in close proximity to Bra, and an enhancer located near the gene Lrig. Randomizing the BraS enhancer demonstrates that although the Zic and ETS sites are necessary for enhancer activity, they are not sufficient. We find that FoxA and Bra sites contribute to BraS enhancer activity. Zic, ETS, FoxA and Bra binding sites occur within the Ciona Bra434 enhancer and vertebrate notochord Brachyury enhancers, suggesting a conserved regulatory logic. Collectively, this study deepens our understanding of how enhancers encode notochord expression, illustrates the importance of enhancer grammar, and hints at the conservation of enhancer logic and grammar across chordates.
Intranasal delivery of lipid nanoparticle encapsulated SARS-CoV-2 and RSV-targeting siRNAs reduces lung infection
Authors: Supramaniam Aroon , Tayyar Yaman , Clarke Daniel. T. W. , Kelly Gabrielle , Morris Kevin V. , McMillan Nigel A. J. , Idris Adi 
Published: July 2022

AbstractRNA interference (RNAi) is an emerging and promising therapy for a wide range of respiratory viral infections. This highly specific suppression can be achieved by the introduction of short-interfering RNA (siRNA) into mammalian systems, resulting in the effective reduction of viral load. Unfortunately, this has been hindered by the lack of a good delivery system, especially via the intranasal (IN) route. Here, we have developed an IN siRNA encapsulated lipid nanoparticle (LNP) in vivo delivery system that is highly efficient at targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV) in infected mouse lungs. Importantly, IN siRNA delivery without the aid of LNPs abolishes anti-SARS-CoV-2 activity in vivo. Our approach using LNPs as the delivery vehicle overcomes the significant barriers seen with IN delivery of siRNA therapeutics and is a significant advancement in our ability to delivery siRNAs. The studies presented here demonstrates an attractive alternate therapeutic delivery strategy for the treatment of both future and emerging respiratory viral diseases.
Profiling and Quantification of Anthocyanins in Novel Purple-Pericarp Sweetcorn and Purple-Pericarp Maize
Authors: Anirban Apurba , Hong Hung T. , O’Hare Tim J 
Published: July 2022

AbstractAnthocyanins, secondary metabolites of pigmented corns consisting of cyanidin-, pelargonidin- and peonidin-based glucoside. While cyanidin-peonidin types are responsible for purple-pigmentation, pelargonidin type is responsible for red-pigmentation. This study examined anthocyanin concentrations in a novel purple-pericarp shrunken2 sweetcorn ‘Tim’ lines in comparison to the parental purple-pericarp ‘Costa Rica’ maize’ and white sweetcorn ‘Tims-white’ lines. The study found similar concentrations of anthocyanin in both ‘Tim1’ and the ‘Costa Rica’, at sweetcorn eating stage, whereas ‘Tims-white’ has no detectable anthocyanin. Total anthocyanins found in the ‘Costa Rica’ and ‘Tim1’, ‘Tim2’, ‘Tim4’ and ‘Tim5’ lines were 255.79, 253.03, 238.10, 198.66, and 221.36 mg/100 g FW (fresh weight), respectively. In all the developed purple-sweetcorn ‘Tim’ lines along with the purple maize parent, the cyanidin-peonidin (purple) proportion of total anthocyanin was 78-93%, as the predominant anthocyanin pigment. The anthocyanin concentration in ‘Tim1’ at eating stage was significantly much higher than currently exists with other coloured fruits.
Longitudinal fundus imaging and its genome-wide association analysis provide evidence for a human retinal aging clock
Authors: Ahadi Sara , Wilson Kenneth A. , Babenko Boris , McLean Cory Y. , Bryant Drew , Pritchard Orion , Carrera Enrique M. , Lamy Ricardo , Stewart Jay M. , Varadarajan Avinash , Berndl Marc , Kapahi Pankaj , Bashir Ali 
Published: July 2022

AbstractBiological age, distinct from an individual’s chronological age, has been studied extensively through predictive aging clocks. However, these clocks have limited accuracy in short time-scales. Deep learning approaches on imaging datasets of the eye have proven powerful for a variety of quantitative phenotype inference tasks and provide an opportunity to explore organismal aging and tissue health.Here we trained deep learning models on fundus images from the EyePACS dataset to predict individuals’ chronological age. These predictions led to the concept of a retinal aging clock, “eyeAge”, which we employed for a series of downstream longitudinal analyses. eyeAge was used to predict chronological age on timescales under a year using longitudinal fundus imaging data from a subset of patients. To further validate the model, it was applied to a separate cohort from the UK Biobank. The difference between individuals’ eyeAge and their chronological age, hereafter “eyeAgeAccel”, was computed and used for genome-wide association analysis (GWAS).EyeAge predicted chronological age more accurately than other aging clocks (mean absolute error of 2.86 and 3.30 years on quality-filtered data from EyePACS and UKBiobank, respectively). Additionally, eyeAgeAccel was highly independent of blood marker-based measures of biological age (e.g. “phenotypic age”), maintaining an all-cause mortality hazard ratio of 1.026 even in the presence of phenotypic age. Longitudinal studies showed that the resulting models were able to predict individuals’ aging, in time-scales less than a year, with 71% accuracy. The individual-specific component to this prediction was confirmed with the identification of multiple GWAS hits in the independent UK Biobank cohort. The knockdown of the fly homolog to the top hit,ALKAL2, which was previously shown to extend lifespan in flies, also slowed age-related decline in vision in flies.In conclusion, predicted age from retinal images can be used as a biomarker of biological aging that is independent from assessment based on blood markers. This study demonstrates the potential utility of a retinal aging clock for studying aging and age-related diseases and quantitatively measuring aging on very short time-scales, opening avenues for quick and actionable evaluation of gero-protective therapeutics.
The frequent occurrence and metabolic versatility of Marinifilaceae bacteria involved in organic matter mineralization as a key member in global deep sea
Authors: Li Jianyang , Dong Chunming , Lai Qiliang , Wang Guangyi , Shao Zongze 
Published: July 2022

ABSTRACTTransfer of animal and plant detritus of both terrestrial and marine origins to the deep sea occurs on the global scale. Microorganisms play an important role in mineralizing them therein, yet to identify in situ. Here we report the family Marinifilaceae that occurred as one of the most predominant bacteria thriving on the new inputs of plant and animal biomasses in both marginal and oceanic areas observed via in situ incubation about their differentiation, environmental adaption, and metabolic mechanisms underlying their prevalence in organic matter mineralizing communities. We described the metabolic features and in situ metabolizing activities of different subgroups (tentative genus level), based on the metagenomic and metatranscriptomic data. One representative subgroup MF-2 dominated plant detritus-enriched cultures and specialized in polysaccharide degradation by encoding many hydrolases involved in the hydrolysis of hemicellulose, pectin, starch, cellulose, and polysaccharides containing N-acetyl groups; this subgroup also encodes a manganese superoxide dismutase with the potential of lignin oxidation and possesses complete nitrogen fixation pathway to compensate for the shortage of nitrogen sources inside the plant detritus. In contrast, those dominating the animal tissue-supported microbiomes were more diverse and formed three subgroups, which distinguished themselves from MF-2 in carbon and nitrogen metabolisms. Regardless of differentiation in carbon and nitrogen metabolisms, they share in common in energy conservation through organic fermentation, and anaerobic respiration of diverse electron receptors. These results highlight the role of Marinifilaceae bacteria neglected before in organic matter mineralizing in marine environments coupling carbon and nitrogen cycling with metals and other elements.IMPORTANCEMicrobial mineralization of organic matters has a significant impact on the global biogeochemical cycle. This report confirmed the role of Marinifilaceae in organic degradation in the oceans, with underestimated contribution in the ocean carbon cycling. It is the dominant taxon thriving on plant and animal biomasses in our in situ incubator, as well as in whale- and wood-falls. At least nine subgroups were revealed, and widely distributed in global oceans but merely predominant in organic-rich environments with an average relative abundance of 8.3 %. Different subgroups display a preference for the degradation of different macromolecules (polysaccharides, lignin, and protein) and adapt themselves to the environments via special metabolic metabolisms.
Drug degradation caused by mce3R mutations confers contezolid (MRX-I) resistance in Mycobacterium tuberculosis
Authors: Pi Rui , Chen Xiaomin , Meng Jian , Liu Qingyun , Chen Yiwang , Bei Cheng , Wang Chuan , Gao Qian 
Published: July 2022

ABSTRACTContezolid (MRX-I), a safer antibiotic of the linezolid oxazolidinone class, is a promising new antibiotic with potent activity against Mycobacterium tuberculosis (MTB) both in vitro and in vivo. To identify resistance mechanisms of contezolid in MTB, we isolated several in vitro spontaneous contezolid-resistant MTB mutants, which exhibited 16-fold increase in MICs of contezolid compared with the parent strain but was still unexpectedly susceptible to linezolid. Whole-genome sequencing revealed that most of the contezolid-resistant mutants bore mutations in the mce3R gene which encode a transcriptional repressor. The mutations in mce3R led to markedly increased expression of a monooxygenase encoding gene Rv1936. We then characterized Rv1936 as a putative flavin-dependent monooxygenase that catalyzes the degradation of contezolid into its inactive DHPO ring-opened metabolites, thereby conferring drug resistance. While contezolid is an attractive drug candidate with potent antimycobacterial activity and low toxicity, the occurrence of mutations in Mce3R should be considered when designing combination therapy using contezolid for treating tuberculosis.IMPORTANCETuberculosis (TB) is one of the leading causes of global death and the second deadliest infectious killer after COVID-19. Compared to drug-sensitive TB, the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB is more difficult and less effective due to longer regimens and higher potential for clinical adverse events. Despite the undisputed medical success of linezolid on MDR/XDR-TB therapy, this drug suffers from severe safety limitation. The new NMPA-approved drug contezolid, as an analogue of linezolid, exhibits a superior safety profile and potent antitubercular activity. Since the less-toxic contezolid is a promising drug candidate to optimize the current longer-duration MDR/XDR-TB therapy, it would be of significance to determine the resistance profiles of contezolid in MTB. Here, we present the first exploration of the frequency, mutational targets and molecular mechanisms of contezolid resistance in MTB, which could provide theoretical guidance for its future clinical application.
Reproduction number of monkeypox in the early stage of the 2022 multi-country outbreak
Authors: Du Zhanwei , Shao Zengyang , Bai Yuan , Wang Lin , Herrera-Diestra Jose L , Fox Spencer J. , Ertem Zeynep , Lau Eric H. Y. , Cowling Benjamin J. 
Published: July 2022

AbstractMonkeypox, a fast-spreading viral zoonosis outside of Africa in May 2022, has scientists on alert. We estimated the reproduction number to be 1.29 (95% CrI: 1.26, 1.33) by aggregating all cases in 70 countries as of July 22, 2022.
Effectiveness of the BNT162b2 vaccine against SARS-CoV-2 infection among children and adolescents in Qatar
Authors: Chemaitelly Hiam , AlMukdad Sawsan , Ayoub Houssein H. , Altarawneh Heba N. , Coyle Peter , Tang Patrick , Yassine Hadi M. , Al-Khatib Hebah A. , Smatti Maria K. , Hasan Mohammad R. , Al-Kanaani Zaina , Al-Kuwari Einas , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul-Rahim Hanan F. , Nasrallah Gheyath K. , Al-Kuwari Mohamed Ghaith , Al-Romaihi Hamad Eid , Butt Adeel A. , Al-Thani Mohamed H. , Al-Khal Abdullatif , Bertollini Roberto , Abu-Raddad Laith J. 
Published: July 2022

AbstractBackgroundThe BNT162b2 COVID-19 vaccine is authorized for children 5-11 years of age and adolescents 12-17 years of age, but in different dose sizes. We assessed BNT162b2 real-world effectiveness against SARS-CoV-2 infection among children and adolescents in Qatar.MethodsThree matched, retrospective, target-trial, cohort studies were conducted to compare incidence of SARS-CoV-2 infection in the national cohort of vaccinated individuals to incidence in the national cohort of unvaccinated individuals. Associations were estimated using Cox proportional-hazards regression models.ResultsEffectiveness of the 10 µg dose for children against Omicron infection was 25.7% (95% CI: 10.0-38.6%). It was highest at 49.6% (95% CI: 28.5-64.5%) right after the second dose, but waned rapidly thereafter and was negligible after 3 months. Effectiveness was 46.3% (95% CI: 21.5-63.3%) among those aged 5-7 years and 16.6% (−4.2-33.2%) among those aged 8-11 years. Effectiveness of the 30 µg dose for adolescents against Omicron infection was 30.6% (95% CI: 26.9-34.1%), but many adolescents were vaccinated months earlier. Effectiveness waned with time after the second dose. Effectiveness was 35.6% (95% CI: 31.2-39.6%) among those aged 12-14 years and 20.9% (13.8-27.4%) among those aged 15-17 years. Effectiveness of the 30 µg dose for adolescents against pre-Omicron infection was 87.6% (95% CI: 84.0-90.4%) and waned relatively slowly after the second dose.ConclusionsPediatric vaccination is associated with modest and rapidly waning protection against Omicron infection. Adolescent vaccination is associated with stronger and more durable protection, perhaps because of the larger dose size. Age at such young age appears to play a role in determining vaccine protection, with greater protection observed in younger than older children or adolescents.
Visual Transformer and Deep CNN Prediction of High-risk COVID-19 Infected Patients using Fusion of CT Images and Clinical Data
Authors: Tehrani Sara Saberi Moghadam , Zarvani Maral , Amiri Paria , Azmi Reza , Ghods Zahra , Nourozi Narges , Raoufi Masoomeh , Safavi-Naini Seyed Amir Ahmad , Soheili Amirali , Abolghasemi Sara , Gharib Mohammad , Abbasi Hamid 
Published: July 2022

AbstractDespite the globally reducing hospitalization rates and the much lower risks of Covid-19 mortality, accurate diagnosis of the infection stage and prediction of outcomes are clinically of interest. Advanced current technology can facilitate automating the process and help identifying those who are at higher risks of developing severe illness. Deep-learning schemes including Visual Transformer and Convolutional Neural Networks (CNNs), in particular, are shown to be powerful tools for predicting clinical outcomes when fed with either CT scan images or clinical data of patients.This paper demonstrates how a novel 3D data fusion approach through concatenating CT scan images with patients’ clinical data can remarkably improve the performance of Visual Transformer and CNN models in predicting Covid-19 infection outcomes. Here, we explore and represent comprehensive research on the efficiency of Video Swin Transformers and a number of CNN models fed with fusion datasets and CT scans only vs a set of conventional classifiers fed with patients’ clinical data only. A relatively large clinical dataset from 380 Covid-19 diagnosed patients was used to train/test the models. Results show that the 3D Video Swin Transformers fed with the fusion datasets of 64 sectional CT scans+67 (or 30 selected) clinical labels outperformed all other approaches for predicting outcomes in Covid-19-infected patients amongst all techniques (i.e., TPR=0.95, FPR=0.40, F0.5 score=0.82, AUC=0.77, Kappa=0.6). Results indicate possibilities of predicting the severity of outcome using patients’ CT images and clinical data collected at the time of admission to hospital.
Contextual incongruency triggers memory reinstatement and the disruption of neural stability
Authors: Wu Xiongbo , Packard-Blasco Pau , García-Arch Josué , Bunzeck Nico , Fuentemilla Lluís 
Published: July 2022

AbstractSchemas, or internal representation models of the environment, are thought to be central in organising our everyday life behaviour by giving stability and predictiveness to the structure of the world. However, when an element from an unfolding event mismatches the schema-derived expectations, the coherent narrative is interrupted and an update to the current event model representation is required. Here, we asked whether the perceived incongruence of an item from an unfolding event and its impact on memory relied on the disruption of neural stability patterns preceded by the neural reactivation of the memory representations of the just-encoded event. Our study includes data from 3 different experiments whereby participants encoded images of target objects preceded by trial-unique sequences of events depicting daily routine. We found that neural stability patterns gradually increased throughout the ongoing exposure to a schema-consistent episodic narrative and that the brain stability pattern was interrupted when the encoding of an object of the event was lowly congruent within the ongoing schema representation. We found that the decrease in neural stability for low-congruence items was best seen at ∼1000 ms from object encoding onset when compared to high-congruence items and that this effect was preceded by an enhanced N400 ERP and an increased degree of neural reactivation of the just-encoded episode for low-congruence items. Current results offer new insights into the neural mechanisms and their temporal orchestration that are engaged during online encoding of schema-consistent episodic narratives and the detection of incongruencies.
Epigenetic plasticity cooperates with emergent cell-cell interactions to drive neoplastic tissue remodeling in the pancreas
Authors: Burdziak Cassandra , Alonso-Curbelo Direna , Walle Thomas , Barriga Francisco M. , Reyes José , Xie Yubin , Zhao Zhen , Zhao Chujun Julia , Chen Hsuan-An , Chaudhary Ojasvi , Masilionis Ignas , Choo Zi-Ning , Gao Vianne , Luan Wei , Wuest Alexandra , Ho Yu-Jui , Wei Yuhong , Quail Daniela , Koche Richard , Mazutis Linas , Nawy Tal , Chaligné Ronan , Lowe Scott W. , Pe’er Dana 
Published: July 2022

AbstractThe response to tumor-initiating inflammatory and genetic insults can vary amongst morphologically indistinguishable cells, suggesting yet uncharacterized roles for epigenetic plasticity during early neoplasia. To investigate the origins and impact of such plasticity, we perform single-cell analyses on normal, inflamed, pre-malignant and malignant tissues in autochthonous models of pancreatic cancer. We reproducibly identify heterogeneous cell-states that are primed for diverse late-emerging neoplastic fates and link these to chromatin remodeling at cell-cell communication loci. Using a new inference approach, we reveal signaling gene modules and tissue-level crosstalk, including a neoplasia-driving feedback loop between discrete epithelial and immune cell populations that we validate by genetic perturbation in mice. Our results uncover a neoplasia-specific tissue remodeling program that may be exploited for pancreas cancer interception.One-Sentence SummarySingle-cell analysis reveals that enhanced epigenetic plasticity drives pro-neoplastic crosstalk in early pancreatic cancer.
SorCS1 inhibits amyloid-β binding to neurexin and rescues amyloid-β-induced synaptic pathology
Authors: Lee Alfred Kihoon , Yi Nayoung , Khaled Husam , Feller Benjamin , Chofflet Nicolas , Takahashi Hideto 
Published: July 2022

AbstractAmyloid-β oligomers (AβOs), toxic peptide aggregates found in Alzheimer’s disease (AD), cause synapse pathology. AβOs interact with Neurexins (NRXs), key synaptic organizers, and this interaction dampens normal trafficking and function of NRXs. Axonal trafficking of NRX is in part regulated by its interaction with SorCS1, a protein sorting receptor, but the impact of SorCS1 regulation of NRXs in Aβ pathology was previously unstudied. Here, we show competitive interaction of SorCS1 and AβOs with β-NRXs and rescue effects of SorCS1 on AβO-induced synaptic pathology. Like AβOs, SorCS1 binds to NRX1β through the histidine-rich-domain (HRD) of NRX1β, and SorCS1 and AβOs compete for NRX1β binding. In cultured hippocampal neurons, SorCS1 colocalizes with NRX1β on the axon surface, and axonal expression of SorCS1 rescues AβO-induced impairment of NRX-mediated presynaptic organization and presynaptic vesicle recycling as well as AβO-induced structural defects in excitatory synapses. Thus, we reveal a role of SorCS1 in the rescue of AβO-induced NRX dysfunction and synaptic pathology, providing the basis for a novel potential therapeutic strategy for AD.