bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Enteral Nutrition and Gastrointestinal Complications in Pediatric Patients on Extracorporeal Membrane Oxygenation
Authors: Pérez Gema , González Elena , Zamora Laura , Fernández Sarah N. , Sánchez Amelia , Bellón Jose María , Santiago María José , Solana María José 
Published: October 2021

ABSTRACTObjectives:To assess the safety of enteral nutrition (EN) in children on extracorporeal membrane oxygenation (ECMO). To describe nutritional status and the characteristics of the nutritional support in this population.Methods:A retrospective single‐center analysis (2006–2016) including children <18 years on ECMO. Demographic data, nutritional status, characteristics of nutritional support, and development of gastrointestinal (GI) complications were recorded.Results:One hundred children, with a median age of 9.7 months (interquartile range [IQR] 3.9–63.1) were enrolled. Undernutrition was prevalent among children on ECMO (33.3%) mainly in patients <2 years (P = 0.042). Most patients (64%) received EN at some point during ECMO therapy. EN was administered in the first 48 hours after ECMO initiation (48HEN) to 60.3% of the children.Mortality rate in the Pediatric Intensive Care Unit was lower in patients who received EN as the initial artificial nutrition support (ANS) (37.7 vs 51%, P = 0.005) and in children on 48HEN (34% vs 50%, P = 0.04). In the logistic regression analysis, duration of ECMO support and low cardiac output indication were the only factors associated with mortality.Although most patients on ECMO (45%) developed digestive complications, they were mostly mild, being constipation the most prevalent. In the logistic regression analysis, EN was not associated with an increase in GI complications (P = 0.09). Only three patients developed intestinal ischemia (one without EN and two on EN).Conclusions:Undernutrition is prevalent among children on ECMO, mainly in infants <2 years. EN is not associated with severe gastrointestinal complications or higher mortality in these children.
Eosinophilic Esophagitis Symptom Scores Are High in Children Without Eosinophilic Disease
Authors: Bose Paroma , Albright Eric , Idrees Muhammad T. , Perkins Anthony , Sawyers Cindy , Gupta Sandeep K. , Hon Emily C. 
Published: October 2021

ABSTRACTObjectives:The Pediatric Eosinophilic Esophagitis (EoE) Symptom Score version 2 (PEESSv2.0) is an EoE‐specific validated metric for disease monitoring, but its use has not been explored outside of EoE. Our aim was to determine if PEESSv2.0 scores differentiate between children with EoE and non‐EoE esophageal dysfunction undergoing initial esophagogastroduodenoscopy (EGD).Methods:A prospective cohort study of pediatric subjects was conducted. Children ages 1–18 undergoing initial EGD for esophageal dysfunction were enrolled. Demographics, clinical history, and child self‐report and parent‐proxy report PEESSv2.0 symptom scores were collected at the time of EGD. Esophageal biopsies were reviewed, and EoE was defined as >15 eosinophils/high powered field (hpf) seen in any level of the esophagus. Non‐EoE was defined as <15 eosinophils/hpf.Results:Seventy‐one children were included in the study from 2015 to 2018 [59% (42/71) males; mean age 9.2 years; range 1–17 years]. Fifty‐eight percent (41/71) met criteria for EoE, and 42% (30/71) were labeled non‐EoE. Non‐EoE children and their parents had higher/worse median PEESSv2.0 total scores than those with EoE [47.0 vs 28.0 (P = 0.001) and 40.5 vs 26.5 (P = 0.012), respectively]. Non‐EoE children reported higher median GERD [9.0 vs 4.0 (P = 0.003)], nausea/vomiting [9.0 vs 4.0 (P = 0.003)], and pain [11.0 vs 6.0 (P = 0.001)] subdomain scores compared to those with EoE. PEESSv2.0 dysphagia subdomain scores (child and parent‐proxy) did not differ between EoE and non‐EoE groups [22.0 vs 15.0 (P = 0.184) and 18.5 vs 17.4 (P = 0.330), respectively].Discussion:Total PEESSv2.0 scores were worse in non‐EoE group compared to EoE group. Although PEESSv2.0 is validated for use in monitoring EoE therapy, it does not distinguish children with EoE from non‐EoE esophageal dysfunction at the time of diagnostic EGD.
Highly sensitive and specific detection of the SARS-CoV-2 Delta variant by double-mismatch allele-specific PCR
Authors: Garson Jeremy A. , Badru Samuel , Parker Eleanor L. , Tedder Richard S. , McClure Myra O. 
Published: October 2021

AbstractThe highly transmissible Delta variant of SARS-CoV-2 (B.1.617.2), first identified in India, is currently replacing pre-existing variants in Europe, the USA, and many other parts of the world. It is essential to monitor efficiently its spread to help guide public health policies. Genome sequencing is the gold standard for identification of Delta, but is time-consuming, expensive, and unavailable in many regions. We describe here a rapid and relatively inexpensive alternative to sequencing for specific identification of the Delta variant, by application of double-mismatch allele-specific RT-PCR (DMAS-RT-PCR). The technique exploits forward and reverse allele-specific primers, targeting two spike gene mutations, L452R and T478K, within the same amplicon. The discriminatory power of each primer is enhanced by the presence of an additional mismatch located at the fourth nucleotide from the 3′ end. Amplicons are detected in real-time by means of a conventional fluorescently-labelled hydrolysis probe. Specificity was assessed by testing a range of well characterised cell culture-derived viral isolates and clinical samples, most of which had previously been fully sequenced. In all cases the results of viral genotyping by DMAS-RT-PCR were entirely concordant with the results of sequencing, and the assay was shown to discriminate reliably between the Delta variant and other variants of concern (Alpha, B.1.1.7 and Beta, B.1.351), and ‘wild-type’ SARS-CoV-2. Other respiratory viruses, including influenza A and respiratory syncytial virus, were non-reactive in the assay. The sensitivity of DMAS-RT-PCR matched that of the diagnostic SARS-CoV-2 RT-qPCR screening assay, which targets the E gene. Several samples that could not be sequenced due to insufficient virus could successfully be genotyped by DMAS-RT-PCR. The method we describe would be simple to establish in any laboratory that has the ability to conduct PCR assays and should greatly facilitate monitoring of the spread of the Delta variant throughout the world, and its proportional representation in any SARS-CoV-2-infected population.
Covid-19 genomic analysis reveals clusters of emerging sublineages within the delta variant
Authors: Rono Evans K. 
Published: October 2021

AbstractThe emerging SARS-CoV-2 variants may potentially have enhanced transmissibility and virulence of the virus, and impacts on performance of diagnostic tools and efficacy of vaccines. Genomic surveillance provides an opportunity to detect and characterize new mutations early enough for effective deployment of control strategies. Here, genomic data from Germany and United Kingdom were examined for genetic diversity by assessing gene mutations and inferring phylogeny, and simplifying genomic data workflow for faster visualization and interpretation. Delta variant sublineages were grouped into seven distinct clusters of spike mutations located in N-terminal domain of S1 region (T95I, D138H, *D142G, Y145H and A222V) and S2 region (T719I and *N950D). The most predominant cluster was T95I mutation, with the highest frequencies (71.1% - 83.9%) in Wales, England and Scotland, and the least frequencies (8.9% - 12.1%) in Germany. Two mutations, *D142G and *N950D here described as *reverse mutations and T719I mutation, were largely unique to Germany. In a month, frequencies of D142G had increased from 55.6% to 67.8 % in Germany. Additionally, a cluster of D142G+T719I/T mutation went up from 27.7% to 34.1%, while a T95I+ D142G+N950D/N cluster rose from 19.2% to 26.2%. Although, two distinct clusters of T95I+D138H (2.6% - 3.8%) and T95I+Y145H+A222V (2.5% - 8.5%) mutations were present in all the countries, they were most predominant in Wales and Scotland respectively. Results suggest divergent evolutionary trajectories between the clusters of T95I mutation and those of D142G mutation. These findings provide insights into underlying dynamics of evolution of the delta variant. Future studies may evaluate the epidemiological and biological implications of these sublineages.
Intelligent Resolution: Integrating Cryo-EM with AI-driven Multi-resolution Simulations to Observe the SARS-CoV-2 Replication-Transcription Machinery in Action
Authors: Trifan Anda , Gorgun Defne , Li Zongyi , Brace Alexander , Zvyagin Maxim , Ma Heng , Clyde Austin , Clark David , Salim Michael , Hardy David J. , Burnley Tom , Huang Lei , McCalpin John , Emani Murali , Yoo Hyenseung , Yin Junqi , Tsaris Aristeidis , Subbiah Vishal , Raza Tanveer , Liu Jessica , Trebesch Noah , Wells Geoffrey , Mysore Venkatesh , Gibbs Thomas , Phillips James , Chennubhotla S. Chakra , Foster Ian , Stevens Rick , Anandkumar Anima , Vishwanath Venkatram , Stone John E. , Tajkhorshid Emad , Harris Sarah A. , Ramanathan Arvind 
Published: October 2021

ABSTRACTThe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replication transcription complex (RTC) is a multi-domain protein responsible for replicating and transcribing the viral mRNA inside a human cell. Attacking RTC function with pharmaceutical compounds is a pathway to treating COVID-19. Conventional tools, e.g., cryo-electron microscopy and all-atom molecular dynamics (AAMD), do not provide sufficiently high resolution or timescale to capture important dynamics of this molecular machine. Consequently, we develop an innovative workflow that bridges the gap between these resolutions, using mesoscale fluctuating finite element analysis (FFEA) continuum simulations and a hierarchy of AI-methods that continually learn and infer features for maintaining consistency between AAMD and FFEA simulations. We leverage a multi-site distributed workflow manager to orchestrate AI, FFEA, and AAMD jobs, providing optimal resource utilization across HPC centers. Our study provides unprecedented access to study the SARS-CoV-2 RTC machinery, while providing general capability for AI-enabled multi-resolution simulations at scale.
Glucocorticoid signaling delays castration-induced regression in murine models of prostate cancer
Authors: Maolake Aerken , Zhang Renyuan , Sha Kai , Singh Shalini , Pan Chunliu , Xu Bo , Chatta Gurkamal , Mastri Michalis , Eng Kevin H. , Krolewski John J. , Nastiuk Kent L. 
Published: October 2021

SUMMARYAndrogen deprivation therapy (ADT) induces regression of recurrent and advanced prostate cancer (PrCa), but many tumors recur. To understand the response to ADT, changes in tumor volume were imaged after castration of murine PrCa models. While mouse (non-tumor) prostate begins to regress within two days of castration, murine PrCa regresses after a delay of 3-14 days in two distinct mouse models. Intra-tumoral androgens are undetectable after castration, but tumor cells proliferate during this period. Intratumoral glucocorticoids and glucocorticoid receptor (GR) protein increase, as does GR mRNA and a set of GR-regulated genes specifically in tumor epithelial cells identified using scRNAseq. A selective GR antagonist (CORT125281, relacorilant), in clinical trials for late-state PrCa, eliminates the delayed regression phenotype in both models. Thus, activated GR signaling and murine tumor proliferation following castration resembles the GR-dependent escape mechanism of castrate resistant PrCa. These results suggest simultaneous inhibition of GR and androgen receptor signaling could improve PrCa therapy.In briefAndrogen deprivation therapy for high risk and recurrent prostate cancers is initially effective, but ultimately fails; better understanding the mechanisms should improve therapy. In two murine prostate cancer models, GR signaling is activated immediately following castration, substituting for the acute reduction in AR signaling, and allowing for continued tumor growth. This continued growth is blocked by relacorilant, selective GR antagonist in clinical trials for late-state PrCa.HighlightsAndrogen deprivation therapy induces regression of prostate cancer, but tumors recurMurine PrCa continues to proliferate for 3-14 days in two distinct mouse prostate cancer modelsTumor cells proliferate during this period, and intratumoral glucocorticoids and glucocorticoid receptor (GR) protein increase, as does GR mRNA and a set of GR-regulated genesRelacorilant, a selective GR antagonist in clinical trials for late-state PrCa, eliminates the delayed regression
Deep Learning Genome-wide Linkage Association Study for Wheat Fusarium Head Blight Resistance Genes Discovery
Authors: Xu Wayne , Bilichak Andriy , Dhariwal Raman , Henriquez Maria A. , Randhawa Harpinder 
Published: October 2021

AbstractBackgroundFusarium head blight (FHB) is one of the most devastating diseases of wheat worldwide and artificial intelligence can assist with understanding resistance to the disease. Considering different sample populations, marker types, reference maps, and statistical methods, we developed a Deep Learning Genome-wide Linkage Association Study (dpGLAS) of FHB resistance in wheat.ResultsThe dpGLAS was first applied to two bi-parental population datasets in which the cultivar AC Barrie was a common parent for FHB resistance. Eight candidate gene markers were discovered in the one AC Barrie population and 10 in the other associated with FHB resistance. Eight of these markers were also supported by the conventional QTL mapping. Most of these candidate marker genes were found associated with the Reactive Oxygen Species (ROS) and Abscisic acid (ABA) axes. These ROS and ABA pathways were further supported by RNA-seq transcriptome data of FHB resistant cv. AAC Tenacious, a parent of the third bi-parental population. In this dataset, the ROS-centered Panther protein families were significantly enriched in those genes that had most different response to FHB when compared the resistance Tenacious and the susceptible Roblin.ConclusionsThis study developed the framework of dpGLAS and identified candidate genes for FHB resistance in the Canadian spring wheat cultivars AC Barrie and AAC Tenacious.
IL-1α secreted by subcapsular sinus macrophages promotes melanoma metastasis in the sentinel lymph node by upregulating STAT3 signaling in the tumor
Authors: Virgilio Tommaso , Bordini Joy , Sartori Giulio , Latino Irene , Molina-Romero Daniel , Leoni Cristina , Akhmedov Murodzhon , Rinaldi Andrea , Arribas Alberto J. , Morone Diego , Jafari S. Morteza Seyed , Bersudsky Marina , Ottolenghi Aner , Kwee Ivo , Chiaravalli Anna Maria , Sessa Fausto , Hunger Robert E. , Bruno Antonino , Mortara Lorenzo , Voronov Elena , Monticelli Silvia , Apte Ron N. , Bertoni Francesco , Gonzalez Santiago F. 
Published: October 2021

ABSTRACTDuring melanoma metastasization, tumor cells originated in the skin migrate via lymphatic vessels to the sentinel lymph node (sLN) in a process that facilitates their spread across the body. Here, we characterized the innate inflammatory responses to melanoma metastasis in the sLN. For this purpose, we confirmed the migration of fluorescent metastatic melanoma cells to the sLN and we characterized the inflammatory response in the metastatic microenvironment. We found that macrophages located in the subcapsular sinus (SSM), produce pro-tumoral IL-1α after recognition of tumor antigens. Moreover, we confirmed that the administration of an anti-IL-1α depleting antibody reduced metastasis. Conversely, the administration of recombinant IL-1α accelerated the lymphatic spreading of the tumor. Additionally, the elimination of the macrophages significantly reduced the progression of the metastatic spread. To understand the mechanism of action of IL-1α in the context of the lymph node microenvironment, we applied single-cell RNA sequencing to dissected metastases obtained from animals treated with an anti-IL-1α blocking antibody. Amongst the different pathways affected, we identified STAT3 as one of the main targets of IL-1α signaling in metastatic cells. Moreover, we found that the anti-IL-1α anti-tumoral effect was not mediated by lymphocytes, as IL-1R1 KO mice did not show any improvement in metastasis growth. Finally, we found a synergistic anti-metastatic effect of the combination of IL-1α blocking and the STAT3 inhibitor (STAT3i) stattic. In summary, we described a new mechanism by which SSM support melanoma metastasis, highlighting a new target for immunotherapy.
Ligand GA: a genetic algorithm for automated protein inhibitor design
Authors: Chalmers Gordon 
Published: October 2021

AbstractLigand GA is introduced in this work and approaches the problem of finding small molecules inhibiting protein functions by using the protein site to find close to optimal or optimal small molecule binders. Genetic algorithms (GA) are an effective means for approximating or solving computationally hard mathematics problems with large search spaces such as this one. The algorithm is designed to include constraints on the generated molecules from ADME restriction, localization in a binding site, specified hydrogen bond requirements, toxicity prevention from multiple proteins, sub-structure restrictions, and database inclusion. This algorithm and work is in the context of computational modeling, ligand design and docking to protein sites.
Viral mediated knockdown of GATA6 in SMA iPSC-derived astrocytes prevents motor neuron loss and microglial activation
Authors: Allison Reilly L. , Welby Emily , Khayrullina Guzal , Burnett Barrington G. , Ebert Allison D. 
Published: October 2021

AbstractSpinal muscular atrophy (SMA), a pediatric genetic disorder, is characterized by the profound loss of spinal cord motor neurons and subsequent muscle atrophy and death. Although the mechanisms underlying motor neuron loss are not entirely clear, data from our work and others support the idea that glial cells contribute to disease pathology. GATA6, a transcription factor that we have previously shown to be upregulated in SMA astrocytes, is negatively regulated by SMN and can increase the expression of inflammatory regulator NFκB. In this study, we identified upregulated GATA6 as a contributor to increased activation, pro-inflammatory ligand production, and neurotoxicity in spinal-cord patterned astrocytes differentiated from SMA patient induced pluripotent stem cells. Reducing GATA6 expression in SMA astrocytes via lentiviral infection ameliorated these effects to healthy control levels. Additionally, we found that SMA astrocytes contribute to SMA microglial phagocytosis, which was again decreased by lentiviral-mediated knockdown of GATA6. Together these data identify a role of GATA6 in SMA astrocyte pathology and further highlight glia as important targets of therapeutic intervention in SMA.
The Evolution of Host Specialization in an Insect Pathogen
Authors: Visher Elisa , Uricchio Lawrence , Bartlett Lewis , DeNamur Nicole , Yarcan Aren , Alhassani Dina , Boots Mike 
Published: October 2021

AbstractNiche breadth coevolution between biotic partners underpins theories of diversity and co-existence and influences patterns of disease emergence and transmission in host-parasite systems. Despite these broad implications, we still do not fully understand how the breadth of parasites’ infectivity evolves, the nature of any associated costs, or the genetic basis of specialization. Here, we serially passage a granulosis virus on multiple inbred populations of its Plodia interpunctella host to explore the dynamics and outcomes of specialization. In particular, we collect time series of phenotypic and genetic data to explore the dynamics of host genotype specialization throughout the course of experimental evolution and examine two fitness components. We find that the Plodia interpunctella granulosis virus consistently evolves increases in overall specialization, but that our two fitness components evolve independently such that lines specialize in either productivity or infectivity. Furthermore, we find that specialization in our experiment is a highly polygenic trait best explained by a combination of evolutionary mechanisms including conditionally positive fitness asymmetries and mutation accumulation. These results are important for understanding the evolution of specialization in host-parasite interactions and its broader implications for co-existence, diversification, and infectious disease management.
Representations of temporal community structure in hippocampus and precuneus predict inductive reasoning decisions
Authors: Pudhiyidath Athula , Morton Neal W , Duran Rodrigo Viveros , Schapiro Anna C. , Momennejad Ida , Hinojosa-Rowland Demitrius M. , Molitor Robert J. , Preston Alison R. 
Published: October 2021

AbstractOur understanding of the world is shaped by inferences about underlying structure. For example, at the gym, you might notice that the same people tend to arrive around the same time and infer that they are friends that work out together. Consistent with this idea, after participants are presented with a temporal sequence of objects that follows an underlying community structure, they are biased to infer that objects from the same community share the same properties. Here, we used fMRI to measure neural representations of objects after temporal community structure learning and examine how these representations support inference about object relationships. We found that community structure learning affected inferred object similarity: when asked to spatially group items based on their experience, participants tended to group together objects from the same community. Neural representations in perirhinal cortex predicted individual differences in object grouping, suggesting that high-level object representations are affected by temporal community learning. Furthermore, participants were biased to infer that objects from the same community would share the same properties. Using computational modeling of temporal learning and inference decisions, we found that inductive reasoning is influenced by both detailed knowledge of temporal statistics and abstract knowledge of the temporal communities. The fidelity of temporal community representations in hippocampus and precuneus predicted the degree to which temporal community membership biased reasoning decisions. Our results suggest that temporal knowledge is represented at multiple levels of abstraction, and that perirhinal cortex, hippocampus, and precuneus may support inference based on this knowledge.